Michele B. Kaufman, PharmD, BSc, RPh

The FDA has approved the first nucleic acid HBV viral DNA test for measuring HBV viral load from a patient’s blood. Via HBV viral load assessment, healthcare professionals now have a highly sensitive method for gauging antiviral therapy progress in patients with chronic HBV infections.

The test is known as the COBAS TaqMan HBV Test (Roche Diagnostic Division). It is used to measure HBV levels before beginning treatment, and then follow-up levels during treatment to assess therapy response. It is estimated that approximately 1.25 million people in the U.S. are infected with HBV, with approximately 60,000 becoming infected each year. About 5,000 people die from HBV-related complications each year.8

New Warnings

In October 2007, the Federal Drug and Food Administration (FDA) issued information for healthcare professionals regarding the subcutaneous use of exenatide (Byetta, Amylin Pharmaceuti-cals).9 Since then, the FDA has received at least six additional case reports of necrotizing or pancreatitis in patients taking exenatide.

Of these six cases, all patients needed hospitalization, two patients died, and four were recovering at the time of the reporting. Exenatide was discontinued in all of these patients.

If pancreatitis is suspected, exenatide and other potentially suspect drugs should be discontinued. There are no signs or symptoms distinguishing acute hemorrhagic or necrotizing pancreatitis associated with exenatide from less severe forms of pancreatitis. If pancreatitis is confirmed, appropriate treatment should be initiated and patients should be carefully monitored until they fully recover. Exenatide should not be restarted. The FDA is working with Amylin Pharmaceuticals to add stronger and more prominent warnings to the product label regarding the noted risks.

Since the last warning of natalizumab injection (Tysabri, Biogen IDEC), the FDA has informed healthcare professionals of two new cases of progressive multifocal leukoencephalopathy (PML) in European patients receiving it for more than a year as monotherapy for multiple sclerosis (MS).10

The agent currently is FDA approved to treat multiple sclerosis and Crohn’s disease. Approximately 39,000 patients have received treatment worldwide, with approximately 12,000 patients receiving treatment for at least a year. No new cases have been reported in the U.S., where approximately 7,500 patients have received the drug for more than a year and approximately 3,300 have received the drug for more than 18 months.

The FDA still believes natalizumab monotherapy may confer a lower risk of PML than usage with other immunomodulatory medications. Prescribing information for natalizumab has been revised to reflect this new information. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

References:

1. Peck P. IV calcium channel blocker wins FDA okay. www.medpagetoday.com/ProductAlert/Prescriptions/10431. Published August 5, 2008. Accessed October 28, 2008.

2. Riley K. www.fda.gov. FDA approves first bone marrow stimulator to treat immune-related low platelet counts. www.fda.gov/bbs/topics/NEWS/2008/NEW01876.html Published August 22, 2008. Accessed October 28, 2008.

4. Waknine Y. www.fda.org. FDA approvals: stavzor, cardene IV, eovist. www.medscape.com/viewarticle/ 579068. Published August 14, 2008. Accessed October 28, 2008.

5. Eisai Pharmaceutical Company. www.eisai.com. FDA approves ALOXI® (palonosetron HCl) capsules for prevention of acute chemotherapy-induced nausea and vomiting. www.eisai.com/view_press_ release.asp? ID=147&press=195. Published August 23, 2008. Accessed October 28, 2008.

6. Monthly Prescribing Reference. www. prescribingreference.com. FDA approves viread for hepatitis B. www. prescribingreference.com/news/showNews/ which/FDAApprovesVireadForHepatitisB8123/. Published August 12, 2008. Accessed October 28, 2008.

7. Nainggolan L. theheart.org. First ARB/CCB combo approved for initial therapy. www.theheart.org/ article/886011.do. Published August 5, 2008. Accessed October 28. 2008.

8. Long P. U.S. Food & Drug Administration. www.fda.org. FDA approves DNA test to measure hepatitis B virus levels. www.fda.gov/bbs/topics/ NEWS/2008/NEW01880.html. Published September 4, 2008. Accessed October 28, 2008.

9. U.S. Food & Drug Administration. www.fda.org. 2007 safety alerts for human medical products—Byetta (exenatide). www.fda.gov/medwatch/safety/2007 /safety07.htm#Byetta. Published August 18, 2008. Accessed October 28, 2008.

10. U.S. Food & Drug Administration. www.fda.org. 2008 safety alerts for human medical products–Tysabri (natalizumab). www.fda.gov/medwatch/ safety/2008/safety08.htm#Tysabri2. Published August 25, 2008. Accessed October 28, 2008.

The FDA has approved the first nucleic acid HBV viral DNA test for measuring HBV viral load from a patient’s blood. Via HBV viral load assessment, healthcare professionals now have a highly sensitive method for gauging antiviral therapy progress in patients with chronic HBV infections.

The test is known as the COBAS TaqMan HBV Test (Roche Diagnostic Division). It is used to measure HBV levels before beginning treatment, and then follow-up levels during treatment to assess therapy response. It is estimated that approximately 1.25 million people in the U.S. are infected with HBV, with approximately 60,000 becoming infected each year. About 5,000 people die from HBV-related complications each year.8

New Warnings

In October 2007, the Federal Drug and Food Administration (FDA) issued information for healthcare professionals regarding the subcutaneous use of exenatide (Byetta, Amylin Pharmaceuti-cals).9 Since then, the FDA has received at least six additional case reports of necrotizing or pancreatitis in patients taking exenatide.

Of these six cases, all patients needed hospitalization, two patients died, and four were recovering at the time of the reporting. Exenatide was discontinued in all of these patients.

If pancreatitis is suspected, exenatide and other potentially suspect drugs should be discontinued. There are no signs or symptoms distinguishing acute hemorrhagic or necrotizing pancreatitis associated with exenatide from less severe forms of pancreatitis. If pancreatitis is confirmed, appropriate treatment should be initiated and patients should be carefully monitored until they fully recover. Exenatide should not be restarted. The FDA is working with Amylin Pharmaceuticals to add stronger and more prominent warnings to the product label regarding the noted risks.

Since the last warning of natalizumab injection (Tysabri, Biogen IDEC), the FDA has informed healthcare professionals of two new cases of progressive multifocal leukoencephalopathy (PML) in European patients receiving it for more than a year as monotherapy for multiple sclerosis (MS).10

The agent currently is FDA approved to treat multiple sclerosis and Crohn’s disease. Approximately 39,000 patients have received treatment worldwide, with approximately 12,000 patients receiving treatment for at least a year. No new cases have been reported in the U.S., where approximately 7,500 patients have received the drug for more than a year and approximately 3,300 have received the drug for more than 18 months.

The FDA still believes natalizumab monotherapy may confer a lower risk of PML than usage with other immunomodulatory medications. Prescribing information for natalizumab has been revised to reflect this new information. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

References:

1. Peck P. IV calcium channel blocker wins FDA okay. www.medpagetoday.com/ProductAlert/Prescriptions/10431. Published August 5, 2008. Accessed October 28, 2008.

2. Riley K. www.fda.gov. FDA approves first bone marrow stimulator to treat immune-related low platelet counts. www.fda.gov/bbs/topics/NEWS/2008/NEW01876.html Published August 22, 2008. Accessed October 28, 2008.

4. Waknine Y. www.fda.org. FDA approvals: stavzor, cardene IV, eovist. www.medscape.com/viewarticle/ 579068. Published August 14, 2008. Accessed October 28, 2008.

5. Eisai Pharmaceutical Company. www.eisai.com. FDA approves ALOXI® (palonosetron HCl) capsules for prevention of acute chemotherapy-induced nausea and vomiting. www.eisai.com/view_press_ release.asp? ID=147&press=195. Published August 23, 2008. Accessed October 28, 2008.

6. Monthly Prescribing Reference. www. prescribingreference.com. FDA approves viread for hepatitis B. www. prescribingreference.com/news/showNews/ which/FDAApprovesVireadForHepatitisB8123/. Published August 12, 2008. Accessed October 28, 2008.

7. Nainggolan L. theheart.org. First ARB/CCB combo approved for initial therapy. www.theheart.org/ article/886011.do. Published August 5, 2008. Accessed October 28. 2008.

8. Long P. U.S. Food & Drug Administration. www.fda.org. FDA approves DNA test to measure hepatitis B virus levels. www.fda.gov/bbs/topics/ NEWS/2008/NEW01880.html. Published September 4, 2008. Accessed October 28, 2008.

9. U.S. Food & Drug Administration. www.fda.org. 2007 safety alerts for human medical products—Byetta (exenatide). www.fda.gov/medwatch/safety/2007 /safety07.htm#Byetta. Published August 18, 2008. Accessed October 28, 2008.

10. U.S. Food & Drug Administration. www.fda.org. 2008 safety alerts for human medical products–Tysabri (natalizumab). www.fda.gov/medwatch/ safety/2008/safety08.htm#Tysabri2. Published August 25, 2008. Accessed October 28, 2008.

The FDA has approved the first nucleic acid HBV viral DNA test for measuring HBV viral load from a patient’s blood. Via HBV viral load assessment, healthcare professionals now have a highly sensitive method for gauging antiviral therapy progress in patients with chronic HBV infections.

The test is known as the COBAS TaqMan HBV Test (Roche Diagnostic Division). It is used to measure HBV levels before beginning treatment, and then follow-up levels during treatment to assess therapy response. It is estimated that approximately 1.25 million people in the U.S. are infected with HBV, with approximately 60,000 becoming infected each year. About 5,000 people die from HBV-related complications each year.8

New Warnings

In October 2007, the Federal Drug and Food Administration (FDA) issued information for healthcare professionals regarding the subcutaneous use of exenatide (Byetta, Amylin Pharmaceuti-cals).9 Since then, the FDA has received at least six additional case reports of necrotizing or pancreatitis in patients taking exenatide.

Of these six cases, all patients needed hospitalization, two patients died, and four were recovering at the time of the reporting. Exenatide was discontinued in all of these patients.

If pancreatitis is suspected, exenatide and other potentially suspect drugs should be discontinued. There are no signs or symptoms distinguishing acute hemorrhagic or necrotizing pancreatitis associated with exenatide from less severe forms of pancreatitis. If pancreatitis is confirmed, appropriate treatment should be initiated and patients should be carefully monitored until they fully recover. Exenatide should not be restarted. The FDA is working with Amylin Pharmaceuticals to add stronger and more prominent warnings to the product label regarding the noted risks.

Since the last warning of natalizumab injection (Tysabri, Biogen IDEC), the FDA has informed healthcare professionals of two new cases of progressive multifocal leukoencephalopathy (PML) in European patients receiving it for more than a year as monotherapy for multiple sclerosis (MS).10

The agent currently is FDA approved to treat multiple sclerosis and Crohn’s disease. Approximately 39,000 patients have received treatment worldwide, with approximately 12,000 patients receiving treatment for at least a year. No new cases have been reported in the U.S., where approximately 7,500 patients have received the drug for more than a year and approximately 3,300 have received the drug for more than 18 months.

The FDA still believes natalizumab monotherapy may confer a lower risk of PML than usage with other immunomodulatory medications. Prescribing information for natalizumab has been revised to reflect this new information. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

References:

1. Peck P. IV calcium channel blocker wins FDA okay. www.medpagetoday.com/ProductAlert/Prescriptions/10431. Published August 5, 2008. Accessed October 28, 2008.

2. Riley K. www.fda.gov. FDA approves first bone marrow stimulator to treat immune-related low platelet counts. www.fda.gov/bbs/topics/NEWS/2008/NEW01876.html Published August 22, 2008. Accessed October 28, 2008.

4. Waknine Y. www.fda.org. FDA approvals: stavzor, cardene IV, eovist. www.medscape.com/viewarticle/ 579068. Published August 14, 2008. Accessed October 28, 2008.

5. Eisai Pharmaceutical Company. www.eisai.com. FDA approves ALOXI® (palonosetron HCl) capsules for prevention of acute chemotherapy-induced nausea and vomiting. www.eisai.com/view_press_ release.asp? ID=147&press=195. Published August 23, 2008. Accessed October 28, 2008.

6. Monthly Prescribing Reference. www. prescribingreference.com. FDA approves viread for hepatitis B. www. prescribingreference.com/news/showNews/ which/FDAApprovesVireadForHepatitisB8123/. Published August 12, 2008. Accessed October 28, 2008.

7. Nainggolan L. theheart.org. First ARB/CCB combo approved for initial therapy. www.theheart.org/ article/886011.do. Published August 5, 2008. Accessed October 28. 2008.

8. Long P. U.S. Food & Drug Administration. www.fda.org. FDA approves DNA test to measure hepatitis B virus levels. www.fda.gov/bbs/topics/ NEWS/2008/NEW01880.html. Published September 4, 2008. Accessed October 28, 2008.

9. U.S. Food & Drug Administration. www.fda.org. 2007 safety alerts for human medical products—Byetta (exenatide). www.fda.gov/medwatch/safety/2007 /safety07.htm#Byetta. Published August 18, 2008. Accessed October 28, 2008.

10. U.S. Food & Drug Administration. www.fda.org. 2008 safety alerts for human medical products–Tysabri (natalizumab). www.fda.gov/medwatch/ safety/2008/safety08.htm#Tysabri2. Published August 25, 2008. Accessed October 28, 2008.

Complementary and alterative medicine (CAM) is defined as any product, including herbal remedies/foods/teas, vitamins, minerals, and natural products, that can be purchased without a prescription at a health food store, supermarket, from a magazine/newspaper or online, for self-treatment.1

Taylor et al. evaluated CAM perceptions of emergency department patients in Australia. They determined 44% of patients felt that by using CAM they were “drug free,” with 29% of patients agreeing (or strongly agreeing) CAM use is always safe to take with prescription medications. In an earlier study, Eisenberg et al. evaluated CAM use perceptions in the United States and found 79% of patients felt that, combined with prescription drugs, CAM was superior to either modality alone.2 They also found 63% to 72% of CAM-using patients that had seen a medical doctor in the prior year did not disclose the therapy.

The two most common reasons cited by patients were “they felt it wasn’t important for the doctor to know (61%)” and “the doctor didn’t ask (60%).” Overall, national CAM-use surveys have revealed that about 80% of adults typically do not disclose CAM use to medical doctors.

It is, therefore, imperative that physicians ask patients about their CAM use. It also is important to remember there are more foods and beverages that contain some of these “natural” ingredients, and patients need to be queried about the use of these products. CAM products can complicate traditional patient management, either when used alone or in combination with prescription drugs.

A clinically significant drug interaction that bears its own warning is that of warfarin and chondroitin/glucosamine. Patients might not tell you that they are taking chondroitin/glucosamine, so you have to ask. Functional foods and beverages that include “natural” ingredients, such as glucosamine and chondroitin, and other CAM abound. Examples include Joint Juice (1,500 mg glucosamine), Vitamin Water, and others.3

Two case reports, and a report from the World Health Organization (WHO) Collaborating Center for International Drug Monitoring, and the MedWatch database point to a potentially serious drug interaction between glucosamine and warfarin.4-7 Although not FDA approved for joint supplementation, the usual daily dose should generally not exceed 1.5 grams of glucosamine and 1.2 grams of chondroitin. Chondroitin may have anti-coagulant activity, which would explain the increase in International Normalized Ratio (INR) seen in patients using it in combination with warfarin. The WHO database identified at least 34 cases of concomitant use, with most cases of increased INR resolving upon glucosamine discontinuation. Nine cases required physician intervention, and in one case a positive rechallenge was documented. In June 2007, there were 81 cases of a possible interaction from the MedWatch database, of these, 61 cases had potential alternate etiologies. Of the 20 possibly-related cases, five led to patient hospitalization due to bleeding complications; the median patient age was 62 years and there were no deaths reported.

Ramsay et al. reported from a United Kingdom survey that 92% of patients admitted to taking herbal medicines while receiving warfarin, noting that significant numbers of patients are in need of close monitoring. They also note that other CAM can interact with warfarin to increase bleeding time or act as anti-platelet agents (e.g., high dose vitamin E [> 400 IU], fish oils, garlic, St. John’s Wort, etc.) They particularly note that all patients receiving warfarin or that will be commencing warfarin be specifically asked about their use of CAM. The mechanism for this interaction still is unclear, but may be due to the inhibition of warfarin metabolism by the CYP2C9 or CYP3A4 enzymes, or a pharmacodynamic interaction between glucosamine and warfarin.

It is critical all patients, particularly those taking warfarin, have a full drug history at all hospitalizations. Make sure you inquire about vitamins and other supplements/CAM. If someone else is doing the intake medication history, make sure they get this information. A nurse might not think to ask. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

References

1. Taylor DM, Walsham N, Taylor SE, Wong LF. Complementary and alternative medicines versus prescription drugs: perceptions of emergency department patients. Emerg Med J. 2006;23:266-268.

2. Eisenberg DM, Kessler RC, Van Rompay MI, et al.. Perceptions about complementary therapies relative to conventional therapies among adults how use both: results from a national survey. Ann Intern Med. 2001;135:344-351.

3. What is Joint Juice? Joint Juice, Inc. www.jointjuice.com/jointjuice.php. Published 1997. Accessed August 1, 2008.

4. Rozenfeld V, Crain JL, Callahan AK. Possible augmentation of warfarin effect by glucosamine-chondroitin. Am J Health-Syst Pharm. 2004;61:306-307.

5. Knudsen JF, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: case report and review of the literature and medwatch database. Pharmacother. 2008;28(4):540-548.

6. Ramsay NA, Kenny MW, Davies G, Patel JP. Complimentary and alternative medicine use among patients starting warfarin. Br J Haematology. 2005;130:777-780.

7. Yue Q-Y, Strandell J, Myrberg O. Concomitant use of glucosamine may potentiate the effect of warfarin. The Uppsalla Monitoring Centre Web site. www.who-umc.org/graphics/9722.pdf; Accessed August 1, 2008.

Complementary and alterative medicine (CAM) is defined as any product, including herbal remedies/foods/teas, vitamins, minerals, and natural products, that can be purchased without a prescription at a health food store, supermarket, from a magazine/newspaper or online, for self-treatment.1

Taylor et al. evaluated CAM perceptions of emergency department patients in Australia. They determined 44% of patients felt that by using CAM they were “drug free,” with 29% of patients agreeing (or strongly agreeing) CAM use is always safe to take with prescription medications. In an earlier study, Eisenberg et al. evaluated CAM use perceptions in the United States and found 79% of patients felt that, combined with prescription drugs, CAM was superior to either modality alone.2 They also found 63% to 72% of CAM-using patients that had seen a medical doctor in the prior year did not disclose the therapy.

The two most common reasons cited by patients were “they felt it wasn’t important for the doctor to know (61%)” and “the doctor didn’t ask (60%).” Overall, national CAM-use surveys have revealed that about 80% of adults typically do not disclose CAM use to medical doctors.

It is, therefore, imperative that physicians ask patients about their CAM use. It also is important to remember there are more foods and beverages that contain some of these “natural” ingredients, and patients need to be queried about the use of these products. CAM products can complicate traditional patient management, either when used alone or in combination with prescription drugs.

A clinically significant drug interaction that bears its own warning is that of warfarin and chondroitin/glucosamine. Patients might not tell you that they are taking chondroitin/glucosamine, so you have to ask. Functional foods and beverages that include “natural” ingredients, such as glucosamine and chondroitin, and other CAM abound. Examples include Joint Juice (1,500 mg glucosamine), Vitamin Water, and others.3

Two case reports, and a report from the World Health Organization (WHO) Collaborating Center for International Drug Monitoring, and the MedWatch database point to a potentially serious drug interaction between glucosamine and warfarin.4-7 Although not FDA approved for joint supplementation, the usual daily dose should generally not exceed 1.5 grams of glucosamine and 1.2 grams of chondroitin. Chondroitin may have anti-coagulant activity, which would explain the increase in International Normalized Ratio (INR) seen in patients using it in combination with warfarin. The WHO database identified at least 34 cases of concomitant use, with most cases of increased INR resolving upon glucosamine discontinuation. Nine cases required physician intervention, and in one case a positive rechallenge was documented. In June 2007, there were 81 cases of a possible interaction from the MedWatch database, of these, 61 cases had potential alternate etiologies. Of the 20 possibly-related cases, five led to patient hospitalization due to bleeding complications; the median patient age was 62 years and there were no deaths reported.

Ramsay et al. reported from a United Kingdom survey that 92% of patients admitted to taking herbal medicines while receiving warfarin, noting that significant numbers of patients are in need of close monitoring. They also note that other CAM can interact with warfarin to increase bleeding time or act as anti-platelet agents (e.g., high dose vitamin E [> 400 IU], fish oils, garlic, St. John’s Wort, etc.) They particularly note that all patients receiving warfarin or that will be commencing warfarin be specifically asked about their use of CAM. The mechanism for this interaction still is unclear, but may be due to the inhibition of warfarin metabolism by the CYP2C9 or CYP3A4 enzymes, or a pharmacodynamic interaction between glucosamine and warfarin.

It is critical all patients, particularly those taking warfarin, have a full drug history at all hospitalizations. Make sure you inquire about vitamins and other supplements/CAM. If someone else is doing the intake medication history, make sure they get this information. A nurse might not think to ask. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

References

1. Taylor DM, Walsham N, Taylor SE, Wong LF. Complementary and alternative medicines versus prescription drugs: perceptions of emergency department patients. Emerg Med J. 2006;23:266-268.

2. Eisenberg DM, Kessler RC, Van Rompay MI, et al.. Perceptions about complementary therapies relative to conventional therapies among adults how use both: results from a national survey. Ann Intern Med. 2001;135:344-351.

3. What is Joint Juice? Joint Juice, Inc. www.jointjuice.com/jointjuice.php. Published 1997. Accessed August 1, 2008.

4. Rozenfeld V, Crain JL, Callahan AK. Possible augmentation of warfarin effect by glucosamine-chondroitin. Am J Health-Syst Pharm. 2004;61:306-307.

5. Knudsen JF, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: case report and review of the literature and medwatch database. Pharmacother. 2008;28(4):540-548.

6. Ramsay NA, Kenny MW, Davies G, Patel JP. Complimentary and alternative medicine use among patients starting warfarin. Br J Haematology. 2005;130:777-780.

7. Yue Q-Y, Strandell J, Myrberg O. Concomitant use of glucosamine may potentiate the effect of warfarin. The Uppsalla Monitoring Centre Web site. www.who-umc.org/graphics/9722.pdf; Accessed August 1, 2008.

Complementary and alterative medicine (CAM) is defined as any product, including herbal remedies/foods/teas, vitamins, minerals, and natural products, that can be purchased without a prescription at a health food store, supermarket, from a magazine/newspaper or online, for self-treatment.1

Taylor et al. evaluated CAM perceptions of emergency department patients in Australia. They determined 44% of patients felt that by using CAM they were “drug free,” with 29% of patients agreeing (or strongly agreeing) CAM use is always safe to take with prescription medications. In an earlier study, Eisenberg et al. evaluated CAM use perceptions in the United States and found 79% of patients felt that, combined with prescription drugs, CAM was superior to either modality alone.2 They also found 63% to 72% of CAM-using patients that had seen a medical doctor in the prior year did not disclose the therapy.

The two most common reasons cited by patients were “they felt it wasn’t important for the doctor to know (61%)” and “the doctor didn’t ask (60%).” Overall, national CAM-use surveys have revealed that about 80% of adults typically do not disclose CAM use to medical doctors.

It is, therefore, imperative that physicians ask patients about their CAM use. It also is important to remember there are more foods and beverages that contain some of these “natural” ingredients, and patients need to be queried about the use of these products. CAM products can complicate traditional patient management, either when used alone or in combination with prescription drugs.

A clinically significant drug interaction that bears its own warning is that of warfarin and chondroitin/glucosamine. Patients might not tell you that they are taking chondroitin/glucosamine, so you have to ask. Functional foods and beverages that include “natural” ingredients, such as glucosamine and chondroitin, and other CAM abound. Examples include Joint Juice (1,500 mg glucosamine), Vitamin Water, and others.3

Two case reports, and a report from the World Health Organization (WHO) Collaborating Center for International Drug Monitoring, and the MedWatch database point to a potentially serious drug interaction between glucosamine and warfarin.4-7 Although not FDA approved for joint supplementation, the usual daily dose should generally not exceed 1.5 grams of glucosamine and 1.2 grams of chondroitin. Chondroitin may have anti-coagulant activity, which would explain the increase in International Normalized Ratio (INR) seen in patients using it in combination with warfarin. The WHO database identified at least 34 cases of concomitant use, with most cases of increased INR resolving upon glucosamine discontinuation. Nine cases required physician intervention, and in one case a positive rechallenge was documented. In June 2007, there were 81 cases of a possible interaction from the MedWatch database, of these, 61 cases had potential alternate etiologies. Of the 20 possibly-related cases, five led to patient hospitalization due to bleeding complications; the median patient age was 62 years and there were no deaths reported.

Ramsay et al. reported from a United Kingdom survey that 92% of patients admitted to taking herbal medicines while receiving warfarin, noting that significant numbers of patients are in need of close monitoring. They also note that other CAM can interact with warfarin to increase bleeding time or act as anti-platelet agents (e.g., high dose vitamin E [> 400 IU], fish oils, garlic, St. John’s Wort, etc.) They particularly note that all patients receiving warfarin or that will be commencing warfarin be specifically asked about their use of CAM. The mechanism for this interaction still is unclear, but may be due to the inhibition of warfarin metabolism by the CYP2C9 or CYP3A4 enzymes, or a pharmacodynamic interaction between glucosamine and warfarin.

It is critical all patients, particularly those taking warfarin, have a full drug history at all hospitalizations. Make sure you inquire about vitamins and other supplements/CAM. If someone else is doing the intake medication history, make sure they get this information. A nurse might not think to ask. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

References

1. Taylor DM, Walsham N, Taylor SE, Wong LF. Complementary and alternative medicines versus prescription drugs: perceptions of emergency department patients. Emerg Med J. 2006;23:266-268.

2. Eisenberg DM, Kessler RC, Van Rompay MI, et al.. Perceptions about complementary therapies relative to conventional therapies among adults how use both: results from a national survey. Ann Intern Med. 2001;135:344-351.

3. What is Joint Juice? Joint Juice, Inc. www.jointjuice.com/jointjuice.php. Published 1997. Accessed August 1, 2008.

4. Rozenfeld V, Crain JL, Callahan AK. Possible augmentation of warfarin effect by glucosamine-chondroitin. Am J Health-Syst Pharm. 2004;61:306-307.

5. Knudsen JF, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: case report and review of the literature and medwatch database. Pharmacother. 2008;28(4):540-548.

6. Ramsay NA, Kenny MW, Davies G, Patel JP. Complimentary and alternative medicine use among patients starting warfarin. Br J Haematology. 2005;130:777-780.

7. Yue Q-Y, Strandell J, Myrberg O. Concomitant use of glucosamine may potentiate the effect of warfarin. The Uppsalla Monitoring Centre Web site. www.who-umc.org/graphics/9722.pdf; Accessed August 1, 2008.

Most of us learned in our professional training that neuroleptic agents cause movement disorders, or extrapyramidal symptoms (EPS).1 Neuroleptics, the older class of antipsychotic agents, which includes dopamine receptor blocking agents (DRBA), can cause tardive dyskinesia (TD), dystonia, akathisia, and Parkinsonism.

We also learned that newer antipsychotic agents, the so-called second-generation antipsychotics, do not cause EPS. However, dose-related EPS has been associated with olanzapine and risperidone use (> 6 mg/day doses), and there have been two reported cases of aripiprazole-induced EPS.2,3

So which symptoms indicate a drug-induced movement disorder (DIMD)? Patients with DIMDs have difficulty with social functioning, motor-task performance, interpersonal communication, and activities of daily living. They also are less likely to adhere to a medication regimen, making disease relapse and rehospitalization more likely.

Some DIMDs are worse than others. Neuroleptic-induced TD, for example, is in some cases irreversible and can lead to functional impairment so severe a patient cannot feed himself, speak clearly, or breathe easily. In addition, removal of the offending agent does not always resolve TD.4

Milder forms of neuroleptic-induced TD occur in about 20% of patients. In higher risk groups, such as older patients, milder forms of neuroleptic-induced TD may exceed 50%.

DIMDs often elude diagnosis by clinicians, partially because they look like other medical conditions such as restless legs syndrome, agitation, or drug withdrawal. Clinicians who understand the most likely DIMD culprits and the effect of each can better manage their patients. It’s also crucial for clinicians to pay attention to

• Patient stress and anxiety levels, as both of these can exacerbate DIMD symptoms;
• Patient drug history; and
• Demographic information. Older women are most likely to develop tardive dyskinesia. Young men more commonly experience dystonic reactions. The elderly are at higher risk for Parkinsonism and akathisia.

Clinicians must watch for DIMD in any patient who has taken antipsychotics. Symptoms can occur within hours to days (acute), weeks (subacute) or even months to years (tardive) following exposure.

The Agents

Causative DRBAs include:

• Haloperidol;
• Thioridazine;
• Perphenazine;
• Droperidol;
• Metoclopramide;
• Prochlorperazine; and
• Promethazine.

DIMDs can also occur from:

• Lithium, which can cause tremors or chorea;
• Stimulants (e.g., amphetamines), which can cause tremor, tics, dystonia, and dyskinesia;
• Selective-serotonin reuptake inhibitors (SSRIs), which can cause tremors, akathisia, and possible dyskinesia, dystonia, and Parkinsonism;
• Tricyclic antidepressants (TCAs) (e.g., amitriptyline, nortriptyline, etc), which can cause myoclonus and tremors;
• Valproic acid, which causes tremors; and
• Cyclosporine A, which was implicated in one study as causing tremors and Parkinsonism.6

Management

For neuroleptics, withdrawal of the offending agent may lead to partial improvement in about half of patients. The outcome, of course, depends on the DIMD.

Early detection of TD is important to improve remission rates, which are inversely related to the disorder’s duration and severity. To treat, gradually taper the patient off the medication. It may take as long as two years after discontinuation for the condition to resolve itself. Continually re-evaluate how much a patient needs this agent. There may be another that’s just as effective but with a lower TD incidence. 7

Treat acute dystonic reactions with a short course of a potent antimuscarinic agent such as oral, intravenous (IV), or intramuscular benztropine, or diphenhydramine. If the patient’s reaction is life-threatening, use IV administration of an antimuscarinic agent and supportive measures. In some cases, you can use benzodiazepines in place of antimuscarinic agents. For tardive dystonia, prevention is the most important treatment since few pharmacologic treatments have proven efficacy.

Prevention also is the key to managing akathisia. To prevent this manifestation, prescribe atypical antipsychotics or use a standardized dose titration to avoid excessive dose escalation. In high-risk patients, consider prophylactic treatment with diphenhydramine or benztropine. Other potentially useful agents include benzodiazepines, propranolol, or cyproheptadine. For acute reactions, remove the causative agent.

Treat drug-induced Parkinsonism by withdrawing the causative agent or reducing the dose, switching to an atypical antipsychotic (if neuroleptic-induced), and possibly prescribing a trial of amantadine, an antimuscarinic agent, a dopamine agonist, or levodopa.

Though antiemetics and conventional antipsychotics are most commonly implicated, other agents also cause DIMDs. To prevent and treat these disorders, clinicians need to be particularly aware of the causative agents and symptoms. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

References

1. Chen JJ. Drug-induced Movement Disorders. Journal of Pharmacy Practice. 2007; 20(6):415-429.
2. Zacher JL, Hatchett AD. Aripiprazole-induced movement disorder. Am J Psychiatry. 2006;163:160-161[letter].
3. Sajbel TA, Cheney EM, DeQuardo JR. Aripiprazole-associated dyskinesia. Ann Pharmacother. 2005;39:200-201[letter].
4. Lee PE, Synkora K, Gill SS., et al. Antipsychotic medications and drug-induced movement disorders other than Parkinsonism: A population-based cohort study in older adults. J Am Geriatr Soc. 2005;53:1374-1379.
5. Munhoz RP, Teive HAG, Germiniani FMB et al. Movement disorders secondary to long-term treatment with cyclosporine A. Arq Neuropsiquiatr. 2005;63(3-A)L592-596.
6. Vernon, Gwen M. Drug-Induced & Tardive Movement Disorders. National Alliance for the Mentally Ill, July 2001.www.namiscc.org/newsletters/July01/tardive.htm

Most of us learned in our professional training that neuroleptic agents cause movement disorders, or extrapyramidal symptoms (EPS).1 Neuroleptics, the older class of antipsychotic agents, which includes dopamine receptor blocking agents (DRBA), can cause tardive dyskinesia (TD), dystonia, akathisia, and Parkinsonism.

We also learned that newer antipsychotic agents, the so-called second-generation antipsychotics, do not cause EPS. However, dose-related EPS has been associated with olanzapine and risperidone use (> 6 mg/day doses), and there have been two reported cases of aripiprazole-induced EPS.2,3

So which symptoms indicate a drug-induced movement disorder (DIMD)? Patients with DIMDs have difficulty with social functioning, motor-task performance, interpersonal communication, and activities of daily living. They also are less likely to adhere to a medication regimen, making disease relapse and rehospitalization more likely.

Some DIMDs are worse than others. Neuroleptic-induced TD, for example, is in some cases irreversible and can lead to functional impairment so severe a patient cannot feed himself, speak clearly, or breathe easily. In addition, removal of the offending agent does not always resolve TD.4

Milder forms of neuroleptic-induced TD occur in about 20% of patients. In higher risk groups, such as older patients, milder forms of neuroleptic-induced TD may exceed 50%.

DIMDs often elude diagnosis by clinicians, partially because they look like other medical conditions such as restless legs syndrome, agitation, or drug withdrawal. Clinicians who understand the most likely DIMD culprits and the effect of each can better manage their patients. It’s also crucial for clinicians to pay attention to

• Patient stress and anxiety levels, as both of these can exacerbate DIMD symptoms;
• Patient drug history; and
• Demographic information. Older women are most likely to develop tardive dyskinesia. Young men more commonly experience dystonic reactions. The elderly are at higher risk for Parkinsonism and akathisia.

Clinicians must watch for DIMD in any patient who has taken antipsychotics. Symptoms can occur within hours to days (acute), weeks (subacute) or even months to years (tardive) following exposure.

The Agents

Causative DRBAs include:

• Haloperidol;
• Thioridazine;
• Perphenazine;
• Droperidol;
• Metoclopramide;
• Prochlorperazine; and
• Promethazine.

DIMDs can also occur from:

• Lithium, which can cause tremors or chorea;
• Stimulants (e.g., amphetamines), which can cause tremor, tics, dystonia, and dyskinesia;
• Selective-serotonin reuptake inhibitors (SSRIs), which can cause tremors, akathisia, and possible dyskinesia, dystonia, and Parkinsonism;
• Tricyclic antidepressants (TCAs) (e.g., amitriptyline, nortriptyline, etc), which can cause myoclonus and tremors;
• Valproic acid, which causes tremors; and
• Cyclosporine A, which was implicated in one study as causing tremors and Parkinsonism.6

Management

For neuroleptics, withdrawal of the offending agent may lead to partial improvement in about half of patients. The outcome, of course, depends on the DIMD.

Early detection of TD is important to improve remission rates, which are inversely related to the disorder’s duration and severity. To treat, gradually taper the patient off the medication. It may take as long as two years after discontinuation for the condition to resolve itself. Continually re-evaluate how much a patient needs this agent. There may be another that’s just as effective but with a lower TD incidence. 7

Treat acute dystonic reactions with a short course of a potent antimuscarinic agent such as oral, intravenous (IV), or intramuscular benztropine, or diphenhydramine. If the patient’s reaction is life-threatening, use IV administration of an antimuscarinic agent and supportive measures. In some cases, you can use benzodiazepines in place of antimuscarinic agents. For tardive dystonia, prevention is the most important treatment since few pharmacologic treatments have proven efficacy.

Prevention also is the key to managing akathisia. To prevent this manifestation, prescribe atypical antipsychotics or use a standardized dose titration to avoid excessive dose escalation. In high-risk patients, consider prophylactic treatment with diphenhydramine or benztropine. Other potentially useful agents include benzodiazepines, propranolol, or cyproheptadine. For acute reactions, remove the causative agent.

Treat drug-induced Parkinsonism by withdrawing the causative agent or reducing the dose, switching to an atypical antipsychotic (if neuroleptic-induced), and possibly prescribing a trial of amantadine, an antimuscarinic agent, a dopamine agonist, or levodopa.

Though antiemetics and conventional antipsychotics are most commonly implicated, other agents also cause DIMDs. To prevent and treat these disorders, clinicians need to be particularly aware of the causative agents and symptoms. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

References

1. Chen JJ. Drug-induced Movement Disorders. Journal of Pharmacy Practice. 2007; 20(6):415-429.
2. Zacher JL, Hatchett AD. Aripiprazole-induced movement disorder. Am J Psychiatry. 2006;163:160-161[letter].
3. Sajbel TA, Cheney EM, DeQuardo JR. Aripiprazole-associated dyskinesia. Ann Pharmacother. 2005;39:200-201[letter].
4. Lee PE, Synkora K, Gill SS., et al. Antipsychotic medications and drug-induced movement disorders other than Parkinsonism: A population-based cohort study in older adults. J Am Geriatr Soc. 2005;53:1374-1379.
5. Munhoz RP, Teive HAG, Germiniani FMB et al. Movement disorders secondary to long-term treatment with cyclosporine A. Arq Neuropsiquiatr. 2005;63(3-A)L592-596.
6. Vernon, Gwen M. Drug-Induced & Tardive Movement Disorders. National Alliance for the Mentally Ill, July 2001.www.namiscc.org/newsletters/July01/tardive.htm

Most of us learned in our professional training that neuroleptic agents cause movement disorders, or extrapyramidal symptoms (EPS).1 Neuroleptics, the older class of antipsychotic agents, which includes dopamine receptor blocking agents (DRBA), can cause tardive dyskinesia (TD), dystonia, akathisia, and Parkinsonism.

We also learned that newer antipsychotic agents, the so-called second-generation antipsychotics, do not cause EPS. However, dose-related EPS has been associated with olanzapine and risperidone use (> 6 mg/day doses), and there have been two reported cases of aripiprazole-induced EPS.2,3

So which symptoms indicate a drug-induced movement disorder (DIMD)? Patients with DIMDs have difficulty with social functioning, motor-task performance, interpersonal communication, and activities of daily living. They also are less likely to adhere to a medication regimen, making disease relapse and rehospitalization more likely.

Some DIMDs are worse than others. Neuroleptic-induced TD, for example, is in some cases irreversible and can lead to functional impairment so severe a patient cannot feed himself, speak clearly, or breathe easily. In addition, removal of the offending agent does not always resolve TD.4

Milder forms of neuroleptic-induced TD occur in about 20% of patients. In higher risk groups, such as older patients, milder forms of neuroleptic-induced TD may exceed 50%.

DIMDs often elude diagnosis by clinicians, partially because they look like other medical conditions such as restless legs syndrome, agitation, or drug withdrawal. Clinicians who understand the most likely DIMD culprits and the effect of each can better manage their patients. It’s also crucial for clinicians to pay attention to

• Patient stress and anxiety levels, as both of these can exacerbate DIMD symptoms;
• Patient drug history; and
• Demographic information. Older women are most likely to develop tardive dyskinesia. Young men more commonly experience dystonic reactions. The elderly are at higher risk for Parkinsonism and akathisia.

Clinicians must watch for DIMD in any patient who has taken antipsychotics. Symptoms can occur within hours to days (acute), weeks (subacute) or even months to years (tardive) following exposure.

The Agents

Causative DRBAs include:

• Haloperidol;
• Thioridazine;
• Perphenazine;
• Droperidol;
• Metoclopramide;
• Prochlorperazine; and
• Promethazine.

DIMDs can also occur from:

• Lithium, which can cause tremors or chorea;
• Stimulants (e.g., amphetamines), which can cause tremor, tics, dystonia, and dyskinesia;
• Selective-serotonin reuptake inhibitors (SSRIs), which can cause tremors, akathisia, and possible dyskinesia, dystonia, and Parkinsonism;
• Tricyclic antidepressants (TCAs) (e.g., amitriptyline, nortriptyline, etc), which can cause myoclonus and tremors;
• Valproic acid, which causes tremors; and
• Cyclosporine A, which was implicated in one study as causing tremors and Parkinsonism.6

Management

For neuroleptics, withdrawal of the offending agent may lead to partial improvement in about half of patients. The outcome, of course, depends on the DIMD.

Early detection of TD is important to improve remission rates, which are inversely related to the disorder’s duration and severity. To treat, gradually taper the patient off the medication. It may take as long as two years after discontinuation for the condition to resolve itself. Continually re-evaluate how much a patient needs this agent. There may be another that’s just as effective but with a lower TD incidence. 7

Treat acute dystonic reactions with a short course of a potent antimuscarinic agent such as oral, intravenous (IV), or intramuscular benztropine, or diphenhydramine. If the patient’s reaction is life-threatening, use IV administration of an antimuscarinic agent and supportive measures. In some cases, you can use benzodiazepines in place of antimuscarinic agents. For tardive dystonia, prevention is the most important treatment since few pharmacologic treatments have proven efficacy.

Prevention also is the key to managing akathisia. To prevent this manifestation, prescribe atypical antipsychotics or use a standardized dose titration to avoid excessive dose escalation. In high-risk patients, consider prophylactic treatment with diphenhydramine or benztropine. Other potentially useful agents include benzodiazepines, propranolol, or cyproheptadine. For acute reactions, remove the causative agent.

Treat drug-induced Parkinsonism by withdrawing the causative agent or reducing the dose, switching to an atypical antipsychotic (if neuroleptic-induced), and possibly prescribing a trial of amantadine, an antimuscarinic agent, a dopamine agonist, or levodopa.

Though antiemetics and conventional antipsychotics are most commonly implicated, other agents also cause DIMDs. To prevent and treat these disorders, clinicians need to be particularly aware of the causative agents and symptoms. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

References

1. Chen JJ. Drug-induced Movement Disorders. Journal of Pharmacy Practice. 2007; 20(6):415-429.
2. Zacher JL, Hatchett AD. Aripiprazole-induced movement disorder. Am J Psychiatry. 2006;163:160-161[letter].
3. Sajbel TA, Cheney EM, DeQuardo JR. Aripiprazole-associated dyskinesia. Ann Pharmacother. 2005;39:200-201[letter].
4. Lee PE, Synkora K, Gill SS., et al. Antipsychotic medications and drug-induced movement disorders other than Parkinsonism: A population-based cohort study in older adults. J Am Geriatr Soc. 2005;53:1374-1379.
5. Munhoz RP, Teive HAG, Germiniani FMB et al. Movement disorders secondary to long-term treatment with cyclosporine A. Arq Neuropsiquiatr. 2005;63(3-A)L592-596.
6. Vernon, Gwen M. Drug-Induced & Tardive Movement Disorders. National Alliance for the Mentally Ill, July 2001.www.namiscc.org/newsletters/July01/tardive.htm

A healthy 30-year-old female presented to the urgent care center with confusion, tremor, and a blood pressure of 160/110 mm Hg. She had no history of hypertension, diabetes, dyslipidemia, renal dysfunction, or smoking. A basic metabolic panel revealed no abnormalities.

Her medication history revealed use of paroxetine (20 mg) subsequent to a depressive episode two years prior. A source of the hypertension was not identified, and she was sent home without further follow-up. The next day, she was admitted to the hospital via the emergency department for stroke symptoms, including numbness and weakness on her right side (extremities and face), with confusion and diplopia. She remained hospitalized for four days during which time she continued to experience transient ischemic attacks. The paroxetine eventually was discontinued. She subsequently has recovered without negative sequelae.

Serotonin syndrome is a consequence of a hyperserotonergic state, due to drug-induced serotonin intensification.1 It can be mild or life-threatening and is characterized by a triad of clinical manifestations: mental status changes, autonomic hyperactivity, and neuromuscular abnormalities.2 Clinicians may miss mild symptoms, such as diarrhea, tremor, tachycardia, diaphoresis, or mydriasis. This can result in an increase in the dose of the causative agent or addition of a serotonergic agent, thus yielding a worsening clinical decline.3

Patients with a more severe clinical presentation include those with severe hypertension (as in the case above), tachycardia, muscular rigidity, and shock. Laboratory abnormalities may be present if the patient develops subsequent rhabdomyolysis, seizures, metabolic acidosis, or renal failure. Serotonin syndrome is diagnosed based on the patient’s presentation, history, and physical examination. It should be differentiated from neuroleptic malignant syndrome, which has a similar presentation.4

Serotonergic agents used alone, or in combination, may lead to serotonin syndrome.5 A recent report discussed the appearance of serotonin syndrome in patients receiving only sumatriptan. Other offenders include such antidepressants as monoamine oxidase inhibitors, buspirone, citalopram, clomipramine, escitalopram, fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine. Other causative agents include dextromethorphan, fentanyl, granisetron, levodopa, linezolid, lithium, meperidine, metoclopramide, ondansetron, pentazocine, sibutramine, sumatriptan, tramadol, valproate, and drugs of abuse (e.g., amphetamines, cocaine, LSD, ecstasy). Additionally, ginseng, St. John’s Wort, and tryptophan have been implicated.

Many of these agents require an adequate washout period prior to beginning other serotonergic agents. Mild to moderately severe cases usually resolve within 24 to 72 hours, although most resolve within a week depending on the half-life of the medication. Serotonin syndrome carries an 11% mortality rate and is best managed by stopping the offending agent and providing supportive care. TH

Michele B. Kaufman is a freelance medical writer based in New York City.

References

1. Sorenson S. Serotonin syndrome. UTox Update 2002;4(4):1-2. A Publication of the Utah Poison Control Center for Health Professionals. Available at http://uuhsc.utah.edu/poison/healthpros/utox/vol4_no4.pdf. Last accessed June 20, 2008.
2. Soldin OP, Tonning JM. Serotonin syndrome associated with triptan monotherapy. N Engl J Med. 2008;358(20):2185-2186.
3. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
4. Nolan S, Scoggin JA. Serotonin syndrome: recognition and management. US Pharm. 2002;23(2). www.uspharmacist.com/oldformat.asp?url=newlook/files/feat/acf2fa6.htm. Last accessed June 20, 2008.
5. Mayo Clinic.com. Diseases and conditions. www.mayoclinic.com/health/serotonin-syndrome/DS00860. Last accessed June 20, 2008.

    

A healthy 30-year-old female presented to the urgent care center with confusion, tremor, and a blood pressure of 160/110 mm Hg. She had no history of hypertension, diabetes, dyslipidemia, renal dysfunction, or smoking. A basic metabolic panel revealed no abnormalities.

Her medication history revealed use of paroxetine (20 mg) subsequent to a depressive episode two years prior. A source of the hypertension was not identified, and she was sent home without further follow-up. The next day, she was admitted to the hospital via the emergency department for stroke symptoms, including numbness and weakness on her right side (extremities and face), with confusion and diplopia. She remained hospitalized for four days during which time she continued to experience transient ischemic attacks. The paroxetine eventually was discontinued. She subsequently has recovered without negative sequelae.

Serotonin syndrome is a consequence of a hyperserotonergic state, due to drug-induced serotonin intensification.1 It can be mild or life-threatening and is characterized by a triad of clinical manifestations: mental status changes, autonomic hyperactivity, and neuromuscular abnormalities.2 Clinicians may miss mild symptoms, such as diarrhea, tremor, tachycardia, diaphoresis, or mydriasis. This can result in an increase in the dose of the causative agent or addition of a serotonergic agent, thus yielding a worsening clinical decline.3

Patients with a more severe clinical presentation include those with severe hypertension (as in the case above), tachycardia, muscular rigidity, and shock. Laboratory abnormalities may be present if the patient develops subsequent rhabdomyolysis, seizures, metabolic acidosis, or renal failure. Serotonin syndrome is diagnosed based on the patient’s presentation, history, and physical examination. It should be differentiated from neuroleptic malignant syndrome, which has a similar presentation.4

Serotonergic agents used alone, or in combination, may lead to serotonin syndrome.5 A recent report discussed the appearance of serotonin syndrome in patients receiving only sumatriptan. Other offenders include such antidepressants as monoamine oxidase inhibitors, buspirone, citalopram, clomipramine, escitalopram, fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine. Other causative agents include dextromethorphan, fentanyl, granisetron, levodopa, linezolid, lithium, meperidine, metoclopramide, ondansetron, pentazocine, sibutramine, sumatriptan, tramadol, valproate, and drugs of abuse (e.g., amphetamines, cocaine, LSD, ecstasy). Additionally, ginseng, St. John’s Wort, and tryptophan have been implicated.

Many of these agents require an adequate washout period prior to beginning other serotonergic agents. Mild to moderately severe cases usually resolve within 24 to 72 hours, although most resolve within a week depending on the half-life of the medication. Serotonin syndrome carries an 11% mortality rate and is best managed by stopping the offending agent and providing supportive care. TH

Michele B. Kaufman is a freelance medical writer based in New York City.

References

1. Sorenson S. Serotonin syndrome. UTox Update 2002;4(4):1-2. A Publication of the Utah Poison Control Center for Health Professionals. Available at http://uuhsc.utah.edu/poison/healthpros/utox/vol4_no4.pdf. Last accessed June 20, 2008.
2. Soldin OP, Tonning JM. Serotonin syndrome associated with triptan monotherapy. N Engl J Med. 2008;358(20):2185-2186.
3. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
4. Nolan S, Scoggin JA. Serotonin syndrome: recognition and management. US Pharm. 2002;23(2). www.uspharmacist.com/oldformat.asp?url=newlook/files/feat/acf2fa6.htm. Last accessed June 20, 2008.
5. Mayo Clinic.com. Diseases and conditions. www.mayoclinic.com/health/serotonin-syndrome/DS00860. Last accessed June 20, 2008.

    

A healthy 30-year-old female presented to the urgent care center with confusion, tremor, and a blood pressure of 160/110 mm Hg. She had no history of hypertension, diabetes, dyslipidemia, renal dysfunction, or smoking. A basic metabolic panel revealed no abnormalities.

Her medication history revealed use of paroxetine (20 mg) subsequent to a depressive episode two years prior. A source of the hypertension was not identified, and she was sent home without further follow-up. The next day, she was admitted to the hospital via the emergency department for stroke symptoms, including numbness and weakness on her right side (extremities and face), with confusion and diplopia. She remained hospitalized for four days during which time she continued to experience transient ischemic attacks. The paroxetine eventually was discontinued. She subsequently has recovered without negative sequelae.

Serotonin syndrome is a consequence of a hyperserotonergic state, due to drug-induced serotonin intensification.1 It can be mild or life-threatening and is characterized by a triad of clinical manifestations: mental status changes, autonomic hyperactivity, and neuromuscular abnormalities.2 Clinicians may miss mild symptoms, such as diarrhea, tremor, tachycardia, diaphoresis, or mydriasis. This can result in an increase in the dose of the causative agent or addition of a serotonergic agent, thus yielding a worsening clinical decline.3

Patients with a more severe clinical presentation include those with severe hypertension (as in the case above), tachycardia, muscular rigidity, and shock. Laboratory abnormalities may be present if the patient develops subsequent rhabdomyolysis, seizures, metabolic acidosis, or renal failure. Serotonin syndrome is diagnosed based on the patient’s presentation, history, and physical examination. It should be differentiated from neuroleptic malignant syndrome, which has a similar presentation.4

Serotonergic agents used alone, or in combination, may lead to serotonin syndrome.5 A recent report discussed the appearance of serotonin syndrome in patients receiving only sumatriptan. Other offenders include such antidepressants as monoamine oxidase inhibitors, buspirone, citalopram, clomipramine, escitalopram, fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine. Other causative agents include dextromethorphan, fentanyl, granisetron, levodopa, linezolid, lithium, meperidine, metoclopramide, ondansetron, pentazocine, sibutramine, sumatriptan, tramadol, valproate, and drugs of abuse (e.g., amphetamines, cocaine, LSD, ecstasy). Additionally, ginseng, St. John’s Wort, and tryptophan have been implicated.

Many of these agents require an adequate washout period prior to beginning other serotonergic agents. Mild to moderately severe cases usually resolve within 24 to 72 hours, although most resolve within a week depending on the half-life of the medication. Serotonin syndrome carries an 11% mortality rate and is best managed by stopping the offending agent and providing supportive care. TH

Michele B. Kaufman is a freelance medical writer based in New York City.

References

1. Sorenson S. Serotonin syndrome. UTox Update 2002;4(4):1-2. A Publication of the Utah Poison Control Center for Health Professionals. Available at http://uuhsc.utah.edu/poison/healthpros/utox/vol4_no4.pdf. Last accessed June 20, 2008.
2. Soldin OP, Tonning JM. Serotonin syndrome associated with triptan monotherapy. N Engl J Med. 2008;358(20):2185-2186.
3. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
4. Nolan S, Scoggin JA. Serotonin syndrome: recognition and management. US Pharm. 2002;23(2). www.uspharmacist.com/oldformat.asp?url=newlook/files/feat/acf2fa6.htm. Last accessed June 20, 2008.
5. Mayo Clinic.com. Diseases and conditions. www.mayoclinic.com/health/serotonin-syndrome/DS00860. Last accessed June 20, 2008.

    

It’s been an active summer for pharmaceutical firms, who’ve been particularly busy adding and removing products from the marketplace and providing fresh information to professional users. Here’s a roundup of vital information that has emerged.

Market Withdrawals

Because of an increased risk of death associated with aprotinin injection (Trasylol) compared with either aminocaproic acid or tranexamic acid, Bayer Pharmaceuticals has removed all remaining stocks of the agent from the U.S. market. Subsequent access to aprotinin injection will be limited to investigational use based on a special treatment protocol. For more information on this, call (888) 842-2937.

Meanwhile, nedocromil sodium inhalation aerosol (Tilade) has been discontinued. Once current supplies are depleted from pharmacies, it no longer will be available. A number of factors led to the decision, including the inability to find a qualified manufacturer of the chlorofluorocarbon propellant.

New Approvals

Certolizumab pegol (Cimzia) injection has been approved by the Food and Drug Administration (FDA) to treat adults with moderate to severe Crohn’s disease who have not responded to conventional therapies. It is a pegylated tumor necrosis factor antagonist. The most common side effects are headache, upper respiratory infections, abdominal pain, injection site reactions, and nausea. It is dosed as an initial 400 mg SC injection followed by 400 mg SC injections at weeks two and our.

A maintenance regimen of 400 mg subcutaneous every four weeks is recommended for patients who obtain a clinical response after the initial three injections. The drug is available as a package that includes everything required to reconstitute and inject the drug (also two vials of drug, each with 200 mg Cimzia). Patients need to be evaluated for increased infection risk and opportunistic infections. Patients should be screened for tuberculosis prior to commencing therapy.

Desvenlafaxine 50 mg tablets (Pristiq), a serotonin-norepinephrine reuptake inhibitor (SNRI), have been FDA approved for the treatment of adults with major depressive disorder. It is dosed once daily. To reach the therapeutic dose, titration is unnecessary. Dose adjustments are necessary for severe renal impairment or end-stage renal disease patients, where the dose should be adjusted to 50 mg every other day. Nausea, dizziness, hyperhidrosis, constipation, and decreased appetite are the most common side effects.

Lubiprostone capsules (Amitiza) have been FDA approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in women 18 or older. Common side effects are nausea, diarrhea, and abdominal pain. It is dosed as 8 mcg twice a day with food and water. Patients should be periodically assessed for therapy continuation need.

Methylnaltrexone bromide (Relistor) has been FDA approved to assist in restoring bowel function in patients who are continuously receiving opioids for pain management and have late-stage, advanced illness. It works by blocking opioid entrance into smooth muscle. It is administered by injection as often as needed, but not to exceed more than one dose in a 24-hour period.

New Indications

Aripiprazole (Abilify) has received a number of new indications from the FDA, mostly in adolescents and children. In adults, it has received approval as an adjunctive treatment to either lithium or valproate for patients age 10 or older with manic and mixed episodes associated with bipolar I disorder with or without psychotic features. When used as monotherapy for bipolar I disorder in adults, the recommended starting dose for these indications in adults is 15 mg/day with a target dose of 30 mg/day.

Other new indications include:

• Lisdexamfetamine dimesylate (Vyvanse) once-daily prodrug of dexamphetamine has been FDA approved for the treatment of attention deficit/hyperactivity disorder (ADHD) in adults;
• Olopatadine hydrochloride (available as the ocular product Patanol) is now available as a nasal spray (Patanase). It was FDA approved for treatment of the symptoms of seasonal allergic rhinitis in patients age 12 or older;
• Quetiapine (Seroquel) has been FDA approved for maintenance treatment in patients with bipolar I disorder. Quetiapine was already approved for the treatment of schizophrenia and depressive or manic episodes; and
• Risedronate sodium 150 mg tablets (Actonel) have been FDA approved as a once-monthly dose to treat postmenopausal osteoporosis.

New Information

Varicella zoster vaccine, live, attenuated (Zostavax): The Centers for Disease Control and Prevention recommends that all adults age 60 or older be vaccinated against herpes zoster with this new vaccine. The recommendation includes patients with a prior shingles episode and those with chronic medical conditions.

Zoster vaccination is not indicated to treat acute zoster, to prevent people with acute zoster from developing post-herpetic neuralgia (PHN), or to treat ongoing PHN. Before administering zoster vaccine, patients do not need to be asked about their history of varicella (chickenpox) or to have varicella immunity testing. It is administered as a single subcutaneous 0.65 mL dose in the deltoid region of the arm. A booster dose is not licensed for the vaccine.

Medication Error Warning

The Institute for Safe Medication Practices (ISMP) has described increased reports of mixups between U-100 and U-500 insulin. These errors can result in dangerous hyperglycemia or hypoglycemia. Mistakes have occurred when prescribers accidentally selected U-500 regular insulin (R) from computer order entry screens instead of U-100.

Potential reasons for this error:

• The two dosage forms appear one line apart on the screen, making it easy to select the wrong one;
• Depending on the screen size, you may only see the first few words of the product listing, so the drug concentration may not be visible;
• Since use of U-500 insulin is uncommon, you may assume the only listed R insulin is U-100 and not look for the drug’s concentration.

ISMP suggests that use of U-500 insulin has increased due to the obesity epidemic, use in insulin pumps, and tight glucose control protocols in the hospital. ISMP says the major suppliers of these computer systems have agreed to add the word “concentrated” on their selection screens, after “insulin” and before U-500, which should help solve the problem.

New Warnings

The acquired immunodeficiency syndrome (AIDS) drugs abacavir (Ziagen) and didanosine (Videx) are being evaluated by the FDA for a possible link to increased risk of myocardial infarction (MI). This is related to the analyses of data collected from “The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study,” which is a large, international observational study of 33,347 HIV-1 infected patients evaluating short- and long-term adverse effects of anti-HIV treatments. The excess risk of MI in patients taking these agents appeared to be greater in patients with other heart disease risk factors. This is an ongoing review.

Meanwhile, the anemia drugs darbepoetin alfa (Aranesp) and epoetin alfa (Epogen/Procrit) have received a boxed warning regarding increased mortality and/or more rapid tumor progression in patients with cancer that are receiving these agents. The warnings section of the package labeling also was updated with additional study information.

Becaplermin gel (Regranex) is a recombinant form of human platelet-derived growth factor FDA approved for treating lower-extremity diabetic neuropathic ulcers. The FDA is evaluating the possibility of an increased cancer risk in diabetic patients who apply becaplermin gel directly to foot/leg ulcers. A recent study involving patients with no previous history of cancer had a greater risk of dying from cancer if they were prescribed becaplermin three or more times. The FDA believes there may be evidence of an increased cancer death risk in patients who had repeated becaplermin treatments.

Montelukast (Singulair) is undergoing a safety review regarding a possible association between it and behavior/mood changes, suicidality, and suicide. However, it may take up to nine months to complete the review. Other leukotriene receptor antagonists also are being evaluated (e.g., zafirlukast, zileuton).

Mycophenolate mofetil (MMF) and the ester of the active metabolite mycophenolic acid (MPA), known as Cellcept and Myfortic, have received an FDA alert regarding reports of infants born with serious congenital anomalies. These anomalies have included microtia, and cleft lip and palate. These women were taking these drugs to prevent organ rejection following transplant, however, some women were receiving the drugs to manage systemic lupus erythematosus (SLE), and erythema multiforme. These women were receiving the agents before their pregnancies and continued into the first trimester or until the pregnancy was detected. Both MMF and MPA increase the risk of spontaneous abortion in the first trimester and can cause congenital malformations in the children that received the drugs in utero.

The FDA and the manufacturer of natalizumab injection (Tysabri) have informed healthcare professionals of reports of clinically significant liver injury (e.g., markedly elevated serum hepatic enzymes, elevated total bilirubin) within six days of starting natalizumab. The agent is FDA approved to treat multiple sclerosis and Crohn’s Disease. Natalizumab should be discontinued in patients with jaundice or other evidence of significant liver injury. Physicians need to inform patients that natalizumab may cause liver injury. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

It’s been an active summer for pharmaceutical firms, who’ve been particularly busy adding and removing products from the marketplace and providing fresh information to professional users. Here’s a roundup of vital information that has emerged.

Market Withdrawals

Because of an increased risk of death associated with aprotinin injection (Trasylol) compared with either aminocaproic acid or tranexamic acid, Bayer Pharmaceuticals has removed all remaining stocks of the agent from the U.S. market. Subsequent access to aprotinin injection will be limited to investigational use based on a special treatment protocol. For more information on this, call (888) 842-2937.

Meanwhile, nedocromil sodium inhalation aerosol (Tilade) has been discontinued. Once current supplies are depleted from pharmacies, it no longer will be available. A number of factors led to the decision, including the inability to find a qualified manufacturer of the chlorofluorocarbon propellant.

New Approvals

Certolizumab pegol (Cimzia) injection has been approved by the Food and Drug Administration (FDA) to treat adults with moderate to severe Crohn’s disease who have not responded to conventional therapies. It is a pegylated tumor necrosis factor antagonist. The most common side effects are headache, upper respiratory infections, abdominal pain, injection site reactions, and nausea. It is dosed as an initial 400 mg SC injection followed by 400 mg SC injections at weeks two and our.

A maintenance regimen of 400 mg subcutaneous every four weeks is recommended for patients who obtain a clinical response after the initial three injections. The drug is available as a package that includes everything required to reconstitute and inject the drug (also two vials of drug, each with 200 mg Cimzia). Patients need to be evaluated for increased infection risk and opportunistic infections. Patients should be screened for tuberculosis prior to commencing therapy.

Desvenlafaxine 50 mg tablets (Pristiq), a serotonin-norepinephrine reuptake inhibitor (SNRI), have been FDA approved for the treatment of adults with major depressive disorder. It is dosed once daily. To reach the therapeutic dose, titration is unnecessary. Dose adjustments are necessary for severe renal impairment or end-stage renal disease patients, where the dose should be adjusted to 50 mg every other day. Nausea, dizziness, hyperhidrosis, constipation, and decreased appetite are the most common side effects.

Lubiprostone capsules (Amitiza) have been FDA approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in women 18 or older. Common side effects are nausea, diarrhea, and abdominal pain. It is dosed as 8 mcg twice a day with food and water. Patients should be periodically assessed for therapy continuation need.

Methylnaltrexone bromide (Relistor) has been FDA approved to assist in restoring bowel function in patients who are continuously receiving opioids for pain management and have late-stage, advanced illness. It works by blocking opioid entrance into smooth muscle. It is administered by injection as often as needed, but not to exceed more than one dose in a 24-hour period.

New Indications

Aripiprazole (Abilify) has received a number of new indications from the FDA, mostly in adolescents and children. In adults, it has received approval as an adjunctive treatment to either lithium or valproate for patients age 10 or older with manic and mixed episodes associated with bipolar I disorder with or without psychotic features. When used as monotherapy for bipolar I disorder in adults, the recommended starting dose for these indications in adults is 15 mg/day with a target dose of 30 mg/day.

Other new indications include:

• Lisdexamfetamine dimesylate (Vyvanse) once-daily prodrug of dexamphetamine has been FDA approved for the treatment of attention deficit/hyperactivity disorder (ADHD) in adults;
• Olopatadine hydrochloride (available as the ocular product Patanol) is now available as a nasal spray (Patanase). It was FDA approved for treatment of the symptoms of seasonal allergic rhinitis in patients age 12 or older;
• Quetiapine (Seroquel) has been FDA approved for maintenance treatment in patients with bipolar I disorder. Quetiapine was already approved for the treatment of schizophrenia and depressive or manic episodes; and
• Risedronate sodium 150 mg tablets (Actonel) have been FDA approved as a once-monthly dose to treat postmenopausal osteoporosis.

New Information

Varicella zoster vaccine, live, attenuated (Zostavax): The Centers for Disease Control and Prevention recommends that all adults age 60 or older be vaccinated against herpes zoster with this new vaccine. The recommendation includes patients with a prior shingles episode and those with chronic medical conditions.

Zoster vaccination is not indicated to treat acute zoster, to prevent people with acute zoster from developing post-herpetic neuralgia (PHN), or to treat ongoing PHN. Before administering zoster vaccine, patients do not need to be asked about their history of varicella (chickenpox) or to have varicella immunity testing. It is administered as a single subcutaneous 0.65 mL dose in the deltoid region of the arm. A booster dose is not licensed for the vaccine.

Medication Error Warning

The Institute for Safe Medication Practices (ISMP) has described increased reports of mixups between U-100 and U-500 insulin. These errors can result in dangerous hyperglycemia or hypoglycemia. Mistakes have occurred when prescribers accidentally selected U-500 regular insulin (R) from computer order entry screens instead of U-100.

Potential reasons for this error:

• The two dosage forms appear one line apart on the screen, making it easy to select the wrong one;
• Depending on the screen size, you may only see the first few words of the product listing, so the drug concentration may not be visible;
• Since use of U-500 insulin is uncommon, you may assume the only listed R insulin is U-100 and not look for the drug’s concentration.

ISMP suggests that use of U-500 insulin has increased due to the obesity epidemic, use in insulin pumps, and tight glucose control protocols in the hospital. ISMP says the major suppliers of these computer systems have agreed to add the word “concentrated” on their selection screens, after “insulin” and before U-500, which should help solve the problem.

New Warnings

The acquired immunodeficiency syndrome (AIDS) drugs abacavir (Ziagen) and didanosine (Videx) are being evaluated by the FDA for a possible link to increased risk of myocardial infarction (MI). This is related to the analyses of data collected from “The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study,” which is a large, international observational study of 33,347 HIV-1 infected patients evaluating short- and long-term adverse effects of anti-HIV treatments. The excess risk of MI in patients taking these agents appeared to be greater in patients with other heart disease risk factors. This is an ongoing review.

Meanwhile, the anemia drugs darbepoetin alfa (Aranesp) and epoetin alfa (Epogen/Procrit) have received a boxed warning regarding increased mortality and/or more rapid tumor progression in patients with cancer that are receiving these agents. The warnings section of the package labeling also was updated with additional study information.

Becaplermin gel (Regranex) is a recombinant form of human platelet-derived growth factor FDA approved for treating lower-extremity diabetic neuropathic ulcers. The FDA is evaluating the possibility of an increased cancer risk in diabetic patients who apply becaplermin gel directly to foot/leg ulcers. A recent study involving patients with no previous history of cancer had a greater risk of dying from cancer if they were prescribed becaplermin three or more times. The FDA believes there may be evidence of an increased cancer death risk in patients who had repeated becaplermin treatments.

Montelukast (Singulair) is undergoing a safety review regarding a possible association between it and behavior/mood changes, suicidality, and suicide. However, it may take up to nine months to complete the review. Other leukotriene receptor antagonists also are being evaluated (e.g., zafirlukast, zileuton).

Mycophenolate mofetil (MMF) and the ester of the active metabolite mycophenolic acid (MPA), known as Cellcept and Myfortic, have received an FDA alert regarding reports of infants born with serious congenital anomalies. These anomalies have included microtia, and cleft lip and palate. These women were taking these drugs to prevent organ rejection following transplant, however, some women were receiving the drugs to manage systemic lupus erythematosus (SLE), and erythema multiforme. These women were receiving the agents before their pregnancies and continued into the first trimester or until the pregnancy was detected. Both MMF and MPA increase the risk of spontaneous abortion in the first trimester and can cause congenital malformations in the children that received the drugs in utero.

The FDA and the manufacturer of natalizumab injection (Tysabri) have informed healthcare professionals of reports of clinically significant liver injury (e.g., markedly elevated serum hepatic enzymes, elevated total bilirubin) within six days of starting natalizumab. The agent is FDA approved to treat multiple sclerosis and Crohn’s Disease. Natalizumab should be discontinued in patients with jaundice or other evidence of significant liver injury. Physicians need to inform patients that natalizumab may cause liver injury. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

It’s been an active summer for pharmaceutical firms, who’ve been particularly busy adding and removing products from the marketplace and providing fresh information to professional users. Here’s a roundup of vital information that has emerged.

Market Withdrawals

Because of an increased risk of death associated with aprotinin injection (Trasylol) compared with either aminocaproic acid or tranexamic acid, Bayer Pharmaceuticals has removed all remaining stocks of the agent from the U.S. market. Subsequent access to aprotinin injection will be limited to investigational use based on a special treatment protocol. For more information on this, call (888) 842-2937.

Meanwhile, nedocromil sodium inhalation aerosol (Tilade) has been discontinued. Once current supplies are depleted from pharmacies, it no longer will be available. A number of factors led to the decision, including the inability to find a qualified manufacturer of the chlorofluorocarbon propellant.

New Approvals

Certolizumab pegol (Cimzia) injection has been approved by the Food and Drug Administration (FDA) to treat adults with moderate to severe Crohn’s disease who have not responded to conventional therapies. It is a pegylated tumor necrosis factor antagonist. The most common side effects are headache, upper respiratory infections, abdominal pain, injection site reactions, and nausea. It is dosed as an initial 400 mg SC injection followed by 400 mg SC injections at weeks two and our.

A maintenance regimen of 400 mg subcutaneous every four weeks is recommended for patients who obtain a clinical response after the initial three injections. The drug is available as a package that includes everything required to reconstitute and inject the drug (also two vials of drug, each with 200 mg Cimzia). Patients need to be evaluated for increased infection risk and opportunistic infections. Patients should be screened for tuberculosis prior to commencing therapy.

Desvenlafaxine 50 mg tablets (Pristiq), a serotonin-norepinephrine reuptake inhibitor (SNRI), have been FDA approved for the treatment of adults with major depressive disorder. It is dosed once daily. To reach the therapeutic dose, titration is unnecessary. Dose adjustments are necessary for severe renal impairment or end-stage renal disease patients, where the dose should be adjusted to 50 mg every other day. Nausea, dizziness, hyperhidrosis, constipation, and decreased appetite are the most common side effects.

Lubiprostone capsules (Amitiza) have been FDA approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in women 18 or older. Common side effects are nausea, diarrhea, and abdominal pain. It is dosed as 8 mcg twice a day with food and water. Patients should be periodically assessed for therapy continuation need.

Methylnaltrexone bromide (Relistor) has been FDA approved to assist in restoring bowel function in patients who are continuously receiving opioids for pain management and have late-stage, advanced illness. It works by blocking opioid entrance into smooth muscle. It is administered by injection as often as needed, but not to exceed more than one dose in a 24-hour period.

New Indications

Aripiprazole (Abilify) has received a number of new indications from the FDA, mostly in adolescents and children. In adults, it has received approval as an adjunctive treatment to either lithium or valproate for patients age 10 or older with manic and mixed episodes associated with bipolar I disorder with or without psychotic features. When used as monotherapy for bipolar I disorder in adults, the recommended starting dose for these indications in adults is 15 mg/day with a target dose of 30 mg/day.

Other new indications include:

• Lisdexamfetamine dimesylate (Vyvanse) once-daily prodrug of dexamphetamine has been FDA approved for the treatment of attention deficit/hyperactivity disorder (ADHD) in adults;
• Olopatadine hydrochloride (available as the ocular product Patanol) is now available as a nasal spray (Patanase). It was FDA approved for treatment of the symptoms of seasonal allergic rhinitis in patients age 12 or older;
• Quetiapine (Seroquel) has been FDA approved for maintenance treatment in patients with bipolar I disorder. Quetiapine was already approved for the treatment of schizophrenia and depressive or manic episodes; and
• Risedronate sodium 150 mg tablets (Actonel) have been FDA approved as a once-monthly dose to treat postmenopausal osteoporosis.

New Information

Varicella zoster vaccine, live, attenuated (Zostavax): The Centers for Disease Control and Prevention recommends that all adults age 60 or older be vaccinated against herpes zoster with this new vaccine. The recommendation includes patients with a prior shingles episode and those with chronic medical conditions.

Zoster vaccination is not indicated to treat acute zoster, to prevent people with acute zoster from developing post-herpetic neuralgia (PHN), or to treat ongoing PHN. Before administering zoster vaccine, patients do not need to be asked about their history of varicella (chickenpox) or to have varicella immunity testing. It is administered as a single subcutaneous 0.65 mL dose in the deltoid region of the arm. A booster dose is not licensed for the vaccine.

Medication Error Warning

The Institute for Safe Medication Practices (ISMP) has described increased reports of mixups between U-100 and U-500 insulin. These errors can result in dangerous hyperglycemia or hypoglycemia. Mistakes have occurred when prescribers accidentally selected U-500 regular insulin (R) from computer order entry screens instead of U-100.

Potential reasons for this error:

• The two dosage forms appear one line apart on the screen, making it easy to select the wrong one;
• Depending on the screen size, you may only see the first few words of the product listing, so the drug concentration may not be visible;
• Since use of U-500 insulin is uncommon, you may assume the only listed R insulin is U-100 and not look for the drug’s concentration.

ISMP suggests that use of U-500 insulin has increased due to the obesity epidemic, use in insulin pumps, and tight glucose control protocols in the hospital. ISMP says the major suppliers of these computer systems have agreed to add the word “concentrated” on their selection screens, after “insulin” and before U-500, which should help solve the problem.

New Warnings

The acquired immunodeficiency syndrome (AIDS) drugs abacavir (Ziagen) and didanosine (Videx) are being evaluated by the FDA for a possible link to increased risk of myocardial infarction (MI). This is related to the analyses of data collected from “The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study,” which is a large, international observational study of 33,347 HIV-1 infected patients evaluating short- and long-term adverse effects of anti-HIV treatments. The excess risk of MI in patients taking these agents appeared to be greater in patients with other heart disease risk factors. This is an ongoing review.

Meanwhile, the anemia drugs darbepoetin alfa (Aranesp) and epoetin alfa (Epogen/Procrit) have received a boxed warning regarding increased mortality and/or more rapid tumor progression in patients with cancer that are receiving these agents. The warnings section of the package labeling also was updated with additional study information.

Becaplermin gel (Regranex) is a recombinant form of human platelet-derived growth factor FDA approved for treating lower-extremity diabetic neuropathic ulcers. The FDA is evaluating the possibility of an increased cancer risk in diabetic patients who apply becaplermin gel directly to foot/leg ulcers. A recent study involving patients with no previous history of cancer had a greater risk of dying from cancer if they were prescribed becaplermin three or more times. The FDA believes there may be evidence of an increased cancer death risk in patients who had repeated becaplermin treatments.

Montelukast (Singulair) is undergoing a safety review regarding a possible association between it and behavior/mood changes, suicidality, and suicide. However, it may take up to nine months to complete the review. Other leukotriene receptor antagonists also are being evaluated (e.g., zafirlukast, zileuton).

Mycophenolate mofetil (MMF) and the ester of the active metabolite mycophenolic acid (MPA), known as Cellcept and Myfortic, have received an FDA alert regarding reports of infants born with serious congenital anomalies. These anomalies have included microtia, and cleft lip and palate. These women were taking these drugs to prevent organ rejection following transplant, however, some women were receiving the drugs to manage systemic lupus erythematosus (SLE), and erythema multiforme. These women were receiving the agents before their pregnancies and continued into the first trimester or until the pregnancy was detected. Both MMF and MPA increase the risk of spontaneous abortion in the first trimester and can cause congenital malformations in the children that received the drugs in utero.

The FDA and the manufacturer of natalizumab injection (Tysabri) have informed healthcare professionals of reports of clinically significant liver injury (e.g., markedly elevated serum hepatic enzymes, elevated total bilirubin) within six days of starting natalizumab. The agent is FDA approved to treat multiple sclerosis and Crohn’s Disease. Natalizumab should be discontinued in patients with jaundice or other evidence of significant liver injury. Physicians need to inform patients that natalizumab may cause liver injury. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

The chronic inflammatory disease lupus, usually traced to environmental and genetic causes, also can be drug-induced (DILE). It occurs in patients differently than systemic lupus erythematosus (SLE).

DILE tends to strike:

• Older patients (ages 50-70);
• Men more than women; and
• Whites more than blacks.

It was first described in 1945 as a side effect of sulfadiazine. Between 15,000 and 20,000 cases of drug-induced lupus erythematosus (DILE) occur yearly. Symptoms usually appear within three to six months of taking an offending drug.1 However, it also can occur within two years of receiving a triggering drug.2,3 The reaction usually resolves within days or months after removal of the offending medication. Care must be taken to correctly diagnose DILE and differentiate it from the systemic autoimmune disease SLE.

DILE arises mainly from the production of autoantibodies in reaction to certain drugs.4 Patients may also have a genetic predisposition, particularly for agents that are metabolically acetylated (e.g., hydralazine, procainamide). DILE is likely to appear more rapidly in patients who are slow acetylators. These patients include those with the HLA-DR4 or HLA-DR0301 genes, the complement C4 null allele, and females.

DILE symptoms include anorexia, arthralgia, fever, lymphadenopathy, malaise, myalgia, rash, serositis, and weight loss.5 The rash usually presents as polycyclic, with scaling and erythema in sun-exposed areas. Serologic findings include a positive antinuclear antibody (ANA) in 75% or more of patients and anti-histone antibodies. Levels of C3/C4 are usually normal. Antibodies to anti-double stranded DNA (anti-ds DNA) are rare, in contrast to SLE where C3/C4 levels usually decrease and anti-ds DNA is usually (50%-70%) positive. An elevated erythrocyte sedimentation rate (ESR 80%) may also be present. The absence of renal or central nervous system involvement is more suggestive of DILE. Renal effects occur in 5% to 10% of hydralazine-induced DILE cases, and renal deaths have been reported in rare cases.

The Agents

Many agents can cause DILE. A large number of these agents rarely are used in present-day medicine. The more commonly used agents/classes include:

• Carbamazepine;
• Diltiazem;
• Docetaxel;
• Hydralazine;
• Isoniazid;
• Minocycline;
• Procainamide; and
• Sulfasalazine.

Other agents that may possibly cause DILE include:

• Anti-tumor necrosis factor agents (adalimumab, etanercept, infliximab);
• Bupropion;
• Fluorouracil;
• Interferon;
• Lisinopril;
• Non-steroidal anti-inflammatory agents;
• Propylthiouracil;
• Statins; and
• Terbinafine.

Diagnosis is made by confirming the patient has:

• One or more clinical symptoms;
• A positive ANA;
• No SLE history prior to using the suspected agent;
• Not taken the drug anytime from three weeks to two years before the symptoms appeared; and
• Clinical resolution occurs rapidly upon “suspected drug” discontinuation.

A complete blood count should be obtained to evaluate for anemia (rare in DILE, common in SLE). Liver function tests, blood urea nitrogen, creatinine, and urinalysis can be performed to evaluate for other complications.

DILE usually resolves following drug discontinuation, but severe cases may require low doses of systemic corticosteroids. TH

Michele B Kaufman, PharmD, BSc, is a registered pharmacist based in New York City.

References

1. Vasoo S. Drug-induced lupus: an update. Lupus 2006;15:757-761.
2. Kauffman CL. Lupus erythematosus, drug-induced. eMedicine 2007. Available at www.emedicine.com/derm/TOPIC107.htm. Accessed April 8, 2008.
3. MedlinePlus. www.nlm.nih.gov/medlineplus/ print/ency/article/000446.htm. Accessed April 8, 2008.
4. Schur PH, Rose BD. Drug-induced lupus 2008; Patients UpToDate Version 16.1. Available www.uptodate.com/patients/content/topic.do;jsessionid=1934E0AFFCBBB588269DBFEE5F96BDF4.1002?topicKey=~kU3CGByPyaH&selectedTitle=2~103&source=search_result. Accessed April 8, 2008.
5. Borchers A, Keen CL, Gershwin ME. Drug-induced lupus. Ann NY Acad Sci. 2007;1108:166-182.

The chronic inflammatory disease lupus, usually traced to environmental and genetic causes, also can be drug-induced (DILE). It occurs in patients differently than systemic lupus erythematosus (SLE).

DILE tends to strike:

• Older patients (ages 50-70);
• Men more than women; and
• Whites more than blacks.

It was first described in 1945 as a side effect of sulfadiazine. Between 15,000 and 20,000 cases of drug-induced lupus erythematosus (DILE) occur yearly. Symptoms usually appear within three to six months of taking an offending drug.1 However, it also can occur within two years of receiving a triggering drug.2,3 The reaction usually resolves within days or months after removal of the offending medication. Care must be taken to correctly diagnose DILE and differentiate it from the systemic autoimmune disease SLE.

DILE arises mainly from the production of autoantibodies in reaction to certain drugs.4 Patients may also have a genetic predisposition, particularly for agents that are metabolically acetylated (e.g., hydralazine, procainamide). DILE is likely to appear more rapidly in patients who are slow acetylators. These patients include those with the HLA-DR4 or HLA-DR0301 genes, the complement C4 null allele, and females.

DILE symptoms include anorexia, arthralgia, fever, lymphadenopathy, malaise, myalgia, rash, serositis, and weight loss.5 The rash usually presents as polycyclic, with scaling and erythema in sun-exposed areas. Serologic findings include a positive antinuclear antibody (ANA) in 75% or more of patients and anti-histone antibodies. Levels of C3/C4 are usually normal. Antibodies to anti-double stranded DNA (anti-ds DNA) are rare, in contrast to SLE where C3/C4 levels usually decrease and anti-ds DNA is usually (50%-70%) positive. An elevated erythrocyte sedimentation rate (ESR 80%) may also be present. The absence of renal or central nervous system involvement is more suggestive of DILE. Renal effects occur in 5% to 10% of hydralazine-induced DILE cases, and renal deaths have been reported in rare cases.

The Agents

Many agents can cause DILE. A large number of these agents rarely are used in present-day medicine. The more commonly used agents/classes include:

• Carbamazepine;
• Diltiazem;
• Docetaxel;
• Hydralazine;
• Isoniazid;
• Minocycline;
• Procainamide; and
• Sulfasalazine.

Other agents that may possibly cause DILE include:

• Anti-tumor necrosis factor agents (adalimumab, etanercept, infliximab);
• Bupropion;
• Fluorouracil;
• Interferon;
• Lisinopril;
• Non-steroidal anti-inflammatory agents;
• Propylthiouracil;
• Statins; and
• Terbinafine.

Diagnosis is made by confirming the patient has:

• One or more clinical symptoms;
• A positive ANA;
• No SLE history prior to using the suspected agent;
• Not taken the drug anytime from three weeks to two years before the symptoms appeared; and
• Clinical resolution occurs rapidly upon “suspected drug” discontinuation.

A complete blood count should be obtained to evaluate for anemia (rare in DILE, common in SLE). Liver function tests, blood urea nitrogen, creatinine, and urinalysis can be performed to evaluate for other complications.

DILE usually resolves following drug discontinuation, but severe cases may require low doses of systemic corticosteroids. TH

Michele B Kaufman, PharmD, BSc, is a registered pharmacist based in New York City.

References

1. Vasoo S. Drug-induced lupus: an update. Lupus 2006;15:757-761.
2. Kauffman CL. Lupus erythematosus, drug-induced. eMedicine 2007. Available at www.emedicine.com/derm/TOPIC107.htm. Accessed April 8, 2008.
3. MedlinePlus. www.nlm.nih.gov/medlineplus/ print/ency/article/000446.htm. Accessed April 8, 2008.
4. Schur PH, Rose BD. Drug-induced lupus 2008; Patients UpToDate Version 16.1. Available www.uptodate.com/patients/content/topic.do;jsessionid=1934E0AFFCBBB588269DBFEE5F96BDF4.1002?topicKey=~kU3CGByPyaH&selectedTitle=2~103&source=search_result. Accessed April 8, 2008.
5. Borchers A, Keen CL, Gershwin ME. Drug-induced lupus. Ann NY Acad Sci. 2007;1108:166-182.

The chronic inflammatory disease lupus, usually traced to environmental and genetic causes, also can be drug-induced (DILE). It occurs in patients differently than systemic lupus erythematosus (SLE).

DILE tends to strike:

• Older patients (ages 50-70);
• Men more than women; and
• Whites more than blacks.

It was first described in 1945 as a side effect of sulfadiazine. Between 15,000 and 20,000 cases of drug-induced lupus erythematosus (DILE) occur yearly. Symptoms usually appear within three to six months of taking an offending drug.1 However, it also can occur within two years of receiving a triggering drug.2,3 The reaction usually resolves within days or months after removal of the offending medication. Care must be taken to correctly diagnose DILE and differentiate it from the systemic autoimmune disease SLE.

DILE arises mainly from the production of autoantibodies in reaction to certain drugs.4 Patients may also have a genetic predisposition, particularly for agents that are metabolically acetylated (e.g., hydralazine, procainamide). DILE is likely to appear more rapidly in patients who are slow acetylators. These patients include those with the HLA-DR4 or HLA-DR0301 genes, the complement C4 null allele, and females.

DILE symptoms include anorexia, arthralgia, fever, lymphadenopathy, malaise, myalgia, rash, serositis, and weight loss.5 The rash usually presents as polycyclic, with scaling and erythema in sun-exposed areas. Serologic findings include a positive antinuclear antibody (ANA) in 75% or more of patients and anti-histone antibodies. Levels of C3/C4 are usually normal. Antibodies to anti-double stranded DNA (anti-ds DNA) are rare, in contrast to SLE where C3/C4 levels usually decrease and anti-ds DNA is usually (50%-70%) positive. An elevated erythrocyte sedimentation rate (ESR 80%) may also be present. The absence of renal or central nervous system involvement is more suggestive of DILE. Renal effects occur in 5% to 10% of hydralazine-induced DILE cases, and renal deaths have been reported in rare cases.

The Agents

Many agents can cause DILE. A large number of these agents rarely are used in present-day medicine. The more commonly used agents/classes include:

• Carbamazepine;
• Diltiazem;
• Docetaxel;
• Hydralazine;
• Isoniazid;
• Minocycline;
• Procainamide; and
• Sulfasalazine.

Other agents that may possibly cause DILE include:

• Anti-tumor necrosis factor agents (adalimumab, etanercept, infliximab);
• Bupropion;
• Fluorouracil;
• Interferon;
• Lisinopril;
• Non-steroidal anti-inflammatory agents;
• Propylthiouracil;
• Statins; and
• Terbinafine.

Diagnosis is made by confirming the patient has:

• One or more clinical symptoms;
• A positive ANA;
• No SLE history prior to using the suspected agent;
• Not taken the drug anytime from three weeks to two years before the symptoms appeared; and
• Clinical resolution occurs rapidly upon “suspected drug” discontinuation.

A complete blood count should be obtained to evaluate for anemia (rare in DILE, common in SLE). Liver function tests, blood urea nitrogen, creatinine, and urinalysis can be performed to evaluate for other complications.

DILE usually resolves following drug discontinuation, but severe cases may require low doses of systemic corticosteroids. TH

Michele B Kaufman, PharmD, BSc, is a registered pharmacist based in New York City.

References

1. Vasoo S. Drug-induced lupus: an update. Lupus 2006;15:757-761.
2. Kauffman CL. Lupus erythematosus, drug-induced. eMedicine 2007. Available at www.emedicine.com/derm/TOPIC107.htm. Accessed April 8, 2008.
3. MedlinePlus. www.nlm.nih.gov/medlineplus/ print/ency/article/000446.htm. Accessed April 8, 2008.
4. Schur PH, Rose BD. Drug-induced lupus 2008; Patients UpToDate Version 16.1. Available www.uptodate.com/patients/content/topic.do;jsessionid=1934E0AFFCBBB588269DBFEE5F96BDF4.1002?topicKey=~kU3CGByPyaH&selectedTitle=2~103&source=search_result. Accessed April 8, 2008.
5. Borchers A, Keen CL, Gershwin ME. Drug-induced lupus. Ann NY Acad Sci. 2007;1108:166-182.

The frequency of drug-induced thrombocytopenia (DIT) in acutely ill patients is thought to be up to 25%, making it a common problem.1,2

Hundreds of drugs have been identified as causing DIT, due to either accelerated immune-mediated platelet destruction, decreased platelet production (bone marrow suppression), or platelet aggregation. The latter is the case in heparin-induced thrombocytopenia and thrombosis (HITT). DIT should be suspected in any patient who presents with acute thrombocytopenia from an unknown cause.3

Normal adult platelet counts usually are in the range of 140,000 to 450,000/mm3. A patient who presents with severe thrombocytopenia (less than 20,000 platelets/mm3) should strongly be suspected as having a drug-induced cause.

A patient also can present with moderate to severe thrombocytopenia (less than 50,000 platelets/mm3) and spontaneous bleeding from a drug-induced cause. The spontaneous bleeding can take the form of simple petechiae or ecchymoses, as well as mucosal bleeding or life-threatening intracranial or gastrointestinal hemorrhage. It may also present itself as bleeding around catheter insertion sites.

When DIT occurs, platelet count usually falls within two to three days of taking a drug that’s been taken before, or seven or more days after starting a drug the patient has not been exposed to. Once the offending drug is discontinued, platelet counts usually recover within 10 days.

Exclusions of other causes of thrombocytopenia, such as inflammatory processes and congenital disorders, as well as nondrug causes including sepsis, malignancy, extensive burns, chronic alcoholism, human immunodeficiency virus, splenomegaly, and disseminated intravascular coagulation, become part of the differential diagnosis.

Generally, the frequency and severity of bleeding manifestations correlate with the actual platelet count. Patients with a platelet count of less than 50,000/mm3 have an increased risk of spontaneous hemorrhage, but the severity may vary. Other risk factors include advanced age, bleeding history, and general bleeding diatheses.

A thorough physical examination and drug history are essential. Agents commonly associated with thrombocytopenia should be identified first followed by a more extensive review for other causes. A careful drug history should include prescriptions, over-the-counter medications (specifically quinine and acetaminophen), dietary supplements, folk remedies, other complementary and alternative therapies, and vaccinations.

The Agents

The top two suspects for DIT are antineoplastic agents and heparin. After these two, the agents most frequently associated with DIT development include:

• Quinine/quinidine;
• Phenytoin;
• Sulfonamide antibiotics;
• Cimetidine;
• Ranitidine;
• Rifampin/rifampicin;
• Carbamazepine;
• Thiazide diuretics;
• Penicillin;
• Oral antidiabetic drugs;
• Nonsteroidal anti-inflammatory drugs;
• Gold salts; and
• Procainamide.

A complete list of all case reports describing DIT, organized by generic

drug names, is available online at http://w3.ouhsc.edu/platelets/ditp.html.4

Management

Removal of the potentially offending agent, if known, is prudent before clinically significant bleeding occurs. If the offending agent is not discontinued, the platelet count will continue to decrease and bleeding will become more severe. If necessary, an alternate agent with a similar pharmacologic effect can be started. Daily platelet count monitoring is also recommended for management. Rare cases may require platelet transfusions, intravenous immunoglobulin therapy or plasmapheresis.

A complete blood count and peripheral blood smear may provide important indications into the mechanism of the disorder, but they’re not necessary for patient management. TH

Michele B Kaufman, PharmD, BSc, is a registere pharmacist based in New York City.

References

1. Visentin GP, Liu CY. Drug-induced thrombocytopenia. Hematol Oncol Clin N Am. 2007;21:685-696.
2. Wazny LD, Ariano RE. Evaluation and management of drug-induced thrombocytopenia in the acutely ill patient. Pharmacother. 2000;20(3):292-307.
3. Aster RH, Bougie DW. Drug-induced thrombocytopenia. N Engl J Med. 2007;357(6):580-587.
4. Majhail NS, Lichtin AE. What is the best way to determine if thrombocytopenia in a patient on multiple medications is drug-induced? Cleve Clin J Med. 2002;69(3):259-262.

The frequency of drug-induced thrombocytopenia (DIT) in acutely ill patients is thought to be up to 25%, making it a common problem.1,2

Hundreds of drugs have been identified as causing DIT, due to either accelerated immune-mediated platelet destruction, decreased platelet production (bone marrow suppression), or platelet aggregation. The latter is the case in heparin-induced thrombocytopenia and thrombosis (HITT). DIT should be suspected in any patient who presents with acute thrombocytopenia from an unknown cause.3

Normal adult platelet counts usually are in the range of 140,000 to 450,000/mm3. A patient who presents with severe thrombocytopenia (less than 20,000 platelets/mm3) should strongly be suspected as having a drug-induced cause.

A patient also can present with moderate to severe thrombocytopenia (less than 50,000 platelets/mm3) and spontaneous bleeding from a drug-induced cause. The spontaneous bleeding can take the form of simple petechiae or ecchymoses, as well as mucosal bleeding or life-threatening intracranial or gastrointestinal hemorrhage. It may also present itself as bleeding around catheter insertion sites.

When DIT occurs, platelet count usually falls within two to three days of taking a drug that’s been taken before, or seven or more days after starting a drug the patient has not been exposed to. Once the offending drug is discontinued, platelet counts usually recover within 10 days.

Exclusions of other causes of thrombocytopenia, such as inflammatory processes and congenital disorders, as well as nondrug causes including sepsis, malignancy, extensive burns, chronic alcoholism, human immunodeficiency virus, splenomegaly, and disseminated intravascular coagulation, become part of the differential diagnosis.

Generally, the frequency and severity of bleeding manifestations correlate with the actual platelet count. Patients with a platelet count of less than 50,000/mm3 have an increased risk of spontaneous hemorrhage, but the severity may vary. Other risk factors include advanced age, bleeding history, and general bleeding diatheses.

A thorough physical examination and drug history are essential. Agents commonly associated with thrombocytopenia should be identified first followed by a more extensive review for other causes. A careful drug history should include prescriptions, over-the-counter medications (specifically quinine and acetaminophen), dietary supplements, folk remedies, other complementary and alternative therapies, and vaccinations.

The Agents

The top two suspects for DIT are antineoplastic agents and heparin. After these two, the agents most frequently associated with DIT development include:

• Quinine/quinidine;
• Phenytoin;
• Sulfonamide antibiotics;
• Cimetidine;
• Ranitidine;
• Rifampin/rifampicin;
• Carbamazepine;
• Thiazide diuretics;
• Penicillin;
• Oral antidiabetic drugs;
• Nonsteroidal anti-inflammatory drugs;
• Gold salts; and
• Procainamide.

A complete list of all case reports describing DIT, organized by generic

drug names, is available online at http://w3.ouhsc.edu/platelets/ditp.html.4

Management

Removal of the potentially offending agent, if known, is prudent before clinically significant bleeding occurs. If the offending agent is not discontinued, the platelet count will continue to decrease and bleeding will become more severe. If necessary, an alternate agent with a similar pharmacologic effect can be started. Daily platelet count monitoring is also recommended for management. Rare cases may require platelet transfusions, intravenous immunoglobulin therapy or plasmapheresis.

A complete blood count and peripheral blood smear may provide important indications into the mechanism of the disorder, but they’re not necessary for patient management. TH

Michele B Kaufman, PharmD, BSc, is a registere pharmacist based in New York City.

References

1. Visentin GP, Liu CY. Drug-induced thrombocytopenia. Hematol Oncol Clin N Am. 2007;21:685-696.
2. Wazny LD, Ariano RE. Evaluation and management of drug-induced thrombocytopenia in the acutely ill patient. Pharmacother. 2000;20(3):292-307.
3. Aster RH, Bougie DW. Drug-induced thrombocytopenia. N Engl J Med. 2007;357(6):580-587.
4. Majhail NS, Lichtin AE. What is the best way to determine if thrombocytopenia in a patient on multiple medications is drug-induced? Cleve Clin J Med. 2002;69(3):259-262.

The frequency of drug-induced thrombocytopenia (DIT) in acutely ill patients is thought to be up to 25%, making it a common problem.1,2

Hundreds of drugs have been identified as causing DIT, due to either accelerated immune-mediated platelet destruction, decreased platelet production (bone marrow suppression), or platelet aggregation. The latter is the case in heparin-induced thrombocytopenia and thrombosis (HITT). DIT should be suspected in any patient who presents with acute thrombocytopenia from an unknown cause.3

Normal adult platelet counts usually are in the range of 140,000 to 450,000/mm3. A patient who presents with severe thrombocytopenia (less than 20,000 platelets/mm3) should strongly be suspected as having a drug-induced cause.

A patient also can present with moderate to severe thrombocytopenia (less than 50,000 platelets/mm3) and spontaneous bleeding from a drug-induced cause. The spontaneous bleeding can take the form of simple petechiae or ecchymoses, as well as mucosal bleeding or life-threatening intracranial or gastrointestinal hemorrhage. It may also present itself as bleeding around catheter insertion sites.

When DIT occurs, platelet count usually falls within two to three days of taking a drug that’s been taken before, or seven or more days after starting a drug the patient has not been exposed to. Once the offending drug is discontinued, platelet counts usually recover within 10 days.

Exclusions of other causes of thrombocytopenia, such as inflammatory processes and congenital disorders, as well as nondrug causes including sepsis, malignancy, extensive burns, chronic alcoholism, human immunodeficiency virus, splenomegaly, and disseminated intravascular coagulation, become part of the differential diagnosis.

Generally, the frequency and severity of bleeding manifestations correlate with the actual platelet count. Patients with a platelet count of less than 50,000/mm3 have an increased risk of spontaneous hemorrhage, but the severity may vary. Other risk factors include advanced age, bleeding history, and general bleeding diatheses.

A thorough physical examination and drug history are essential. Agents commonly associated with thrombocytopenia should be identified first followed by a more extensive review for other causes. A careful drug history should include prescriptions, over-the-counter medications (specifically quinine and acetaminophen), dietary supplements, folk remedies, other complementary and alternative therapies, and vaccinations.

The Agents

The top two suspects for DIT are antineoplastic agents and heparin. After these two, the agents most frequently associated with DIT development include:

• Quinine/quinidine;
• Phenytoin;
• Sulfonamide antibiotics;
• Cimetidine;
• Ranitidine;
• Rifampin/rifampicin;
• Carbamazepine;
• Thiazide diuretics;
• Penicillin;
• Oral antidiabetic drugs;
• Nonsteroidal anti-inflammatory drugs;
• Gold salts; and
• Procainamide.

A complete list of all case reports describing DIT, organized by generic

drug names, is available online at http://w3.ouhsc.edu/platelets/ditp.html.4

Management

Removal of the potentially offending agent, if known, is prudent before clinically significant bleeding occurs. If the offending agent is not discontinued, the platelet count will continue to decrease and bleeding will become more severe. If necessary, an alternate agent with a similar pharmacologic effect can be started. Daily platelet count monitoring is also recommended for management. Rare cases may require platelet transfusions, intravenous immunoglobulin therapy or plasmapheresis.

A complete blood count and peripheral blood smear may provide important indications into the mechanism of the disorder, but they’re not necessary for patient management. TH

Michele B Kaufman, PharmD, BSc, is a registere pharmacist based in New York City.

References

1. Visentin GP, Liu CY. Drug-induced thrombocytopenia. Hematol Oncol Clin N Am. 2007;21:685-696.
2. Wazny LD, Ariano RE. Evaluation and management of drug-induced thrombocytopenia in the acutely ill patient. Pharmacother. 2000;20(3):292-307.
3. Aster RH, Bougie DW. Drug-induced thrombocytopenia. N Engl J Med. 2007;357(6):580-587.
4. Majhail NS, Lichtin AE. What is the best way to determine if thrombocytopenia in a patient on multiple medications is drug-induced? Cleve Clin J Med. 2002;69(3):259-262.

Venous thromboembolism (VTE) affects more than 2 million Americans every year.1 Pulmonary embolism (PE) is one of the most common preventable causes of in-hospital deaths in the United States. Clinical manifestations of PE may be the first indication the patient has a VTE, and fatal PEs occur in at least 75% of hospitalized medical patients. More than 300,000 patients die from PE each year—an estimated incidence of 10%. This makes VTE prevention a top patient-safety goal in hospitals.2,3

Thromboprophylaxis can be accomplished with unfractionated heparin (UFH), low-molecular-weight heparin (LMWH; e.g., enoxaparin, dalteparin, tinzaparin) or heparinoid, or a selective factor Xa inhibitor (e.g., fondaparinux).4 For long-term treatment, oral warfarin is often used. Doses and duration of prophylaxis and treatment regimens vary.

Current guidelines should be reviewed for specific recommendations. Two current guidelines are the American College of Chest Physicians (ACCP) Seventh Conference on the Prevention of VTE and the American Society of Clinical Oncology (ASCO) Guideline for VTE prophylaxis and treatment in oncology patients. Although guidelines are available, thromboprophylaxis continues to baffle many healthcare providers. There are many advantages to thromboprophylaxis including the prevention of significant morbidity, prevention of PE, decreases in resource consumption, and decreases in the long-term clinical and economic sequelae.

The ACCP notes that most surgical patients will require thromboprophylaxis. Contraindications need to be evaluated prior to antithrombotic/anticoagulant use. Additionally, all trauma patients with at least one VTE risk factor should receive thromboprophylaxis. Acutely ill patients hospitalized with congestive heart failure or severe respiratory distress or who are confined to bed and have one or more additional risk factors, should receive VTE prophylaxis. Additionally, most patients upon admission to an intensive-care unit should be assessed for VTE risk and receive thromboprophylaxis as required.

VTE is a major complication in up to 20% of cancer patients, with hospitalized oncology patients and those undergoing treatment at the highest risk. Some of the newer drug treatments used in these patients have higher VTE rates (e.g., bevacizumab, thalidomide, lenalidomide). These patients need to be carefully evaluated for VTE prophylaxis and closely monitored.5

Generally, in hospitalized patients with cancer, VTE prophylaxis should be considered with UFH, LMWH, or fondaparinux, in the absence of bleeding or other contraindications to anticoagulation. Relative contraindications to anticoagulation include (but are not limited to):

• Active uncontrolled bleeding;
• Active cerebrovascular hemorrhage;
• Dissecting or cerebral aneurysm;
• Bacterial endocarditis;
• Pericarditis;
• Active peptic or gastrointestinal ulceration;
• Severe uncontrolled or malignant hypertension;
• Severe head trauma;
• Pregnancy (warfarin contraindication);
• Heparin-induced thrombocytopenia (heparin, LMWH); and
• Epidural catheter placement.

These same contraindications can be applied to the non-oncology patient, as well.

An important aspect of VTE management is the “Clinical Practice Guideline from the American Academy of Family Physicians and the American College of Physicians on the Diagnosis of VTE from the Annals of Family Medicine.” Consult this for a review of diagnostic tests for VTE.

Thromboprophylaxis is a necessity in a number of at-risk hospitalized patients. Knowing which patients will benefit, and the contraindications for use, will improve patient outcomes. Consult current guidelines for diagnosis recommendations as well as agents of choice, dosing regimens, and therapy duration. TH

Michele B. Kaufman is registered pharmacist based in New York City.

References

1. DVT: Assess Your Patients’ Risk, Take Preventive Measures. ASHP Foundation Discoveries, Summer 2007;19(1):1,5. Available at www.ashpfoundation.org/MainMenuCategories/AboutUs/Newsletter/DiscoveriesSummer2007.aspx. Last accessed Nov. 26, 2007.
2. Geertz WH, Pineo Graham F, Heit JA et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:338-400.
3. Wein L, Wein S, Haas SJ, et al. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients, a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167:1476-1486.
4. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25(34): 5490–5505.
5. Qaseem A, Snow V, Barry P for the Joint American Academy of Family Physicians/American College of Physicians Panel on Deep Vein Thrombosis/Pulmonary Embolism. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 2007;5:57-62.

Venous thromboembolism (VTE) affects more than 2 million Americans every year.1 Pulmonary embolism (PE) is one of the most common preventable causes of in-hospital deaths in the United States. Clinical manifestations of PE may be the first indication the patient has a VTE, and fatal PEs occur in at least 75% of hospitalized medical patients. More than 300,000 patients die from PE each year—an estimated incidence of 10%. This makes VTE prevention a top patient-safety goal in hospitals.2,3

Thromboprophylaxis can be accomplished with unfractionated heparin (UFH), low-molecular-weight heparin (LMWH; e.g., enoxaparin, dalteparin, tinzaparin) or heparinoid, or a selective factor Xa inhibitor (e.g., fondaparinux).4 For long-term treatment, oral warfarin is often used. Doses and duration of prophylaxis and treatment regimens vary.

Current guidelines should be reviewed for specific recommendations. Two current guidelines are the American College of Chest Physicians (ACCP) Seventh Conference on the Prevention of VTE and the American Society of Clinical Oncology (ASCO) Guideline for VTE prophylaxis and treatment in oncology patients. Although guidelines are available, thromboprophylaxis continues to baffle many healthcare providers. There are many advantages to thromboprophylaxis including the prevention of significant morbidity, prevention of PE, decreases in resource consumption, and decreases in the long-term clinical and economic sequelae.

The ACCP notes that most surgical patients will require thromboprophylaxis. Contraindications need to be evaluated prior to antithrombotic/anticoagulant use. Additionally, all trauma patients with at least one VTE risk factor should receive thromboprophylaxis. Acutely ill patients hospitalized with congestive heart failure or severe respiratory distress or who are confined to bed and have one or more additional risk factors, should receive VTE prophylaxis. Additionally, most patients upon admission to an intensive-care unit should be assessed for VTE risk and receive thromboprophylaxis as required.

VTE is a major complication in up to 20% of cancer patients, with hospitalized oncology patients and those undergoing treatment at the highest risk. Some of the newer drug treatments used in these patients have higher VTE rates (e.g., bevacizumab, thalidomide, lenalidomide). These patients need to be carefully evaluated for VTE prophylaxis and closely monitored.5

Generally, in hospitalized patients with cancer, VTE prophylaxis should be considered with UFH, LMWH, or fondaparinux, in the absence of bleeding or other contraindications to anticoagulation. Relative contraindications to anticoagulation include (but are not limited to):

• Active uncontrolled bleeding;
• Active cerebrovascular hemorrhage;
• Dissecting or cerebral aneurysm;
• Bacterial endocarditis;
• Pericarditis;
• Active peptic or gastrointestinal ulceration;
• Severe uncontrolled or malignant hypertension;
• Severe head trauma;
• Pregnancy (warfarin contraindication);
• Heparin-induced thrombocytopenia (heparin, LMWH); and
• Epidural catheter placement.

These same contraindications can be applied to the non-oncology patient, as well.

An important aspect of VTE management is the “Clinical Practice Guideline from the American Academy of Family Physicians and the American College of Physicians on the Diagnosis of VTE from the Annals of Family Medicine.” Consult this for a review of diagnostic tests for VTE.

Thromboprophylaxis is a necessity in a number of at-risk hospitalized patients. Knowing which patients will benefit, and the contraindications for use, will improve patient outcomes. Consult current guidelines for diagnosis recommendations as well as agents of choice, dosing regimens, and therapy duration. TH

Michele B. Kaufman is registered pharmacist based in New York City.

References

1. DVT: Assess Your Patients’ Risk, Take Preventive Measures. ASHP Foundation Discoveries, Summer 2007;19(1):1,5. Available at www.ashpfoundation.org/MainMenuCategories/AboutUs/Newsletter/DiscoveriesSummer2007.aspx. Last accessed Nov. 26, 2007.
2. Geertz WH, Pineo Graham F, Heit JA et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:338-400.
3. Wein L, Wein S, Haas SJ, et al. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients, a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167:1476-1486.
4. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25(34): 5490–5505.
5. Qaseem A, Snow V, Barry P for the Joint American Academy of Family Physicians/American College of Physicians Panel on Deep Vein Thrombosis/Pulmonary Embolism. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 2007;5:57-62.

Venous thromboembolism (VTE) affects more than 2 million Americans every year.1 Pulmonary embolism (PE) is one of the most common preventable causes of in-hospital deaths in the United States. Clinical manifestations of PE may be the first indication the patient has a VTE, and fatal PEs occur in at least 75% of hospitalized medical patients. More than 300,000 patients die from PE each year—an estimated incidence of 10%. This makes VTE prevention a top patient-safety goal in hospitals.2,3

Thromboprophylaxis can be accomplished with unfractionated heparin (UFH), low-molecular-weight heparin (LMWH; e.g., enoxaparin, dalteparin, tinzaparin) or heparinoid, or a selective factor Xa inhibitor (e.g., fondaparinux).4 For long-term treatment, oral warfarin is often used. Doses and duration of prophylaxis and treatment regimens vary.

Current guidelines should be reviewed for specific recommendations. Two current guidelines are the American College of Chest Physicians (ACCP) Seventh Conference on the Prevention of VTE and the American Society of Clinical Oncology (ASCO) Guideline for VTE prophylaxis and treatment in oncology patients. Although guidelines are available, thromboprophylaxis continues to baffle many healthcare providers. There are many advantages to thromboprophylaxis including the prevention of significant morbidity, prevention of PE, decreases in resource consumption, and decreases in the long-term clinical and economic sequelae.

The ACCP notes that most surgical patients will require thromboprophylaxis. Contraindications need to be evaluated prior to antithrombotic/anticoagulant use. Additionally, all trauma patients with at least one VTE risk factor should receive thromboprophylaxis. Acutely ill patients hospitalized with congestive heart failure or severe respiratory distress or who are confined to bed and have one or more additional risk factors, should receive VTE prophylaxis. Additionally, most patients upon admission to an intensive-care unit should be assessed for VTE risk and receive thromboprophylaxis as required.

VTE is a major complication in up to 20% of cancer patients, with hospitalized oncology patients and those undergoing treatment at the highest risk. Some of the newer drug treatments used in these patients have higher VTE rates (e.g., bevacizumab, thalidomide, lenalidomide). These patients need to be carefully evaluated for VTE prophylaxis and closely monitored.5

Generally, in hospitalized patients with cancer, VTE prophylaxis should be considered with UFH, LMWH, or fondaparinux, in the absence of bleeding or other contraindications to anticoagulation. Relative contraindications to anticoagulation include (but are not limited to):

• Active uncontrolled bleeding;
• Active cerebrovascular hemorrhage;
• Dissecting or cerebral aneurysm;
• Bacterial endocarditis;
• Pericarditis;
• Active peptic or gastrointestinal ulceration;
• Severe uncontrolled or malignant hypertension;
• Severe head trauma;
• Pregnancy (warfarin contraindication);
• Heparin-induced thrombocytopenia (heparin, LMWH); and
• Epidural catheter placement.

These same contraindications can be applied to the non-oncology patient, as well.

An important aspect of VTE management is the “Clinical Practice Guideline from the American Academy of Family Physicians and the American College of Physicians on the Diagnosis of VTE from the Annals of Family Medicine.” Consult this for a review of diagnostic tests for VTE.

Thromboprophylaxis is a necessity in a number of at-risk hospitalized patients. Knowing which patients will benefit, and the contraindications for use, will improve patient outcomes. Consult current guidelines for diagnosis recommendations as well as agents of choice, dosing regimens, and therapy duration. TH

Michele B. Kaufman is registered pharmacist based in New York City.

References

1. DVT: Assess Your Patients’ Risk, Take Preventive Measures. ASHP Foundation Discoveries, Summer 2007;19(1):1,5. Available at www.ashpfoundation.org/MainMenuCategories/AboutUs/Newsletter/DiscoveriesSummer2007.aspx. Last accessed Nov. 26, 2007.
2. Geertz WH, Pineo Graham F, Heit JA et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:338-400.
3. Wein L, Wein S, Haas SJ, et al. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients, a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167:1476-1486.
4. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25(34): 5490–5505.
5. Qaseem A, Snow V, Barry P for the Joint American Academy of Family Physicians/American College of Physicians Panel on Deep Vein Thrombosis/Pulmonary Embolism. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 2007;5:57-62.

A serious adverse drug event (ADE) is defined as one that causes death, disability, or permanent damage, hospitalization (initial or prolonged), or birth defects.

According to Moore, et al., the number of serious ADEs has increased significantly since 1998 through 2005, according to reports in the Food and Drug Administration (FDA) adverse event reporting system, also known as MedWatch.1 During that time, 467,809 serious ADEs were reported, and the annual number of reports had increased from 34,966 to 89,842.

The number of fatal ADEs increased in that period as well, from 4,419 to 15,109. Further, ADEs related to biotech drugs increased 15.8-fold. The most commonly reported classes with serious ADEs included anti-tumor necrosis factor drugs, interferons, and insulins. Drugs associated with ADEs included some that had been withdrawn from the U.S. market over safety concerns, as well as products that remained on the market.

On Sept. 27, the FDA Amendments Act of 2007 was passed. The measure includes the Prescription Drug User Fee Act (PDUFA), which authorizes the FDA to collect fees from drug makers to supplement funding for the drug-review process.2 A key revision now lets the agency require—not just request—that drug companies perform phase four clinical studies. The PDUFA also includes additional staff for reviewing medical devices. Additional stipulations are that the FDA will:

• Assess signals of serious risk related to drug use as they arise;
• Identify unexpected serious risks;
• Identify when post-marketing studies are needed; and
• Quickly submit a supplement proposing changes to the approved labeling of a drug to reflect new safety information, including changes to boxed warnings, contraindications, warnings, precautions, or adverse reactions within 30 days of identification.

This legislation has brought a number of new warnings on FDA-approved products.

The Warnings

A study in the May 2007 issue of Lancet Infectious Diseases noted higher all-cause mortality in patients treated with cefepime (Maxipime) compared with other beta-lactam antibiotics.3 Cefepime is FDA approved for the treatment of infections caused by susceptible gram-positive and gram-negative micro-organisms. The risk ratio (RR) was 1.26 (95% confidence interval [CI] 1.08–1.49) for cefepime and for the subgroup of patients with febrile neutropenia (RR 1.42 [95% CI 1.09–1.84]). The FDA is reviewing safety data and has requested additional data from Bristol-Myers Squibb to further evaluate the risk of death in cefepime-treated patients. The FDA asks healthcare professionals to report adverse events from cefepime and other agents to MedWatch at www.fda.gov/medwatch/report.htm.

A new warning regarding the pregnancy category and teratogenic effects has been added to the label of mycophenolic acid (MPA) delayed-release tablets (Myfortic). The FDA notes that use of MPA during pregnancy is associated with increased risks of pregnancy loss and congenital malformations, thereby changing the pregnancy category to D (positive evidence of fetal risk) from C (risk of fetal harm cannot be ruled out).

The MPA warnings and precautions sections also have changed. Results from postmarketing data from the U.S. National Transplantation Pregnancy Registry and additional postmarketing data collected in women exposed to systemic mycophenolate mofetil (MMF) during pregnancy brought these revisions. MMF is converted to the active ingredient in MPA following intravenous or oral administration. A patient planning to get pregnant should not use MMF/MPA unless she cannot be treated with other immunosuppressant drugs. Additionally, female patients of childbearing potential must receive contraceptive counseling and use contraception while on this agent. Remember, not only transplant patients receive MMF/MPA; patients with lupus nephritis also use it.

On Nov. 27, the Pediatric Advisory Committee of the FDA recommended changing the label of the two neuraminidase inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza), to reflect the potential for neuropsychiatric effects (mostly in children). Last year, Roche revised the oseltamivir label to add warnings of potential confusion and self-injury with the product. According to the FDA, about five patients died as a result of these neuropsychiatric effects, and nearly 600 cases of psychiatric problems were reported.

On Nov. 14, the FDA added to the black box label of rosiglitazone (Avandia) regarding an increased risk of myocardial infarction. The warning states that a recent meta-analysis of 42 clinical studies (mean duration six months, n=14,237) mostly comparing rosiglitazone with placebo, showed it to be associated with an increased risk of myocardial ischemic events. Further, three other studies (mean duration 41 months; n=14,067), comparing rosiglitazone with other oral antidiabetic agents or placebo, have not confirmed or excluded this risk. The available data on the risk of myocardial ischemia are currently inconclusive.

The FDA has asked that GlaxoSmithKline conduct extensive long-term, post-marketing trials to determine rosiglitazone’s cardiovascular safety. A study of this type, is a direct result of the new PDUFA legislation. The trial is expected to begin after July and end by 2014. Updates to the warnings, precautions, and indications sections were also added to the label. For example, rosiglitazone is not recommended for heart disease patients who are taking nitrates, nor is it recommended in combination with insulin.

Finally, the FDA is evaluating postmarketing adverse event reports for varenicline (Chantix) describing suicidal ideation, suicide, and aggressive and erratic behavior in patients taking it for smoking cessation. While the review proceeds, physicians are advised to evaluate patients for behavior and mood disorders, as well as drowsiness. In patients taking varenicline, caution is advised while driving or operating machinery until the patient’s response to it is known. TH

Michele B. Kaufman is a freelance medical writer based in New York City.

References

1. Moore TJ, Cohen MJ, Furberg CD. Serious adverse drug events reported to the Food and Drug Administration, 1998-2005. Arch Intern Med. 2007;167:1752-1759.
2. Wechsler J. No shortage of recommendations for PDUFA IV as Congress and professional organizations weigh in on drug safety. Formulary 2007;42:264-265.
3. Yahav D, Paul M, Fraser A, Sarid N, Leibovici L. Efficacy and safety of cefepime: a systematic review and meta-analysis. Lancet Infect Dis. 2007 May;7(5):338-348.

A serious adverse drug event (ADE) is defined as one that causes death, disability, or permanent damage, hospitalization (initial or prolonged), or birth defects.

According to Moore, et al., the number of serious ADEs has increased significantly since 1998 through 2005, according to reports in the Food and Drug Administration (FDA) adverse event reporting system, also known as MedWatch.1 During that time, 467,809 serious ADEs were reported, and the annual number of reports had increased from 34,966 to 89,842.

The number of fatal ADEs increased in that period as well, from 4,419 to 15,109. Further, ADEs related to biotech drugs increased 15.8-fold. The most commonly reported classes with serious ADEs included anti-tumor necrosis factor drugs, interferons, and insulins. Drugs associated with ADEs included some that had been withdrawn from the U.S. market over safety concerns, as well as products that remained on the market.

On Sept. 27, the FDA Amendments Act of 2007 was passed. The measure includes the Prescription Drug User Fee Act (PDUFA), which authorizes the FDA to collect fees from drug makers to supplement funding for the drug-review process.2 A key revision now lets the agency require—not just request—that drug companies perform phase four clinical studies. The PDUFA also includes additional staff for reviewing medical devices. Additional stipulations are that the FDA will:

• Assess signals of serious risk related to drug use as they arise;
• Identify unexpected serious risks;
• Identify when post-marketing studies are needed; and
• Quickly submit a supplement proposing changes to the approved labeling of a drug to reflect new safety information, including changes to boxed warnings, contraindications, warnings, precautions, or adverse reactions within 30 days of identification.

This legislation has brought a number of new warnings on FDA-approved products.

The Warnings

A study in the May 2007 issue of Lancet Infectious Diseases noted higher all-cause mortality in patients treated with cefepime (Maxipime) compared with other beta-lactam antibiotics.3 Cefepime is FDA approved for the treatment of infections caused by susceptible gram-positive and gram-negative micro-organisms. The risk ratio (RR) was 1.26 (95% confidence interval [CI] 1.08–1.49) for cefepime and for the subgroup of patients with febrile neutropenia (RR 1.42 [95% CI 1.09–1.84]). The FDA is reviewing safety data and has requested additional data from Bristol-Myers Squibb to further evaluate the risk of death in cefepime-treated patients. The FDA asks healthcare professionals to report adverse events from cefepime and other agents to MedWatch at www.fda.gov/medwatch/report.htm.

A new warning regarding the pregnancy category and teratogenic effects has been added to the label of mycophenolic acid (MPA) delayed-release tablets (Myfortic). The FDA notes that use of MPA during pregnancy is associated with increased risks of pregnancy loss and congenital malformations, thereby changing the pregnancy category to D (positive evidence of fetal risk) from C (risk of fetal harm cannot be ruled out).

The MPA warnings and precautions sections also have changed. Results from postmarketing data from the U.S. National Transplantation Pregnancy Registry and additional postmarketing data collected in women exposed to systemic mycophenolate mofetil (MMF) during pregnancy brought these revisions. MMF is converted to the active ingredient in MPA following intravenous or oral administration. A patient planning to get pregnant should not use MMF/MPA unless she cannot be treated with other immunosuppressant drugs. Additionally, female patients of childbearing potential must receive contraceptive counseling and use contraception while on this agent. Remember, not only transplant patients receive MMF/MPA; patients with lupus nephritis also use it.

On Nov. 27, the Pediatric Advisory Committee of the FDA recommended changing the label of the two neuraminidase inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza), to reflect the potential for neuropsychiatric effects (mostly in children). Last year, Roche revised the oseltamivir label to add warnings of potential confusion and self-injury with the product. According to the FDA, about five patients died as a result of these neuropsychiatric effects, and nearly 600 cases of psychiatric problems were reported.

On Nov. 14, the FDA added to the black box label of rosiglitazone (Avandia) regarding an increased risk of myocardial infarction. The warning states that a recent meta-analysis of 42 clinical studies (mean duration six months, n=14,237) mostly comparing rosiglitazone with placebo, showed it to be associated with an increased risk of myocardial ischemic events. Further, three other studies (mean duration 41 months; n=14,067), comparing rosiglitazone with other oral antidiabetic agents or placebo, have not confirmed or excluded this risk. The available data on the risk of myocardial ischemia are currently inconclusive.

The FDA has asked that GlaxoSmithKline conduct extensive long-term, post-marketing trials to determine rosiglitazone’s cardiovascular safety. A study of this type, is a direct result of the new PDUFA legislation. The trial is expected to begin after July and end by 2014. Updates to the warnings, precautions, and indications sections were also added to the label. For example, rosiglitazone is not recommended for heart disease patients who are taking nitrates, nor is it recommended in combination with insulin.

Finally, the FDA is evaluating postmarketing adverse event reports for varenicline (Chantix) describing suicidal ideation, suicide, and aggressive and erratic behavior in patients taking it for smoking cessation. While the review proceeds, physicians are advised to evaluate patients for behavior and mood disorders, as well as drowsiness. In patients taking varenicline, caution is advised while driving or operating machinery until the patient’s response to it is known. TH

Michele B. Kaufman is a freelance medical writer based in New York City.

References

1. Moore TJ, Cohen MJ, Furberg CD. Serious adverse drug events reported to the Food and Drug Administration, 1998-2005. Arch Intern Med. 2007;167:1752-1759.
2. Wechsler J. No shortage of recommendations for PDUFA IV as Congress and professional organizations weigh in on drug safety. Formulary 2007;42:264-265.
3. Yahav D, Paul M, Fraser A, Sarid N, Leibovici L. Efficacy and safety of cefepime: a systematic review and meta-analysis. Lancet Infect Dis. 2007 May;7(5):338-348.

A serious adverse drug event (ADE) is defined as one that causes death, disability, or permanent damage, hospitalization (initial or prolonged), or birth defects.

According to Moore, et al., the number of serious ADEs has increased significantly since 1998 through 2005, according to reports in the Food and Drug Administration (FDA) adverse event reporting system, also known as MedWatch.1 During that time, 467,809 serious ADEs were reported, and the annual number of reports had increased from 34,966 to 89,842.

The number of fatal ADEs increased in that period as well, from 4,419 to 15,109. Further, ADEs related to biotech drugs increased 15.8-fold. The most commonly reported classes with serious ADEs included anti-tumor necrosis factor drugs, interferons, and insulins. Drugs associated with ADEs included some that had been withdrawn from the U.S. market over safety concerns, as well as products that remained on the market.

On Sept. 27, the FDA Amendments Act of 2007 was passed. The measure includes the Prescription Drug User Fee Act (PDUFA), which authorizes the FDA to collect fees from drug makers to supplement funding for the drug-review process.2 A key revision now lets the agency require—not just request—that drug companies perform phase four clinical studies. The PDUFA also includes additional staff for reviewing medical devices. Additional stipulations are that the FDA will:

• Assess signals of serious risk related to drug use as they arise;
• Identify unexpected serious risks;
• Identify when post-marketing studies are needed; and
• Quickly submit a supplement proposing changes to the approved labeling of a drug to reflect new safety information, including changes to boxed warnings, contraindications, warnings, precautions, or adverse reactions within 30 days of identification.

This legislation has brought a number of new warnings on FDA-approved products.

The Warnings

A study in the May 2007 issue of Lancet Infectious Diseases noted higher all-cause mortality in patients treated with cefepime (Maxipime) compared with other beta-lactam antibiotics.3 Cefepime is FDA approved for the treatment of infections caused by susceptible gram-positive and gram-negative micro-organisms. The risk ratio (RR) was 1.26 (95% confidence interval [CI] 1.08–1.49) for cefepime and for the subgroup of patients with febrile neutropenia (RR 1.42 [95% CI 1.09–1.84]). The FDA is reviewing safety data and has requested additional data from Bristol-Myers Squibb to further evaluate the risk of death in cefepime-treated patients. The FDA asks healthcare professionals to report adverse events from cefepime and other agents to MedWatch at www.fda.gov/medwatch/report.htm.

A new warning regarding the pregnancy category and teratogenic effects has been added to the label of mycophenolic acid (MPA) delayed-release tablets (Myfortic). The FDA notes that use of MPA during pregnancy is associated with increased risks of pregnancy loss and congenital malformations, thereby changing the pregnancy category to D (positive evidence of fetal risk) from C (risk of fetal harm cannot be ruled out).

The MPA warnings and precautions sections also have changed. Results from postmarketing data from the U.S. National Transplantation Pregnancy Registry and additional postmarketing data collected in women exposed to systemic mycophenolate mofetil (MMF) during pregnancy brought these revisions. MMF is converted to the active ingredient in MPA following intravenous or oral administration. A patient planning to get pregnant should not use MMF/MPA unless she cannot be treated with other immunosuppressant drugs. Additionally, female patients of childbearing potential must receive contraceptive counseling and use contraception while on this agent. Remember, not only transplant patients receive MMF/MPA; patients with lupus nephritis also use it.

On Nov. 27, the Pediatric Advisory Committee of the FDA recommended changing the label of the two neuraminidase inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza), to reflect the potential for neuropsychiatric effects (mostly in children). Last year, Roche revised the oseltamivir label to add warnings of potential confusion and self-injury with the product. According to the FDA, about five patients died as a result of these neuropsychiatric effects, and nearly 600 cases of psychiatric problems were reported.

On Nov. 14, the FDA added to the black box label of rosiglitazone (Avandia) regarding an increased risk of myocardial infarction. The warning states that a recent meta-analysis of 42 clinical studies (mean duration six months, n=14,237) mostly comparing rosiglitazone with placebo, showed it to be associated with an increased risk of myocardial ischemic events. Further, three other studies (mean duration 41 months; n=14,067), comparing rosiglitazone with other oral antidiabetic agents or placebo, have not confirmed or excluded this risk. The available data on the risk of myocardial ischemia are currently inconclusive.

The FDA has asked that GlaxoSmithKline conduct extensive long-term, post-marketing trials to determine rosiglitazone’s cardiovascular safety. A study of this type, is a direct result of the new PDUFA legislation. The trial is expected to begin after July and end by 2014. Updates to the warnings, precautions, and indications sections were also added to the label. For example, rosiglitazone is not recommended for heart disease patients who are taking nitrates, nor is it recommended in combination with insulin.

Finally, the FDA is evaluating postmarketing adverse event reports for varenicline (Chantix) describing suicidal ideation, suicide, and aggressive and erratic behavior in patients taking it for smoking cessation. While the review proceeds, physicians are advised to evaluate patients for behavior and mood disorders, as well as drowsiness. In patients taking varenicline, caution is advised while driving or operating machinery until the patient’s response to it is known. TH

Michele B. Kaufman is a freelance medical writer based in New York City.

References

1. Moore TJ, Cohen MJ, Furberg CD. Serious adverse drug events reported to the Food and Drug Administration, 1998-2005. Arch Intern Med. 2007;167:1752-1759.
2. Wechsler J. No shortage of recommendations for PDUFA IV as Congress and professional organizations weigh in on drug safety. Formulary 2007;42:264-265.
3. Yahav D, Paul M, Fraser A, Sarid N, Leibovici L. Efficacy and safety of cefepime: a systematic review and meta-analysis. Lancet Infect Dis. 2007 May;7(5):338-348.

Drug-induced liver injury (DILI) or hepatotoxicity accounts for more than 50% of all cases of acute liver failure. DILI, often life-threatening, is the leading cause of patient referral for liver transplantation.1,2

DILI is an important diagnostic challenge for the treating clinician because of its presentation, which is often a diagnosis of exclusion. Determination of all potential causes of hepatic injury need to be assessed through onset of symptoms and a careful drug history (including prescription and over-the-counter medication, dietary supplements, and complementary and alternative therapies).3

DILI has brought an increase in Food and Drug Administration (FDA) “black box” warnings. Among the drugs affected are ketoconazole, pemoline, tolcapone, valproate sodium, and zalcitabine.4

A number of drugs have been withdrawn from the U.S. market after DILI or interactions with those that are hepatically metabolized, such as:

• Astemizole (cardiotoxicity);
• Bromfenac sodium, cisapride (cardiotoxicity);
• Felbamate, mibefradil (cardiotoxicity);
• Temafloxacin (abnormal liver function tests, as well as renal failure and other serious adverse events);
• Terfenadine (cardiotoxicity);
• Troglitazone; and
• Trovafloxacin mesylate.

One of the most common causes of DILI is intentional or unintentional overdose with acetaminophen.

DILI has been classified into two major types: cholestatic and hepatocellular, or cytolytic injury. In cholestatic liver injury, the serum alkaline phosphatase (ALP) is elevated; total bilirubin level (TBL) and the alanine aminotransferase (ALT) may also be elevated. In hepatocellular injury, initial elevation is noted in the ALT.

There may also be overlap in the pattern of injury (mixed-pattern injury) whereby ALP and ALT are elevated. These patterns of injury may be defined further by the degree of enzyme elevation, such as an ALT level of three or more times the upper limit of normal (ULN), an ALP level two or more times ULN, and TBL two or more times ULN if associated with an elevation of ALP or ALT.

Hepatotoxicity is often predictable—but not always. When predictable, the reaction is usually dose-dependent, such as in the case of acetaminophen. These reactions usually occur shortly after a threshold for toxicity has been reached. Unpredictable reactions can occur days or months after exposure, usually without warning. Hypersensitivity reactions are often delayed and occur upon repeated exposure to the agent. Symptoms of immunologic injury may include rash, fever, or eosinophilia. More severe forms include Stevens-Johnson syndrome, toxic epidermal necrolysis, or cytopenias. Reactions are more severe upon repeat exposure or rechallenge of the offending agent.

Symptomatology

Patients usually present with vague symptoms that may include nausea, anorexia, fatigue, right upper-quadrant discomfort, jaundice, or dark urine. Patients with cholestatic liver disease may also present with pruritus.

Any of these along with laboratory evidence of liver injury should indicate further investigation into possible DILI. Impaired hepatic function such as increased prothrombin time and encephalopathy (signs of acute liver failure) indicate severe hepatic injury.

The Agents

Common causes of hepatocellular injury include: acetaminophen, fluoxetine, highly active antiretroviral therapies, kava kava (other herbal products), non-steroidal anti-inflammatory drugs, paroxetine, rifampin, risperidone, statins, trazodone, and troglitazone.

Common causes of cholestatic injury include: ampicillin-clavulanic acid, anabolic steroids, chlorpromazine, clopidogrel, estrogens, mirtazapine, terbinafine, and tricyclics.

Common causes of mixed-pattern injury include: amitriptyline, azathioprine, captopril, carbamazepine, enalapril, erythromycins, flutamide, phenytoin, sulfonamides, trazodone, and trimethoprim-sulfamethoxazole.

Most cases of non-fulminant hepatitis will improve upon cessation of offending or potentially offending agent(s). Assess hepatic injury immediately via continuously obtained biochemical tests.

Consult a hepatologist or gastroenterologist immediately if jaundice, impaired hepatic function or clinical signs of acute hepatic failure (e.g., encephalopathy) are evident.

Report all cases of potential DILI to the FDA’s adverse events reporting program, Medwatch, at www.fda.gov/ medwatch or by calling (800) 332-1088. For patients receiving potentially hepatotoxic agents, liver function test monitoring is recommended following a baseline assessment. Some agents require monthly rather than periodic monitoring. For a list of some agents that require hepatic monitoring and the recommended frequency, visit www.factsandcomparisons.com/assets/hospitalpharm/feb2002_HepSp.pdf.5 TH

Michele B. Kaufman is a freelance medical writer based in New York City.

References

1. Nathwani RA, Kaplowitz N. Drug hepatotoxicity. Clin Liver Dis. 2006;10:207-217.
2. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731-739.
3. Hepatic Toxicity Possibly Associated with Kava-Containing Products—United States, Germany, and Switzerland, 1999-2002. MMWR Weekly, Nov. 29, 2002/51(47):1065-1067. Available at: www.cdc.gov/MMWR/previews/mmwrhtml/mm5147a1.htm. Last accessed Nov. 5, 2007.
4. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002;287:17:2215-2220.
5. Tice SA, Parr D. Medications that require hepatic monitoring. Hospital Pharmacy 2004;39(6):595-606.

Drug-induced liver injury (DILI) or hepatotoxicity accounts for more than 50% of all cases of acute liver failure. DILI, often life-threatening, is the leading cause of patient referral for liver transplantation.1,2

DILI is an important diagnostic challenge for the treating clinician because of its presentation, which is often a diagnosis of exclusion. Determination of all potential causes of hepatic injury need to be assessed through onset of symptoms and a careful drug history (including prescription and over-the-counter medication, dietary supplements, and complementary and alternative therapies).3

DILI has brought an increase in Food and Drug Administration (FDA) “black box” warnings. Among the drugs affected are ketoconazole, pemoline, tolcapone, valproate sodium, and zalcitabine.4

A number of drugs have been withdrawn from the U.S. market after DILI or interactions with those that are hepatically metabolized, such as:

• Astemizole (cardiotoxicity);
• Bromfenac sodium, cisapride (cardiotoxicity);
• Felbamate, mibefradil (cardiotoxicity);
• Temafloxacin (abnormal liver function tests, as well as renal failure and other serious adverse events);
• Terfenadine (cardiotoxicity);
• Troglitazone; and
• Trovafloxacin mesylate.

One of the most common causes of DILI is intentional or unintentional overdose with acetaminophen.

DILI has been classified into two major types: cholestatic and hepatocellular, or cytolytic injury. In cholestatic liver injury, the serum alkaline phosphatase (ALP) is elevated; total bilirubin level (TBL) and the alanine aminotransferase (ALT) may also be elevated. In hepatocellular injury, initial elevation is noted in the ALT.

There may also be overlap in the pattern of injury (mixed-pattern injury) whereby ALP and ALT are elevated. These patterns of injury may be defined further by the degree of enzyme elevation, such as an ALT level of three or more times the upper limit of normal (ULN), an ALP level two or more times ULN, and TBL two or more times ULN if associated with an elevation of ALP or ALT.

Hepatotoxicity is often predictable—but not always. When predictable, the reaction is usually dose-dependent, such as in the case of acetaminophen. These reactions usually occur shortly after a threshold for toxicity has been reached. Unpredictable reactions can occur days or months after exposure, usually without warning. Hypersensitivity reactions are often delayed and occur upon repeated exposure to the agent. Symptoms of immunologic injury may include rash, fever, or eosinophilia. More severe forms include Stevens-Johnson syndrome, toxic epidermal necrolysis, or cytopenias. Reactions are more severe upon repeat exposure or rechallenge of the offending agent.

Symptomatology

Patients usually present with vague symptoms that may include nausea, anorexia, fatigue, right upper-quadrant discomfort, jaundice, or dark urine. Patients with cholestatic liver disease may also present with pruritus.

Any of these along with laboratory evidence of liver injury should indicate further investigation into possible DILI. Impaired hepatic function such as increased prothrombin time and encephalopathy (signs of acute liver failure) indicate severe hepatic injury.

The Agents

Common causes of hepatocellular injury include: acetaminophen, fluoxetine, highly active antiretroviral therapies, kava kava (other herbal products), non-steroidal anti-inflammatory drugs, paroxetine, rifampin, risperidone, statins, trazodone, and troglitazone.

Common causes of cholestatic injury include: ampicillin-clavulanic acid, anabolic steroids, chlorpromazine, clopidogrel, estrogens, mirtazapine, terbinafine, and tricyclics.

Common causes of mixed-pattern injury include: amitriptyline, azathioprine, captopril, carbamazepine, enalapril, erythromycins, flutamide, phenytoin, sulfonamides, trazodone, and trimethoprim-sulfamethoxazole.

Most cases of non-fulminant hepatitis will improve upon cessation of offending or potentially offending agent(s). Assess hepatic injury immediately via continuously obtained biochemical tests.

Consult a hepatologist or gastroenterologist immediately if jaundice, impaired hepatic function or clinical signs of acute hepatic failure (e.g., encephalopathy) are evident.

Report all cases of potential DILI to the FDA’s adverse events reporting program, Medwatch, at www.fda.gov/ medwatch or by calling (800) 332-1088. For patients receiving potentially hepatotoxic agents, liver function test monitoring is recommended following a baseline assessment. Some agents require monthly rather than periodic monitoring. For a list of some agents that require hepatic monitoring and the recommended frequency, visit www.factsandcomparisons.com/assets/hospitalpharm/feb2002_HepSp.pdf.5 TH

Michele B. Kaufman is a freelance medical writer based in New York City.

References

1. Nathwani RA, Kaplowitz N. Drug hepatotoxicity. Clin Liver Dis. 2006;10:207-217.
2. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731-739.
3. Hepatic Toxicity Possibly Associated with Kava-Containing Products—United States, Germany, and Switzerland, 1999-2002. MMWR Weekly, Nov. 29, 2002/51(47):1065-1067. Available at: www.cdc.gov/MMWR/previews/mmwrhtml/mm5147a1.htm. Last accessed Nov. 5, 2007.
4. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002;287:17:2215-2220.
5. Tice SA, Parr D. Medications that require hepatic monitoring. Hospital Pharmacy 2004;39(6):595-606.

Drug-induced liver injury (DILI) or hepatotoxicity accounts for more than 50% of all cases of acute liver failure. DILI, often life-threatening, is the leading cause of patient referral for liver transplantation.1,2

DILI is an important diagnostic challenge for the treating clinician because of its presentation, which is often a diagnosis of exclusion. Determination of all potential causes of hepatic injury need to be assessed through onset of symptoms and a careful drug history (including prescription and over-the-counter medication, dietary supplements, and complementary and alternative therapies).3

DILI has brought an increase in Food and Drug Administration (FDA) “black box” warnings. Among the drugs affected are ketoconazole, pemoline, tolcapone, valproate sodium, and zalcitabine.4

A number of drugs have been withdrawn from the U.S. market after DILI or interactions with those that are hepatically metabolized, such as:

• Astemizole (cardiotoxicity);
• Bromfenac sodium, cisapride (cardiotoxicity);
• Felbamate, mibefradil (cardiotoxicity);
• Temafloxacin (abnormal liver function tests, as well as renal failure and other serious adverse events);
• Terfenadine (cardiotoxicity);
• Troglitazone; and
• Trovafloxacin mesylate.

One of the most common causes of DILI is intentional or unintentional overdose with acetaminophen.

DILI has been classified into two major types: cholestatic and hepatocellular, or cytolytic injury. In cholestatic liver injury, the serum alkaline phosphatase (ALP) is elevated; total bilirubin level (TBL) and the alanine aminotransferase (ALT) may also be elevated. In hepatocellular injury, initial elevation is noted in the ALT.

There may also be overlap in the pattern of injury (mixed-pattern injury) whereby ALP and ALT are elevated. These patterns of injury may be defined further by the degree of enzyme elevation, such as an ALT level of three or more times the upper limit of normal (ULN), an ALP level two or more times ULN, and TBL two or more times ULN if associated with an elevation of ALP or ALT.

Hepatotoxicity is often predictable—but not always. When predictable, the reaction is usually dose-dependent, such as in the case of acetaminophen. These reactions usually occur shortly after a threshold for toxicity has been reached. Unpredictable reactions can occur days or months after exposure, usually without warning. Hypersensitivity reactions are often delayed and occur upon repeated exposure to the agent. Symptoms of immunologic injury may include rash, fever, or eosinophilia. More severe forms include Stevens-Johnson syndrome, toxic epidermal necrolysis, or cytopenias. Reactions are more severe upon repeat exposure or rechallenge of the offending agent.

Symptomatology

Patients usually present with vague symptoms that may include nausea, anorexia, fatigue, right upper-quadrant discomfort, jaundice, or dark urine. Patients with cholestatic liver disease may also present with pruritus.

Any of these along with laboratory evidence of liver injury should indicate further investigation into possible DILI. Impaired hepatic function such as increased prothrombin time and encephalopathy (signs of acute liver failure) indicate severe hepatic injury.

The Agents

Common causes of hepatocellular injury include: acetaminophen, fluoxetine, highly active antiretroviral therapies, kava kava (other herbal products), non-steroidal anti-inflammatory drugs, paroxetine, rifampin, risperidone, statins, trazodone, and troglitazone.

Common causes of cholestatic injury include: ampicillin-clavulanic acid, anabolic steroids, chlorpromazine, clopidogrel, estrogens, mirtazapine, terbinafine, and tricyclics.

Common causes of mixed-pattern injury include: amitriptyline, azathioprine, captopril, carbamazepine, enalapril, erythromycins, flutamide, phenytoin, sulfonamides, trazodone, and trimethoprim-sulfamethoxazole.

Most cases of non-fulminant hepatitis will improve upon cessation of offending or potentially offending agent(s). Assess hepatic injury immediately via continuously obtained biochemical tests.

Consult a hepatologist or gastroenterologist immediately if jaundice, impaired hepatic function or clinical signs of acute hepatic failure (e.g., encephalopathy) are evident.

Report all cases of potential DILI to the FDA’s adverse events reporting program, Medwatch, at www.fda.gov/ medwatch or by calling (800) 332-1088. For patients receiving potentially hepatotoxic agents, liver function test monitoring is recommended following a baseline assessment. Some agents require monthly rather than periodic monitoring. For a list of some agents that require hepatic monitoring and the recommended frequency, visit www.factsandcomparisons.com/assets/hospitalpharm/feb2002_HepSp.pdf.5 TH

Michele B. Kaufman is a freelance medical writer based in New York City.

References

1. Nathwani RA, Kaplowitz N. Drug hepatotoxicity. Clin Liver Dis. 2006;10:207-217.
2. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731-739.
3. Hepatic Toxicity Possibly Associated with Kava-Containing Products—United States, Germany, and Switzerland, 1999-2002. MMWR Weekly, Nov. 29, 2002/51(47):1065-1067. Available at: www.cdc.gov/MMWR/previews/mmwrhtml/mm5147a1.htm. Last accessed Nov. 5, 2007.
4. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002;287:17:2215-2220.
5. Tice SA, Parr D. Medications that require hepatic monitoring. Hospital Pharmacy 2004;39(6):595-606.