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sumatriptan succinate injection, solution
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Acute Treatment of Migraine Attacks and Cluster Headache
ALSUMA (sumatriptan injection) 6 mg/0.5 mL is indicated for the acute treatment of migraine attacks, with or without aura, and the acute treatment of cluster headache episodes.
1.2 Important Limitations
ALSUMA should only be used where a clear diagnosis of migraine or cluster headache has been established. 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.
For a given attack, if a patient does not respond to the first dose of ALSUMA, the diagnosis of migraine or cluster headache should be reconsidered before administration of a second dose.
ALSUMA is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. [see Contraindications (4.7)]
2 DOSAGE AND ADMINISTRATION
ALSUMA is only for subcutaneous use.
The maximum single recommended adult dose of ALSUMA is 6 mg injected subcutaneously. The maximum recommended dose that may be given in 24 hours is two doses of ALSUMA separated by at least 1 hour. Controlled clinical trials have failed to show that clear benefit is associated with the administration of a second 6 mg dose in patients who have failed to respond to a first dose.
Since the injection is intended to be given subcutaneously, intramuscular or intravascular delivery must be avoided. Patients should be directed to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle. ALSUMA is for single use only. Discard unused portions. [see Patient Counseling Information (17.5)]
3 DOSAGE FORMS AND STRENGTHS
ALSUMA contains 6 mg of sumatriptan (as 8.4mg sumatriptan succinate), which is delivered as a subcutaneous injection in a single dose. ALSUMA is supplied as a single-use auto-injector pre-filled with sumatriptan succinate drug solution and fully-assembled for use.
4.1 Intravenous Administration
ALSUMA is not designed to administer sumatriptan intravenously. Do not administer intravenously since sumatriptan may cause coronary vasospasm.
4.2 Ischemic or Vasospastic Coronary Artery Disease
Do not use ALSUMA in patients with ischemic heart disease (e.g. angina pectoris, history of myocardial infarction, or documented silent ischemia), or to patients who have symptoms or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal’s variant angina or other significant underlying cardiovascular disease. [see Warnings and Precautions (5.1)]
4.3 Cerebrovascular Syndromes
Do not use ALSUMA in patients with cerebrovascular syndromes including (but not limited to) strokes of any type as well as transient ischemic attacks. [see Warnings and Precautions (5.3)]
4.4 Peripheral Vascular Disease
Do not use ALSUMA in patients with peripheral vascular disease including (but not limited to) ischemic bowel disease. [see Warnings and Precautions (5.4)]
4.5 Uncontrolled Hypertension
Because ALSUMA may increase blood pressure, do not use in patients with uncontrolled hypertension. [see Warnings and Precautions (5.6)]
4.6 Do Not Use Within 24 hours of Treatment with Ergotamine-Containing or Ergot-Type Medications or Other 5-HT1 Agonists (e.g. Triptans)
Do not use ALSUMA and any ergotamine-containing or ergot-type medication (such as dihydroergotamine or methysergide) within 24 hours of each other; do not use ALSUMA and another 5-HT1 agonist (e.g. triptan) within 24 hours of each other. [see Drug Interactions (7.3)]
4.7 Hemiplegic or Basilar Migraine
Do not use ALSUMA in patients with hemiplegic or basilar migraine.
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events
Cardiac Events and Fatalities with 5-HT1 Agonists
Serious adverse cardiac events, including acute myocardial infarction, life threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of sumatriptan. Considering the extent of use of sumatriptan in patients with migraine, the incidence of these events is extremely low.
Sumatriptan can cause coronary vasospasm. Some of these events have occurred in patients with no prior cardiac disease history and with documented absence of CAD with close proximity of the events to sumatriptan use. Because ALSUMA may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following ALSUMA administration 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.
Premarketing Experience with Sumatriptan
Among the more than 1,900 patients with migraine who participated in reported premarketing controlled clinical trials of subcutaneous sumatriptan, there were 8 patients who sustained clinical events during or shortly after receiving sumatriptan that may have reflected coronary artery vasospasm. Six of these 8 patients had ECG changes consistent with transient ischemia, without accompanying clinical symptoms or signs. Of these 8 patients, 4 had either findings suggestive of CAD or risk factors predictive of CAD prior to study enrollment.
Of 6,348 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of oral sumatriptan, 2 experienced clinical adverse events shortly after receiving oral sumatriptan that may have reflected coronary vasospasm. Neither of these adverse events was associated with a serious clinical outcome.
Among approximately 4,000 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of sumatriptan nasal spray, 1 patient experienced an asymptomatic subendocardial infarction possibly subsequent to a coronary vasospastic event.
Postmarketing Experience with Sumatriptan
Serious cardiovascular events, some resulting in death, have been reported in association with the use of subcutaneous sumatriptan injection. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by sumatriptan or to reliably assess causation in individual cases. On clinical grounds, the longer the latency between the administration of sumatriptan and the onset of the clinical event, the less likely the association is to be causative. Interest has focused on events beginning within 1 hour of the administration of sumatriptan.
Cardiac events that have been observed to have onset within 1 hour of sumatriptan administration include coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation, cardiac arrest, and death.
Some of these events occurred in patients who had no findings of CAD and appear to represent consequences of coronary artery vasospasm. However, among reports of serious cardiac events within 1 hour of sumatriptan administration, the majority had risk factors predictive of CAD, and the presence of significant underlying CAD was established in most cases. [see Contraindications (4.2)]
Patients with Documented Coronary Artery Disease
Because of the potential of this class of compound (5-HT1 agonists) to cause coronary vasospasm, ALSUMA should not be given to patients with documented ischemic or vasospastic coronary artery disease. [see Contraindications (4.2)]
Patients with Risk Factors for CAD
It is strongly recommended that ALSUMA not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoking, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, 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, ALSUMA should not be administered. [see Contraindications (4.2)]
For patients with risk factors predictive of CAD who have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of ALSUMA 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 use of ALSUMA in these patients with risk factors.
It is recommended that patients who are intermittent long-term users of ALSUMA and who have or acquire risk factors predictive of CAD, as described above, undergo cardiovascular evaluation periodically 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.
5.2 Sensations of Pain, Tightness, Pressure in the Chest and/or Throat, Neck and Jaw
Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw are relatively common after treatment with sumatriptan. Only rarely have these symptoms been associated with ischemic ECG changes.
However, because sumatriptan may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal’s variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms occur. Patients shown to have CAD and those with Prinzmetal’s variant angina should not receive 5-HT1 agonists. [see Contraindications (4.2) and Warnings and Precautions (5.1)]
Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud syndrome, following sumatriptan should be evaluated for atherosclerosis or predisposition to vasospasm. [see Contraindications (4.4) and Warnings and Precautions (5.4)]
5.3 Drug-Associated Cerebrovascular Events and Fatalities
Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with subcutaneous sumatriptan, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, sumatriptan having been administered in the incorrect belief the symptoms experienced were a consequence of migraine when they were not. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should also be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). [see Contraindications (4.3)]
5.4 Other Vasospasm-Related Events, including Peripheral Vascular Ischemia and Colonic Ischemia
5-HT1 agonists, including ALSUMA, may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported.
Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of sumatriptan. Visual disorders may also be part of a migraine attack.
Patients who experience other symptoms or signs suggestive of decreased arterial flow following the use of any 5-HT1 agonist, such as ischemic bowel syndrome or Raynaud’s syndrome, are candidates for further evaluation. [see Contraindications (4.4)]
5.5 Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome may occur with triptans, including ALSUMA, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). [see Drug Interactions (7.4)]
5.6 Increase in Blood Pressure
ALSUMA is contraindicated in patients with uncontrolled hypertension. Sumatriptan should be administered with caution to patients with controlled hypertension, as transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients. Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients with and without a history of hypertension. [see Contraindications (4.5)]
5.7 Concomitant MAO-A Inhibitors
The coadministration of ALSUMA and an MAO-A inhibitor is not generally recommended. In patients taking MAO-A inhibitors, sumatriptan plasma levels are nearly doubled. If such therapy is clinically warranted, however, suitable dose adjustment (e.g. using a different sumatriptan product, as ALSUMA only exists as a 6mg sumatriptan auto-injector) and appropriate observation of the patient are advised. [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]
Hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred on rare occasions in patients receiving sumatriptan. Such reactions can be life threatening or fatal. [see Contraindications (4.8)]
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 conditions associated with a lowered seizure threshold.
ALSUMA should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. [see Use in Specific Populations (8.1)]
5.11 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 Nonclinical Toxicology (13.2)]
6 ADVERSE REACTIONS
This section provides a summary of adverse reactions reported in subjects in clinical studies conducted with ALSUMA and sumatriptan injection. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug, and may not reflect the rates observed in practice.
Serious cardiac reactions, including myocardial infarction, have occurred following the use of sumatriptan. These reactions are extremely rare and most have been reported in patients with risk factors predictive of CAD. Reactions reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation. [see Contraindications (4.2) and Warnings and Precautions (5.1)]
Significant hypertensive episodes, including hypertensive crises, have been reported on rare occasions in patients with or without a history of hypertension. [see Warnings and Precautions (5.6)]
The following other adverse reactions are discussed in more detail in other sections of labeling:
Sensations of Chest Pain and Tightness [see Warnings and Precautions (5.2)]
Cerebrovascular Events and Fatalities [see Warnings and Precautions (5.3)]
Other Vasospasm related Events including Peripheral Vascular Ischemia and Colonic Ischemia [see Warnings and Precautions (5.4)]
Serotonin Syndrome [see Warnings and Precautions (5.5)]
Among patients in clinical trials of subcutaneous sumatriptan succinate injection (n=6,218), up to 3.5% of patients withdrew for reasons related to adverse reactions.
6.1 Controlled Clinical Trials in Patients with Migraine Headache
Table 1 lists adverse reactions that occurred in 2 large placebo-controlled clinical trials in migraine patients following either a single 6 mg sumatriptan injection or placebo. Only adverse reactions that occurred at a frequency of 2% or more in groups treated with sumatriptan injection 6 mg and occurred at a frequency greater than in the placebo group are included in Table 1.
Table 1. Treatment-Emergent Adverse Reactions Incidence in 2 Large, Placebo-Controlled Clinical Trials in Patients with Migraine: Events Reported by at Least 2% of Patients Treated with Sumatriptan Injection 6 mg*
The incidence of adverse reactions in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse events.
6.2 Controlled Clinical Trials in Patients with Cluster Headache
In the controlled clinical trials assessing sumatriptan injection as a treatment for cluster headache, no new significant adverse reactions 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 studies of cluster headache was generally lower. Exceptions include reports of paresthesia (5% sumatriptan, 0% placebo), nausea and vomiting (4% sumatriptan, 0% placebo), and bronchospasm (1% sumatriptan, 0% placebo).
6.3 Other Adverse Reactions Observed in Association with the Administration of Sumatriptan Injection
The frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include events observed in open and uncontrolled studies, the role of sumatriptan injection in their causation cannot be reliably determined. Furthermore, variability associated with adverse reactions reporting, the terminology used to describe adverse reactions limits the value of the quantitative frequency estimates provided.
Adverse reactions frequencies are calculated as the number of patients reporting an event divided by the total number of patients (N = 6,218) exposed to subcutaneous sumatriptan. All reported adverse reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Adverse reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring in at least 1/100 patients, infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients, and rare adverse reactions are those occurring in fewer than 1/1,000 patients.
Cardiovascular: Infrequent were 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 were pallor, arrhythmia, abnormal pulse, vasodilation, and Raynaud syndrome.
Endocrine and Metabolic: Infrequent was thirst. Rare were polydipsia and dehydration.
Eye: Frequent were vision alterations. Infrequent was irritation of the eye.
Gastrointestinal: Frequent were abdominal discomfort and dysphagia. Infrequent were gastroesophageal reflux and diarrhea. Rare were peptic ulcer, retching, flatulence/eructation, and gallstones.
Musculoskeletal: Frequent were muscle cramps. Infrequent were various joint disturbances (pain, stiffness, swelling, ache). Rare were muscle stiffness, need to flex calf muscles, backache, muscle tiredness, and swelling of the extremities.
Neurological: Frequent was anxiety. Infrequent were 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 were 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 was dyspnea. Rare were influenza, diseases of the lower respiratory tract, and hiccoughs.
Skin: Infrequent were erythema, pruritus, and skin rashes and eruptions. Rare was skin tenderness.
Urogenital: Rare were dysuria, frequency, dysmenorrhea, and renal calculus.
Miscellaneous: Infrequent were miscellaneous laboratory abnormalities, including minor disturbances in liver function tests, “serotonin agonist effect,” and hypersensitivity to various agents. Rare was fever.
6.4 Other Adverse Reactions Observed in the Clinical Development of Sumatriptan
The following adverse reactions occurred in clinical trials with sumatriptan tablets and sumatriptan nasal spray. Because the reports include events observed in open and uncontrolled studies, the role of sumatriptan 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 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).
6.5 Postmarketing Experience (Reports for Subcutaneous or Oral Sumatriptan)
The following adverse reactions have been identified during postapproval use of Sumatriptan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. However, 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 and Precautions (5.5)], Prinzmetal variant angina, pulmonary embolism, shock, thrombophlebitis.
Ear, Nose, and Throat: Deafness.
Eye: Ischemic optic neuropathy, retinal artery occlusion, retinal vein thrombosis, loss of vision.
Gastrointestinal: Ischemic colitis with rectal bleeding [see Warnings and Precautions (5.5)], xerostomia.
Hepatic: Elevated liver function tests.
Neurological: Central nervous system vasculitis, cerebrovascular accident, dysphasia, serotonin syndrome, subarachnoid hemorrhage.
Non-Site Specific: Angioneurotic edema, cyanosis, death [see Warnings and Precautions (5.3)], 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 and Precautions (5.8)]), 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) has been reported.
Urogenital: Acute renal failure.
6.6 Adverse Reactions Observed In Association With The Administration of ALSUMA
The safety of ALSUMA was evaluated in an open-label clinical trial evaluating the usability of ALSUMA during a migraine attack. Adverse reactions that occurred at a frequency of 5% or higher were injection site bruising (16%), injection site pain (6%), and injection site hemorrhage (6%).
7 DRUG INTERACTIONS
7.1 Monoamine Oxidase Inhibitors
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 Warnings and Precautions (5.7)and Clinical Pharmacology (12.3)]
7.2 5-HT1B/1D agonists (e.g. triptans)
Concomitant use of other 5-HT1B/1D agonists within 24 hours of sumatriptan treatment is not recommended. [see Contraindications (4.6)]
7.3 Ergot-Containing Drugs
Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Since these effects may be additive, use of ergotamine containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. [see Contraindications (4.6)]
7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome
Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant treatment with sumatriptan injection is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. [see Warnings and Precautions (5.5)]
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C. Sumatriptan produced evidence of developmental toxicity (embryolethality and increased incidences of fetal abnormalities) in rabbits. Embryolethality was observed at a dose less than the maximum recommended human dose (MRHD) of 12 mg/day on a body surface area (mg/m2) basis. There are no adequate and well-controlled studies of ALSUMA in pregnant women. ALSUMA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
When sumatriptan was administered intravenously to pregnant rabbits daily throughout the period of organogenesis, embryolethality was observed at doses at or close to those producing maternal toxicity. These doses were less than the MRHD of 12 mg/day on a mg/m2 basis. Oral administration of sumatriptan to rabbits during organogenesis was associated with increased incidences of fetal vascular and skeletal abnormalities. The highest no-effect dose for these effects was 15 mg/kg/day. The intravenous administration of sumatriptan to pregnant rats throughout organogenesis at doses that are approximately 10 times the MRHD on a mg/m2 basis, did not produce evidence of embryolethality. The subcutaneous administration of sumatriptan to pregnant rats prior to and throughout pregnancy did not produce evidence of embryolethality or teratogenicity.
8.3 Nursing Mothers
Sumatriptan is excreted in human breast milk following subcutaneous administration. Therefore, caution should be exercised when considering the administration of ALSUMA to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of sumatriptan injection in pediatric patients under 18 years of age have not been established; therefore, sumatriptan injection is not recommended for use in patients under 18 years of age.
Two controlled clinical trials evaluating sumatriptan nasal spray (5 to 20 mg) in pediatric patients aged 12 to 17 years enrolled a total of 1,248 adolescent migraineurs who treated a single attack. The studies did not establish the efficacy of sumatriptan nasal spray compared to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults.
Five controlled clinical trials (2 single-attack studies, 3 multiple-attack studies) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These studies did not establish the efficacy of oral sumatriptan compared to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse events in these patients appeared to be both dose- and age-dependent, with younger patients reporting events more commonly than older adolescents.
Postmarketing experience documents that serious adverse events have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports include events similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration.
Patients (N = 269) have received single injections of 8 to 12 mg sumatriptan without significant adverse effects. Volunteers (N = 47) have received single subcutaneous doses of up to 16 mg without serious adverse events.
No gross overdoses in clinical practice have been reported. The half-life of elimination of sumatriptan is about 2 hours [see Clinical Pharmacology (12.3)], and therefore monitoring of patients after overdose with subcutaneous sumatriptan should continue while symptoms or signs persist, and for at least 10 hours. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.
Sumatriptan is a selective 5-hydroxy-tryptamine receptor subtype 1 (5-HT1) agonist. Sumatriptan delivered as the succinate salt is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure:
The empirical formula is C14H21N3O2S • C4H6O4, representing a molecular weight of 413.5.
ALSUMA is a clear, colorless to pale yellow, sterile, non-pyrogenic solution for subcutaneous injection. Each 0.5 mL of ALSUMA 12 mg/mL solution contains 6 mg of sumatriptan (base) as the succinate salt and 3.5 mg of sodium chloride, USP in Water for Injection, USP. The pH range of the solution is approximately 4.2 to 5.3.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Sumatriptan is the active component of ALSUMA. Sumatriptan is a selective agonist for the 5-HT1B and 5-HT1D receptors. Sumatriptan presumably exerts its antimigrainous effect through binding to vascular 5-HT1-type receptors, which have 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.
Blood Pressure: ALSUMA is contraindicated in patients with uncontrolled hypertension. [see Contraindications (4.5)] It should be administered with caution to patients with controlled hypertension. [see Warnings and Precautions (5.6)]
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.
Absorption and Elimination
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: 1,194 ± 149 mL/min (mean ± S.D.), 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 auto-injector 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 range of 10 to 1,000 ng/mL, is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated.
Monoamine Oxidase 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 an MAO-A inhibitor decreased the clearance of sumatriptan, resulting in a two-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life.
Migraine Prophylactic Medications
There is no evidence that concomitant use of migraine prophylactic medications has any effect on the efficacy of sumatriptan. In 2 clinical trials in the United States, 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 injection, whether or not prophylactic medications were used.
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 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.
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 those in healthy male subjects (mean age, 30 years).
Race: The systemic clearance and Cmax of sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In carcinogenicity studies, rats and mice were given sumatriptan by oral gavage (rats, 104 weeks) or drinking water (mice, 78 weeks). There was no evidence of an increase in tumors in either species related to sumatriptan administration.
Sumatriptan was not mutagenic when tested in the Ames test or the in vitro mammalian Chinese hamster V79/HGPRT assay. Sumatriptan was not clastogenic when tested in the in vitro human lymphocyte assay or the in vivo rat micronucleus assay.
Subcutaneous administration of sumatriptan to male and female rats prior to and throughout the mating period at doses approximately 50 times the maximum recommended human dose (MRHD) of 12 mg/day on a body surface area (mg/m2 ) basis produced no evidence of adverse effects on fertility. 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/day. It is not clear whether the problem is associated with the treatment of males or females or both.
13.2 Animal Toxicology and/or Pharmacology
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/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.
14 CLINICAL STUDIES
In US controlled clinical trials enrolling more than 1,000 patients during migraine attacks who were experiencing moderate or severe pain and 1 or more of the symptoms enumerated in Table 3, onset of relief began as early as 10 minutes following a 6 mg sumatriptan 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 in which placebo (n = 62) was compared to 6 different doses of sumatriptan injection (n = 30 each group) in a single-attack, parallel-group design, the dose response relationship was found to be as shown in Table 2.
Table 2. Dose-Response Relationship for Efficacy
* Relief is defined as the reduction of moderate or severe pain to no pain or mild pain after dosing without use of rescue medication.
In two US well-controlled clinical trials in 1,104 migraine patients with moderate or severe migraine pain, the onset of relief was rapid (less than 10 minutes) with a 6 mg subcutaneous dose of sumatriptan injection. Headache relief, as evidenced by a reduction in pain from severe or moderately severe to mild or no headache, was achieved in 70% of the patients within 1 hour of a single 6 mg subcutaneous dose of sumatriptan injection. Headache relief was achieved in approximately 82% of patients within 2 hours, and 65% of all patients were pain-free within 2 hours. Table 3 shows the 1- and 2-hour efficacy results for subcutaneous sumatriptan 6 mg.
Table 3. Efficacy Data from US Clinical Efficacy Trials with Sumatriptan Injection in Patients with Migraine
* p<0.05 versus placebo.
a A successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally.
b Includes patients who may have received an additional injection of the assigned treatment (placebo or sumatriptan 6 mg) 1 hour after the initial injection.
Subcutaneous sumatriptan also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks.
The efficacy of subcutaneous sumatriptan 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).
14.2 Cluster Headache
The efficacy of sumatriptan injection in the acute treatment of cluster headache was demonstrated in 2 randomized, double-blind, placebo-controlled, 2-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 injection compared to those who received placebo (see Table 4). 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.
Table 4. Efficacy Data from the Cluster Headache Efficacy Trials with Sumatriptan Injection
* p<0.05 (n = Number of headaches treated)
The Kaplan-Meier (product limit) Survivorship Plot (Figure 1) provides an estimate of the cumulative probability of a patient with a cluster headache obtaining relief after being treated with either sumatriptan or placebo.
Figure 1. Time to Relief from Time of Injection*
*Patients taking rescue medication were censored at 15 minutes.
The plot was constructed with data from patients who either experienced relief or did not require (request) rescue medication within a period of 2 hours following treatment. As a consequence, the data in the plot are derived from only a subset of the 258 headaches treated (rescue medication was required in 52 of the 127 placebo-treated headaches and 18 of the 131 sumatriptan-treated headaches).
Other data suggest that sumatriptan treatment is not associated with an increase in early recurrence of headache, and that treatment with sumatriptan has little effect on the incidence of later-occurring headaches (i.e., those occurring after 2, but before 18 or 24 hours).
16 HOW SUPPLIED/STORAGE AND HANDLING
ALSUMA contains sumatriptan (base) as the succinate salt and is supplied as a clear, colorless to pale yellow, sterile, nonpyrogenic solution in a single-dose pre-filled auto-injector.
Store at 25°C, excursions permitted 15° to 30°C (59° to 86° F). Protect from light. Do not refrigerate.
17 PATIENT COUNSELING INFORMATION
17.1 Risk of Myocardial Ischemia and/or Infarction, Other Adverse Cardiac Events, Other Vasospasm-related Events, and Cerebrovascular Events
Inform patients that ALSUMA may cause serious cardiovascular side effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Apprise patients of the importance of this follow-up. [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4)]
17.2 Serotonin Syndrome
Caution patients about the risk of serotonin syndrome with the use of ALSUMA or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). [see Warnings and Precautions (5.5)]
Inform patients that ALSUMA should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. [see Use in Specific Populations (8.1)]
17.4 Nursing Mothers
Advise patients to notify their physician if they are breast-feeding or plan to breast-feed. [see Use in Specific Populations (8.3)]
17.5 Patient Instructions for Use of ALSUMA
ALSUMA is a pre-filled, fully-assembled, single-use device intended to deliver a 6 mg dose of sumatriptan.
Instruct patients on the proper use of the product prior their first use in a medically unsupervised situation. Since the injection is intended to be given subcutaneously, intramuscular or intravascular delivery must be avoided. Direct patients to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle (e.g. lateral thigh or upper arms).
Prescribing Information as of June 2010
Meridian Medical Technologies™, Inc., Columbia, MD 21046
A wholly-owned subsidiary of King Pharmaceuticals®, Inc.
ALSUMA is a trademark of Meridian Medical Technologies™, Inc.,
a wholly-owned subsidiary of King Pharmaceuticals®, Inc.
US WorldMeds, LLC, Louisville, KY 40207
Patient Package Insert
FOOD AND DRUG ADMINISTRATION
Patient Information ALSUMA™ (Awl-SOO’-mah) (sumatriptan injection) Auto-Injector
Read the Patient Information that comes with ALSUMA™ before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about ALSUMA when you start taking it and at regular checkups.
What is the most important information I should know about ALSUMA?
ALSUMA, which contains sumatriptan, may increase your chance of getting a heart attack or stroke that can lead to death. This chance is higher in people who have heart disease.
ALSUMA is not for people with risk factors for heart disease unless a heart exam is done and shows no problem.
The risk factors for heart disease include:
“Seratonin syndrome” is a serious and life-threatening problem that can be caused by ALSUMA, especially if used with anti-depressant medicines called: selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors (SNRIs).
Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.
Call your healthcare provider if you have symptoms of serotonin syndrome, which include:
• mental changes (seeing things that are not there, unusual tension and restlessness)
• fast heartbeat
• changes in blood pressure
• high body temperature
• tight muscles
• trouble walking
• nausea, vomiting, diarrhea
What is ALSUMA?
The ALSUMA Auto-injector is a prescription medicine injection used to treat people who have been diagnosed with migraine or cluster headaches.
ALSUMA is not used to prevent or lessen the number of migraine or cluster headaches you have.
ALSUMA is not used to treat other types of headaches.
It is not known if ALSUMA is safe or effective in people under 18 years of age.
Who should not take ALSUMA?
Do not take ALSUMA if you have:
What should I tell my healthcare provider before taking ALSUMA?
Before taking ALSUMA, tell your healthcare provider about all your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.
Using ALSUMA with certain other medicines can affect each other causing serious side effects.
Especially tell your healthcare provider if you take anti-depressant medicines called:
Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.
How should I take ALSUMA?
What are the possible side effects of ALSUMA?
ALSUMA can cause serious side effects or even death. See “What is the most important information I should know about ALSUMA?”
Serious side effects include:
Get medical help right away, if you have:
The most common side effects of ALSUMA include:
Tell your healthcare provider if you have any side effect that bothers you or does not go away.
These are not all of the possible side effects of ALSUMA. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ALSUMA?
Store ALSUMA between 59°F to 86°F (15°C-30°C).
Keep ALSUMA and all medicines out of the reach of children.
General information about the safe and effective use of ALSUMA.
Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use ALSUMA for a condition for which it was not prescribed. Do not give ALSUMA to other people, even if they have the same symptoms that you have. It may harm them.
This patient information leaflet summarizes the most important information about ALSUMA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ALSUMA that is written for health professionals.
For more information, go to www.alsuma.com or call 1-877-770-8796.
What are the Ingredients in ALSUMA?
Active ingredient: sumatriptan
Inactive ingredient: sodium chloride
PATIENT INSTRUCTIONS FOR USE
ALSUMA™ (Awl-SOO’-mah) (sumatriptan injection) Auto-Injector
Read the Patient Instructions for Use that come with the ALSUMA™ Auto-Injector before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment.
Before you use ALSUMA for the first time, make sure your healthcare provider teaches you the right way to use it.
Follow these instructions each time you use ALSUMA.
ALSUMA is a disposable one time use, prefilled auto-injector used for the treatment of acute migraine or cluster headaches.
Each ALSUMA Auto-Injector is filled with medicine and ready to use. No assembly is required.
ALSUMA is packaged with two doses to a box, with each ALSUMA dose stored in a separate storage and disposal case. (see Figure 1)
ALSUMA Important Tips
The Storage and Disposal Case (see Figure 2)
The ALSUMA Auto-Injector
[Figure 3] [Figure 4]
Holding the ALSUMA Auto-Injector
Always hold the ALSUMA Auto-Injector in the middle with the orange needle end pointing down. (see Figure 5)
[Figure 5] [Figure 6] [Figure 7] [Figure 8]
How to Use ALSUMA
1. Choose an injection site.
[Figure 9] [Figure 10]
2. Preparing Your ALSUMA Auto-Injector.
An Inside Look
ALSUMA (SUMATRIPTAN INJECTION) 6 mg/0.5mL AUTO-INJECTOR BEFORE ACTIVATION (see Figure 11)
ALSUMA (SUMATRIPTAN INJECTION) 6 mg/0.5mL AUTO-INJECTOR WHEN ACTIVATED (see Figure 12)
3. Giving Your Injection
Give yourself the injection exactly the way your healthcare provider showed you.
[Figure 17] [Figure 18]
4. After your injection, throw away (dispose of) the ALSUMA Auto-Injector.
Check with your healthcare provider about the right way to throw away your used ALSUMA Auto-Injector.
Each ALSUMA Auto-Injector can be used only one time.
Important Tips on Storing and Using Your Auto-Injector
Louisville, KY 40207
Meridian Medical Technologies™, Inc.,
Columbia, MD 21046
A wholly-owned subsidiary of King Pharmaceuticals®, Inc.
ALSUMA is a trademark of Meridian Medical Technologies™, Inc.,
a wholly-owned subsidiary of King Pharmaceuticals®, Inc.
Revised: 06/2010 US WorldMeds, LLC
Reproduced with permission of U.S. National Library of Medicine
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