Michele B. Kaufman, PharmD, BSc, RPh

Discontinued Products

• Amoxicillin powder for oral suspension and pediatric drops for oral suspension1
• Amoxicillin powder for oral suspension (Amoxil brand usually for adults), 250mg/5mL (100mL and 150mL sizes)2
• Insulin isophane suspension (Humulin 50/50), due to limited use.3 Current patient demand and existing inventory note product availability through April 2010. There are about 3,000 patients in the U.S. who will be affected by this action.
• Phenytoin 30 mg (Dilantin Kapseals brand) are being reformulated in a new, extended-release formulation, but Kapseals will be discontinued.4

New Generics

• Tacrolimus (generic Prograf) capsules5

New Drugs, Indications, and Dosage Forms

• Asenapine tablets (Saphris) have been approved by the Food and Drug Administration (FDA) to treat adults with schizophrenia and bipolar I disorder. The most common adverse effects in trials were akathisia, oral hypoesthesia, and somnolence. The most common adverse effects that were reported in the bipolar disorder trials were somnolence, dizziness, movement disorders other than akathisia, and weight gain.6
• Colchicine 0.6 mg tablets (Colcrys) have been approved by the FDA to treat gout flares and familial Mediterranean fever.7 Colchicine has been used for many years but has not received FDA approval until recently. The FDA is re-evaluating some older drugs and drug classes. For example, the pancrelipase products fall under a similar ruling. Now that colchicine is approved, the manufacturer has shown that it meets modern standards for safety, effectiveness, quality, and labeling. Historically, physicians have administered colchicine hourly to treat acute gout flares until symptoms subsided or the patient developed adverse gastrointestinal symptoms. A dosing study determined that one 1.2-mg dose of this formulation followed by 0.6 mg one hour later was as effective as hourly dosing in patients without renal or hepatic dysfunction. This two-dose regimen was less toxic than prior dosing regimens and, therefore, it received the FDA’s approval.8
• Fentanyl buccal soluble film (Onsolis) has been approved by the FDA as an opioid for managing breakthrough cancer pain in patients 18 years and older who already are receiving and are tolerant to opioid therapy.9 It is available in 200-, 400-, 600-, 800- and 1,200-mcg strengths. A Risk Evaluation and Mitigation Strategies (REMS) will be available with dispensing.
• Insulin aspart injection (NovoLog) has undergone a label change. NovoLog can now be used in an insulin pump for up to six days. The infusion set should be changed at least every three days. The updated label includes information about discarding the drug if temperatures exceed 37oC (98.6oF).10
• Interferon beta-1b injection (Extavia): A new brand of interferon has been approved by the FDA for treating relapsing forms of multiple sclerosis (MS), as well as for patients who have experienced a first clinical episode of MS with magnetic resonance imaging (MRI) features consistent of the disease.11
• Morphine/naltrexone capsules (Embeda), a long-acting opioid designed to reduce drug euphoria, have been approved by the FDA to treat moderate to severe chronic pain. It was developed with the abuse-deterrent drug naltrexone, which reduces euphoria when crushed or chewed.12
• Pitavastatin 4 mg (Livalo) has been approved by the FDA to treat hypercholesterolemia and combined dyslipidemia.13 It’s a potent statin with a new base structure. Additionally, it is only minimally metabolized by the cytochrome P450 (CYP) pathway. It will be available in early 2010 in 1-, 2- and 4-mg strengths. Only time will tell whether this is truly a benefit for this new agent.
• Saxagliptin (Onglyza), a new oral dipeptidyl peptidase-4 (DPP-4) inhibitor, has been approved by the FDA to treat Type 2 diabetes mellitus as an adjunct to diet and exercise.14 It is administered once daily at a starting dose of 2.5 mg or 5 mg, without regard to meal.15 The lower dose is recommended in patients with moderate to severe renal impairment or end-stage renal disease (CrCL < 50 mL/min). The lower dose (2.5 mg) also is recommended for patients taking strong CYP3A4/5 inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, or telithromycin). The most common adverse effects in clinical trials were respiratory tract infection, urinary tract infection, and headache.

Pipeline

• Roflumilast (Daxas), a phosphodiesterase 4 enzyme inhibitor, has been submitted to the FDA. It is a once-daily oral treatment for patients with symptomatic chronic obstructive pulmonary disease (COPD).16
• Tocilizumab (Actemra), an interleukin-6 receptor-inhibiting monoclonal antibody to treat rheumatoid arthritis (RA), has been approved for use in Europe. Its manufacturer has announced that the FDA has accepted its reapplication for treating moderate to severe RA. It is available in Japan for treating RA, juvenile idiopathic arthritis, and Castleman’s disease.17
• TZP-102, an investigational oral prokinetic agent for treating diabetic gastroparesis, has received FDA fast-track status. A multinational study is under way for this ghrelin receptor agonist.18 TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

Discontinued Products

• Amoxicillin powder for oral suspension and pediatric drops for oral suspension1
• Amoxicillin powder for oral suspension (Amoxil brand usually for adults), 250mg/5mL (100mL and 150mL sizes)2
• Insulin isophane suspension (Humulin 50/50), due to limited use.3 Current patient demand and existing inventory note product availability through April 2010. There are about 3,000 patients in the U.S. who will be affected by this action.
• Phenytoin 30 mg (Dilantin Kapseals brand) are being reformulated in a new, extended-release formulation, but Kapseals will be discontinued.4

New Generics

• Tacrolimus (generic Prograf) capsules5

New Drugs, Indications, and Dosage Forms

• Asenapine tablets (Saphris) have been approved by the Food and Drug Administration (FDA) to treat adults with schizophrenia and bipolar I disorder. The most common adverse effects in trials were akathisia, oral hypoesthesia, and somnolence. The most common adverse effects that were reported in the bipolar disorder trials were somnolence, dizziness, movement disorders other than akathisia, and weight gain.6
• Colchicine 0.6 mg tablets (Colcrys) have been approved by the FDA to treat gout flares and familial Mediterranean fever.7 Colchicine has been used for many years but has not received FDA approval until recently. The FDA is re-evaluating some older drugs and drug classes. For example, the pancrelipase products fall under a similar ruling. Now that colchicine is approved, the manufacturer has shown that it meets modern standards for safety, effectiveness, quality, and labeling. Historically, physicians have administered colchicine hourly to treat acute gout flares until symptoms subsided or the patient developed adverse gastrointestinal symptoms. A dosing study determined that one 1.2-mg dose of this formulation followed by 0.6 mg one hour later was as effective as hourly dosing in patients without renal or hepatic dysfunction. This two-dose regimen was less toxic than prior dosing regimens and, therefore, it received the FDA’s approval.8
• Fentanyl buccal soluble film (Onsolis) has been approved by the FDA as an opioid for managing breakthrough cancer pain in patients 18 years and older who already are receiving and are tolerant to opioid therapy.9 It is available in 200-, 400-, 600-, 800- and 1,200-mcg strengths. A Risk Evaluation and Mitigation Strategies (REMS) will be available with dispensing.
• Insulin aspart injection (NovoLog) has undergone a label change. NovoLog can now be used in an insulin pump for up to six days. The infusion set should be changed at least every three days. The updated label includes information about discarding the drug if temperatures exceed 37oC (98.6oF).10
• Interferon beta-1b injection (Extavia): A new brand of interferon has been approved by the FDA for treating relapsing forms of multiple sclerosis (MS), as well as for patients who have experienced a first clinical episode of MS with magnetic resonance imaging (MRI) features consistent of the disease.11
• Morphine/naltrexone capsules (Embeda), a long-acting opioid designed to reduce drug euphoria, have been approved by the FDA to treat moderate to severe chronic pain. It was developed with the abuse-deterrent drug naltrexone, which reduces euphoria when crushed or chewed.12
• Pitavastatin 4 mg (Livalo) has been approved by the FDA to treat hypercholesterolemia and combined dyslipidemia.13 It’s a potent statin with a new base structure. Additionally, it is only minimally metabolized by the cytochrome P450 (CYP) pathway. It will be available in early 2010 in 1-, 2- and 4-mg strengths. Only time will tell whether this is truly a benefit for this new agent.
• Saxagliptin (Onglyza), a new oral dipeptidyl peptidase-4 (DPP-4) inhibitor, has been approved by the FDA to treat Type 2 diabetes mellitus as an adjunct to diet and exercise.14 It is administered once daily at a starting dose of 2.5 mg or 5 mg, without regard to meal.15 The lower dose is recommended in patients with moderate to severe renal impairment or end-stage renal disease (CrCL < 50 mL/min). The lower dose (2.5 mg) also is recommended for patients taking strong CYP3A4/5 inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, or telithromycin). The most common adverse effects in clinical trials were respiratory tract infection, urinary tract infection, and headache.

Pipeline

• Roflumilast (Daxas), a phosphodiesterase 4 enzyme inhibitor, has been submitted to the FDA. It is a once-daily oral treatment for patients with symptomatic chronic obstructive pulmonary disease (COPD).16
• Tocilizumab (Actemra), an interleukin-6 receptor-inhibiting monoclonal antibody to treat rheumatoid arthritis (RA), has been approved for use in Europe. Its manufacturer has announced that the FDA has accepted its reapplication for treating moderate to severe RA. It is available in Japan for treating RA, juvenile idiopathic arthritis, and Castleman’s disease.17
• TZP-102, an investigational oral prokinetic agent for treating diabetic gastroparesis, has received FDA fast-track status. A multinational study is under way for this ghrelin receptor agonist.18 TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

Discontinued Products

• Amoxicillin powder for oral suspension and pediatric drops for oral suspension1
• Amoxicillin powder for oral suspension (Amoxil brand usually for adults), 250mg/5mL (100mL and 150mL sizes)2
• Insulin isophane suspension (Humulin 50/50), due to limited use.3 Current patient demand and existing inventory note product availability through April 2010. There are about 3,000 patients in the U.S. who will be affected by this action.
• Phenytoin 30 mg (Dilantin Kapseals brand) are being reformulated in a new, extended-release formulation, but Kapseals will be discontinued.4

New Generics

• Tacrolimus (generic Prograf) capsules5

New Drugs, Indications, and Dosage Forms

• Asenapine tablets (Saphris) have been approved by the Food and Drug Administration (FDA) to treat adults with schizophrenia and bipolar I disorder. The most common adverse effects in trials were akathisia, oral hypoesthesia, and somnolence. The most common adverse effects that were reported in the bipolar disorder trials were somnolence, dizziness, movement disorders other than akathisia, and weight gain.6
• Colchicine 0.6 mg tablets (Colcrys) have been approved by the FDA to treat gout flares and familial Mediterranean fever.7 Colchicine has been used for many years but has not received FDA approval until recently. The FDA is re-evaluating some older drugs and drug classes. For example, the pancrelipase products fall under a similar ruling. Now that colchicine is approved, the manufacturer has shown that it meets modern standards for safety, effectiveness, quality, and labeling. Historically, physicians have administered colchicine hourly to treat acute gout flares until symptoms subsided or the patient developed adverse gastrointestinal symptoms. A dosing study determined that one 1.2-mg dose of this formulation followed by 0.6 mg one hour later was as effective as hourly dosing in patients without renal or hepatic dysfunction. This two-dose regimen was less toxic than prior dosing regimens and, therefore, it received the FDA’s approval.8
• Fentanyl buccal soluble film (Onsolis) has been approved by the FDA as an opioid for managing breakthrough cancer pain in patients 18 years and older who already are receiving and are tolerant to opioid therapy.9 It is available in 200-, 400-, 600-, 800- and 1,200-mcg strengths. A Risk Evaluation and Mitigation Strategies (REMS) will be available with dispensing.
• Insulin aspart injection (NovoLog) has undergone a label change. NovoLog can now be used in an insulin pump for up to six days. The infusion set should be changed at least every three days. The updated label includes information about discarding the drug if temperatures exceed 37oC (98.6oF).10
• Interferon beta-1b injection (Extavia): A new brand of interferon has been approved by the FDA for treating relapsing forms of multiple sclerosis (MS), as well as for patients who have experienced a first clinical episode of MS with magnetic resonance imaging (MRI) features consistent of the disease.11
• Morphine/naltrexone capsules (Embeda), a long-acting opioid designed to reduce drug euphoria, have been approved by the FDA to treat moderate to severe chronic pain. It was developed with the abuse-deterrent drug naltrexone, which reduces euphoria when crushed or chewed.12
• Pitavastatin 4 mg (Livalo) has been approved by the FDA to treat hypercholesterolemia and combined dyslipidemia.13 It’s a potent statin with a new base structure. Additionally, it is only minimally metabolized by the cytochrome P450 (CYP) pathway. It will be available in early 2010 in 1-, 2- and 4-mg strengths. Only time will tell whether this is truly a benefit for this new agent.
• Saxagliptin (Onglyza), a new oral dipeptidyl peptidase-4 (DPP-4) inhibitor, has been approved by the FDA to treat Type 2 diabetes mellitus as an adjunct to diet and exercise.14 It is administered once daily at a starting dose of 2.5 mg or 5 mg, without regard to meal.15 The lower dose is recommended in patients with moderate to severe renal impairment or end-stage renal disease (CrCL < 50 mL/min). The lower dose (2.5 mg) also is recommended for patients taking strong CYP3A4/5 inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, or telithromycin). The most common adverse effects in clinical trials were respiratory tract infection, urinary tract infection, and headache.

Pipeline

• Roflumilast (Daxas), a phosphodiesterase 4 enzyme inhibitor, has been submitted to the FDA. It is a once-daily oral treatment for patients with symptomatic chronic obstructive pulmonary disease (COPD).16
• Tocilizumab (Actemra), an interleukin-6 receptor-inhibiting monoclonal antibody to treat rheumatoid arthritis (RA), has been approved for use in Europe. Its manufacturer has announced that the FDA has accepted its reapplication for treating moderate to severe RA. It is available in Japan for treating RA, juvenile idiopathic arthritis, and Castleman’s disease.17
• TZP-102, an investigational oral prokinetic agent for treating diabetic gastroparesis, has received FDA fast-track status. A multinational study is under way for this ghrelin receptor agonist.18 TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

In the Pipeline

• A new drug application (NDA) has been submitted to the Food and Drug Administration (FDA) for Acetavance, an intravenous (IV) form of acetaminophen used in the treatment of acute pain and fever in adults and children who cannot take oral medications.1
• An NDA for a low-dose aspirin and esomeprazole combination product has been submitted for risk reduction of low-dose-aspirin-associated gastric and/or duodenal ulcers. A supplemental NDA was submitted for esomeprazole for risk reduction of low-dose-aspirin-associated peptic ulcer disease.2
• An NDA for a new formulation of ondansetron, as an orally dissolving film strip, has been submitted to the FDA.3 The product has shown comparable bioequivalence to ondansetron (Zofran) as an anti-emetic for preventing chemotherapy-induced nausea and vomiting, nausea and vomiting associated with radiotherapy, and post-operative nausea and vomiting.
• An NDA for tesamorelin to treat HIV-lipodystrophy has been submitted to the FDA.4

New Generics

• Acarbose 25-, 50- and 100-mg tablets (generic precose)5
• Bicalutamide (Casodex)6

New Drugs, Indications and Dosage Forms

• Artemether and lumefantrine (Coartem) tablets have been approved by the FDA for the treatment of acute, uncomplicated malarial infections in adults and children who weigh at least 5 kg.7 Coartem should be taken with food, particularly food that contains fat, because it improves drug absorption. Common adverse effects include headache, anorexia, dizziness, asthenia, arthralgia, and myalgia.
• Besifloxacin 0.6% (Besivance) ophthalmic suspension has been approved by the FDA to treat bacterial conjunctivitis. Adverse effects include eye redness, blurred vision, eye pain, irritation, itching, and headache.8
• Dexamethasone intravitreal implant (Ozurdex) has been approved by the FDA for treating macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).9 The implant is biodegradable and delivers dexamethasone via an extended-release mechanism over one to three months. Ozurdex is administered as an in-office procedure and is expected to be available soon.
• Dronedarone (Multaq) tablets have been approved by the FDA as an antiarrhythmic agent.10 It is indicated to reduce the risk of cardiovascular hospitalization in patients with atrial flutter, or paroxysmal or persistent atrial fibrillation, with a recent episode of atrial fibrillation/atrial flutter and associated cardiovascular risk, who are in sinus rhythm or who will be cardioverted.11 Risk factors include age >70, hypertension, diabetes, prior cerebrovascular accident, a left atrial diameter ≥50 mm, and left ventricular ejection fraction [LVEF] <40%.
• Hyoscyamine sulfate (NuLev) chewable antispasmodic orally disintegrating tablets (0.125 mg) have been reintroduced and are available to treat patients age 2 and older with gastrointestinal spasticity disorders.12
• Lacosamide (Vimpat) has been approved by the FDA for add-on therapy in the treatment of partial-onset seizures in epilepsy patients age 17 and older.13
• Lamotrigine extended-release (Lamictal XR) has been approved by the FDA as a once-daily add-on therapy for partial-onset seizures in epilepsy patients age 13 and older.14
• Pioglitazone/metformin (ACTOplus met XR) combination tablets have been approved by the FDA for treating Type 2 diabetes.15 It should be available later this year.
• Risperidone (Risperdal Consta) has received additional FDA approval as a biweekly injection as monotherapy, and as adjunctive therapy to lithium or valproate, in the maintenance of bipolar I disorder.16
• Tadalafil (Adcirc) has been approved by the FDA for improving exercise ability in patients with pulmonary arterial hypertension (PAH).17 Tadalafil already is approved as brand-name Cialis for treating erectile dysfunction. Tadalafil is the first once-daily phosphodiesterase type-5 inhibitor for treating PAH, and it is hoped it will gain some of the sildenafil (Revatio) market.

Update

As a followup to the August “Market Watch,” pancrelipase (Creon) has been approved by the FDA and is available in three FDA-approved prescription strengths based on the lipase content (6,000, 12,000, and 24,000).18 TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. NDA submitted for acetavance, a treatment for acute pain and fever. Monthly Prescribing Reference Web site. Available at: www.empr.com/NDA-submitted-for-Acetavance-a-treatment-for-acute-pain-and-fever/article/136799/. Accessed July 8, 2009.
2. AstraZeneca submits NDA for low dose aspirin/esomeprazole combination product. AstraZeneca Web site. Available at: www.astrazeneca-us.com/about-astrazeneca-us/newsroom/all/5762542?itemId=5762542. Accessed July 8, 2009.
3. MonoSol Rx and Strativa Pharmaceuticals submit new drug application for ondansetron orally dissolving film strip. Available at: www.monosolrx.com/news_09/news_040909.html. Accessed July 8, 2009.
4. Theratech shares jump 8 pct on FDA filing. Reuters Web site. Available at: www.reuters.com/article/idUSN0126728920090601. Accessed July 8, 2009.
5. Impax receives FDA approval for generic precos tablets, 25 mg, 50 mg and 100 mg. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c=67240&p=irol-newsArticle&ID=1289907&highlight=. Accessed July 8, 2009.
6. Caraco: FDA approves generic prostate cancer drug. Forbes Web site. Available at: www.forbes.com/feeds/ap/2009/07/07/ap6626628.html. Accessed July 8, 2009.
7. Walsh S. FDA approved coartem tablets to treat malaria. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149559.htm. Accessed July 8, 2009.
8. Walsh S. FDA approves besivance to treat bacterial conjunctivitis. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm162486.htm. Accessed July 8, 2009.
9. Ozurdex approved for treatment of macular edema. Monthly Prescribing Reference Web site. Available at: www.empr.com/Ozurdex-approved-for-treatment-of-macular-edema/article/138708/. Accessed July 8, 2009.
10. Walsh S. FDA approves multaq to treat heart rhythm disorder. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170276.htm. Accessed July 21, 2009.
11. Multaq label. FDA Web site: Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2009/022425lbl.pdf. Accessed July 21, 2009.
12. NuLev chewable melt tablets available again. Monthly Prescribing Reference Web site. Available at: www.empr.com/NuLev-Chewable-Melt-Tablets-available-again/article/138396/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed July 8, 2009.
13. UCB’s Vimpat (lacosamide) approved by FDA as add-on therapy for partial onset seizures in adults. Epilepsy Foundation Web site. Available at: www.epilepsyfoundation.org/epilepsyusa/news/UCB_Vimpat.cfm. Accessed July 8, 2009.
14. Bratulic A. FDA approves GlaxoSmithKline’s lamictal XR. Available at: www.firstwordplus.com/Fws.do?articleid=62DD8DEA3F594BDC98DA97F80AB13ABB&logRowId=307825. Accessed July 8, 2009.
15. FDA approves ACTOplus met XR (pioglitazone HCL and metformin HCl extended-release) tablets for the treatment of Type 2 diabetes. Available at: www.pipelinereview.com/index.php/2009051326959/Small-Molecules/FDA-Approves-ACTOplus-met-XR-pioglitazone-HCl-and-metformin-HCl-extended-release-Tablets-for-the-Treatment-of-Type-2-Diabetes.html. Accessed July 8, 2009.
16. FDA approval letter for risperdal consta. FDA Web site. Available at: www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/021346s025,021346s028ltr.pdf. Accessed July 8, 2009.
17. Todoruk M. United Therapeutics’ Adcirca approved for pulmonary arterial hypertension in US. FirstWord Web site. Available at: www.firstwordplus.com/Fws.do?articleid=E71E91953E9844D2A776B021E19AEE22&logRowId=306627. Accessed July 8, 2009.
18. Creon delayed-release capsules available for exocrine pancreatic insufficiency. Monthly Prescribing Reference Web site. Available at: www.empr.com/Creon-delayed-release-capsules-available-for-exocrine-pancreatic-insufficiency/article/139668/. Accessed August 10, 2009.

In the Pipeline

• A new drug application (NDA) has been submitted to the Food and Drug Administration (FDA) for Acetavance, an intravenous (IV) form of acetaminophen used in the treatment of acute pain and fever in adults and children who cannot take oral medications.1
• An NDA for a low-dose aspirin and esomeprazole combination product has been submitted for risk reduction of low-dose-aspirin-associated gastric and/or duodenal ulcers. A supplemental NDA was submitted for esomeprazole for risk reduction of low-dose-aspirin-associated peptic ulcer disease.2
• An NDA for a new formulation of ondansetron, as an orally dissolving film strip, has been submitted to the FDA.3 The product has shown comparable bioequivalence to ondansetron (Zofran) as an anti-emetic for preventing chemotherapy-induced nausea and vomiting, nausea and vomiting associated with radiotherapy, and post-operative nausea and vomiting.
• An NDA for tesamorelin to treat HIV-lipodystrophy has been submitted to the FDA.4

New Generics

• Acarbose 25-, 50- and 100-mg tablets (generic precose)5
• Bicalutamide (Casodex)6

New Drugs, Indications and Dosage Forms

• Artemether and lumefantrine (Coartem) tablets have been approved by the FDA for the treatment of acute, uncomplicated malarial infections in adults and children who weigh at least 5 kg.7 Coartem should be taken with food, particularly food that contains fat, because it improves drug absorption. Common adverse effects include headache, anorexia, dizziness, asthenia, arthralgia, and myalgia.
• Besifloxacin 0.6% (Besivance) ophthalmic suspension has been approved by the FDA to treat bacterial conjunctivitis. Adverse effects include eye redness, blurred vision, eye pain, irritation, itching, and headache.8
• Dexamethasone intravitreal implant (Ozurdex) has been approved by the FDA for treating macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).9 The implant is biodegradable and delivers dexamethasone via an extended-release mechanism over one to three months. Ozurdex is administered as an in-office procedure and is expected to be available soon.
• Dronedarone (Multaq) tablets have been approved by the FDA as an antiarrhythmic agent.10 It is indicated to reduce the risk of cardiovascular hospitalization in patients with atrial flutter, or paroxysmal or persistent atrial fibrillation, with a recent episode of atrial fibrillation/atrial flutter and associated cardiovascular risk, who are in sinus rhythm or who will be cardioverted.11 Risk factors include age >70, hypertension, diabetes, prior cerebrovascular accident, a left atrial diameter ≥50 mm, and left ventricular ejection fraction [LVEF] <40%.
• Hyoscyamine sulfate (NuLev) chewable antispasmodic orally disintegrating tablets (0.125 mg) have been reintroduced and are available to treat patients age 2 and older with gastrointestinal spasticity disorders.12
• Lacosamide (Vimpat) has been approved by the FDA for add-on therapy in the treatment of partial-onset seizures in epilepsy patients age 17 and older.13
• Lamotrigine extended-release (Lamictal XR) has been approved by the FDA as a once-daily add-on therapy for partial-onset seizures in epilepsy patients age 13 and older.14
• Pioglitazone/metformin (ACTOplus met XR) combination tablets have been approved by the FDA for treating Type 2 diabetes.15 It should be available later this year.
• Risperidone (Risperdal Consta) has received additional FDA approval as a biweekly injection as monotherapy, and as adjunctive therapy to lithium or valproate, in the maintenance of bipolar I disorder.16
• Tadalafil (Adcirc) has been approved by the FDA for improving exercise ability in patients with pulmonary arterial hypertension (PAH).17 Tadalafil already is approved as brand-name Cialis for treating erectile dysfunction. Tadalafil is the first once-daily phosphodiesterase type-5 inhibitor for treating PAH, and it is hoped it will gain some of the sildenafil (Revatio) market.

Update

As a followup to the August “Market Watch,” pancrelipase (Creon) has been approved by the FDA and is available in three FDA-approved prescription strengths based on the lipase content (6,000, 12,000, and 24,000).18 TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. NDA submitted for acetavance, a treatment for acute pain and fever. Monthly Prescribing Reference Web site. Available at: www.empr.com/NDA-submitted-for-Acetavance-a-treatment-for-acute-pain-and-fever/article/136799/. Accessed July 8, 2009.
2. AstraZeneca submits NDA for low dose aspirin/esomeprazole combination product. AstraZeneca Web site. Available at: www.astrazeneca-us.com/about-astrazeneca-us/newsroom/all/5762542?itemId=5762542. Accessed July 8, 2009.
3. MonoSol Rx and Strativa Pharmaceuticals submit new drug application for ondansetron orally dissolving film strip. Available at: www.monosolrx.com/news_09/news_040909.html. Accessed July 8, 2009.
4. Theratech shares jump 8 pct on FDA filing. Reuters Web site. Available at: www.reuters.com/article/idUSN0126728920090601. Accessed July 8, 2009.
5. Impax receives FDA approval for generic precos tablets, 25 mg, 50 mg and 100 mg. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c=67240&p=irol-newsArticle&ID=1289907&highlight=. Accessed July 8, 2009.
6. Caraco: FDA approves generic prostate cancer drug. Forbes Web site. Available at: www.forbes.com/feeds/ap/2009/07/07/ap6626628.html. Accessed July 8, 2009.
7. Walsh S. FDA approved coartem tablets to treat malaria. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149559.htm. Accessed July 8, 2009.
8. Walsh S. FDA approves besivance to treat bacterial conjunctivitis. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm162486.htm. Accessed July 8, 2009.
9. Ozurdex approved for treatment of macular edema. Monthly Prescribing Reference Web site. Available at: www.empr.com/Ozurdex-approved-for-treatment-of-macular-edema/article/138708/. Accessed July 8, 2009.
10. Walsh S. FDA approves multaq to treat heart rhythm disorder. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170276.htm. Accessed July 21, 2009.
11. Multaq label. FDA Web site: Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2009/022425lbl.pdf. Accessed July 21, 2009.
12. NuLev chewable melt tablets available again. Monthly Prescribing Reference Web site. Available at: www.empr.com/NuLev-Chewable-Melt-Tablets-available-again/article/138396/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed July 8, 2009.
13. UCB’s Vimpat (lacosamide) approved by FDA as add-on therapy for partial onset seizures in adults. Epilepsy Foundation Web site. Available at: www.epilepsyfoundation.org/epilepsyusa/news/UCB_Vimpat.cfm. Accessed July 8, 2009.
14. Bratulic A. FDA approves GlaxoSmithKline’s lamictal XR. Available at: www.firstwordplus.com/Fws.do?articleid=62DD8DEA3F594BDC98DA97F80AB13ABB&logRowId=307825. Accessed July 8, 2009.
15. FDA approves ACTOplus met XR (pioglitazone HCL and metformin HCl extended-release) tablets for the treatment of Type 2 diabetes. Available at: www.pipelinereview.com/index.php/2009051326959/Small-Molecules/FDA-Approves-ACTOplus-met-XR-pioglitazone-HCl-and-metformin-HCl-extended-release-Tablets-for-the-Treatment-of-Type-2-Diabetes.html. Accessed July 8, 2009.
16. FDA approval letter for risperdal consta. FDA Web site. Available at: www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/021346s025,021346s028ltr.pdf. Accessed July 8, 2009.
17. Todoruk M. United Therapeutics’ Adcirca approved for pulmonary arterial hypertension in US. FirstWord Web site. Available at: www.firstwordplus.com/Fws.do?articleid=E71E91953E9844D2A776B021E19AEE22&logRowId=306627. Accessed July 8, 2009.
18. Creon delayed-release capsules available for exocrine pancreatic insufficiency. Monthly Prescribing Reference Web site. Available at: www.empr.com/Creon-delayed-release-capsules-available-for-exocrine-pancreatic-insufficiency/article/139668/. Accessed August 10, 2009.

In the Pipeline

• A new drug application (NDA) has been submitted to the Food and Drug Administration (FDA) for Acetavance, an intravenous (IV) form of acetaminophen used in the treatment of acute pain and fever in adults and children who cannot take oral medications.1
• An NDA for a low-dose aspirin and esomeprazole combination product has been submitted for risk reduction of low-dose-aspirin-associated gastric and/or duodenal ulcers. A supplemental NDA was submitted for esomeprazole for risk reduction of low-dose-aspirin-associated peptic ulcer disease.2
• An NDA for a new formulation of ondansetron, as an orally dissolving film strip, has been submitted to the FDA.3 The product has shown comparable bioequivalence to ondansetron (Zofran) as an anti-emetic for preventing chemotherapy-induced nausea and vomiting, nausea and vomiting associated with radiotherapy, and post-operative nausea and vomiting.
• An NDA for tesamorelin to treat HIV-lipodystrophy has been submitted to the FDA.4

New Generics

• Acarbose 25-, 50- and 100-mg tablets (generic precose)5
• Bicalutamide (Casodex)6

New Drugs, Indications and Dosage Forms

• Artemether and lumefantrine (Coartem) tablets have been approved by the FDA for the treatment of acute, uncomplicated malarial infections in adults and children who weigh at least 5 kg.7 Coartem should be taken with food, particularly food that contains fat, because it improves drug absorption. Common adverse effects include headache, anorexia, dizziness, asthenia, arthralgia, and myalgia.
• Besifloxacin 0.6% (Besivance) ophthalmic suspension has been approved by the FDA to treat bacterial conjunctivitis. Adverse effects include eye redness, blurred vision, eye pain, irritation, itching, and headache.8
• Dexamethasone intravitreal implant (Ozurdex) has been approved by the FDA for treating macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).9 The implant is biodegradable and delivers dexamethasone via an extended-release mechanism over one to three months. Ozurdex is administered as an in-office procedure and is expected to be available soon.
• Dronedarone (Multaq) tablets have been approved by the FDA as an antiarrhythmic agent.10 It is indicated to reduce the risk of cardiovascular hospitalization in patients with atrial flutter, or paroxysmal or persistent atrial fibrillation, with a recent episode of atrial fibrillation/atrial flutter and associated cardiovascular risk, who are in sinus rhythm or who will be cardioverted.11 Risk factors include age >70, hypertension, diabetes, prior cerebrovascular accident, a left atrial diameter ≥50 mm, and left ventricular ejection fraction [LVEF] <40%.
• Hyoscyamine sulfate (NuLev) chewable antispasmodic orally disintegrating tablets (0.125 mg) have been reintroduced and are available to treat patients age 2 and older with gastrointestinal spasticity disorders.12
• Lacosamide (Vimpat) has been approved by the FDA for add-on therapy in the treatment of partial-onset seizures in epilepsy patients age 17 and older.13
• Lamotrigine extended-release (Lamictal XR) has been approved by the FDA as a once-daily add-on therapy for partial-onset seizures in epilepsy patients age 13 and older.14
• Pioglitazone/metformin (ACTOplus met XR) combination tablets have been approved by the FDA for treating Type 2 diabetes.15 It should be available later this year.
• Risperidone (Risperdal Consta) has received additional FDA approval as a biweekly injection as monotherapy, and as adjunctive therapy to lithium or valproate, in the maintenance of bipolar I disorder.16
• Tadalafil (Adcirc) has been approved by the FDA for improving exercise ability in patients with pulmonary arterial hypertension (PAH).17 Tadalafil already is approved as brand-name Cialis for treating erectile dysfunction. Tadalafil is the first once-daily phosphodiesterase type-5 inhibitor for treating PAH, and it is hoped it will gain some of the sildenafil (Revatio) market.

Update

As a followup to the August “Market Watch,” pancrelipase (Creon) has been approved by the FDA and is available in three FDA-approved prescription strengths based on the lipase content (6,000, 12,000, and 24,000).18 TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. NDA submitted for acetavance, a treatment for acute pain and fever. Monthly Prescribing Reference Web site. Available at: www.empr.com/NDA-submitted-for-Acetavance-a-treatment-for-acute-pain-and-fever/article/136799/. Accessed July 8, 2009.
2. AstraZeneca submits NDA for low dose aspirin/esomeprazole combination product. AstraZeneca Web site. Available at: www.astrazeneca-us.com/about-astrazeneca-us/newsroom/all/5762542?itemId=5762542. Accessed July 8, 2009.
3. MonoSol Rx and Strativa Pharmaceuticals submit new drug application for ondansetron orally dissolving film strip. Available at: www.monosolrx.com/news_09/news_040909.html. Accessed July 8, 2009.
4. Theratech shares jump 8 pct on FDA filing. Reuters Web site. Available at: www.reuters.com/article/idUSN0126728920090601. Accessed July 8, 2009.
5. Impax receives FDA approval for generic precos tablets, 25 mg, 50 mg and 100 mg. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c=67240&p=irol-newsArticle&ID=1289907&highlight=. Accessed July 8, 2009.
6. Caraco: FDA approves generic prostate cancer drug. Forbes Web site. Available at: www.forbes.com/feeds/ap/2009/07/07/ap6626628.html. Accessed July 8, 2009.
7. Walsh S. FDA approved coartem tablets to treat malaria. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149559.htm. Accessed July 8, 2009.
8. Walsh S. FDA approves besivance to treat bacterial conjunctivitis. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm162486.htm. Accessed July 8, 2009.
9. Ozurdex approved for treatment of macular edema. Monthly Prescribing Reference Web site. Available at: www.empr.com/Ozurdex-approved-for-treatment-of-macular-edema/article/138708/. Accessed July 8, 2009.
10. Walsh S. FDA approves multaq to treat heart rhythm disorder. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170276.htm. Accessed July 21, 2009.
11. Multaq label. FDA Web site: Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2009/022425lbl.pdf. Accessed July 21, 2009.
12. NuLev chewable melt tablets available again. Monthly Prescribing Reference Web site. Available at: www.empr.com/NuLev-Chewable-Melt-Tablets-available-again/article/138396/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed July 8, 2009.
13. UCB’s Vimpat (lacosamide) approved by FDA as add-on therapy for partial onset seizures in adults. Epilepsy Foundation Web site. Available at: www.epilepsyfoundation.org/epilepsyusa/news/UCB_Vimpat.cfm. Accessed July 8, 2009.
14. Bratulic A. FDA approves GlaxoSmithKline’s lamictal XR. Available at: www.firstwordplus.com/Fws.do?articleid=62DD8DEA3F594BDC98DA97F80AB13ABB&logRowId=307825. Accessed July 8, 2009.
15. FDA approves ACTOplus met XR (pioglitazone HCL and metformin HCl extended-release) tablets for the treatment of Type 2 diabetes. Available at: www.pipelinereview.com/index.php/2009051326959/Small-Molecules/FDA-Approves-ACTOplus-met-XR-pioglitazone-HCl-and-metformin-HCl-extended-release-Tablets-for-the-Treatment-of-Type-2-Diabetes.html. Accessed July 8, 2009.
16. FDA approval letter for risperdal consta. FDA Web site. Available at: www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/021346s025,021346s028ltr.pdf. Accessed July 8, 2009.
17. Todoruk M. United Therapeutics’ Adcirca approved for pulmonary arterial hypertension in US. FirstWord Web site. Available at: www.firstwordplus.com/Fws.do?articleid=E71E91953E9844D2A776B021E19AEE22&logRowId=306627. Accessed July 8, 2009.
18. Creon delayed-release capsules available for exocrine pancreatic insufficiency. Monthly Prescribing Reference Web site. Available at: www.empr.com/Creon-delayed-release-capsules-available-for-exocrine-pancreatic-insufficiency/article/139668/. Accessed August 10, 2009.

Product Withdrawal

• Efalizumab (Raptiva), the once-weekly monoclonal antibody used to treat moderate to severe plaque psoriasis, has been withdrawn from the U.S. market due to its association with an increased risk of developing progressive multifocal leukoencephalopathy (PML).1 Four cases of PML have been confirmed, and the manufacturer has decided the risks outweigh the benefits.2

New Generics

• Carbamazepine extended-release (generic Tegretol-XR) tablets (100 mg, 200 mg and 400 mg)3
• Mycophenolate mofetil (generic Cellcept)4

New Drugs, Indications & Dosage Forms

• You might have noticed some difficulty getting pancrelipase products for your patients with exocrine pancreatic insufficiency (EPI), pancreatitis, or cystic fibrosis. Here’s why: Pancreatic enzyme replacement therapies (PERT), pancreatic enzyme products (PEP), pancrelipase products, or EPI products were available prior to the formation of the U.S. Food and Drug Administration (FDA) and the Federal Food, Drug and Cosmetic Act (FDCA) of 1938.
  

  
  

  Until recently, none of these drug products had been marketed under approved new drug applications (NDAs). Since none of the products were subject to the NDA process, they were never subjected to safety, efficacy, bioavailability, or dose-ranging studies.5 The FDA has since decided that these agents must undergo the NDA process and, if approved, will only be available with a prescription.6
  

  
  

  Part of the guidance states that all approved formulations will contain “zero overfill.” In other words, the products will not have a range of lipase (90% to 165%), as they had before. Overfill leads to side effects, including diarrhea, flatulence, hyperuricosuria, hyperuricosemia, and fibrosing colonopathy.
  

  
  

  The new deadline to submit an NDA is April 29, 2010. The FDA has approved its first PEP agent, Creon pancrelipase, under the new guidance. It is expected to be available later this year.7

• Amlodipine, hydrochlorothiazide (HCTZ), and valsartan (Exforge HCT) is the first—and currently only—triple-combination antihypertensive agent to receive FDA approval.8 It can be used in patients already on these three medications, or it can be used as add-on therapy in patients not adequately controlled on two agents. The manufacturer plans to price the agent the same as amlodipine/valsartan (Exforge). Dose options are amlodipine 5 mg/valsartan 160 mg/HCTZ 12.5 mg, up to a maximum of two tablets daily.9
• Bromocriptine (Cycloset) is reformulated in a lower dose that is fast-acting and should be taken in the morning to boost dopamine levels and improve glycemic control in Type 2 diabetes patients.10 The drug is approved for monotherapy, as an adjunct to sulfonylurea therapy, or metformin plus a sulfonylurea. It’s the first diabetes agent to be FDA-approved since the guidance on cardiovascular risks. The most common side effects in clinical trials were nausea and dizziness. It should be used cautiously in patients taking antihypertensive treatment. Women who are nursing should not use it. The launch date is unknown.11
• Golimumab (Simponi), a once-a-month tumor necrosis factor-alpha inhibitor injection, has been FDA-approved for treating moderate to severe rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis.12 It carries the same warnings as other agents in the same class, including the risk of developing tuberculosis and invasive fungal infections. A risk evaluation mitigation strategy (REMS) and medication guide are required for this agent.
• Iloperidone (Fanapt), an atypical antipsychotic, has been FDA-approved to treat adults with schizophrenia. The most common side effects in clinical trials were dizziness, dry mouth, fatigue, nasal congestion, and orthostatic hypotension. Similar to other atypical antipsychotics, iloperidone carries a boxed warning regarding increased risk of death associated with treating behavioral problems in older patients with dementia-related psychosis, as it is not FDA-approved for this use.13

New Warnings

• Topical testosterone products (e.g., Androgel and Testim) have received a boxed warning.14 This warning is due to multiple reports of adverse effects in children exposed to the drug via contact with a topical testosterone-treated person. There are current product label precautions; however, the FDA has received reports of secondary exposure to testosterone in children 5 years old or younger. Adverse events included inappropriate genitalia enlargement, premature pubic hair development, bone age advancement, increased libido, and aggressive behavior. The FDA has provided recommendations to minimize secondary exposure. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. FDA statement on the voluntary withdrawal of Raptiva from the U.S. market. Food and Drug Administration Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149561.htm Accessed July 2, 2009.
2. Withdrawal of Raptiva from U.S. market. The Medical News Web site. Available at: www.news-medical.net/news/48133.aspx. Accessed May 12, 2009.
3. Taro receives final FDA approval for carbamazepine extended-release tablets. Medicine News Today Web site. Available at: www.medicalnewstoday.com/articles/145217.php. Accessed May 12, 2009.
4. FDA OKs Mylan generic version of transplant drug. Forbes Web site. Available at: www.forbes.com/feeds/ap/2009/05/07/ap6392275.html. Accessed May 8, 2009.
5. Exocrine Pancreatic Insufficiency Drug Products. Federal Register Web site. Available at: www.fda.gov/ohrms/dockets/98fr/04-9652.htm. Accessed May 7, 2009.
6. Guidance for industry exocrine pancreatic insufficiency drug products—submitting NDAs. FDA Web site. Available at: www.fda.gov/ohrms/dockets/98fr/2003d-0206-gdl0001.pdf. Accessed May 7, 2009.
7. Phend C. FDA formally approves Creon pancrelipase. Medpage Today Web site. Available at: www.medpagetoday.com/ProductAlert/Prescriptions/14021. Accessed May 7, 2009.
8. FDA approves Exforge HCT—the only high blood pressure treatment to combine three medications in a single pill. Novartis Web site. Available at: www.novartis.com/newsroom/media-releases/en/2009/1310474.shtml. Accessed May 7, 2009.
9. Phend C. FDA approves triple-drug antihypertensive polypill. Medpage Today Web site. Available at: www.medpagetoday.com/ProductAlert/Prescriptions/14032. Accessed May 7, 2009.
10. Neergaard L. FDA backs drug that treats diabetes via the brain. Physorg.com Web site. Available at: www.physorg.com/news160843146.html. Last Accessed May 8, 2009.
11. FDA approves Cycloset. Drugs.com Web site. Available at: www.drugs.com/newdrugs/veroscience-announces-fda-approval-cycloset-type-2-diabetes-1344.html. Accessed May 8, 2009.
12. FDA approves monthly injectable drug for treating three types of immune-related arthritis. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149569.htm. Accessed April 24, 2009.
13. FDA approves Fanapt to treat schizophrenia. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149578.htm. Accessed May 7, 2009.
14. Testosterone gel safety concerns prompt FDA to require label changes, medication guide. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149580.htm. Accessed May 12, 2009.

Product Withdrawal

• Efalizumab (Raptiva), the once-weekly monoclonal antibody used to treat moderate to severe plaque psoriasis, has been withdrawn from the U.S. market due to its association with an increased risk of developing progressive multifocal leukoencephalopathy (PML).1 Four cases of PML have been confirmed, and the manufacturer has decided the risks outweigh the benefits.2

New Generics

• Carbamazepine extended-release (generic Tegretol-XR) tablets (100 mg, 200 mg and 400 mg)3
• Mycophenolate mofetil (generic Cellcept)4

New Drugs, Indications & Dosage Forms

• You might have noticed some difficulty getting pancrelipase products for your patients with exocrine pancreatic insufficiency (EPI), pancreatitis, or cystic fibrosis. Here’s why: Pancreatic enzyme replacement therapies (PERT), pancreatic enzyme products (PEP), pancrelipase products, or EPI products were available prior to the formation of the U.S. Food and Drug Administration (FDA) and the Federal Food, Drug and Cosmetic Act (FDCA) of 1938.
  

  
  

  Until recently, none of these drug products had been marketed under approved new drug applications (NDAs). Since none of the products were subject to the NDA process, they were never subjected to safety, efficacy, bioavailability, or dose-ranging studies.5 The FDA has since decided that these agents must undergo the NDA process and, if approved, will only be available with a prescription.6
  

  
  

  Part of the guidance states that all approved formulations will contain “zero overfill.” In other words, the products will not have a range of lipase (90% to 165%), as they had before. Overfill leads to side effects, including diarrhea, flatulence, hyperuricosuria, hyperuricosemia, and fibrosing colonopathy.
  

  
  

  The new deadline to submit an NDA is April 29, 2010. The FDA has approved its first PEP agent, Creon pancrelipase, under the new guidance. It is expected to be available later this year.7

• Amlodipine, hydrochlorothiazide (HCTZ), and valsartan (Exforge HCT) is the first—and currently only—triple-combination antihypertensive agent to receive FDA approval.8 It can be used in patients already on these three medications, or it can be used as add-on therapy in patients not adequately controlled on two agents. The manufacturer plans to price the agent the same as amlodipine/valsartan (Exforge). Dose options are amlodipine 5 mg/valsartan 160 mg/HCTZ 12.5 mg, up to a maximum of two tablets daily.9
• Bromocriptine (Cycloset) is reformulated in a lower dose that is fast-acting and should be taken in the morning to boost dopamine levels and improve glycemic control in Type 2 diabetes patients.10 The drug is approved for monotherapy, as an adjunct to sulfonylurea therapy, or metformin plus a sulfonylurea. It’s the first diabetes agent to be FDA-approved since the guidance on cardiovascular risks. The most common side effects in clinical trials were nausea and dizziness. It should be used cautiously in patients taking antihypertensive treatment. Women who are nursing should not use it. The launch date is unknown.11
• Golimumab (Simponi), a once-a-month tumor necrosis factor-alpha inhibitor injection, has been FDA-approved for treating moderate to severe rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis.12 It carries the same warnings as other agents in the same class, including the risk of developing tuberculosis and invasive fungal infections. A risk evaluation mitigation strategy (REMS) and medication guide are required for this agent.
• Iloperidone (Fanapt), an atypical antipsychotic, has been FDA-approved to treat adults with schizophrenia. The most common side effects in clinical trials were dizziness, dry mouth, fatigue, nasal congestion, and orthostatic hypotension. Similar to other atypical antipsychotics, iloperidone carries a boxed warning regarding increased risk of death associated with treating behavioral problems in older patients with dementia-related psychosis, as it is not FDA-approved for this use.13

New Warnings

• Topical testosterone products (e.g., Androgel and Testim) have received a boxed warning.14 This warning is due to multiple reports of adverse effects in children exposed to the drug via contact with a topical testosterone-treated person. There are current product label precautions; however, the FDA has received reports of secondary exposure to testosterone in children 5 years old or younger. Adverse events included inappropriate genitalia enlargement, premature pubic hair development, bone age advancement, increased libido, and aggressive behavior. The FDA has provided recommendations to minimize secondary exposure. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. FDA statement on the voluntary withdrawal of Raptiva from the U.S. market. Food and Drug Administration Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149561.htm Accessed July 2, 2009.
2. Withdrawal of Raptiva from U.S. market. The Medical News Web site. Available at: www.news-medical.net/news/48133.aspx. Accessed May 12, 2009.
3. Taro receives final FDA approval for carbamazepine extended-release tablets. Medicine News Today Web site. Available at: www.medicalnewstoday.com/articles/145217.php. Accessed May 12, 2009.
4. FDA OKs Mylan generic version of transplant drug. Forbes Web site. Available at: www.forbes.com/feeds/ap/2009/05/07/ap6392275.html. Accessed May 8, 2009.
5. Exocrine Pancreatic Insufficiency Drug Products. Federal Register Web site. Available at: www.fda.gov/ohrms/dockets/98fr/04-9652.htm. Accessed May 7, 2009.
6. Guidance for industry exocrine pancreatic insufficiency drug products—submitting NDAs. FDA Web site. Available at: www.fda.gov/ohrms/dockets/98fr/2003d-0206-gdl0001.pdf. Accessed May 7, 2009.
7. Phend C. FDA formally approves Creon pancrelipase. Medpage Today Web site. Available at: www.medpagetoday.com/ProductAlert/Prescriptions/14021. Accessed May 7, 2009.
8. FDA approves Exforge HCT—the only high blood pressure treatment to combine three medications in a single pill. Novartis Web site. Available at: www.novartis.com/newsroom/media-releases/en/2009/1310474.shtml. Accessed May 7, 2009.
9. Phend C. FDA approves triple-drug antihypertensive polypill. Medpage Today Web site. Available at: www.medpagetoday.com/ProductAlert/Prescriptions/14032. Accessed May 7, 2009.
10. Neergaard L. FDA backs drug that treats diabetes via the brain. Physorg.com Web site. Available at: www.physorg.com/news160843146.html. Last Accessed May 8, 2009.
11. FDA approves Cycloset. Drugs.com Web site. Available at: www.drugs.com/newdrugs/veroscience-announces-fda-approval-cycloset-type-2-diabetes-1344.html. Accessed May 8, 2009.
12. FDA approves monthly injectable drug for treating three types of immune-related arthritis. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149569.htm. Accessed April 24, 2009.
13. FDA approves Fanapt to treat schizophrenia. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149578.htm. Accessed May 7, 2009.
14. Testosterone gel safety concerns prompt FDA to require label changes, medication guide. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149580.htm. Accessed May 12, 2009.

Product Withdrawal

• Efalizumab (Raptiva), the once-weekly monoclonal antibody used to treat moderate to severe plaque psoriasis, has been withdrawn from the U.S. market due to its association with an increased risk of developing progressive multifocal leukoencephalopathy (PML).1 Four cases of PML have been confirmed, and the manufacturer has decided the risks outweigh the benefits.2

New Generics

• Carbamazepine extended-release (generic Tegretol-XR) tablets (100 mg, 200 mg and 400 mg)3
• Mycophenolate mofetil (generic Cellcept)4

New Drugs, Indications & Dosage Forms

• You might have noticed some difficulty getting pancrelipase products for your patients with exocrine pancreatic insufficiency (EPI), pancreatitis, or cystic fibrosis. Here’s why: Pancreatic enzyme replacement therapies (PERT), pancreatic enzyme products (PEP), pancrelipase products, or EPI products were available prior to the formation of the U.S. Food and Drug Administration (FDA) and the Federal Food, Drug and Cosmetic Act (FDCA) of 1938.
  

  
  

  Until recently, none of these drug products had been marketed under approved new drug applications (NDAs). Since none of the products were subject to the NDA process, they were never subjected to safety, efficacy, bioavailability, or dose-ranging studies.5 The FDA has since decided that these agents must undergo the NDA process and, if approved, will only be available with a prescription.6
  

  
  

  Part of the guidance states that all approved formulations will contain “zero overfill.” In other words, the products will not have a range of lipase (90% to 165%), as they had before. Overfill leads to side effects, including diarrhea, flatulence, hyperuricosuria, hyperuricosemia, and fibrosing colonopathy.
  

  
  

  The new deadline to submit an NDA is April 29, 2010. The FDA has approved its first PEP agent, Creon pancrelipase, under the new guidance. It is expected to be available later this year.7

• Amlodipine, hydrochlorothiazide (HCTZ), and valsartan (Exforge HCT) is the first—and currently only—triple-combination antihypertensive agent to receive FDA approval.8 It can be used in patients already on these three medications, or it can be used as add-on therapy in patients not adequately controlled on two agents. The manufacturer plans to price the agent the same as amlodipine/valsartan (Exforge). Dose options are amlodipine 5 mg/valsartan 160 mg/HCTZ 12.5 mg, up to a maximum of two tablets daily.9
• Bromocriptine (Cycloset) is reformulated in a lower dose that is fast-acting and should be taken in the morning to boost dopamine levels and improve glycemic control in Type 2 diabetes patients.10 The drug is approved for monotherapy, as an adjunct to sulfonylurea therapy, or metformin plus a sulfonylurea. It’s the first diabetes agent to be FDA-approved since the guidance on cardiovascular risks. The most common side effects in clinical trials were nausea and dizziness. It should be used cautiously in patients taking antihypertensive treatment. Women who are nursing should not use it. The launch date is unknown.11
• Golimumab (Simponi), a once-a-month tumor necrosis factor-alpha inhibitor injection, has been FDA-approved for treating moderate to severe rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis.12 It carries the same warnings as other agents in the same class, including the risk of developing tuberculosis and invasive fungal infections. A risk evaluation mitigation strategy (REMS) and medication guide are required for this agent.
• Iloperidone (Fanapt), an atypical antipsychotic, has been FDA-approved to treat adults with schizophrenia. The most common side effects in clinical trials were dizziness, dry mouth, fatigue, nasal congestion, and orthostatic hypotension. Similar to other atypical antipsychotics, iloperidone carries a boxed warning regarding increased risk of death associated with treating behavioral problems in older patients with dementia-related psychosis, as it is not FDA-approved for this use.13

New Warnings

• Topical testosterone products (e.g., Androgel and Testim) have received a boxed warning.14 This warning is due to multiple reports of adverse effects in children exposed to the drug via contact with a topical testosterone-treated person. There are current product label precautions; however, the FDA has received reports of secondary exposure to testosterone in children 5 years old or younger. Adverse events included inappropriate genitalia enlargement, premature pubic hair development, bone age advancement, increased libido, and aggressive behavior. The FDA has provided recommendations to minimize secondary exposure. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. FDA statement on the voluntary withdrawal of Raptiva from the U.S. market. Food and Drug Administration Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149561.htm Accessed July 2, 2009.
2. Withdrawal of Raptiva from U.S. market. The Medical News Web site. Available at: www.news-medical.net/news/48133.aspx. Accessed May 12, 2009.
3. Taro receives final FDA approval for carbamazepine extended-release tablets. Medicine News Today Web site. Available at: www.medicalnewstoday.com/articles/145217.php. Accessed May 12, 2009.
4. FDA OKs Mylan generic version of transplant drug. Forbes Web site. Available at: www.forbes.com/feeds/ap/2009/05/07/ap6392275.html. Accessed May 8, 2009.
5. Exocrine Pancreatic Insufficiency Drug Products. Federal Register Web site. Available at: www.fda.gov/ohrms/dockets/98fr/04-9652.htm. Accessed May 7, 2009.
6. Guidance for industry exocrine pancreatic insufficiency drug products—submitting NDAs. FDA Web site. Available at: www.fda.gov/ohrms/dockets/98fr/2003d-0206-gdl0001.pdf. Accessed May 7, 2009.
7. Phend C. FDA formally approves Creon pancrelipase. Medpage Today Web site. Available at: www.medpagetoday.com/ProductAlert/Prescriptions/14021. Accessed May 7, 2009.
8. FDA approves Exforge HCT—the only high blood pressure treatment to combine three medications in a single pill. Novartis Web site. Available at: www.novartis.com/newsroom/media-releases/en/2009/1310474.shtml. Accessed May 7, 2009.
9. Phend C. FDA approves triple-drug antihypertensive polypill. Medpage Today Web site. Available at: www.medpagetoday.com/ProductAlert/Prescriptions/14032. Accessed May 7, 2009.
10. Neergaard L. FDA backs drug that treats diabetes via the brain. Physorg.com Web site. Available at: www.physorg.com/news160843146.html. Last Accessed May 8, 2009.
11. FDA approves Cycloset. Drugs.com Web site. Available at: www.drugs.com/newdrugs/veroscience-announces-fda-approval-cycloset-type-2-diabetes-1344.html. Accessed May 8, 2009.
12. FDA approves monthly injectable drug for treating three types of immune-related arthritis. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149569.htm. Accessed April 24, 2009.
13. FDA approves Fanapt to treat schizophrenia. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149578.htm. Accessed May 7, 2009.
14. Testosterone gel safety concerns prompt FDA to require label changes, medication guide. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149580.htm. Accessed May 12, 2009.

According to the American Diabetes Association, a normal fasting plasma glucose (FPG) level is less than 100 mg/dl; impaired fasting glucose (IFG) is defined as an FPG from 100 to 125 mg/dl; and any patient with an FPG greater than or equal to 126 mg/dL carries a provisional diagnosis of diabetes.1 When the oral glucose tolerance test is used for evaluation, similar definitions exist. Patients with IFG or impaired glucose tolerance (IGT) have “pre-diabetes,” and are at a high risk for developing diabetes. Elevated blood glucose levels can have major consequences, particularly in high-risk populations.2

Macrovascular and microvascular complications, impaired wound healing, and a compromised immune system can occur in the setting of sustained, elevated blood glucose concentrations. Aside from patients with diabetes who have elevated blood glucose levels, schizophrenic patients might be predisposed to glucose intolerance and diabetes independent of treatment.3

It is not known whether IGT seen in schizophrenics is due to lifestyle risk factors (e.g., smoking, poor diet, being overweight, lack of exercise) or some genetic or biological component of the disease. However, this is complicated by the fact that many of these patients are treated with second-generation antipsychotics (SGAs), which might increase the risk of developing diabetes.4 Because of this, a warning regarding the risk of developing hyperglycemia and diabetes was mandated by the Food and Drug Administration (FDA) for SGA manufacturers.5

Hyperglycemia symptoms include polyuria, polydipsia, weight loss (sometimes with polyphagia), and blurred vision. Impairment of growth and susceptibility to certain infections might occur with chronic hyperglycemia. Hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome are acute, life-threatening consequences of uncontrolled diabetes. It is important for hospitalists and other healthcare professionals to be aware of drugs that can cause hyperglycemia or impair glucose tolerance. In some cases, the drug can be continued; in other cases, an alternate agent should be provided if necessary for patient management.

Certain drugs and drug classes known to cause hyperglycemia include: thiazide diuretics, glucocorticoids, oral contraceptives and sex hormones (e.g., testosterone), protease inhibitors, SGAs, thyroid hormone, phenytoin, niacin/nicotinic acid, diazoxide, and alfa-interferon.1-3,6

Limited evidence exists for some other agents/classes, including: asparaginase, beta-agonists, beta-blockers, calcium channel blockers, clonidine, cyclosporine, levodopa, lithium, minoxidil, phenothiazines, and others.7 The Seventh Report of the Joint National Committee (JNC 7) recommends thiazide diuretics as a first-line treatment for most patients with Stage 1 hypertension, alone or in combination for patients with diabetes.8 These thiazide doses tend to be smaller and, therefore, tend to have minimal effects on blood glucose levels.

In 2004, a consensus guideline was developed on antipsychotic drugs, obesity, and diabetes.9 It describes baseline and followup monitoring of patients treated with SGAs. The baseline includes personal/family history, weight/body mass index, waist circumference, blood pressure, FPG, and a fasting lipid profile. Monitoring of these parameters is then designated at specified times throughout treatment (e.g., weeks four, eight, 12, etc.). Haupt et al recently compared monitoring of lipids and glucose in a population of insured patients receiving SGAs in a retrospective cohort of patients pre- and post-guideline.10 Baseline lipid and glucose testing rates increased minimally post-guideline versus pre-guideline.

The results of this study demonstrate that even though monitoring guidelines to prevent potentially adverse outcomes in a patient population at high risk for developing adverse outcomes are available, clinicians do not always follow them. In order to improve patient outcomes, identified at-risk populations (e.g., patients receiving SGAs) need to be more closely evaluated and monitored throughout therapy to prevent IGT and/or diabetes. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2009;32:S62-S67.
2. Luna B, Feinglos MN. Drug-induced hyperglycemia. JAMA. 2001;286:1945-1948.
3. Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry. 2007;68(Suppl 1):20-27.
4. Tahir R. Metabolic effects of atypical antipsychotics. US Pharm. 2007;32:HS3-HS14.
5. Warning about hyperglycemia and atypical antipsychotic drugs. U.S. Food & Drug Administration Web site. Available at: www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/printer.cfm?id=229. Accessed March 31, 2009.
6. Kaufman MB, Simionatto C. A review of protease inhibitor-induced hyperglycemia. Pharmacotherapy. 1999;19:114-117.
7. Pandit MK, Burke J, Gustafson AB, Minocha A, Peiris AN. Drug-induced disorders of glucose tolerance. Ann Intern Med. 1993;118:529-539.
8. Chobanian AV, Bakris GL, Clack HR, et al. The seventh report of the joint national committee on prevention, detection, evaluations, and treatment of high blood pressure. JAMA. 2003;289:2560-2572.
9. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27:596-601.
10. Haupt DW, Rosenblatt LC, Kim E, Baker RA, Whitehead R, Newcomer JW. Prevalence and predictors of lipid and glucose monitoring in commercially insured patients treated with second-generation antipsychotic agents. Am J Psychiatry. 2009;166:345-353.
11. FDA approves generic treatment for emesis. Drug Store News Web site. Available at: www.drugstorenews.com/story.aspx?id=96143. Accessed March 6, 2009.
12. Aurobindo Pharma gets tentative approval from US FDA for tenofovir disoproxil fumarate tabs. RTT News Web site. Available at: www.rttnews.com/ArticleView.aspx?id=860423. Accessed March 4, 2009.
13. Teva announces approval and launch of generic Topamax tablets.Teva Web site. Available at: www.tevapharm.com/pr/2009/pr_835.asp. Accessed March 30, 2009.
14. FDA approves Symbicort for chronic obstructive pulmonary disease (COPD). AstraZeneca Web site. Available at: www.astrazeneca-us.com/about-astrazenecaus/newsroom/all/4939997?itemId=4939997. Accessed June 5, 2009.
15. Copaxone approved by the FDA for patients with a first clinical event suggestive of multiple sclerosis. Teva Web site. Available at: www.tevapharm.com/pr/2009/ pr_826.asp? Accessed June 5, 2009.
16. Todoruk M. FDA approves new use for Wyeth’s Tygacil antibiotic. Available at: www.firstwordplus.com/Fws.do?articleid=CF71DE6056CE4120A295243AE2D6EC00. Accessed March 25, 2009.
17. FDA Web site. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2009/021821s013s017s018lbl.pdf. Accessed June 5, 2009.
18. Transdermal drug patches with metallic backings. FDA Web site. Available at: www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm111493.htm. Accessed June 5, 2009.
19. FDA warns about risk of wearing medicated patches during MRIs. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149537.htm. Accessed March 6, 2009.
20. FDA requires boxed warning and risk mitigation strategy for metoclopramide-containing drugs. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149533.htm. Accessed March 4, 2009.
21. Zonisamide (marketed as Zonegran, and generics). FDA Web site. Available at: www.fda.gov/ForConsumers/ConsumerUpdates/ucm095251.htm. Accessed March 4, 2009.

According to the American Diabetes Association, a normal fasting plasma glucose (FPG) level is less than 100 mg/dl; impaired fasting glucose (IFG) is defined as an FPG from 100 to 125 mg/dl; and any patient with an FPG greater than or equal to 126 mg/dL carries a provisional diagnosis of diabetes.1 When the oral glucose tolerance test is used for evaluation, similar definitions exist. Patients with IFG or impaired glucose tolerance (IGT) have “pre-diabetes,” and are at a high risk for developing diabetes. Elevated blood glucose levels can have major consequences, particularly in high-risk populations.2

Macrovascular and microvascular complications, impaired wound healing, and a compromised immune system can occur in the setting of sustained, elevated blood glucose concentrations. Aside from patients with diabetes who have elevated blood glucose levels, schizophrenic patients might be predisposed to glucose intolerance and diabetes independent of treatment.3

It is not known whether IGT seen in schizophrenics is due to lifestyle risk factors (e.g., smoking, poor diet, being overweight, lack of exercise) or some genetic or biological component of the disease. However, this is complicated by the fact that many of these patients are treated with second-generation antipsychotics (SGAs), which might increase the risk of developing diabetes.4 Because of this, a warning regarding the risk of developing hyperglycemia and diabetes was mandated by the Food and Drug Administration (FDA) for SGA manufacturers.5

Hyperglycemia symptoms include polyuria, polydipsia, weight loss (sometimes with polyphagia), and blurred vision. Impairment of growth and susceptibility to certain infections might occur with chronic hyperglycemia. Hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome are acute, life-threatening consequences of uncontrolled diabetes. It is important for hospitalists and other healthcare professionals to be aware of drugs that can cause hyperglycemia or impair glucose tolerance. In some cases, the drug can be continued; in other cases, an alternate agent should be provided if necessary for patient management.

Certain drugs and drug classes known to cause hyperglycemia include: thiazide diuretics, glucocorticoids, oral contraceptives and sex hormones (e.g., testosterone), protease inhibitors, SGAs, thyroid hormone, phenytoin, niacin/nicotinic acid, diazoxide, and alfa-interferon.1-3,6

Limited evidence exists for some other agents/classes, including: asparaginase, beta-agonists, beta-blockers, calcium channel blockers, clonidine, cyclosporine, levodopa, lithium, minoxidil, phenothiazines, and others.7 The Seventh Report of the Joint National Committee (JNC 7) recommends thiazide diuretics as a first-line treatment for most patients with Stage 1 hypertension, alone or in combination for patients with diabetes.8 These thiazide doses tend to be smaller and, therefore, tend to have minimal effects on blood glucose levels.

In 2004, a consensus guideline was developed on antipsychotic drugs, obesity, and diabetes.9 It describes baseline and followup monitoring of patients treated with SGAs. The baseline includes personal/family history, weight/body mass index, waist circumference, blood pressure, FPG, and a fasting lipid profile. Monitoring of these parameters is then designated at specified times throughout treatment (e.g., weeks four, eight, 12, etc.). Haupt et al recently compared monitoring of lipids and glucose in a population of insured patients receiving SGAs in a retrospective cohort of patients pre- and post-guideline.10 Baseline lipid and glucose testing rates increased minimally post-guideline versus pre-guideline.

The results of this study demonstrate that even though monitoring guidelines to prevent potentially adverse outcomes in a patient population at high risk for developing adverse outcomes are available, clinicians do not always follow them. In order to improve patient outcomes, identified at-risk populations (e.g., patients receiving SGAs) need to be more closely evaluated and monitored throughout therapy to prevent IGT and/or diabetes. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2009;32:S62-S67.
2. Luna B, Feinglos MN. Drug-induced hyperglycemia. JAMA. 2001;286:1945-1948.
3. Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry. 2007;68(Suppl 1):20-27.
4. Tahir R. Metabolic effects of atypical antipsychotics. US Pharm. 2007;32:HS3-HS14.
5. Warning about hyperglycemia and atypical antipsychotic drugs. U.S. Food & Drug Administration Web site. Available at: www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/printer.cfm?id=229. Accessed March 31, 2009.
6. Kaufman MB, Simionatto C. A review of protease inhibitor-induced hyperglycemia. Pharmacotherapy. 1999;19:114-117.
7. Pandit MK, Burke J, Gustafson AB, Minocha A, Peiris AN. Drug-induced disorders of glucose tolerance. Ann Intern Med. 1993;118:529-539.
8. Chobanian AV, Bakris GL, Clack HR, et al. The seventh report of the joint national committee on prevention, detection, evaluations, and treatment of high blood pressure. JAMA. 2003;289:2560-2572.
9. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27:596-601.
10. Haupt DW, Rosenblatt LC, Kim E, Baker RA, Whitehead R, Newcomer JW. Prevalence and predictors of lipid and glucose monitoring in commercially insured patients treated with second-generation antipsychotic agents. Am J Psychiatry. 2009;166:345-353.
11. FDA approves generic treatment for emesis. Drug Store News Web site. Available at: www.drugstorenews.com/story.aspx?id=96143. Accessed March 6, 2009.
12. Aurobindo Pharma gets tentative approval from US FDA for tenofovir disoproxil fumarate tabs. RTT News Web site. Available at: www.rttnews.com/ArticleView.aspx?id=860423. Accessed March 4, 2009.
13. Teva announces approval and launch of generic Topamax tablets.Teva Web site. Available at: www.tevapharm.com/pr/2009/pr_835.asp. Accessed March 30, 2009.
14. FDA approves Symbicort for chronic obstructive pulmonary disease (COPD). AstraZeneca Web site. Available at: www.astrazeneca-us.com/about-astrazenecaus/newsroom/all/4939997?itemId=4939997. Accessed June 5, 2009.
15. Copaxone approved by the FDA for patients with a first clinical event suggestive of multiple sclerosis. Teva Web site. Available at: www.tevapharm.com/pr/2009/ pr_826.asp? Accessed June 5, 2009.
16. Todoruk M. FDA approves new use for Wyeth’s Tygacil antibiotic. Available at: www.firstwordplus.com/Fws.do?articleid=CF71DE6056CE4120A295243AE2D6EC00. Accessed March 25, 2009.
17. FDA Web site. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2009/021821s013s017s018lbl.pdf. Accessed June 5, 2009.
18. Transdermal drug patches with metallic backings. FDA Web site. Available at: www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm111493.htm. Accessed June 5, 2009.
19. FDA warns about risk of wearing medicated patches during MRIs. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149537.htm. Accessed March 6, 2009.
20. FDA requires boxed warning and risk mitigation strategy for metoclopramide-containing drugs. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149533.htm. Accessed March 4, 2009.
21. Zonisamide (marketed as Zonegran, and generics). FDA Web site. Available at: www.fda.gov/ForConsumers/ConsumerUpdates/ucm095251.htm. Accessed March 4, 2009.

According to the American Diabetes Association, a normal fasting plasma glucose (FPG) level is less than 100 mg/dl; impaired fasting glucose (IFG) is defined as an FPG from 100 to 125 mg/dl; and any patient with an FPG greater than or equal to 126 mg/dL carries a provisional diagnosis of diabetes.1 When the oral glucose tolerance test is used for evaluation, similar definitions exist. Patients with IFG or impaired glucose tolerance (IGT) have “pre-diabetes,” and are at a high risk for developing diabetes. Elevated blood glucose levels can have major consequences, particularly in high-risk populations.2

Macrovascular and microvascular complications, impaired wound healing, and a compromised immune system can occur in the setting of sustained, elevated blood glucose concentrations. Aside from patients with diabetes who have elevated blood glucose levels, schizophrenic patients might be predisposed to glucose intolerance and diabetes independent of treatment.3

It is not known whether IGT seen in schizophrenics is due to lifestyle risk factors (e.g., smoking, poor diet, being overweight, lack of exercise) or some genetic or biological component of the disease. However, this is complicated by the fact that many of these patients are treated with second-generation antipsychotics (SGAs), which might increase the risk of developing diabetes.4 Because of this, a warning regarding the risk of developing hyperglycemia and diabetes was mandated by the Food and Drug Administration (FDA) for SGA manufacturers.5

Hyperglycemia symptoms include polyuria, polydipsia, weight loss (sometimes with polyphagia), and blurred vision. Impairment of growth and susceptibility to certain infections might occur with chronic hyperglycemia. Hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome are acute, life-threatening consequences of uncontrolled diabetes. It is important for hospitalists and other healthcare professionals to be aware of drugs that can cause hyperglycemia or impair glucose tolerance. In some cases, the drug can be continued; in other cases, an alternate agent should be provided if necessary for patient management.

Certain drugs and drug classes known to cause hyperglycemia include: thiazide diuretics, glucocorticoids, oral contraceptives and sex hormones (e.g., testosterone), protease inhibitors, SGAs, thyroid hormone, phenytoin, niacin/nicotinic acid, diazoxide, and alfa-interferon.1-3,6

Limited evidence exists for some other agents/classes, including: asparaginase, beta-agonists, beta-blockers, calcium channel blockers, clonidine, cyclosporine, levodopa, lithium, minoxidil, phenothiazines, and others.7 The Seventh Report of the Joint National Committee (JNC 7) recommends thiazide diuretics as a first-line treatment for most patients with Stage 1 hypertension, alone or in combination for patients with diabetes.8 These thiazide doses tend to be smaller and, therefore, tend to have minimal effects on blood glucose levels.

In 2004, a consensus guideline was developed on antipsychotic drugs, obesity, and diabetes.9 It describes baseline and followup monitoring of patients treated with SGAs. The baseline includes personal/family history, weight/body mass index, waist circumference, blood pressure, FPG, and a fasting lipid profile. Monitoring of these parameters is then designated at specified times throughout treatment (e.g., weeks four, eight, 12, etc.). Haupt et al recently compared monitoring of lipids and glucose in a population of insured patients receiving SGAs in a retrospective cohort of patients pre- and post-guideline.10 Baseline lipid and glucose testing rates increased minimally post-guideline versus pre-guideline.

The results of this study demonstrate that even though monitoring guidelines to prevent potentially adverse outcomes in a patient population at high risk for developing adverse outcomes are available, clinicians do not always follow them. In order to improve patient outcomes, identified at-risk populations (e.g., patients receiving SGAs) need to be more closely evaluated and monitored throughout therapy to prevent IGT and/or diabetes. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2009;32:S62-S67.
2. Luna B, Feinglos MN. Drug-induced hyperglycemia. JAMA. 2001;286:1945-1948.
3. Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry. 2007;68(Suppl 1):20-27.
4. Tahir R. Metabolic effects of atypical antipsychotics. US Pharm. 2007;32:HS3-HS14.
5. Warning about hyperglycemia and atypical antipsychotic drugs. U.S. Food & Drug Administration Web site. Available at: www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/printer.cfm?id=229. Accessed March 31, 2009.
6. Kaufman MB, Simionatto C. A review of protease inhibitor-induced hyperglycemia. Pharmacotherapy. 1999;19:114-117.
7. Pandit MK, Burke J, Gustafson AB, Minocha A, Peiris AN. Drug-induced disorders of glucose tolerance. Ann Intern Med. 1993;118:529-539.
8. Chobanian AV, Bakris GL, Clack HR, et al. The seventh report of the joint national committee on prevention, detection, evaluations, and treatment of high blood pressure. JAMA. 2003;289:2560-2572.
9. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27:596-601.
10. Haupt DW, Rosenblatt LC, Kim E, Baker RA, Whitehead R, Newcomer JW. Prevalence and predictors of lipid and glucose monitoring in commercially insured patients treated with second-generation antipsychotic agents. Am J Psychiatry. 2009;166:345-353.
11. FDA approves generic treatment for emesis. Drug Store News Web site. Available at: www.drugstorenews.com/story.aspx?id=96143. Accessed March 6, 2009.
12. Aurobindo Pharma gets tentative approval from US FDA for tenofovir disoproxil fumarate tabs. RTT News Web site. Available at: www.rttnews.com/ArticleView.aspx?id=860423. Accessed March 4, 2009.
13. Teva announces approval and launch of generic Topamax tablets.Teva Web site. Available at: www.tevapharm.com/pr/2009/pr_835.asp. Accessed March 30, 2009.
14. FDA approves Symbicort for chronic obstructive pulmonary disease (COPD). AstraZeneca Web site. Available at: www.astrazeneca-us.com/about-astrazenecaus/newsroom/all/4939997?itemId=4939997. Accessed June 5, 2009.
15. Copaxone approved by the FDA for patients with a first clinical event suggestive of multiple sclerosis. Teva Web site. Available at: www.tevapharm.com/pr/2009/ pr_826.asp? Accessed June 5, 2009.
16. Todoruk M. FDA approves new use for Wyeth’s Tygacil antibiotic. Available at: www.firstwordplus.com/Fws.do?articleid=CF71DE6056CE4120A295243AE2D6EC00. Accessed March 25, 2009.
17. FDA Web site. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2009/021821s013s017s018lbl.pdf. Accessed June 5, 2009.
18. Transdermal drug patches with metallic backings. FDA Web site. Available at: www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm111493.htm. Accessed June 5, 2009.
19. FDA warns about risk of wearing medicated patches during MRIs. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149537.htm. Accessed March 6, 2009.
20. FDA requires boxed warning and risk mitigation strategy for metoclopramide-containing drugs. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149533.htm. Accessed March 4, 2009.
21. Zonisamide (marketed as Zonegran, and generics). FDA Web site. Available at: www.fda.gov/ForConsumers/ConsumerUpdates/ucm095251.htm. Accessed March 4, 2009.

Let’s look at a case: A known diabetic patient has been in good control, with glycosylated hemoglobin (HbA1c) levels lower than 6.5 gm/dL the past two years. Her medication regimen has remained relatively stable during that time. Her daily medications include simvastatin, 40 mg; metformin extended release, 2,000 mg; sitagliptin, 100 mg; glimepiride, 8 mg; quinapril, 20 mg; a multivitamin; calcium carbonate, 1,500 mg; and an 81-mg aspirin.

Her lipid panel, liver and renal function tests, and blood pressure are all within normal limits. However, she was admitted to the hospital with a plasma glucose level of 38 mg/dL.

Upon physical examination, she appears diaphoretic, with weakness, confusion, tremulousness, and palpitations. She is treated with glucose to maintain a level of above 50 mg/dL, and she responds without long-term sequelae.

What precipitated this event?

Drug-Induced Hypoglycemia

Hypoglycemia may represent a lab error or artifactual hypoglycemia due to glycolysis in the collection sample. To determine a pathological cause of hypoglycemia, the triad of low plasma glucose, hypoglycemia symptoms, and symptom resolution with correction of the blood glucose level should be used.1 Hypoglycemia is most often seen in diabetic patients and is the most commonly noted endocrine emergency in the inpatient setting, as well as in the ambulatory setting. Some common causes of hypoglycemia in diabetes patients include alcohol consumption, skipping meals, too much exercise, and intentional or unintentional medication overdoses.2

Treatment is required when the blood glucose level is below 45 gm/dL. Symptoms include anxiety, tremulousness, nausea, sweating, palpitation, and hunger.3 More severe symptoms related to compromised central nervous system function include weakness, fatigue, confusion, seizures, focal neurologic deficits, and coma.

The most common causes of drug-induced hypoglycemia are insulin, ethanol, or sulfonylureas. Risk factors associated with unintentional overdose of sulfonylureas include advanced age, drug-to-drug interactions, and decreased renal or hepatic clearance. Other drugs have been reported to cause hypoglycemia. Some of these include high-dose salicylates, beta-blockers, haloperidol, monoamine oxidase inhibitors, other sulfonamides (particularly trimethoprim-sulfamethoxazole), pentamidine, quinine/quinidine, and quinolone antibiotics (e.g., gatifloxacin or levofloxacin).4

Diabetics use more than 120 natural medicines, either alone or in combination with their prescribed diabetes medications, to lower blood glucose and/or improve HbA1c.5 Some of the most commonly used products are banaba, bitter melon, fenugreek, and Gymnema (hypoglycemics), along with American or panax ginseng, cassia cinnamon, chromium, prickly pear cactus, soy, or vanadium (insulin sensitizers).

Diagnosis

Patient history aids in the clinical diagnosis of hypoglycemia and should be reviewed to determine a potential drug-induced cause. History also might identify a medication dispensing error (e.g., the onset of hypoglycemia following a recent medication refill). Hospitalists should question the patient or the patient’s family as to medication use, including over-the-counter drugs, vitamins, supplements, natural foods, and other related products.

Treatment

Glucose should be administered to maintain a plasma glucose level of at least 50 gm/dL. This may be achieved orally via frequent meals or snacks, or intravenously. The underlying cause should be addressed. In drug- or medication-induced cases, the causative agent should be removed or retitrated to an effective dose that does not cause hypoglycemia.

Upon further questioning, the patient admitted she’d been taking 3,000 mg of a bitter melon product per day. She took this in addition to all her prescribed medications. Because bitter melon has an insulin-like effect, its use in combination with glimepiride led to the clinically significant hypoglycemic reaction, which required hospitalization and treatment. Prior to discharge, the patient promised to discuss the use of alternative and natural products with her pharmacist or physician before trying anything new. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Guettier JM, Gorden P. Hypoglycemia. Endocrinol Metab Clin North Am. 2006;35:753-766.
2. Holt HH. Drug-induced hypoglycemia: overview. The University of Maryland Medical Center Web site. Available at: www.umm.edu/ency/article/000310.htm. Accessed March 2, 2009.
3. Hurd R. Drug-induced hypoglycemia. Drugs.com Web site. Available at: www.drugs.com/enc/drug-induced-hypoglycemia.html. Accessed March 2, 2009.
4. Mehlhorn AJ, Brown DA. Safety concerns with fluoroquinolones. Ann Pharmacother. 2007; 41:1859-1866.
5. Natural medicines in the clinical management of diabetes. Natural Medicines Comprehensive Database Web site. Available at: www.naturaldatabase.com. Accessed March 3, 2009.
6. Teva announces approval and launch of generic Imitrex tablets. Available at: finance.yahoo.com/news/Teva-Announces-Approval-and-bw-14308223.html/print. Accessed March 2, 2009.
7. Additional strengths of Avinza available. Monthly Prescribing Reference Web site. Available at: www.empr.com/Additional-strengths-of-Avinza-available/article/126905/. Accessed March 2, 2009.
8. Gelnique treatment for overactive bladder. Drugs.com Web site. Available at: www.drugs.com/gelnique.html. Accessed March 2, 2009.
9. Reclast label. The U.S. Food and Drug Administration Web site. Available at: www.fda.gov/cder/foi/label/2008/021817s002lbl.pdf. Accessed March 2, 2009.
10. Clopidogrel bisulfate (marketed as Plavix). The U.S. Food and Drug Administration Web site. Available at: www.fda.gov/medwatch/safety/2009/safety09.htm#plavix. Accessed March 2, 2009.
11. PPI interactions with clopidogrel. Med Lett Drugs Ther. 2009;51 (1303):2-3.
12. PPI interactions with clopidogrel revisited. Med Lett Drugs Ther. 2009;51(1306):13-4.
13. Xigris (Drotrecogin alfa [activated]): early communication about an ongoing safety review. The U.S. Food and Drug Administration Web site. Available at: www.fda.gov/medwatch/safety/2009/safety09.htm#Xigris. Accessed March 2, 2009.

Let’s look at a case: A known diabetic patient has been in good control, with glycosylated hemoglobin (HbA1c) levels lower than 6.5 gm/dL the past two years. Her medication regimen has remained relatively stable during that time. Her daily medications include simvastatin, 40 mg; metformin extended release, 2,000 mg; sitagliptin, 100 mg; glimepiride, 8 mg; quinapril, 20 mg; a multivitamin; calcium carbonate, 1,500 mg; and an 81-mg aspirin.

Her lipid panel, liver and renal function tests, and blood pressure are all within normal limits. However, she was admitted to the hospital with a plasma glucose level of 38 mg/dL.

Upon physical examination, she appears diaphoretic, with weakness, confusion, tremulousness, and palpitations. She is treated with glucose to maintain a level of above 50 mg/dL, and she responds without long-term sequelae.

What precipitated this event?

Drug-Induced Hypoglycemia

Hypoglycemia may represent a lab error or artifactual hypoglycemia due to glycolysis in the collection sample. To determine a pathological cause of hypoglycemia, the triad of low plasma glucose, hypoglycemia symptoms, and symptom resolution with correction of the blood glucose level should be used.1 Hypoglycemia is most often seen in diabetic patients and is the most commonly noted endocrine emergency in the inpatient setting, as well as in the ambulatory setting. Some common causes of hypoglycemia in diabetes patients include alcohol consumption, skipping meals, too much exercise, and intentional or unintentional medication overdoses.2

Treatment is required when the blood glucose level is below 45 gm/dL. Symptoms include anxiety, tremulousness, nausea, sweating, palpitation, and hunger.3 More severe symptoms related to compromised central nervous system function include weakness, fatigue, confusion, seizures, focal neurologic deficits, and coma.

The most common causes of drug-induced hypoglycemia are insulin, ethanol, or sulfonylureas. Risk factors associated with unintentional overdose of sulfonylureas include advanced age, drug-to-drug interactions, and decreased renal or hepatic clearance. Other drugs have been reported to cause hypoglycemia. Some of these include high-dose salicylates, beta-blockers, haloperidol, monoamine oxidase inhibitors, other sulfonamides (particularly trimethoprim-sulfamethoxazole), pentamidine, quinine/quinidine, and quinolone antibiotics (e.g., gatifloxacin or levofloxacin).4

Diabetics use more than 120 natural medicines, either alone or in combination with their prescribed diabetes medications, to lower blood glucose and/or improve HbA1c.5 Some of the most commonly used products are banaba, bitter melon, fenugreek, and Gymnema (hypoglycemics), along with American or panax ginseng, cassia cinnamon, chromium, prickly pear cactus, soy, or vanadium (insulin sensitizers).

Diagnosis

Patient history aids in the clinical diagnosis of hypoglycemia and should be reviewed to determine a potential drug-induced cause. History also might identify a medication dispensing error (e.g., the onset of hypoglycemia following a recent medication refill). Hospitalists should question the patient or the patient’s family as to medication use, including over-the-counter drugs, vitamins, supplements, natural foods, and other related products.

Treatment

Glucose should be administered to maintain a plasma glucose level of at least 50 gm/dL. This may be achieved orally via frequent meals or snacks, or intravenously. The underlying cause should be addressed. In drug- or medication-induced cases, the causative agent should be removed or retitrated to an effective dose that does not cause hypoglycemia.

Upon further questioning, the patient admitted she’d been taking 3,000 mg of a bitter melon product per day. She took this in addition to all her prescribed medications. Because bitter melon has an insulin-like effect, its use in combination with glimepiride led to the clinically significant hypoglycemic reaction, which required hospitalization and treatment. Prior to discharge, the patient promised to discuss the use of alternative and natural products with her pharmacist or physician before trying anything new. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Guettier JM, Gorden P. Hypoglycemia. Endocrinol Metab Clin North Am. 2006;35:753-766.
2. Holt HH. Drug-induced hypoglycemia: overview. The University of Maryland Medical Center Web site. Available at: www.umm.edu/ency/article/000310.htm. Accessed March 2, 2009.
3. Hurd R. Drug-induced hypoglycemia. Drugs.com Web site. Available at: www.drugs.com/enc/drug-induced-hypoglycemia.html. Accessed March 2, 2009.
4. Mehlhorn AJ, Brown DA. Safety concerns with fluoroquinolones. Ann Pharmacother. 2007; 41:1859-1866.
5. Natural medicines in the clinical management of diabetes. Natural Medicines Comprehensive Database Web site. Available at: www.naturaldatabase.com. Accessed March 3, 2009.
6. Teva announces approval and launch of generic Imitrex tablets. Available at: finance.yahoo.com/news/Teva-Announces-Approval-and-bw-14308223.html/print. Accessed March 2, 2009.
7. Additional strengths of Avinza available. Monthly Prescribing Reference Web site. Available at: www.empr.com/Additional-strengths-of-Avinza-available/article/126905/. Accessed March 2, 2009.
8. Gelnique treatment for overactive bladder. Drugs.com Web site. Available at: www.drugs.com/gelnique.html. Accessed March 2, 2009.
9. Reclast label. The U.S. Food and Drug Administration Web site. Available at: www.fda.gov/cder/foi/label/2008/021817s002lbl.pdf. Accessed March 2, 2009.
10. Clopidogrel bisulfate (marketed as Plavix). The U.S. Food and Drug Administration Web site. Available at: www.fda.gov/medwatch/safety/2009/safety09.htm#plavix. Accessed March 2, 2009.
11. PPI interactions with clopidogrel. Med Lett Drugs Ther. 2009;51 (1303):2-3.
12. PPI interactions with clopidogrel revisited. Med Lett Drugs Ther. 2009;51(1306):13-4.
13. Xigris (Drotrecogin alfa [activated]): early communication about an ongoing safety review. The U.S. Food and Drug Administration Web site. Available at: www.fda.gov/medwatch/safety/2009/safety09.htm#Xigris. Accessed March 2, 2009.

Let’s look at a case: A known diabetic patient has been in good control, with glycosylated hemoglobin (HbA1c) levels lower than 6.5 gm/dL the past two years. Her medication regimen has remained relatively stable during that time. Her daily medications include simvastatin, 40 mg; metformin extended release, 2,000 mg; sitagliptin, 100 mg; glimepiride, 8 mg; quinapril, 20 mg; a multivitamin; calcium carbonate, 1,500 mg; and an 81-mg aspirin.

Her lipid panel, liver and renal function tests, and blood pressure are all within normal limits. However, she was admitted to the hospital with a plasma glucose level of 38 mg/dL.

Upon physical examination, she appears diaphoretic, with weakness, confusion, tremulousness, and palpitations. She is treated with glucose to maintain a level of above 50 mg/dL, and she responds without long-term sequelae.

What precipitated this event?

Drug-Induced Hypoglycemia

Hypoglycemia may represent a lab error or artifactual hypoglycemia due to glycolysis in the collection sample. To determine a pathological cause of hypoglycemia, the triad of low plasma glucose, hypoglycemia symptoms, and symptom resolution with correction of the blood glucose level should be used.1 Hypoglycemia is most often seen in diabetic patients and is the most commonly noted endocrine emergency in the inpatient setting, as well as in the ambulatory setting. Some common causes of hypoglycemia in diabetes patients include alcohol consumption, skipping meals, too much exercise, and intentional or unintentional medication overdoses.2

Treatment is required when the blood glucose level is below 45 gm/dL. Symptoms include anxiety, tremulousness, nausea, sweating, palpitation, and hunger.3 More severe symptoms related to compromised central nervous system function include weakness, fatigue, confusion, seizures, focal neurologic deficits, and coma.

The most common causes of drug-induced hypoglycemia are insulin, ethanol, or sulfonylureas. Risk factors associated with unintentional overdose of sulfonylureas include advanced age, drug-to-drug interactions, and decreased renal or hepatic clearance. Other drugs have been reported to cause hypoglycemia. Some of these include high-dose salicylates, beta-blockers, haloperidol, monoamine oxidase inhibitors, other sulfonamides (particularly trimethoprim-sulfamethoxazole), pentamidine, quinine/quinidine, and quinolone antibiotics (e.g., gatifloxacin or levofloxacin).4

Diabetics use more than 120 natural medicines, either alone or in combination with their prescribed diabetes medications, to lower blood glucose and/or improve HbA1c.5 Some of the most commonly used products are banaba, bitter melon, fenugreek, and Gymnema (hypoglycemics), along with American or panax ginseng, cassia cinnamon, chromium, prickly pear cactus, soy, or vanadium (insulin sensitizers).

Diagnosis

Patient history aids in the clinical diagnosis of hypoglycemia and should be reviewed to determine a potential drug-induced cause. History also might identify a medication dispensing error (e.g., the onset of hypoglycemia following a recent medication refill). Hospitalists should question the patient or the patient’s family as to medication use, including over-the-counter drugs, vitamins, supplements, natural foods, and other related products.

Treatment

Glucose should be administered to maintain a plasma glucose level of at least 50 gm/dL. This may be achieved orally via frequent meals or snacks, or intravenously. The underlying cause should be addressed. In drug- or medication-induced cases, the causative agent should be removed or retitrated to an effective dose that does not cause hypoglycemia.

Upon further questioning, the patient admitted she’d been taking 3,000 mg of a bitter melon product per day. She took this in addition to all her prescribed medications. Because bitter melon has an insulin-like effect, its use in combination with glimepiride led to the clinically significant hypoglycemic reaction, which required hospitalization and treatment. Prior to discharge, the patient promised to discuss the use of alternative and natural products with her pharmacist or physician before trying anything new. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Guettier JM, Gorden P. Hypoglycemia. Endocrinol Metab Clin North Am. 2006;35:753-766.
2. Holt HH. Drug-induced hypoglycemia: overview. The University of Maryland Medical Center Web site. Available at: www.umm.edu/ency/article/000310.htm. Accessed March 2, 2009.
3. Hurd R. Drug-induced hypoglycemia. Drugs.com Web site. Available at: www.drugs.com/enc/drug-induced-hypoglycemia.html. Accessed March 2, 2009.
4. Mehlhorn AJ, Brown DA. Safety concerns with fluoroquinolones. Ann Pharmacother. 2007; 41:1859-1866.
5. Natural medicines in the clinical management of diabetes. Natural Medicines Comprehensive Database Web site. Available at: www.naturaldatabase.com. Accessed March 3, 2009.
6. Teva announces approval and launch of generic Imitrex tablets. Available at: finance.yahoo.com/news/Teva-Announces-Approval-and-bw-14308223.html/print. Accessed March 2, 2009.
7. Additional strengths of Avinza available. Monthly Prescribing Reference Web site. Available at: www.empr.com/Additional-strengths-of-Avinza-available/article/126905/. Accessed March 2, 2009.
8. Gelnique treatment for overactive bladder. Drugs.com Web site. Available at: www.drugs.com/gelnique.html. Accessed March 2, 2009.
9. Reclast label. The U.S. Food and Drug Administration Web site. Available at: www.fda.gov/cder/foi/label/2008/021817s002lbl.pdf. Accessed March 2, 2009.
10. Clopidogrel bisulfate (marketed as Plavix). The U.S. Food and Drug Administration Web site. Available at: www.fda.gov/medwatch/safety/2009/safety09.htm#plavix. Accessed March 2, 2009.
11. PPI interactions with clopidogrel. Med Lett Drugs Ther. 2009;51 (1303):2-3.
12. PPI interactions with clopidogrel revisited. Med Lett Drugs Ther. 2009;51(1306):13-4.
13. Xigris (Drotrecogin alfa [activated]): early communication about an ongoing safety review. The U.S. Food and Drug Administration Web site. Available at: www.fda.gov/medwatch/safety/2009/safety09.htm#Xigris. Accessed March 2, 2009.

There has been a lot of talk recently about pharmacogenomics and personalized medicine. Pharmaco-genomics—the way an individual responds to a medication—includes both positive and negative reactions, and how individual genetic differences affect drug response. It also examines the inherited variations in genes that dictate drug response and explores how these variations can be used to predict what type of response a patient will have to a particular drug, whether that is a good response, a bad response, or no response at all.1

In the race to catalog all the different gene variations, variations known as single nucleotide polymorphisms (SNPs, or “snips”) are used diagnostically to predict a patient’s response to a drug. In the future, pharmaceutical companies could use pharmacogenomics to predict which patients will have a negative response to a particular drug in clinical trials and, therefore, not study the medication in those patients.2 In essence, it would be a way to “streamline” therapy to those in most need of it or for those who likely will have a positive response with minimal adverse events.

By pre-screening patients, clinical trials could be smaller, faster, and less costly. The capability to pre-assess whether a patient will benefit from a particular medication before it is prescribed is a major advantage when it comes to medication use. It also might increase a prescriber’s confidence before starting a patient on a medication, and it might improve a patient’s confidence in taking the medication, which could increase medication adherence and lead to better patient outcomes.

Researchers have found that when patients with certain SNP variants of cytochrome P450 (CYP) take warfarin, metabolism and patient sensitivity are affected. Once this was discovered, the Food and Drug Administration (FDA) subsequently approved prescribing label changes for warfarin that incorporated pharmacogenomics information.3 This change included information on increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles.4

More recently, Eckman et al published a cost-effectiveness analysis evaluating pharmacogenetic information related to warfarin dosing in patients with nonvalvular atrial fibrillation.5 In the study, the authors concluded that currently limited data exist utilizing pharmacogenomics for dosing of warfarin and its effects on major bleeding. They did note, however, that genotyping may be beneficial and cost-effective in patients who are at high risk of hemorrhage.

Additionally, there has been recent media coverage of the genetic variations of CYP2C19 affecting clopidogrel metabolism and efficacy.6,7 Both Mega et al and Collet et al noted that patients carrying at least one genetic variation of CYP2C19 had diminished platelet inhibition. Published earlier this year, both studies noted that patients carrying the genetic variation of CYP2C19 exhibited a higher rate of major cardiovascular events—including death, stent thrombosis, myocardial infarction, or stroke—than did noncarriers.

The FDA warned healthcare providers in November 2008 about using phenytoin or fosphenytoin in patients with the HLA-B*1502 allele due to a potentially increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis. A similar warning exists for carbamazepine in the same patient population. This is another example of pharmacogenomics information at work.8

Patient-specific variables have been identified that can help determine how an individual will respond to certain medications. Ultimately, this could decrease healthcare costs. It is a slow process and might be the wave of the future, but we are not there yet. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Just the facts: a basic introduction to the science underlying NCBI resources. National Center for Biotechnology Information Web site. Available at: www.ncbi.nlm.nih.gov/About/primer/pharm.html. Accessed Jan. 31, 2009.
2. Gulseth MP, Grice GR, Dager WE. Pharmacogenomics of warfarin: uncovering a piece of the warfarin mystery. Am J Health Syst Pharm. 2009;66:123-133.
3. FDA letter on approval of pharmacogenomics information for Coumadin label. Food and Drug Administration Web site. Available at: www.fda.gov/cder/foi/appletter/2007/009218s105ltr.pdf. Accessed Feb. 4, 2009.
4. Coumadin label updated. Food and Drug Administration Web site. Available at: www.fda.gov/cder/foi/label/2007/009218s105lblv2.pdf. Accessed Feb. 4, 2009.
5. Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med. 2009;150:73-83.
6. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354-362.
7. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450) 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009;373:309-317.
8. Phenytoin and fosphenytoin information. Food and Drug Administration Web site. Available at: www.fda.gov/cder/drug/infopage/phenytoin_fosphenytoin/default.htm. Accessed Feb. 4, 2009.
9. Mylan receives final approval for first-to-file generic version of antiepileptic Keppra and launches immediately. Mylan Web site. Available at: investor.mylan.com/phoenix.zhtml?c=66563&p=irol-newsArticle&ID=1221778. Accessed Feb. 4, 2009.
10. Prism pharmaceuticals receives FDA approval of Nexterone for life-threatening ventricular fibrillation and ventricular tachycardia. Prism Pharmaceuticals Web site. Available at: www.prismpharma.com/news.html. Accessed Feb. 4, 2009.
11. Now in double concentration. E-Pharm/alert Web site. Available at: whatcounts.jobson.com/dm?id=0CCEED6291EC025CFED437DC0261D862. Accessed Feb. 4, 2009.
12. Meeting of the Cardiovascular and Renal Drugs Advisory Committee. Food and Drug Administration Web site. Available at: www.fda.gov/cder/audiences/acspage/meetings/crdac_meeting_20090203.htm. Accessed Feb. 4, 2009.
13. Bratulic, A. FDA panel recommends Eli Lilly’s, Daiichi Sankyo’s Effient. FirstWord Web site. Available at: www.firstwordplus.com/Fws.do?articleid=F4B502BDC684486986AE56DED7B532F3&logRowId=281890. Accessed Feb. 4, 2009.
14. Now available 12-mg tablets. E-Pharm/alert Web site. Available at: whatcounts.jobson.com/dm?id=0CCEED6291EC025C1D5D3BD762CE3ECB. Accessed Feb. 4, 2009.
15. Tom WC. New venlafaxine extended-release formulation. Pharmacist’s Letter/Prescriber’s Letter. 2009;25(1)250108.

There has been a lot of talk recently about pharmacogenomics and personalized medicine. Pharmaco-genomics—the way an individual responds to a medication—includes both positive and negative reactions, and how individual genetic differences affect drug response. It also examines the inherited variations in genes that dictate drug response and explores how these variations can be used to predict what type of response a patient will have to a particular drug, whether that is a good response, a bad response, or no response at all.1

In the race to catalog all the different gene variations, variations known as single nucleotide polymorphisms (SNPs, or “snips”) are used diagnostically to predict a patient’s response to a drug. In the future, pharmaceutical companies could use pharmacogenomics to predict which patients will have a negative response to a particular drug in clinical trials and, therefore, not study the medication in those patients.2 In essence, it would be a way to “streamline” therapy to those in most need of it or for those who likely will have a positive response with minimal adverse events.

By pre-screening patients, clinical trials could be smaller, faster, and less costly. The capability to pre-assess whether a patient will benefit from a particular medication before it is prescribed is a major advantage when it comes to medication use. It also might increase a prescriber’s confidence before starting a patient on a medication, and it might improve a patient’s confidence in taking the medication, which could increase medication adherence and lead to better patient outcomes.

Researchers have found that when patients with certain SNP variants of cytochrome P450 (CYP) take warfarin, metabolism and patient sensitivity are affected. Once this was discovered, the Food and Drug Administration (FDA) subsequently approved prescribing label changes for warfarin that incorporated pharmacogenomics information.3 This change included information on increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles.4

More recently, Eckman et al published a cost-effectiveness analysis evaluating pharmacogenetic information related to warfarin dosing in patients with nonvalvular atrial fibrillation.5 In the study, the authors concluded that currently limited data exist utilizing pharmacogenomics for dosing of warfarin and its effects on major bleeding. They did note, however, that genotyping may be beneficial and cost-effective in patients who are at high risk of hemorrhage.

Additionally, there has been recent media coverage of the genetic variations of CYP2C19 affecting clopidogrel metabolism and efficacy.6,7 Both Mega et al and Collet et al noted that patients carrying at least one genetic variation of CYP2C19 had diminished platelet inhibition. Published earlier this year, both studies noted that patients carrying the genetic variation of CYP2C19 exhibited a higher rate of major cardiovascular events—including death, stent thrombosis, myocardial infarction, or stroke—than did noncarriers.

The FDA warned healthcare providers in November 2008 about using phenytoin or fosphenytoin in patients with the HLA-B*1502 allele due to a potentially increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis. A similar warning exists for carbamazepine in the same patient population. This is another example of pharmacogenomics information at work.8

Patient-specific variables have been identified that can help determine how an individual will respond to certain medications. Ultimately, this could decrease healthcare costs. It is a slow process and might be the wave of the future, but we are not there yet. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Just the facts: a basic introduction to the science underlying NCBI resources. National Center for Biotechnology Information Web site. Available at: www.ncbi.nlm.nih.gov/About/primer/pharm.html. Accessed Jan. 31, 2009.
2. Gulseth MP, Grice GR, Dager WE. Pharmacogenomics of warfarin: uncovering a piece of the warfarin mystery. Am J Health Syst Pharm. 2009;66:123-133.
3. FDA letter on approval of pharmacogenomics information for Coumadin label. Food and Drug Administration Web site. Available at: www.fda.gov/cder/foi/appletter/2007/009218s105ltr.pdf. Accessed Feb. 4, 2009.
4. Coumadin label updated. Food and Drug Administration Web site. Available at: www.fda.gov/cder/foi/label/2007/009218s105lblv2.pdf. Accessed Feb. 4, 2009.
5. Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med. 2009;150:73-83.
6. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354-362.
7. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450) 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009;373:309-317.
8. Phenytoin and fosphenytoin information. Food and Drug Administration Web site. Available at: www.fda.gov/cder/drug/infopage/phenytoin_fosphenytoin/default.htm. Accessed Feb. 4, 2009.
9. Mylan receives final approval for first-to-file generic version of antiepileptic Keppra and launches immediately. Mylan Web site. Available at: investor.mylan.com/phoenix.zhtml?c=66563&p=irol-newsArticle&ID=1221778. Accessed Feb. 4, 2009.
10. Prism pharmaceuticals receives FDA approval of Nexterone for life-threatening ventricular fibrillation and ventricular tachycardia. Prism Pharmaceuticals Web site. Available at: www.prismpharma.com/news.html. Accessed Feb. 4, 2009.
11. Now in double concentration. E-Pharm/alert Web site. Available at: whatcounts.jobson.com/dm?id=0CCEED6291EC025CFED437DC0261D862. Accessed Feb. 4, 2009.
12. Meeting of the Cardiovascular and Renal Drugs Advisory Committee. Food and Drug Administration Web site. Available at: www.fda.gov/cder/audiences/acspage/meetings/crdac_meeting_20090203.htm. Accessed Feb. 4, 2009.
13. Bratulic, A. FDA panel recommends Eli Lilly’s, Daiichi Sankyo’s Effient. FirstWord Web site. Available at: www.firstwordplus.com/Fws.do?articleid=F4B502BDC684486986AE56DED7B532F3&logRowId=281890. Accessed Feb. 4, 2009.
14. Now available 12-mg tablets. E-Pharm/alert Web site. Available at: whatcounts.jobson.com/dm?id=0CCEED6291EC025C1D5D3BD762CE3ECB. Accessed Feb. 4, 2009.
15. Tom WC. New venlafaxine extended-release formulation. Pharmacist’s Letter/Prescriber’s Letter. 2009;25(1)250108.

There has been a lot of talk recently about pharmacogenomics and personalized medicine. Pharmaco-genomics—the way an individual responds to a medication—includes both positive and negative reactions, and how individual genetic differences affect drug response. It also examines the inherited variations in genes that dictate drug response and explores how these variations can be used to predict what type of response a patient will have to a particular drug, whether that is a good response, a bad response, or no response at all.1

In the race to catalog all the different gene variations, variations known as single nucleotide polymorphisms (SNPs, or “snips”) are used diagnostically to predict a patient’s response to a drug. In the future, pharmaceutical companies could use pharmacogenomics to predict which patients will have a negative response to a particular drug in clinical trials and, therefore, not study the medication in those patients.2 In essence, it would be a way to “streamline” therapy to those in most need of it or for those who likely will have a positive response with minimal adverse events.

By pre-screening patients, clinical trials could be smaller, faster, and less costly. The capability to pre-assess whether a patient will benefit from a particular medication before it is prescribed is a major advantage when it comes to medication use. It also might increase a prescriber’s confidence before starting a patient on a medication, and it might improve a patient’s confidence in taking the medication, which could increase medication adherence and lead to better patient outcomes.

Researchers have found that when patients with certain SNP variants of cytochrome P450 (CYP) take warfarin, metabolism and patient sensitivity are affected. Once this was discovered, the Food and Drug Administration (FDA) subsequently approved prescribing label changes for warfarin that incorporated pharmacogenomics information.3 This change included information on increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles.4

More recently, Eckman et al published a cost-effectiveness analysis evaluating pharmacogenetic information related to warfarin dosing in patients with nonvalvular atrial fibrillation.5 In the study, the authors concluded that currently limited data exist utilizing pharmacogenomics for dosing of warfarin and its effects on major bleeding. They did note, however, that genotyping may be beneficial and cost-effective in patients who are at high risk of hemorrhage.

Additionally, there has been recent media coverage of the genetic variations of CYP2C19 affecting clopidogrel metabolism and efficacy.6,7 Both Mega et al and Collet et al noted that patients carrying at least one genetic variation of CYP2C19 had diminished platelet inhibition. Published earlier this year, both studies noted that patients carrying the genetic variation of CYP2C19 exhibited a higher rate of major cardiovascular events—including death, stent thrombosis, myocardial infarction, or stroke—than did noncarriers.

The FDA warned healthcare providers in November 2008 about using phenytoin or fosphenytoin in patients with the HLA-B*1502 allele due to a potentially increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis. A similar warning exists for carbamazepine in the same patient population. This is another example of pharmacogenomics information at work.8

Patient-specific variables have been identified that can help determine how an individual will respond to certain medications. Ultimately, this could decrease healthcare costs. It is a slow process and might be the wave of the future, but we are not there yet. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Just the facts: a basic introduction to the science underlying NCBI resources. National Center for Biotechnology Information Web site. Available at: www.ncbi.nlm.nih.gov/About/primer/pharm.html. Accessed Jan. 31, 2009.
2. Gulseth MP, Grice GR, Dager WE. Pharmacogenomics of warfarin: uncovering a piece of the warfarin mystery. Am J Health Syst Pharm. 2009;66:123-133.
3. FDA letter on approval of pharmacogenomics information for Coumadin label. Food and Drug Administration Web site. Available at: www.fda.gov/cder/foi/appletter/2007/009218s105ltr.pdf. Accessed Feb. 4, 2009.
4. Coumadin label updated. Food and Drug Administration Web site. Available at: www.fda.gov/cder/foi/label/2007/009218s105lblv2.pdf. Accessed Feb. 4, 2009.
5. Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med. 2009;150:73-83.
6. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354-362.
7. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450) 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009;373:309-317.
8. Phenytoin and fosphenytoin information. Food and Drug Administration Web site. Available at: www.fda.gov/cder/drug/infopage/phenytoin_fosphenytoin/default.htm. Accessed Feb. 4, 2009.
9. Mylan receives final approval for first-to-file generic version of antiepileptic Keppra and launches immediately. Mylan Web site. Available at: investor.mylan.com/phoenix.zhtml?c=66563&p=irol-newsArticle&ID=1221778. Accessed Feb. 4, 2009.
10. Prism pharmaceuticals receives FDA approval of Nexterone for life-threatening ventricular fibrillation and ventricular tachycardia. Prism Pharmaceuticals Web site. Available at: www.prismpharma.com/news.html. Accessed Feb. 4, 2009.
11. Now in double concentration. E-Pharm/alert Web site. Available at: whatcounts.jobson.com/dm?id=0CCEED6291EC025CFED437DC0261D862. Accessed Feb. 4, 2009.
12. Meeting of the Cardiovascular and Renal Drugs Advisory Committee. Food and Drug Administration Web site. Available at: www.fda.gov/cder/audiences/acspage/meetings/crdac_meeting_20090203.htm. Accessed Feb. 4, 2009.
13. Bratulic, A. FDA panel recommends Eli Lilly’s, Daiichi Sankyo’s Effient. FirstWord Web site. Available at: www.firstwordplus.com/Fws.do?articleid=F4B502BDC684486986AE56DED7B532F3&logRowId=281890. Accessed Feb. 4, 2009.
14. Now available 12-mg tablets. E-Pharm/alert Web site. Available at: whatcounts.jobson.com/dm?id=0CCEED6291EC025C1D5D3BD762CE3ECB. Accessed Feb. 4, 2009.
15. Tom WC. New venlafaxine extended-release formulation. Pharmacist’s Letter/Prescriber’s Letter. 2009;25(1)250108.

The worst of the nationwide Clostri-dium difficile epidemic is yet to come. The current, highly virulent NAP1/027 strain has reached all 50 states and Canada, with a total burden estimated at more than 500,000 annual cases.1

The economic burden associated with managing C. difficile-associated disease (CDAD) in Massachusetts hospitals over a two-year period was estimated at $51.2 million and associated with 55,380 inpatient days.2 A retrospective review (n=3,692) identified a mean cost per stay for a first hospitalization with a primary CDAD diagnosis at $10,212. This was associated with a mean length of stay (LOS) of 6.4 days. For patients with a secondary CDAD diagnosis, the LOS was estimated at 15.7 days, most likely due to time spent in the intensive-care unit (ICU) and not likely related to CDAD management. The CDAD-related increased LOS in these patients was estimated to be an additional 2.95 days, with an additional cost of $13,675.

More recently, CDAD-associated costs were noted to be more than $7,000 per case, according to data from 439 cases evaluated by two statistical methods.3

Bacillus Background

C. difficile is a spore-forming, gram-positive, anaerobic bacillus that has become one of the most significant causes of hospitalization-associated diarrhea in adults.4 The number of infections occurring with the more virulent strain is disquieting. It is associated with a spectrum of illnesses, which include uncomplicated diarrhea presenting as mild, watery stools, life-threatening pseudomembranous colitis, and toxic megacolon, leading to sepsis and death.

CDAD might be an unrecognized and under-reported cause of death in the U.S.5 From 1999 to 2004, CDAD was reported as a cause of death for 24,642 people and an underlying cause of death for an additional 12,264 people.6 The median patient age was 82.

As an aside, CDAD is the older terminology for what is now being referred to as C. difficile infection (CDI).

CDI is predominantly seen as a nosocomial or long-term-care facility concern, although community-acquired infections have been reported.7 Risk factors include previous antimicrobial use, particularly with clindamycin, fluoroquinolones, cephalosporins, ampicillin, or ß-lactams. Other risk factors include use of immunosuppressants or chemotherapeutic agents, advanced age, surgery, exposure to gastric acid suppressants, host immunity, and serious underlying illnesses or comorbidities.8,9 Gastric acid suppressant use outside a healthcare facility might be a significant risk factor for outpatient CDI.

Prevention

Healthcare-facility-based CDI prevention strategies include discontinuing any suspected antibiotic, as this alone has been known to resolve CDI in up to 25% of patients. C. difficile spores are resistant to bactericidal effects of alcohol and most hospital disinfectants. Therefore, additional prevention measures should include:

• Meticulous and proper hand hygiene for healthcare workers, patients, and visitors;
• Utilizing soap and water and avoiding alcohol-based rubs that are not sporicidal;
• Environmental cleaning with sporicidal cleaning agents;
• Placing patients under contact isolation infection control procedures until resolution of the diarrhea; and
• Adopting antibiotic restriction policies to limit excessive antimicrobial use.

Two additional principles include not giving prophylactic antimicrobials for patients at high risk of developing CDI and not treating or attempting to decolonize asymptomatic C. difficile carriers. The Centers for Disease Control recently developed a patient-safety initiative to assist healthcare facilities in dealing with multidrug-resistant organisms (MDRO) and CDAD.10

Management

General management strategies for CDI patients include:

• Discontinuing all unnecessary antimicrobials or utilizing lower-risk agents when able;
• Monitoring volume status and electrolytes and appropriately replete when necessary;
• Avoiding anti-diarrheal agents, such as loperamide, atropine, or diphenoxylate, as these agents do not allow the toxin to be excreted and can worsen symptoms and lead to serious complications;
• Encouraging patient hand hygiene through use of soap and water;
• Possibly avoiding the use of lactose-containing foods;
• Possibly discontinuing proton pump inhibitors and other acid suppressants; and
• Administering specific anti-Clostridial antibiotics, if necessary, based on infection severity.

Severe CDI causes volume depletion, electrolyte imbalances, and hypotension, as well as renal impairment, hemodynamic instability, leukocytosis, toxic megacolon, and death. Severe diarrhea associated with this form of CDI might include 10 or more loose stools per day. A surgical consultation should be obtained for a complete evaluation in the most severe cases, as patients may require colectomy.

Recent reports suggest oral (OP) vancomycin be considered as first-line therapy for severe CDI. Intravenous (IV) vancomycin should not be used, because it does not reach high enough stool levels to treat the infection. Vancomycin should be dosed at 500 mg four times daily for 10 to 14 days (severe CDI) and 125 mg four times daily for 10 to 14 days in cases of mild to moderate CDI; alternatively, the duration of treatment can be extended for several days after the diarrhea resolves. This usually occurs within a few days after commencing treatment.

The treatment of choice for mild to moderate CDI is metronidazole. It is dosed at either 500 mg PO three times daily or 250 mg PO four times daily. Oral metronidazole achieves higher stool concentrations than IV metronidazole, so it is the preferred route for CDI management.

Metronidazole can cause nausea and a metallic taste. It also interacts with warfarin, so the international normalized ratio (INR) must be followed. Concomitant administration of alcohol can lead to a reaction similar to that associated with use of Antabuse. The drug should not be used in pregnant women or children. Metronidazole and vancomycin usually are equally effective for treating mild to moderate CDI, but some resistance has been noted. Vancomycin PO currently is available only as a branded drug with a high cost, but this may soon change.11

Recurrence

Recurrence can occur in approximately 20% of patients within 60 days, and these patients can be treated with the same antibiotics as were previously utilized. Subsequent recurrences can be managed with pulse dosing, or by tapering the dose at the end of therapy. Due to a lack of controlled studies, the use of probiotics, such as Lactobacillus, in the prevention of CDI cannot be routinely recommended.12 However, Lactobacillus-containing products generally are considered safe in immunocompetent individuals.

The Future

Generic oral vancomycin is on the horizon and a number of agents are currently undergoing phase 3 clinical trials for CDI management. These include rifaximin, nitazoxanide, and rifampin in combination with current agents.13-16 For now, prevention is key. Utilize some of the measures noted above to prevent this potentially serious, nosocomial infection. For infected patients, current treatments are effective and new ones will be here soon. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1.Walker EP. ICAAC-IDSA: C. difficile epidemic continues to worsen. MedPage Web site. Available at: www.medpagetoday.com/MeetingCoverage/ ICAAC/11518. Accessed Jan. 13, 2009.

2.O’Brien JA, Lahue BJ, Caro JJ, Davidson DM. The emerging infectious challenge of Clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol. 2007;28:1219-1227.

3.Dubberke ER, Reske RA, Olsen MA, McDonald C, Fraser VJ. Short- and long-term attributable costs of Clostridium difficile-associated disease in nonsurgical patients. Clin Infect Dis. 2008;46:497-504.

4.Jodlowski TZ, Oehler R, Kam LW, Melnychuk I. Emerging therapies in the treatment of Clostridium difficile-associated disease. Ann Pharmacother. 2006;40:2164-2169.

5.Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile-related mortality rates, United States, 1999-2004. Emerg Infect Dis. 2007;13:1417-1419.

6.The national healthcare safety network protocol multi-drug-resistant organism and Clostridium difficile-associated disease module version 4.1. CDC Web site. Available at: www.cdc.gov/ncidod/dhqp/ pdf/nhsn/MDRO_CDADprotocolv41Dec08final.pdf. Accessed Jan. 14, 2009.

7.Severe Clostridium difficile-associated disease in populations previously at low risk—four states, 2005. CDC Web site. Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm5447a1.htm. Accessed Jan. 14, 2009.

8.Lawrence SJ. Contemporary management of Clostridium difficile-associated disease. IDSE Web site. Available at: www.idse.net/download/079idse0907WM.pdf. Accessed Jan. 14, 2009.

9.Dubberke ER, Gerding DN, Classen D, et al. Strategies to prevent Clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29:S81-S92.

10.Multidrug-resistant organisms (MDRO) and Clostridium difficile-associated disease (CDAD) module. CDC Web site. Available at: www.cdc.gov/ncidod/dhqp/nhsn_MDRO_CDAD.html. Accessed Jan. 14, 2009.

11.ViroPharma files FOIA complaint seeking administrative record for vancocin. ViroPharma Inc. Web site. Available at: phx.corporateir.net/phoenix.zhtml?c=92320&p=irol-newsArticle&ID=1237649. Published Dec. 18, 2008. Accessed Jan. 14, 2009.

12.Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;6. Available at: www.bmj.com/cgi/reprint/bmj.39231.599815.55v1. Accessed Jan. 14, 2009.

13. A trial to compare xifaxan to vancomycin for the treatment of Clostridium difficile-associated diarrhea (CDAD). National Institutes of Health Web site. Available at: www.clinicaltrials.gov/ct2/show/ NCT00269399?term=rifaximin+and+clostridium&rank=1. Accessed Jan. 10, 2009.

14. Efficacy of metronidazole versus metronidazole and rifampin in CDAD treatment. National Institutes of Health Web site. Available at www.clinicaltrials.gov/ct2/show/NCT00182429?term=rifampin+and+cdad&rank=1. Accessed Jan. 10, 2009.

15. Compassionate use of nitazoxanide for the treatment of Clostridium difficile infection. National Institutes of Health Web site. Available at: www.clinicaltrials.gov/ct2/show/NCT00304356?term=Nitazoxanide+and+clostridium&rank=2. Accessed Jan. 10, 2009.

16. Vancomycin vs. nitazoxanide to treat recurrent C. difficile colitis. National Institutes of Health Web site. Available at: www.clinicaltrials.gov/ct2/show/NCT00304889?term=Nitazoxanide+and+vancomycin&rank=2. Accessed Jan. 10, 2009.

The worst of the nationwide Clostri-dium difficile epidemic is yet to come. The current, highly virulent NAP1/027 strain has reached all 50 states and Canada, with a total burden estimated at more than 500,000 annual cases.1

The economic burden associated with managing C. difficile-associated disease (CDAD) in Massachusetts hospitals over a two-year period was estimated at $51.2 million and associated with 55,380 inpatient days.2 A retrospective review (n=3,692) identified a mean cost per stay for a first hospitalization with a primary CDAD diagnosis at $10,212. This was associated with a mean length of stay (LOS) of 6.4 days. For patients with a secondary CDAD diagnosis, the LOS was estimated at 15.7 days, most likely due to time spent in the intensive-care unit (ICU) and not likely related to CDAD management. The CDAD-related increased LOS in these patients was estimated to be an additional 2.95 days, with an additional cost of $13,675.

More recently, CDAD-associated costs were noted to be more than $7,000 per case, according to data from 439 cases evaluated by two statistical methods.3

Bacillus Background

C. difficile is a spore-forming, gram-positive, anaerobic bacillus that has become one of the most significant causes of hospitalization-associated diarrhea in adults.4 The number of infections occurring with the more virulent strain is disquieting. It is associated with a spectrum of illnesses, which include uncomplicated diarrhea presenting as mild, watery stools, life-threatening pseudomembranous colitis, and toxic megacolon, leading to sepsis and death.

CDAD might be an unrecognized and under-reported cause of death in the U.S.5 From 1999 to 2004, CDAD was reported as a cause of death for 24,642 people and an underlying cause of death for an additional 12,264 people.6 The median patient age was 82.

As an aside, CDAD is the older terminology for what is now being referred to as C. difficile infection (CDI).

CDI is predominantly seen as a nosocomial or long-term-care facility concern, although community-acquired infections have been reported.7 Risk factors include previous antimicrobial use, particularly with clindamycin, fluoroquinolones, cephalosporins, ampicillin, or ß-lactams. Other risk factors include use of immunosuppressants or chemotherapeutic agents, advanced age, surgery, exposure to gastric acid suppressants, host immunity, and serious underlying illnesses or comorbidities.8,9 Gastric acid suppressant use outside a healthcare facility might be a significant risk factor for outpatient CDI.

Prevention

Healthcare-facility-based CDI prevention strategies include discontinuing any suspected antibiotic, as this alone has been known to resolve CDI in up to 25% of patients. C. difficile spores are resistant to bactericidal effects of alcohol and most hospital disinfectants. Therefore, additional prevention measures should include:

• Meticulous and proper hand hygiene for healthcare workers, patients, and visitors;
• Utilizing soap and water and avoiding alcohol-based rubs that are not sporicidal;
• Environmental cleaning with sporicidal cleaning agents;
• Placing patients under contact isolation infection control procedures until resolution of the diarrhea; and
• Adopting antibiotic restriction policies to limit excessive antimicrobial use.

Two additional principles include not giving prophylactic antimicrobials for patients at high risk of developing CDI and not treating or attempting to decolonize asymptomatic C. difficile carriers. The Centers for Disease Control recently developed a patient-safety initiative to assist healthcare facilities in dealing with multidrug-resistant organisms (MDRO) and CDAD.10

Management

General management strategies for CDI patients include:

• Discontinuing all unnecessary antimicrobials or utilizing lower-risk agents when able;
• Monitoring volume status and electrolytes and appropriately replete when necessary;
• Avoiding anti-diarrheal agents, such as loperamide, atropine, or diphenoxylate, as these agents do not allow the toxin to be excreted and can worsen symptoms and lead to serious complications;
• Encouraging patient hand hygiene through use of soap and water;
• Possibly avoiding the use of lactose-containing foods;
• Possibly discontinuing proton pump inhibitors and other acid suppressants; and
• Administering specific anti-Clostridial antibiotics, if necessary, based on infection severity.

Severe CDI causes volume depletion, electrolyte imbalances, and hypotension, as well as renal impairment, hemodynamic instability, leukocytosis, toxic megacolon, and death. Severe diarrhea associated with this form of CDI might include 10 or more loose stools per day. A surgical consultation should be obtained for a complete evaluation in the most severe cases, as patients may require colectomy.

Recent reports suggest oral (OP) vancomycin be considered as first-line therapy for severe CDI. Intravenous (IV) vancomycin should not be used, because it does not reach high enough stool levels to treat the infection. Vancomycin should be dosed at 500 mg four times daily for 10 to 14 days (severe CDI) and 125 mg four times daily for 10 to 14 days in cases of mild to moderate CDI; alternatively, the duration of treatment can be extended for several days after the diarrhea resolves. This usually occurs within a few days after commencing treatment.

The treatment of choice for mild to moderate CDI is metronidazole. It is dosed at either 500 mg PO three times daily or 250 mg PO four times daily. Oral metronidazole achieves higher stool concentrations than IV metronidazole, so it is the preferred route for CDI management.

Metronidazole can cause nausea and a metallic taste. It also interacts with warfarin, so the international normalized ratio (INR) must be followed. Concomitant administration of alcohol can lead to a reaction similar to that associated with use of Antabuse. The drug should not be used in pregnant women or children. Metronidazole and vancomycin usually are equally effective for treating mild to moderate CDI, but some resistance has been noted. Vancomycin PO currently is available only as a branded drug with a high cost, but this may soon change.11

Recurrence

Recurrence can occur in approximately 20% of patients within 60 days, and these patients can be treated with the same antibiotics as were previously utilized. Subsequent recurrences can be managed with pulse dosing, or by tapering the dose at the end of therapy. Due to a lack of controlled studies, the use of probiotics, such as Lactobacillus, in the prevention of CDI cannot be routinely recommended.12 However, Lactobacillus-containing products generally are considered safe in immunocompetent individuals.

The Future

Generic oral vancomycin is on the horizon and a number of agents are currently undergoing phase 3 clinical trials for CDI management. These include rifaximin, nitazoxanide, and rifampin in combination with current agents.13-16 For now, prevention is key. Utilize some of the measures noted above to prevent this potentially serious, nosocomial infection. For infected patients, current treatments are effective and new ones will be here soon. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1.Walker EP. ICAAC-IDSA: C. difficile epidemic continues to worsen. MedPage Web site. Available at: www.medpagetoday.com/MeetingCoverage/ ICAAC/11518. Accessed Jan. 13, 2009.

2.O’Brien JA, Lahue BJ, Caro JJ, Davidson DM. The emerging infectious challenge of Clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol. 2007;28:1219-1227.

3.Dubberke ER, Reske RA, Olsen MA, McDonald C, Fraser VJ. Short- and long-term attributable costs of Clostridium difficile-associated disease in nonsurgical patients. Clin Infect Dis. 2008;46:497-504.

4.Jodlowski TZ, Oehler R, Kam LW, Melnychuk I. Emerging therapies in the treatment of Clostridium difficile-associated disease. Ann Pharmacother. 2006;40:2164-2169.

5.Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile-related mortality rates, United States, 1999-2004. Emerg Infect Dis. 2007;13:1417-1419.

6.The national healthcare safety network protocol multi-drug-resistant organism and Clostridium difficile-associated disease module version 4.1. CDC Web site. Available at: www.cdc.gov/ncidod/dhqp/ pdf/nhsn/MDRO_CDADprotocolv41Dec08final.pdf. Accessed Jan. 14, 2009.

7.Severe Clostridium difficile-associated disease in populations previously at low risk—four states, 2005. CDC Web site. Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm5447a1.htm. Accessed Jan. 14, 2009.

8.Lawrence SJ. Contemporary management of Clostridium difficile-associated disease. IDSE Web site. Available at: www.idse.net/download/079idse0907WM.pdf. Accessed Jan. 14, 2009.

9.Dubberke ER, Gerding DN, Classen D, et al. Strategies to prevent Clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29:S81-S92.

10.Multidrug-resistant organisms (MDRO) and Clostridium difficile-associated disease (CDAD) module. CDC Web site. Available at: www.cdc.gov/ncidod/dhqp/nhsn_MDRO_CDAD.html. Accessed Jan. 14, 2009.

11.ViroPharma files FOIA complaint seeking administrative record for vancocin. ViroPharma Inc. Web site. Available at: phx.corporateir.net/phoenix.zhtml?c=92320&p=irol-newsArticle&ID=1237649. Published Dec. 18, 2008. Accessed Jan. 14, 2009.

12.Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;6. Available at: www.bmj.com/cgi/reprint/bmj.39231.599815.55v1. Accessed Jan. 14, 2009.

13. A trial to compare xifaxan to vancomycin for the treatment of Clostridium difficile-associated diarrhea (CDAD). National Institutes of Health Web site. Available at: www.clinicaltrials.gov/ct2/show/ NCT00269399?term=rifaximin+and+clostridium&rank=1. Accessed Jan. 10, 2009.

14. Efficacy of metronidazole versus metronidazole and rifampin in CDAD treatment. National Institutes of Health Web site. Available at www.clinicaltrials.gov/ct2/show/NCT00182429?term=rifampin+and+cdad&rank=1. Accessed Jan. 10, 2009.

15. Compassionate use of nitazoxanide for the treatment of Clostridium difficile infection. National Institutes of Health Web site. Available at: www.clinicaltrials.gov/ct2/show/NCT00304356?term=Nitazoxanide+and+clostridium&rank=2. Accessed Jan. 10, 2009.

16. Vancomycin vs. nitazoxanide to treat recurrent C. difficile colitis. National Institutes of Health Web site. Available at: www.clinicaltrials.gov/ct2/show/NCT00304889?term=Nitazoxanide+and+vancomycin&rank=2. Accessed Jan. 10, 2009.

The worst of the nationwide Clostri-dium difficile epidemic is yet to come. The current, highly virulent NAP1/027 strain has reached all 50 states and Canada, with a total burden estimated at more than 500,000 annual cases.1

The economic burden associated with managing C. difficile-associated disease (CDAD) in Massachusetts hospitals over a two-year period was estimated at $51.2 million and associated with 55,380 inpatient days.2 A retrospective review (n=3,692) identified a mean cost per stay for a first hospitalization with a primary CDAD diagnosis at $10,212. This was associated with a mean length of stay (LOS) of 6.4 days. For patients with a secondary CDAD diagnosis, the LOS was estimated at 15.7 days, most likely due to time spent in the intensive-care unit (ICU) and not likely related to CDAD management. The CDAD-related increased LOS in these patients was estimated to be an additional 2.95 days, with an additional cost of $13,675.

More recently, CDAD-associated costs were noted to be more than $7,000 per case, according to data from 439 cases evaluated by two statistical methods.3

Bacillus Background

C. difficile is a spore-forming, gram-positive, anaerobic bacillus that has become one of the most significant causes of hospitalization-associated diarrhea in adults.4 The number of infections occurring with the more virulent strain is disquieting. It is associated with a spectrum of illnesses, which include uncomplicated diarrhea presenting as mild, watery stools, life-threatening pseudomembranous colitis, and toxic megacolon, leading to sepsis and death.

CDAD might be an unrecognized and under-reported cause of death in the U.S.5 From 1999 to 2004, CDAD was reported as a cause of death for 24,642 people and an underlying cause of death for an additional 12,264 people.6 The median patient age was 82.

As an aside, CDAD is the older terminology for what is now being referred to as C. difficile infection (CDI).

CDI is predominantly seen as a nosocomial or long-term-care facility concern, although community-acquired infections have been reported.7 Risk factors include previous antimicrobial use, particularly with clindamycin, fluoroquinolones, cephalosporins, ampicillin, or ß-lactams. Other risk factors include use of immunosuppressants or chemotherapeutic agents, advanced age, surgery, exposure to gastric acid suppressants, host immunity, and serious underlying illnesses or comorbidities.8,9 Gastric acid suppressant use outside a healthcare facility might be a significant risk factor for outpatient CDI.

Prevention

Healthcare-facility-based CDI prevention strategies include discontinuing any suspected antibiotic, as this alone has been known to resolve CDI in up to 25% of patients. C. difficile spores are resistant to bactericidal effects of alcohol and most hospital disinfectants. Therefore, additional prevention measures should include:

• Meticulous and proper hand hygiene for healthcare workers, patients, and visitors;
• Utilizing soap and water and avoiding alcohol-based rubs that are not sporicidal;
• Environmental cleaning with sporicidal cleaning agents;
• Placing patients under contact isolation infection control procedures until resolution of the diarrhea; and
• Adopting antibiotic restriction policies to limit excessive antimicrobial use.

Two additional principles include not giving prophylactic antimicrobials for patients at high risk of developing CDI and not treating or attempting to decolonize asymptomatic C. difficile carriers. The Centers for Disease Control recently developed a patient-safety initiative to assist healthcare facilities in dealing with multidrug-resistant organisms (MDRO) and CDAD.10

Management

General management strategies for CDI patients include:

• Discontinuing all unnecessary antimicrobials or utilizing lower-risk agents when able;
• Monitoring volume status and electrolytes and appropriately replete when necessary;
• Avoiding anti-diarrheal agents, such as loperamide, atropine, or diphenoxylate, as these agents do not allow the toxin to be excreted and can worsen symptoms and lead to serious complications;
• Encouraging patient hand hygiene through use of soap and water;
• Possibly avoiding the use of lactose-containing foods;
• Possibly discontinuing proton pump inhibitors and other acid suppressants; and
• Administering specific anti-Clostridial antibiotics, if necessary, based on infection severity.

Severe CDI causes volume depletion, electrolyte imbalances, and hypotension, as well as renal impairment, hemodynamic instability, leukocytosis, toxic megacolon, and death. Severe diarrhea associated with this form of CDI might include 10 or more loose stools per day. A surgical consultation should be obtained for a complete evaluation in the most severe cases, as patients may require colectomy.

Recent reports suggest oral (OP) vancomycin be considered as first-line therapy for severe CDI. Intravenous (IV) vancomycin should not be used, because it does not reach high enough stool levels to treat the infection. Vancomycin should be dosed at 500 mg four times daily for 10 to 14 days (severe CDI) and 125 mg four times daily for 10 to 14 days in cases of mild to moderate CDI; alternatively, the duration of treatment can be extended for several days after the diarrhea resolves. This usually occurs within a few days after commencing treatment.

The treatment of choice for mild to moderate CDI is metronidazole. It is dosed at either 500 mg PO three times daily or 250 mg PO four times daily. Oral metronidazole achieves higher stool concentrations than IV metronidazole, so it is the preferred route for CDI management.

Metronidazole can cause nausea and a metallic taste. It also interacts with warfarin, so the international normalized ratio (INR) must be followed. Concomitant administration of alcohol can lead to a reaction similar to that associated with use of Antabuse. The drug should not be used in pregnant women or children. Metronidazole and vancomycin usually are equally effective for treating mild to moderate CDI, but some resistance has been noted. Vancomycin PO currently is available only as a branded drug with a high cost, but this may soon change.11

Recurrence

Recurrence can occur in approximately 20% of patients within 60 days, and these patients can be treated with the same antibiotics as were previously utilized. Subsequent recurrences can be managed with pulse dosing, or by tapering the dose at the end of therapy. Due to a lack of controlled studies, the use of probiotics, such as Lactobacillus, in the prevention of CDI cannot be routinely recommended.12 However, Lactobacillus-containing products generally are considered safe in immunocompetent individuals.

The Future

Generic oral vancomycin is on the horizon and a number of agents are currently undergoing phase 3 clinical trials for CDI management. These include rifaximin, nitazoxanide, and rifampin in combination with current agents.13-16 For now, prevention is key. Utilize some of the measures noted above to prevent this potentially serious, nosocomial infection. For infected patients, current treatments are effective and new ones will be here soon. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1.Walker EP. ICAAC-IDSA: C. difficile epidemic continues to worsen. MedPage Web site. Available at: www.medpagetoday.com/MeetingCoverage/ ICAAC/11518. Accessed Jan. 13, 2009.

2.O’Brien JA, Lahue BJ, Caro JJ, Davidson DM. The emerging infectious challenge of Clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol. 2007;28:1219-1227.

3.Dubberke ER, Reske RA, Olsen MA, McDonald C, Fraser VJ. Short- and long-term attributable costs of Clostridium difficile-associated disease in nonsurgical patients. Clin Infect Dis. 2008;46:497-504.

4.Jodlowski TZ, Oehler R, Kam LW, Melnychuk I. Emerging therapies in the treatment of Clostridium difficile-associated disease. Ann Pharmacother. 2006;40:2164-2169.

5.Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile-related mortality rates, United States, 1999-2004. Emerg Infect Dis. 2007;13:1417-1419.

6.The national healthcare safety network protocol multi-drug-resistant organism and Clostridium difficile-associated disease module version 4.1. CDC Web site. Available at: www.cdc.gov/ncidod/dhqp/ pdf/nhsn/MDRO_CDADprotocolv41Dec08final.pdf. Accessed Jan. 14, 2009.

7.Severe Clostridium difficile-associated disease in populations previously at low risk—four states, 2005. CDC Web site. Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm5447a1.htm. Accessed Jan. 14, 2009.

8.Lawrence SJ. Contemporary management of Clostridium difficile-associated disease. IDSE Web site. Available at: www.idse.net/download/079idse0907WM.pdf. Accessed Jan. 14, 2009.

9.Dubberke ER, Gerding DN, Classen D, et al. Strategies to prevent Clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29:S81-S92.

10.Multidrug-resistant organisms (MDRO) and Clostridium difficile-associated disease (CDAD) module. CDC Web site. Available at: www.cdc.gov/ncidod/dhqp/nhsn_MDRO_CDAD.html. Accessed Jan. 14, 2009.

11.ViroPharma files FOIA complaint seeking administrative record for vancocin. ViroPharma Inc. Web site. Available at: phx.corporateir.net/phoenix.zhtml?c=92320&p=irol-newsArticle&ID=1237649. Published Dec. 18, 2008. Accessed Jan. 14, 2009.

12.Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;6. Available at: www.bmj.com/cgi/reprint/bmj.39231.599815.55v1. Accessed Jan. 14, 2009.

13. A trial to compare xifaxan to vancomycin for the treatment of Clostridium difficile-associated diarrhea (CDAD). National Institutes of Health Web site. Available at: www.clinicaltrials.gov/ct2/show/ NCT00269399?term=rifaximin+and+clostridium&rank=1. Accessed Jan. 10, 2009.

14. Efficacy of metronidazole versus metronidazole and rifampin in CDAD treatment. National Institutes of Health Web site. Available at www.clinicaltrials.gov/ct2/show/NCT00182429?term=rifampin+and+cdad&rank=1. Accessed Jan. 10, 2009.

15. Compassionate use of nitazoxanide for the treatment of Clostridium difficile infection. National Institutes of Health Web site. Available at: www.clinicaltrials.gov/ct2/show/NCT00304356?term=Nitazoxanide+and+clostridium&rank=2. Accessed Jan. 10, 2009.

16. Vancomycin vs. nitazoxanide to treat recurrent C. difficile colitis. National Institutes of Health Web site. Available at: www.clinicaltrials.gov/ct2/show/NCT00304889?term=Nitazoxanide+and+vancomycin&rank=2. Accessed Jan. 10, 2009.

There are multiple reasons for crushing tablets or capsule contents before administering medications, but there are numerous medications that should not be crushed. These medications should not be chewed, either, usually due to their specific formulations and their pharmacokinetic properties.1 Most of the no-crush medications are sustained-release, oral-dosage formulas. The majority of extended-release products should not be crushed or chewed, although there are some newer slow-release tablet formulations available that are scored and can be divided or halved (e.g., Toprol XL).

A common reason for crushing a tablet or capsule is for use by a hospitalized patient with an enteral feeding tube. A recent review in the American Journal of Health-System Pharmacy provides more details about administering medications in patients with enteral feeding tubes.2 Oral solutions can be used when commercially available and medically appropriate. If an oral solution or suspension is not available, the hospital pharmacy should be consulted to determine if a liquid formulation of the product can be extemporaneously prepared. In some cases, after careful consideration of compatibility, stability, and drug absorption changes, an injectable formulation of a product may be used. You should always consult your hospital pharmacist for information on this modality of drug administration.

Some patients have difficulty swallowing tablets or capsules; some dislike the taste. In these cases, crushing of medication for powdered delivery (to be mixed with food or beverages) should be considered. But beware of certain caveats, as not all medications are suitable for crushing. Generally, meds that should not be crushed fall into one of these categories:

• Sustained-release tablets, which can be composed of multiple layers for different drug release times, as can beads within capsules. Some of the more common prefixes or suffixes for sustained-release, controlled-release, or controlled-delivery products include: 12-hour, 24-hour, CC, CD, CR, ER, LA, Retard, SA, Slo-, SR, XL, XR, or XT.
• Enteric-coated tablets, which are formulated because certain drugs can be irritating to the stomach or are degraded by stomach acid. By enteric-coating tablets or capsule beads, the drug’s release can be delayed until it reaches the small intestine. Prefixes include EN- and EC-.

Other medications have objectionable tastes and are sugar-coated to improve tolerability. If this type of medication is crushed, the patient would be subject to its unpleasant taste, which could significantly impair medication adherence. Additionally, both sublingual and effervescent medications should not be crushed because it will decrease the medication’s effectiveness.

Hospital Pharmacy publishes a wall chart that includes many of these types of formulations, along with their do’s and don’ts. If there is ever any doubt about the best way to administer a particular product or whether it can be halved or crushed, ask your pharmacist.3 TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Mitchell J. Oral dosage forms that should not be crushed or chewed: facts and comparisons 4.0. Hospital Pharmacy Web site. Available at: online.factsandcomparisons.com/Viewer.aspx?book=atoz&monoID=fandc-atoz1040. Accessed March 5, 2009.

2. Williams NT. Medication administration through enteral feeding tubes. Am J Health Syst Pharm. 2008;65(24):2347-2357.

3. Mitchell JF. Oral dosage forms that should not be crushed: wall ch­art. Wolters Kluwer Health Web site. Available at: www.factsandcomparisons.com/Products/product.aspx?id=1111. Accessed Jan. 26, 2009.

4. Mylan's Matrix receives final FDA approval for the generic version of the antiretroviral Zerit capsules. Wolters Kluwer Health Web site. Available at: http://mylan.mediaroom.com/index.php?s=43&item=399. Accessed Jan. 23, 2009.

5. Product approval information. U.S. Food and Drug Administration Web site. Available at: www.fda.gov/Cber/products/Cinryze.htm. Accessed Jan. 14, 2009.

6. FDA licenses for marketing new therapy for rare genetic disease. U.S. Food and Drug Administration Web site. Available at: www.fda.gov/bbs/topics/NEWS/2008/NEW01903.html. Accessed Jan. 14, 2009.

7. Sancuso patch approved for nausea and vomiting. Monthly Prescribing Reference Web site. Available at: www.empr.com/Sancusopatchapprovedfornauseaandvomiting/article/122384/. Accessed Jan. 14, 2009.

8. TussiCaps now available for cough suppression. Monthly Prescribing Reference Web site. Available at: www.empr.com/TussiCapsnowavailableforcoughsuppression/article/122377/. Accessed Jan. 14, 2009.

9. UCB’s Vimpat approved by U.S. FDA as adjunctive therapy for partial onset seizures in adults. Medical News Today Web site. Available at: www.medicalnewstoday.com/articles/127354.php. Accessed Jan. 14, 2009.

10. Apriso granted FDA marketing approval for maintenance of remission of ulcerative colitis. Medical News Today Web site. Available at: http://www.medicalnewstoday.com/articles/127839.php. Accessed Jan. 14, 2009.

11. http://biz.yahoo.com/ap/081106/cv_therapeutics _ranexa.html?.v=1. Accessed February 2, 2009.

12. FDA approves Seroquel for bipolar maintenance. Monthly Prescribing Reference Web site. Available at: www.prescribingreference.com/news/showNews/which/SeroquelXRForBipolar10101. Accessed Jan. 14, 2009.

13. Seroquel XR Web site. Available at: www.pharmacistelink.com/news/2009/01/14_seroquel.pdf. Accessed Jan. 23, 2009.

14. Peck P. Smoking cessation drug linked to 1,001 new serious adverse events. Medpage Today Web site. Available at: www.medpagetoday.com/PrimaryCare/Smoking/11428. Accessed Jan. 14, 2009.

15. Public health advisory: important information on Chantix (varenicline). U.S. Food and Drug Administration Web site. Available at: www.fda.gov/CDER/Drug/advisory/varenicline.htm. Accessed Jan. 14, 2009.

There are multiple reasons for crushing tablets or capsule contents before administering medications, but there are numerous medications that should not be crushed. These medications should not be chewed, either, usually due to their specific formulations and their pharmacokinetic properties.1 Most of the no-crush medications are sustained-release, oral-dosage formulas. The majority of extended-release products should not be crushed or chewed, although there are some newer slow-release tablet formulations available that are scored and can be divided or halved (e.g., Toprol XL).

A common reason for crushing a tablet or capsule is for use by a hospitalized patient with an enteral feeding tube. A recent review in the American Journal of Health-System Pharmacy provides more details about administering medications in patients with enteral feeding tubes.2 Oral solutions can be used when commercially available and medically appropriate. If an oral solution or suspension is not available, the hospital pharmacy should be consulted to determine if a liquid formulation of the product can be extemporaneously prepared. In some cases, after careful consideration of compatibility, stability, and drug absorption changes, an injectable formulation of a product may be used. You should always consult your hospital pharmacist for information on this modality of drug administration.

Some patients have difficulty swallowing tablets or capsules; some dislike the taste. In these cases, crushing of medication for powdered delivery (to be mixed with food or beverages) should be considered. But beware of certain caveats, as not all medications are suitable for crushing. Generally, meds that should not be crushed fall into one of these categories:

• Sustained-release tablets, which can be composed of multiple layers for different drug release times, as can beads within capsules. Some of the more common prefixes or suffixes for sustained-release, controlled-release, or controlled-delivery products include: 12-hour, 24-hour, CC, CD, CR, ER, LA, Retard, SA, Slo-, SR, XL, XR, or XT.
• Enteric-coated tablets, which are formulated because certain drugs can be irritating to the stomach or are degraded by stomach acid. By enteric-coating tablets or capsule beads, the drug’s release can be delayed until it reaches the small intestine. Prefixes include EN- and EC-.

Other medications have objectionable tastes and are sugar-coated to improve tolerability. If this type of medication is crushed, the patient would be subject to its unpleasant taste, which could significantly impair medication adherence. Additionally, both sublingual and effervescent medications should not be crushed because it will decrease the medication’s effectiveness.

Hospital Pharmacy publishes a wall chart that includes many of these types of formulations, along with their do’s and don’ts. If there is ever any doubt about the best way to administer a particular product or whether it can be halved or crushed, ask your pharmacist.3 TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Mitchell J. Oral dosage forms that should not be crushed or chewed: facts and comparisons 4.0. Hospital Pharmacy Web site. Available at: online.factsandcomparisons.com/Viewer.aspx?book=atoz&monoID=fandc-atoz1040. Accessed March 5, 2009.

2. Williams NT. Medication administration through enteral feeding tubes. Am J Health Syst Pharm. 2008;65(24):2347-2357.

3. Mitchell JF. Oral dosage forms that should not be crushed: wall ch­art. Wolters Kluwer Health Web site. Available at: www.factsandcomparisons.com/Products/product.aspx?id=1111. Accessed Jan. 26, 2009.

4. Mylan's Matrix receives final FDA approval for the generic version of the antiretroviral Zerit capsules. Wolters Kluwer Health Web site. Available at: http://mylan.mediaroom.com/index.php?s=43&item=399. Accessed Jan. 23, 2009.

5. Product approval information. U.S. Food and Drug Administration Web site. Available at: www.fda.gov/Cber/products/Cinryze.htm. Accessed Jan. 14, 2009.

6. FDA licenses for marketing new therapy for rare genetic disease. U.S. Food and Drug Administration Web site. Available at: www.fda.gov/bbs/topics/NEWS/2008/NEW01903.html. Accessed Jan. 14, 2009.

7. Sancuso patch approved for nausea and vomiting. Monthly Prescribing Reference Web site. Available at: www.empr.com/Sancusopatchapprovedfornauseaandvomiting/article/122384/. Accessed Jan. 14, 2009.

8. TussiCaps now available for cough suppression. Monthly Prescribing Reference Web site. Available at: www.empr.com/TussiCapsnowavailableforcoughsuppression/article/122377/. Accessed Jan. 14, 2009.

9. UCB’s Vimpat approved by U.S. FDA as adjunctive therapy for partial onset seizures in adults. Medical News Today Web site. Available at: www.medicalnewstoday.com/articles/127354.php. Accessed Jan. 14, 2009.

10. Apriso granted FDA marketing approval for maintenance of remission of ulcerative colitis. Medical News Today Web site. Available at: http://www.medicalnewstoday.com/articles/127839.php. Accessed Jan. 14, 2009.

11. http://biz.yahoo.com/ap/081106/cv_therapeutics _ranexa.html?.v=1. Accessed February 2, 2009.

12. FDA approves Seroquel for bipolar maintenance. Monthly Prescribing Reference Web site. Available at: www.prescribingreference.com/news/showNews/which/SeroquelXRForBipolar10101. Accessed Jan. 14, 2009.

13. Seroquel XR Web site. Available at: www.pharmacistelink.com/news/2009/01/14_seroquel.pdf. Accessed Jan. 23, 2009.

14. Peck P. Smoking cessation drug linked to 1,001 new serious adverse events. Medpage Today Web site. Available at: www.medpagetoday.com/PrimaryCare/Smoking/11428. Accessed Jan. 14, 2009.

15. Public health advisory: important information on Chantix (varenicline). U.S. Food and Drug Administration Web site. Available at: www.fda.gov/CDER/Drug/advisory/varenicline.htm. Accessed Jan. 14, 2009.

There are multiple reasons for crushing tablets or capsule contents before administering medications, but there are numerous medications that should not be crushed. These medications should not be chewed, either, usually due to their specific formulations and their pharmacokinetic properties.1 Most of the no-crush medications are sustained-release, oral-dosage formulas. The majority of extended-release products should not be crushed or chewed, although there are some newer slow-release tablet formulations available that are scored and can be divided or halved (e.g., Toprol XL).

A common reason for crushing a tablet or capsule is for use by a hospitalized patient with an enteral feeding tube. A recent review in the American Journal of Health-System Pharmacy provides more details about administering medications in patients with enteral feeding tubes.2 Oral solutions can be used when commercially available and medically appropriate. If an oral solution or suspension is not available, the hospital pharmacy should be consulted to determine if a liquid formulation of the product can be extemporaneously prepared. In some cases, after careful consideration of compatibility, stability, and drug absorption changes, an injectable formulation of a product may be used. You should always consult your hospital pharmacist for information on this modality of drug administration.

Some patients have difficulty swallowing tablets or capsules; some dislike the taste. In these cases, crushing of medication for powdered delivery (to be mixed with food or beverages) should be considered. But beware of certain caveats, as not all medications are suitable for crushing. Generally, meds that should not be crushed fall into one of these categories:

• Sustained-release tablets, which can be composed of multiple layers for different drug release times, as can beads within capsules. Some of the more common prefixes or suffixes for sustained-release, controlled-release, or controlled-delivery products include: 12-hour, 24-hour, CC, CD, CR, ER, LA, Retard, SA, Slo-, SR, XL, XR, or XT.
• Enteric-coated tablets, which are formulated because certain drugs can be irritating to the stomach or are degraded by stomach acid. By enteric-coating tablets or capsule beads, the drug’s release can be delayed until it reaches the small intestine. Prefixes include EN- and EC-.

Other medications have objectionable tastes and are sugar-coated to improve tolerability. If this type of medication is crushed, the patient would be subject to its unpleasant taste, which could significantly impair medication adherence. Additionally, both sublingual and effervescent medications should not be crushed because it will decrease the medication’s effectiveness.

Hospital Pharmacy publishes a wall chart that includes many of these types of formulations, along with their do’s and don’ts. If there is ever any doubt about the best way to administer a particular product or whether it can be halved or crushed, ask your pharmacist.3 TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Mitchell J. Oral dosage forms that should not be crushed or chewed: facts and comparisons 4.0. Hospital Pharmacy Web site. Available at: online.factsandcomparisons.com/Viewer.aspx?book=atoz&monoID=fandc-atoz1040. Accessed March 5, 2009.

2. Williams NT. Medication administration through enteral feeding tubes. Am J Health Syst Pharm. 2008;65(24):2347-2357.

3. Mitchell JF. Oral dosage forms that should not be crushed: wall ch­art. Wolters Kluwer Health Web site. Available at: www.factsandcomparisons.com/Products/product.aspx?id=1111. Accessed Jan. 26, 2009.

4. Mylan's Matrix receives final FDA approval for the generic version of the antiretroviral Zerit capsules. Wolters Kluwer Health Web site. Available at: http://mylan.mediaroom.com/index.php?s=43&item=399. Accessed Jan. 23, 2009.

5. Product approval information. U.S. Food and Drug Administration Web site. Available at: www.fda.gov/Cber/products/Cinryze.htm. Accessed Jan. 14, 2009.

6. FDA licenses for marketing new therapy for rare genetic disease. U.S. Food and Drug Administration Web site. Available at: www.fda.gov/bbs/topics/NEWS/2008/NEW01903.html. Accessed Jan. 14, 2009.

7. Sancuso patch approved for nausea and vomiting. Monthly Prescribing Reference Web site. Available at: www.empr.com/Sancusopatchapprovedfornauseaandvomiting/article/122384/. Accessed Jan. 14, 2009.

8. TussiCaps now available for cough suppression. Monthly Prescribing Reference Web site. Available at: www.empr.com/TussiCapsnowavailableforcoughsuppression/article/122377/. Accessed Jan. 14, 2009.

9. UCB’s Vimpat approved by U.S. FDA as adjunctive therapy for partial onset seizures in adults. Medical News Today Web site. Available at: www.medicalnewstoday.com/articles/127354.php. Accessed Jan. 14, 2009.

10. Apriso granted FDA marketing approval for maintenance of remission of ulcerative colitis. Medical News Today Web site. Available at: http://www.medicalnewstoday.com/articles/127839.php. Accessed Jan. 14, 2009.

11. http://biz.yahoo.com/ap/081106/cv_therapeutics _ranexa.html?.v=1. Accessed February 2, 2009.

12. FDA approves Seroquel for bipolar maintenance. Monthly Prescribing Reference Web site. Available at: www.prescribingreference.com/news/showNews/which/SeroquelXRForBipolar10101. Accessed Jan. 14, 2009.

13. Seroquel XR Web site. Available at: www.pharmacistelink.com/news/2009/01/14_seroquel.pdf. Accessed Jan. 23, 2009.

14. Peck P. Smoking cessation drug linked to 1,001 new serious adverse events. Medpage Today Web site. Available at: www.medpagetoday.com/PrimaryCare/Smoking/11428. Accessed Jan. 14, 2009.

15. Public health advisory: important information on Chantix (varenicline). U.S. Food and Drug Administration Web site. Available at: www.fda.gov/CDER/Drug/advisory/varenicline.htm. Accessed Jan. 14, 2009.

Terfenadine, cisapride, astemizole … do you remember these drugs? They all were removed from the U.S. market subsequent to adverse outcomes related to QTc interval prolongation, including ventricular arrhythmias.1-3 Many drugs prolong the QTc interval, particularly if a drug is combined with others that affect its metabolism.

QTc interval prolongation can lead to torsades de pointes (TdP). Certain individuals are particularly predisposed to developing TdP, including: women, people with hypokalemia or hypomagnesemia, and those with a history of congenital or idiopathic QTc syndrome, cardiac arrest, syncope, congestive heart failure, bradycardia, baseline QT prolongation, renal failure, or cardiac failure.4 Some agents can prolong the QTc interval by five to 10 milliseconds and cause TdP, while others require a 50-millisecond increase or more.

Drugs that confer a risk of ventricular arrhythmias include: disopyramide, dofetilide, ibutilide, procainamide, quinidine, sotalol, and amiodarone (antiarrhythmic agents); clarithromycin, erythromycin, levofloxacin, gatifloxacin, gemifloxacin, moxifloxacin, telithromycin (anti-infectives); domperidone and droperidol antiemetics; chlorpromazine, haloperidol, mesoridazine, thioridazine, and pimozide (antipsychotics); amitriptyline, desipramine, doxepin, fluoxetine, imipramine, sertraline, and venlafaxine (antidepressants); fluconazole, itraconazole, and ketoconazole (antifungals); naratriptan, sumatriptan, and zolmitriptan; and methadone.4-8 Other related agents, such as voriconazole and ondansetron, have been reported to cause QTc prolongation.

Drugs of special concern are those that frequently inhibit the metabolism of other agents, including erythromycin, clarithromycin, ketoconazole, itraconazole, amiodarone, and quinidine, and many antidepressants and antiretroviral agents. Of the deaths associated with drug-induced QTc prolongation related to the prokinetic agent cisapride, many were due to drug interactions with an imidazole or macrolide antibiotic. In these cases, increased serum concentrations of cisapride occurred due to inhibition of the cytochrome P450 CYP3A4 isoenzyme.9

If treatment with a drug that has the potential for causing QTc prolongation is begun, tell your patient to report any “potential cardiac” symptoms, such as palpitations, syncope, or near-syncope with or without palpitations, to a member of the healthcare team. Always be on the lookout for any concomitant conditions or treatments that can cause hypokalemia (e.g., diuretic use, gastroenteritis, diarrhea, excessive vomiting), or other agents that inhibit drug metabolism.

Obtaining a complete medication history, including the use of herbal products and over-the-counter medications, can help identify and prevent QTc prolongation from a drug interaction. A routine, 12-lead electrocardiogram (EKG) should be utilized during treatment to detect asymptomatic QTc prolongation or abnormal postectopic QTc intervals. Additionally, any patient predisposed to QTc prolongation should have an EKG performed before commencing treatment as well as after treatment is complete. If a drug prolongs the QTc interval beyond normal limits, the benefit of continuing the drug should be weighed against the risk of serious adverse cardiac events.10 TH

Michele B Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Kupec IF. Seldane and generic terfenadine withdrawn from market. Food and Drug Administration Web site. Available at: www.fda.gov/bbs/topics/answers/ ans00853.html. Accessed Nov. 7, 2008.

2. Zalewski JM. Cisapride withdrawal requires alternate therapy. Cleveland Clinic Web site. Available at: www.clevelandclinicmeded.com/medicalpubs/pharmacy/mayjune2000/cisapride.htm. Accessed Nov. 7, 2008.

3. Drugs removed from or restricted in the U.S. market because of drug interactions. Food and Drug Administration Web site. Available at: www.fda.gov/cder/drug/drugReactions/CERT%20Educational%20Module%201/sld013.htm. Updated Dec. 22, 2008. Accessed Nov. 7, 2008.

4. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350:1013-1022.

5. Pham CP, de Feiter PW, van der Kuy PHM, van Mook WN. Long QTc interval and torsades de pointes caused by fluconazole. Ann Pharmacother. 2006;40:1456-1461.

6. Nykamp DL, Blackmon CL, Schmidt PE, Roberson AG. QTc prolongation associated with combination therapy of levofloxacin, imipramine, and fluoxetine. Ann Pharmacother. 1005;39:543-546.

7. Philips JA, Marty FM, Stone RM et al. Torsades de pointes associated with voriconazole use. Transpl Infect Dis. 2007;9:33-36.

8. Charbit B, Alvarez JC, Dasque E, Abe E, Démolis JL, Funck-Brentano C. Droperidol and ondansetron-induced QT interval prolongation. Anesthesiol. 2008;109:206-212.

9. Yap YG, Camm AJ. Drug induced qt prolongation and torsades de pointes. Heart. 2003;89:1363-1372.

10. Jayasinghe R, Registrar S, Kovoor P. Drugs and the QTc interval. Aust Prescr. 2002;25:63-65.

11. Atacand HCT 32/25 mg gives patients and physicians more treatment flexibility. Available at: www.pharmacitelink.com/news/2008/08/14_az.pdf. Accessed Nov. 4, 2008.

12. FDA approves astellas’ vaprisol (conivaptan hydrochloride injection) premixed in 5% dextrose for the treatment of hyponatremia. Sandoz Web site. Available at: sandoz.yellowbrix.com/pages/sandoz/Story.nsp?story_id=122559939. Accessed Nov. 4, 2008.

13. U.S. FDA drug shortages. Available at: www.fda.gov/cder/drug/shortages/default.htm#Foscavir. Accessed Nov. 3, 2008.

14. FDA Drug Shortages. Food and Drug Administration Web site. Available at: www.fda.gov/cder/drug/ shortages/discontinuation.pdf. Accessed Nov. 6, 2008.

15. Waknine Y. FDA safety changes: mirena, zyvox, orencia. Medscape Web site. Available at: www.medscape.com/viewarticle/580101. Accessed Nov. 3, 2008.

16. MannKind and Pfizer announce collaboration for certain exubera patients to transition to Mannkind’s inhaled insulin therapy. Drugs.com Web site. Available at: www.drugs.com/news/mannkind-pfizer-announce-collaboration-certain-exubera-patients-transition-mannkind-s-inhaled-13677.html. Accessed Nov. 3, 2008.

17. MannKind reports positive data from a phase 3 clinical study of technosphere insulin in Type 1 diabetics. Drugs.com Web site. Available at: www.drugs.com/ clinical_trials/mannkind-reports-positive-data-phase-3-clinical-study-technosphere-insulin-type-1-diabetes-5554.html. Accessed Nov. 3, 2008.

18. Bratulic A. Sanofi-aventis to halt all Acomplia trials. FirstWord Web site. Available at: www.firstwordplus.com/Fws.do?articleid=34DAB2DC3D7A48939A1D24AB97204CB4&logRowId=263560. Accessed Nov. 6, 2008.

Terfenadine, cisapride, astemizole … do you remember these drugs? They all were removed from the U.S. market subsequent to adverse outcomes related to QTc interval prolongation, including ventricular arrhythmias.1-3 Many drugs prolong the QTc interval, particularly if a drug is combined with others that affect its metabolism.

QTc interval prolongation can lead to torsades de pointes (TdP). Certain individuals are particularly predisposed to developing TdP, including: women, people with hypokalemia or hypomagnesemia, and those with a history of congenital or idiopathic QTc syndrome, cardiac arrest, syncope, congestive heart failure, bradycardia, baseline QT prolongation, renal failure, or cardiac failure.4 Some agents can prolong the QTc interval by five to 10 milliseconds and cause TdP, while others require a 50-millisecond increase or more.

Drugs that confer a risk of ventricular arrhythmias include: disopyramide, dofetilide, ibutilide, procainamide, quinidine, sotalol, and amiodarone (antiarrhythmic agents); clarithromycin, erythromycin, levofloxacin, gatifloxacin, gemifloxacin, moxifloxacin, telithromycin (anti-infectives); domperidone and droperidol antiemetics; chlorpromazine, haloperidol, mesoridazine, thioridazine, and pimozide (antipsychotics); amitriptyline, desipramine, doxepin, fluoxetine, imipramine, sertraline, and venlafaxine (antidepressants); fluconazole, itraconazole, and ketoconazole (antifungals); naratriptan, sumatriptan, and zolmitriptan; and methadone.4-8 Other related agents, such as voriconazole and ondansetron, have been reported to cause QTc prolongation.

Drugs of special concern are those that frequently inhibit the metabolism of other agents, including erythromycin, clarithromycin, ketoconazole, itraconazole, amiodarone, and quinidine, and many antidepressants and antiretroviral agents. Of the deaths associated with drug-induced QTc prolongation related to the prokinetic agent cisapride, many were due to drug interactions with an imidazole or macrolide antibiotic. In these cases, increased serum concentrations of cisapride occurred due to inhibition of the cytochrome P450 CYP3A4 isoenzyme.9

If treatment with a drug that has the potential for causing QTc prolongation is begun, tell your patient to report any “potential cardiac” symptoms, such as palpitations, syncope, or near-syncope with or without palpitations, to a member of the healthcare team. Always be on the lookout for any concomitant conditions or treatments that can cause hypokalemia (e.g., diuretic use, gastroenteritis, diarrhea, excessive vomiting), or other agents that inhibit drug metabolism.

Obtaining a complete medication history, including the use of herbal products and over-the-counter medications, can help identify and prevent QTc prolongation from a drug interaction. A routine, 12-lead electrocardiogram (EKG) should be utilized during treatment to detect asymptomatic QTc prolongation or abnormal postectopic QTc intervals. Additionally, any patient predisposed to QTc prolongation should have an EKG performed before commencing treatment as well as after treatment is complete. If a drug prolongs the QTc interval beyond normal limits, the benefit of continuing the drug should be weighed against the risk of serious adverse cardiac events.10 TH

Michele B Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Kupec IF. Seldane and generic terfenadine withdrawn from market. Food and Drug Administration Web site. Available at: www.fda.gov/bbs/topics/answers/ ans00853.html. Accessed Nov. 7, 2008.

2. Zalewski JM. Cisapride withdrawal requires alternate therapy. Cleveland Clinic Web site. Available at: www.clevelandclinicmeded.com/medicalpubs/pharmacy/mayjune2000/cisapride.htm. Accessed Nov. 7, 2008.

3. Drugs removed from or restricted in the U.S. market because of drug interactions. Food and Drug Administration Web site. Available at: www.fda.gov/cder/drug/drugReactions/CERT%20Educational%20Module%201/sld013.htm. Updated Dec. 22, 2008. Accessed Nov. 7, 2008.

4. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350:1013-1022.

5. Pham CP, de Feiter PW, van der Kuy PHM, van Mook WN. Long QTc interval and torsades de pointes caused by fluconazole. Ann Pharmacother. 2006;40:1456-1461.

6. Nykamp DL, Blackmon CL, Schmidt PE, Roberson AG. QTc prolongation associated with combination therapy of levofloxacin, imipramine, and fluoxetine. Ann Pharmacother. 1005;39:543-546.

7. Philips JA, Marty FM, Stone RM et al. Torsades de pointes associated with voriconazole use. Transpl Infect Dis. 2007;9:33-36.

8. Charbit B, Alvarez JC, Dasque E, Abe E, Démolis JL, Funck-Brentano C. Droperidol and ondansetron-induced QT interval prolongation. Anesthesiol. 2008;109:206-212.

9. Yap YG, Camm AJ. Drug induced qt prolongation and torsades de pointes. Heart. 2003;89:1363-1372.

10. Jayasinghe R, Registrar S, Kovoor P. Drugs and the QTc interval. Aust Prescr. 2002;25:63-65.

11. Atacand HCT 32/25 mg gives patients and physicians more treatment flexibility. Available at: www.pharmacitelink.com/news/2008/08/14_az.pdf. Accessed Nov. 4, 2008.

12. FDA approves astellas’ vaprisol (conivaptan hydrochloride injection) premixed in 5% dextrose for the treatment of hyponatremia. Sandoz Web site. Available at: sandoz.yellowbrix.com/pages/sandoz/Story.nsp?story_id=122559939. Accessed Nov. 4, 2008.

13. U.S. FDA drug shortages. Available at: www.fda.gov/cder/drug/shortages/default.htm#Foscavir. Accessed Nov. 3, 2008.

14. FDA Drug Shortages. Food and Drug Administration Web site. Available at: www.fda.gov/cder/drug/ shortages/discontinuation.pdf. Accessed Nov. 6, 2008.

15. Waknine Y. FDA safety changes: mirena, zyvox, orencia. Medscape Web site. Available at: www.medscape.com/viewarticle/580101. Accessed Nov. 3, 2008.

16. MannKind and Pfizer announce collaboration for certain exubera patients to transition to Mannkind’s inhaled insulin therapy. Drugs.com Web site. Available at: www.drugs.com/news/mannkind-pfizer-announce-collaboration-certain-exubera-patients-transition-mannkind-s-inhaled-13677.html. Accessed Nov. 3, 2008.

17. MannKind reports positive data from a phase 3 clinical study of technosphere insulin in Type 1 diabetics. Drugs.com Web site. Available at: www.drugs.com/ clinical_trials/mannkind-reports-positive-data-phase-3-clinical-study-technosphere-insulin-type-1-diabetes-5554.html. Accessed Nov. 3, 2008.

18. Bratulic A. Sanofi-aventis to halt all Acomplia trials. FirstWord Web site. Available at: www.firstwordplus.com/Fws.do?articleid=34DAB2DC3D7A48939A1D24AB97204CB4&logRowId=263560. Accessed Nov. 6, 2008.

Terfenadine, cisapride, astemizole … do you remember these drugs? They all were removed from the U.S. market subsequent to adverse outcomes related to QTc interval prolongation, including ventricular arrhythmias.1-3 Many drugs prolong the QTc interval, particularly if a drug is combined with others that affect its metabolism.

QTc interval prolongation can lead to torsades de pointes (TdP). Certain individuals are particularly predisposed to developing TdP, including: women, people with hypokalemia or hypomagnesemia, and those with a history of congenital or idiopathic QTc syndrome, cardiac arrest, syncope, congestive heart failure, bradycardia, baseline QT prolongation, renal failure, or cardiac failure.4 Some agents can prolong the QTc interval by five to 10 milliseconds and cause TdP, while others require a 50-millisecond increase or more.

Drugs that confer a risk of ventricular arrhythmias include: disopyramide, dofetilide, ibutilide, procainamide, quinidine, sotalol, and amiodarone (antiarrhythmic agents); clarithromycin, erythromycin, levofloxacin, gatifloxacin, gemifloxacin, moxifloxacin, telithromycin (anti-infectives); domperidone and droperidol antiemetics; chlorpromazine, haloperidol, mesoridazine, thioridazine, and pimozide (antipsychotics); amitriptyline, desipramine, doxepin, fluoxetine, imipramine, sertraline, and venlafaxine (antidepressants); fluconazole, itraconazole, and ketoconazole (antifungals); naratriptan, sumatriptan, and zolmitriptan; and methadone.4-8 Other related agents, such as voriconazole and ondansetron, have been reported to cause QTc prolongation.

Drugs of special concern are those that frequently inhibit the metabolism of other agents, including erythromycin, clarithromycin, ketoconazole, itraconazole, amiodarone, and quinidine, and many antidepressants and antiretroviral agents. Of the deaths associated with drug-induced QTc prolongation related to the prokinetic agent cisapride, many were due to drug interactions with an imidazole or macrolide antibiotic. In these cases, increased serum concentrations of cisapride occurred due to inhibition of the cytochrome P450 CYP3A4 isoenzyme.9

If treatment with a drug that has the potential for causing QTc prolongation is begun, tell your patient to report any “potential cardiac” symptoms, such as palpitations, syncope, or near-syncope with or without palpitations, to a member of the healthcare team. Always be on the lookout for any concomitant conditions or treatments that can cause hypokalemia (e.g., diuretic use, gastroenteritis, diarrhea, excessive vomiting), or other agents that inhibit drug metabolism.

Obtaining a complete medication history, including the use of herbal products and over-the-counter medications, can help identify and prevent QTc prolongation from a drug interaction. A routine, 12-lead electrocardiogram (EKG) should be utilized during treatment to detect asymptomatic QTc prolongation or abnormal postectopic QTc intervals. Additionally, any patient predisposed to QTc prolongation should have an EKG performed before commencing treatment as well as after treatment is complete. If a drug prolongs the QTc interval beyond normal limits, the benefit of continuing the drug should be weighed against the risk of serious adverse cardiac events.10 TH

Michele B Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Kupec IF. Seldane and generic terfenadine withdrawn from market. Food and Drug Administration Web site. Available at: www.fda.gov/bbs/topics/answers/ ans00853.html. Accessed Nov. 7, 2008.

2. Zalewski JM. Cisapride withdrawal requires alternate therapy. Cleveland Clinic Web site. Available at: www.clevelandclinicmeded.com/medicalpubs/pharmacy/mayjune2000/cisapride.htm. Accessed Nov. 7, 2008.

3. Drugs removed from or restricted in the U.S. market because of drug interactions. Food and Drug Administration Web site. Available at: www.fda.gov/cder/drug/drugReactions/CERT%20Educational%20Module%201/sld013.htm. Updated Dec. 22, 2008. Accessed Nov. 7, 2008.

4. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350:1013-1022.

5. Pham CP, de Feiter PW, van der Kuy PHM, van Mook WN. Long QTc interval and torsades de pointes caused by fluconazole. Ann Pharmacother. 2006;40:1456-1461.

6. Nykamp DL, Blackmon CL, Schmidt PE, Roberson AG. QTc prolongation associated with combination therapy of levofloxacin, imipramine, and fluoxetine. Ann Pharmacother. 1005;39:543-546.

7. Philips JA, Marty FM, Stone RM et al. Torsades de pointes associated with voriconazole use. Transpl Infect Dis. 2007;9:33-36.

8. Charbit B, Alvarez JC, Dasque E, Abe E, Démolis JL, Funck-Brentano C. Droperidol and ondansetron-induced QT interval prolongation. Anesthesiol. 2008;109:206-212.

9. Yap YG, Camm AJ. Drug induced qt prolongation and torsades de pointes. Heart. 2003;89:1363-1372.

10. Jayasinghe R, Registrar S, Kovoor P. Drugs and the QTc interval. Aust Prescr. 2002;25:63-65.

11. Atacand HCT 32/25 mg gives patients and physicians more treatment flexibility. Available at: www.pharmacitelink.com/news/2008/08/14_az.pdf. Accessed Nov. 4, 2008.

12. FDA approves astellas’ vaprisol (conivaptan hydrochloride injection) premixed in 5% dextrose for the treatment of hyponatremia. Sandoz Web site. Available at: sandoz.yellowbrix.com/pages/sandoz/Story.nsp?story_id=122559939. Accessed Nov. 4, 2008.

13. U.S. FDA drug shortages. Available at: www.fda.gov/cder/drug/shortages/default.htm#Foscavir. Accessed Nov. 3, 2008.

14. FDA Drug Shortages. Food and Drug Administration Web site. Available at: www.fda.gov/cder/drug/ shortages/discontinuation.pdf. Accessed Nov. 6, 2008.

15. Waknine Y. FDA safety changes: mirena, zyvox, orencia. Medscape Web site. Available at: www.medscape.com/viewarticle/580101. Accessed Nov. 3, 2008.

16. MannKind and Pfizer announce collaboration for certain exubera patients to transition to Mannkind’s inhaled insulin therapy. Drugs.com Web site. Available at: www.drugs.com/news/mannkind-pfizer-announce-collaboration-certain-exubera-patients-transition-mannkind-s-inhaled-13677.html. Accessed Nov. 3, 2008.

17. MannKind reports positive data from a phase 3 clinical study of technosphere insulin in Type 1 diabetics. Drugs.com Web site. Available at: www.drugs.com/ clinical_trials/mannkind-reports-positive-data-phase-3-clinical-study-technosphere-insulin-type-1-diabetes-5554.html. Accessed Nov. 3, 2008.

18. Bratulic A. Sanofi-aventis to halt all Acomplia trials. FirstWord Web site. Available at: www.firstwordplus.com/Fws.do?articleid=34DAB2DC3D7A48939A1D24AB97204CB4&logRowId=263560. Accessed Nov. 6, 2008.

Remember all the hype leading up to the approval of the dry-powder formulation of human insulin, produced by means of recombinant DNA technology, a.k.a. inhaled insulin (Exubera)? That was three years ago (January 2006). Remember all the press releases regarding the removal of inhaled insulin from the market? That was October 2007.1,2

Almost immediately after Pfizer “pulled the plug” on inhaled insulin, cases of lung cancer started being reported—albeit it had occurred in Exubera-treated patients that had a history of smoking cigarettes—a contraindication within the drug’s approved label. Some clinicians questioned whether it was due to insulin being a weak growth factor when binding to the type 1 insulin-like growth factor receptor; others wondered if it was related to smoking history.3,4 Three other collaboration efforts for inhaled insulin—NovoNordisk/Aradigm, MannKind, and Alkermes/Eli Lilly AIR insulin— were in the pipeline when Pfizer bowed out of the market. MannKind’s Technosphere insulin and Alkermes/Eli Lilly AIR insulin are still being investigated. Both are in phase 3 clinical trials.5

So, contrary to popular belief, inhaled insulin is not dead, yet. These other companies are looking to improve upon what Pfizer lost out on. The AIR system uses a smaller, breathable inhaler, which would fit into a patient’s hand. The inhaled powder has a smaller particle size and a larger surface area, which provides deeper lung penetration of drug.6

More Drugs Via the Pulmonary Route

Aside from asthma, chronic obstructive pulmonary disease, pulmonary hypertension, and cystic fibrosis, where a hospitalist could expect to use pulmonary delivered drugs, other medicines are being investigated for administration via this route. The pulmonary route may be used for tuberculosis (TB), where lower doses can be given since high doses of systemic therapy lead to significant drug toxicity.7

Inhaled vaccines are being developed, including Bacillus Calmette-Guérin (BCG) TB and respiratory syncytial virus (RSV). Parathyroid hormone for osteoporosis, human factor IX for hemophilia, and interferon α-2b for hepatitis B virus, are potential and current inhaled treatments.

New Delivery Systems: Will They Pan Out?

Knowing the lung absorbs biologic drugs with a wide range of molecular weights, solubility, and charges, is a plus for pulmonary delivery. However, pulmonary drug delivery also presents challenges. These include local toxic effects, such as cell injury, edema, and altered tissue defenses. Drug carriers, preservatives, and propellants, such as sulfites, might harm pulmonary tissue or the body.

Safety is one of the biggest concerns when companies develop new drug delivery systems. These inhaled products and methods of delivering inhaled insulin are quickly moving through clinical trials.

Only time will tell when approvals will take place, but it looks as though there will be some innovative insulin products in the near future. TH

Michele B Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Alvey L. U.S. Food and Drug Administration. FDA ap-proves first ever inhaled insulin combination product for treatment of diabetes. www.fda.gov/bbs/topics/ news/2006/NEW01304.html. Published Jan. 27, 2006. Accessed Dec. 1, 2008.

2. U.S. Food and Drug Administration. Drug discontinuations. www.fda.gov/cder/drug/shortages/#disc. Published Oct. 19, 2007. Accessed Dec. 1, 2008.

3. von Kriegstein E, von Kriegstein K. Inhaled insulin for diabetes. N Engl J Med. 2007;356:2106-2108.

4. McMahon GT, Arky RA. Inhaled insulin for diabetes. N Engl J Med. 2007;356:497-502.

5. Opar A. Another blow for inhaled protein therapeutics. Nat Rev Drug Discov. 2008;7:189-190.

6. Dubin CH. The state of systemic pulmonary delivery: one year after Exubera’s approval. Nat Rev Drug Discov. 2007;7(4):61-67.

7. Greb E. Inhalable drugs in the launch pad: will they take off? Pharm Tech. 2008;4:48-55.

8. Riley K, Long P. FDA approves treatment for rare neurologic disease. www.fda.gov/bbs/topics/ NEWS/2008/NEW01884.html. Published Sept. 12, 2008. Accessed Dec. 1, 2008.

9. Keppra XR approved in the U.S. hugin.info/133973/ R/1251192/271964.pdf. Published Sept. 15, 2008. Accessed Sept. 15, 2008.

10. U.S. Food and Drug Administration. 2008 safety alerts for human medical products (drugs, biologics, medical devices, special nutritionals, and cosmetics). www.fda.gov/medwatch/safety/2008/rituxan_DHCP_Final%209411700.pdf Published Sept. 2008. Accessed Sept. 15, 2008.

11. U.S. Food and Drug Administration. Pregnacy and lactation labeling. www.fda.gov/cder/regulatory/ pregnancy_labeling/default.htm Published June 11, 2008. Accessed Sept. 15, 2008.

12. Cruzan S. U.S. Food and Drug Administration. FDA proposes new rule to provide updated information on the use of prescription drugs and biological products during pregnancy and breast-feeding. www. fda.gov/bbs/topics/NEWS/2008/NEW018 41.html. Published May 28, 2008. Accessed Sept. 15, 2008.

13. Peggy P. FDA to take A, B, and C out of pregnancy labeling. www.medpagetoday.com/OBGYN/Pregnancy/ tb/9626. Published May 28, 2008. Accessed Sept. 15, 2008.

Remember all the hype leading up to the approval of the dry-powder formulation of human insulin, produced by means of recombinant DNA technology, a.k.a. inhaled insulin (Exubera)? That was three years ago (January 2006). Remember all the press releases regarding the removal of inhaled insulin from the market? That was October 2007.1,2

Almost immediately after Pfizer “pulled the plug” on inhaled insulin, cases of lung cancer started being reported—albeit it had occurred in Exubera-treated patients that had a history of smoking cigarettes—a contraindication within the drug’s approved label. Some clinicians questioned whether it was due to insulin being a weak growth factor when binding to the type 1 insulin-like growth factor receptor; others wondered if it was related to smoking history.3,4 Three other collaboration efforts for inhaled insulin—NovoNordisk/Aradigm, MannKind, and Alkermes/Eli Lilly AIR insulin— were in the pipeline when Pfizer bowed out of the market. MannKind’s Technosphere insulin and Alkermes/Eli Lilly AIR insulin are still being investigated. Both are in phase 3 clinical trials.5

So, contrary to popular belief, inhaled insulin is not dead, yet. These other companies are looking to improve upon what Pfizer lost out on. The AIR system uses a smaller, breathable inhaler, which would fit into a patient’s hand. The inhaled powder has a smaller particle size and a larger surface area, which provides deeper lung penetration of drug.6

More Drugs Via the Pulmonary Route

Aside from asthma, chronic obstructive pulmonary disease, pulmonary hypertension, and cystic fibrosis, where a hospitalist could expect to use pulmonary delivered drugs, other medicines are being investigated for administration via this route. The pulmonary route may be used for tuberculosis (TB), where lower doses can be given since high doses of systemic therapy lead to significant drug toxicity.7

Inhaled vaccines are being developed, including Bacillus Calmette-Guérin (BCG) TB and respiratory syncytial virus (RSV). Parathyroid hormone for osteoporosis, human factor IX for hemophilia, and interferon α-2b for hepatitis B virus, are potential and current inhaled treatments.

New Delivery Systems: Will They Pan Out?

Knowing the lung absorbs biologic drugs with a wide range of molecular weights, solubility, and charges, is a plus for pulmonary delivery. However, pulmonary drug delivery also presents challenges. These include local toxic effects, such as cell injury, edema, and altered tissue defenses. Drug carriers, preservatives, and propellants, such as sulfites, might harm pulmonary tissue or the body.

Safety is one of the biggest concerns when companies develop new drug delivery systems. These inhaled products and methods of delivering inhaled insulin are quickly moving through clinical trials.

Only time will tell when approvals will take place, but it looks as though there will be some innovative insulin products in the near future. TH

Michele B Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Alvey L. U.S. Food and Drug Administration. FDA ap-proves first ever inhaled insulin combination product for treatment of diabetes. www.fda.gov/bbs/topics/ news/2006/NEW01304.html. Published Jan. 27, 2006. Accessed Dec. 1, 2008.

2. U.S. Food and Drug Administration. Drug discontinuations. www.fda.gov/cder/drug/shortages/#disc. Published Oct. 19, 2007. Accessed Dec. 1, 2008.

3. von Kriegstein E, von Kriegstein K. Inhaled insulin for diabetes. N Engl J Med. 2007;356:2106-2108.

4. McMahon GT, Arky RA. Inhaled insulin for diabetes. N Engl J Med. 2007;356:497-502.

5. Opar A. Another blow for inhaled protein therapeutics. Nat Rev Drug Discov. 2008;7:189-190.

6. Dubin CH. The state of systemic pulmonary delivery: one year after Exubera’s approval. Nat Rev Drug Discov. 2007;7(4):61-67.

7. Greb E. Inhalable drugs in the launch pad: will they take off? Pharm Tech. 2008;4:48-55.

8. Riley K, Long P. FDA approves treatment for rare neurologic disease. www.fda.gov/bbs/topics/ NEWS/2008/NEW01884.html. Published Sept. 12, 2008. Accessed Dec. 1, 2008.

9. Keppra XR approved in the U.S. hugin.info/133973/ R/1251192/271964.pdf. Published Sept. 15, 2008. Accessed Sept. 15, 2008.

10. U.S. Food and Drug Administration. 2008 safety alerts for human medical products (drugs, biologics, medical devices, special nutritionals, and cosmetics). www.fda.gov/medwatch/safety/2008/rituxan_DHCP_Final%209411700.pdf Published Sept. 2008. Accessed Sept. 15, 2008.

11. U.S. Food and Drug Administration. Pregnacy and lactation labeling. www.fda.gov/cder/regulatory/ pregnancy_labeling/default.htm Published June 11, 2008. Accessed Sept. 15, 2008.

12. Cruzan S. U.S. Food and Drug Administration. FDA proposes new rule to provide updated information on the use of prescription drugs and biological products during pregnancy and breast-feeding. www. fda.gov/bbs/topics/NEWS/2008/NEW018 41.html. Published May 28, 2008. Accessed Sept. 15, 2008.

13. Peggy P. FDA to take A, B, and C out of pregnancy labeling. www.medpagetoday.com/OBGYN/Pregnancy/ tb/9626. Published May 28, 2008. Accessed Sept. 15, 2008.

Remember all the hype leading up to the approval of the dry-powder formulation of human insulin, produced by means of recombinant DNA technology, a.k.a. inhaled insulin (Exubera)? That was three years ago (January 2006). Remember all the press releases regarding the removal of inhaled insulin from the market? That was October 2007.1,2

Almost immediately after Pfizer “pulled the plug” on inhaled insulin, cases of lung cancer started being reported—albeit it had occurred in Exubera-treated patients that had a history of smoking cigarettes—a contraindication within the drug’s approved label. Some clinicians questioned whether it was due to insulin being a weak growth factor when binding to the type 1 insulin-like growth factor receptor; others wondered if it was related to smoking history.3,4 Three other collaboration efforts for inhaled insulin—NovoNordisk/Aradigm, MannKind, and Alkermes/Eli Lilly AIR insulin— were in the pipeline when Pfizer bowed out of the market. MannKind’s Technosphere insulin and Alkermes/Eli Lilly AIR insulin are still being investigated. Both are in phase 3 clinical trials.5

So, contrary to popular belief, inhaled insulin is not dead, yet. These other companies are looking to improve upon what Pfizer lost out on. The AIR system uses a smaller, breathable inhaler, which would fit into a patient’s hand. The inhaled powder has a smaller particle size and a larger surface area, which provides deeper lung penetration of drug.6

More Drugs Via the Pulmonary Route

Aside from asthma, chronic obstructive pulmonary disease, pulmonary hypertension, and cystic fibrosis, where a hospitalist could expect to use pulmonary delivered drugs, other medicines are being investigated for administration via this route. The pulmonary route may be used for tuberculosis (TB), where lower doses can be given since high doses of systemic therapy lead to significant drug toxicity.7

Inhaled vaccines are being developed, including Bacillus Calmette-Guérin (BCG) TB and respiratory syncytial virus (RSV). Parathyroid hormone for osteoporosis, human factor IX for hemophilia, and interferon α-2b for hepatitis B virus, are potential and current inhaled treatments.

New Delivery Systems: Will They Pan Out?

Knowing the lung absorbs biologic drugs with a wide range of molecular weights, solubility, and charges, is a plus for pulmonary delivery. However, pulmonary drug delivery also presents challenges. These include local toxic effects, such as cell injury, edema, and altered tissue defenses. Drug carriers, preservatives, and propellants, such as sulfites, might harm pulmonary tissue or the body.

Safety is one of the biggest concerns when companies develop new drug delivery systems. These inhaled products and methods of delivering inhaled insulin are quickly moving through clinical trials.

Only time will tell when approvals will take place, but it looks as though there will be some innovative insulin products in the near future. TH

Michele B Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1. Alvey L. U.S. Food and Drug Administration. FDA ap-proves first ever inhaled insulin combination product for treatment of diabetes. www.fda.gov/bbs/topics/ news/2006/NEW01304.html. Published Jan. 27, 2006. Accessed Dec. 1, 2008.

2. U.S. Food and Drug Administration. Drug discontinuations. www.fda.gov/cder/drug/shortages/#disc. Published Oct. 19, 2007. Accessed Dec. 1, 2008.

3. von Kriegstein E, von Kriegstein K. Inhaled insulin for diabetes. N Engl J Med. 2007;356:2106-2108.

4. McMahon GT, Arky RA. Inhaled insulin for diabetes. N Engl J Med. 2007;356:497-502.

5. Opar A. Another blow for inhaled protein therapeutics. Nat Rev Drug Discov. 2008;7:189-190.

6. Dubin CH. The state of systemic pulmonary delivery: one year after Exubera’s approval. Nat Rev Drug Discov. 2007;7(4):61-67.

7. Greb E. Inhalable drugs in the launch pad: will they take off? Pharm Tech. 2008;4:48-55.

8. Riley K, Long P. FDA approves treatment for rare neurologic disease. www.fda.gov/bbs/topics/ NEWS/2008/NEW01884.html. Published Sept. 12, 2008. Accessed Dec. 1, 2008.

9. Keppra XR approved in the U.S. hugin.info/133973/ R/1251192/271964.pdf. Published Sept. 15, 2008. Accessed Sept. 15, 2008.

10. U.S. Food and Drug Administration. 2008 safety alerts for human medical products (drugs, biologics, medical devices, special nutritionals, and cosmetics). www.fda.gov/medwatch/safety/2008/rituxan_DHCP_Final%209411700.pdf Published Sept. 2008. Accessed Sept. 15, 2008.

11. U.S. Food and Drug Administration. Pregnacy and lactation labeling. www.fda.gov/cder/regulatory/ pregnancy_labeling/default.htm Published June 11, 2008. Accessed Sept. 15, 2008.

12. Cruzan S. U.S. Food and Drug Administration. FDA proposes new rule to provide updated information on the use of prescription drugs and biological products during pregnancy and breast-feeding. www. fda.gov/bbs/topics/NEWS/2008/NEW018 41.html. Published May 28, 2008. Accessed Sept. 15, 2008.

13. Peggy P. FDA to take A, B, and C out of pregnancy labeling. www.medpagetoday.com/OBGYN/Pregnancy/ tb/9626. Published May 28, 2008. Accessed Sept. 15, 2008.