Sumatriptan, Sumatriptan Succinate

[Section Outline]

Vascular Headaches
Other Types of Headache
Other 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.1,2,3,6,7,8,9,10,13,48,49,75,80,145,148,183,184,195,214,217,225,249,279,280 Sumatriptan should be used only in patients in whom a clear diagnosis of migraine or cluster headache has been established.1,148,198,236,237 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.1,7,114,158 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.1,61,148,236,237 (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.244,245,246,247,248,267,268,269 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.244,245,246,247,248,268,269 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.237,244 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.269 Management also should include appropriate nondrug therapy such as lifestyle modification, avoidance of precipitating factors, and behavioral and/or psychologic therapy.237,246,247,251,269 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.246,247,251,267 The possible presence of other types of headaches (e.g., tension-type, cluster) should be evaluated.237,244,246,247,267

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.237,244,245,246,251 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.245,246 Over 80% of migraine sufferers experience some degree of headache-associated disability.244 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.198,236,237,244,246,251,267 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;198,236,237,244,267 some experts also consider osmophobia a diagnostic criterion.244 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.198,244,246,247

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.244 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.269 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.269 Failure to promptly use an effective treatment may increase pain, disability, and the impact of the headache.269 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.244,248,251,269 Medical attention (including hospitalization) may be necessary for detoxification from drug overuse or abuse.237,245 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.269 Antiemetics should not be restricted to patients who are vomiting or likely to vomit.269 In some patients, concomitant therapy with an antiemetic and an oral antimigraine drug may be appropriate.269 In addition, some experts state that IV metoclopramide may be considered as monotherapy for relief of migraine pain.269

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.237,244,246,247,248,267,269 In addition to these analgesics, an antiemetic (e.g., dimenhydrinate, metoclopramide, prochlorperazine), mild vasoconstrictor (e.g., isometheptene), or sedative-hypnotic may be beneficial.237,244,246,247,248,267,269

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.244,246,247,248,249,250,257,267 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.237,269 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.244,246,247,248,249,250,258,259,262,263,264,267,269 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.236,237,269 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.244,246,247,248,249,250,269 Although the role of ergotamine has been questioned (e.g., because of toxicity profile [including severe nausea and vomiting], rebound effect),244,248,251,256 some patients continue to find the drug useful, particularly when combined with an antiemetic.236,237,244,267

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).237,244,248,262,264,267,269 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.244,247 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 treatments269 once the drugs' abuse potential has been addressed.237,244,248,258,259,260,261,269 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.269

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.244,247,269 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.237 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).244,247,269 Parenteral opiate-agonist therapy generally is considered a last resort because of the risks of dependence, tolerance, and associated adverse effects.237,244,246,247,248

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.268 Such recommendations have been described by some experts as being arbitrary and as failing to account for individual patient needs or other migraine characteristics.268 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).268 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.268 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.244,245,246,247,248,251,265,266,267,268 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.268

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.268 Comparative studies have demonstrated few clinically important differences in efficacy among these agents.268 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.268 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.268 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.268 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.268 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.268

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).268 Such experts recommend use of drugs that are effective for both the concomitant illness and migraine prophylaxis whenever possible.268

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 dosa such therapy should be given for several months and then withdrawn slowly to prevent rebound headaches.244,245,246,247,268 If initial drug therapy is not effective, a combination of drugs may be used.244,268

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.268 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.268

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.1,13,148,217,225,236,237 (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.1,2,8,9,13,56,84,92,93,108,148,162,171,173,180,190,225,226 Few comparative studies evaluating the efficacy and safety of sumatriptan relative to other antimigraine therapies have been performed to date.4,13,236 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.3,13,84,124,167,226,236,237 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.3,211,212,213 While clinical studies directly comparing subcutaneous versus oral therapy with sumatriptan in patients with migraine have not been performed,236,237 response to oral sumatriptan therapy occurs later and generally is somewhat less than that with subcutaneous therapy.3,178,236,237 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.123,171,178,190,195,214,236,237

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.1,2,8,13,50,55,58,92,93,108,124,142,145,148,158,180,217,214,225 Unlike other antimigraine drugs (e.g., ergotamine), sumatriptan has been effective even when given late in the attack.8,59,176 However, subsequent doses of sumatriptan in patients not responding adequately to an initial dose generally have not provided additional benefit.8,145,237

Most controlled clinical studies of sumatriptan therapy involved patients who had migraine with aura or migraine without aura8,9,10,13,15,84,92,93,108,111,123,124,142,145,162,171,173,189,190,191,217,226 as defined by criteria established by the Headache Classification Committee of the International Headache Society (IHS).198 However, while a clear diagnosis of migraine is recommended before initiation of sumatriptan therapy,1,148,198,236,237 some evidence suggests that response to sumatriptan may be similar in patients not meeting strict IHS criteria for migraine.181,237 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).1,13,148 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.1,8,9,13,37,56,93,162,171,214,225 Relief of migraine headache generally begins as early as 10 minutes following subcutaneous administration of sumatriptan and is maximal at 2 hours.1,13 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.1,3,57,72 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.1,3,57,72

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;13,92,148,162,178,191,217 maximum pain relief is attained within 3-6 hours.13,148,178,191,217 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.13,108,148,190 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.13,92,108,148,178,180,190

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.281,282 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%).281,282 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%).281,282 Combined therapy with sumatriptan and naproxen also relieved manifestations of migraine other than headache (including nausea, photophobia, and phonophobia).281,282

Since migraine is a chronic, recurrent condition, successful therapy may require long-term, intermittent use of sumatriptan.40,82,178 In several controlled studies of 6-24 months' duration in patients with migraine, intermittent sumatriptan has remained effective throughout subsequent attacks.40,173,181,191 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.191 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.56,236 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.40 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.40,82 The mean number of doses used was similar in patients with frequent (more than 30) and infrequent (less than 10) attacks.82

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.84,124,167,226 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.167,226 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).226 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^®).124 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.124 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).84 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.84 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.84

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.2,8,46,47,50,59,93,162,173,181,189,214 The high rate of recurrent migraine with sumatriptan may be related to the short half-life of sumatriptan2,6,13,16,47,93,173,181,189,214,236,237 or the reversibility of the drug's binding to 5-HT receptors;47,59,189,236,237 however, in some cases, apparent repeat attacks of migraine may have been the result of breakthrough of the suppressed but ongoing original attack.47,51,82,91,176,189 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.189,236,237 Recurrence of migraine appears to be more common with sumatriptan therapy than with ergotamine, dihydroergotamine, combined therapy with aspirin and metoclopramide, or placebo.3,13,84,124,167,226,236,237 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.8,40,47,84,173,181,189 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.173,181,214 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.162,173,181 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.6,8,9,93,176,181,236,237

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.9,56,82,84,148,154,171,180,181,190,191 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,9,48,56,174,181 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.56,143,173

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.82,114,191 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.40,154,172,182,184 In some patients with a history of frequent migraines or dependence on other antimigraine drugs, such as analgesics or ergot-alkaloid-containing compounds,113,140,165,170,172 this increased frequency of migraine attacks has been associated with inappropriate use/misuse of the drug.63,64,165,172 (See Cautions: Precautions and Contraindications.) The contribution of sumatriptan to the increased frequency of migraine headaches in such patients has not been established.64,114,165,170,172

Intranasal administration of sumatriptan is more effective than placebo in relieving migraine headache.13,123,243,268 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.13,123,243,249,270,271 Smaller doses (5 or 10 mg) also may be effective, although in several studies the proportion of patients obtaining relief was reduced.249 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);13,90,239 the manufacturers and most clinicians state that the drug should not be given IV.1,13,236,237 (See Cautions: Precautions and Contraindications.)

The manufacturers state that sumatriptan is not to be used for prophylaxis of migraine headache†,1,148 and prophylactic use of the drug following successful treatment of an initial attack has produced equivocal results.40,173,189 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.173 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.189

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.1,2,49,75,183,184,185,210,214 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.2,49,75,183,184,210 Management of cluster headaches is difficult since the onset of action of many therapies often is delayed beyond the duration of the attack.2,13,49,61,75,199,200,201,205,210,217 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.2,13,49,75,199,200,201,205,210,217 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.49,61,75,205,210,217

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.40,61,75,183,205,217 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.1,49,75 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.13,49,75,184 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.49,75 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.49,75 Use of higher subcutaneous doses of sumatriptan (12 mg) does not appear to increase the response rate in patients with cluster headache;13,75,214 in fact, lower subcutaneous doses (e.g., 3 mg) reportedly may be effective in the management of acute cluster headache episodes.13,210,285

Although an increased frequency of cluster headache attacks has been reported in some patients receiving sumatriptan in uncontrolled studies,13,184 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.13,214 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.13,209 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).1,13,183,209,214,236 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.13,185 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.1,185,205

Sumatriptan has been used with some success in a limited number of patients with chronic paroxysmal hemicrania†, a rare, variant form of cluster headache.13,210,229,230 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.13,202,231,236 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).202,231

Other Types of Headache

Sumatriptan has been used subcutaneously or orally in a limited number of patients with chronic tension-type headache†,13,80,134 acute post-traumatic (e.g., post-dural puncture) headache†,13,54,203,227,228 drug-induced headache† (e.g., in combination with amitriptyline and dexamethasone),232 or high-altitude headache†.147,204 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.54,203,227 Additional study and experience are required to elucidate the safety and efficacy of sumatriptan therapy in these conditions.13,54,134,147,203,204,227,228,229,230

Other Uses

Sumatriptan has been used in a few patients with intractable cyclic vomiting†, which appears to share some common pathogenesis to migraine,206 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.13,233 The safety and efficacy of sumatriptan therapy in these conditions require further evaluation.13,206,233

Dosage and Administration ⬆ ⬇

[Section Outline]

Administration
Dosage
Dosage in Renal and Hepatic Impairment

Administration

Sumatriptan succinate is administered orally.1,12,148 The drug also can be administered parenterally but only by subcutaneous injection.1,12,148 Sumatriptan also can be administered intranasally.249 Sumatriptan should not be given IV because of the potential risk of inducing coronary vasospasm. 1,13,40,90,236,237,279,280 (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.286,287 (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.281 The fixed-combination tablets should not be split, crushed, or chewed.281

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.1,279,280 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).1 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.279 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.1,279,284 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.280 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.1,171,279,280

The patient information provided by the manufacturer should be consulted for directions on intranasal administration of sumatriptan.268

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.1,29,34,37,94,148,249 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.1,148,249

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.1,148,249

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.50,92,108,124,148,180,237

Dosage

Dosage of sumatriptan succinate is expressed in terms of sumatriptan.1,148

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.1,72,111 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.1,111 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.1 The manufacturers state that efficacy of doses lower than 6 mg have not been established for the treatment of cluster headache;1 however, some patients may derive benefit from such doses (e.g., 3 mg).13,210,285 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.1

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.2,3,6,7,8,9,174,176,181,236,237 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.1,148,236 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.1,184,185

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.148 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.148 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.148 The maximum recommended single oral dose is 100 mg.148 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.148 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.148,173 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).148,162,181,236 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.180 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.180,237 The safety of treating an average of more than 4 headaches per 30-day period has not been established.148

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.281 Efficacy of more than 1 dose has not been established.281 If a second dose is administered, an interval of at least 2 hours should elapse between the first and second doses.281 No more than 2 doses (total sumatriptan dosage of 170 mg) should be administered in any 24-hour period.281 The safety of treating an average of more than 5 headaches per 30-day period has not been established.281

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.249 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.249 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.249 Single doses exceeding 20 mg do not provide greater benefit.249

If the headache returns, the dose of intranasal sumatriptan may be repeated once after 2 hours, not to exceed 40 mg daily.249 The safety of treating an average of more than 4 headaches per 30-day period has not been established.249

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.1,13,14,146,148

The liver plays an important role in the presystemic clearance of orally administered sumatriptan.148 Accordingly, the bioavailability of sumatriptan following oral administration may be increased markedly in patients with liver disease.148 (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.148 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.281 Sumatriptan is contraindicated in patients with severe hepatic impairment.1,148,249

Cautions ⬆ ⬇

[Section Outline]

Local Effects
Nervous System Effects
Cardiovascular Effects
GI Effects
Musculoskeletal Effects
Dermatologic and Sensitivity Reactions
Respiratory Effects
Renal and Genitourinary Effects
Ocular Effects
Otic Effects
Endocrine and Metabolic Effects
Hematologic Effects
Other Adverse Effects
Precautions and Contraindications
Pediatric Precautions
Geriatric Precautions
Mutagenicity and Carcinogenicity
Pregnancy, Fertility, and Lactation

Sumatriptan generally is well tolerated when given in recommended dosage.2,3,6,13,148,217 Most adverse effects associated with sumatriptan are well defined, transient, and mild to moderate in intensity,16,75,82,108,143,158,161,171,173,174,178,180,181,183 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.1,2,13,16,23,29,31,48,93,94,143,148,161,171,178,183,194,249 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).2,8,9,13,15,16,56,72,75,78,82,94,111,143,162,174,178,214,236 The incidence of adverse effects associated with sumatriptan generally remains unchanged or decreases with repeated use of the drug.108,173,178,181,183,189 However, the incidence of adverse effects appears to increase with higher than recommended doses of the drug.72,111,180 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.1

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.1,12 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.49,148,178,180,185,191 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.51,61,72,82,84,87,94,108,110,111,118,143,178,190,191,220 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.12,249 For adverse effects reported with sumatriptan therapy in the Cautions section, a causal relationship to the drug has not always been established.1,24,183,189,191 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.1,148,249

Local Effects

Pooled data from controlled studies178 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.1,2,3,8,13,49,55,56,58,72,75,78,93,94,111,143,171,189,220 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.1 Injection site reactions occurred in 59% of patients receiving the drug by subcutaneous injection in controlled trials;1,9 in some studies, this effect occurred with less frequency in patients using a needle-based autoinjector to administer the drug.2,58,93,142,143,171,174 In one uncontrolled study, bruising, pain, and hemorrhage each occurred in 6-16% of patients receiving sumatriptan via a needle-based autoinjector.279 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.280

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.249 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.249 Limited examination of the nose and throat did not reveal clinically noticeable injury in these patients.249 In addition, an increased incidence of local irritation has not been observed in patients receiving intranasal sumatriptan repeatedly for up to 1 year.249 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).249 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).249 The changes observed in both species are not considered to be signs of preneoplastic or neoplastic transformation.249 Local effects on nasal and respiratory tissues after chronic, repeated intranasal administration of sumatriptan have not been studied in animals or humans.249

Burns and scarring have been reported at the application site of sumatriptan iontophoretic transdermal system (Zecuity^®).286,287 Reactions have included severe erythema, cracked skin, blistering or welts, burns or scars, skin discoloration, severe pain, pruritus, and burning sensation.286,287 Although many cases resolved within hours to weeks, some reactions, typically skin discoloration, were unresolved after several months.286 Because of these serious application site reactions, the manufacturer voluntarily suspended marketing of the formulation.286,287

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.1,72,148,158,183,220 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.1,148,249 The incidence of these sensations varies, ranging from 0.4-14% of patients receiving sumatriptan.1,148,249

Although sumatriptan distributes poorly into the CNS, adverse CNS effects have been reported in patients receiving the drug.6,13,14,67,87,138,146,176 Dizziness/vertigo1,8,9,49,55,58,72,93,143,148,162,174,181,183,185,189,220,249 has been reported in up to 12%1 of patients receiving subcutaneous sumatriptan in clinical trials. In addition, agitation,16,148,249 anxiety,1,9,58,143,148,249 drowsiness/sedation,1,8,9,58,143,148,181,220,249 headache,1,72,143,171,174,185,220 and malaise/fatigue8,9,49,57,58,72,75,93,143,148,183 have been reported in up to 3% of patients receiving sumatriptan in controlled trials.1,148 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.64,170,237 Other adverse nervous system effects occurring in up to 1% of patients receiving sumatriptan therapy include aggressiveness,148 apathy,148,249 bradylogia,148 chills,249 cluster headache,148 confusion,1,148,249 depression,148,153,249 detachment,148 difficulties in concentration,148,249 disturbance of smell,148,249 drug abuse,148 dysarthria,148,249 dysesthesia,148 dysphoria,222 dystonia,1,148,156 emotional disturbance,249 euphoria,1,148,249 facial pain,148,249 facial paralysis,148 hallucinations,1,148 heat sensitivity,148 hyperesthesia,148 hysteria,148 incoordination,148,249 increased alertness,148 increased intracranial pressure,148 intoxication,249 lacrimation, 148,249 memory disturbance,148,249 monoplegia/diplegia,148,249 motor dysfunction,148 myoclonia,1 neuralgia,148 neurotic disorders,148 panic disorder,148 paralysis,148 personality change,148 phobia,148 phonophobia/photophobia,148 psychomotor disorders,148 radiculopathy,148 restlessness,16 rigidity,148 seizures,1,148 sensations of lightness,148,161,249 “serotonin agonist effect” or serotonin syndrome,1,148,249 shivering,148,249 sleep disturbance,1,148,190,249 stress, 148,249 suicide,1,148 syncope,1,148,249 transient hemiplegia,148 tremor,1,148,249 twitching,1,148 unsteadiness,57 speech disturbance,148 voice disturbance,148,249 and yawning.148 Although some patients who experienced seizures had a history of seizures or conditions predisposing to seizures, other patients had no apparent predisposing factors.1

Cardiovascular Effects

The most common adverse cardiovascular effect associated with subcutaneous administration of sumatriptan is flushing,1,8,9,58,75,143,148,171,181,185,189,220 which has been reported in 7% of patients receiving the drug by this route in placebo-controlled trials.1 Flushing has been reported infrequently in patients receiving the drug intranasally or orally.148,249 Chest discomfort/pain, pressure, or tightness1,3,9,16,17,27,28,29,46,55,75,94,143,144,162,171,174,181,183,184,185,189,220,249 occurred in up to 5% of patients receiving subcutaneous sumatriptan in controlled trials;1,173,180,181,191 these adverse effects have been reported in up to 2% of patients receiving intranasal or oral sumatriptan.148,249 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.16,17,22,56,75,162,163 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.16,17,21,22,148,173,181,185 Several patients receiving subcutaneous sumatriptan in controlled trials experienced chest pain/pressure17,21,25,184,189 and paresthesia17,21,174,181,185 that was severe enough to necessitate discontinuance of the drug; upon rechallenge, some patients developed similar reactions.17,21,25,220

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.1,148,236,249 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.17,18,20,29,148,163,194 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.148,249 Coronary vasospasm may result in myocardial ischemia or infarction or Prinzmetal variant angina.1,17,18,20,27,28,30,148,155,163,194,218 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.1,148,249 Cardiac arrhythmias/ECG abnormalities associated with chest pain, coronary artery disease, or myocardial ischemia in patients receiving sumatriptan include ST-wave changes,18,27,28,29,30,94,155,164,181,220 ventricular fibrillation or tachycardia,16,23,148,163,164,173,194,220 abnormal T waves,27,56,94,164,181,218 abnormal Q waves,27,28,164 and sinus bradycardia or atrial fibrillation.56,148,194 Some of these events occurred in patients without known coronary artery disease and may represent sequelae of coronary artery vasospasm.1,218 Sumatriptan may cause coronary artery vasospasm even in patients without a history of coronary artery disease.1

Other arrhythmias or ECG abnormalities reported infrequently in patients receiving sumatriptan therapy include bradycardia,1,249 tachycardia,1,143,148,249 nonspecific ST or T wave changes, 148 prolongation of PR or QT_c intervals,148,173,249 abnormal P waves with nodal rhythm,57 QRS/T-axis deviations,173 nonsustained ventricular premature complexes,148,183,249 isolated junctional ectopic beats,249 atrial ectopic beats,249 and delayed activation of the right ventricle.249

Transient increases in systolic and/or diastolic blood pressure have been observed in patients receiving sumatriptan.9,45,148,174,178,249 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.45,148,178 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.1,148,189,249

Other adverse cardiovascular effects reported in up to 1% of patients receiving sumatriptan include edema,1,249 abdominal aortic aneurysm, 148,249 angina,1,148 atherosclerosis,148 cardiomyopathy,148 cerebral ischemia,148 cerebrovascular lesion,1,148 heart block,1,148 increased heart rate,174 pallor,148,174,249 palpitation,1,148,249 peripheral cyanosis,1,148 phlebitis,1,249 pulmonary embolism,148 pulsating sensations,148 Raynaud's syndrome,1 retinal artery occlusion,148 syncope,1 temporal arteritis,1,148 thrombosis,1,148 transient myocardial ischemia,148 and vasodilation.148

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.1,36,42,53,148,152 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).1,36,53,148 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).1,148,152,249

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.249 Dysgeusia/taste disturbance164,180,190 also has been reported with oral sumatriptan therapy; this adverse effect appears to be minimized with the currently available film-coated tablets.8,9,15,59,72,75,82,93,94,108,143,145,148,164,178,180 In addition, nausea75,183,184,185,190,191 and vomiting108,148,164,173,180,181,185,190,191 have been reported in up to 14% of patients receiving sumatriptan for the treatment of migraine.249 The incidence of nausea and vomiting was greater among patients receiving the drug subcutaneously for cluster headache than for the treatment of migraine.1,158,162,164,171 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.51,61,72,82,84,87,94,108,110,111,118,143,178,190,191,220

Other adverse GI effects reported in up to 5% of patients receiving sumatriptan include abdominal discomfort,1,9,108,148,191,220,249 abdominal distention,1,148 colitis or ischemic colitis,1,148,249 constipation,148,249 dental pain,148 diarrhea,148,249 dyspeptic symptoms,148 dysphagia,148,249 flatulence/eructation,148,249 gallstone,148 gastric symptoms (e.g., pain, pressure),148 gastritis,148 gastroenteritis,148,249 gastroesophageal reflux,148,249 GI hemorrhage,148,249 hematemesis,148,249 hypersalivation,148 intestinal obstruction,148,249 jaw discomfort,1,9 melena,148,249 orolingual disorders9,72,249,181,249 (e.g., burning or numbness of tongue,249 discomfort,1,249 swallowing disorders,148 dry mouth249 ), oral itching and irritation,148 pancreatitis,148 peptic ulcer,148,249 rectal bleeding,249 retching,148 salivary gland swelling,148 and xerostomia.249 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.159,220 (See Pharmacology: Other Effects.)

Musculoskeletal Effects

Neck pain/stiffness1,9,46,72,75,93,94,181,184,185,189 and weakness have been reported in up to 5% of patients receiving sumatriptan in controlled trials.1,8,9,56,72,94,148,180 Neck stiffness was severe enough in at least one patient receiving the drug to necessitate discontinuance.148,190,191 Myalgia1,9,148,181,220,249 has been reported in up to 2% of patients receiving sumatriptan in controlled clinical trials.1,148,249

Other adverse musculoskeletal effects reported in patients receiving sumatriptan include acquired musculoskeletal deformity,148 arthritis,249 articular rheumatitis,148 backache,249 swelling of the extremities,1 intervertebral disc disorder,249 muscle atrophy,148 muscle cramps,1,148,249 muscle stiffness,148,249 muscle tightness,148 the need to flex calf muscles,148 muscle tiredness/rigidity,148 muscle weakness,148 musculoskeletal inflammation,148 tetany,148,249 difficulty walking,249 and various joint disturbances (e.g., arthralgia,148 edema, pain, stiffness).249

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.1,52,75,148,174,183,184,185,189,221,249 Hypersensitivity reactions to sumatriptan can be life-threatening or fatal.1,148 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.174 In general, hypersensitivity reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens.1,148,249

Other adverse dermatologic or sensitivity reactions associated with sumatriptan include dry/scaly skin,148 eczema,148 exacerbation of sunburn,1,148,249 peeling of skin,249 photosensitivity,1,249 seborrheic dermatitis,148 skin eruptions,249 nodules,148 skin tenderness,148 tightness/wrinkling of skin,148 sweating,1,148,249 and facial swelling.1,249

Respiratory Effects

Discomfort of the nasal cavity/sinuses or throat1,9,56,72,148,181,191,249 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.1,148,158,174,183,191,220 Dyspnea or hyperventilation has been reported in up to 1% of patients receiving sumatriptan.1,9,57,143,144,148,174,191,220,249 Upon rechallenge, some patients again experienced dyspnea.220 Bronchospasm has been reported in at least 1% of patients with or without a history of asthma receiving sumatriptan;1,148,249 the incidence of bronchospasm among patients with cluster headaches appears to be greater than the incidence among those with migraine receiving the drug subcutaneously.1 Influenza,183 diseases of the upper9,148,249 and lower respiratory tract,148,249 hiccups,148 asthma,148,249 bronchitis,148 and cough have been reported in up to 1% of patients receiving sumatriptan.24,148,191

Renal and Genitourinary Effects

Adverse renal effects reported in up to 1% of patients receiving sumatriptan include acute renal failure,1,148,249 bladder inflammation,148 dysuria,148,191,249 hematuria,148 increased urination,148,249 micturition disorders,148 urethritis,148 urinary infections,148 and urinary frequency.148

Adverse genitourinary effects reported in up to 1% of patients receiving sumatriptan include abnormal menstrual cycle,148 abortion,148 disorders of the breast249 (e.g., tenderness,148 nipple discharge,148 ) dysmenorrhea,148,249 endometriosis,249 inflammation of fallopian tubes,148 intermenstrual bleeding,148 and menstruation or menstrual cycle symptoms.148

Ocular Effects

Vision alteration/disturbance,148,249 ocular irritation,148 accommodation disorders,148 conjunctivitis,148 disorders of sclera,148 external ocular muscle disorders,148 keratitis,148 lacrimation,16 blindness/low vision,148 miosis,16 mydriasis,148 and ocular edema, hemorrhage, itching, pain, or swelling148 have been reported in up to 1% of patients receiving sumatriptan in clinical studies.148,249 In addition, ischemic optic neuropathy, 1,148,249 retinal artery occlusion, 1,148,249 retinal vein thrombosis, 1,148,249 and vision loss148,249 have been reported during postmarketing surveillance. 1,148,249 Transient or permanent blindness and substantial partial vision loss have been reported very rarely with sumatriptan use.1,148,249 (Vision disorders also may be part of a migraine attack.)1,148,249

Corneal opacities and defects in the corneal epithelium have been noted in dogs receiving sumatriptan.1,148,249 Defects in the corneal epithelium were evident in a 60-week study.1,148,249 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).1,148,249 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/m² basis.148,249 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.1

Otic Effects

Adverse otic effects reported in up to 1% of patients receiving sumatriptan include ear infection,249 external otitis, 249 feeling of fullness in the ears,148 hearing disturbances (e.g., increased sensitivity to noise, hearing loss),148 Ménière's disease,249 otalgia,148,249 and tinnitus.249 In addition, deafness1,9,148 has been reported during postmarketing surveillance.1,148,249

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),148 endocrine cysts, lumps, or masses,148 fluid disturbances (e.g., retention),148 galactorrhea,148,249 hyperglycemia,148 hypoglycemia,148 hypothyroidism,148,249 thirst,148,249 hunger,148,249 increased/decreased appetite,148,249 and weight gain/loss.148,249

Hematologic Effects

Anemia,148 elevated platelet count183 and lymphadenopathy,148,249 have been reported in up to 1% of patients receiving sumatriptan.148 In addition, hemolytic anemia,1,148,249 pancytopenia,1,148,249 and thrombocytopenia have been reported during postmarketing surveillance. 1,148,249

Other Adverse Effects

Other adverse effects reported in up to 1% of patients receiving sumatriptan include diaphoresis,9,72,75,143,181 fever,148,185 overdose,148 and pituitary neoplasm.249

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.1,148,198,236,237,249 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.1 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.1,148,249 Patients with a history of migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).1,148,249

Patients should be cautioned about potential misuse (e.g., for prophylaxis) of sumatriptan for vascular headache.1,148,237 Patients also should be cautioned against frequent use/misuse of sumatriptan,1,148,237,249 since abuse of sumatriptan has resulted in rebound headache in patients with a history of analgesic or ergot alkaloid abuse.63,64,114,165,170 Patients should be encouraged to record headache frequency and drug use so that the effectiveness of treatment may be monitored.1,148,249,276 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.1,148,249,276,277 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.1,148,249,276,277

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.1,148,249

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.1,148,249

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.1,148,249 Sumatriptan should be used with caution in patients with controlled hypertension,3,11,148,249 and blood pressure should be monitored in all patients receiving the drug.1

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.148,249 (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.281

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).1,148,249,272 Serotonin syndrome also may occur in patients receiving 5-HT₁ receptor agonists concomitantly with monoamine oxidase (MAO) inhibitors or tricyclic antidepressants.1 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).1,148,249,272 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.272 (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.1,148,249,278 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.1,148,249

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.1,3,11,16,17,18,23,24,29,33,35,148,249 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 drug1,148,249 and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur.148,249 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.1,148,249 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;1,148,249 however, a cardiac evaluation should be performed if the patient is at high cardiac risk.1 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.1,148,249

Patients with multiple cardiovascular risk factors (e.g., postmenopausal women; men older than 40 years of a 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.1,34,148,164,249 (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.112,115,116 ) If the cardiovascular evaluation provides evidence of coronary artery disease or coronary artery vasospasm, the drug should not be administered.1,148,249 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).1,148,236,237,249 Because myocardial ischemia can occur in the absence of clinical symptoms,33,40 clinicians should consider obtaining an ECG immediately following the initial dose of sumatriptan in these patients.1,40,148,249 Patients with risk factors for the development of coronary artery disease should undergo periodic cardiovascular evaluation while receiving intermittent long-term sumatriptan therapy.1,148,236,237,249 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.1,29,34,148,220,249 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.150

Because the incidence of adverse effects and the risk of precipitating coronary vasospasm increases with IV administration, sumatriptan should not be administered IV.1,13,40,90,236,237,279,280

If life-threatening disturbances of cardiac rhythm (e.g., ventricular tachycardia or fibrillation) occur, therapy with sumatriptan should be discontinued.1 Sumatriptan is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.1

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.1,26,37,48,148,157,236,249 (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.1,148,237,249 (See Drug Interactions: Ergot Alkaloids.)

Sumatriptan is contraindicated in patients with hemiplegic or basilar migraine.1,36,48,148,249

Sumatriptan also is contraindicated in patients with severe hepatic impairment and/or known hypersensitivity to sumatriptan or any of its components.1,148,249 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.1,148,249

Pediatric Precautions

The manufacturers state that safety and efficacy of sumatriptan in those younger than 18 years of age have not been established.1,12,148,236,237,249

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†.1,148,249 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.1,148,249 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.1,148,249 Myocardial infarction reportedly occurred in one 14-year-old boy within 1 day of receiving oral sumatriptan.1,148,249 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.1,148,249

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.1 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.1 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.1 Increases in blood pressure may be more pronounced in geriatric patients than in younger adults.148,249 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.1 (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.1,148 No increase in chromosomal aberrations was observed in the in vitro human lymphocyte assay or in the in vivo rat micronucleus assay.1,148

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.1,148 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/m² basis for 104 weeks.1,148

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate and well-controlled studies evaluating the use of sumatriptan in pregnant women.1,148,249 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.173 Sumatriptan should be used during pregnancy only if the potential benefit justifies the risk to the fetus.1,148,249

Sumatriptan has been associated with fetal abnormalities and embryo and fetal mortality in animals.1,148,249 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/m² basis).1 The mechanism of the embryolethality is not known.148 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/m² basis) or in pregnant rats given subcutaneous sumatriptan prior to and throughout pregnancy.1 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/m² basis) throughout the period of organogenesis produced embryolethality and maternotoxicity; these effects were not observed at oral sumatriptan dosages of 50 mg/kg daily.148 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/m² basis).148

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/m² basis); an increased incidence of a syndrome of malformations (short tail/short body and vertebral disorganization) was observed in these animals.148 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/m² basis); these effects were not observed at lower dosages.1,148 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/m² 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/m² basis).148 In a study in rats dosed daily with subcutaneous sumatriptan prior to and throughout pregnancy, there was no evidence of teratogenicity.1,148

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/m² 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/m² basis).148 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/m² 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.148

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/m² basis) prior to and during the mating period have shown no evidence of impaired fertility.1,148 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/m² basis).1,148 Whether mating impairment is related to sumatriptan in females or males has not been determined.1,148

Lactation

Sumatriptan is distributed into breast milk following administration of the drug to lactating animals or nursing women.14,40,148,242,249,279,280,283 (See Pharmacokinetics: Distribution.) Some manufacturers state that caution is advised when sumatriptan is administered to nursing women.279,280 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.242,283 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.148,249

Drug Interactions ⬆ ⬇

[Section Outline]

Monoamine Oxidase Inhibitors
Ergot Alkaloids
Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors
Protein-bound Drugs
Acetaminophen
Alcohol
Topical Vasoconstrictors
Other Drugs

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.1,37,48,148,249 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).1,148 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.148,249 In contrast, pretreatment with an MAO-B inhibitor does not have an appreciable effect on the metabolism of sumatriptan.148,193 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.249 Concurrent use of sumatriptan and MAO-A inhibitors or use of sumatriptan within 2 weeks of discontinuance of MAO-A inhibitor therapy is contraindicated.1,26,37,148,157,236,249

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,1,26,33,60 the manufacturers state that use of ergot alkaloids and sumatriptan within 24 hours of each other is contraindicated.1,148,249 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.142

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).1,148,249,272 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).1,148,249,272 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.272 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.1,148,249,236,237,272

Oral or subcutaneous sumatriptan and serotonin reuptake inhibitors were used concomitantly in some clinical studies without unusual adverse effects.192,193,234 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.151

Protein-bound Drugs

The effect of sumatriptan on the protein binding of other drugs has not been evaluated1 but would be expected to be minor because of the low-level protein binding of sumatriptan.148,249

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.187 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.76,187

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.44,45,148,236

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.249

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. 40,62 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.62

Other Information ⬆ ⬇

[Section Outline]

Cerebrovascular Effects
Cardiovascular Effects
Hormonal and Metabolic Effects
Other Effects
Absorption
Distribution
Elimination
Chemistry
Stability

Laboratory Test Interferences

Sumatriptan is not known to interfere with commonly employed clinical laboratory tests.148

Acute Toxicity

No gross overdoses in clinical practice have been reported.1 Single oral or intranasal doses of 140-300 or up to 40 mg, respectively, have been administered to patients with migraine, and single oral or intranasal doses of 140-400 or up to 40 mg, respectively, have been administered to healthy individuals, without clinically important adverse effects.148,249 However, coronary vasospasm has been observed after IV administration of usual doses of sumatriptan.1 (See Cautions: Precautions and Contraindications.) Based on studies in animals given high doses of sumatriptan (0.1 g/kg in dogs and 2 g/kg in rats), overdosage with the drug may be expected to cause seizures, tremor, inactivity, ptosis, erythema of the extremities, reduced respiratory rate, cyanosis, ataxia, mydriasis, salivation, lacrimation, injection site reactions (desquamation, hair loss, scab formation), and paralysis.1,148,249 Since the elimination half-life of sumatriptan is about 2-2.5 hours, monitoring of patients after overdosage should continue while symptoms persist or for at least 10-12 hours.1,148,249

The effect of hemodialysis or peritoneal dialysis on serum concentrations of sumatriptan is not known.1,148,249

Chronic Toxicity

Currently available data from long-term and/or postmarketing surveillance studies suggest that subcutaneous or oral sumatriptan use is not associated with dose escalation or withdrawal symptoms in patients using the drug as recommended for acute treatment of migraine or cluster headache attacks.114,148,170,236,237 However, misuse of sumatriptan (e.g., daily use as prophylaxis) has been reported in a few patients receiving the drug orally or subcutaneously for migraine headache, most of whom had a history of analgesic or ergot alkaloid abuse.63,64,114,165,170,172 Some clinicians state that frequent (e.g., daily) use of sumatriptan may be associated with rebound headache;237 overuse of sumatriptan has been reported to sustain ergotamine-induced headache, with the addition of superimposed migraine-like episodes, in at least one patient.172 Patients should be cautioned against frequent use/misuse of sumatriptan for headache prophylaxis.1,148,237 (See Cautions: Precautions and Contraindications.)

Pharmacology

Sumatriptan is a selective agonist of vascular serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors.1,2,3,4,5,6,7,8,223,224 The mechanisms involved in the pathogenesis of migraine and cluster headache are not clearly understood; consequently, the precise mechanism of action of sumatriptan in the management of these disorders has not been established.4,6,9,13,77,87 However, current data suggest that sumatriptan may ameliorate migraine and cluster headache through selective constriction of certain large cranial blood vessels and/or inhibition of neurogenic inflammatory processes in the CNS.1,2,3,6,7,9,10,13,47,66,73,77,88,110,119,131,177,184,186,217,236,237 While some features of migraine clearly reflect effects on cerebral blood vessels, neurogenic mechanisms involving activation of the trigeminovascular system also have been implicated; current evidence suggests that both mechanisms may be involved.1,3,6,13,77,87,95,117,195,197,217

No single pathogenic mechanism has been identified to explain the various manifestations of cluster headache, although several pathophysiologic abnormalities that appear to involve direct or indirect activation of the trigeminovascular and cranial parasympathetic nervous systems have been identified in patients with this disorder.103,184,186,188,196,217 It has been suggested that the neuroendocrinologic abnormalities associated with cluster headache may indicate dysfunction of the “biologic clock” in the hypothalamus.217

Although sumatriptan therapy has been associated with adverse CNS effects such as drowsiness, sedation, fatigue, dizziness, and vertigo, available evidence from animal studies indicates that the drug penetrates the blood-brain barrier poorly; therefore, it has been suggested that disruption of the blood-brain barrier may occur during migraine attacks.6,13,14,41,47,48,49,67,87,136,138,141,146,176,217 However, since sumatriptan also decreases migraine-associated nausea and vomiting,1,8,9,55,56,58,76,93,108,118,162,171,173,180 a more likely hypothesis is that sumatriptan acts on areas of the brain not protected by the blood-brain barrier (e.g., the circumventricular organs, the chemoreceptor trigger zone).4,6,38,47,76,118,126,127,128,129,236,237

Indirect evidence suggests that serotonin is involved in the pathogenesis of migraine because of observed correlations between the physiologic effects of serotonin, which include vasoconstriction, and the clinical features of migraine.2,3,6,13,26,57,73,77,87,88,119,131,215,216,217 Serotonin levels in platelets within the vascular system have been shown to increase before, and decrease rapidly during, a migraine attack.2,13,57,59,87,127,131,215 In addition, increases in the urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), a major metabolite of serotonin, have been found in patients with migraine, suggesting rapid degradation of serotonin during migraine attacks.13,87 Both spontaneous migraine and that induced by reserpine, a drug that depletes serotonin stores, are ameliorated by IV administration of serotonin.13,87 However, clinical use of serotonin is precluded by adverse effects such as nausea, syncope, hyperpnea, peripheral vasoconstriction, and paresthesia.59,87,141,215,216

Sumatriptan and other currently available drugs that are effective for acute migraine, including dihydroergotamine and ergotamine, have binding affinity for serotonin type 1 (5-HT₁) receptors, particularly the 5-HT_1D (also called 5-HT_1Dα) and 5-HT_1B (also called 5-HT_1Dβ) subtypes located on trigeminal sensory neurons innervating dural blood vessels.4,13,38,60,66,73,74,95,100,101,105,106,110,120,126,130,132,135,138,139,177,195,223,224 The 5-HT_1B and 5-HT_1D receptors function as autoreceptors, activation of which leads to inhibition of firing of serotonin neurons and a reduction in the synthesis and release of serotonin.223 Upon binding to these 5-HT₁ receptor subtypes, sumatriptan inhibits adenylate cyclase activity via regulatory G proteins, increases intracellular calcium, and affects other intracellular events that lead to vasoconstriction and inhibition of sensory nociceptive (trigeminal) nerve firing and vasoactive neuropeptide release.2,3,4,6,38,74,86,109,121,128,130,132,137,177,217 Sumatriptan has the highest affinity for the 5-HT_1D receptor, the most common serotonin receptor subtype in the brain,2,13,98 and a 2- to 17-fold lower affinity for 5-HT_1A receptors; agonist activity at 5-HT_1A and other serotonin receptors may be responsible for some of the adverse effects noted with administration of serotonin or serotonergic antimigraine drugs (e.g., ergotamine, dihydroergotamine).2,4,6,77,83,98,101,128,131 Sumatriptan has essentially no affinity for (based on standard radioligand binding assays) nor pharmacologic activity at other serotonin receptors (e.g., 5-HT₂, 5-HT₃) or at receptors of the dopamine₁, dopamine₂, muscarinic,2,4,6,22,83,98 histamine,66 benzodiazepine,2,4,83,98 or α₁-, α₂-, or β-adrenergic type.2,4,39,40,66,73,77,98,101,132,137,148,177

Cerebrovascular Effects

Some evidence suggests that migraine may be caused by initial vasoconstriction of cerebral vessels, opening of arteriovenous anastomoses, and diversion of blood from capillary beds;4,6,47,65,98,110,118 these vascular changes may result in ischemia and hypoxia, vasodilation of intracranial and scalp vessels, and extravasation of plasma proteins into the dura mater.4,6,10,47,65,98,110,118,133,158,169 Sumatriptan and ergot alkaloids appear to exert their therapeutic effects in migraine by reducing blood flow to anastomoses and redirecting flow to capillary beds.65,68,70,77,110,118,119 Sumatriptan selectively constricts certain large cranial blood vessels (e.g., as indicated by a selective increase in blood flow velocity in the internal carotid and middle cerebral arteries) and arteriovenous anastomoses in the carotid circulation that become inflamed and dilated during a migraine attack.1,2,3,6,7,9,10,11,13,43,66,73,77,88,107,110,131,177 These vasoconstrictor effects occur apparently without compromising blood flow in the cerebral or extracerebral circulation.43,70,77,119,138,169,176 It has been suggested that the vasoconstriction observed following administration of sumatriptan may be related in part to a direct action on vascular smooth muscle.66,103,184,186

Sumatriptan inhibits activation of the trigeminovascular system and associated release of vasoactive neuropeptides (i.e., substance P, neurokinin A, calcitonin gene-related peptide [CGRP]) from trigeminal nerve terminals, thereby preventing subsequent vasodilation, inflammation, and plasma extravasation from dural blood vessels.2,3,6,13,38,47,67,71,74,75,87,95,106,117,118,125,133,176 Sumatriptan also has been shown to reduce the ultrastructural changes resulting from trigeminal sensory nerve stimulation in the dura mater, such as vesiculation, vacuolation, microvillus projections within the endothelium of postcapillary venules, platelet aggregation and adhesion, and mast cell degranulation.95,121,125

In cluster headache, activation of trigeminal nerves and the parasympathetic nervous system leads to frontotemporal vasodilation, neuroinflammation, and venous stasis; these effects may be manifested as nasal congestion, rhinorrhea, lacrimation, abnormal sweating, and/or periorbital edema.103,184,186,188,217 Limited data currently suggest that sumatriptan, like oxygen, may alleviate cluster headache attacks through normalization of elevated CGRP concentrations in cranial venous blood; such normalization of CGRP levels reflects termination of activity in the trigeminovascular system.103,196,217 In addition, vasoconstriction following administration of sumatriptan may be related in part to a return of firing of sympathetic nerve fibers following a decrease in neuroinflammation.66,103,184,186

Although sumatriptan does not appear to have a direct analgesic effect, the drug inhibits firing of sensory nociceptive nerves in the trigeminovascular system that may be involved in central pain modulatory mechanisms (as indicated by inhibition of c-fos protein expression, an indicator of neuronal activation).13,38,47,49,67,71,74,77,95,217

Cardiovascular Effects

Sumatriptan has shown modest vasoconstrictor effects on the coronary, pulmonary, and systemic circulation in in vitro studies in animals and in most studies in humans, but these effects are much less potent than those of ergot alkaloids.100,118,119,124,141 In vitro studies of human diseased and normal coronary artery rings and angiographic evidence in patients undergoing coronary arteriography indicate that sumatriptan causes relatively weak contractions of coronary arteries compared with the effects of serotonin or ergotamine.5,28,32,69,102,130 Although coronary vasospasm and myocardial ischemia or infarction have been reported in a few patients receiving sumatriptan,1,17,18,23,27,29,30,148,194 most of these patients had risk factors predictive of coronary artery disease, and use of the drug may have been contraindicated in some of these cases.1,20,29,35,130,148,194 (See Cautions: Precautions and Contraindications.) It has been suggested that the presence of atherosclerosis and/or associated changes in the function of vasoactive factors (e.g., substance P, nitric oxide, thromboxane A) in damaged coronary artery endothelium may result in enhanced sensitivity of the coronary vessels to the vasoconstrictor effects of sumatriptan in patients with coronary artery disease.31,34,69,85,102,130,164

Sumatriptan selectively reduces carotid arterial blood flow and/or constricts carotid arteriovenous anastomoses in anesthetized animals without appreciable effects on arterial blood pressure or total peripheral resistance.45,100,148,178 The drug produces contraction of vascular smooth muscle in vitro in saphenous veins in dogs and humans, but such contractions are weaker than those produced by serotonin or ergot alkaloids (e.g., methysergide).105,120 Administration of sumatriptan in healthy individuals did not appreciably increase arterial resistance (as measured by decreases in mean toe-arm systolic blood pressure gradients) in small peripheral arteries of the leg.1,60,236,238 Increases in systolic and diastolic blood pressure noted in patients receiving sumatriptan in clinical studies generally have been small and transient and have not been accompanied by appreciable changes in heart rate;5,45,100,148,178 however, clinically important increases in blood pressure, including hypertensive crisis with acute impairment of organ systems, have been reported rarely with sumatriptan therapy in patients with or without a history of hypertension.1,5 (See Cautions: Cardiovascular Effects.)

Hormonal and Metabolic Effects

Limited data in healthy individuals indicate that subcutaneous administration of sumatriptan may increase plasma somatotropin (growth hormone), corticotropin (ACTH), and β-endorphin concentrations through stimulation of serotonin (possibly 5-HT_1D) receptors on the pituitary gland, which is not protected by the blood-brain barrier.47,97,122 The effect of sumatriptan on the hypothalamic-pituitary-adrenal (HPA) axis has not been studied in patients with migraine.47 Limited data in healthy individuals suggest that stimulation of corticotropin secretion by sumatriptan may be accompanied by increased secretion of cortisol;97 however, increased cortisol concentrations have not been consistently demonstrated with single-dose subcutaneous or oral administration of sumatriptan.122,161 Secretion of other pituitary hormones, such as prolactin, luteinizing hormone (LH), or follicle-stimulating hormone (FSH, follitropin), does not appear to be affected in healthy individuals receiving subcutaneous sumatriptan (6 mg); however, increases in thyrotropin (TSH) have been reported rarely in patients receiving the drug.122,148

Other Effects

Sumatriptan has been shown to prolong GI transit time following IV administration in healthy individuals.76 In addition, large subcutaneous doses of sumatriptan (16 mg) increase esophageal motility (as measured by increases in the frequency, strength, and duration of repetitive peristaltic contractions upon swallowing).76,159 It has been suggested that some instances of chest pain reported in patients receiving sumatriptan in clinical trials may have been attributable to increased esophageal motility, which may itself be associated with chest pain, rather than to cardiac problems.5,159,160,163 (See Cautions: Cardiovascular Effects.)

Clinical experience with sumatriptan in patients with migraine suggests that the drug has no appreciable effect on respiratory rate.144 Bronchospasm has been reported with sumatriptan therapy, but a causal relationship between asthmatic symptoms and sumatriptan or an increase in adverse effects in asthmatic patients receiving the drug has not been established.1,13,24,148,236,237 (See Cautions: Respiratory Effects.)

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.3,13,44,168

The pharmacokinetics of sumatriptan do not appear to be altered by patient age or gender.1,3,45,146,148 Limited data suggest that the systemic clearance and peak plasma concentrations of sumatriptan are similar in black and white healthy individuals.1,236

Absorption

Sumatriptan is rapidly absorbed following subcutaneous or oral administration; oral absorption appears to occur in the small intestine.1,45,61,89,166,168 The drug also is absorbed rapidly following intranasal administration.2,13,123 The bioavailability of sumatriptan given subcutaneously is almost complete, averaging about 97% of that obtained with IV administration of the drug.1,44 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.2,13,14,44,45,61,89,146,148,166,168,249 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.2,72,78 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.148,168,236 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.2,13,89,90,146,168 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.146,168 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.281

Food does not appreciably affect the oral bioavailability of sumatriptan but prolongs the time to peak concentration.2,13,44 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.148 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.281 Oral absorption of the drug does not appear to be affected appreciably by gastric stasis that may occur during a migraine attack;3,13,45,146 however, the time to peak concentration is prolonged by about 30 minutes.3,13,45,96,146,148 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.1,281 Absorption of subcutaneous sumatriptan is not affected by race or gender.1,13,15,45,146

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.3,13,45,78,89,146,168 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.1,148,236 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.1 In this study, the time to peak plasma concentration and the amount of drug absorbed were not affected by injection site or technique.1 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.280

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.3,13,45,79,89,96,146,148,168 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,166,168 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.148 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).281

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.123 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.2,123,243

The onset of action of sumatriptan in patients with migraine or cluster headaches correlates well with peak plasma drug concentrations.1,9,10,13,40,49,75,184 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.2,91,175 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.1,8,9,13,47,56,162,176,181 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.40,49,75,184 Onset of relief of migraine symptoms with oral sumatriptan therapy generally occurs 1-3 hours after single oral doses of 25-100 mg,92,148,162,178,191 with maximum pain relief attained within 3-6 hours.148,178,191 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.96,168 Compared with subcutaneous sumatriptan, the prolonged absorption observed with oral administration may lead to sustained plasma drug concentrations that delay recurrences of headache.3,173,189 (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.173

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.123,243

Distribution

After subcutaneous administration, sumatriptan is rapidly and widely distributed into body tissues, with an apparent volume of distribution of 2.4 L/kg.1,14,146,148,168 Following IV administration of radiolabeled sumatriptan in rats, the drug was detected in the liver, small intestine, and kidney within 10 minutes.14 Sumatriptan is approximately 14-21% bound to plasma proteins over a concentration range of 10-1000 ng/mL.1,14,45,148

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.6,13,14,67,87,138,146,176

In vitro studies in isolated, perfused human placenta suggest that only small amounts of sumatriptan cross the placenta by passive transport.235

Sumatriptan is distributed into milk in humans and animals; in animals, sumatriptan concentrations are eightfold higher than concurrent maternal plasma concentrations.13,14,242 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.242

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.1

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.1,6,44,45,78,79,89,91,148,166,168,280,281 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.3,6,15,45,62,79,146,168,236 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.6,15,146,168 Most of a dose of sumatriptan is excreted within 10-24 hours.14,236 Following intranasal administration of sumatriptan, the elimination half-life reportedly is about 2 hours.249

Metabolism is the principal clearance process for sumatriptan.1,3,13,14,45,148,166 Sumatriptan is metabolized in the liver and possibly in the GI tract and is eliminated in urine and feces.1,3,13,14,148,166 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.1,37,48,148 (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.1,2,13,14,104,148,166 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.2,45,166 Other minor metabolites of sumatriptan, an ester glucuronide of the indole acetic acid derivative and an indole ethyl alcohol derivative, also have been identified.2,14,104

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.13,44,148,236 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.1 The pharmacokinetics of sumatriptan following subcutaneous injection have not been elucidated in patients with severe hepatic impairment.1 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Sumatriptan is excreted in urine via glomerular filtration and tubular secretion,89,146,168 but renal plasma clearance accounts for only 22% of the systemic clearance of 1176-1200 mL/minute.1,2,3,6,13,45,78,146,166,168 Since the major route of elimination is by metabolism in the liver, reduction of renal elimination is unlikely to be clinically important.1,13,14,146,148 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.1,45,168 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.2,13,14,45

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.14,45,148 Only 3 and 9% of the dose of radiolabeled sumatriptan is excreted unchanged in urine and feces, respectively, after oral administration.13,45,148,166,168 Urinary and fecal recovery of sumatriptan metabolites average 46 and 11% of the administered dose, respectively.45,166 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.166

Chemistry and Stability

Chemistry

Sumatriptan is a selective agonist of vascular serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors.1,2,3,4,5,6,7,8,223,224,249 Sumatriptan is structurally and pharmacologically related to serotonin, differing structurally from serotonin principally by the substitution of methane sulfonamide for the alcohol group on the indole ring of serotonin.2,3,6

Sumatriptan and sumatriptan succinate occur as white to off-white powders and are freely soluble in water and in 0.9% sodium chloride. The drug reportedly has pK_as of 4.21 and 5.67 (succinic acid), 9.63 (tertiary amine group), and 12 or greater (sulfonamide group).2,236

Sumatriptan succinate is commercially available as a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection and as tablets for oral administration.1,148,279,280 Each 0.5 mL of the 8-mg/mL injection contains 4 mg of sumatriptan and 3.8 mg of sodium chloride.1 Each 0.5 mL of the 12-mg/mL injection contains 6 mg of sumatriptan and 3.5 mg of sodium chloride.1,279,280 The commercially available injection has a pH of approximately 4.2-5.3 and an osmolality of 291 mOsm/kg.1,236,279,280 Commercially available sumatriptan tablets contain 35, 70, or 140 mg of sumatriptan succinate equivalent to 25, 50 or 100 mg, respectively, of sumatriptan.148

Sumatriptan nasal spray is commercially available as aqueous buffered solutions in single-use delivery devices.249 The solutions have a pH of approximately 5.5 and osmolalities of 372 and 742 mOsm/kg for the 5 and 20 mg per 0.1 mL single-use doses, respectively.249

Stability

Sumatriptan succinate injection in cartridges and vials, sumatriptan succinate tablets, and sumatriptan nasal spray should be stored at 2-30°C; the injection should be protected from light.1,148,249 The fixed-combination tablets containing sumatriptan succinate and naproxen sodium should be stored in the original container with the desiccant packet at 25°C but may be exposed to temperatures ranging from 15-30°C; the fixed-combination tablets should not be repackaged.281 Sumatriptan succinate prefilled, single-use injection pens should be protected from light and stored at 25°C but may be exposed to temperatures ranging from 15-30°C; refrigeration should be avoided.279 Sumatriptan succinate prefilled, single-use needleless devices should be stored at 20-25°C but may be exposed to temperatures ranging from 15-30°C; freezing should be avoided.280

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

SUMAtriptan

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Nasal	Solution	5 mg/0.1 mL*	Imitrex^® Nasal Spray	GlaxoSmithKline
			SUMAtriptan Nasal Spray
		20 mg/0.1 mL*	Imitrex^® Nasal Spray	GlaxoSmithKline
			SUMAtriptan Nasal Spray

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

SUMAtriptan Succinate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	25 mg (of sumatriptan)*	Imitrex^®	GlaxoSmithKline
			SUMAtriptan Succinate Tablets
		50 mg (of sumatriptan)*	Imitrex^®	GlaxoSmithKline
			SUMAtriptan Succinate Tablets
		100 mg (of sumatriptan)*	Imitrex^®	GlaxoSmithKline
			SUMAtriptan Succinate Tablets
Parenteral	Injection, for subcutaneous use only	4 mg (of sumatriptan) per 0.5 mL*	Imitrex^® (available in 0.5-mL unit-of-use injection-pen cartridges)	GlaxoSmithKline
			SUMAtriptan Succinate Injection (available in 0.5-mL unit-of-use injection-pen cartridges)
		6 mg (of sumatriptan) per 0.5 mL*	Alsuma^® (available in prefilled disposable single-use 0.5-mL injection pen)	Pfizer
			Imitrex^® (available in 0.5-mL unit-of-use injection-pen cartridges and as 0.5-mL single-dose vials)	GlaxoSmithKline
			SUMAtriptan Succinate Injection (available in 0.5-mL unit-of-use injection-pen cartridges and as 0.5-mL single-dose vials)
			Sumavel^® (available in prefilled disposable single-use 0.5-mL needleless delivery device)	Zogenix

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

SUMAtriptan Succinate Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	85 mg (of sumatriptan) with 500 mg Naproxen Sodium	Treximet^®	GlaxoSmithKline

AHFS^® Drug Information. © Copyright, 1959-2024, Selected Revisions November 20, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

1. GlaxoSmithKline. Imitrex^® (sumatriptan succinate) injection prescribing information. Research Triangle Park, NC; 2012 Oct.

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section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Chemical Name:

Molecular Formula:

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

SUMAtriptan

SUMAtriptan Succinate

SUMAtriptan Succinate Combinations

Copyright ⬆ ⬇

References ⬆