Ava-Sumatriptan Product Monograph

CLINICAL PHARMACOLOGY

Sumatriptan succinate has been shown to be effective in relieving migraine headache. It is an agonist for a vascular 5-hydroxytryptamine_1D (5-HT_1D) receptor subtype (a member of the 5-HT₁ family), and has only weak affinity for 5-HT_1A receptors and no significant activity (as measured using standard radioligand binding assays) or pharmacological activity at 5-HT₂, 5-HT₃, 5-HT₄, 5-HT_5A,or 5-HT₇ receptor subtypes, or at alpha₁-, alpha₂-, or beta-adrenergic; dopamine₁ or dopamine₂; muscarinic; or benzodiazepine receptors.

The therapeutic activity of sumatriptan succinate in migraine is generally attributed to its agonist activity at 5-HT_1B/5-HT_1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT₁ receptor agonists in migraine. One theory suggests that activation of 5-HT₁ receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is believed to be correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT₁ receptors on perivascular fibres of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. These theories are not mutually exclusive.

Experimental data from animal studies shows that sumatriptan also activates 5-HT₁ receptors on peripheral terminals of the trigeminal nerve which innervates cranial blood vessels. This causes the inhibition of neuropeptide release. It is thought that such an action may contribute to the antimigraine action of sumatriptan in humans.

Cardiovascular Effects

In vitro studies in human isolated epicardial coronary arteries suggest that the predominant contractile effect of 5-HT is mediated via 5-HT₂ receptors. However, 5-HT₁ receptors also contribute to some degree to the contractile effect seen. Transient increases in systolic and diastolic blood pressure (up to 20 mmHg) of rapid onset (within minutes), have occurred after intravenous administration of up to 64 mcg/kg (3.2 mg for 50 kg subject) to healthy volunteers. These changes were not dose related and returned to normal within 10-15 minutes. Following oral administration of 200 mg or intranasal administration of 40 mg, however, mean peak increases in blood pressure were smaller and of slower onset than after intravenous or subcutaneous administration.

PHARMACOKINETICS

Pharmacokinetics parameters following oral administration are shown in Table 1. Sumatriptan is rapidly absorbed after oral administration. The low oral bioavailability is primarily due to metabolism (hepatic and presystemic) and partly due to incomplete absorption. The oral absorption of sumatriptan is not significantly affected either during migraine attacks or by food. Inter-patient and intra-patient variability was noted in most pharmacokinetic parameters assessed.

Table 1: Summary of Pharmacokinetic Parameters

* 70 % to 80 % of C_max values were attained within 30-45 minutes of dosing.

In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme. In studies conducted in a limited number of patients, MAO inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure.

Non-renal clearance of sumatriptan accounts for about 80% of the total clearance. The major metabolite, the indole acetic acid analogue of sumatriptan is mainly excreted in the urine where it is present as a free acid (35%) and the glucuronide conjugate (11%). It has no known 5-HT₁ or 5-HT₂ activity. Minor metabolites have not been identified.

No differences have been observed between the pharmacokinetic parameters in healthy elderly volunteers compared with younger volunteers (less than 65 years old).

Significant relief begins about 30 minutes following oral administration.

Comparative Bioavailability Study

A single dose crossover comparative bioavailability study of sumatriptan 50 and 100 mg tablets was conducted under fasted conditions. Bioavailability data were measured and the results are summarized in Tables 2 and 3 below.

Table 2: Summary of Pharmacokinetic Parameters (50 mg sumatriptan tablets)

^† Imitrex^® manufactured by GlaxoWellcome Inc. was purchased in Canada. * expressed as arithmetic mean (CV%) only.

Table 3: Summary of Pharmacokinetic Parameters (100 mg sumatriptan tablets)

^† Imitrex^® manufactured by GlaxoWellcome Inc. was purchased in Canada. * expressed as arithmetic mean (CV%) only.

CLINICAL STUDIES

Migraine

The efficacy of sumatriptan succinate tablets for the treatment of migraine was established in four multicentre, randomized, placebo-controlled studies. Patients enrolled and treated in these studies were primarily female (84%), Caucasian (98%) and with a mean age of 40 years (range of 18 to 65 years). Patients were instructed to treat a moderate to severe headache. In Study 2, up to three doses were permitted to treat a single attack within a 24 hour period, nonresponders could take a second dose at two hours, while any recurrence of migraine could be treated with a third dose. Study 1, 3 and 4 were designed to allow for the treatment of up to three attacks.

Headache relief at two hours was statistically significantly greater for all sumatriptan groups when compared to placebo (see Table 4).

Table 4: Percentage of Patients with Headache Relief (0/1) at 2 Hours Post Oral Dose for the Treatment of

Migraine

Headache relief is defined as a reduction in headache severity from grade 3 or 2 (severe or moderate) to grade 1 or 0 (mild or no pain)

• Not evaluated

* p<0.001 vs placebo

** p=0.001 vs placebo

In Study 4, the 50 mg (p=0.002) and 100 mg (p=0.003) groups had significantly more patients experience headache relief compared to the 25 mg group at 2 hours.

For patients with migraine-associated nausea, photophobia, phonophobia at baseline, there was a decrease incidence of these symptoms following administration of sumatriptan succinate tablets compared to placebo.

Menstrually-Associated Migraine

Two mean multicentre, randomized, placebo-controlled studies evaluated sumatriptan succinate 50 mg and 100 mg tablets administered during the mild phase of a menstrually-associated migraine attack. A total of 816 subjects with a mean age of 37 (18-65 years of age), with at least a 1-year history of migraine, and a 6-month history of regularly occurring MAM, were enrolled and treated. MAM was defined as any migraine beginning on Day -2, to +4 with day 1 = the first day of flow. Patients were instructed to treat a single, mild, moderate or severe headache within one hour of mild pain onset.

A statistically significantly higher proportion of patients following sumatriptan succinate 50 mg and 100 mg achieved pain-free status at 2 hours post-dose compared with placebo in the treatment of menstrually-associated migraine (see Table 5).

Table 5: Percentage of Patients with Complete Headache Pain Relief¹ at 2 hours Post Oral Dose for the

Treatment of Menstrually-Associated Migraine

Complete Headache Pain Relief is defined as grade 1 (mild pain) reduced to grade 0 (no pain) * p<0.001 vs placebo

For patients with migraine-associated nausea, photophobia, phonophobia at baseline, there was a decrease incidence of these symptoms following administration of sumatriptan succinate tablets compared to placebo.

INDICATIONS AND CLINICAL USE

Ava-Sumatriptan (sumatriptan succinate) is indicated for the acute treatment of migraine attacks with or without aura.

Ava-Sumatriptan is not for use in the management of hemiplegic, basilar, or ophthalmoplegic migraine (see CONTRAINDICATIONS). Safety and efficacy have not been established for cluster headache which is present in an older, predominantly male population.

CONTRAINDICATIONS

Ava-Sumatriptan (sumatriptan succinate) is contraindicated in patients with history, symptoms, or signs of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes, valvular heart disease or cardiac arrhythmias (especially tachycardias). In addition, patients with other significant underlying cardiovascular diseases (e.g. atherosclerotic disease, congenital heart disease) should not receive Ava-Sumatriptan. Ischemic cardiac syndromes include, but are not limited to, angina pectoris of any type (e.g. stable angina of effort and vasospastic forms of angina such as the Prinzmetal’s variant), all forms of myocardial infarction, and silent myocardial ischemia. Cerebrovascular syndromes include, but are not limited to, strokes of any type as well as transient ischemic attacks (TIAs). Peripheral vascular disease includes, but is not limited to, ischemic bowel disease, or Raynaud’s syndrome (see WARNINGS)

Because Ava-Sumatriptan may increase blood pressure, it is contraindicated in patients with uncontrolled or severe hypertension.

Concurrent administration of MAO inhibitors or use within 2 weeks of discontinuation of MAO inhibitor therapy is contraindicated (see CLINICAL PHARMACOLOGY and PRECAUTIONS, Drug Interactions).

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because Ava-Sumatriptan may also cause coronary vasospasm and these effects may be additive, the use of Ava-Sumatriptan within 24 hours before or after treatment with other 5-HT₁ receptor agonists, or ergotamine-containing drugs or their derivatives (e.g. dihydroergotamine, methysergide) is contraindicated.

Ava-Sumatriptan should not be administered to patients with severe hepatic impairment.

Ava-Sumatriptan is contraindicated in patients with hemiplegic, basilar, or ophthalmoplegic migraine.

Ava-Sumatriptan is contraindicated in patients with hypersensitivity to sumatriptan or any of the ingredients of the formulations.

WARNINGS

Ava-Sumatriptan (sumatriptan succinate) should only be used where a clear diagnosis of migraine has been established.

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events

Sumatriptan succinate has been associated with transient chest and/or neck pain and tightness which may resemble angina pectoris. In rare cases, the symptoms have been identified as being the likely result of coronary vasospasm or myocardial ischemia. Rare cases of serious coronary events or arrhythmia have occurred following use of sumatriptan succinate. Ava-Sumatriptan should not be given to patients who have documented ischemic or vasospastic coronary artery disease (CAD) (see CONTRAINDICATIONS). It is strongly recommended that Ava-Sumatriptan 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 who is surgically or physiologically postmenopausal, or male who is over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is unknown. If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, Ava-Sumatriptan should not be administered (see

CONTRAINDICATIONS).

For patients with risk factors predictive of CAD, who are considered to have a satisfactory cardiovascular evaluation, the first dose of Ava-Sumatriptan should be administered in the setting of a physician’s office or similar medically staffed and equipped facility. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining electrocardiograms in patients with risk factors during the interval immediately following Ava-Sumatriptan administration on the first occasion of use. However, an absence of drug-induced cardiovascular effects on the occasion of the initial dose does not preclude the possibility of such effects occurring with subsequent administrations.

Intermittent long term users of Ava-Sumatriptan who have or acquire risk factors predictive of CAD, as described above, should receive periodic interval cardiovascular evaluations over the course of treatment.

If symptoms consistent with angina occur after the use of Ava-Sumatriptan, ECG evaluation should be carried out to look for ischemic changes.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to Ava-Sumatriptan.

Cardiac Events and Fatalities Associated with 5-HT₁ Agonists

Sumatriptan succinate can cause coronary artery vasospasm. Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of 5-HT₁ agonists. Considering the extent of use of 5-HT₁ agonists in patients with migraine, the incidence of these events is extremely low. The fact that some of these events have occurred in patients with no prior cardiac disease history and with documented absence of CAD, and the close proximity of the events to sumatriptan succinate use support the conclusion that some of these cases were caused by the drug. In many cases, however, where there has been known underlying coronary artery disease, the relationship is uncertain.

Premarketing Experience With Sumatriptan Succinate

Of 6 348 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of oral sumatriptan succinate, two experienced clinical adverse events shortly after receiving oral sumatriptan succinate that may have reflected coronary vasospasm. Neither of these adverse events was associated with a serious clinical outcome.

Postmarketing Experience With Sumatriptan Succinate

Serious cardiovascular events, some resulting in death, have been reported in association with the use of sumatriptan succinate tablets. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by sumatriptan succinate or to reliably assess causation in individual cases. On clinical grounds, the longer the latency between the administration of sumatriptan succinate and the onset of the clinical event, the less likely the association is to be causative. Accordingly, interest has focused on events beginning within 1 hour of the administration of sumatriptan succinate.

Cardiac events that have been observed to have onset within 1 hour of sumatriptan succinate administration include: coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation, cardiac arrest, and death.

Some of these events occurred in patients who had no findings of CAD and appear to represent consequences of coronary artery vasospasm. However, among reports from the USA of serious cardiac events occurring within 1 hour of sumatriptan succinate administration, almost all of the patients had risk factors predictive of CAD and the presence of significant underlying CAD was established in most cases (see CONTRAINDICATIONS).

Cerebrovascular Events and Fatalities with 5-HT₁ Agonists

Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with oral sumatriptan succinate, and some have resulted in fatalities. The relationship of sumatriptan succinate to these events is uncertain. In a number of cases, it appears possible that the cerebrovascular events were primary, sumatriptan succinate having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Ava-Sumatriptan should not be administered if the headache being experienced is atypical for the patient. It should also be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g. stroke, hemorrhage, TIA). If a patient does not respond to the first dose, the opportunity should be taken to review the diagnosis before a second dose is given.

Special Cardiovascular Pharmacology Studies

In subjects (n=10) with suspected coronary artery disease undergoing angiography, a 5-HT₁ agonist at a subcutaneous dose of 1.5 mg produced an 8% increase in aortic blood pressure, an 18% increase in pulmonary artery blood pressure, and an 8% increase in systemic vascular resistance. In addition, mild chest pain or tightness was reported by four subjects. Clinically significant increases in blood pressure were experienced by three of the subjects (two of whom also had chest pain/discomfort). Diagnostic angiogram results revealed that 9 subjects had normal coronary arteries and 1 had insignificant coronary artery disease.

In an additional study with this same drug, migraine patients (n=35) free of cardiovascular disease were subjected to assessments of myocardial perfusion by positron emission tomography while receiving a subcutaneous 1.5 mg dose in the absence of a migraine attack. Reduced coronary vasodilatory reserve (∼ 10%), increase in coronary resistance (∼ 20%), and decrease in hyperemic myocardial blood flow (∼ 10%) were noted. The relevance of these finding to the use of the recommended oral doses of this 5-HT₁ agonist is not known.

Similar studies have not been done with Ava-Sumatriptan. However, owing to the common pharmacodynamic actions of 5-HT₁ agonists, the possibility of cardiovascular effects of the nature described above should be considered for any agent of this pharmacological class.

Hypersensitivity

Rare hypersensitivity (anaphylaxis/anaphylactoid) reactions may occur in patients receiving 5-HT₁ agonists such as sumatriptan succinate. Such reactions can be life-threatening or fatal. In general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens (see CONTRAINDICATIONS). Owing to the possibility of cross-reactive hypersensitivity reactions, Ava-Sumatriptan should not be used in patients having a history of hypersensitivity to chemically-related 5-HT₁ receptor agonists. There have been reports of patients with known hypersensitivity to sulphonamides exhibiting an allergic reaction following administration of sumatriptan succinate. Reactions ranged from cutaneous hypersensitivity to anaphylaxis.

Other Vasospasm Related Events

5-HT₁ agonists may cause vasospastic reactions other than coronary artery vasospasm. Extensive postmarket experience has shown the use of sumatriptan succinate to be associated with rare occurrences of peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea.

Increase in Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients with and without a history of hypertension. Ava-Sumatriptan is contraindicated in patients with uncontrolled or severe hypertension (see CONTRAINDICATIONS). In patients with controlled hypertension, Ava-Sumatriptan should be administered with caution, as transient increases in blood pressure and peripheral vascular resistance have been observed in a small portion of patients.

PRECAUTIONS

Cluster Headache

There is insufficient information on the efficacy and safety of sumatriptan succinate in the treatment of cluster headache, which is present in an older, predominantly male population. The need for prolonged use and the demand for repeated medication in this condition renders the dosing information inapplicable for cluster headache.

Cardiovascular

Discomfort in the chest, neck, throat and jaw (including pain, pressure, heaviness and tightness) has been reported after administration of sumatriptan succinate. Because 5-HT₁ agonists may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following Ava-Sumatriptan should be evaluated for the presence of CAD or a predisposition to variant angina before receiving additional doses, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud’s syndrome following sumatriptan succinate should be evaluated for atherosclerosis or predisposition to vasospasm (see CONTRAINDICATIONS and WARNINGS).

Neurological Conditions

Care should be taken to exclude other potentially serious neurologic conditions before treating headache in patients not previously diagnosed with migraine headache or who experience a headache that is atypical for them. There have been rare reports where patients received 5-HT₁ agonists for severe headaches that were subsequently shown to have been secondary to an evolving neurologic lesion. For newly diagnosed patients or patients presenting with atypical symptoms, the diagnosis of migraine should be reconsidered if no response is seen after the first dose of Ava-Sumatriptan.

Seizures

Caution should be observed if Ava-Sumatriptan is to be used in patients with a history of epilepsy or structural brain lesions which lower the convulsion threshold.

Psychomotor Impairment

Patients should be cautioned that drowsiness may occur as a result of treatment with Ava-Sumatriptan. They should be advised not to perform skilled tasks (e.g. driving or operating machinery) if drowsiness occurs.

Renal Impairment

The effects of renal impairment on the efficacy and safety of sumatriptan succinate have not been evaluated. Therefore Ava-Sumatriptan is not recommended in this patient population.

Hepatic Impairment

The effect of hepatic impairment on the efficacy and safety of sumatriptan succinate has not been evaluated, however, the pharmacokinetic profile of sumatriptan in patients with moderate¹ hepatic impairment shows that these patients, following an oral dose of 50 mg, have much higher plasma sumatriptan concentrations than healthy subjects (Table 6). Therefore, an oral dose of 25 mg may be considered in patients with hepatic impairment. Please note, Ava-Sumatriptan does not exist in a 25 mg strength

Table 6: Pharmacokinetic Parameters After Oral Administration of

Sumatriptan Succinate 50 mg to Healthy Volunteers and

¹Assessed by aminopyrine breath test (>0.2-0.4 scaling units.)

Moderately Hepatically Impaired Patients

* Statistically significant

Drug Interactions

Single dose pharmacokinetic drug interaction studies have not shown evidence of interactions with propranolol, flunarizine, pizotifen or alcohol. Multiple dose interaction studies have not been performed.

Ergot-Containing Drugs

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis for these effects being additive, ergot-containing or ergot-type medications (like dihydroergotamine or methysergide) are contraindicated within 24 hours of Ava-Sumatriptan administration (see CONTRAINDICATIONS).

MAO Inhibitors

In studies conducted in a limited number of patients, MAO inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of Ava-Sumatriptan in patients receiving MAO inhibitors is contraindicated (see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY).

Other Serotonergic Drugs

Rare postmarketing reports describe patients with weakness, hyperreflexia, and incoordination following the combined use of selective serotonin reuptake inhibitor (SSRI) and 5-HT₁ agonists. If concomitant treatment with Ava-Sumatriptan and an SSRI (e.g. fluoxetine, fluvoxamine, paroxetine, sertraline), tricyclic antidepressant, or other drug with serotonergic activity is clinically warranted, appropriate observation of the patient for acute and long-term adverse events is advised.

Other 5-HT₁ agonists

The administration of sumatriptan succinate with other 5-HT₁ agonists has not been evaluated in migraine patients. As an increased risk of coronary vasospasm is a theoretical possibility with coadministration of 5-HT₁ agonists, use of these drugs within 24 hours of each other is contraindicated.

Drug/Laboratory Test Interactions

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

Use in Elderly (>65 years)

Experience of the use of sumatriptan succinate in patients aged over 65 years is limited. Therefore the use of Ava-Sumatriptan in patients over 65 years is not recommended.

Use in Children (<18 years)

The safety and efficacy of sumatriptan succinate in children has not been established and its use in this age group is not recommended.

Use in Pregnancy

Reproduction studies, performed in rats, have not revealed any evidence of impaired fertility, teratogenicity, or postnatal development due to sumatriptan succinate. Reproduction studies, performed in rabbits by the oral route, have shown increased incidence of variations in cervicothoracic blood vessel configuration in the fœtuses. These effects were only seen at the highest dose tested, which affected weight gain in the dams, and at which blood levels were in excess of 50 times those seen in humans after therapeutic doses. A direct association with sumatriptan succinate treatment is considered unlikely but cannot be excluded. Therefore, the use of Ava-Sumatriptan is not recommended in pregnancy.

In a rat fertility study, oral doses of sumatriptan succinate resulting in plasma levels approximately 150 times those seen in humans after a 6 mg subcutaneous dose and approximately 200 times those seen in humans after a 100 mg oral dose were associated with a reduction in the success of insemination. This effect did not occur during a subcutaneous study where maximum plasma levels achieved approximately 100 times those in humans by the subcutaneous route and approximately 150 times those in humans by the oral route.

Lactation

Sumatriptan is excreted in human breast milk. Therefore, caution is advised when administering Ava-Sumatriptan to nursing women. Infant exposure can be minimized by avoiding breast feeding for 24 hours after treatment.

Binding to Melanin Containing Tissues

In rats treated with a single subcutaneous dose (0.5 mg/kg) or oral dose (2 mg/kg) of radiolabeled sumatriptan, the elimination half-life of radioactivity from the eye was 15 and 23 days, respectively, suggesting that sumatriptan and/or its metabolites bind to the melanin of the eye. Because there could be an accumulation in melanin rich tissues over time, this raises the possibility that sumatriptan could cause toxicity in these tissues after extended use. However, no effects on the retina related to treatment with sumatriptan were noted in any of the oral toxicity studies. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term opthalmologic effects.

Laboratory Tests

No specific laboratory tests are recommended for monitoring patients prior to and/or after treatment with Ava-Sumatriptan.

ADVERSE REACTIONS

Serious cardiac events, including some that have been fatal, have occurred following the use of 5-HT₁ agonists. These events are extremely rare and most 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).

Experience in Controlled Clinical Trials with Sumatriptan Succinate Typical 5-HT₁ Agonist Adverse Reactions: As with other 5-HT₁ agonists, sumatriptan succinate has been associated with sensations of heaviness, pressure, tightness or pain which may be intense. These may occur in any part of the body including the chest, throat, neck, jaw and upper limb.

Acute Safety

In placebo-controlled migraine trials, 3 095 patients received at least one dose of sumatriptan succinate. The following table (Table 7) lists adverse events occurring in these trials at an incidence of 1% or more that occurred at a higher incidence than in the placebo groups.

Table 7: Treatment-Emergent Adverse Events in Oral Placebo-Controlled Clinical

Trials Reported by at Least 1% of Patients with Migraine

•Head/Face Sensations* 1.3% 2.3% 2.5% 4.7%

* The term “sensations” encompasses adverse events described as pain & discomfort, pressure, heaviness, constriction, tightness, heat/burning sensation, paresthesia, numbness, tingling, and strange sensations. ** Includes patients receiving up to 3 doses of 100 mg

NR Not Reported

Sumatriptan succinate is generally well tolerated. Most of the events were transient in nature and resolved within 2 hours of oral administration.

Minor disturbances of liver function tests have occasionally been observed with sumatriptan treatment. There is no evidence that clinically significant abnormalities occurred more frequently with sumatriptan than with placebo.

Patients treated with sumatriptan succinate rarely exhibit visual disorders like flickering and diplopia. Additionally cases of nystagmus, scotoma and reduced vision have been observed. Very rarely a transient loss of vision has been reported. However, visual disorders may also occur during a migraine attack itself.

SYMPTOMS AND TREATMENT OF OVERDOSE

There have been some reports of overdosage with sumatriptan succinate. Doses of up to 400 mg were not associated with side effects other than those mentioned.

If overdosage with Ava-Sumatriptan occurs, the patient should be monitored and standard supportive treatment applied as required. Toxicokinetics are not available.

The effect of hæmodialysis or peritoneal dialysis on the serum concentration of sumatriptan succinate is unknown.

DOSAGE AND ADMINISTRATION

General

Ava-Sumatriptan (sumatriptan succinate) is indicated for the acute treatment of migraine headache with or without aura. Sumatriptan should not be used prophylactically. The safety of treating an average of more than four headaches in a 30 day period has not been established.

Significant relief begins about 30 minutes following oral administration.

In addition to relieving the pain of migraine, sumatriptan has also been shown to be effective in relieving associated symptoms of migraine (nausea, vomiting, phonophobia, photophobia). Sumatriptan is equally effective when administered at any stage of a migraine attack. Long-term (12-24 months) clinical studies with maximum recommended doses of sumatriptan indicate that there is no evidence of the development of tachyphylaxis, or medication-induced (rebound) headache.

The minimal effective single adult dose of sumatriptan succinate tablets is 25 mg. However, Ava-Sumatriptan is not available in the 25 mg strength. The maximum recommended single dose is 100 mg.

The optimal dose is a single 50 mg tablet. However, depending on individual patient’s needs and response to treatment, some patients may require 100 mg.

Clinical trials have shown that approximately 50-75% of patients have headache relief within two hours after oral dosing with 100 mg, and that a further 15-25% have headache relief by 4 hours. Comparator studies have shown similar efficacy rates with the 50 mg and 100 mg tablets. There is evidence that doses of 50 and 100 mg may provide greater effect than 25 mg.

If the migraine headache returns, or if a patient has a partial response to the initial dose, the dose may be repeated after 2 hours. Not more than 200 mg should be taken in any 24 hour period.

If a patient does not respond to the first dose of Ava-Sumatriptan tablets, a second dose should not be taken for the same attack, as it is unlikely to be of clinical benefit. Ava-Sumatriptan may be taken to treat subsequent migraine attacks.

The tablet should be swallowed whole with water, not crushed, chewed or split.

Hepatic Impairment

In patients with mild or moderate hepatic impairment, plasma sumatriptan concentrations up to two times those seen in healthy subjects have been observed. Therefore, a 25 mg dose may be considered in these patients (see PRECAUTIONS). Please note, Ava-Sumatriptan does not exist in a 25 mg strength. Sumatriptan should not be administered to patients with severe hepatic impairment (see CONTRAINDICATIONS).

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper Name: sumatriptan succinate (Ph.Eur.)

Chemical Name: 3-[2-(dimethyl amino)ethyl]-N-methyl– indole-5-methane sulphonamide, succinate (1:1)

Structural Formula:

Molecular Formula: C₁₄H₂₁N₃O₂S · C₄H₆O₄

Molecular Weight: 413.5

Physical Characteristics: White to off-white powder with a melting point between 164.6°-

165.5°C. Solubility:

pH and pKa: The pH of a 1% w/v solution of sumatriptan succinate in water is approximately 4.9. pKa₁ (succinic acid) = 4.21, 5.67

pKa₂ (3°amine group) = 9.63

pKa₃ (sulphonamide group) = >12

Partition Coefficient (between n-octanol and water): Log P = 1.07 at a pH of 10.7

N H₃CNHSO₂H₂C CH2CH2N(CH3)2

CH2COOH CH2COOH H

COMPOSITION

Ava-Sumatriptan tablets contain 100 mg or 50 mg sumatriptan (base) as the succinate salt. Ava-Sumatriptan tablets also contain ferric oxide red and yellow (100 mg only), lactose monohydrate, carboxymethylcellulose sodium, grapefruit flavour (contains maltodextrin and natural and artificial flavours), microcrystalline cellulose, crosscarmellose sodium, magnesium stearate and ammonio methacrylate copolymer type A.

STABILITY AND STORAGE RECOMMENDATIONS

Ava-Sumatriptan tablets should be stored between 15 and 30°C.

AVAILABILITY OF DOSAGE FORMS

Ava-Sumatriptan tablets are available as white triangular, biconvex tablets embossed “RXP” on one side and plain on the other ( 50 mg) and pink triangular, biconvex tablets embossed “RXP” on one side and plain on the other (100 mg). They are packaged in blister packs containing 6 tablets.