SUMATRIPTAN SUCC 100 MG TABLET (Generic Imitrex)

Uses Dosage and Administration Cautions Drug Interactions Pharmacokinetics

Uses

Vascular Headaches

Sumatriptan is used orally, by subcutaneous injection, or intranasally for the acute management of attacks of migraine with aura (also called classic migraine) or migraine without aura (also called common migraine) and by subcutaneous injection for the acute management of cluster headache episodes. Sumatriptan should be used only in patients in whom a clear diagnosis of migraine or cluster headache has been established. The manufacturers and some clinicians state that the drug is not to be used for the management of hemiplegic or basilar migraine or for prophylaxis of migraine or cluster headache. In patients with a history of migraine or cluster headache who present with atypical symptoms (e.g., ataxia, vertigo, tinnitus, mental status changes, visual field cuts/ blindness, paresthesia, hemiparesis), care should be taken to exclude other potentially serious neurologic conditions (e.g., cerebrovascular accident, subarachnoid hemorrhage) before initiation of sumatriptan therapy.(See Cautions: Precautions and Contraindications.)

General Principles in Migraine Therapy

Drug therapy in the management of migraine headache must be individualized and adjusted based on the severity and frequency of attacks, response to therapy (single or multiple drugs), and tolerance to drug-induced adverse effects. Important considerations in the choice of drug therapy include the wide range in severity of the attacks, considerable interindividual variation in response and tolerance, toxic potentials of the drugs, presence of concomitant illness (e.g., cardiovascular disease, uncontrolled hypertension) or pregnancy, potential tolerance to the therapeutic effects of the drugs, the potential for abuse and misuse of the drugs, and cost. Decisions regarding drug therapy in the management of migraine headache should be weighed carefully (e.g., do the headaches threaten to disrupt the patient's normal functioning), particularly when potentially toxic, habituating, and/or potent drugs are considered. Although the benefit of therapy may principally be pain relief, the long-term goals of therapy are to prevent or reduce the frequency and severity of attacks, reduce the disability associated with migraine headaches, improve quality of life, avoid escalation of antimigraine drug therapy, and educate and enable patients to manage their illness. Management also should include appropriate nondrug therapy such as lifestyle modification, avoidance of precipitating factors, and behavioral and/or psychologic therapy. Although the pathogenesis of migraine headache has not been fully elucidated (see Pharmacology), it is known that avoidance of certain triggering factors such as alcohol (e.g., red wine), certain foods or food additives (e.g., chocolate, certain cheeses, monosodium glutamate, nitrates), irregular eating habits, irregular sleep, and acute changes in stress level as well as proper management of other factors such as travel across time zones, high-altitude barometric pressure changes, and association with the menstrual cycle may be useful in the management of migraine attacks. The possible presence of other types of headaches (e.g., tension-type, cluster) should be evaluated.

Although migraine headache is common (about 15-18% of women and 6% of men in the general population suffer migraine attacks), the condition is underrecognized and undertreated probably because of the lack of biologic markers to confirm the diagnosis. About two-thirds of patients with migraine headache experience infrequent attacks (e.g., 1 or 2 per year), with the remainder experiencing one or more migraine attacks each month. Over 80% of migraine sufferers experience some degree of headache-associated disability. For a diagnosis of migraine without aura (also called common migraine) or with aura (also called classic migraine), the criteria established by the International Headache Society (IHS) usually are used. According to IHS, migraine without aura is an idiopathic, recurring headache disorder manifested by untreated or unsuccessfully treated attacks lasting 4-72 hours and characterized by unilateral, pulsating headache of moderate to severe intensity that may disrupt routine physical activity and is associated with nausea, vomiting, photophobia, and/or phonophobia and worsens with movement; some experts also consider osmophobia a diagnostic criterion. Migraine with aura is characterized by the same manifestations as migraine without aura, but it also is accompanied before or during the attack by neurologic manifestations (e.g., visual disturbance) indicating focal cerebral cortical and/or brain stem dysfunction.

Acute Attacks

Because patients may experience a wide spectrum of severity in migraine attacks with variable effects on functioning, multiple appropriate therapies for attacks of differing severity generally are made available to the patient. The goals of acute migraine therapy are as follows: provide rapid and consistent relief of migraine attacks without recurrence; restore the patient's ability to function; minimize the use of back-up and rescue medications (i.e., drugs used at home when other therapies fail); optimize self-care and reduce subsequent use of medical resources; be cost-effective for overall management; and relieve the headache while minimizing or avoiding adverse effects of therapy. To meet these goals, some experts recommend use of selective 5-HT₁ receptor agonists, dihydroergotamine, or ergotamine in patients with moderate or severe migraine or in those with mild to moderate headaches that respond poorly to nonsteroidal anti-inflammatory agents (NSAIAs) or fixed-combination analgesics such as those containing aspirin, acetaminophen, and caffeine. Failure to promptly use an effective treatment may increase pain, disability, and the impact of the headache. Patients should be advised, however, that excessive use of some of these drugs (e.g., ergotamine [but not dihydroergotamine], opiates, selective 5-HT₁ analgesics [including fixed combinations containing butalbital, caffeine, or isometheptene]) may cause rebound headache. Medical attention (including hospitalization) may be necessary for detoxification from drug overuse or abuse. Because nausea is one of the most aversive and disabling symptoms of migraine attacks, selection of nonoral routes of administration and/or use of antiemetics is recommended in patients in whom nausea and/or vomiting are prominent early symptoms of migraine attacks. Antiemetics should not be restricted to patients who are vomiting or likely to vomit. In some patients, concomitant therapy with an antiemetic and an oral antimigraine drug may be appropriate. In addition, some experts state that IV metoclopramide may be considered as monotherapy for relief of migraine pain.

Some clinicians recommend that mild migraine headache (patient's normal activities are minimally disrupted; headache usually lasts for 4-8 hours and may be accompanied by nausea) be treated with an NSAIA (e.g., aspirin, ibuprofen, indomethacin, naproxen sodium) or combined acetaminophen, aspirin, and caffeine. In addition to these analgesics, an antiemetic (e.g., dimenhydrinate, metoclopramide, prochlorperazine), mild vasoconstrictor (e.g., isometheptene), or sedative-hypnotic may be beneficial.

For the management of moderate migraine headache (patient's normal activities are moderately disrupted; headache may last for more than 4 hours and up to about 24 hours and may be accompanied by nausea and vomiting), many clinicians recommend an oral NSAIA either given alone or in fixed combination with acetaminophen, an opiate analgesic (e.g., codeine), a barbiturate (e.g., butalbital), and/or caffeine. However, because of the risk of dependency and misuse or abuse, some clinicians recommend that use of opiate analgesics and barbiturates be reserved for patients with infrequent migraine headaches, for those who do not respond to other drugs, and when the sedative effects of the drugs will not put the patient at risk and the abuse potential has been addressed. In addition, many clinicians state that moderate migraine headache can be treated with a 5-HT₁ selective (e.g., almotriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan [given orally, subcutaneously, or intranasally], zolmitriptan) or nonselective (e.g., dihydroergotamine [given parenterally or intranasally], or possibly ergotamine [given alone or in fixed combination with caffeine and/or a barbiturate]) receptor agonist. Parenteral dihydroergotamine or 5-HT₁ selective receptor agonists are particularly useful in patients with rapid onset of migraine, and parenteral and intranasal preparations of these drugs may be particularly useful in those unable to take oral drugs because of severe nausea and/or vomiting. Many moderate headaches may respond to an NSAIA alone; combinations of an NSAIA or acetaminophen with an opiate or barbiturate may be useful for attacks not responding to initial therapy or if vasoconstrictors are not tolerated. Although the role of ergotamine has been questioned (e.g., because of toxicity profile [including severe nausea and vomiting], rebound effect), some patients continue to find the drug useful, particularly when combined with an antiemetic.

For the initial management of severe migraine headache (patient's normal activities are severely disrupted; headache generally lasts for longer than 12 hours and usually is accompanied by nausea, and vomiting occasionally may occur), many clinicians recommend dihydroergotamine (given parenterally or intranasally) or a 5-HT₁ selective receptor agonist, including almotriptan (given orally), frovatriptan (given orally), naratriptan (given orally), rizatriptan (given orally), zolmitriptan (given orally), or sumatriptan (given orally, subcutaneously, or intranasally). Alternatively, a phenothiazine (e.g., chlorpromazine given IM, IV, or rectally) may be used; if pain is not relieved, a parenteral NSAIA (e.g., ketorolac given IM) or a corticosteroid (e.g., dexamethasone given IV) may be considered.Self-administration of rescue medications (e.g., butorphanol nasal solution, parenteral opiates) in a home setting also should be considered for patients with severe migraine attacks that do not respond adequately to other treatments once the drugs' abuse potential has been addressed. Although rescue medications often do not completely eliminate pain and return patients to normal functioning, they permit the patient to achieve relief without the discomfort and expense of an office or emergency department visit.

For the management of ultra-severe migraine attacks, including status migrainosus (patient's normal activities are severely disrupted for more than 72 hours) that are accompanied by vomiting, it is recommended that patients be rehydrated initially, which should be followed by administration of dihydroergotamine (given IV every 8 hours for 24 hours), and each dose should be preceded by a dose of metoclopramide to prevent nausea. Some clinicians state, however, that IV dihydroergotamine should be reserved for patients who do not respond to any other drug therapy, including 5-HT₁ selective receptor agonists. Alternatively, for ultra-severe migraine attacks, an IV phenothiazine (e.g., chlorpromazine, prochlorperazine) may be given alone or in combination with a parenteral corticosteroid (e.g., dexamethasone, methylprednisolone) and/or an opiate agonist (e.g., meperidine). Parenteral opiate-agonist therapy generally is considered a last resort because of the risks of dependence, tolerance, and associated adverse effects.

Prophylaxis of Chronic Attacks

Previously accepted recommendations for prophylaxis of chronic migraine attacks principally focused on patients who had 2 or more attacks per month. Such recommendations have been described by some experts as being arbitrary and as failing to account for individual patient needs or other migraine characteristics. Therefore, prophylactic therapy currently can be considered in patients with recurring migraine attacks when, in the opinion of the patient and despite acute therapy, the attacks substantially interfere with daily routines; in patients in whom the frequency of migraine attacks and resultant reliance on acute therapy would increase the potential for drug-induced (rebound) headache; in patients in whom acute therapy is ineffective, contraindicated, or not tolerated; in patients who prefer prophylactic therapy; and in those with uncommon migraine conditions, including hemiplegic migraine, basilar migraine, migraine with prolonged aura, or migrainous infarction (to prevent neurologic damage). The goals of prophylactic therapy are to decrease the frequency, severity, and duration of migraine attacks and the disability associated with such attacks; improve responsiveness of acute attacks to therapy; and improve patient functioning. For prevention of migraine headache, a β-adrenergic blocking agent (e.g., atenolol, metoprolol, nadolol, propranolol, timolol), calcium-channel blocking agent (e.g., verapamil), tricyclic antidepressant (e.g., amitriptyline), anticonvulsant (e.g., valproate sodium), high-dose riboflavin (e.g., 400 mg daily), or NSAIA (e.g., naproxen sodium) may be used. However, analysis of clinical studies in which these agents were used for prophylaxis of chronic migraine attacks has shown that efficacy and safety of individual agents, even within the same class of drugs, may exhibit substantial interpatient variation.

Although most studies of drugs used for prophylaxis of migraine attacks are limited by poor study design and/or interpretation of study findings, analysis of these studies by the US Headache Consortium suggests that drugs with medium to high efficacy, good strength of evidence, and mild to moderate adverse effects include amitriptyline, divalproex sodium, propranolol, and timolol. Comparative studies have demonstrated few clinically important differences in efficacy among these agents. Agents with lower efficacy or limited strength of clinical evidence, and mild to moderate adverse effects include aspirin (alone), atenolol, fenoprofen, flurbiprofen, fluoxetine, gabapentin, guanfacine, ketoprofen, magnesium, mefenamic acid, metoprolol, nadolol, naproxen/naproxen sodium, nimodipine, riboflavin, and verapamil. While clinical efficacy has not been established in controlled studies for bupropion, cyproheptadine, diltiazem, doxepin, fluvoxamine, ibuprofen, imipramine, mirtazepine, nortriptyline, paroxetine, protriptyline, sertraline, tiagabine, topiramate, trazodone, or venlafaxine, experts consider these agents efficacious based on consensus and clinical experience. Experts consider phenelzine to be efficacious based on consensus and clinical experience, but the drug has adverse effects that are of concern to some experts. Similarly, methysergide (no longer commercially available in the US) has medium to high efficacy for prophylaxis of migraine attacks, but its usefulness is limited by reports of retroperitoneal and retropleural fibrosis associated with long-term (principally uninterrupted) therapy. Evidence from clinical studies indicate that efficacy of agents such as acebutolol, carbamazepine, clomipramine, clonazepam, clonidine, indomethacin, lamotrigine, nabumetone, nicardipine, nifedipine, and pindolol is comparable to that of placebo for prophylaxis of migraine attacks in patients with chronic migraine.

Experts from the US Headache Consortium currently recommend that the choice of an initial agent for prophylaxis of migraine attacks be individualized, taking into account concomitant illness (e.g., stroke, myocardial infarction, Raynaud's syndrome, seizure disorder, affective or anxiety disorders). Such experts recommend use of drugs that are effective for both the concomitant illness and migraine prophylaxis whenever possible.

Some clinicians recommend that drug therapy for migraine prophylaxis be initiated as monotherapy at a low dosage and then titrated upward as tolerated to a maximum effective dosage; such therapy should be given for several months and then withdrawn slowly to prevent rebound headaches. If initial drug therapy is not effective, a combination of drugs may be used.

Selection of an agent for prophylaxis of migraine attacks in women who are or may become pregnant should take into account the teratogenic potential of such agents. If drug therapy for migraine prophylaxis is absolutely necessary, some experts state that the prophylactic agent with the lowest risk of adverse effects to the fetus should be used.

Use of Sumatriptan in Migraine

Sumatriptan provides rapid relief of migraine headache and generally is well tolerated when appropriate precautions regarding patient selection are employed.(See Cautions: Precautions and Contraindications.) The drug also relieves manifestations of migraine other than headache (including nausea, vomiting, photophobia, and phonophobia), decreases the need for supplemental analgesic therapy, and improves functional ability. Few comparative studies evaluating the efficacy and safety of sumatriptan relative to other antimigraine therapies have been performed to date. However, available evidence suggests that sumatriptan is at least as effective as current therapies for migraine (e.g., ergot alkaloids, oral analgesics) and generally provides more rapid headache relief and return to normal functioning than these therapies but may be associated more frequently with headache recurrence. Although cost considerations and concerns about the potential for headache recurrence may favor the use of other antimigraine agents (e.g., dihydroergotamine) over subcutaneous sumatriptan, effective self-management of migraine through patient self-administration of sumatriptan may be cost-effective if associated with a reduced need for hospital visits. While clinical studies directly comparing subcutaneous versus oral therapy with sumatriptan in patients with migraine have not been performed, response to oral sumatriptan therapy occurs later and generally is somewhat less than that with subcutaneous therapy. Therefore, subcutaneous therapy with the drug may be particularly advantageous in patients with severe migraine headache in whom the most rapid onset of action is desirable and/or in those who have appreciable nausea and vomiting associated with migraine; oral sumatriptan therapy should be less costly and may be useful in patients who are unable to tolerate subcutaneous sumatriptan, unwilling or unable to self-administer the injection, or who have relatively less severe migraine symptoms.

The efficacy of sumatriptan in alleviating established migraine attacks does not appear to be influenced by type of migraine (i.e., with or without aura), duration of the attack, timing of the attack (e.g., early morning, menstruation-associated), concomitant use of non-ergot-alkaloid drugs for migraine prophylaxis (e.g., β-blockers, calcium-channel blockers, tricyclic antidepressants), or by patient gender or age. Unlike other antimigraine drugs (e.g., ergotamine), sumatriptan has been effective even when given late in the attack. However, subsequent doses of sumatriptan in patients not responding adequately to an initial dose generally have not provided additional benefit.

Most controlled clinical studies of sumatriptan therapy involved patients who had migraine with aura or migraine without aura as defined by criteria established by the Headache Classification Committee of the International Headache Society (IHS). However, while a clear diagnosis of migraine is recommended before initiation of sumatriptan therapy, some evidence suggests that response to sumatriptan may be similar in patients not meeting strict IHS criteria for migraine. The efficacy of therapy for migraine in controlled studies generally was evaluated in terms of a reduction in headache severity as rated by the patient (i.e., a reduction in pain from severe or moderately severe to mild or absent using a 4-point scale). In placebo-controlled clinical studies, approximately 70-88% of patients receiving a single 6-mg subcutaneous dose of sumatriptan attained relief of migraine headache within 1-2 hours compared with 18-39% of placebo recipients; at 2 hours, 48-65% of sumatriptan-treated patients were pain free. Relief of migraine headache generally begins as early as 10 minutes following subcutaneous administration of sumatriptan and is maximal at 2 hours. Smaller doses (less than 6 mg) of sumatriptan also may be effective in relieving migraine, although the proportion of patients obtaining adequate relief is reduced and the time to obtain relief is greater. Subcutaneous doses exceeding 6 mg (e.g., 8 mg) do not appear to provide additional therapeutic benefit and are associated with a greater incidence of adverse effects.

Onset of relief of migraine symptoms with oral sumatriptan therapy is slower than that with subcutaneous administration of the drug, generally occurring 0.5-3 hours after single oral doses of 25-100 mg; maximum pain relief is attained within 3-6 hours. In clinical trials, 50-73% of patients receiving sumatriptan in single oral doses of 25-300 mg obtained relief of headache pain (defined as no pain or only mild pain) within 2 hours compared with 10-33% of patients receiving placebo; 65-78% of patients receiving sumatriptan reported relief of pain at 4 hours. The proportion of patients obtaining relief from single oral doses of sumatriptan appears to be greater with doses of 50 or 100 mg than with 25 mg; however, doses of 100 mg do not appear to provide greater benefit than doses of 50 mg.

In 2 controlled clinical studies in adults with moderate to severe migraine headache, efficacy of a single oral dose of sumatriptan 85 mg given in fixed combination with naproxen sodium 500 mg was compared with that of placebo and of each drug given in the same dosage as monotherapy. In these studies, a greater proportion of patients receiving combined therapy with sumatriptan and naproxen (57-65%) obtained relief of headache pain (defined as mild or no pain) within 2 hours of treatment compared with those receiving sumatriptan alone (50-55%) or placebo (28-29%). In addition, a greater proportion of patients receiving sumatriptan and naproxen (23-25%) remained free of headache pain without the use of rescue therapy through 24 hours after treatment compared with those receiving sumatriptan or naproxen monotherapy (14-16 or 10%, respectively) or placebo (7-8%). Combined therapy with sumatriptan and naproxen also relieved manifestations of migraine other than headache (including nausea, photophobia, and phonophobia).

Since migraine is a chronic, recurrent condition, successful therapy may require long-term, intermittent use of sumatriptan. In several controlled studies of 6-24 months' duration in patients with migraine, intermittent sumatriptan has remained effective throughout subsequent attacks. Among patients receiving oral sumatriptan during 9 migraine attacks, approximately 14% of patients responded during all 9 migraine episodes, 24% responded during 8 of 9 attacks, and 62% responded during 7 of 9 attacks. Among patients in a controlled study who were treated for 4 migraine attacks (3 with subcutaneous sumatriptan and one with placebo), 73% of patients responded to therapy during all 3 sumatriptan-treated attacks, 89% responded in at least 2 of 3 such attacks, and 93% responded in at least 1 of 3 such attacks; only 7% of patients receiving sumatriptan therapy did not respond at all. Data from long-term (1 year) uncontrolled studies suggest that oral sumatriptan was effective in 82-86% of patients and in 55% of all attacks treated. Patients who received subcutaneous or oral sumatriptan treated a median of 18 and 22 attacks per year, respectively, and used a mean of 1.4 injections or 1.9 tablets per attack. The mean number of doses used was similar in patients with frequent (more than 30) and infrequent (less than 10) attacks.

Data from comparative trials suggest that sumatriptan is at least as effective as current antimigraine therapies (e.g., ergot alkaloids, oral analgesics) and generally provides more rapid headache relief than these therapies. In a double-blind, controlled study in patients with migraine, subcutaneous therapy with sumatriptan was associated with headache relief and improvement in functional ability in a greater proportion of patients than was dihydroergotamine at 1 hour (78 versus 57%, respectively) and 2 hours (85 versus 73%, respectively) following the dose; headache relief and functional ability at 3 and 4 hours were similar with both drugs. However, the rate of headache recurrence within 24 hours after treatment was approximately 2.5 times as great with sumatriptan as with dihydroergotamine (45 versus 18%, respectively). In another placebo-controlled, comparative study, 66% of patients receiving oral sumatriptan (100 mg) obtained pain relief (reduction in headache intensity from severe or moderate to mild or none) at 2 hours compared with 48% of patients receiving the combination of ergotamine tartrate 2 mg and caffeine 200 mg (Cafergot). The onset of headache relief was more rapid with sumatriptan therapy, although more patients reported recurrence of migraine within 48 hours with sumatriptan; the incidence of adverse effects with both therapies was similar. In another controlled study in patients who treated up to 3 migraine attacks during a 3-month period either with oral sumatriptan (100 mg) or with oral aspirin (900 mg) and metoclopramide hydrochloride (10 mg), the proportion of patients who had pain relief at 2 hours during the initial attack (the primary end point) with sumatriptan versus aspirin and metoclopramide was similar (56 versus 45%, respectively), although sumatriptan was more effective than aspirin and metoclopramide during attack 2 (58 versus 36%, respectively, of patients with pain relief) and attack 3 (65 versus 34%, respectively, of patients with pain relief). In addition, sumatriptan therapy was associated with a reduced need for supplemental analgesics and greater incidence of improvement in functional ability than aspirin and metoclopramide therapy. Relief of nausea, vomiting, photophobia, and phonophobia was similar for both therapies, while the incidence of adverse effects, which usually were mild to moderate in intensity and transient, was higher with sumatriptan.

Recurrence of migraine within 24 hours after successful treatment of the initial migraine attack occurs in up to about 60% or up to about 40% of patients receiving initial therapy with subcutaneous or oral sumatriptan, respectively. The high rate of recurrent migraine with sumatriptan may be related to the short half-life of sumatriptan or the reversibility of the drug's binding to 5-HT receptors; however, in some cases, apparent repeat attacks of migraine may have been the result of breakthrough of the suppressed but ongoing original attack. Recurrent migraine has been characterized as resolution followed by return of headache within the typical 4-72 hours of a migraine attack without recurrence of aura or other premigraine symptoms. Recurrence of migraine appears to be more common with sumatriptan therapy than with ergotamine, dihydroergotamine, combined therapy with aspirin and metoclopramide, or placebo. The median time to headache recurrence has been reported to be approximately 9-13 hours in patients receiving sumatriptan subcutaneously and 14-24 hours in patients receiving the oral drug. Data from a limited number of controlled studies and clinical experience in patients treated for 3-12 episodes of migraine with oral or subcutaneous sumatriptan indicate that the incidence of migraine recurrence decreases as the number of successfully treated migraine attacks increases. An additional dose of oral sumatriptan appears to be more effective than placebo in treating recurrent migraine after successful treatment of the initial attack; 65-81% of patients receiving oral sumatriptan (100 mg) for the treatment of a recurrent headache following initial use of oral or subcutaneous sumatriptan experience relief of headache pain. However, the benefit or safety of administering a second dose of subcutaneous or oral sumatriptan in patients who have not responded to an initial dose has not been demonstrated conclusively in controlled studies.

While most patients with migraine respond to initial subcutaneous or oral doses of sumatriptan, some patients do not experience relief; exacerbation of migraine has been reported in a few patients. Although administration of a second subcutaneous dose of sumatriptan generally does not provide relief of ongoing migraine headache in patients not responding to an initial subcutaneous dose for that attack, data from several studies in which multiple doses of subcutaneous or oral sumatriptan were administered over several episodes of migraine indicate that patients who fail to respond to therapy for one episode may respond to sumatriptan during subsequent episodes; only 5-7% of patients are consistent nonresponders.

Data from several long-term (1-2 year) studies suggest that subcutaneous or oral therapy with sumatriptan does not alter the frequency of migraine attacks. However, some case reports and data from uncontrolled and/or postmarketing surveillance studies indicate an increased frequency of initial or recurrent migraine attacks in some patients taking sumatriptan. In some patients with a history of frequent migraines or dependence on other antimigraine drugs, such as analgesics or ergot-alkaloid-containing compounds, this increased frequency of migraine attacks has been associated with inappropriate use/misuse of the drug.(See Cautions: Precautions and Contraindications.) The contribution of sumatriptan to the increased frequency of migraine headaches in such patients has not been established.

Intranasal administration of sumatriptan is more effective than placebo in relieving migraine headache. In double-blind, controlled studies in patients with migraine, headache relief (defined as reduction in pain from moderate or severe to mild or none) at 2 hours following the dose occurred in approximately 55-75% of patients receiving intranasal sumatriptan (20 mg) versus about 25-36% of those receiving placebo; associated nausea, vomiting, photophobia, and functional disability also were improved in sumatriptan-treated patients. Smaller doses (5 or 10 mg) also may be effective, although in several studies the proportion of patients obtaining relief was reduced. Although sumatriptan has been given IV in patients with acute migraine attacks, this route of administration has been associated with a high incidence of adverse effects (probably because of the rapid increase in plasma drug concentrations associated with such administration); the manufacturers and most clinicians state that the drug should not be given IV.(See Cautions: Precautions and Contraindications.)

The manufacturers state that sumatriptan is not to be used for prophylaxis of migraine headache, and prophylactic use of the drug following successful treatment of an initial attack has produced equivocal results. In one study, routine addition of a second oral dose of sumatriptan (100 mg) 2 hours after successful treatment of the initial migraine episode did not influence the frequency or time to recurrence of subsequent attacks. However, in another study, routine administration of a single oral dose of sumatriptan (100 mg) 4 hours after successful treatment with a subcutaneous dose of the drug (6 mg) delayed recurrence of the migraine attack.

Cluster Headache

Sumatriptan also is used subcutaneously for the acute management of cluster headache episodes; oral therapy with sumatriptan is unlikely to be beneficial because of its slower onset of action and is not indicated in the management of cluster headache. Cluster headache occurs principally in older men and is characterized by brief, unilateral, extremely intense headaches occurring up to 8 times daily and generally accompanied by ipsilateral manifestations of autonomic dysfunction, such as lacrimation, conjunctival injection, and rhinorrhea. Management of cluster headaches is difficult since the onset of action of many therapies often is delayed beyond the duration of the attack. Inhalation of 100% oxygen, rectal or sublingual ergotamine, or parenteral dihydroergotamine typically has been used effectively to treat cluster headache; intranasal administration of lidocaine, cocaine, or capsaicin also has been used with some success in treating acute attacks. Oral agents (e.g., ergot alkaloids, analgesics, oral sumatriptan) generally have not been effective in treating these brief headaches, as the onset of action of these drugs is too slow.

While comparative studies with oxygen and/or oral analgesic therapy have not been performed, subcutaneous sumatriptan may be particularly useful in patients with cluster headache because of its ease of administration compared with oxygen and its rapid onset of action compared with oral analgesics. In 2 placebo-controlled studies in which patients were treated for up to 3 consecutive cluster headache attacks, headache improvement (as indicated by a reduction in headache pain to mild or no pain) occurred within 15 minutes in about 75% of patients receiving subcutaneous sumatriptan (6 mg) compared with 26-35% of patients receiving placebo. Amelioration of autonomic manifestations associated with cluster headache, such as nasal congestion, rhinorrhea, lacrimation, miosis, ptosis, photophobia, and periorbital edema, also has been reported with subcutaneous sumatriptan therapy. In the 2 placebo-controlled studies, conjunctival injection persisted in 36-38 or 60-74% of patients 15 minutes after receiving subcutaneous sumatriptan or placebo, respectively. Approximately 14% of patients receiving subcutaneous sumatriptan and 38-49% of patients receiving placebo in these studies required supplemental therapy with oxygen 15 minutes after administration of the study drug. Use of higher subcutaneous doses of sumatriptan (12 mg) does not appear to increase the response rate in patients with cluster headache; in fact, lower subcutaneous doses (e.g., 3 mg) reportedly may be effective in the management of acute cluster headache episodes.

Although an increased frequency of cluster headache attacks has been reported in some patients receiving sumatriptan in uncontrolled studies, such increases in attack frequency generally have been transient (lasting up to a few weeks) and may have been related in part to withdrawal of prophylactic antimigraine medication prior to initiation of sumatriptan therapy. Limited data based on long-term (e.g., up to 3 months) experience with the drug in patients with cluster headache suggest that tolerance to the effects of sumatriptan does not develop with such use; at least one patient used a total of 480 injections (6 mg each) of the drug over an 11-month period with reportedly consistent efficacy. Sumatriptan therapy is not associated with an increase in early recurrence of cluster headache and has little effect on the incidence of subsequent episodes (i.e., those occurring from 2-24 hours after the first cluster headache). In a controlled study, prophylactic administration of oral sumatriptan (100 mg 3 times daily for 7 days) did not reduce the number, severity, or duration of subsequent cluster headache attacks in patients who responded successfully to a single 6-mg subcutaneous dose of the drug for the first cluster attack of a series. Patients with a history of more than 2 cluster headaches per day may require prophylactic therapy in addition to the use of sumatriptan for the management of acute breakthrough cluster attacks, as 12 mg (two 6-mg injections) is the maximum recommended daily subcutaneous dose of sumatriptan.

Sumatriptan has been used with some success in a limited number of patients with chronic paroxysmal hemicrania, a rare, variant form of cluster headache. Sumatriptan also has been used in at least one patient with short-lasting, unilateral, neuralgiform headache with conjunctival injection and tearing (SUNCT), a possible variant of cluster headache characterized by brief (30-60 seconds), recurrent episodes of intense pain. In this patient, sumatriptan therapy was associated with relief of pain and limited relief of accompanying manifestations (e.g., conjunctival injection, Horner's syndrome, lacrimation).

Other Types of Headache

Sumatriptan has been used subcutaneously or orally in a limited number of patients with chronic tension-type headache, acute post-traumatic (e.g., post-dural puncture) headache, drug-induced headache (e.g., in combination with amitriptyline and dexamethasone), or high-altitude headache. In a limited number of patients receiving sumatriptan subcutaneously for the treatment of postdural puncture headache, a complication of spinal anesthesia and unintentional dural puncture during attempted epidural anesthesia, the onset of pain relief and the potential for headache recurrence was similar to that reported in patients with migraine. Additional study and experience are required to elucidate the safety and efficacy of sumatriptan therapy in these conditions.

Other Uses

Sumatriptan has been used in a few patients with intractable cyclic vomiting, which appears to share some common pathogenesis to migraine, and in the management of adverse events (e.g., perioperative migraine, severe anesthesia-associated vomiting) associated with general anesthesia in patients with a history of migraine. The safety and efficacy of sumatriptan therapy in these conditions require further evaluation.

Dosage and Administration

Administration

Sumatriptan succinate is administered orally. The drug also can be administered parenterally but only by subcutaneous injection. Sumatriptan also can be administered intranasally.Sumatriptan should not be given IV because of the potential risk of inducing coronary vasospasm.(See Cautions: Precautions and Contraindications.) Sumatriptan has been administered as an iontophoretic transdermal system; however, the manufacturer voluntarily suspended marketing of the formulation because of reports of serious application site reactions.(See Cautions: Local Effects.)

The manufacturer states that tablets containing sumatriptan succinate in fixed combination with naproxen sodium may be administered without regard to meals. The fixed-combination tablets should not be split, crushed, or chewed.

Autoinjection devices are available for subcutaneous administration of sumatriptan to facilitate self-administration of the drug by patients for whom the commercially available doses of 4 or 6 mg are deemed appropriate. An injection pen is available for use with prefilled cartridges labeled as containing 4 or 6 mg of sumatriptan; the needles that accompany this device penetrate approximately 5-6 mm (¼ inch). In addition, a prefilled, single-use injection pen labeled as containing 6 mg of sumatriptan (also with ¼-inch projection of the needle following activation of the device) is available. Patients using these devices should be instructed to use injection sites with adequate skin and subcutaneous thickness to accommodate the length of the needle (e.g., lateral thigh, upper arm); care should be taken to avoid IM or IV administration. A prefilled needleless device for subcutaneous administration that is labeled as containing 6 mg of sumatriptan also is available; patients using this device should be instructed to use sites on the abdomen (avoiding the 2-inch area around the umbilicus) or thigh with adequate subcutaneous thickness to accommodate penetration of the injection solution into the subcutaneous space; use of administration sites on the upper arm should be avoided since the delivered dose may be suboptimal. Patients should be given adequate instructions by their clinician, as well as the written instructions supplied with the autoinjection device, before they self-administer sumatriptan injection for the first time.

The patient information provided by the manufacturer should be consulted for directions on intranasal administration of sumatriptan.

Consideration should be given to administering the initial dose of sumatriptan under medical supervision in patients with multiple risk factors for cardiovascular disease (e.g., postmenopausal women, men older than 40 years of age, smokers, patients with hypertension, hypercholesterolemia, obesity, diabetes mellitus, or a family history of coronary artery disease) but who have had a satisfactory cardiovascular evaluation. Electrocardiographic evaluation during the interval immediately after administration of sumatriptan should be considered in these patients since cardiac ischemia can occur in the absence of symptoms.

If a patient does not respond to the first dose of sumatriptan for a given attack, the diagnosis of migraine or cluster headache should be reconfirmed before administration of subsequent doses.

Although sumatriptan generally is effective at whatever stage of a migraine attack it is administered, it is advisable to initiate therapy with the drug as soon as possible after the onset of an attack so that the patient may experience maximum relief.

Dosage

Dosage of sumatriptan succinate is expressed in terms of sumatriptan.

Subcutaneous Dosage

For the symptomatic treatment of acute attacks of migraine with aura (also called classic migraine) or migraine without aura (also called common migraine) or cluster headache, the maximum single adult subcutaneous dose of sumatriptan recommended by the manufacturers is 6 mg given as a single injection. Smaller subcutaneous doses of the drug may also prove effective for the symptomatic treatment of migraine, although the proportion of patients obtaining adequate relief is decreased and the time to attain that relief is greater. In patients in whom dose-limiting adverse effects occur following a single 6-mg dose of sumatriptan, lower doses (e.g., 1-5 mg) of the drug may be given. The manufacturers state that efficacy of doses lower than 6 mg have not been established for the treatment of cluster headache; however, some patients may derive benefit from such doses (e.g., 3 mg). In patients receiving doses other than 4 or 6 mg, only the single-dose vials containing 6 mg/0.5 mL should be used to provide the desired dose.

If the patient fails to respond to an initial 6-mg subcutaneous dose of sumatriptan for the symptomatic treatment of migraine, additional subcutaneous or oral doses are unlikely to provide benefit. However, following successful treatment with an initial subcutaneous dose, a second 6-mg subcutaneous dose or additional oral doses of sumatriptan (see following section on oral dosage) may be given if manifestations of migraine recur. The manufacturers state that the maximum subcutaneous dosage of sumatriptan to be administered in any 24-hour period is 12 mg (i.e., two 6-mg injections); doses should be given at least 1 hour apart.

Oral Dosage

For the management of acute migraine pain and associated symptoms, single oral sumatriptan doses of 25, 50, or 100 mg were effective in adults in clinical studies. Available evidence suggests that oral doses of 50 or 100 mg may provide greater benefit than 25 mg, but doses of 100 mg do not provide substantially greater relief than doses of 50 mg. Because individuals may vary in their response to oral sumatriptan, dosage selection should be individualized, weighing the possible benefit of higher doses with the potential for an increased risk of adverse effects. The maximum recommended single oral dose is 100 mg. If a satisfactory response has not been obtained within 2 hours following the initial dose, a second oral dose of up to 100 mg may be given. If headache recurs, additional oral doses of sumatriptan may be taken at intervals of not less than 2 hours up to a maximum oral dosage of 200 mg daily. If headache recurs following an initial subcutaneous dose of sumatriptan, additional oral doses may be given at intervals of not less than 2 hours (up to a maximum oral dosage of 100 mg daily). Oral sumatriptan dosages of up to 300 mg daily have been given, administered either as a single 300-mg dose or as 3 single doses of 100 mg each given at intervals of not less than 2 hours. However, while these doses generally have been well tolerated, there is no evidence that such doses afford greater relief than the recommended dose, and these high doses are associated with an increased incidence of adverse effects. The safety of treating an average of more than 4 headaches per 30-day period has not been established.

When sumatriptan is used in fixed combination with naproxen sodium for the acute management of migraine attacks in adults, the recommended dosage of sumatriptan is 85 mg (given in fixed combination with naproxen sodium 500 mg) as a single dose. Efficacy of more than 1 dose has not been established. If a second dose is administered, an interval of at least 2 hours should elapse between the first and second doses. No more than 2 doses (total sumatriptan dosage of 170 mg) should be administered in any 24-hour period. The safety of treating an average of more than 5 headaches per 30-day period has not been established.

Intranasal Dosage

For the management of acute migraine pain and associated symptoms, single intranasal sumatriptan doses of 5, 10, or 20 mg were effective in adults in clinical studies, although the 20-mg dose was effective in a greater proportion of patients. Individuals vary in their response to intranasal sumatriptan, and the choice of dose in this range should be individualized, weighing the possible benefit of the 20-mg dose with the potential for an increased risk of adverse effects. A 5- or 20-mg dose is administered into one nostril using the corresponding single-use nasal spray; if a 10-mg dose is used, it is administered by spraying a 5-mg dose into each nostril. Single doses exceeding 20 mg do not provide greater benefit.

If the headache returns, the dose of intranasal sumatriptan may be repeated once after 2 hours, not to exceed 40 mg daily. The safety of treating an average of more than 4 headaches per 30-day period has not been established.

Dosage in Renal and Hepatic Impairment

Although the effect of renal impairment on the pharmacokinetics of sumatriptan has not been evaluated, little clinical effect would be expected since the drug is largely inactivated metabolically.

The liver plays an important role in the presystemic clearance of orally administered sumatriptan. Accordingly, the bioavailability of sumatriptan following oral administration may be increased markedly in patients with liver disease.(See Pharmacokinetics: Elimination.) If oral sumatriptan therapy is considered in patients with hepatic impairment, the manufacturers state that the maximum single dose generally should not exceed 50 mg. Fixed-combination tablets containing sumatriptan 85 mg and naproxen sodium 500 mg should not be used in patients with hepatic impairment since sumatriptan dosage cannot be appropriately adjusted. Sumatriptan is contraindicated in patients with severe hepatic impairment.

Cautions

Sumatriptan generally is well tolerated when given in recommended dosage. Most adverse effects associated with sumatriptan are well defined, transient, and mild to moderate in intensity, although serious adverse events (e.g., coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, ventricular fibrillation, stroke, subarachnoid hemorrhage) have been reported rarely. Adverse effects associated with the drug usually occur within 1 hour after subcutaneous or oral administration of sumatriptan and generally resolve within 10-30 minutes (subcutaneous) or 1 hour (oral). The incidence of adverse effects associated with sumatriptan generally remains unchanged or decreases with repeated use of the drug. However, the incidence of adverse effects appears to increase with higher than recommended doses of the drug. In addition, the overall incidence of adverse effects among patients receiving sumatriptan injection for the treatment of cluster headache is lower than that in patients being treated with the drug for migraine.

The most frequently reported adverse effects associated with subcutaneous sumatriptan succinate therapy are injection site reaction (e.g., minor pain, edema, tingling at the site of injection, stinging/burning, bruising, bleeding, transient erythema); tingling; dizziness or vertigo; sensations of warmth, heat, or burning; sensations of heaviness, pressure, or tightness; flushing; and numbness. Common adverse effects reported in patients receiving oral sumatriptan for the treatment of migraine or cluster headache include malaise or fatigue, nausea or vomiting, dizziness or vertigo, tingling, nasal discomfort, atypical sensations (e.g., sensations of warmth or cold, paresthesia), and sensations of pain, heaviness, pressure, or tightness. Since some adverse effects noted with sumatriptan therapy (e.g., nausea or gastric symptoms, tingling, photophobia, visual disturbances, headache, numbness, neck pain, drowsiness/sedation, asthenia, fatigue) also are symptoms associated with migraine attacks and/or the postdromal period, it may be difficult to distinguish the effects of underlying disease processes from drug-induced effects. The most frequently reported adverse effects associated with intranasal sumatriptan include disturbances of taste, nausea or vomiting, throat discomfort, and disease or discomfort of nasal cavity or sinuses. For adverse effects reported with sumatriptan therapy in the Cautions section, a causal relationship to the drug has not always been established. In addition, the incidence of adverse effects reported in clinical trials may not predict precisely the likelihood of encountering these effects under usual medical practice where patient characteristics and other factors differ from those prevailing in the trials.

Local Effects

Pooled data from controlled studies indicate that the most frequently reported adverse effect associated with subcutaneous sumatriptan succinate therapy is injection site reaction, consisting of minor pain, edema, induration, swelling, contusions, subcutaneous bleeding, stinging or tingling at the site of injection, burning, and/or transient erythema. Lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) has been reported in less than 0.1% of patients receiving the drug subcutaneously. Injection site reactions occurred in 59% of patients receiving the drug by subcutaneous injection in controlled trials; in some studies, this effect occurred with less frequency in patients using a needle-based autoinjector to administer the drug. In one uncontrolled study, bruising, pain, and hemorrhage each occurred in 6-16% of patients receiving sumatriptan via a needle-based autoinjector. In studies comparing the safety and tolerability of subcutaneous administration of sumatriptan using a needleless device versus needle-based injection, local reactions (minor bleeding, swelling, erythema, and bruising at the administration site) occurred more frequently immediately after administration via the needleless system; however, most such reactions resolved spontaneously and differences between the 2 administration techniques had largely disappeared by 8 hours (for bleeding and bruising) or 24 hours (for swelling and erythema) after the dose.

Nasal and/or throat irritation were reported in approximately 5% of patients receiving 5-, 10-, or 20-mg doses of intranasal sumatriptan on 1 or 2 occasions in controlled clinical studies. Transient irritative symptoms (e.g., burning, numbness, paresthesia, discharge, pain or soreness) were reported to be severe in about 1% of patients receiving intranasal sumatriptan; these symptoms generally resolved in less than 2 hours. Limited examination of the nose and throat did not reveal clinically noticeable injury in these patients. In addition, an increased incidence of local irritation has not been observed in patients receiving intranasal sumatriptan repeatedly for up to 1 year. However, epithelial hyperplasia (with and without keratinization) and squamous metaplasia were observed in the larynx of rats receiving inhaled sumatriptan daily for 1 month at dosages as low as one-half the maximum daily human exposure (based on dose per surface area of nasal cavity). In addition, evidence of epithelial hyperplasia, focal squamous metaplasia, granulomata, bronchitis, and fibrosing alveolitis was observed in the respiratory and nasal mucosa in dogs administered various formulations of sumatriptan by intranasal instillation daily for up to 13 weeks, at exposure rates of 2-4 times the maximum daily human exposure (based on dose per surface area of nasal cavity). The changes observed in both species are not considered to be signs of preneoplastic or neoplastic transformation. Local effects on nasal and respiratory tissues after chronic, repeated intranasal administration of sumatriptan have not been studied in animals or humans.

Burns and scarring have been reported at the application site of sumatriptan iontophoretic transdermal system (Zecuity). Reactions have included severe erythema, cracked skin, blistering or welts, burns or scars, skin discoloration, severe pain, pruritus, and burning sensation. Although many cases resolved within hours to weeks, some reactions, typically skin discoloration, were unresolved after several months. Because of these serious application site reactions, the manufacturer voluntarily suspended marketing of the formulation.

Nervous System Effects

Atypical sensations are the most commonly reported adverse nervous system effects of sumatriptan, occurring in up to 42% of patients receiving sumatriptan in controlled trials. Atypical sensations include sensations of warmth, heat, burning, cold, tingling, or numbness; paresthesia; pressure sensation or feelings of heaviness or tightness; and/or strange feeling. The incidence of these sensations varies, ranging from 0.4-14% of patients receiving sumatriptan.

Although sumatriptan distributes poorly into the CNS, adverse CNS effects have been reported in patients receiving the drug. Dizziness/vertigo has been reported in up to 12% of patients receiving subcutaneous sumatriptan in clinical trials. In addition, agitation, anxiety, drowsiness/sedation, headache, and malaise/fatigue have been reported in up to 3% of patients receiving sumatriptan in controlled trials. Severe rebound migraine headache, which occurred upon withdrawal of sumatriptan therapy and persisted for a few days, has been reported in several patients inappropriately taking sumatriptan on a daily basis for headache prophylaxis. Other adverse nervous system effects occurring in up to 1% of patients receiving sumatriptan therapy include aggressiveness, apathy, bradylogia, chills, cluster headache, confusion, depression, detachment, difficulties in concentration,disturbance of smell, drug abuse, dysarthria, dysesthesia, dysphoria, dystonia, emotional disturbance, euphoria, facial pain, facial paralysis, hallucinations, heat sensitivity, hyperesthesia, hysteria, incoordination, increased alertness, increased intracranial pressure, intoxication, lacrimation, memory disturbance, monoplegia/diplegia, motor dysfunction, myoclonia, neuralgia, neurotic disorders, panic disorder, paralysis, personality change, phobia, phonophobia/photophobia, psychomotor disorders, radiculopathy, restlessness, rigidity, seizures, sensations of lightness, ''serotonin agonist effect'' or serotonin syndrome, shivering, sleep disturbance, stress, suicide, syncope, transient hemiplegia, tremor, twitching, unsteadiness, speech disturbance, voice disturbance, and yawning. Although some patients who experienced seizures had a history of seizures or conditions predisposing to seizures, other patients had no apparent predisposing factors.

Cardiovascular Effects

The most common adverse cardiovascular effect associated with subcutaneous administration of sumatriptan is flushing, which has been reported in 7% of patients receiving the drug by this route in placebo-controlled trials. Flushing has been reported infrequently in patients receiving the drug intranasally or orally. Chest discomfort/pain, pressure, or tightness occurred in up to 5% of patients receiving subcutaneous sumatriptan in controlled trials; these adverse effects have been reported in up to 2% of patients receiving intranasal or oral sumatriptan. In patients experiencing chest pain while receiving subcutaneous sumatriptan therapy, onset of pain was within 1-60 minutes after injection of the drug, and the duration of chest pain was 2 minutes to 12 hours. In some patients, chest pain was severe and accompanied by other manifestations such as paresthesia or numbness; nausea; syncope; flushing; anxiety; diaphoresis; pain radiating into shoulders, neck, or throat; dyspnea; palpitation; bronchospasm; decreases in heart rate and blood pressure; and fatigue. Several patients receiving subcutaneous sumatriptan in controlled trials experienced chest pain/pressure and paresthesia that was severe enough to necessitate discontinuance of the drug; upon rechallenge, some patients developed similar reactions.

Chest, jaw, throat, and/or neck tightness, pain, pressure, and heaviness are relatively common in patients receiving subcutaneous sumatriptan and have been reported following use of oral or intranasal sumatriptan, but usually are noncardiac in origin. Data from patients who participated in clinical trials with subcutaneous or oral sumatriptan indicate that 8 of more than 1900 patients receiving subcutaneous sumatriptan and 2 of 6348 patients receiving the drug orally may have developed coronary vasospasm shortly after receiving the drug. In addition, data from patients who participated in clinical trials with intranasal sumatriptan indicate that 1 of approximately 4000 patients receiving the drug experienced asymptomatic subendocardial infarction, possibly secondary to coronary vasospasm. Coronary vasospasm may result in myocardial ischemia or infarction or Prinzmetal variant angina. Serious adverse cardiac effects reported within a few hours following administration of subcutaneous or oral sumatriptan include acute myocardial infarction, life-threatening or fatal disturbances of cardiac rhythm, and death. Cardiac arrhythmias/ECG abnormalities associated with chest pain, coronary artery disease, or myocardial ischemia in patients receiving sumatriptan include ST-wave changes, ventricular fibrillation or tachycardia, abnormal T waves, abnormal Q waves, and sinus bradycardia or atrial fibrillation. Some of these events occurred in patients without known coronary artery disease and may represent sequelae of coronary artery vasospasm. Sumatriptan may cause coronary artery vasospasm even in patients without a history of coronary artery disease.

Other arrhythmias or ECG abnormalities reported infrequently in patients receiving sumatriptan therapy include bradycardia, tachycardia, nonspecific ST or T wave changes, prolongation of PR or QT_c intervals, abnormal P waves with nodal rhythm, QRS/T-axis deviations, nonsustained ventricular premature complexes, isolated junctional ectopic beats, atrial ectopic beats, and delayed activation of the right ventricle.

Transient increases in systolic and/or diastolic blood pressure have been observed in patients receiving sumatriptan. Increases of 2-6 mm Hg in diastolic pressure have been noted after oral administration of the drug in some but not in other studies. Increases or decreases in blood pressure have been reported in up to 1% of patients receiving subcutaneous sumatriptan; hypertensive episodes, including hypertensive crises, have occurred on rare occasions in patients with or without a history of hypertension who were receiving the drug.

Other adverse cardiovascular effects reported in up to 1% of patients receiving sumatriptan include edema, abdominal aortic aneurysm, angina, atherosclerosis, cardiomyopathy, cerebral ischemia, cerebrovascular lesion, heart block, increased heart rate, pallor, palpitation, peripheral cyanosis, phlebitis, pulmonary embolism, pulsating sensations, Raynaud's syndrome, retinal artery occlusion, syncope, temporal arteritis, thrombosis, transient myocardial ischemia, and vasodilation.

Impairment or death attributed to stroke, cerebral hemorrhage, cerebral infarction, CNS vasculitis, subarachnoid hemorrhage, and other cerebrovascular events have been reported in patients treated with oral or subcutaneous sumatriptan. In some of these patients, sumatriptan was used to treat severe, atypical headaches thought to be migraine but actually secondary to an evolving neurologic lesion (e.g., cerebrovascular accident, subarachnoid hemorrhage). Patients with migraine may be at increased risk for the development of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack, aphasia, or hemiparesis).

GI Effects

Dysgeusia/taste disturbance has occurred in approximately 14-25% of patients receiving intranasal sumatriptan compared with 1.7% of those receiving placebo in controlled trials. Dysgeusia/taste disturbance also has been reported with oral sumatriptan therapy; this adverse effect appears to be minimized with the currently available film-coated tablets. In addition, nausea and vomiting have been reported in up to 14% of patients receiving sumatriptan for the treatment of migraine. The incidence of nausea and vomiting was greater among patients receiving the drug subcutaneously for cluster headache than for the treatment of migraine. However, nausea and vomiting also are symptoms associated with migraine attacks and/or the postdromal period, and it may be difficult to distinguish the effects of underlying disease processes from drug-induced effects.

Other adverse GI effects reported in up to 5% of patients receiving sumatriptan include abdominal discomfort, abdominal distention, colitis or ischemic colitis, constipation, dental pain, diarrhea, dyspeptic symptoms, dysphagia, flatulence/eructation, gallstone, gastric symptoms (e.g., pain, pressure), gastritis, gastroenteritis, gastroesophageal reflux, GI hemorrhage, hematemesis, hypersalivation, intestinal obstruction, jaw discomfort, melena, orolingual disorders (e.g., burning or numbness of tongue, discomfort, swallowing disorders, dry mouth), oral itching and irritation, pancreatitis, peptic ulcer, rectal bleeding, retching, salivary gland swelling, and xerostomia. Changes in esophageal motility also have been reported in patients receiving high doses (16 mg) of subcutaneous sumatriptan, and some clinicians suggest that chest pain occurring in the absence of cardiac manifestations may be related to changes in esophageal motility.(See Pharmacology: Other Effects.)

Musculoskeletal Effects

Neck pain/stiffness and weakness have been reported in up to 5% of patients receiving sumatriptan in controlled trials. Neck stiffness was severe enough in at least one patient receiving the drug to necessitate discontinuance. Myalgia has been reported in up to 2% of patients receiving sumatriptan in controlled clinical trials.

Other adverse musculoskeletal effects reported in patients receiving sumatriptan include acquired musculoskeletal deformity, arthritis, articular rheumatitis, backache, swelling of the extremities, intervertebral disc disorder, muscle atrophy, muscle cramps, muscle stiffness, muscle tightness, the need to flex calf muscles, muscle tiredness/rigidity, muscle weakness, musculoskeletal inflammation, tetany, difficulty walking, and various joint disturbances (e.g., arthralgia, edema, pain, stiffness).

Dermatologic and Sensitivity Reactions

Hypersensitivity reactions, including allergic vasculitis, rash, urticaria, pruritus, erythema, wheal and flare at injection site, shortness of breath, angioedema, hypertension, increased heart rate, pallor, hyperventilation, diaphoresis, shock, and anaphylaxis or anaphylactoid reactions have occurred rarely in patients receiving sumatriptan. Hypersensitivity reactions to sumatriptan can be life-threatening or fatal. At least one patient receiving subcutaneous sumatriptan in a controlled trial discontinued therapy as a result of moderate urticaria; this patient also had a history of intolerance to ergotamine. In general, hypersensitivity reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens.

Other adverse dermatologic or sensitivity reactions associated with sumatriptan include dry/scaly skin, eczema, exacerbation of sunburn, peeling of skin, photosensitivity, seborrheic dermatitis, skin eruptions, nodules, skin tenderness, tightness/wrinkling of skin, sweating, and facial swelling.

Respiratory Effects

Discomfort of the nasal cavity/sinuses or throat has been reported in up to 4% of patients receiving sumatriptan in controlled trials; several of these patients discontinued therapy after moderate to severe throat tightness/discomfort. Dyspnea or hyperventilation has been reported in up to 1% of patients receiving sumatriptan. Upon rechallenge, some patients again experienced dyspnea. Bronchospasm has been reported in at least 1% of patients with or without a history of asthma receiving sumatriptan; the incidence of bronchospasm among patients with cluster headaches appears to be greater than the incidence among those with migraine receiving the drug subcutaneously. Influenza, diseases of the upper and lower respiratory tract, hiccups, asthma, bronchitis, and cough have been reported in up to 1% of patients receiving sumatriptan.

Renal and Genitourinary Effects

Adverse renal effects reported in up to 1% of patients receiving sumatriptan include acute renal failure, bladder inflammation, dysuria, hematuria, increased urination, micturition disorders, urethritis, urinary infections, and urinary frequency.

Adverse genitourinary effects reported in up to 1% of patients receiving sumatriptan include abnormal menstrual cycle, abortion, disorders of the breast (e.g., tenderness, nipple discharge,) dysmenorrhea, endometriosis, inflammation of fallopian tubes, intermenstrual bleeding, and menstruation or menstrual cycle symptoms.

Ocular Effects

Vision alteration/disturbance, ocular irritation, accommodation disorders, conjunctivitis, disorders of sclera, external ocular muscle disorders, keratitis, lacrimation, blindness/low vision, miosis, mydriasis, and ocular edema, hemorrhage, itching, pain, or swelling have been reported in up to 1% of patients receiving sumatriptan in clinical studies. In addition, ischemic optic neuropathy, retinal artery occlusion, retinal vein thrombosis, and vision loss have been reported during postmarketing surveillance. Transient or permanent blindness and substantial partial vision loss have been reported very rarely with sumatriptan use. (Vision disorders also may be part of a migraine attack.)

Corneal opacities and defects in the corneal epithelium have been noted in dogs receiving sumatriptan. Defects in the corneal epithelium were evident in a 60-week study. Corneal opacities were noted after 1 month of treatment in dogs receiving oral sumatriptan 2 mg/kg daily (representing about 5, 22, or 3 times the human exposure after a 100-mg oral, 20-mg intranasal, or 6-mg subcutaneous dose, respectively). Changes in corneal appearance were evident in dogs receiving intranasal sumatriptan on the first day of dosing and at a dosage representing 0.5 or 2 times the human exposure after a 100-mg oral or 20-mg intranasal dose, respectively, on a mg/m basis. Results of studies in rats given a single subcutaneous (0.5 mg/kg) dose of radiolabeled sumatriptan suggest that sumatriptan and its metabolites bind to melanin in the eye (as indicated by an ocular elimination half-life of 15 days); the clinical importance of this binding is unknown.

Otic Effects

Adverse otic effects reported in up to 1% of patients receiving sumatriptan include ear infection, external otitis, feeling of fullness in the ears, hearing disturbances (e.g., increased sensitivity to noise, hearing loss), Meniere's disease, otalgia, and tinnitus. In addition, deafness has been reported during postmarketing surveillance.

Endocrine and Metabolic Effects

Adverse endocrine and metabolic effects reported in up to 1% of patients receiving sumatriptan in clinical studies include elevations in thyrotropin (TSH), endocrine cysts, lumps, or masses, fluid disturbances (e.g., retention), galactorrhea, hyperglycemia, hypoglycemia, hypothyroidism, thirst, hunger, increased/decreased appetite, and weight gain/loss.

Hematologic Effects

Anemia, elevated platelet count and lymphadenopathy, have been reported in up to 1% of patients receiving sumatriptan. In addition, hemolytic anemia, pancytopenia, and thrombocytopenia have been reported during postmarketing surveillance.

Other Adverse Effects

Other adverse effects reported in up to 1% of patients receiving sumatriptan include diaphoresis, fever, overdose, and pituitary neoplasm.

Precautions and Contraindications

Because sumatriptan rarely can cause potentially serious or life-threatening adverse effects, the manufacturers caution that the drug should be used subcutaneously only in patients in whom a clear diagnosis of migraine or cluster headache has been established, and the drug should be used orally or intranasally only in patients with a clear diagnosis of migraine. If the first attack of migraine treated with sumatriptan fails to respond to the drug, the diagnosis of migraine should be reconsidered before sumatriptan is administered to treat subsequent attacks. In patients not previously diagnosed with migraine attacks and in those with a history of migraine or cluster headache who present with atypical symptoms, care should be taken to exclude other potentially serious neurologic conditions (e.g., cerebrovascular accident, subarachnoid hemorrhage) before initiation of sumatriptan therapy. Patients with a history of migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).

Patients should be cautioned about potential misuse (e.g., for prophylaxis) of sumatriptan for vascular headache. Patients also should be cautioned against frequent use/misuse of sumatriptan, since abuse of sumatriptan has resulted in rebound headache in patients with a history of analgesic or ergot alkaloid abuse. Patients should be encouraged to record headache frequency and drug use so that the effectiveness of treatment may be monitored. Excessive use of drugs indicated for the management of acute migraine attacks (e.g., use of 5-HT₁ receptor agonists, ergotamine, opiates, or certain analgesic combinations on a regular basis for 10 or more days per month) may result in migraine-like daily headaches or a marked increase in the frequency of migraine attacks. Detoxification, including withdrawal of the overused drugs; treatment of withdrawal symptoms (which often include transient worsening of headaches); and consideration of prophylactic therapy for migraine attacks may be necessary.

Because sumatriptan can cause somnolence and dizziness, patients should be advised to avoid performing hazardous activities that require mental alertness (e.g., operating machinery, driving a motor vehicle) if such effects occur.

Because there have been rare reports of seizure following administration of sumatriptan, the drug should be used with caution in patients with a history of seizure disorders or conditions associated with a lowered seizure threshold.

Because substantial increases in blood pressure, including hypertensive crisis with acute impairment of organ systems, have been reported rarely in patients with or without a history of hypertension, sumatriptan is contraindicated in patients with uncontrolled hypertension. Sumatriptan should be used with caution in patients with controlled hypertension, and blood pressure should be monitored in all patients receiving the drug.

Sumatriptan should be used with caution in patients with diseases that may alter the absorption, metabolism, or excretion of the drug, such as impaired renal or hepatic function.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

When sumatriptan is used in fixed combination with naproxen sodium, the cautions, precautions, and contraindications associated with naproxen must be considered in addition to those associated with sumatriptan.

Cases of potentially life-threatening serotonin syndrome have been reported in patients receiving 5-HT₁ receptor agonists, particularly in those receiving concomitant therapy with selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs). Serotonin syndrome also may occur in patients receiving 5-HT₁ receptor agonists concomitantly with monoamine oxidase (MAO) inhibitors or tricyclic antidepressants. Symptoms of serotonin syndrome 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 GI symptoms (e.g., nausea, vomiting, diarrhea). If concurrent therapy with a 5-HT₁ receptor agonist and an SSRI or SNRI is clinically warranted, the patient should be observed carefully, particularly during initiation of therapy, when dosage is increased, or when another serotonergic agent is initiated.(See Drug Interactions: Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors.) If manifestations of serotonin syndrome occur, treatment with sumatriptan and any concurrently administered serotonergic agents should be discontinued and supportive and symptomatic treatment should be initiated. Patients receiving sumatriptan should be cautioned about the risk of serotonin syndrome, particularly with concomitant use of SSRIs, SNRIs, MAO inhibitors, or tricyclic antidepressants, and they should be instructed to report symptoms suggestive of serotonin syndrome to their clinician immediately.

Because sumatriptan has the potential to cause vasospasm, the drug is contraindicated in patients with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), coronary artery vasospasm (e.g., Prinzmetal variant angina), history of stroke or transient ischemic attack, peripheral vascular disease, or ischemic bowel disease. Patients who experience signs or symptoms suggestive of angina following sumatriptan administration should be evaluated for the presence of coronary artery disease or a predisposition to Prinzmetal variant angina before receiving additional doses of the drug and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience symptoms or signs suggestive of noncoronary vasospastic reactions (e.g., manifestations of peripheral vascular ischemia, GI vascular ischemia or infarction, splenic infarction, or Raynaud's syndrome) following administration of any 5-HT₁ receptor agonist should be evaluated to rule out vasospastic reactions before receiving additional doses of sumatriptan. Although sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after administration of sumatriptan, these sensations usually are noncardiac in origin; however, a cardiac evaluation should be performed if the patient is at high cardiac risk. Patients receiving sumatriptan should be advised of the importance of seeking medical care if symptoms of vasospastic reactions (e.g., shortness of breath; weakness; slurring of speech; sudden or severe abdominal pain; difficulty in seeing; tightness, pain, pressure, or heaviness in the chest, throat, neck, or jaw) occur following administration of sumatriptan and to not take sumatriptan again until they are evaluated by a clinician.

Patients with multiple cardiovascular risk factors (e.g., postmenopausal women; men older than 40 years of age; patients with risk factors such as hypertension, hypercholesterolemia, obesity, diabetes, smoking, or family history of coronary artery disease) who have not previously received therapy with a 5-HT₁ receptor agonist should undergo cardiovascular evaluation prior to initiation of sumatriptan therapy. (In addition to these recognized risk factors contributing to the development of coronary vasospasm, history of migraine also may be a possible risk factor in that migraine may be part of a generalized vasospastic disorder predisposing to the development of cardiomyopathy.) If the cardiovascular evaluation provides evidence of coronary artery disease or coronary artery vasospasm, the drug should not be administered. For patients with risk factors for coronary artery disease who nevertheless have completed a satisfactory cardiovascular evaluation, consideration should be given to administering the initial dose of sumatriptan under medical supervision (e.g., in the clinician's office). Because myocardial ischemia can occur in the absence of clinical symptoms, clinicians should consider obtaining an ECG immediately following the initial dose of sumatriptan in these patients. Patients with risk factors for the development of coronary artery disease should undergo periodic cardiovascular evaluation while receiving intermittent long-term sumatriptan therapy. If symptoms of angina occur after sumatriptan administration, electrocardiographic evaluation should be used to identify possible ischemic changes associated with coronary artery disease or a predisposition to Prinzmetal variant angina before sumatriptan therapy is continued. IV nitroglycerin has been shown to reverse mild coronary artery vasoconstriction that was associated with subcutaneous sumatriptan therapy in patients with suspected coronary artery disease.

Because the incidence of adverse effects and the risk of precipitating coronary vasospasm increases with IV administration, sumatriptan should not be administered IV.

If life-threatening disturbances of cardiac rhythm (e.g., ventricular tachycardia or fibrillation) occur, therapy with sumatriptan should be discontinued. Sumatriptan is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.

Concomitant use of sumatriptan and MAO-A inhibitor therapy or use of sumatriptan within 2 weeks of discontinuance of MAO-A inhibitor therapy is contraindicated because of the potential of these drugs to substantially increase systemic exposure to sumatriptan.(See Drug Interactions: Monoamine Oxidase Inhibitors.) In addition, use of sumatriptan within 24 hours of treatment with ergot alkaloids (e.g., ergotamine, dihydroergotamine, methysergide [no longer commercially available in the US]) or another 5-HT₁ receptor agonist is contraindicated.(See Drug Interactions: Ergot Alkaloids.)

Sumatriptan is contraindicated in patients with hemiplegic or basilar migraine.

Sumatriptan also is contraindicated in patients with severe hepatic impairment and/or known hypersensitivity to sumatriptan or any of its components. Patients should be advised to discontinue use of sumatriptan and contact their clinician immediately if they experience symptoms suggestive of hypersensitivity to the drug, such as shortness of breath, wheezing, palpitations, swelling of the eyelids, face or lips, rash, or urticaria.

Pediatric Precautions

The manufacturers state that safety and efficacy of sumatriptan in those younger than 18 years of age have not been established.

Available data from placebo-controlled clinical trials have failed to establish the efficacy of oral sumatriptan (25-100 mg) or intranasal sumatriptan (5-20 mg) for the treatment of migraine in adolescents 12-17 years of age. Adverse effects observed in adolescents who received sumatriptan in clinical trials were similar in nature to those reported in clinical trials in adults; the incidence of all adverse effects in adolescents appears to be both dose and age dependent, with younger patients reporting adverse effects more commonly than older adolescents. Serious adverse effects, including effects similar in nature to those rarely reported in adults (including stroke, loss of vision, and death), have been reported during postmarketing surveillance in children following use of sumatriptan. Myocardial infarction reportedly occurred in one 14-year-old boy within 1 day of receiving oral sumatriptan. Because there are insufficient data to determine the incidence of serious adverse effects in pediatric patients receiving sumatriptan, use of the drug in patients younger than 18 years of age is not recommended by the manufacturers.

Geriatric Precautions

Clinical trials of sumatriptan injection did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults. While other clinical experience has not revealed age-related differences in response, dosage selection generally should be cautious in geriatric patients, usually starting at the low end of the dosage range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered. Increases in blood pressure may be more pronounced in geriatric patients than in younger adults. Because advanced age is a risk factor for coronary artery disease, geriatric patients with additional cardiovascular risk factors should undergo a cardiovascular evaluation prior to receiving sumatriptan.(See Cautions: Precautions and Contraindications.)

Mutagenicity and Carcinogenicity

Sumatriptan did not exhibit evidence of mutagenicity in vitro in gene mutation assays (i.e., the Ames microbial mutagen test and the V-79/HGPRT assay in Chinese hamster cells) with or without metabolic activation. No increase in chromosomal aberrations was observed in the in vitro human lymphocyte assay or in the in vivo rat micronucleus assay.

No evidence of carcinogenicity was demonstrated in a 78-week study in mice given oral sumatriptan dosages representing up to 40 or 110 times, respectively, the exposure in humans receiving the maximum recommended single dose of 100 mg orally or 6 mg subcutaneously. In addition, no evidence of carcinogenicity was seen in rats given dosages representing 15 or 260 times, respectively, the exposure in humans receiving the maximum recommended single dose of 100 mg orally or 6 mg subcutaneously on a mg/m basis for 104 weeks.

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate and well-controlled studies evaluating the use of sumatriptan in pregnant women. Although a causal relationship to the drug has not been definitely established, agenesis of the corpus callosum has been reported in an infant whose mother received oral sumatriptan at week 4 and 6 of pregnancy. Sumatriptan should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Sumatriptan has been associated with fetal abnormalities and embryo and fetal mortality in animals. Embryolethality was noted in pregnant rabbits given IV sumatriptan throughout the period of organogenesis in daily doses at or close to those producing maternal toxicity, representing systemic exposures less than the maximum recommended daily subcutaneous dosage in humans of 12 mg (on a mg/m basis). The mechanism of the embryolethality is not known. This effect was not seen in pregnant rats given IV sumatriptan throughout organogenesis at dosages representing approximately 10 times the maximum recommended daily subcutaneous human dosage of 12 mg (on a mg/m basis) or in pregnant rats given subcutaneous sumatriptan prior to and throughout pregnancy. In pregnant rabbits, oral sumatriptan dosages of 100 mg/kg daily (representing 18 times the maximum single human oral dose of 100 mg on a mg/m basis) throughout the period of organogenesis produced embryolethality and maternotoxicity; these effects were not observed at oral sumatriptan dosages of 50 mg/kg daily. No fetal effects were observed in rats receiving 50 mg/kg daily (representing 5 times the maximum single oral human dose of 100 mg on a mg/m basis).

Sumatriptan has been shown to be teratogenic in pregnant rats given long-term oral sumatriptan dosages of 500 mg/kg daily (representing 50 times the maximum single human oral dose of 100 mg on a mg/m basis); an increased incidence of a syndrome of malformations (short tail/short body and vertebral disorganization) was observed in these animals. Sumatriptan was associated with an increased incidence of cervicothoracic vascular defects and skeletal abnormalities in fetuses of rabbits receiving oral dosages greater than 15 mg/kg daily (representing 3 times the maximum single human oral dose of 100 mg on a mg/m basis); these effects were not observed at lower dosages. Blood vessel abnormalities (cervicothoracic and umbilical) occurred in offspring of pregnant rats given oral dosages of 250 mg/kg daily or greater (representing 25 times the maximum single human oral dose of 100 mg on a mg/m basis); these effects were not observed at oral dosages of approximately 60 mg/kg daily or less (representing 6 times the maximum single human oral dose of 100 mg on a mg/m basis). In a study in rats dosed daily with subcutaneous sumatriptan prior to and throughout pregnancy, there was no evidence of teratogenicity.

Oral sumatriptan produced a decrease in pup survival between birth and postnatal day 4 when administered to pregnant rats at dosages of 250 mg/kg daily or higher (representing 25 times the maximum single human oral dose of 100 mg on a mg/m basis) during the period of organogenesis; pups were not affected when dams were given 60 mg/kg daily (representing 6 times the maximum single human dose of 100 mg on a mg/m basis). In rats given oral dosages of 1000 mg/kg daily (representing 100 times the maximum single human oral dose of 100 mg on a mg/m basis) from gestational day 17 through postnatal day 21, decreased pup survival was found at postnatal days 2, 4, and 20; pups were not affected when dams were given 100 mg/kg of sumatriptan daily.

Fertility

Reproduction studies in rats given subcutaneous sumatriptan at a dosage representing 100 times the maximum recommended single subcutaneous human dose of 6 mg (on a mg/m basis) prior to and during the mating period have shown no evidence of impaired fertility. However, similar reproduction studies in rats given oral dosages of 50 and 500 mg/kg daily prior to and during mating revealed evidence of drug-induced decreases in mating ability; no effects on fertility were observed at oral doses representing half the maximum recommended single oral dose of 100 mg or 8 times the maximum recommended single subcutaneous dose of 6 mg in humans (on a mg/m basis). Whether mating impairment is related to sumatriptan in females or males has not been determined.

Lactation

Sumatriptan is distributed into breast milk following administration of the drug to lactating animals or nursing women.(See Pharmacokinetics: Distribution.) Some manufacturers state that caution is advised when sumatriptan is administered to nursing women. It has been suggested that exposure of the infant to the limited amount of drug distributed into milk following a single 6-mg subcutaneous dose could be minimized by expressing and discarding all milk for 8 hours after the dose. The manufacturers recommend minimizing infant exposure to sumatriptan by avoiding breast-feeding for 12 hours after receiving the drug as oral tablets or nasal spray.

Drug Interactions

Monoamine Oxidase Inhibitors

Because of the important role of monoamine oxidase (MAO), particularly the A isoenzyme (MAO-A), in the presystemic clearance of sumatriptan, concomitant therapy with MAO-A inhibitors may decrease sumatriptan clearance and increase half-life and blood concentrations of the drug. In healthy women receiving sumatriptan subcutaneously, pretreatment with an MAO-A inhibitor resulted in a 40% increase in the half-life of sumatriptan, a decrease in plasma clearance, and a twofold increase in area under the plasma concentration-time curve (AUC). In one small study, pretreatment with an MAO-A inhibitor resulted in an approximately sevenfold increase in systemic exposure to sumatriptan following administration of a single 25-mg oral dose of the drug. In contrast, pretreatment with an MAO-B inhibitor does not have an appreciable effect on the metabolism of sumatriptan. The manufacturer states that although studies of this interaction have not been performed with intranasal sumatriptan, the effects of an MAO-A inhibitor on intranasal sumatriptan bioavailability would be expected to be greater than those seen with subcutaneous sumatriptan but less than those seen with the oral drug, since only swallowed drug would be subject to first-pass effects. Concurrent use of sumatriptan and MAO-A inhibitors or use of sumatriptan within 2 weeks of discontinuance of MAO-A inhibitor therapy is contraindicated.

Ergot Alkaloids

Because ergot alkaloids (e.g., ergotamine, dihydroergotamine, methysergide [no longer commercially available in the US]) have been reported to cause prolonged vasospastic reactions and the vasoconstrictor effects of these drugs may be additive to those of sumatriptan, the manufacturers state that use of ergot alkaloids and sumatriptan within 24 hours of each other is contraindicated. However, in a placebo-controlled study in patients with a history of migraine who were receiving dihydroergotamine prophylaxis, no clinical evidence of a drug interaction was observed when subcutaneous sumatriptan was used to treat breakthrough migraine attacks.

Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Cases of potentially life-threatening serotonin syndrome have been reported during concurrent therapy with 5-HT₁ receptor agonists and selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs). Symptoms of serotonin syndrome 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 GI symptoms (e.g., nausea, vomiting, diarrhea). If concurrent therapy with a 5-HT₁ receptor agonist and an SSRI or SNRI is clinically warranted, the patient should be observed carefully, particularly during initiation of therapy, when dosage is increased, or when another serotonergic agent is initiated. In addition, patients receiving such concomitant therapy should be advised of potential drug interaction symptoms (e.g., weakness, progressive agitation, tingling, incoordination, chest pain, dyspnea) and be instructed to report such symptoms to their clinician immediately.

Oral or subcutaneous sumatriptan and serotonin reuptake inhibitors were used concomitantly in some clinical studies without unusual adverse effects. However, an increase in the frequency of migraine attacks and a decrease in the effectiveness of sumatriptan in relieving migraine headache have been reported in a patient receiving subcutaneous injections of sumatriptan intermittently while undergoing fluoxetine therapy.

Protein-bound Drugs

The effect of sumatriptan on the protein binding of other drugs has not been evaluated but would be expected to be minor because of the low-level protein binding of sumatriptan.

Acetaminophen

In patients with migraine, pretreatment with oral sumatriptan followed by administration of oral acetaminophen delayed the absorption of acetaminophen, although the extent of acetaminophen absorption over 8 hours was not affected. Since IV sumatriptan has been shown to delay gastric emptying time in healthy individuals, it has been suggested that delayed absorption of acetaminophen following pretreatment with oral sumatriptan may be the result of a delay in gastric emptying time.

Alcohol

In a limited number of healthy individuals, administration of alcohol (0.8 mg/kg) 30 minutes prior to oral sumatriptan (200 mg) did not affect the pharmacokinetics (e.g., peak plasma concentration, time to peak plasma concentration, area under the plasma concentration-time curve, half-life) of the drug.

Topical Vasoconstrictors

Topical application of xylometazoline to the nasal mucosa 15 minutes prior to an intranasal sumatriptan dose of 20 mg reportedly did not affect the pharmacokinetics of sumatriptan.

Other Drugs

Retrospective evaluation of phase III clinical trials in which certain drugs used for migraine prophylaxis, such as verapamil, amitriptyline, or propranolol, were used concomitantly with sumatriptan did not indicate any effect of such concomitant therapy on the efficacy of sumatriptan. Pretreatment with propranolol (80 mg twice daily for 7 days) did not alter the pharmacokinetics (e.g., plasma concentrations, time to peak plasma concentration, half-life) or pharmacodynamics (as determined by changes in heart rate and blood pressure) of oral sumatriptan given as a single 300-mg dose.

Pharmacokinetics

In all studies described in the Pharmacokinetics section, sumatriptan was administered as the base (nasal spray) or as the succinate salt (oral tablets or injection); dosages and concentrations of the drug are expressed in terms of sumatriptan. Most of the early pharmacokinetic studies of oral sumatriptan used a dispersible formulation of the drug rather than the currently marketed film-coated tablet; the dispersible tablet is bioequivalent to the film-coated tablet.

The pharmacokinetics of sumatriptan do not appear to be altered by patient age or gender. Limited data suggest that the systemic clearance and peak plasma concentrations of sumatriptan are similar in black and white healthy individuals.

Absorption

Sumatriptan is rapidly absorbed following subcutaneous or oral administration; oral absorption appears to occur in the small intestine. The drug also is absorbed rapidly following intranasal administration. The bioavailability of sumatriptan given subcutaneously is almost complete, averaging about 97% of that obtained with IV administration of the drug. The bioavailability of sumatriptan following oral or intranasal administration averages only about 15 or 17%, respectively, principally because of presystemic metabolism of the drug and in part because of incomplete absorption. The area under the plasma concentration-time curve (AUC) and peak serum concentration of sumatriptan increase linearly with single subcutaneous doses of 1-16 mg. The extent of sumatriptan absorption (AUC) also is dose-proportional following single oral doses of 25-200 mg; however, peak plasma concentrations after a 100-mg oral dose of sumatriptan are approximately 25% less than those predicted from a 25-mg oral dose. Interindividual variability in the absorption of sumatriptan after oral administration results in multiple peaks in plasma concentration, possibly because of differences in the rates of gastric emptying, small-bowel transit, and/or presystemic metabolism; however, 75-80% of the final peak plasma concentration is reached within 45 minutes after dosing. Administration of higher than recommended single oral doses of sumatriptan (i.e., 200-400 mg) is associated with a decrease in the rate of absorption. Following oral administration of sumatriptan 85 mg in fixed combination with naproxen sodium 500 mg, the AUC of sumatriptan was similar to that achieved following oral administration of sumatriptan 100 mg alone.

Food does not appreciably affect the oral bioavailability of sumatriptan but prolongs the time to peak concentration. In healthy individuals, oral administration of sumatriptan 100 mg with a high-fat meal increased AUC and peak plasma concentrations by 12 and 15%, respectively, compared with administration in the fasted state. Following oral administration of the fixed combination of sumatriptan 85 mg and naproxen sodium 500 mg with food, the time to peak sumatriptan concentration was delayed slightly (by about 0.6 hour), but bioavailability of sumatriptan was not appreciably affected. Oral absorption of the drug does not appear to be affected appreciably by gastric stasis that may occur during a migraine attack; however, the time to peak concentration is prolonged by about 30 minutes. The pharmacokinetics of sumatriptan following subcutaneous injection or following oral administration in fixed combination with naproxen sodium reportedly are similar during migraine attacks and pain-free periods. Absorption of subcutaneous sumatriptan is not affected by race or gender.

Peak plasma sumatriptan concentrations after administration of a single 6-mg subcutaneous dose of the drug in healthy individuals reportedly have ranged from 55-108 ng/mL at 5-20 minutes after the dose. Peak plasma sumatriptan concentrations averaged about 75 ng/mL and median time to peak concentration was 12 minutes in healthy men receiving a single 6-mg subcutaneous dose of the drug by manual injection in the deltoid area. Following subcutaneous injection of a single 6-mg dose into the thigh in these individuals, peak plasma sumatriptan concentrations averaged 61 ng/mL with manual injection of the drug and 52 ng/mL when a needle-based autoinjection device was used. In this study, the time to peak plasma concentration and the amount of drug absorbed were not affected by injection site or technique. When a single 6-mg dose of sumatriptan was administered subcutaneously via a needleless delivery device at sites on the thigh or abdomen, peak plasma concentrations averaged 72 or 79 ng/mL, respectively, and the time to peak plasma concentration was 12 minutes; administration using this technique at sites on the upper arm may result in delivery of a suboptimal dose.

Peak plasma concentrations of 27-137 ng/mL have been reported 0.5-5 hours after administration of a single 100-mg oral dose in healthy individuals and patients with migraine. After a single 25- or 50-mg oral dose, peak plasma sumatriptan concentrations averaged 18 or 31 ng/mL, respectively, at 0.5-3 hours, while a single 100-mg oral dose of sumatriptan produced peak plasma drug concentrations averaging 51 ng/mL approximately 2-2.5 hours after drug administration. Following oral administration of sumatriptan 85 mg in fixed combination with naproxen sodium 500 mg, peak plasma concentrations of sumatriptan were similar to those achieved following oral administration of sumatriptan 100 mg, and the median time to peak plasma sumatriptan concentrations was about 1 hour (versus 1.5 hours with oral sumatriptan alone).

In a randomized, controlled study in patients with migraine receiving sumatriptan 10, 20, or 40 mg intranasally in one or both nostrils, peak plasma sumatriptan concentrations averaged 7.7-8.7, 11.8-12.4, or 20.1-21.7 ng/mL at 0.8, 1, or 1.8 hours, respectively, following the dose. The possible contribution of oral absorption of the drug to sumatriptan plasma concentrations as a result of swallowing the intranasal dose has not been determined.

The onset of action of sumatriptan in patients with migraine or cluster headaches correlates well with peak plasma drug concentrations. Plasma sumatriptan concentrations associated with therapeutic effects in patients with migraine have ranged from 8-66 ng/mL with subcutaneous therapy and from 18-60 ng/mL with oral sumatriptan. In controlled clinical studies in patients with moderate to severe migraine headache pain, onset of pain relief following subcutaneous injection of sumatriptan usually occurred within 10-34 minutes, maximum relief was achieved within 1-2 hours, and pain relief persisted for 9-24 hours in some patients. In patients with cluster headache, the onset of pain relief following subcutaneous injection of sumatriptan generally occurs within 4-7 minutes, with resolution of the headache shortly thereafter. Onset of relief of migraine symptoms with oral sumatriptan therapy generally occurs 1-3 hours after single oral doses of 25-100 mg, with maximum pain relief attained within 3-6 hours. Although the delayed onset of action of oral versus subcutaneous sumatriptan may result from slower absorption, a small decrease in oral bioavailability of the drug also has been reported during migraine attacks. Compared with subcutaneous sumatriptan, the prolonged absorption observed with oral administration may lead to sustained plasma drug concentrations that delay recurrences of headache.(See Uses: Vascular Headaches.) However, administration of a second oral dose of sumatriptan 2 hours after the first dose during a migraine attack does not influence the development of recurrences, and factors other than pharmacokinetic alterations may contribute to the development of recurrent migraine attacks.

In patients with migraine who received sumatriptan 10, 20, or 40 mg intranasally, the onset of headache relief occurred within 30 minutes following the dose.

Distribution

After subcutaneous administration, sumatriptan is rapidly and widely distributed into body tissues, with an apparent volume of distribution of 2.4 L/kg. Following IV administration of radiolabeled sumatriptan in rats, the drug was detected in the liver, small intestine, and kidney within 10 minutes. Sumatriptan is approximately 14-21% bound to plasma proteins over a concentration range of 10-1000 ng/mL.

Sumatriptan, like exogenously administered serotonin, does not cross the blood-brain barrier in appreciable amounts in animals; however, the occurrence of adverse effects such as transient drowsiness, sedation, dizziness, vertigo, and fatigue with sumatriptan therapy in humans suggests that the drug may have access to the CNS.

In vitro studies in isolated, perfused human placenta suggest that only small amounts of sumatriptan cross the placenta by passive transport.

Sumatriptan is distributed into milk in humans and animals; in animals, sumatriptan concentrations are eightfold higher than concurrent maternal plasma concentrations. In a limited number of healthy lactating women, the total recovery of sumatriptan in breast milk averaged 0.24% of a single 6-mg subcutaneous dose, corresponding to an average infant exposure of 3.5% of the maternal dose on a weight-adjusted basis.

Results of studies in rats given a single subcutaneous (0.5 mg/kg) dose of radiolabeled sumatriptan suggest that sumatriptan and its metabolites bind to melanin in the eye (as indicated by an ocular elimination half-life of 15 days); the clinical importance of this binding is unknown.

Elimination

Following single subcutaneous (6 mg) or oral (50-100 mg) doses of sumatriptan in healthy individuals, the terminal elimination half-life of the drug is 1.5-2.6 hours. Following single-dose oral administration of large doses of sumatriptan (300-400 mg) or repeated administration of smaller doses (100 mg), a second terminal elimination phase has been observed but not characterized. The prolonged elimination half-life with multiple dosing or administration of large single doses may indicate enterohepatic recycling or prolonged oral absorption and does not appear to affect substantially the disposition of the drug. Most of a dose of sumatriptan is excreted within 10-24 hours. Following intranasal administration of sumatriptan, the elimination half-life reportedly is about 2 hours.

Metabolism is the principal clearance process for sumatriptan. Sumatriptan is metabolized in the liver and possibly in the GI tract and is eliminated in urine and feces. In vitro studies suggest that sumatriptan is metabolized by monoamine oxidase (MAO), principally the A isoenzyme (MAO-A); inhibitors of this enzyme may increase systemic exposure to sumatriptan.(See Drug Interactions: Monoamine Oxidase Inhibitors.)

The principal metabolite of sumatriptan is its inactive indole acetic acid analog, which is formed by oxidative N-deamination of the N-dimethyl side chain. The indole acetic acid metabolite of sumatriptan achieves plasma concentrations 6-7 times higher than those of sumatriptan but has a half-life similar to that of the parent compound, suggesting that clearance of this metabolite is formation-rate limited. Other minor metabolites of sumatriptan, an ester glucuronide of the indole acetic acid derivative and an indole ethyl alcohol derivative, also have been identified.

Data in a limited number of patients with hepatic impairment indicate that the area under plasma concentration-time curve (AUC) and peak concentration of sumatriptan increase by 70%, and time to peak plasma concentration occurs 40 minutes earlier compared with such values in healthy individuals receiving a single 50-mg oral dose of sumatriptan. When sumatriptan was administered by subcutaneous injection, the pharmacokinetic profile of the drug in patients with moderate hepatic impairment was similar to that in healthy individuals. The pharmacokinetics of sumatriptan following subcutaneous injection have not been elucidated in patients with severe hepatic impairment.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Sumatriptan is excreted in urine via glomerular filtration and tubular secretion, but renal plasma clearance accounts for only 22% of the systemic clearance of 1176-1200 mL/minute. Since the major route of elimination is by metabolism in the liver, reduction of renal elimination is unlikely to be clinically important. Following subcutaneous administration of a single 6-mg dose of sumatriptan, approximately 22 and 38-53% of the dose is excreted in urine as unchanged drug and as the indole acetic acid metabolite, respectively. Approximately 0.6 and 3.3% of the sumatriptan dose is excreted in feces as unchanged sumatriptan and as the indole acetic acid metabolite, respectively, after subcutaneous administration.

Following administration of a single oral radiolabeled dose of sumatriptan (200 mg) in healthy individuals, 37-40 and 57-60% of the dose is excreted in feces and urine, respectively. Only 3 and 9% of the dose of radiolabeled sumatriptan is excreted unchanged in urine and feces, respectively, after oral administration. Urinary and fecal recovery of sumatriptan metabolites average 46 and 11% of the administered dose, respectively. It is not known whether sumatriptan metabolites excreted in feces are the metabolic product of MAO enzymes present in the GI tract or are derived from biliary excretion.