Zolminap

Each spray delivers:

Zolmitriptan   5 mg
Composition:

Zolmitriptan………………5.00% w/v

Benzalkonium chloride    BP 0.01% w/v (as preservative)

Excipient       q.s.

CHEMISTRY:

(4s)-4{ [3-(2-dimethylami noethyl)-1H-indo1-5- yl]methyll-1,1-oxazolidin-2-one.

CATEGORY: Antimigraine Preparations

PHARMACOLOGY

PHARMACODYNAMICS:

Zolmitriptan binds with high affinity to human recombinant 5-HT1D and 5-HT1B receptors. The therapeutic activity of zolmitriptan for the treatment of migraine headache can most likely be attributed to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arteriovenous anastomoses) and sensory nerves of the trigeminal system which resuft in cranial vessel constriction and inhibition of proinflammatory neuropeptide release.

PHARMACOKINETICS:

Absorption:

Zolmitriptan nasal spray is rapidly absorbed via the nasopharynx. Plasma concentrations of zolmitriptan are sustained for 4 to 6 hours after dosing. The mean relative bioavailability of the nasal spray formulation is 102%. Food has no significant effect on the bioavailability of zolmitriptan.

Distribution:

Plasma protein binding of zolmitriptan is 25% over the concentration range of 10-1000 ng/mL.

Metabolism:

Zolmitriptan is converted to an active N-desmethyl metabolite such that the metabolite concentrations are about two-thirds that of zolmitriptan. Because the 5HT1B/1D potency of the metabolite is 2 to 6 times that of the parent compound, the metabolite may contribute a substantial portion of the overall effect afterzolmitriptan administration.

Excretion:

The mean elimination half-life for zolmitriptan and its active N-desmethyl metabolite following nasal spray administration are approximately 3 hours. The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion.

INDICATIONS:

Acute Treatment of Migraine Attacks

Zolmitriptan nasal spray is indicated for the acute treatment of migraine with orwithout aura in adults.

Important Limitations

Zolmitriptan nasal spray should only be used where a clear diagnosis of migraine has been established. If a patient has no response for the first migraine attack treated with Zolmitriptan nasal spray, the diagnosis of migraine should be reconsidered before Zolmitriptan nasal spray is administered to treat any subsequent attacks.

DOSAGE AND ADMINISTRATION:

Acute Treatment of Migraine Attacks

Administer one dose of Zolmitriptan nasal spray 5 mg for the treatment of acute migraine. If the headache returns, the dose may be repeated after 2 hours. The maximum daily dose should not exceed 10 mg in any 24-hour period.

The safety of treating an average of more than four headaches in a 30-day period has not been established.

Hepatic Impairment

Patients with moderate to severe hepatic impairment have decreased clearance of zolmitriptan and significant elevation in blood pressure has been reported in some patients. Use of doses less than 2.5mg of an alternate formulation with blood pressure monitoring is recommended.

CONTRAINDICATIONS:

Ischemic or Vasospastic Coronary Artery Disease Zolmitriptan nasal spray should not be given to patients with ischemic heart or to patients who have symptoms or with ischemic heart disease, coronary artery vasospasm, including Prinzmetal’s variant angina, or other significant underlying cardiovascular disease.

Cerebrovascular Syndromes

Zolmitriptan nasal spray should not be given to patients with cerebrovascular syndromes including (but not limited to) stroke of any type as well as transient ischemic attacks.

Peripheral Vascular Disease

Zolmitriptan nasal spray should not be given to patients with peripheral vascular disease including (but not limited to) ischemic bowel disease.

Uncontrolled Hypertension

Because Zolmitriptan nasal spray may increase blood pressure, it should not be given to patients with uncontrolled hypertension.

Use within 24 hours of treatment with another 5- HT1 agonist, or ergotamine containing medication, or ergot type medication

Zolmitriptan nasal spray and any ergotamine­containing or ergot-type medication should not be used within 24 hours of each other, nor should Zolmitriptan nasal spray and another 5-HT1 agonist be used within 24 hours of each other.

Hemiplegic or Basilar Migraine

Zolmitriptan nasal spray should not be administered to patients with hemiplegic or basilar migraine.

Administration of MAO-A inhibitors within 2 weeks Concurrent administration of MAO-A inhibitors or use of zolmitriptan within 2 weeks of discontinuation of MAO-A inhibitor therapy is contraindicated.

WARNINGS AND PRECAUTIONS:

Zolmitriptan nasal srpay 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

Cardiac Events and Fatalities with 5-HT1 Agonists

Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following administration of zolmitriptan.

Patients with documented coronary artery disease

Because of the potential of this class of compound (5-HT1 agonists) to cause coronary vasospasm, Zolmitriptan nasal spray should not be given to patients with documented ischemic or vasospastic coronary artery disease.

Patients with risk factors for CAD

It is strongly recommended that zolmitriptan not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors 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.

Serotonin Syndrome

If concomitant treatment with Zolmitriptan nasal spray and an SSRI is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

DRUG INTERACTIONS:

Xylometazoline: Administered 30 minutes prior to a 5 mg nasal dose of zolmitriptan did not atter the pharmacokinetics of zolmitriptan.

Fluoxetine: The pharmacokinetics of zolmitriptan, as well as its effect on blood pressure, were unaffected by 4 weeks of pre-treatment with oral fluoxetine (20 mg/day).

Propranolol: There were no interactive effects on blood pressure or pulse rate following administration of propranolol with zolmitriptan.

Acetaminophen: A single 1 g dose of acetaminophen does not alter the pharmacokinetics of zolmitriptan and its N­desmethyl metabolite.

Metoclopramide: A single 10 mg dose of metoclopramide had no effect on the pharmacokinetics of zolmitriptan or its metabolites.

Cimetidine: Following the administration of cimetidine, the half-life and AUC of a 5 mg dose of zolmitriptan and its active metabolite were approximately doubled

PREGNANCY AND LACTATION:

Pregnancy

PregnancyCategory C.

There are no adequate and well controlled studies in pregnant women; therefore, zolmitriptan should be used during pregnancy only if the potential benefit justifies the potential ris kto the fetus.

Nursing Mothers

It is not known whether zolmitriptan is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when zolmitriptan is administered to a nursing woman.

SPECIAL POPULATION

Pediatric Use

Safety and effectiveness of Zolmitriptan nasal spray in pediatric patients have not been established; therefore, Zolmitriptan nasal spray is not recommended for use in patients under 18 years of age.

Geriatric Use

Although the pharmacokinetic disposition of the drug in the elderly is similar to that seen in younger adutts, there is no information about the safety and effectiveness of zolmitriptan in this patients population overthe age of 65.

Hepatic Impairment

Because of the similarity in exposure, zolmitriptan tablets and nasal spray should have similar dosage adjustments and should be administered with

caution in subjects with liver disease, generally using doses less than 2.5 mg. Doses lower than 5 mg can only be achieved through the use of an oral formulation.

Effect to Drive & Use the Machine: Use is unlikely to result in an impairment of the ability of patients to drive or operate machinery. However it should be taken into accountthat somnolence may occur.

ADVERSE DRUG REACTIONS:

The most common adverse reactions reported are: unusual taste, paresthesia, hyperesthesia, nausea, pain location specified, pain throat, somnolence, asthenia, disorder/discomfort of nasal cavity, dry mouth, tightness throat

OVERDOSAGE:

There are no reports with acute overdose. Clinical study reports with single 50 mg oral doses of zolmitriptan commonly experienced sedation. The elimination half-life of Zolmitriptan nasal spray is 3 hours and therefore monitoring of patients after overdose with Zolmitriptan nasal spray should continue for at least 15 hours or while symptoms or signs persist.

There is no specific antidote to zolmitriptan. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system. It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of zolmitriptan.

PRESENTATION:

15 metered doses [2 ml]

STORAGE: Store in a dry place below 30°C.

Keep out of reach of children.