maxalt

DESCRIPTION
MAXALT * contains rizatriptan benzoate, a selective 5-hydroxytryptamine 1B/1D(5-HT 1B/1D ) receptor agonist maxalt.

Rizatriptan benzoate is described chemically as: N,N -dimethyl-5-(1 H -1,2,4-triazol-1-ylmethyl)-1H -indole-3-ethanamine monobenzoate and its structural formula is:

Its empirical formula is C 15 H 19 N 5 ·C 7 H 6 O 2 , representing amolecular weight of the free base of 269.4 maxalt. Rizatriptan benzoate is a whiteto off-white, crystalline solid that is soluble in water at about 42 mg permL (expressed as free base) at 25°C maxalt.

MAXALT Tablets and MAXALT-MLT * Orally Disintegrating Tablets are availablefor oral administration in strengths of 5 and 10 mg (corresponding to 7.265mg or 14.53 mg of the benzoate salt, respectively) maxalt. Each compressed tablet containsthe following inactive ingredients: lactose monohydrate, microcrystalline cellulose,pregelatinized starch, ferric oxide (red), and magnesium stearate maxalt.

Each lyophilized orally disintegrating tablet contains the following inactiveingredients: gelatin, mannitol, glycine, aspartame, and peppermint flavor maxalt.

CLINICAL PHARMACOLOGY
Mechanism of Action

Rizatriptan binds with high affinity to human cloned 5-HT 1B and 5-HT 1D receptors maxalt. Rizatriptan has weak affinity for other 5-HT 1 receptor subtypes (5-HT 1A ,5-HT 1E , 5-HT 1F ) and the 5-HT 7 receptor, but has no significant activityat 5-HT 2 , 5-HT 3 , alpha- and beta-adrenergic, dopaminergic, histaminergic,muscarinic or benzodiazepine receptors maxalt.

Current theories on the etiology of migraine headache suggest that symptomsare due to local cranial vasodilatation and/or to the release of vasoactiveand pro-inflammatory peptides from sensory nerve endings in an activated trigeminalsystem maxalt. The therapeutic activity of rizatriptan in migraine can most likelybe attributed to agonist effects at 5-HT 1B/1D receptors on the extracerebral,intracranial blood vessels that become dilated during a migraine attack andon nerve terminals in the trigeminal system maxalt. Activation of these receptors resultsin cranial vessel constriction, inhibition of neuropeptide release and reducedtransmission in trigeminal pain pathways maxalt.

Pharmacokinetics

Rizatriptan is completely absorbed following oral administration maxalt. The meanoral absolute bioavailability of the MAXALT Tablet is about 45%, and mean peakplasma concentrations (C max ) are reached in approximately 1-1.5 hours (T max) maxalt. The presence of a migraine headache did not appear to affect the absorptionor pharmacokinetics of rizatriptan maxalt. Food has no significant effect on the bioavailabilityof rizatriptan but delays the time to reach peak concentration by an hour maxalt. Inclinical trials, MAXALT was administered without regard to food maxalt. The plasmahalf-life of rizatriptan in males and females averages 2-3 hours maxalt.

The bioavailability and C max of rizatriptan were similar following administrationof MAXALT Tablets and MAXALT-MLT Orally Disintegrating Tablets, but the rateof absorption is somewhat slower with MAXALT-MLT, with T max averaging 1.6-2.5hours maxalt. AUC of rizatriptan is approximately 30% higher in females than in males maxalt. No accumulation occurred on multiple dosing maxalt.

The mean volume of distribution is approximately 140 liters in male subjectsand 110 liters in female subjects maxalt. Rizatriptan is minimally bound (14%) to plasmaproteins maxalt.

The primary route of rizatriptan metabolism is via oxidative deamination bymonoamine oxidase-A (MAO-A) to the indole acetic acid metabolite, which is notactive at the 5-HT 1B/1D receptor maxalt. N-monodesmethyl-rizatriptan, a metabolitewith activity similar to that of parent compound at the 5-HT 1B/1D receptor,is formed to a minor degree maxalt. Plasma concentrations of N-monodesmethyl-rizatriptanare approximately 14% of those of parent compound, and it is eliminated at asimilar rate maxalt. Other minor metabolites the N-oxide, the 6-hydroxy compound, andthe sulfate conjugate of the 6-hydroxy metabolite are not active at the 5-HT1B/1D receptor maxalt.

The total radioactivity of the administered dose recovered over 120 hours inurine and feces was 82% and 12%, respectively, following a single 10 mg oraladministration of 14 C-rizatriptan maxalt. Following oral administration of 14 C-rizatriptan,rizatriptan accounted for about 17% of circulating plasma radioactivity maxalt. Approximately14% of an oral dose is excreted in urine as unchanged rizatriptan while 51%is excreted as indole acetic acid metabolite, indicating substantial first passmetabolism maxalt.

Cytochrome P450 Isoforms: Rizatriptan is not an inhibitor of the activitiesof human liver cytochrome P450 isoforms 3A4/5, 1A2, 2C9, 2C19, or 2E1; rizatriptanis a competitive inhibitor (Ki=1400 nM) of cytochrome P450 2D6, but only athigh, clinically irrelevant concentrations maxalt.

Special Populations

Age: Rizatriptan pharmacokinetics in healthy elderly non-migraineur volunteers(age 65-77 years) were similar to those in younger non-migraineur volunteers(age 18-45 years) maxalt.

Gender: The mean AUC 0-(infinity) and C max of rizatriptan (10 mg orally) wereabout 30% and 11% higher in females as compared to males, respectively, whileT max occurred at approximately the same time maxalt.

Hepatic impairment: Following oral administration in patients with hepaticimpairment caused by mild to moderate alcoholic cirrhosis of the liver, plasmaconcentrations of rizatriptan were similar in patients with mild hepatic insufficiencycompared to a control group of healthy subjects; plasma concentrations of rizatriptanwere approximately 30% greater in patients with moderate hepatic insufficiency maxalt. (See PRECAUTIONS .)

Renal impairment: In patients with renal impairment (creatinine clearance 10-60mL/min/1.73 m 2 ), the AUC 0-(infinity) of rizatriptan was not significantlydifferent from that in healthy subjects maxalt. In hemodialysis patients, (creatinineclearance < 2 mL/min/1.73 m 2 ), however, the AUC for rizatriptan was approximately44% greater than that in patients with normal renal function maxalt. (See PRECAUTIONS.)

Race: Pharmacokinetic data revealed no significant differences between AfricanAmerican and Caucasian subjects maxalt.

Drug Interactions (See also PRECAUTIONS , Drug Interactions .)

Monoamine oxidase inhibitors: Rizatriptan is principally metabolized via monoamineoxidase, `A' subtype (MAO-A) maxalt. Plasma concentrations of rizatriptan may be increasedby drugs that are selective MAO-A inhibitors (e.g., moclobemide) or nonselectiveMAO inhibitors [type A and B] (e.g., isocarboxazid, phenelzine, tranylcypromine,and pargyline) maxalt. In a drug interaction study, when MAXALT 10 mg was administeredto subjects (n=12) receiving concomitant therapy with the selective, reversibleMAO-A inhibitor, moclobemide 150 mg t.i.d., there were mean increases in rizatriptanAUC and C max of 119% and 41% respectively; and the AUC of the active N-monodesmethylmetabolite of rizatriptan was increased more than 400% maxalt. The interaction wouldbe expected to be greater with irreversible MAO inhibitors maxalt. No pharmacokineticinteraction is anticipated in patients receiving selective MAO-B inhibitors maxalt. (See CONTRAINDICATIONS ; PRECAUTIONS , Drug Interactions .)

Propranolol: In a study of concurrent administration of propranolol 240 mg/dayand a single dose of rizatriptan 10 mg in healthy subjects (n=11), mean plasmaAUC for rizatriptan was increased by 70% during propranolol administration,and a fourfold increase was observed in one subject maxalt. The AUC of the active N-monodesmethylmetabolite of rizatriptan was not affected by propranolol maxalt. (See PRECAUTIONS; DOSAGE AND ADMINISTRATION .)

Nadolol/Metoprolol: In a drug interactions study, effects of multiple dosesof nadolol 80 mg or metoprolol 100 mg every 12 hours on the pharmacokineticsof a single dose of 10 mg rizatriptan were evaluated in healthy subjects (n=12) maxalt. No pharmacokinetic interactions were observed maxalt.

Paroxetine: In a study of the interaction between the selective serotonin reuptakeinhibitor (SSRI) paroxetine 20 mg/day for two weeks and a single dose of MAXALT10 mg in healthy subjects (n=12), neither the plasma concentrations of rizatriptannor its safety profile were affected by paroxetine maxalt.

Oral contraceptives: In a study of concurrent administration of an oral contraceptiveduring 6 days of administration of MAXALT (10-30 mg/day) in healthy female volunteers(n=18), rizatriptan did not affect plasma concentrations of ethinyl estradiolor norethindrone maxalt.

Clinical Studies

The efficacy of MAXALT Tablets was established in four multicenter, randomized,placebo-controlled trials maxalt. Patients enrolled in these studies were primarilyfemale (84%) and Caucasian (88%), with a mean age of 40 years (range of 18 to71) maxalt. Patients were instructed to treat a moderate to severe headache maxalt. Headacheresponse, defined as a reduction of moderate or severe headache pain to no ormild headache pain, was assessed for up to 2 hours (Study 1) or up to 4 hoursafter dosing (Studies 2, 3 and 4) maxalt. Associated symptoms of nausea

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