Serotonin Syndrome

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Serotonin Syndrome

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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.

Market watch

New Drugs, Indications, and Dosage Forms

Almivopan (Entereg) has been approved by the Food and Drug Administration (FDA) for treating postoperative ileus in hospitalized adults only. The dose is one 12 mg capsule given immediately pre-operatively and another 12 mg dose given twice daily for up to seven days post-operatively (not to exceed 15 doses).

Darunavir (Prezista) is available as a new 600 mg tablet.

Duloxetine (Cymbalta) has been FDA approved as a once-daily (60 mg) treatment for fibromyalgia in adults.

Ropinirole extended-release (Requip XL): has been FDA approved as a once daily treatment for Parkinson’s disease.

Zoledronic acid intravenous injection (Reclast IV) has been FDA approved for the prevention of new clinical fractures in patients who have recently had a low-trauma hip.

Pipeline

A supplemental new drug application for IV esomeprazole (Nexium) has been submitted to the FDA for the management of peptic ulcer bleeding subsequent to endoscopy.

New Information

Metered-dose inhaler (MDI) phase-out: MDIs for asthma and chronic obstructive pulmonary are subject to the Clean Air Act and the Montreal Protocol. The Montreal Protocol is an international treaty signed in 1987 to protect the ozone layer. It includes the phaseout of substances believed to cause ozone layer depletion.

The 1978 rule prohibits the use of chlorofluorocarbons (CFCs) as propellants in self-pressurized containers in any food, drug, medical device, or cosmetic with a subsequent phasing-out out of these containers. Many of the drug products have switched to non-CFC MDIs (e.g., hydrofluoroalkane [HFA] propellants) and dry-powder inhalers (DPIs).

The deadline for product removal of CFCs is at the end of 2008, although the change has been slow. Some newer CFC-free inhalers include Proair HFA, Proventil HFA, Ventolin HFA, and Xopenex HFA. Some of these branded products are more costly then their generic counterparts. Please convert any of your patients who are still using CFC inhalers to CFC-free inhalers.

The FDA is planning public service announcements for patients to educate them about the changes. The newer albuterol HFA inhalers have prescription assistance programs for patients in financial need from the manufacturers (e.g., GlaxoSmithKline, Teva, Schering-Plough, Sepracor). The Partnership for Prescription Assistance can be reached at (888) 477-2669 or at www.pparx.org.

New Warnings

Becaplermin gel (Regranex), the recombinant human platelet-derived growth factor used to treat lower extremity diabetic neuropathic ulcers, has undergone a label change with the addition of a boxed warning. A literature review determined there is a five-times greater risk of death in those who used three or more tubes of the gel, compared with those who did not use becaplermin gel. The follow-up duration was not long enough to detect new cancers. The warning also notes becaplermin only should be used when the benefits outweigh the risks and it should be used with caution in patients with known cancers.

Conventional antipsychotic agents: The FDA has notified healthcare providers that both conventional and atypical antipsychotics are associated with increased mortality risk in elderly patients treated for dementia-related psychosis subsequent to a continued information review of conventional antipsychotics. Antipsychotics are not FDA approved to treat dementia-related psychosis. The boxed warning and warning sections of all antipsychotic agents have been updated to include this new information.—MK

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

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.

Soldin OP, Tonning JM. Serotonin syndrome associated with triptan monotherapy. N Engl J Med. 2008;358(20):2185-2186.

Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.

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.

Mayo Clinic.com. Diseases and conditions. www.mayoclinic.com/health/serotonin-syndrome/DS00860. Last accessed June 20, 2008.

Issue

The Hospitalist - 2008(09)

Publications

Sections

Author(s)

Michele B. Kaufman, PharmD, BSc, RPh

Author(s)

Michele B. Kaufman, PharmD, BSc, RPh

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.

Market watch

New Drugs, Indications, and Dosage Forms

Almivopan (Entereg) has been approved by the Food and Drug Administration (FDA) for treating postoperative ileus in hospitalized adults only. The dose is one 12 mg capsule given immediately pre-operatively and another 12 mg dose given twice daily for up to seven days post-operatively (not to exceed 15 doses).

Darunavir (Prezista) is available as a new 600 mg tablet.

Duloxetine (Cymbalta) has been FDA approved as a once-daily (60 mg) treatment for fibromyalgia in adults.

Ropinirole extended-release (Requip XL): has been FDA approved as a once daily treatment for Parkinson’s disease.

Zoledronic acid intravenous injection (Reclast IV) has been FDA approved for the prevention of new clinical fractures in patients who have recently had a low-trauma hip.

Pipeline

A supplemental new drug application for IV esomeprazole (Nexium) has been submitted to the FDA for the management of peptic ulcer bleeding subsequent to endoscopy.

New Information

Metered-dose inhaler (MDI) phase-out: MDIs for asthma and chronic obstructive pulmonary are subject to the Clean Air Act and the Montreal Protocol. The Montreal Protocol is an international treaty signed in 1987 to protect the ozone layer. It includes the phaseout of substances believed to cause ozone layer depletion.

The 1978 rule prohibits the use of chlorofluorocarbons (CFCs) as propellants in self-pressurized containers in any food, drug, medical device, or cosmetic with a subsequent phasing-out out of these containers. Many of the drug products have switched to non-CFC MDIs (e.g., hydrofluoroalkane [HFA] propellants) and dry-powder inhalers (DPIs).

The deadline for product removal of CFCs is at the end of 2008, although the change has been slow. Some newer CFC-free inhalers include Proair HFA, Proventil HFA, Ventolin HFA, and Xopenex HFA. Some of these branded products are more costly then their generic counterparts. Please convert any of your patients who are still using CFC inhalers to CFC-free inhalers.

The FDA is planning public service announcements for patients to educate them about the changes. The newer albuterol HFA inhalers have prescription assistance programs for patients in financial need from the manufacturers (e.g., GlaxoSmithKline, Teva, Schering-Plough, Sepracor). The Partnership for Prescription Assistance can be reached at (888) 477-2669 or at www.pparx.org.

New Warnings

Becaplermin gel (Regranex), the recombinant human platelet-derived growth factor used to treat lower extremity diabetic neuropathic ulcers, has undergone a label change with the addition of a boxed warning. A literature review determined there is a five-times greater risk of death in those who used three or more tubes of the gel, compared with those who did not use becaplermin gel. The follow-up duration was not long enough to detect new cancers. The warning also notes becaplermin only should be used when the benefits outweigh the risks and it should be used with caution in patients with known cancers.

Conventional antipsychotic agents: The FDA has notified healthcare providers that both conventional and atypical antipsychotics are associated with increased mortality risk in elderly patients treated for dementia-related psychosis subsequent to a continued information review of conventional antipsychotics. Antipsychotics are not FDA approved to treat dementia-related psychosis. The boxed warning and warning sections of all antipsychotic agents have been updated to include this new information.—MK

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

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.

Soldin OP, Tonning JM. Serotonin syndrome associated with triptan monotherapy. N Engl J Med. 2008;358(20):2185-2186.

Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.

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.

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.

Market watch

New Drugs, Indications, and Dosage Forms

Almivopan (Entereg) has been approved by the Food and Drug Administration (FDA) for treating postoperative ileus in hospitalized adults only. The dose is one 12 mg capsule given immediately pre-operatively and another 12 mg dose given twice daily for up to seven days post-operatively (not to exceed 15 doses).

Darunavir (Prezista) is available as a new 600 mg tablet.

Duloxetine (Cymbalta) has been FDA approved as a once-daily (60 mg) treatment for fibromyalgia in adults.

Ropinirole extended-release (Requip XL): has been FDA approved as a once daily treatment for Parkinson’s disease.

Zoledronic acid intravenous injection (Reclast IV) has been FDA approved for the prevention of new clinical fractures in patients who have recently had a low-trauma hip.

Pipeline

A supplemental new drug application for IV esomeprazole (Nexium) has been submitted to the FDA for the management of peptic ulcer bleeding subsequent to endoscopy.

New Information

Metered-dose inhaler (MDI) phase-out: MDIs for asthma and chronic obstructive pulmonary are subject to the Clean Air Act and the Montreal Protocol. The Montreal Protocol is an international treaty signed in 1987 to protect the ozone layer. It includes the phaseout of substances believed to cause ozone layer depletion.

The 1978 rule prohibits the use of chlorofluorocarbons (CFCs) as propellants in self-pressurized containers in any food, drug, medical device, or cosmetic with a subsequent phasing-out out of these containers. Many of the drug products have switched to non-CFC MDIs (e.g., hydrofluoroalkane [HFA] propellants) and dry-powder inhalers (DPIs).

The deadline for product removal of CFCs is at the end of 2008, although the change has been slow. Some newer CFC-free inhalers include Proair HFA, Proventil HFA, Ventolin HFA, and Xopenex HFA. Some of these branded products are more costly then their generic counterparts. Please convert any of your patients who are still using CFC inhalers to CFC-free inhalers.

The FDA is planning public service announcements for patients to educate them about the changes. The newer albuterol HFA inhalers have prescription assistance programs for patients in financial need from the manufacturers (e.g., GlaxoSmithKline, Teva, Schering-Plough, Sepracor). The Partnership for Prescription Assistance can be reached at (888) 477-2669 or at www.pparx.org.

New Warnings

Becaplermin gel (Regranex), the recombinant human platelet-derived growth factor used to treat lower extremity diabetic neuropathic ulcers, has undergone a label change with the addition of a boxed warning. A literature review determined there is a five-times greater risk of death in those who used three or more tubes of the gel, compared with those who did not use becaplermin gel. The follow-up duration was not long enough to detect new cancers. The warning also notes becaplermin only should be used when the benefits outweigh the risks and it should be used with caution in patients with known cancers.

Conventional antipsychotic agents: The FDA has notified healthcare providers that both conventional and atypical antipsychotics are associated with increased mortality risk in elderly patients treated for dementia-related psychosis subsequent to a continued information review of conventional antipsychotics. Antipsychotics are not FDA approved to treat dementia-related psychosis. The boxed warning and warning sections of all antipsychotic agents have been updated to include this new information.—MK

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

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.

Soldin OP, Tonning JM. Serotonin syndrome associated with triptan monotherapy. N Engl J Med. 2008;358(20):2185-2186.

Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.

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.