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Sumatriptan Succinate (subcutaneous)
Sumatriptan succinate injection is a selective 5-hydroxytryptamine1, receptor subtype agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1). The empirical formula is C14H21N3O2S·C4H6O4, representing a molecular weight of 413.5. Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in saline. Imitrex injection is a
clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous
injection. Each 0.5 ml of solution
contains 6 mg of sumatriptan (base) as the succinate
salt and 3.5 mg of sodium
chloride in water for injection.
The pH range
of the solution is approximately
4.2 to 5.3. The osmolality of the injection
is 291 mOsmol.
Mechanism of Action Sumatriptan has been demonstrated to be a selective agonist for a vascular 5-hydroxytryptamine1 receptor subtype (probably a member of the 5-HT1D family) with no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5-HT2, 5-HT3 receptor subtypes or at alpha1-, alpha2-, or beta-adrenergic; dopamine1; dopamine2; muscarinic; or benzodiazepine receptors. The vascular 5-HT1 receptor subtype to which sumatriptan binds selectively, and through which it presumably exerts its antimigranious effect, has been shown to be present on cranial arteries in both dog and primate, on the human basilar artery, and in the vasculature of the isolated dura mater of humans. In these tissues, sumatriptan activates this receptor to cause vasoconstriction, an action in humans correlating with the relief of migraine and cluster headache. In the anesthetized dog, sumatriptan selectively reduces the carotid arterial blood wflow with little or no effect on arterial blood pressure or total peripheral resistance. In the cat, sumatriptan selectively constricts the carotid arteriovenous anastomoses while having little effect on blood wflow or resistance in cerebral or extracerebral tissues. Corneal Opacities Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dosage tested, 2 mg/kg per day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established; however, the relative exposure at the lowest dose tested was approximately 5 times the human exposure after a 100-mg oral dose or 3 times the human exposure after a 6-mg subcutaneous dose. Melanin Binding In rats with a single subcutaneous dose (0.5 mg/kg) of radiolabeled sumatriptan, the elimination half-life of radioactivity from the eye was 15 days, suggesting that sumatriptan and its metabolites bind to the melanin of the eye. The clinical significance of this binding is unknown. Pharmacokinetics Pharmacokinetic parameters following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age: 33 years; mean weight: 77 kg) were systemic clearance: 1194±149 ml/min (mean ±SD), distribution half-life: 15±2 minutes, terminal half-life: 115±19 minutes, and volume of distribution central compartment: 50±8 liters. Of this dose, 22±4% was excreted in the urine as unchanged sumatriptan and 38±7% as the indole acetic acid metabolite. After a single 6 mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males, (age: 24 ±6 years; weight: 70 kg), the maximum serum concentration (Cmax) was (mean ± standard deviation) 74±15 ng/ml and the time to peak concentration (tmax) was 12 minutes after injection (range: 5 to 20 minutes). In this study, the same dose injected subcutaneously in the thigh gave a Cmax of 61±15 ng/ml by manual injection versus 52±15 ng/ml by autoinjector techniques. The tmax or amount absorbed was not significantly altered by either the site or technique of injection. The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97±16% of that obtained following intravenous injection. Protein binding, determined by equilibrium dialysis over the concentration of 10 to 1000 ng/ml, is low, approximately 14% to 21%. The effect of sumatriptan on protein binding of other drugs has not yet been evaluated. Special Populations Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined, but little clinical effect would be expected as sumatriptan is largely metabolized to an inactive substance. Hepatic Impairment: The effect of hepatic disease on the pharmacokinetics of subcutaneously and orally administered sumatriptan has been evaluated. There were no statistically significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in hepatically impaired patients compared to healthy controls. However, the liver plays an important role in the presystemic clearance of orally administered sumatriptan. Accordingly, the bioavailability of sumatriptan following oral administration may be markedly increased in patients with liver disease. In one small study of hepatically impaired patients (n=8) matched for sex, age, and weight with healthy subjects, the hepatically impaired patients had an approximately 70% increase in AUC and Cmax and a tmax 40 minutes earlier compared to the healthy subjects. Age: The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years; 2 males and 4 females) and in patients with migraine (mean age: 38 years; 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years) (see PRECAUTIONS, Geriatric Use). Race: The systemic clearance and Cmax of sumatriptan were similar in black (n=34) and Caucasian (n=38) healthy male subjects. Drug Interactions MAO Inhibitors: In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme. In a study of 14 healthy females, pretreatment with MAO-A inhibitor decreased the clearance of sumatriptan. Under the conditions of this experiment, the result was a twofold increase in the area under the sumatriptan plasma concentration ´ time curve (AUC), corresponding to a 40% increase in elimination half-life. No significant effect was seen with an MAO-B inhibitor. Pharmacodynamics Typical Physiologic Responses Blood Pressure: See WARNINGS. Peripheral (Small) Arteries: In healthy volunteers (n=18), a study evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance. Heart Rate: Transient increases in blood pressure observed in some patients in clinical studies carried out during sumatriptan's development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate. Respiratory Rate: Experience gained during the clinical development of sumatriptan as a treatment for migraine failed to detect an effect of the drug on respiratory rate. CLINICAL STUDIESMigraine: In U.S. controlled clinical trials enrolling more than 1000 patients during migraine attacks who were experiencing moderate or severe pain and one or more of the symptoms enumerated in TABLE 4A and TABLE 4B, onset of relief began as early as 10 minutes following a 6-mg sumatriptan succinate injection. Smaller doses of sumatriptan may also prove effective, although the proportion of patients obtaining adequate relief is decreased and the latency to that relief is greater. In one well-controlled study where placebo (n=62) was compared to six different doses of sumatriptan succinate injection (n=30 each group) in a single attack, parallel-group design, the dose response relationship was found to be as shown in TABLE 3.
TABLE 4A and TABLE 4B wshow the 1- and 2-hour efficacy results.
The efficacy of sumatriptan succinate injection is unaffected by whether or not migraine is associated with aura, duration of attack, gender or age of the patient, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers). Cluster Headache: The efficacy of sumatriptan succinate injection in the acute treatment of cluster headache was demonstrated in 2 randomized, double-blind, placebo-controlled, two-period crossover trials. Patients age 21 to 65 were enrolled and were instructed to treat a moderate to very severe headache within 10 minutes of onset. Headache relief was defined as a reduction in headache severity to mild or no pain. In both trials, the proportion of individuals gaining relief at 10 or 15 minutes was significantly greater among patients receiving 6 mg of sumatriptan succinate injection compared to those who received placebo (see TABLE 5). One study evaluated a 12-mg dose; there was no statistically significant difference in outcome between patients randomized to the 6- and 12-mg doses.
Sumatriptan succinate injection is indicated for 1) the acute treatment of migraine attacks with or without aura and 2) the acute treatment of cluster headache episodes. Sumatriptan succinate
injection is not for
use in the management of hemiplegic or basilar
migraine (see CONTRA
The maximum single recommended adult dose of sumatriptan succinate injection is 6 mg injected subcutaneously. Controlled clinical trials have failed to wshow that clear benefit is associated with the administration of a second 6-mg dose in patients who have failed to respond to a first injection. The maximum recommended dose that may be given in 24 hours is two-6 mg injections separated by at least 1 hour. Although the recommended dose is 6 mg, if side effects are dose limiting, then lower doses may be used (see CLINICAL PHARMACOLOGY). In patients receiving MAO inhibitors, decreased doses of sumatriptan should be considered (see WARNINGS and CLINICAL PHARMACOLOGY). In patients receiving doses lower than 6 mg, only the single-dose vial dosage form should be used. An autoinjection device is available for use with 6-mg prefilled syringes cartridges to facilitate self-administration in patients in whom this dose is deemed necessary. With this device, the needle penetrates approximately ¼ inch (5 to 6 mm). Since the injection is intended to be given subcutaneously, intramuscular or intravascular delivery should be avoided. Patients should be directed to use injection sites with an adequate skin and subcutaneous thickness to accomodate the length of the needle. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit. HOW SUPPLIED Imitrex injection 6 mg (12 mg/ml) containing sumatriptan (base) as the succinate salt is supplied as a clear, colorless to pale yellow, sterile, nonpyrogenic solution. Store between 2-30°C (36-86°F). Protect from light. PRODUCT LISTING
Serious cardiac events, including some that have been fatal, have occurred following use of sumatriptan succinate injection or tablets. These events are extremely rare and must have been reported in patients with risk factors predictive of CAD . Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS). Significant hypertensive episodes, including hypertensive crises, have been reported on rare occasions in patients with or without a history of hypertension (see WARNINGS). Among patients in clinical trials of subcutaneous sumatriptan succinate injection (n=6128), up to 3.5% of patients withdrew for reasons related to adverse events. Incidence in Controlled Clinical Trials of Migraine Headache TABLE 6 lists adverse events that occurred in two large U.S., Phase III, placebo-controlled clinical trials in migraine patients following either a single dose of sumatriptan succinate injection or placebo. Only events that occurred at a frequency of 1% or more in groups treated with sumatriptan succinate injection and were at least as frequent as in the placebo group are included in TABLE 6.
The incidence of adverse events in controlled clinical trials was not affected by gender or age of the patients. There was insufficient data to assess the impact of race on the incidence of adverse events. Incidence in Controlled Trials of Cluster Headache In the controlled clinical trials assessing sumatriptan's efficacy as a treatment for cluster headache, no new significant adverse events associated with the use of sumatriptan were detected that had not already been identified in association with the drug's use in migraine. Overall, the frequency of adverse events reported in the studies of cluster headache were generally lower. Exceptions include reports of paresthesia (5% sumatriptan succinate, 0% placebo), nausea and vomiting (4% sumatriptan succinate, 0% placebo) and bronchospasm (1% sumatriptan succinate, 0% placebo). Other Events Observed in Association with the Administration of Sumatriptan Succinate Injection In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. Because the reports include events observed in open and uncontrolled studies, the role of sumatriptan succinate injection in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe the adverse events, etc., limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (n=6128) exposed to subcutaneous sumatriptan succinate injection. All reported events are included except those already listed in TABLE 6, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: Frequent: adverse events are defined as those occurring in at least 1/100 patients, Infrequent: adverse events are those occurring in 1/100 to 1/1000 patients, and Rare: adverse events are those occurring in fewer than 1/1000 patients. Cardiovascular: Infrequent: Hypertension, hypotension, bradycardia, tachycardia, palpitations, pulsating sensations, various transient ECG changes (nonspecific ST or T wave changes, prolongation of PR or QTc intervals, sinus arrhythmia, nonsustained ventricular premature beats, isolated junctional ectopic beats, atrial ectopic beats, delayed activation of the right ventricle), and syncope. Rare: Pallor, arrhythmia, abnormal pulse, vasodilation, and Raynaud syndrome. Endocrine and Metabolic: Infrequent: Thirst. Rare: Polydipsia and dehydration. Eye: Infrequent: Irritation of the eye. Gastrointestinal: Infrequent: Gastroesophageal reflux, diarrhea, and disturbances of liver function tests. Rare: Peptic ulcer, retching, flatulence/eructation, and gallstones. Musculoskeletal: Infrequent: Various joint disturbances (pain, stiffness, swelling, ache). Rare: Muscle stiffness, need to flex calf muscles, backache, muscle tiredness, and swelling of the extremities. Neurological: Infrequent: Mental confusion, euphoria, agitation, relaxation, chills, sensation of lightness, tremor, shivering, disturbances of taste, prickling sensations, paresthesia, stinging sensations, facial pain, photophobia, and lacrimation. Rare: Transient hemiplegia, hysteria, globus hystericus, intoxication, depression, myoclonia, monoplegia/diplegia, sleep disturbance, difficulties in concentration, disturbances of smell, hyperesthesia, dysesthesia, simultaneous hot and cold sensations, tickling sensations, dysarthria, yawning, reduced appetite, hunger, and dystonia. Respiratory: Infrequent: Dyspnea. Rare: Influenza, diseases of the lower respiratory tract, and hiccoughs. Skin: Infrequent: Erythema, pruritus, and skin rashes and eruptions. Rare: Skin tenderness. Urogenital: Rare: Dysuria, frequency, dysmenorrhea, and renal calculus. Miscellaneous: Infrequent: Miscellaneous laboratory abnormalities, including minor disturbances in liver function tests, "serotonin agonist effect", and hypersensitivity to various agents. Rare: Fever. Other Events Observed in the Clinical Development of Sumatriptan Succinate Injection The following adverse events occurred in clinical trials with sumatriptan succinate tablets and nasal spray. Because the reports include events observed in open and uncontrolled studies, the role of sumatriptan succinate in their causation cannot be reliably determined. All reported events are included except those already listed, those too general to be informative, and those not reasonably associated with the use of the drug. Breasts: Breast swelling, cysts, disorder of breasts, lumps, masses of breasts, nipple discharge, primary malignant breast neoplasm, and tenderness. Cardiovascular: Abdominal aortic aneurysm, angina, atherosclerosis, cerebral ischemia, cerebrovascular lesion, heart block, peripheral cyanosis, phlebitis, thrombosis, and transient myocardial ischemia. Ear, Nose, and Throat: Allergic rhinitis; disorder of nasal cavity/sinuses; ear, nose, and throat hemorrhage; ear infection, external otitis; feeling of fullness in the ear(s); hearing disturbances; hearing loss; Meniere disease; nasal inflammation; otalgia; sensitivity to noise; sinusitis; tinnitus; and upper respiratory inflammation. Endocrine and Metabolic: Elevated thyrotropin stimulating hormone (TSH) levels; endocrine cysts, lumps, and masses; fluid disturbances; galactorrhea; hyperglycemia; hypoglycemia; hypothyroidism; weight gain; and weight loss. Eye: Accommodation disorders, blindness and low vision, conjunctivitis, disorders of sclera, external ocular muscle disorders, eye edema and swelling, eye hemorrhage, eye itching, eye pain, keratitis, mydriasis, and visual disturbances. Gastrointestinal: Abdominal distention, colitis, constipation, dental pain, dyspeptic symptoms, feelings of gastrointestinal pressure, gastric symptoms, gastritis, gastroenteritis, gastrointestinal bleeding, gastrointestinal pain, hematemesis, hypersalivation, hyposalivation, intestinal obstruction, melena, nausea and/or vomiting, oral itching and irritation, pancreatitis, salivary gland swelling, and swallowing disorders. Hematological Disorders: Anemia. Mouth and Teeth: Disorder of mouth and tongue (e.g., burning of tongue, numbness of tongue, dry mouth). Musculoskeletal: Acquired musculoskeletal deformity, arthralgia and articular rheumatitis, arthritis, intervertebral disc disorder, muscle atrophy, muscle atrophy, muscle tightness and rigidity, musculoskeletal inflammation, and tetany. Neurological: Apathy, aggressiveness, bad/unusual taste, bradylogia, cluster headache, convulsions, depressive disorders, detachment, disturbance of emotions, drug abuse, facial paralysis, hallucinations, heat sensitivity, incoordination, increased alertness, memory disturbance, migraine, motor dysfunction, neoplasm of pituitary, neuralgia, neurotic disorders, paralysis, personality change, phobia, phonophobia, psychomotor disorders, radiculopathy, raised intracranial pressure, rigidity, stress, syncope, suicide, and twitching. Respiratory: Asthma, breathing disorders, bronchitis, cough, and lower respiratory tract infection. Skin: Dry/scaly skin, eczema, herpes, seborrheic dermatitis, skin nodules, tightness of skin, and wrinkling of skin. Urogenital: Abnormal menstrual cycle, abortion, bladder inflammation, endometriosis, hematuria, increased urination, inflammation of fallopian tubes, intermenstrual bleeding, menstruation symptoms, micturition disorders, urethritis, and urinary infections. Miscellaneous: Contusions, difficulty in walking, edema, hematoma, hypersensitivity, fever, fluid retention, lymphadenopathy, overdose, speech disturbance, swelling of extremities, swelling of face, and voice disturbances. Pain and Other Pressure Sensations: Chest pain and/or heaviness, neck/throat/jaw pain/tightness/pressure, and pain (location specified). Postmarketing Experience (Reports for Subcutaneous or Oral Sumatriptan) The following section enumerates potentially important adverse events that have occurred in clinical practice and that have been reported spontaneously to various surveillance systems. The events enumerated represent reports arising from both domestic and nondomestic use of oral or subcutaneous dosage forms of sumatriptan. The events enumerated include all except those already listed in SIDE EFFECTSor those too general to be informative. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of sumatriptan in their causation cannot be reliably determined. It is assumed, however, that systemic reactions following sumatriptan use are likely to be similar regardless of route of administration.Blood: Hemolytic anemia, pancytopenia, thrombocytopenia. Cardiovascular: Atrial fibrillation, cardiomyopathy, colonic ischemia (see WARNINGS), Prinzmetal variant angina, pulmonary embolism, shock, thrombophlebitis. Ear, Nose, and Throat: Deafness. Eye: Ischemic optic neuropathy, retinal artery occlusion, retinal vein thrombosis. Gastrointestinal: Ischemic colitis with rectal bleeding (see WARNINGS), xerostomia. Hepatic: Elevated liver function tests. Neurological: Central nervous system vasculitis, cerebrovascular accident, dysphasia, subarachnoid hemorrhage. Non-Site Specific: Angioneurotic edema, cyanosis, temporal arteritis. Psychiatry: Panic disorder. Respiratory: Bronchospasm in patients with and without a history of asthma. Skin: Exacerbation of sunburn, hypersensitivity reactions (allergic vasculitis, erythema, pruritus, rash, shortness of breath, urticaria; in addition, severe anaphylaxis/anaphylactoid reactions have been reported [see WARNINGS], photosensitivity. Following subcutaneous administration of sumatriptan, pain, redness, stinging, induration, swelling, contusion, subcutaneous bleeding, and, on rare occasions, lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) have been reported. Urogenital: Acute renal failure. DRUG ABUSE AND DEPENDENCEThe abuse potential of sumatriptan succinate injection cannot be fully delineated in advance of extensive marketing experience. One clinical study enrolling 12 patients with a history of substance abuse failed to induce subjective behavior and/or physiological response ordinarily associated with drugs that have an established potential for abuse.
There is no evidence that concomitant use of migraine prophylactic medications has any effect on the efficacy of sumatriptan. In two Phase III trials in the U.S., a retrospective analysis of 282 patients who had been using prophylactic drugs (verapamil n=63, amitriptyline n=57, propranolol n=94, for 45 other drugs n=123) were compared to those who had not used prophylaxis (n=452). There were no differences in relief rates at 60 minutes postdose for sumatriptan succinate injection, whether or not prophylactic medications were used. Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine¾containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided (see CONTRAINDICATIONS). MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan in patients receiving MAO-A inhibitors is not ordinarily recommended. If the clinical situation warrants the combined use of sumatriptan and an MAOI, the dose of sumatriptan employed should be reduced (see CLINICAL PHARMACOLOGY and WARNINGS). Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised.
Sumatriptan succinate injection should only be used where a clear diagnosis migraine or cluster headache has been established. The prescriber should be aware that cluster headache patients often possess one or more predictive risk factors for coronary artery disease (CAD). Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events: Sumatriptan should not be given to patients with documented ischemic or vasospastic CAD (see CONTRAINDICATIONS). It is strongly recommended that sumatriptan not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological postmenopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient's medical history or electrocardiographic investigations reveal findings indicative of or consistent with coronary artery vasospasm or myocardial ischemia, sumatriptan should not be administered (see CONTRAINDICATIONS). For patients with risk factors predictive of CAD who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of sumatriptan injection take place in the setting of a physician's office or similar medically staffed and equipped facility. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following sumatriptan succinate injection, in these patients with risk factors. It is recommended that patients who are intermittent long-term users of sumatriptan and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use sumatriptan. In considering this recommendation for periodic cardiovascular evaluation, it is noted that patients with cluster headache are predominantly male and over 40 years of age, which are risk factors for CAD. The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to sumatriptan. Drug-Associated Cardiac Events and Fatalities: See Premarketing Experience with Sumatriptan: See Postmarketing Experience: See Drug-Associated Cerebrovascular Events and Fatalities:
See Other Vasospasm-Related Events: See Increase in Blood Pressure: See Concomitant Drug Use: In patients taking MAO-A inhibitors, sumatriptan plasma levels attained after treatment with recommended doses are nearly double those obtained under other conditions. Accordingly, the coadministration of sumatriptan and an MAO-A inhibitor is not generally recommended. If such therapy is clinically warranted, however, suitable dose adjustment and appropriate observation of the patient is advised (see CLINICAL PHARMACOLOGY). Use in Women of Childbearing Potential: See Hypersensitivity: See
General Chest, jaw, or neck tightness
is relatively common after administration of sumatriptan succinate
injection. Chest discomfort and wjaw
or neck tightness has been reported
following use of sumatriptan succinate
tablets and has also been reported infrequently following the administration
of sumatriptan nasal spray. Only rarely have these symptoms been associated
with ischemic ECG changes. However, because sumatriptan may cause
coronary artery vasospasm, patients who experience
signs or symptoms suggestive
of angina following sumatriptan
should be evaluated for the presence of CAD
or a predisposition to Prinzmetal variant
angina before receiving additional
doses of sumatriptan and should be monitored electrocardiographically
if dosing is resumed and similar symptoms recur. Similarly, patients who
experience other symptoms
or signs suggestive of
decreasing arterial flow,
such as ischemic bowel syndrome or Raynaud syndrome, following sumatriptan
should be evaluated for atherosclerosis
or predisposition to
vasospasm (see Sumatriptan succinate injection should also be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as impaired hepatic or renal function. There have been rare reports of seizure following administration of sumatriptan. Sumatriptan should be used with caution in patients with a history of epilepsy or structural brain lesions that lower their seizure threshold. Care should be taken to exclude other potentially serious neurologic
conditions before treating headache
in patients not previously diagnosed with migraine
or cluster headache
or who experience a headache
that is atypical for them. There have been rare reports where patients
received sumatriptan for severe headaches that were subsequently shown
to have been secondary to an evolving neurologic lesion
(see Binding to Melanin-Containing Tissues Because sumatriptan binds to melanin, it could accumulate in melanin-rich tissues (such as the eye) over time. This raises the possibility that sumatriptan could cause toxicity in these tissues after extended use. However, no effects on the retina related to treatment with sumatriptan were noted in any of the toxicity studies. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects (see CLINICAL PHARMACOLOGY). Corneal Opacities Sumatriptan causes corneal opacities and defects in the corneal epithelium in dogs; this raises the possibility that these changes may occur in humans. While patients were not systematically evaluated for these changes in clinical trials, and no specific recommendations for monitoring are being offered, prescribers should be aware of the possibility of these changes (see CLINICAL PHARMACOLOGY). Patients who are advised to self-administer sumatriptan succinate injection in medically unsupervised situations should receive instruction on the proper use of the product from the physician or other suitably qualified health care professional prior to doing so for the first time. Information for the Patient With the autoinjector, the needle penetrates approximately ¼ of an inch (5 to 6 mm). Since the injection is intended to be given subcutaneously, intramuscular or intravascular delivery should be avoided. Patients should be directed to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle. See PATIENT PACKAGE INSERT for additional information for patients. Laboratory Tests No specific laboratory tests are recommended for monitoring patients prior to and/or after treatment with sumatriptan. Drug/Laboratory Test Interactions Sumatriptan succinate is not known to interfere with commonly employed clinical laboratory tests. Carcinogenesis, Mutagenesis, and Impairment of Fertility In carcinogenicity studies, rats and mice were given sumatriptan by oral gavage (rats: 104 weeks), or drinking water (mice: 78 weeks). Average exposures achieved in mice receiving the highest dose were approximately 110 times the exposure attained in humans after the maximum recommended single dose of 6 mg. The highest dose to rats was approximately 260 times the maximum single dose of 6 mg on a mg/m2 basis. There was no evidence of an increase in tumors in either species related to sumatriptan administration. Sumatriptan was not mutagenic in the presence or absence of metabolic activation when tested in two gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/HGPRT assay). In two cytogenetics assays (the in vitro human lymphocyte assay and the in vivo rat micronucleus assay) sumatriptan was not associated with clastogenic activity. A fertility study (Segment I) by the subcutaneous route, during which male and female rats were dosed daily with sumatriptan prior to and throughout the mating period, has shown no evidence of impaired fertility at doses equivalent to approximately 100 times the maximum recommended single human dose of 6 mg on a mg/m2 basis. However, following oral administration, a treatment-related decrease in fertility, secondary to a decrease in mating, was seen for rats treated with 50 and 500 mg/kg per day. The no-effect dose for this finding was approximately eight times the maximum recommended single human dose of 6 mg on a mg/m2 basis. It is not clear whether the problem is associated with the treatment of males or females or both. Pregnancy Category C Sumatriptan has been shown to be embryolethal in rabbits when given daily at a dose approximately equivalent to the maximum recommended single human subcutaneous dose of 6 mg on a mg/m2 basis. There is no evidence that establishes that sumatriptan is a human teratogen; however, there are no adequate and well-controlled studies in pregnant women. Sumatriptan succinate injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In assessing this information, the following additional findings should be considered. Embryolethality: When given intravenously to pregnant rabbits daily throughout the period of organogenesis, sumatriptan caused embryolethality at doses at or close to those producing maternal toxicity. The mechanism of the embryolethality is not known. These doses were approximately equivalent to the maximum single human dose of 6 mg on a mg/m2 basis. The intravenous administration of sumatriptan to pregnant rats throughout organogenesis at doses that are approximately 20 times a human dose of 6 mg on a mg/m2 basis, did not cause embryolethality. Additionally, in a study of pregnant rats given subcutaneous sumatriptan daily prior to and throughout pregnancy, there was no evidence of increase embryo/fetal lethality. Teratogenicity: Term fetuses from Dutch Stride rabbits treated during organogenesis with oral sumatriptan exhibited an increased incidence of cervicothoracic vascular and skeletal abnormalities. The functional significance of these abnormalities is not known. The highest no-effect dose for these effects was 15 mg/kg per day, approximately 50 times the maximum single dose of 6 mg on a mg/m2 basis. In a study in rats dosed daily with subcutaneous sumatriptan prior to and throughout pregnancy, there was no evidence of teratogenicity. To monitor fetal outcomes of pregnant women exposed to sumatriptan succinate, Glaxo Wellcome Inc. maintains a Sumatriptan Pregnancy Registry. Physicians are encouraged to register patients by calling (800) 336-2176. Nursing Mothers Sumatriptan is excreted in human breast milk. Therefore, caution should be exercised when considering the administration of any form of sumatriptan succinate to a nursing woman. Pediatric Use See Geriatric Use The use of sumatriptan in elderly patients is not recommended because
elderly patients are more likely to have decreased hepatic
function, they are at higher risk
for CAD, and blood pressure
increases may be more pronounced in the elderly (see
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