General: pms-SUMATRIPTAN should only be used where a clear diagnosis of migraine has been established.
Cluster Headache: There is insufficient information on the efficacy and safety of sumatriptan succinate in the treatment of cluster headache, which is present in an older, predominantly male population. The need for prolonged use and the demand for repeated medication in this condition renders the dosing information inapplicable for cluster headache.
Psychomotor Impairment: Patients should be cautioned that drowsiness may occur as a result of treatment with pms-SUMATRIPTAN. They should be advised not to perform skilled tasks (e.g. driving or operating machinery) if drowsiness occurs.
Medication Overuse Headache: Overuse of acute headache treatments has been associated with the exacerbation of headache (medication overuse headache, MOH) in susceptible patients. Withdrawal of the treatment may be necessary.
Cardiovascular: Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events: Sumatriptan succinate has been associated with transient chest and/or neck pain, pressure, heaviness and tightness which may resemble angina pectoris. In rare cases, the symptoms have been identified as being the likely result of coronary vasospasm or myocardial ischemia. Rare cases of serious coronary events or arrhythmia have occurred following use of sumatriptan succinate. pms-SUMATRIPTAN should not be given to patients who have documented ischemic or vasospastic coronary artery disease (CAD) (see Contraindications). It is strongly recommended that pms-SUMATRIPTAN not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hyper-cholesterolemia, smoking, obesity, diabetes, strong family history of CAD, female who is surgically or physiologically postmenopausal, or male who is over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is unknown. If, during the cardiovascular evaluation, the patient's medical history or electrocardiographic investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, pms-SUMATRIPTAN should not be administered (see Contraindications).
For patients with risk factors predictive of CAD who are considered to have a satisfactory cardiovascular evaluation, the first dose of pms-SUMATRIPTAN should be administered in the setting of a physician's office or similar medically staffed and equipped facility. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining electrocardiograms in patients with risk factors during the interval immediately following pms-SUMATRIPTAN administration on the first occasion of use.
However, an absence of drug-induced cardiovascular effects on the occasion of the initial dose does not preclude the possibility of such effects occurring with subsequent administrations.
Intermittent long term users of sumatriptan succinate who have or acquire risk factors predictive of CAD, as described previously, should receive periodic interval cardiovascular evaluations over the course of treatment.
If symptoms consistent with angina occur after the use of pms-SUMATRIPTAN, ECG evaluation should be carried out to look for ischemic changes.
The systematic approach described previously is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to pms-SUMATRIPTAN.
Discomfort in the chest, neck, throat and jaw (including pain, pressure, heaviness, tightness, dyspnea) has been reported after administration of sumatriptan succinate. Because 5-HT1 agonists may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following pms-SUMATRIPTAN should be evaluated for the presence of CAD or a predisposition to variant angina before receiving additional doses, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud's syndrome, following pms-SUMATRIPTAN should be evaluated for atherosclerosis or predisposition to vasospasm (see Contraindications; Clinical Trial Adverse Drug Reactions under Adverse Reactions).
Cardiac Events and Fatalities Associated with 5-HT1-Agonists: pms-SUMATRIPTAN can cause coronary artery vasospasm. Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of 5-HT1 agonists. Considering the extent of use of 5-HT1 agonists in patients with migraine, the incidence of these events is extremely low. The fact that some of these events have occurred in patients with no prior cardiac disease history and with documented absence of CAD, and the close proximity of the events to sumatriptan succinate use support the conclusion that some of these cases were caused by the drug. In many cases, however, where there has been known underlying coronary artery disease, the relationship is uncertain.
Premarketing Experience With Sumatriptan Succinate: Of 6348 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of oral sumatriptan succinate two experienced clinical adverse events shortly after receiving oral sumatriptan succinate that may have reflected coronary vasospasm. Neither of these adverse events was associated with a serious clinical outcome.
Among the more than 1900 patients with migraine who participated in premarketing controlled clinical trials of subcutaneous sumatriptan succinate, there were eight patients who sustained clinical events during or shortly after receiving sumatriptan succinate that may have reflected coronary artery vasospasm. Six of these eight patients had ECG changes consistent with transient ischemia, but without accompanying clinical symptoms or signs. Of these eight patients, four had either findings suggestive of CAD or risk factors predictive of CAD prior to study enrollment.
Among approximately 4,000 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of sumatriptan nasal spray, one patient experienced an asymptomatic subendocardial infarction possibly subsequent to a coronary vasospastic event.
Postmarketing Experience With Sumatriptan Succinate: Serious cardiovascular events, some resulting in death, have been reported in association with the use of sumatriptan succinate tablets. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by sumatriptan succinate or to reliably assess causation in individual cases. On clinical grounds, the longer the latency between the administration of sumatriptan succinate and the onset of the clinical event, the less likely the association is to be causative. Accordingly, interest has focused on events beginning within 1 hour of the administration of sumatriptan succinate.
Cardiac events that have been observed to have onset within 1 hour of sumatriptan succinate administration include: coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation, cardiac arrest, and death.
Some of these events occurred in patients who had no findings of CAD and appear to represent consequences of coronary artery vasospasm. However, among reports from the USA of serious cardiac events occurring within 1 hour of sumatriptan succinate administration, almost all of the patients had risk factors predictive of CAD and the presence of significant underlying CAD was established in most cases (see Contraindications).
Cerebrovascular Events and Fatalities with 5-HT1 Agonists: Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with oral sumatriptan succinate and some have resulted in fatalities. The relationship of sumatriptan succinate to these events is uncertain. In a number of cases, it appears possible that the cerebrovascular events were primary, sumatriptan succinate having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Before treating migraine headaches with pms-Sumatriptan in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. If a patient does not respond to the first dose, the opportunity should be taken to review the diagnosis before a second dose is given. It should also be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA).
Special Cardiovascular Pharmacology Studies: In subjects (n=10) with suspected coronary artery disease undergoing angiography, a 5-HT1 agonist at a subcutaneous dose of 1.5 mg produced an 8% increase in aortic blood pressure, an 18% increase in pulmonary artery blood pressure, and an 8% increase in systemic vascular resistance. In addition, mild chest pain or tightness was reported by four subjects. Clinically significant increases in blood pressure were experienced by three of the subjects (two of whom also had chest pain/discomfort). Diagnostic angiogram results revealed that 9 subjects had normal coronary arteries and 1 had insignificant coronary artery disease.
In an additional study with this same drug, migraine patients (n=35) free of cardiovascular disease were subjected to assessments of myocardial perfusion by positron emission tomography while receiving a subcutaneous 1.5 mg dose in the absence of a migraine attack. Reduced coronary vasodilatory reserve (~10%), increase in coronary resistance (~20%), and decrease in hyperemic myocardial blood flow (~10%) were noted. The relevance of these finding to the use of the recommended oral doses of this 5-HT1 agonist is not known.
Similar studies have not been done with sumatriptan succinate. However, owing to the common pharmacodynamic actions of 5-HT1 agonists, the possibility of cardiovascular effects of the nature described previously should be considered for any agent of this pharmacological class.
Other Vasospasm-Related Events: 5-HT1 agonists may cause vasospastic reactions other than coronary artery vasospasm. Extensive post-market experience has shown the use of sumatriptan succinate to be associated with rare occurrences of peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea, and in isolated cases there was no previous history or concomitant medications.
Increase in Blood Pressure: Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients with and without a history of hypertension. pms-SUMATRIPTAN is contraindicated in patients with uncontrolled or severe hypertension (see Contraindications). In patients with controlled hypertension, pms-SUMATRIPTAN should be administered with caution, as transient increases in blood pressure and peripheral vascular resistance have been observed in a small portion of patients.
Immune: Rare hypersensitivity (anaphylaxis/anaphylactoid) reactions may occur in patients receiving 5-HT1 agonists such as pms-SUMATRIPTAN. Such reactions can be life threatening or fatal. In general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens (see Contraindications). Owing to the possibility of cross-reactive hypersensitivity reactions, pms-SUMATRIPTAN should not be used in patients having a history of hypersensitivity to chemically related 5-HT1 receptor agonists. There have been reports of patients with known hypersensitivity to sulphonamides exhibiting an allergic reaction following administration of sumatriptan succinate. Reactions ranged from cutaneous hypersensitivity to anaphylaxis.
Neurologic: Care should be taken to exclude other potentially serious neurologic conditions before treating headache in patients not previously diagnosed with migraine headache or who experience a headache that is atypical for them. There have been rare reports where patients received 5-HT1 agonists for severe headaches that were subsequently shown to have been secondary to an evolving neurologic lesion. For newly diagnosed patients or patients presenting with atypical symptoms, the diagnosis of migraine should be reconsidered if no response is seen after the first dose of pms-SUMATRIPTAN.
Seizures: Caution should be observed if pms-SUMATRIPTAN is to be used in patients with a history of seizures or other risk factors, such as structural brain lesions, which lower the convulsion threshold. There have also been rare post-market reports of seizures following administration of sumatriptan succinate in patients without risk factors or previous history of seizures. (See Post-Market Adverse Drug Reactions: Nervous System Disorders under Adverse Reactions.)
Selective Serotonin Reuptake Inhibitors (SSRIs)/Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) and Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant treatment with pms-SUMATRIPTAN and SSRIs (e.g., fluoxetine, paroxetine, sertraline) or SNRIs (e.g., venlafaxine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) (see Drug-Drug Interactions: Selective Serotonin Reuptake Inhibitors (SSRIs)/Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) under Interactions).
Ophthalmologic: Binding to Melanin Containing Tissues: In rats treated with a single subcutaneous dose (0.5 mg/kg) or oral dose (2 mg/kg) of radiolabeled sumatriptan, the elimination half life of radioactivity from the eye was 15 and 23 days, respectively, suggesting that sumatriptan and/or its metabolites bind to the melanin of the eye. Because there could be an accumulation in melanin rich tissues over time, this raises the possibility that sumatriptan could cause toxicity in these tissues after extended use. However, no effects on the retina related to treatment with sumatriptan were noted in any of the oral or subcutaneous toxicity studies. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long term ophthalmologic effects.
Hepatic Impairment: The effect of hepatic impairment on the efficacy and safety of sumatriptan succinate has not been evaluated; however, the pharmacokinetic profile of sumatriptan in patients with moderate1 hepatic impairment (Child Pugh B) shows that these patients, following an oral dose of 50 mg, have much higher plasma sumatriptan concentrations than healthy subjects (Table 6). Therefore, an oral dose of 25 mg may be considered in patients with mild or moderate hepatic impairment. (See Special Populations: Adults with Mild to Moderate Hepatic Impairment under Dosage & Administration.) (See Table 6.)
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1Assessed by aminopyrine breath test (>0.2-0.4 scaling units).
The pharmacokinetic parameters of 6 mg subcutaneous sumatriptan do not differ statistically between normal volunteers and moderately hepatically impaired subjects (Child Pugh B). All formulations of sumatriptan are contraindicated in patients with severe hepatic impairment (see Special Populations: Adults with Severe Hepatic Impairment under Dosage & Administration; Contraindications).
Renal: The effects of renal impairment on the efficacy and safety of sumatriptan succinate have not been evaluated. Therefore, pms-SUMATRIPTAN is not recommended in this patient population.
Monitoring and Laboratory Tests: No specific laboratory tests are recommended for monitoring patients prior to and/or after treatment with sumatriptan succinate.
Use in Children: The safety and efficacy of sumatriptan succinate in children (<18 years of age) has not been established and its use in this age group is not recommended.
Use in the Elderly: Experience of the use of sumatriptan succinate in patients aged over 65 years is limited. Therefore the use of pms-SUMATRIPTAN in patients over 65 years is not recommended.