Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1) 1(((3-(2-(Dimethylamino)ethyl)indol-5-yl)methyl)-
2) sulfonyl)pyrrolidine
3) Dimethyl (2-(5-(pyrrolidin-1-ylsulfonylmethyl)
4) indol-3-yl)ethyl)amine
5) LAS 31416
6) Molecular Formula: C17-H25-N3-O2-S
7) CAS 154323-57-6

1) BMS-180048
2) BMS-180048-02
3) 1H-Indole-5-methanesulfonamide, 3-(3-(4-
4) (5-methoxy-4-pyrimidinyl)-1-piperazinyl)-propyl)
5) -N-methyl-,(E)-2-butenedioate (1:1)
6) 3-(3-(4-(5-Methoxy-4-pyrimidinyl)-1-piperazinyl)
7) propyl)-N-methylindole-5-methanesulfonamide
8) fumarate (1:1)
9) Molecular Formula: C22-H30-N6-O3-S . C4-H4-O4
10) CAS 171171-42-9

1) (R)-2-(3-(1-Methylpyrrolidin-2-ylmethyl)indol
2) -5-yl) ethyl phenyl sulfone
3) Relpax
4) UK-116044
5) UK-116044-04
6) Molecular Formula: C22-H26-N2-O2-S
7) CAS 143322-58-1

1) (6R)-5,6,7,8-Tetrahydro-6-methylaminocarbazole-3-
2) carboxamide
3) Miguard
4) SB-209509
5) SB-209509AX
6) VML-251
7) Molecular Formula: C14-H17-N3-O
8) CAS 158747-02-5 (frovatriptan)
9) CAS 158930-17-7 (frovatriptan succinate
10) monohydrate)

1) GR-85548A (naratriptan hydrochloride)
2) GR-85548X (naratriptan)
3) N-Methyl-3-(1-methyl-4-piperidyl)indole-5-
4) ethanesulfonamide hydrochloride
5) Molecular Formula: C17-H25-N3-O2-S-HCl
6) CAS 121679-13-8 (naratriptan)
7) CAS 121679-19-4 (naratriptan hydrochloride)

1) 3-(2-(dimethylamino)ethyl)-N-methyl-1H-indole-5-
2) methanesulfonamide butane-1,4dioate(1:1)
3) GR-43175C
4) GR-43175X
5) Imitrex (Glaxo, Inc)
6) 3-(2-(dimethylamino)ethyl)-N-methyl-1H-indole-5-
7) methanesulfonamide succinate
8) CAS 103628-46-2 (sumatriptan)
9) CAS 103628-48-4 (sumatriptan succinate)

1) MK-462

1) 311C90
2) (S)-4-(3-(2-(Dimethylamino)ethyl)indol-5-ylmethyl)
3) -1,3-oxazolidin-2-one
4) Molecular Formula: C16-H21-N3-O2
5) CAS 139264-17-8

1.2.1) MOLECULAR FORMULA
1) ALMOTRIPTAN MALATE: C17H25N3O2S-C4H6O5
2) ELETRIPTAN HYDROBROMIDE: C22H26N2O2S.HBr
3) FROVATRIPTAN SUCCINATE: C14H17N3O.C4H6O4.H2O
4) NARATRIPTAN HYDROCHLORIDE: C17H25N3O2S.HCl
5) RIZATRIPTAN BENZOATE: C15H19N5.C7H6O2
6) SUMATRIPTAN: C14H21N3O2S
7) SUMATRIPTAN SUCCINATE: C14H21N3O2S.C4H6O4
8) ZOLMITRIPTAN: C16H21N3O2

Available Forms Sources

A)

1) ALMOTRIPTAN

a) ORAL: Available in 6.25 and 12.5 mg tablets (Prod Info AXERT(R) oral tablets, 2009).

2) ELETRIPTAN

a) ORAL: Available in 20 mg and 40 mg orange, round, convex shaped, film-coated tablets (Prod Info RELPAX(R) oral tablets, 2008).

3) NARATRIPTAN

a) ORAL: Available in 1 (white) and 2.5 mg (green) in D-shaped, film coated tablets (Prod Info AMERGE(R) oral tablets, 2010a).

4) SUMATRIPTAN

a) ORAL: Available in 25, 50 and 100 mg tablets (Prod Info IMITREX(R) oral tablets, 2010).
b) INJECTION: Available in 4 mg and 6 mg single-dose prefilled syringe cartridges (4 mg or 6 mg base per 0.5 mL solution) (Prod Info IMITREX(R) injection, 2010).
c) NASAL SPRAY: Available in 5 mg and 20 mg nasal spray (Prod Info IMITREX(R) nasal spray, 2010).
d) TRANSDERMAL PATCH: As of June 2016, Teva Pharmaceuticals, the manufacturer of sumatriptan transdermal patch, has decided to temporarily suspend the sale, marketing and distribution of their product due to reports of burns and scarring of the skin after removal of the patch. Symptoms have included severe redness, pain, skin discoloration, blistering and cracked skin. Patients and healthcare providers are urged to report any possible side effects to the FDA Medwatch Program (US Food and Drug Administration (FDA), 2016).

B)

1) These agents are selective serotonin agonists, which act at 5-HT(1) receptors, and are used for acute treatment of migraine headaches with or without aura in adults (Prod Info AXERT(R) oral tablets, 2009; Prod Info RELPAX(R) oral tablets, 2008; Prod Info AMERGE(R) oral tablets, 2010a; Prod Info IMITREX(R) oral tablets, 2010; Prod Info IMITREX(R) injection, 2010).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Sumatriptan and related medications are selective serotonin agonists indicated for the treatment of migraine headaches and cluster headaches.
B) PHARMACOLOGY: Triptans activate vascular serotonin 5-HT1 receptors, producing vasoconstriction. This theoretically antagonizes the cerebral vasodilation that causes migraine headaches.
C) TOXICOLOGY: In overdose, triptans lose their selectivity for the cerebral vasculature and causes excessive vasoconstriction via activation of vascular serotonin receptors. This excess vasoconstriction can result in hypertension, and could cause end-organ ischemia. Triptans can cause serotonin syndrome.
D) EPIDEMIOLOGY: Overdoses of sumatriptan are relatively rare. Deaths have not been reported with poisoning, but severe cardiovascular effects have been associated with therapeutic doses.
E) WITH THERAPEUTIC USE

1) ADVERSE EVENTS: Common adverse effects of sumatriptan include nausea, vomiting, dyspepsia, flushing and paresthesias. Chest pressure is reported in up to 15% of sumatriptan users but does not appear to be related to coronary vasospasm. Triptans have been reported to cause serotonin syndrome in isolation as well as when taken in conjunction with selective serotonin reuptake inhibitors (SSRIs) or MAO inhibitors.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Hypertension is common; patients are often asymptomatic. Triptans can cause serotonin syndrome in isolation or in conjunction with selective serotonin reuptake inhibitors (SSRIs) or MAO inhibitors. Symptoms of serotonin syndrome include altered mental status, hyperreflexia greater in the lower extremities, nystagmus, tremor, diaphoresis, and autonomic instability.
2) SEVERE TOXICITY: While not described in the literature, overdose can theoretically cause vasoconstriction with severe hypertension, myocardial infarction, cardiac dysrhythmias, renal infarction, splenic infarction, ischemic colitis, and cerebral vascular accident (ischemic and hemorrhagic). Triptans can cause serotonin syndrome in isolation or in conjunction with selective serotonin reuptake inhibitors (SSRIs) or MAO inhibitors. Symptoms of serotonin syndrome include altered mental status, hyperreflexia greater in the lower extremities, nystagmus, tremor, diaphoresis, autonomic instability, rigidity and hyperthermia.

0.2.3)

A) WITH THERAPEUTIC USE

1) Hypertension may occur.

0.2.20)

A) Sumatriptan and related agents are classified as FDA pregnancy category C. Several studies have shown no congenital anomalies following the use of sumatriptan and naratriptan. The possibility of sumatriptan exposure during pregnancy leading to low-birth-weight infants or premature delivery was suggested based on analysis of the Danish Birth Registry. Animal reproductive studies of sumatriptan and related agents have shown fetal developmental and maternal toxicities. Sumatriptan and eletriptan were both shown to be excreted in human milk. Several other agents were excreted in the milk of lactating rats. In animal fertility studies, there was evidence of prolonged estrous cycles in rats following exposure to several of the agents during mating.

0.2.21)

A) At the time of this review, the manufacturers do not report any carcinogenic potential for sumatriptan and related agents.

Laboratory Monitoring

A)

B)

C)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Care is symptomatic and supportive.

B) MANAGEMENT OF SEVERE TOXICITY

1) HYPERTENSION: Treat severe hypertension (end organ effects) with sodium nitroprusside or nitroglycerin. Labetalol, dihydropyridine calcium channel blockers and phentolamine are alternatives. Triptan-associated myocardial ischemia has been successfully treated with aspirin, heparin and nitroglycerin. VENTRICULAR DYSRHYTHMIAS: Treat dysrhythmias per ACLS protocols. SEROTONIN SYNDROME: Treat with benzodiazepines. In severe cases (uncontrollable agitation and myoclonus, hyperthermia) neuromuscular paralysis, mechanical ventilation and sedation may be necessary. CYPROHEPTADINE is used to improve mild to moderate symptoms of serotonin syndrome. DOSE: ADULT: Initial dose of 12 mg, then 2 mg every 2 hours if the patient remains symptomatic. Maintenance: 8 mg every 6 hours. Maximum dose: 32 mg in 24 hours. CHILD 0.25 mg/kg/day divided every 6 hours, maximum 12 mg/day.

C) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal can be given to patients with a significant oral overdose in patients who are alert and can protect their airway. Activated charcoal is not indicated for those medications designed to be insufflated or dissolved on the tongue.
2) HOSPITAL: Activated charcoal can be given to patients with a significant oral overdose in patients who are alert and can protect their airway. Activated charcoal and gastric lavage are not indicated for those medications designed to be insufflated or dissolved on the tongue.

D) AIRWAY MANAGEMENT

1) Endotracheal intubation should be considered for patients who present with significant CNS symptoms.

E) ANTIDOTE

1) There is no known antidote.

F) VENTRICULAR DYSRHYTHMIAS

1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia (VT). Sotalol may be an alternative for stable monomorphic VT. Amiodarone and sotalol should generally not be used if QT prolongation or torsades de pointes is present.

G) SEROTONIN SYNDROME

1) These agents are selective serotonin agonists, which act at 5-HT(1) receptors and theoretically may produce serotonin syndrome. If symptoms are present, benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, may also be used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with nondepolarizing agents.

H) ENHANCED ELIMINATION

1) Sumatriptan has a large volume of distribution; therefore, hemodialysis is unlikely to be effective.

I) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic patients with inadvertent exposure to therapeutic or near-therapeutic doses can be managed at home with observation.
2) OBSERVATION CRITERIA: Symptomatic patients and patients with deliberate overdose should be referred to a health care facility.
3) ADMISSION CRITERIA: Patients who develop significant hypertension or signs/symptoms or end-organ ischemia should be admitted for observation and treatment.
4) CONSULT CRITERIA: Consultation with a medical toxicologist or poison center should be considered for any patient with significant symptoms or a significant overdose.

J) PITFALLS

1) Failing to realize that signs and/or symptoms may be related to significant end-organ ischemia or infarction.

K) PHARMACOKINETICS

1) Triptans overall have large volumes of distribution (2 L/kg or more), low protein binding (15% to 35%), undergo hepatic metabolism, with primarily renal elimination of both metabolites and unchanged drug. Half-life of various agents: amlotriptan 3 to 4 hours, frovitriptan 25 hours, naratriptan 6 hours, rizatriptan 2 hours, sumatriptan 2 hours and zolmitriptan 3 hours.

L) PREDISPOSING CONDITIONS

1) Elderly patients with increased atherosclerosis and arterial narrowing are theoretically at increased risk for end-organ ischemia.

M) DIFFERENTIAL DIAGNOSIS

1) Hypertensive emergency, myocardial infarction, and cerebral vascular accident from other etiologies.

N) DRUG INTERACTION

1) Administration with other agents that increase serotonin may cause serotonin syndrome.

0.4.6)

A) HYPERTENSION: Monitor vital signs regularly. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Sedation with benzodiazepines may be helpful in agitated patients with hypertension and tachycardia. For severe hypertension sodium nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. See main treatment section for doses.
B) VENTRICULAR DYSRHYTHMIAS/SUMMARY: Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) ADVERSE EVENTS: Common adverse effects of sumatriptan include nausea, vomiting, dyspepsia, flushing and paresthesias. Chest pressure is reported in up to 15% of sumatriptan users but does not appear to be related to coronary vasospasm. Triptans have been reported to cause serotonin syndrome in isolation as well as when taken in conjunction with selective serotonin reuptake inhibitors (SSRIs) or MAO inhibitors.

F)

1) MILD TO MODERATE TOXICITY: Hypertension is common; patients are often asymptomatic. Triptans can cause serotonin syndrome in isolation or in conjunction with selective serotonin reuptake inhibitors (SSRIs) or MAO inhibitors. Symptoms of serotonin syndrome include altered mental status, hyperreflexia greater in the lower extremities, nystagmus, tremor, diaphoresis, and autonomic instability.
2) SEVERE TOXICITY: While not described in the literature, overdose can theoretically cause vasoconstriction with severe hypertension, myocardial infarction, cardiac dysrhythmias, renal infarction, splenic infarction, ischemic colitis, and cerebral vascular accident (ischemic and hemorrhagic). Triptans can cause serotonin syndrome in isolation or in conjunction with selective serotonin reuptake inhibitors (SSRIs) or MAO inhibitors. Symptoms of serotonin syndrome include altered mental status, hyperreflexia greater in the lower extremities, nystagmus, tremor, diaphoresis, autonomic instability, rigidity and hyperthermia.

Vital Signs

3.3.1)

A) WITH THERAPEUTIC USE

1) Hypertension may occur.

3.3.4)

A) WITH THERAPEUTIC USE

1) CASE REPORT: One patient experienced a transient increase in blood pressure to 200/120 mmHg, which later fell to 160/90 mmHg with no therapeutic intervention (Stricker, 1993).

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) Photophobia was frequently reported with naratriptan therapy; infrequent was blurred vision (Prod Info AMERGE(R) oral tablets, 2010a).

Cardiovascular

3.5.2)

A) MYOCARDIAL INFARCTION

1) WITH THERAPEUTIC USE

a) Acute myocardial infarction has been reported following single therapeutic subcutaneous injections and oral doses of sumatriptan, and in one case, cardiac arrest occurred.
b) CASE REPORT: A 47-year-old woman experienced 15 to 20 minutes of chest pain after each of 2 sumatriptan 6-mg subcutaneous injections, one week apart. Fifteen minutes following a third injection, she developed nausea and substernal pain radiating to her left shoulder. A diagnosis of transmural myocardial infarction was made and the patient recovered without complications (Ottervanger et al, 1993).
c) CASE REPORT: A 48-year-old woman developed cardiac arrest and inferior and right ventricular myocardial infarction within minutes following a 6 mg subcutaneous injection of sumatriptan. Following resuscitation, an ECG revealed diffuse ST-segment elevation, with subsequent ECGs showing inferior and right precordial ST-segment elevation. The patient gradually stabilized with supportive therapy (Main et al, 1998).
d) CASE REPORT: A 45-year-old woman, with no past medical history of cardiac disease, experienced severe waxing and waning right-sided chest pain associated with right shoulder pain, diaphoresis, and nausea approximately 1 hour after taking 100 mg of oral sumatriptan for her headache. The symptoms lasted 1 hour and then spontaneously resolved. Two hours after resolution, the patient presented to the ED. Her physical examination was completely normal; however an initial ECG revealed normal sinus rhythm with first degree heart block. Cardiac enzymes measured on arrival to the ED and 8 hours later, showed an increase in creatine kinase level (238 Units/L to 332 Units/L), an increase in CK-MB level (3.1 ng/mL to 21.1 ng/mL) and an increase in troponin I (less than 0.1 to 3.3). Cardiac catheterization indicated normal heart function, but also revealed 60% to 70% stenosis within the first septal perforator artery. The patient was discharged 2 days later without further sequelae (Hack, 2004).

B) VENTRICULAR ARRHYTHMIA

1) WITH THERAPEUTIC USE

a) Ventricular tachycardia and fibrillation have been reported following therapeutic use of these agents. Atrial fibrillation has been reported, but is uncommon (Morgan et al, 2000).
b) CASE REPORT: A 42-year-old woman with no prior cardiac history experienced coarse ventricular fibrillation within 10 minutes of sumatriptan injection. Sinus rhythm was restored by defibrillation; no further treatment was necessary (Curtain et al, 1992).
c) CASE REPORT: A 67-year-old woman with a history of mitral valve repair experienced ventricular tachycardia after injecting sumatriptan. Each of 8 previous doses had been accompanied by 'hot surges in the throat'; 4 were followed by palpitations. The patient required synchronized cardioversion and amiodarone to correct the dysrhythmias (Curtain et al, 1992).
d) CASE REPORT: Following a nasal sumatriptan inhalation for severe headache, a 34-year-old man presented with palpitations to the ED. Except for atrial fibrillation, with a ventricular rate of 130 beats/min, physical examination was normal. Sumatriptan was felt to be the causative agent because the patient reported irregular tachycardia after a previous use (Morgan et al, 2000).

C) TORSADES DE POINTES

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 42-year-old woman with a history of hypertension and migraines was admitted with a unilateral headache and left-sided vision changes typical of her migraine symptoms. Hypertension was present. Pulmonary edema developed shortly after admission. The patient was treated with morphine and other analgesics. Clonidine and furosemide were added. By the following day, worsening migraine symptoms and hypertension were present. In addition, to pain medications, sumatriptan 6 mg SubQ was administered. Ten minutes after administration the patient became lethargic with slurred speech and a BP of 244/175 mmHg with a heart rate of 143. This was followed 20 minutes later by a seizure and an ECG showed torsades de pointes followed by ventricular fibrillation. The patient was successfully resuscitated with an ECG showing atrial fibrillation. A CT of the head was negative. Patient history was significant for a possible thyroid disorder; laboratory studies suggested thyrotoxicosis. On day 4, a diltiazem infusion was stopped and later that day she developed pulseless ventricular fibrillation; defibrillation and CPR were initiated. Although resuscitation was successful, the patient had persistent atrial flutter. A temporary transvenous pacer was added followed by the placement of an automatic implantable cardioverter-defibrillator. She was discharged to home by day 16 in stable condition. The authors suggested that the patient's prolonged baseline QT interval (a corrected QT interval of 507 milliseconds) found later on her initial ECG to the ED may have potentiated her adverse drug reaction (Hill & Kirsten, 2014).

D) VASOSPASM

1) WITH THERAPEUTIC USE

a) Subcutaneous sumatriptan can precipitate coronary vasospasm at therapeutic doses. This class of drugs is contraindicated in patients with a history of coronary artery disease or vasospastic angina.
b) CASE REPORT: A 47-year-old man, with a history of atypical chest pain, experienced coronary vasospasm with ECG changes 4 minutes after injection of 6 mg of sumatriptan subcutaneously. His symptoms subsided within 22 minutes of injection (Willett et al, 1992).
c) CASE REPORT: Following an overdose of 7.5 mg naratriptan (maximum therapeutic dose: 5 mg/day), an adult experienced asymptomatic ischemic ECG changes, most likely the result of coronary artery vasospasm about 2 hours after ingestion (Prod Info AMERGE(R) oral tablets, 2010a).
d) CASE SERIES: Twelve cases of coronary vasospasm have been reported in the Netherlands, where sumatriptan is available both orally and subcutaneously. These patients experienced a range of symptoms including substernal tightness to severe angina-like pain radiating to the arm and hand. Symptoms resolved without complications in all cases (Stricker, 1993).

E) CHEST PAIN

1) WITH THERAPEUTIC USE

a) Chest tightness and pressure occurred with oral and subcutaneous therapeutic doses.
b) CASE SERIES: Chest tightness or pressure with therapeutic doses occurred in 5% of patients after subcutaneous sumatriptan and 3% of patients after oral sumatriptan (Bateman, 1993).

F) HYPERTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) SUMMARY: Increased blood pressure has been reported infrequently with therapeutic naratriptan use (Prod Info AMERGE(R) oral tablets, 2010a).

2) WITH POISONING/EXPOSURE

a) Increased blood pressure may occur following an overdose (Prod Info AMERGE(R) oral tablets, 2010a).
b) CASE REPORT: A mildly hypertensive adult experienced significant increase in blood pressure (150/98 mmHg baseline to 204/144 mmHg 225 minutes after a 10 mg oral dose of naratriptan) (Prod Info AMERGE(R) oral tablets, 2010a).
c) CASE REPORT: Approximately 6 hours after a 25 mg oral naratriptan dose, a young man adult experienced an increase from baseline blood pressure (120/67 mmHg) to 191/113 mmHg (Prod Info AMERGE(R) oral tablets, 2010a).

G) CARDIOVASCULAR FINDING

1) WITH THERAPEUTIC USE

a) Palpitations, tachydysrhythmias, and abnormal ECG (PR prolongation, QTc prolongation, ST/T wave abnormalities, premature ventricular contractions, atrial flutter or atrial fibrillation) have been reported infrequently with therapeutic use of naratriptan (Prod Info AMERGE(R) oral tablets, 2010a).

Neurologic

3.7.2)

A) HEMIPLEGIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Hypoesthesia and hemiparesis occurred in a 46-year-old man one week following 6 mg of subQ sumatriptan. CT indicated a region of low attenuation in the left thalamic region. Recovery was complete following 3 months of physical therapy (Luman, 1993).
b) CASE REPORT: A 25-year-old woman experienced right hemiparesis 12 hours after 6 mg of subQ sumatriptan. Spontaneous recovery occurred within 1 week (Luman, 1993).

B) VERTIGO

1) WITH THERAPEUTIC USE

a) SUMMARY: Vertigo was frequently reported with naratriptan therapy (Prod Info AMERGE(R) oral tablets, 2010a). It has been infrequently reported with sumatriptan therapy (Prod Info IMITREX(R) oral tablets, 2010)
b) CASE REPORT: Light-headedness, fatigue, and loss of coordination have been reported following a 25 mg naratriptan dose in a healthy young adult (Prod Info Amerge(TM), naratriptan hydrochloride, 1998).

C) CEREBRAL HEMORRHAGE

1) WITH THERAPEUTIC USE

a) A temporal association between subcutaneous dosing with sumatriptan for migraine and subsequent episodes of intracranial bleeding was reported in 2 patients. Both women had 15- to 20-year histories of migraine headache with previous uncomplicated exposure to sumatriptan. One case involved a 44-year-old normotensive who suffered an abrupt increase in headache intensity, nausea and vomiting, left hemiplegia, and loss of consciousness within 30 minutes after her second dose of sumatriptan in 2 hours. Workup revealed a right parietal arteriovenous malformation treated successfully with surgery. The second patient treated her typical migraine pain (throbbing fronto-temporal hemicrania without aura) with 2 injections of sumatriptan separated by 24 hours. Three hours following the second injection, she experienced an abrupt worsening in pain and character (non-throbbing, right-side base of the skull), with subarachnoid hemorrhage subsequently diagnosed (Combremont & Marcus, 2001).
b) During follow-up commentary, the authors defend the causal relationship noting that in the first case, the hemorrhage was associated with the only time the patient had used 2 injections within a 24-hour period (single injections had been used 5 times previously). Similarly, the second patient's episode was also associated with the first use of 2 injections within 24 hours, while single injections, separated by 1- to 4-week intervals had characterized her use of sumatriptan over the prior 4 to 5 years (Combremont & Marcus, 2001a).

D) SEIZURE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 42-year-old woman with a history of hypertension and migraines was admitted with a unilateral headache and left-sided vision changes typical of her migraine symptoms. Hypertension was present. Pulmonary edema developed shortly after admission. The patient was treated with morphine and other analgesics. Clonidine and furosemide were added. By the following day, worsening migraine symptoms and hypertension were present. In addition, to pain medications, sumatriptan 6 mg SubQ was administered. Ten minutes after administration the patient became lethargic with slurred speech and a BP of 244/175 mmHg with a heart rate of 143. This was followed 20 minutes later by a seizure and an ECG showed torsades de pointes followed by ventricular fibrillation. The patient was successfully resuscitated with an ECG showing atrial fibrillation. A CT of the head was negative. Patient history was significant for a possible thyroid disorder; laboratory studies suggested thyrotoxicosis. On day 4, a diltiazem infusion was stopped and later that day she developed pulseless ventricular fibrillation; defibrillation and CPR were initiated. Although resuscitation was successfully, the patient had persistent atrial flutter. A temporary transvenous pacer was added followed by the placement of an automatic implantable cardioverter-defibrillator. She was discharged to home by day 16 in stable condition. The authors suggested that the patient's prolonged baseline QT interval (a corrected QT interval of 507 milliseconds) found later on her initial ECG to the ED may have potentiated her adverse drug reaction (Hill & Kirsten, 2014).

Gastrointestinal

3.8.2)

A) COLITIS

1) WITH THERAPEUTIC USE

a) Mesenteric ischemia has been reported in several cases following sumatriptan therapeutic use, due to its vasoconstrictor properties.
b) CASE REPORTS: Ischemic colitis developed in 2 patients following the recommended use of sumatriptan for migraines. Both women developed symptoms (abdominal cramping and hematochezia) within 24 to 48 hours after only 4 doses. Colonic biopsy in one patient was consistent with a diagnosis of segmental sigmoid colitis with ischemic origin, while colonoscopy in the other patient revealed significant inflammation of the descending colon (Knudsen et al, 1998).
c) CASE REPORTS: Mesenteric ischemia has been reported in 2 patients following the use of sumatriptan. In one patient, several episodes of bloody diarrhea, abdominal pain and hypotension occurred after receipt of subcutaneous sumatriptan above the recommended dose. This patient had an emergency exploratory laparotomy and right hemicolectomy for transmural bowel necrosis. The other patient was diagnosed with ischemic colitis following a flexible sigmoidoscopy with biopsies (Liu et al, 2000).

2) WITH POISONING/EXPOSURE

a) EXCESSIVE THERAPEUTIC DOSE: A 35-year-old nonsmoking, woman with a history of refractory migraine headaches took more than twice the recommended daily dose (300 mg of sumatriptan orally AND 12 mg subQ [maximum daily dose: 200 mg orally OR 12 mg subQ]) and 36 hours later developed severe abdominal pain and was initially diagnosed with colitis of undetermined etiology. The patient was not receiving oral contraceptives or other serotonin agonists. A computed tomography of the abdomen showed left-sided colitis. The patient received pain medication and was discharged to home and readmitted the same day with severe abdominal pain and prescribed bowel rest, pain medication, and intravenous hydration. The patient gradually improved and a colonoscopy a few days later revealed ischemic colitis felt to be secondary to sumatriptan use (Hodge & Hodge, 2010).

B) VOMITING

1) WITH THERAPEUTIC USE

a) Vomiting has frequently been reported with naratriptan therapy (Prod Info AMERGE(R) oral tablets, 2010a).

Genitourinary

3.10.2)

A) RENAL INFARCTION

1) WITH THERAPEUTIC USE

a) CASE REPORTS: Renal infarction was confirmed in two patients following therapeutic use of rizatriptan and zolmitriptan. The first patient was a 57-year-old man with stable medication-controlled hypertension, who received two 10-mg doses of rizatriptan for cluster headaches and developed nausea and abdominal pain. The second patient was a healthy 34-year-old man, with a chronic history of migraines controlled with zolmitriptan as needed. Two hours after ingesting a 2.5 mg dose he developed nausea and colicky left flank pain. Abdominal and pelvic computed tomography revealed wedge-shaped renal infarction(s), which were confirmed by renal arteriogram in each patient. Both patients improved following supportive care and renal function remained normal (Fulton et al, 2006).

Dermatologic

3.14.2)

A) INJECTION SITE REACTION

1) WITH THERAPEUTIC USE

a) CASE SERIES: Pain and inflammation at the site of injection occurred in 40% of patients following subcutaneous injection of 4 to 8 mg sumatriptan (Brown et al, 1991).

B) FLUSHING

1) WITH THERAPEUTIC USE

a) CASE SERIES: Tingling, flushing, burning, and hot/warm sensations occurred in 8% to 9% of patients following subcutaneous injection of 4 to 8 mg sumatriptan (Brown et al, 1991).

Endocrine

3.16.2)

A) INCREASED HORMONAL ACTIVITY

1) WITH THERAPEUTIC USE

a) Plasma growth hormone and cortisol levels were markedly increased after 3 men and 3 women were given 6 mg sumatriptan or placebo subQ (Rolandi et al, 1992).

Reproductive

3.20.1)

A) Sumatriptan and related agents are classified as FDA pregnancy category C. Several studies have shown no congenital anomalies following the use of sumatriptan and naratriptan. The possibility of sumatriptan exposure during pregnancy leading to low-birth-weight infants or premature delivery was suggested based on analysis of the Danish Birth Registry. Animal reproductive studies of sumatriptan and related agents have shown fetal developmental and maternal toxicities. Sumatriptan and eletriptan were both shown to be excreted in human milk. Several other agents were excreted in the milk of lactating rats. In animal fertility studies, there was evidence of prolonged estrous cycles in rats following exposure to several of the agents during mating.

3.20.2)

A) LACK OF INFORMATION

1) ELETRIPTAN

a) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans (Prod Info RELPAX(R) oral tablets, 2013).

2) ZOLMITRIPTAN

a) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans (Prod Info ZOMIG-ZMT(R) oral disintegrating tablets, 2012; Prod Info ZOMIG(R) nasal spray, 2013).

B) EMBRYO/FETAL RISK

1) NAPROXEN SODIUM/SUMATRIPTAN SUCCINATE

a) There were no reports of major birth defects following exposure to naproxen sodium/sumatriptan succinate during the first trimester of pregnancy. There were a total of 5 pregnancies with first trimester exposure and of these pregnancies, 4 resulted in live births and one spontaneous abortion for which no information available. There was one report of second trimester exposure resulting in a live birth with no reports of major birth defects (Ephross & Sinclair, 2014).

2) NARATRIPTAN

a) Among 52 pregnancies with first trimester exposure to naratriptan, outcomes included 45 live births with no reported major birth defects. A major birth defect was reported in one infant following exposure to naratriptan and sumatriptan during the first trimester and 5 reports of spontaneous abortion for which major birth defects were unknown. Five pregnancies with second trimester exposure to naratriptan all resulted in live births with no reports of major birth defects. The risk of major birth defects following first trimester naratriptan exposure was 2.2% compared with a 2% risk with exposure during any trimester (Ephross & Sinclair, 2014).

3) SUMATRIPTAN

a) Among 528 pregnancies with first trimester exposure to sumatriptan, outcomes included 458 live births with no reports of major birth defects and 16 live births with major birth defects, including 4 reports of ventricular septal defect (0.84%). A total of 78 pregnancies had second trimester exposure to sumatriptan. Of these pregnancies, all 78 resulted in live births with major birth defects reported in 3 cases. Third trimester exposure to sumatriptan was reported in 16 cases all of which resulted in live births with no reports of major birth defects. The risk of a major birth defect following first trimester sumatriptan exposure was 4.2%, which was the same risk reported with exposure during any trimester (Ephross & Sinclair, 2014).
b) In a report from an international Sumatriptan Registry, 9 of 206 infants born to women treated with sumatriptan during the first trimester were reported to have congenital anomalies. No apparent pattern of anomalies was noted among the affected infants in this group. Nor was there a pattern among 14 other infants or fetuses with congenital anomalies born to women treated with sumatriptan during the first trimester of pregnancy and reported to the registry after delivery (Reiff-Eldridge et al, 2000).

C) CONGENITAL ANOMALY

1) RIZATRIPTAN

a) Data collected by Merck's pregnancy registry which monitors the outcomes of pregnant women exposed to rizatriptan indicates that there have been 2 congenital abnormalities (3.1%, 95% confidence interval (CI), 0.4% to 11.1%) out of 65 prospective live birth reports. Among 55 women enrolled as of mid-2004, rizatriptan exposure occurred in all trimesters and, in some cases, throughout pregnancy. In 25 pregnancy outcomes out of 51 prospective reports, there have been 20 live births, 3 spontaneous abortions (at approximately 6, 8, and 12 weeks' gestation), 1 elective abortion at 21 weeks' gestation after diagnosis of multiple fetal anomalies (attributed to advanced maternal age) and 1 fetal death at 36 weeks' gestation due to a cord accident. Among 4 retrospective reports, in one case, where rizatriptan exposure occurred during the first 4 months' of gestation, the infant was delivered at term with multiple brain and other abnormalities; and in another case, an elective abortion was performed at 16 weeks' gestation subsequent to prenatal diagnosis of anencephaly. The manufacturer believes that these anomalies are not likely due to drug exposure. Data collected by Merck from its subsidiaries outside the United States included 6 instances of live, normal births and 8 spontaneous abortions out of 14 outcomes reported. Additional data obtained from the Swedish Medical Birth Registry (SMBR) included 1 case of glandular hypospadias out of 41 successful pregnancy outcomes in mothers with rizatriptan exposure during pregnancy (Fiore et al, 2005).

D) LACK OF EFFECT

1) No excessive fetal risk was apparent from analysis of 912 infant births to 905 mothers exposed to various antimigraine agents during pregnancy, including 658 births with maternal exposure to sumatriptan alone or in combination. Data were extracted from the Swedish National Board of Health Medical Birth Registry between July 1, 1995 to June 30, 1999. Odds ratios (ORs) were identical for both consideration of all births and antimigraine agent exposure, or when restricted to just exposure to sumatriptan. The OR for sumatriptan and premature birth was 1.29, while the OR for low birth rate was 1.18 with sumatriptan exposure. Some congenital malformations were reported in 3.1% of the antimigraine agent-exposed births, and 2.7% of those exposed to sumatriptan, compared with a general population rate of 3.6%. No trends in malformation type were apparent; 16 were classified as major, 12 as minor. Eight cardiac defects were predicted and observed. Weaknesses of the study included full information on drug exposure and timing; and that only births were studied, and not exposure to drugs in pregnancies which were terminated early (Kallen & Lygner, 2001).
2) SUMATRIPTAN

a) The rate of congenital anomalies was no greater than expected among the infants of 86 women treated with sumatriptan during the first trimester of pregnancy (Shuhaiber et al, 1997). In another series of reports, no malformations were observed among 23 infants born to women who had been treated with sumatriptan during the first trimester of pregnancy (Wilton et al, 1998).

3) NARATRIPTAN

a) The number of women exposed to naratriptan reported in the literature is so small that no pattern or estimate of risk can be determined at this time. Fourteen cases have been reported prospectively to the manufacturer's pregnancy registry, all involving first trimester exposure. All infants were delivered without congenital abnormalities (Eldridge, 2000).

E) ANIMAL STUDIES

1) ALMOTRIPTAN

a) RATS: There was an increased incidence of fetal skeletal variations (decreased ossification) when rats were given oral almotriptan at doses of 250 mg/kg/day. The no-effect doses for embryo-fetal developmental toxicity in rats was 125 and 20 mg/kg/day (approximately 100 times the maximum recommended human dose (MRHD) of 25 mg/day on a mg/m(2) basis) (Prod Info AXERT(R) oral tablets, 2009).

2) ELETRIPTAN

a) RATS, RABBITS: In animal reproductive toxicity studies, administration of eletriptan 100 mg/kg/day (approximately 12 times the maximum recommended human dose (MRHD)) during organogenesis in pregnant rats resulted in a decreased fetal weights and increased vertebral and sternebral variations. The no effect dose for developmental toxicity in rats was 30 mg/kg/day (approximately 4 times the MRHD on a mg/m(2) basis). In a similar study, administration of eletriptan 5, 10, or 50 mg/kg/day (up to 12 times the MRHD) during organogenesis in pregnant rabbits resulted in decreased fetal weight at the 50 mg/kg/day dose level. There was an increased incidence of fused sternebrae and vena cava deviations at all dose levels. A no effect dose was not established (Prod Info RELPAX(R) oral tablets, 2013).

3) FROVATRIPTAN

a) RATS, RABBITS: There were dose-related increases in incidences of both litters and total numbers of fetuses with dilated ureters, unilateral and bilateral pelvic cavitation, hydronephrosis, and hydroureters when pregnant rats were administered oral frovatriptan at doses of 100, 500 and 1000 mg/kg/day (130, 650 and 1300 times the maximum recommended human dose (MRHD) on a mg/m(2) basis) during organogenesis. A no-effect dose for renal effects was not established. This is consistent with a slight delay in fetal maturation. There was also treatment-related embryolethality, fetal weight reduction, and an increased incidence of incomplete ossification of the sternebrae, skull and nasal bones in all treated groups; however, the lowest dose level (100 mg/kg/day, equivalent to 130 times the MRHD) did not cause an increase in embryolethality. There was no evidence of effects on fetal development when pregnant rabbits were given frovatriptan oral doses up to 80 mg/kg/day (equivalent to 210 times the MRHD) throughout organogenesis (Prod Info FROVA(R) oral tablets, 2013).

4) NARATRIPTAN

a) In animal studies, fetal abnormalities were observed when rats and rabbits were given oral naratriptan corresponding to maternal plasma drug exposures as low as 11 and 2.5 times, respectively, the exposure in humans receiving the maximum recommended daily dose (MRDD) of 5 mg. Fetal structural variations (incomplete/irregular ossification of skull bones, sternebrae, and ribs) were observed in rats given 10, 60, or 340 mg/kg/day (approximately 11, 70, and 470 times the exposure in humans at the MRDD) during organogenesis. In another rat study, offspring tremors were observed when female rats were administered oral naratriptan at doses of 60 or 340 mg/kg/day during late gestation and lactation. Maternal exposures at the no-effect dose for developmental effects was approximately 11 times the MRDD. Fetal variations (major blood vessel variations, supernumerary ribs, incomplete skeletal ossification) were observed in rabbits administered oral naratriptan at doses of 1, 5 or 30 mg/kg/day (4, 20, and 120 times the MRDD, based on body surface area) during organogenesis. Specific fetal skeletal malformation (fused sternebrae) was also observed at the highest dose, which was maternally toxic. In a separate study, increased incidences of fetal skeletal variations were also observed in rabbits administered naratriptan at doses of 1, 5, or 30 mg/kg/day (2.5, 19, and 140 times exposure in humans receiving the MRDD) during organogenesis, while maternal body weight gain was reduced at 5 mg/kg or greater (Prod Info AMERGE(R) oral tablets, 2013).

5) RIZATRIPTAN

a) RATS, RABBITS: No teratogenic effects were observed when pregnant rats and rabbits were administered rizatriptan at doses of 100 and 50 mg/kg/day, respectively (approximately 225 and 115 times the human exposure at MRDD in rats and rabbits, respectively) during organogenesis. The no-effect dose in these studies was 10 mg/kg/day in both rats and rabbits (approximately 15 times the human exposure at MRDD). Toxicokinetics studies revealed placental transfer of rizatriptan in both species (Prod Info MAXALT(R), MAXALT-MLT(R) oral tablets, orally disintegrating tablets, 2009).

6) SUMATRIPTAN

a) There was an increased incidence of vascular (cervicothoracic and umbilical) anomalies when rats were administered oral sumatriptan at doses of approximately 250 mg/kg/day or higher during organogenesis with the highest no-effect dose for these adverse events being 60 mg/kg/day (approximately 6 times the oral maximum recommended human dose (MRHD) of 100 mg on a mg/m(2) basis. Increased cervicothoracic vascular and skeletal abnormalities were reported in pregnant rabbits given oral sumatriptan during organogenesis with the highest no-effect dose being 15 mg/kg/day (approximately 6 times the oral MRHD) (Prod Info IMITREX(R) oral tablets, 2010).
b) Fetal vascular and skeletal abnormalities were observed in pregnant rabbits administered oral sumatriptan during organogenesis, with the highest no-effect dose being 15 mg/kg/day. There was no evidence of embryolethality in pregnant rats administered doses approximately 10 times the MRHD, based on mg/m(2), during organogenesis (Prod Info Sumavel(R) DosePro(R) subcutaneous injection solution, 2013).
c) No evidence of teratogenicity was observed in pregnant rats administered subQ sumatriptan prior to and throughout pregnancy (Prod Info ALSUMA(TM) subcutaneous injection, 2010; Prod Info Sumavel(R) DosePro(R) subcutaneous injection solution, 2013).

7) ZOLMITRIPTAN

a) Fetal malformations were observed in the offspring of pregnant rabbits administered oral zolmitriptan during organogenesis at doses of 3, 10, and 30 mg/kg/day (approximately 1, 11 and 42 times the MRHD). Hydronephrosis was observed in the offspring of female rats administered oral zolmitriptan during gestation, parturition, and lactation at doses of 25, 100, and 400 mg/kg/day (approximately 70, 280, and 1100 times the MRHD) (Prod Info ZOMIG-ZMT(R) oral disintegrating tablets, 2012; Prod Info ZOMIG(R) nasal spray, 2013).

3.20.3)

A) LACK OF INFORMATION

1) ELETRIPTAN

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info RELPAX(R) oral tablets, 2013).

2) NARATRIPTAN

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info AMERGE(R) oral tablets, 2013).

3) ZOLMITRIPTAN

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info ZOMIG-ZMT(R) oral disintegrating tablets, 2012; Prod Info ZOMIG(R) nasal spray, 2013).

B) PREGNANCY CATEGORY

1) The manufacturers have classified SUMATRIPTAN, ALMOTRIPTAN, ELETRIPTAN, FROVATRIPTAN, NARATRIPTAN, RIZATRIPTAN, AND ZOLMITRIPTAN as FDA pregnancy category C (Prod Info RELPAX(R) oral tablets, 2013; Prod Info ALSUMA(TM) subcutaneous injection, 2010; Prod Info Sumavel(R) DosePro(R) subcutaneous injection solution, 2013; Prod Info IMITREX(R) injection, 2010; Prod Info IMITREX(R) oral tablets, 2010; Prod Info IMITREX(R) nasal spray, 2010; Prod Info AXERT(R) oral tablets, 2009; Prod Info FROVA(R) oral tablets, 2013; Prod Info AMERGE(R) oral tablets, 2013; Prod Info MAXALT(R), MAXALT-MLT(R) oral tablets, orally disintegrating tablets, 2009; Prod Info ZOMIG-ZMT(R) oral disintegrating tablets, 2012; Prod Info ZOMIG(R) nasal spray, 2013)
2) The combination product naproxen sodium/sumatriptan succinate has been classified as FDA pregnancy category C during the first and second trimesters and as FDA pregnancy category X during the third trimester due to naproxen. As with other NSAIDs, inhibitors of prostaglandin synthesis (including naproxen) can cause premature closure of the ductus arteriosus in humans (Prod Info TREXIMET(R) oral tablets, 2015).

C) LOW BIRTH WEIGHT/PREMATURE DELIVERY

1) The possibility of sumatriptan exposure during pregnancy leading to low-birth-weight infants or premature delivery was suggested based on analysis of the Danish Birth Registry. However, the data involved only 34 women exposed to sumatriptan during pregnancy and 89 other migraine sufferers who did not take antimigraine medications during pregnancy (migraine controls), while 15,955 births during 1991 to 1996 served as the baseline population. Preterm delivery prior to gestation week 37 occurred in 5 of 34 sumatriptan patients (15%), compared with 3 (3%) of the migraine-control patients, and 6% of the general population. Rates of low birth weight (under 2500 g) were 3%, 6%, and 2%, respectively (Olesen et al, 2000).

D) ANIMAL STUDIES

1) ALMOTRIPTAN

a) RATS, RABBITS: There was an increased incidence of embryolethality when rats were given oral almotriptan 1000 mg/kg/day. There were also increases in embryolethality when rabbits were given oral almotriptan at doses of 60 mg/kg/day. The no-effect doses for embryo-fetal developmental toxicity in rats and rabbits were 125 and 20 mg/kg/day (approximately 100 and 15 times the maximum recommended human dose (MRHD) of 25 mg/day on a mg/m(2) basis, respectively). In another rat study, there was an increased gestation length as well as decreased litter size and offspring body weight when rats were given oral almotriptan 400 mg/kg/day was administered orally to rats throughout gestation and lactation. Reduced pup weight was evident throughout lactation. The no-effect dose in this study was 100 mg/kg/day (40 times the MRHD on a mg/m(2) basis) (Prod Info AXERT(R) oral tablets, 2009).

2) ELETRIPTAN

a) RATS, RABBITS: In animal reproductive toxicity studies, administration of eletriptan 100 mg/kg/day (approximately 12 times the maximum recommended human dose (MRHD)) during organogenesis in pregnant rats resulted in a decreased fetal weights. Maternal toxicity, defined as decreased maternal weight gain during gestation, was reported at eletriptan doses of 30 mg/kg/day and 100 mg/kg/day. The no effect dose for developmental toxicity in rats was 30 mg/kg/day (approximately 4 times the MRHD). In a similar study, administration of eletriptan 5, 10, or 50 mg/kg/day (up to 12 times the MRHD) during organogenesis in pregnant rabbits resulted in decreased fetal weight at the 50 mg/kg/day dose level. There were no reports of maternal toxicity and a no effect dose was not established (Prod Info RELPAX(R) oral tablets, 2013).

3) NARATRIPTAN

a) In animal studies, developmental toxicity (embryolethality, pup mortality, offspring growth retardation) was observed when rats and rabbits were given oral naratriptan corresponding to maternal plasma drug exposures as low as 11 and 2.5 times, respectively, the exposure in humans receiving the maximum recommended daily dose (MRDD) of 5 mg. Embryonic death was observed in rats given 10, 60, or 340 mg/kg/day (approximately 11, 70, and 470 times the exposure in humans at the MRDD) during organogenesis. In another rat study, decreased offspring viability and growth were observed when female rats were administered oral naratriptan at doses of 60 or 340 mg/kg/day during late gestation and lactation. Maternal exposures at the no-effect dose for developmental effects was approximately 11 times the MRDD. Embryonic death was observed in rabbits administered oral naratriptan at doses of 1, 5 or 30 mg/kg/day (4, 20, and 120 times the MRDD, based on body surface area) during organogenesis. In another study, decreased fetal weight was observed in rabbits administered naratriptan at doses of 1, 5, or 30 mg/kg/day (2.5, 19, and 140 times exposure in humans receiving the MRDD) during organogenesis, while maternal body weight gain was reduced at 5 mg/kg or greater (Prod Info AMERGE(R) oral tablets, 2013).

4) RIZATRIPTAN

a) RATS: There was no maternal toxicity when rats were administered rizatriptan at doses of 10 and 100 mg/kg/day (approximately 15 and 225 times, respectively, the human exposure at a maximum recommended daily dose (MRDD) of 30 mg). However, reduced birth weights and pre- and post-weaning weight gain were observed in the offspring. Doses of 100 and 250 mg/kg/day resulted in increased mortality of the offspring at birth, decreased performance in a passive avoidance test, and decreased average weight gain, the latter of which often persisted into adulthood. The no-effect dose for these effects was 5 mg/kg/day (approximately 7.5 times the human exposure at MRDD). Toxicokinetics studies revealed placental transfer of rizatriptan in both species (Prod Info MAXALT(R), MAXALT-MLT(R) oral tablets, orally disintegrating tablets, 2009).

5) SUMATRIPTAN

a) Embryolethality was observed in pregnant rabbits administered intravenous sumatriptan during organogenesis at doses at or close to those producing maternal toxicity (less than the maximum recommended human dose (MRHD) of 12 mg/day, based on mg/m(2)). (Prod Info ALSUMA(TM) subcutaneous injection, 2010; Prod Info IMITREX(R) injection, 2010; Prod Info Sumavel(R) DosePro(R) subcutaneous injection solution, 2013).
b) There was a decrease in pup survival between birth and postnatal day 4 when rats were administered oral sumatriptan at doses of approximately 250 mg/kg/day or higher with the highest no-effect dose being approximately 60 mg/kg/day (6 times the maximum single recommended human dose of 100 mg on a mg/m(2) basis). In another study, decreased pup survival measured at postnatal days 2, 4, and 20 was observed when pregnant rats were given oral sumatriptan at a dose of 1000 mg/kg/day with the no-effect dose being 100 mg/kg/day (approximately 10 times the maximum single recommended human dose) (Prod Info IMITREX(R) oral tablets, 2010).
c) There was no evidence of embryolethality in pregnant rats administered doses approximately 10 times the MRHD, based on mg/m(2), during organogenesis (Prod Info ALSUMA(TM) subcutaneous injection, 2010; Prod Info Sumavel(R) DosePro(R) subcutaneous injection solution, 2013). There was also no increase in pup death when rats were given subQ sumatriptan at 81 mg/kg/day (8 times the maximum single recommended human oral dose of 100 mg on a mg/m(2) basis) (Prod Info IMITREX(R) oral tablets, 2010).
d) There was no evidence of embryolethality or teratogenicity in pregnant rats administered subQ sumatriptan prior to and throughout pregnancy (Prod Info Sumavel(R) DosePro(R) subcutaneous injection solution, 2013).

6) ZOLMITRIPTAN

a) Dose-dependent embryolethality was observed in the offspring of pregnant rats administered oral zolmitriptan during organogenesis at doses of 100, 400, and 1200 mg/kg/day (approximately 280, 1100, and 5000 times the maximum recommended human dose (MRHD)). Embryolethality was also observed in the offspring of pregnant rabbits administered oral zolmitriptan during organogenesis at doses of 3, 10, and 30 mg/kg/day (approximately 1, 11 and 42 times the MRHD) (Prod Info ZOMIG-ZMT(R) oral disintegrating tablets, 2012; Prod Info ZOMIG(R) nasal spray, 2013).

3.20.4)

A) LACK OF INFORMATION

1) NARATRIPTAN

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info AMERGE(R) oral tablets, 2013).

2) ZOLMITRIPTAN

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info ZOMIG-ZMT(R) oral disintegrating tablets, 2012; Prod Info ZOMIG(R) nasal spray, 2013).

B) BREAST MILK

1) SUMATRIPTAN

a) Sumatriptan is excreted in human breast milk following subQ administration (Prod Info ALSUMA(TM) subcutaneous injection, 2010). In one study, five lactating volunteer subjects with mean duration of lactation of 22.2 weeks (range, 10.8 to 28.4 weeks) received a 6-mg subQ dose of sumatriptan. Drug levels in milk and plasma were obtained hourly for 8 hours. The mean milk-to-plasma ratio was estimated to be 4.9, and the mean total recovery of drug in milk was estimated to be only 0.24% of the usual 6-mg dose. It is suggested that a nursing infant who continued to breastfeed following a 6-mg subQ maternal dose would receive a maximum of 3.5% of the maternal dose (on a weight-adjusted basis). Since the usual mode of administration of sumatriptan is as a single dose given at infrequent intervals, the amount excreted in breast milk would most likely be too small to cause any problems in the nursing infant (Wojar-Horton et al, 1996).

2) ELETRIPTAN

a) Lactation studies with eletriptan have not been conducted, however eletriptan is known to be excreted into human breast milk. Therefore, exercise caution when administering eletriptan to a nursing mother (Prod Info RELPAX(R) oral tablets, 2013).

C) ANIMAL STUDIES

1) ALMOTRIPTAN

a) RATS: Milk levels of almotriptan were up to 7 times higher than in rat plasma when almotriptan was administered to lactating rats (Prod Info AXERT(R) oral tablets, 2009).

2) FROVATRIPTAN

a) RATS: Frovatriptan and/or its metabolites are excreted in the milk of lactating rats with a maximum concentration that is 4-fold higher than in blood. Therefore, it is recommended to either discontinue nursing or discontinue frovatriptan, considering the importance of the drug to the mother (Prod Info FROVA(R) oral tablets, 2013).

3) NARATRIPTAN

a) Naratriptan is secreted into the milk of rats (Prod Info AMERGE(R) oral tablets, 2013).

4) RIZATRIPTAN

a) RATS: Rizatriptan is excreted in the milk of lactating rats at levels of 5 times and greater than in maternal plasma levels (Prod Info MAXALT(R), MAXALT-MLT(R) oral tablets, orally disintegrating tablets, 2009).

5) ZOLMITRIPTAN

a) Zolmitriptan is excreted in the milk of lactating rats at exposures 4 times higher than maternal plasma levels (Prod Info ZOMIG-ZMT(R) oral disintegrating tablets, 2012; Prod Info ZOMIG(R) nasal spray, 2013).

3.20.5)

A) LACK OF INFORMATION

1) ELETRIPTAN

a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent in humans (Prod Info RELPAX(R) oral tablets, 2013).

2) NARATRIPTAN

a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent in humans (Prod Info AMERGE(R) oral tablets, 2013).

3) SUMATRIPTAN

a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent in humans (Prod Info Sumavel(R) DosePro(R) subcutaneous injection solution, 2013).

4) ZOLMITRIPTAN

a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent in humans (Prod Info ZOMIG-ZMT(R) oral disintegrating tablets, 2012; Prod Info ZOMIG(R) nasal spray, 2013).

B) ANIMAL STUDIES

1) ALMOTRIPTAN

a) RATS: No adverse effects on fertility were found in reproduction studies in female rats given oral almotriptan at doses up to 25 mg/kg/day orally (approximately 10 times the maximum recommended human dose (MRHD) on a mg/m(2) basis). Prolongation of the estrus cycle was observed at a dose of 100 mg/kg/day (approximately 40 times the MRHD) (Prod Info AXERT(R) oral tablets, 2009).

2) ELETRIPTAN

a) FEMALE RATS: There was a prolongation of the estrous cycle at the 200 mg/kg/day dose due to an increase in estrous duration. There were also dose-related reductions in numbers of corpora lutea per female rat, in all doses. This resulted in a decreased number of implants and viable fetuses per female rat, which suggests a partial inhibition of ovulation due to eletriptan. There was no effect on fertility of male rats (Prod Info RELPAX(R) oral tablets, 2013).

3) FROVATRIPTAN

a) RATS: There was an increase at all dose levels in the number of females that mated on the first day of pairing compared with control animals when male and female rats were given frovatriptan at doses of 100, 500, and 1000 mg/kg/day. This occurred in conjunction with a prolongation of the estrous cycle. Females also had a decreased mean number of corpora lutea and a lower number of live fetuses per litter, which suggested a partial impairment of ovulation (Prod Info FROVA(R) oral tablets, 2013).

4) NARATRIPTAN

a) A treatment-related decrease in the number of females exhibiting normal estrous cycles was reported when rats were exposed to naratriptan doses of 170 mg/kg/day or greater (approximately 230 times the maximum recommended human dose (MRHD)) prior to and throughout the mating period. Preimplantation loss was also observed at doses of 60 mg/kg/day or greater (70 times the MRHD). In the high-dose group males, testicular and/or epididymal atrophy along with spermatozoa depletion resulted in reduced mating success. Preimplantation loss in females may have been due to the testicular and/or epididymal atrophy in males. In another rat study, changes in the female reproductive tract (eg, atrophic or cystic ovaries) was reported in female rats following exposure to naratriptan 340 mg/kg/day for 6 months (Prod Info AMERGE(R) oral tablets, 2013).

5) RIZATRIPTAN

a) RATS: There were changes in estrus cyclicity and delays in time to mating when female rats received oral rizatriptan at dose up to 100 mg/kg/day (approximately 225 times the AUC in humans receiving the maximum recommended daily dose (MRDD)). The no-effect dose was 10 mg/kg per day (approximately 15 times the human exposure at the MRDD). Additionally, there was no impairment of fertility or reproductive performance when male rats received 250 mg/kg/day (approximately 550 times the human exposure at the MRDD) (Prod Info MAXALT(R), MAXALT-MLT(R) oral tablets, orally disintegrating tablets, 2009).

6) SUMATRIPTAN

a) There was no evidence of impaired fertility in male and female rats administered subQ sumatriptan at a dose 100 times the maximum recommended single human dose (MRHD) of 6 mg/, based on mg/m(2), prior to and throughout the mating period (Prod Info Sumavel(R) DosePro(R) subcutaneous injection solution, 2013). A treatment-related decrease in fertility was observed secondary to a decrease in mating in male and female rats following exposure to oral sumatriptan at doses of 50 and 500 mg/kg/day (Prod Info ALSUMA(TM) subcutaneous injection, 2010; Prod Info Sumavel(R) DosePro(R) subcutaneous injection solution, 2013). There was no evidence of impaired fertility in rats given subQ sumatriptan at doses up to 60 mg/kg/day (Prod Info IMITREX(R) oral tablets, 2010)

7) ZOLMITRIPTAN

a) Reproduction studies in male and female rats given zolmitriptan doses of up to 400 mg/kg/day (approximately 3000 times the maximum recommended human dose) found no effect on fertility (Prod Info ZOMIG-ZMT(R) oral disintegrating tablets, 2012; Prod Info ZOMIG(R) nasal spray, 2013).

Carcinogenicity

3.21.2)

A) At the time of this review, the manufacturers do not report any carcinogenic potential for sumatriptan and related agents.

3.21.4)

A) HEPATOCELLULAR ADENOMAS

1) ELETRIPTAN

a) MICE: The incidence of hepatocellular adenomas was increased when mice were given eletriptan 400 mg/kg/day (approximately 18 times the AUC achieved in humans receiving the maximum recommended daily dose (MRDD) of 80 mg). The no-effect dose was 90 mg/kg/day, which was approximately 7 times the AUC with the MRDD (Prod Info RELPAX(R) oral tablets, 2008).

B) PITUITARY ADENOMAS

1) FROVATRIPTAN

a) RATS: There was a statistically significant increase in the incidence of pituitary adenomas in males rats after exposure to 85 mg/kg/day of frovatriptan, which was 250 times the exposure achieved at the maximum recommended daily human dose of 7.5 mg based on AUC comparisons (Prod Info FROVA(R) oral tablets, 2007).

C) SARCOMAS

1) FROVATRIPTAN

a) MICE: Subcutaneous sarcomas occurred at an increased frequency in female mice following frovatriptan doses of 200 and 400 mg/kg/day (390 and 630 times the exposure achieved at the maximum recommended daily human dose (MRHD) of 7.5 mg using AUC comparisons); however, the sarcomas were associated with subcutaneously implanted animal identification transponders. The sarcomas are not considered clinically relevant to human use of frovatriptan (Prod Info FROVA(R) oral tablets, 2007).

D) TESTICULAR INTERSTITIAL CELL ADENOMAS

1) ELETRIPTAN

a) RATS: The incidence of testicular interstitial cell adenomas was increased when rats were given eletriptan 75 mg/kg/day (approximately 6 times the AUC achieved in humans receiving the maximum recommended daily dose (MRDD) of 80 mg) in 104-week lifetime carcinogenicity studies. The no-effect dose was 15 mg/kg/day, which was approximately 2 times the AUC with the MRDD (Prod Info RELPAX(R) oral tablets, 2008).

E) THYROID HYPERPLASIA/ADENOMAS

1) NARATRIPTAN

a) RATS: There was an increased incidence of thyroid follicular hyperplasia in male and female rats, and thyroid follicular adenomas in male rats, who received high doses of naratriptan in 2 studies. One study used a standard diet and the other a nitrite-supplemented diet. Nitrosated naratriptan (in vitro WHO nitrosation assay) forms a mutagenic product that is also found in the stomachs of rats who are given high nitrite diets. Both studies used doses of 5, 20, and 90 mg/kg that produced AUC exposures with the standard diet of 7, 40, and 236 times, respectively, and with the nitrite-supplemented diet of 7, 29, and 180 times, respectively, the human exposure with the maximum recommended daily dose (MRHD) of 5 mg. There was also an increased incidence of benign c-cell thyroid adenomas with high-dose male and female rats in the standard diet study only. The no-effect dose for thyroid tumors was equivalent to exposures of 40 and 29 times the human exposure with the MRHD in the standard and nitrite-supplemented diets, respectively. The incidence of benign lymphocytic thymoma was increased in all female groups with the nitrite-supplemented diet only. Although it was not determined whether the nitrosated product was systemically absorbed in this study, there were no changes in the stomachs of the rats (Prod Info AMERGE(R) oral tablets, 2010).

2) ZOLMITRIPTAN

a) RATS: There was an increased incidence of thyroid follicular cell hyperplasia and thyroid follicular cell adenomas in male rats after 101 weeks of 400 mg/kg/day of zolmitriptan by oral gavage (AUC exposure was approximately 3000 times that of a human exposure based on a dose of 10 mg) (Prod Info ZOMIG(R) ZOMIG-ZMT(R) oral tablets, orally disintegrating tablets, 2008).

F) LACK OF EFFECT

1) ALMOTRIPTAN

a) MICE/RATS: There was no increase in tumors when mice and rats were given oral almotriptan at doses up to 250 mg/kg/day and 75 mg/kg/day, respectively, for up to 104 weeks. The doses were approximately 40 and 80 times, in mice and rats respectively, the AUC in humans at the maximum recommended dose of 25 mg/day. All female rats, male mice, and high-dose female mice were terminated between study weeks 96 and 98 due to high mortality rates; mortality rates reached statistical significance in high-dose female mice (Prod Info AXERT(R) oral tablets, 2009).

2) FROVATRIPTAN

a) MICE: There were no increases in tumor incidence when mice were given frovatriptan in doses producing 140 times the exposure achieved at the maximum recommended daily human dose (MRHD) of 7.5 mg based on AUC comparisons in an 84-week study (Prod Info FROVA(R) oral tablets, 2007).

3) NARATRIPTAN

a) MICE: There was no evidence of an increase in tumors when mice received up to 200 mg/kg/day of naratriptan by oral gavage (AUC exposure was 110 times the human exposure with the maximum recommended daily dose of 5 mg) in a 104-week lifetime carcinogenicity study (Prod Info AMERGE(R) oral tablets, 2010).

4) RIZATRIPTAN

a) MICE/RATS: There was no evidence of an increased tumor incidence when mice and rats were given up to 125 mg/kg/day of rizatriptan by oral gavage for 100 weeks (mice) or 106 weeks (rats) in lifetime carcinogenicity studies. Exposure data were not measured; however, exposures at the highest dose level were approximated at 150 times (mice) and 240 times (rats) the average AUC measured for humans after a maximum recommended total daily dose of 30 mg using data from previous studies with oral rizatriptan in mice and rats (Prod Info MAXALT(R), MAXALT-MLT(R) oral tablets, orally disintegrating tablets, 2009).

5) SUMATRIPTAN

a) MICE/RATS: There was no evidence of increased tumors when rats and mice were given sumatriptan by oral gavage for 104 weeks and in drinking water for 78 weeks, respectively (Prod Info ALSUMA(TM) subcutaneous injection, 2010).

6) ZOLMITRIPTAN

a) MICE/RATS: There was no evidence of tumorigenicity when mice were given zolmitriptan by oral gavage at doses up to 400 mg/kg/day (AUC exposure at the highest dose level was approximately 800 times the human exposure after a maximum recommended total daily dose of 10 mg) for 85 to 92 weeks. No tumors were noted in rats who were given up to 400 mg/kg/day of zolmitriptan by oral gavage for 86 to 105 weeks (AUC exposure at the highest dose level was approximately 3000 times that of a human exposure based on a dose of 10 mg). Due to excessive mortality, the high-dose male and female rats were sacrificed at 101 weeks and 86 weeks, respectively (Prod Info ZOMIG(R) ZOMIG-ZMT(R) oral tablets, orally disintegrating tablets, 2008).

Genotoxicity

A)

1) Almotriptan was neither mutagenic nor clastogenic in the following tests: 2 in vitro gene mutation assays, Ames test, and mouse lymphoma assay, and an in vivo mouse micronucleus assay (Prod Info AXERT(R) oral tablets, 2009).

B)

1) Eletriptan was neither mutagenic nor clastogenic in the following tests: in vitro bacterial or mammalian cell assays, Ames reverse mutation test, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) mutation test in Chinese hamster ovary cells, and 2 in vivo mouse micronucleus assays. Equivocal results were demonstrated with in vitro human lymphocyte clastogenicity tests; polyploidy was increased in the absence of metabolic activation (-S9 conditions), but not in the presence of metabolic activation (Prod Info RELPAX(R) oral tablets, 2008).

C)

1) Frovatriptan was clastogenic in human lymphocyte cultures in the absence of metabolic activation. Frovatriptan was neither mutagenic nor clastogenic in the following tests: an in vitro mouse lymphoma assay, an in vivo mouse bone marrow micronucleus test, and an ex vivo assay for unscheduled DNA synthesis in rat liver. In the absence of metabolic activation frovatriptan demonstrated an equivocal response in the Ames test (Prod Info FROVA(R) oral tablets, 2007).

D)

1) Naratriptan was neither mutagenic nor clastogenic in the following tests: 2 gene mutation assays, Ames test, in vitro thymidine locus mouse lymphoma assay, 2 cytogenetics assays, in vitro human lymphocyte assay, and the in vivo mouse micronucleus assay. Nitrosated naratriptan (in vitro WHO nitrosation assay) forms a mutagenic product that is also found in the stomachs of rats who are given high nitrite diets (Prod Info AMERGE(R) oral tablets, 2010).

E)

1) Rizatriptan, with and without metabolic activation, was not mutagenic or clastogenic in the following tests: microbial mutagenesis (Ames) assay, in vitro mammalian cell mutagenesis assay in V-79 Chinese hamster lung cells, in vitro alkaline elution assay in rat hepatocytes, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and the in vivo chromosomal aberration assay in mouse bone marrow (Prod Info MAXALT(R), MAXALT-MLT(R) oral tablets, orally disintegrating tablets, 2009).

F)

1) Sumatriptan was neither mutagenic nor clastogenic in the following tests: Ames test, in vitro mammalian Chinese hamster V79/HGPRT assay, in vitro human lymphocyte assay, or in vivo rat micronucleus assay (Prod Info ALSUMA(TM) subcutaneous injection, 2010).

G)

1) Zolmitriptan was mutagenic in an Ames test with 2 of 5 strains of S. typhimurium in the presence of metabolic activation; it was not mutagenic in the absence of metabolic activation. It was clastogenic in the presence and absence of metabolic activation in an in vitro human lymphocyte assay. Zolmitriptan was not mutagenic, clastogenic, or genotoxic in an in vitro mammalian gene cell mutation assay (CHO/HGPRT), in vivo mouse micronucleus assay, and an unscheduled DNA synthesis study, respectively (Prod Info ZOMIG(R) ZOMIG-ZMT(R) oral tablets, orally disintegrating tablets, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise indicated.
B) Sumatriptan and naratriptan levels are not clinically useful.
C) Obtain a 12-lead ECG in patients with symptoms suggesting myocardial ischemia or dysrhythmias. Institute continuous cardiac monitoring in all symptomatic patients.

4.1.2)

A) SUMMARY

1) Sumatriptan and naratriptan levels are not clinically useful.
2) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise indicated.

4.1.4)

A) OTHER

1) ECG

a) Obtain a 12-lead ECG in patients with symptoms suggesting myocardial ischemia or dysrhythmias. Institute continuous cardiac monitoring in all symptomatic patients.

Methods

A)

1) Reversed-phase high-performance liquid chromatography has been reported for sumatriptan and zolmitriptan (Andrew et al, 1991) (Dixon & Warrander, 1997).
2) Thermospray liquid chromatography-mass spectrometry (Oxford & Lant, 1989).
3) Dixon & Warrander (1997) report a more sensitive liquid chromatography with tandem mass spectrometry method (LC-MS-MS) for quantification of zolmitriptan in plasma.

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients who develop significant hypertension or signs/symptoms or end-organ ischemia should be admitted for observation and treatment.

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic patients with inadvertent exposure to therapeutic or near-therapeutic doses can be managed at home with observation.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consultation with a medical toxicologist or poison center should be considered for any patient with significant symptoms or a significant overdose.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Symptomatic patients and patients with deliberate overdose should be referred to a health care facility.

Monitoring

A)

B)

C)

Oral Exposure

6.5.1)

A) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) SUPPORT

1) Monitor for development of hypertension and/or ventricular dysrhythmias. No specific antidote exists. Treatment includes supportive and pharmacological management of cardiovascular effects, and countershock as clinically indicated.

B) HYPERTENSIVE EPISODE

1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.

C) MALIGNANT HYPERTENSION

1) SODIUM NITROPRUSSIDE/INDICATIONS

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

2) SODIUM NITROPRUSSIDE/DOSE

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

3) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

4) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

5) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

6) NITROGLYCERIN/INDICATIONS

a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).

7) NITROGLYCERIN/ADULT DOSE

a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).

8) NITROGLYCERIN/PEDIATRIC DOSE

a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

9) PHENTOLAMINE/INDICATIONS

a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).

10) PHENTOLAMINE/ADULT DOSE

a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).

11) PHENTOLAMINE/PEDIATRIC DOSE

a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).

12) PHENTOLAMINE/ADVERSE EFFECTS

a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).

13) CAUTION

a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).

D) CONDUCTION DISORDER OF THE HEART

1) VENTRICULAR DYSRHYTHMIAS SUMMARY

a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

2) LIDOCAINE

a) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

b) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

c) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

d) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

3) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

4) PROCAINAMIDE

a) PROCAINAMIDE/INDICATIONS

1) An alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. It should be avoided when the ingestion involves agents with quinidine-like effects (e.g. tricyclic antidepressants, phenothiazines, chloroquine, antidysrhythmics) and when the ECG reveals QRS widening or QT prolongation suspected to be secondary to overdose(Neumar et al, 2010; Vanden Hoek,TL,et al).

b) PROCAINAMIDE/ADULT LOADING DOSE

1) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010).
2) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010).
3) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010).

c) PROCAINAMIDE/CONTROLLED INFUSION

1) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)

d) PROCAINAMIDE/ADULT MAINTENANCE DOSE

1) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010).

e) PROCAINAMIDE/PEDIATRIC LOADING DOSE

1) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).

f) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE

1) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).

g) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE

1) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).

h) MONITORING PARAMETERS

1) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).

i) AVOID

1) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010).

E) SEROTONIN SYNDROME

1) SUMMARY

a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).

2) HYPERTHERMIA

a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
c) Non-depolarizing paralytics may be used in severe cases.

3) CYPROHEPTADINE

a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).

4) HYPERTENSION

a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.

5) HYPOTENSION

a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
c) NOREPINEPHRINE

1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
2) INITIAL DOSE

a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.

3) MAINTENANCE DOSE

a) 0.5 to 1 mL (2 to 4 mcg)/minute.

6) SEIZURES

a) DIAZEPAM

1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.

b) LORAZEPAM

1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).

c) RECURRING SEIZURES

1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.

d) PHENOBARBITAL

1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.

7) CHLORPROMAZINE

a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.

8) NOT RECOMMENDED

a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

Enhanced Elimination

A)

1) Sumatriptan has a large volume of distribution; therefore, hemodialysis is unlikely to be effective.

Abstracts

Case Reports

A)

1) CORONARY VASOSPASM: A 47-year-old male smoker with a history of chest pain with methysergide and ergotamine use experienced severe chest pain within minutes of sumatriptan subcutaneous injection. He was admitted to the hospital complaining of chest pain at rest; electrocardiogram and cardiac enzyme concentrations were normal. A trial was performed in which sumatriptan 6 mg was administered while monitoring ECG changes. Four minutes after injection he developed chest pain and widespread ST elevation in the inferior and anterolateral leads. Sublingual nitroglycerin had no effect; chest pain resolved and ECG returned to normal after 22 minutes (Willett et al, 1992).
2) VENTRICULAR FIBRILLATION: A 42-year-old woman with no previous cardiac history collapsed within 3 minutes of an initial subcutaneous sumatriptan injection. She was found in coarse ventricular fibrillation. A single 200 kJ DC shock restored sinus rhythm; no further treatment was required. Further investigation showed a normal 24 hour ambulatory ECG, equivocal stress test, and 40% left anterior descending artery stenosis (Curtin et al, 1992).
3) VENTRICULAR TACHYCARDIA: A 43-year-old man with a history of rheumatic fever and mitral valve repair, presented with ventricular tachycardia without angina. DC cardioversion and amiodarone were required to correct the dysrhythmia. He had been using sumatriptan subcutaneously for 30 days prior to admission. Following each injection he reported "hot surges" in the throat." Four injections had been followed by palpitations (Curtin et al, 1992).
4) MYOCARDIAL INFARCTION: A 47-year-old woman with no previous cardiac history presented with severe substernal pain radiating to the left shoulder and nausea. Onset was 15 minutes after self-administration of sumatriptan 6 mg subcutaneously. Blood pressure was normal on admission; ECG showed inverted T waves and abnormal Q waves. Creatine kinase was 873 Units/L the following day. Diagnosis was transmural inferior myocardial infarction and the patient was treated with nitrates and heparin, recovering without complications (Ottervanger et al, 1993).
5) HYPOESTHESIA: A 46-year-old man experienced right-sided hypoesthesia and hemiparesis 1 week after his fifth subcutaneous sumatriptan injection in 2 weeks (Luman, 1993).
6) HEMIPARESIS: A 25-year-old woman experienced right hemiparesis 12 hours after 6 mg of subcutaneous sumatriptan. Spontaneous recovery occurred within 1 week (Luman, 1993).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) ALMOTRIPTAN

1) Recommended dose is 6.25 to 12.5 mg ORALLY at the onset of headache; may repeat dose after 2 hours, if no relief. MAXIMUM DOSE: 25 mg/day. The safety of treating more than 4 headaches in a 30-day period has not been established (Prod Info AXERT(R) oral tablets, 2009).

B) ELETRIPTAN

1) Recommended dose is 20 to 40 mg ORALLY at the onset of headache; may repeat dose after a minimum of 2 hours, if no relief. MAXIMUM SINGLE DOSE: 40 mg; MAXIMUM DAILY DOSE: 80 mg. The safety of treating more than 3 headaches in a 30-day period has not been established (Prod Info RELPAX(R) oral tablets, 2008).

C) FROVATRIPTAN

1) Recommended dose is 2.5 mg ORALLY at the onset of headache; may repeat dose after a minimum of 2 hours, if no relief. MAXIMUM DAILY DOSE: 7.5 mg. The safety of treating more than 4 headaches in a 30-day period has not been established (Prod Info FROVA(R) oral tablets, 2007).

D) NARATRIPTAN

1) Recommended dose is 1 to 2.5 mg ORALLY at the onset of headache; may repeat dose after 4 hours, if no relief. MAXIMUM DOSE: 5 mg/day. The safety of treating more than 4 headaches in a 30-day period has not been established (Prod Info AMERGE(R) oral tablets, 2010).

E) RIZATRIPTAN

1) Recommended dose is 5 to 10 mg ORALLY at the onset of headache; may repeat dose after a minimum of 2 hours, if no relief. MAXIMUM DOSE: 30 mg/day. The safety of treating more than 4 headaches in a 30-day period has not been established (Prod Info MAXALT(R), MAXALT-MLT(R) oral tablets, orally disintegrating tablets, 2009).

F) SUMATRIPTAN

1) NASAL POWDER AEROSOL: Recommended dose is 22 mg (2 nosepieces) at the onset of headache; may repeat dose after 2 hours if no relief. MAXIMUM DOSE: 44 mg/day (4 nosepieces) or one dose of nasal powder and one dose of another sumatriptan product, separated by at least 2 hours. The safety of treating an average of more than 4 headaches in a 30-day period has not been established (Prod Info ONZETRA(TM) Xsail(TM) nasal powder, 2016).
2) NASAL SPRAY: Recommended dose is 5 to 20 mg at the onset of headache; may repeat dose after 2 hours, if no relief. MAXIMUM DOSE: 40 mg/day. The safety of treating more than 4 headaches in a 30-day period has not been established (Prod Info IMITREX(R) nasal spray, 2010).
3) ORAL: Recommended dose is 25 to 100 mg at the onset of headache; may repeat dose after 2 hours, if no relief. MAXIMUM DOSE: 200 mg/day. The safety of treating more than 4 headaches in a 30-day period has not been established (Prod Info IMITREX(R) oral tablets, 2010).
4) SUBQ INJECTION: Recommended dose for cluster headache is 6 mg at the onset of headache; may repeat dose after a minimum of 1 hour, if no relief. MAXIMUM DOSE: 12 mg/day (Prod Info ALSUMA(TM) subcutaneous injection, 2010; Prod Info IMITREX(R) injection, 2010; Prod Info SUMAVEL DOSEPRO(R) subcutaneous injection, 2009). The recommended doses for a migraine are 1 to 6 mg (Imitrex(R)), 3 mg (Zembrace SymTouch(TM)), 4 or 6 mg (Sumavel(R) DosePro(R)), or 6 mg (Alsuma(TM)) SUBQ as a single dose; may repeat after 1 hour if needed; MAX 6 mg/dose and 12 mg/24 hours; devices do not accommodate doses less than 3, 4 or 6 mg (Prod Info IMITREX(R) subcutaneous injection, 2012; Prod Info ZEMBRACE(TM) SymTouch(TM) subcutaneous injection, 2016; Prod Info Sumavel(R) DosePro(R) subcutaneous injection solution, 2013; Prod Info ALSUMA(TM) subcutaneous injection, 2010).

G) SUMATRIPTAN SUCCINATE/NAPROXEN SODIUM

1) Recommended dose is 1 tablet (sumatriptan 85 mg/naproxen 500 mg) ORALLY; may repeat dose once after 2 hours MAX DOSE, 2 tablets (sumatriptan 170 mg/naproxen 1000 mg) in 24 hours (Prod Info TREXIMET(R) oral tablets, 2015)

H) ZOLMITRIPTAN

1) NASAL: Recommended starting dose is 2.5 mg into one nostril; may repeat after 2 hours, if headache does not resolve or returns after transient improvement. MAXIMUM DOSE: 5 mg/single dose; 10 mg/24 hours. The safety of treating more than 4 headaches in a 30-day period has not been established (Prod Info ZOMIG(R) nasal spray solution, 2015).
2) ORAL: REGULAR TABLET: Recommended dose is 1.25 to 2.5 mg at the onset of headache; may repeat dose after 2 hours, if no relief; MAXIMUM DOSE: 5 mg/single dose; 10 mg/24 hr. The safety of treating more than 3 headaches in a 30-day period has not been established (Prod Info ZOMIG(R) oral tablets, 2012).
3) ORAL: ORALLY DISINTEGRATING TABLET: Recommended dose is 2.5 mg at the onset of headache; may repeat dose after 2 hours, if no relief; MAXIMUM DOSE: 5 mg/single dose; 10 mg/24 hours. The safety of treating more than 3 headaches in a 30-day period has not been established (Prod Info ZOMIG-ZMT(R) oral disintegrating tablets, 2012).

7.2.2)

A) ALMOTRIPTAN

1) 12 TO 17 YEARS OF AGE: Recommended dose is 6.25 to 12.5 mg ORALLY at the onset of headache; may repeat dose after 2 hours if no relief. MAXIMUM DOSE: 25 mg/day. The safety of treating more than 4 headaches in a 30-day period has not been established (Prod Info AXERT(R) oral tablets, 2009).
2) LESS THAN 12 YEARS OF AGE: Safety and efficacy have not been established (Prod Info AXERT(R) oral tablets, 2009).

B) ELETRIPTAN

1) Use is NOT recommended in children under 18 years of age; safety and efficacy have not been established in this age group (Prod Info RELPAX(R) oral tablets, 2008).

C) FROVATRIPTAN

1) Use is NOT recommended in children under 18 years of age; safety and efficacy have not been established in this age group (Prod Info FROVA(R) oral tablets, 2007).

D) NARATRIPTAN

1) Safety and efficacy have not been established in children under 18 years of age (Prod Info AMERGE(R) oral tablets, 2010).

E) RIZATRIPTAN

1) 6 TO 17 YEARS OF AGE

a) LESS THAN 40 KG (88 LB): The recommended dose is 5 mg (Prod Info MAXALT(R) oral tablets, 2011; Prod Info MAXALT-MLT(R) oral disintegrating tablets, 2011).
b) 40 KG (88 LB) OR GREATER: The recommended dose is 10 mg (Prod Info MAXALT(R) oral tablets, 2011; Prod Info MAXALT-MLT(R) oral disintegrating tablets, 2011).
c) The safety and effectiveness of treatment with more than one dose within 24 hours have not been established (Prod Info MAXALT(R) oral tablets, 2011; Prod Info MAXALT-MLT(R) oral disintegrating tablets, 2011).

2) LESS THAN 6 YEARS OF AGE

a) Safety and efficacy have not been established (Prod Info MAXALT(R) oral tablets, 2011; Prod Info MAXALT-MLT(R) oral disintegrating tablets, 2011).

3) OPEN-LABEL STUDY

a) A long-term safety and efficacy study of rizatriptan was conducted in children (n=606) with a history of migraines. Children 12 to 17 years and weighing less than 40 kg received 5 mg of orally disintegrating tablet and those weighing greater than 40 kg received 10 mg. Patients were able to treat up to 8 mild/moderate or severe migraine attacks per month for up to 12 months with one dose of medication per day. Most patients tolerated therapy well with typical adverse events (ie, asthenia, chest discomfort, dizziness, dry mouth, fatigue, somnolence, myalgia, nausea and paresthesia) reported in 25% of patients. Twenty-five serious adverse events were reported in 22 patients receiving 10 mg therapy. Two patients reported suicidal ideation and 3 patients experienced attempted suicide. All had a history of depression and a temporal relationship between rizatriptan therapy and suicidal behavior could not be determined (Hewitt et al, 2013).

F) SUMATRIPTAN

1) NASAL, ORAL, SUBQ INJECTION: Use is NOT recommended in children under 18 years of age; safety and efficacy have not been established in this age group (Prod Info ONZETRA(TM) Xsail(TM) nasal powder, 2016; Prod Info IMITREX(R) nasal spray, 2010; Prod Info IMITREX(R) oral tablets, 2010; Prod Info ALSUMA(TM) subcutaneous injection, 2010; Prod Info IMITREX(R) injection, 2010; Prod Info Sumavel(R) DosePro(R) subcutaneous injection solution, 2013; Prod Info ZEMBRACE(TM) SymTouch(TM) subcutaneous injection, 2016).

G) SUMATRIPTAN SUCCINATE/NAPROXEN SODIUM

1) 12 YEARS OF AGE AND OLDER: Recommended dose is 1 tablet (sumatriptan 10 mg/naproxen 60 mg) ORALLY. MAX DOSE, 1 tablet, adult strength (sumatriptan 85 mg/naproxen 500 mg) in 24 hours (Prod Info TREXIMET(R) oral tablets, 2015).

H) ZOLMITRIPTAN

1) 12 YEARS OF AGE AND OLDER: NASAL: Recommended starting dose is 2.5 mg into one nostril; may repeat after 2 hours, if headache does not resolve or returns after transient improvement. MAXIMUM DOSE: 5 mg/single dose; 10 mg/24 hours. The safety of treating more than 4 headaches in a 30-day period has not been established (Prod Info ZOMIG(R) nasal spray solution, 2015).
2) ORAL: Use is NOT recommended in children under 18 years of age; safety and efficacy have not been established in this age group (Prod Info ZOMIG(R) oral tablets, 2012; Prod Info ZOMIG-ZMT(R) oral disintegrating tablets, 2012; Prod Info ZOMIG(R) nasal spray, 2013).

Minimum Lethal Exposure

A)

1) At the time of this review, a minimum toxic dose has not been established for these agents.

Maximum Tolerated Exposure

A)

1) SUMATRIPTAN

a) 47 milligrams in a single injection was tolerated without serious adverse effects (Prod Info Imitrex(R), sumatriptan (injection), 1993).
b) Single oral doses of up to 400 mg have been tolerated without serious adverse effects (Prod Info IMITREX(R) oral tablets, 2010).
c) Four occasions of injections of 36 mg/24 hours within 10 days has been reported in a 36-year-old man. Brief duration of paresthesias and malaise were reported. No other adverse effects nor changes in blood chemistries were noted (Turhal, 2001).
d) EXCESSIVE THERAPEUTIC DOSE: A 35-year-old nonsmoking, woman with a history of refractory migraine headaches took more than twice the recommended daily dose (300 mg of sumatriptan orally and 12 mg subQ [maximum daily dose: 200 mg orally OR 12 mg subQ]) and 36 hours later developed severe abdominal pain and was initially diagnosed with colitis of undetermined etiology. The patient was not receiving oral contraceptives or other serotonin agonists. A computed tomography of the abdomen showed left-sided colitis. The patient received pain medication and was discharged to home and readmitted the same day with severe abdominal pain and prescribed bowel rest, pain medication, and IV hydration. The patient gradually improved and a colonoscopy a few days later revealed ischemic colitis felt to be secondary to sumatriptan use (Hodge & Hodge, 2010).
e) CASE REPORT: A 45-year-old woman, without a past history of cardiac disease, experienced severe chest pain associated with diaphoresis and nausea approximately 1 hour after taking 100 mg sumatriptan orally for a headache. Her initial ECG, after arrival to the ED, revealed normal sinus rhythm with first degree heart block and laboratory findings showed an increase in cardiac enzyme levels. The patient recovered and was discharged 2 days later without further sequelae (Hack, 2004).

2) NARATRIPTAN

a) A single 10 mg dose resulted in significant increase in blood pressure in a mildly hypertensive patient (baseline 150/98 up to 204/144 mmHg) (Prod Info AMERGE(R) oral tablets, 2010a).
b) A single dose of 25 mg in a young adult resulted in blood pressure increase from 120/67 mmHg baseline to 191/113 mmHg about 6 hours after the dose. Other adverse effects included loss of coordination, light-headedness, tiredness and neck tension (Prod Info AMERGE(R) oral tablets, 2010a).
c) A 7.5 mg oral dose resulted in asymptomatic ischemic ECG changes, probably coronary artery vasospasm, approximately 2 hours after the dose (Prod Info AMERGE(R) oral tablets, 2010a).

3) ALMOTRIPTAN

a) In clinical trials, 6 patients received single oral doses of 200 mg each with no serious adverse effects (Prod Info AXERT(R) oral tablets, 2009).

Pharmacology Toxicology

Pharmacologic Mechanism

A)

Toxicologic Mechanism

A)

Physicochemical

Physical Characteristics

1)

2)

3)

4)

5)

6)

7)

8)

9)

10)

Ph

1)

2)

3)

Molecular Weight

1)

2)

3)

4)

5)

6)

7)

8)

Animal Toxicology

References

General Bibliography

1)

2)

3)

4)

5)

6)

7)

8)

9)

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

FeedBack

SUMATRIPTAN AND RELATED AGENTS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Neurologic

Gastrointestinal

Genitourinary

Dermatologic

Endocrine

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography