Maxalt-Mlt (Rizatriptan Benzoate) - Description and Clinical Pharmacology

DESCRIPTION

1 contains rizatriptan benzoate, a selective 5-hydroxytryptamine_1B/1D (5-HT_1B/1D) receptor agonist.

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

Its empirical formula is C₁₅H₁₉N₅•C₇H₆O₂, representing a molecular weight of the free base of 269.4. Rizatriptan benzoate is a white to off-white, crystalline solid that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C.

MAXALT Tablets and MAXALT-MLT 1 Orally Disintegrating Tablets are available for oral administration in strengths of 5 and 10 mg (corresponding to 7.265 mg or 14.53 mg of the benzoate salt, respectively). Each compressed tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, ferric oxide (red), and magnesium stearate.

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

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Registered trademark of MERCK & CO., Inc. COPYRIGHT © 1998, 2006 MERCK & CO., Inc. All rights reserved

CLINICAL PHARMACOLOGY

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

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).

Gender: The mean AUC_0-∞ and C_max of rizatriptan (10 mg orally) were about 30% and 11% higher in females as compared to males, respectively, while T_max occurred at approximately the same time.

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

Renal impairment: In patients with renal impairment (creatinine clearance 10-60 mL/min/1.73 m²), the AUC_0-∞ of rizatriptan was not significantly different from that in healthy subjects. In hemodialysis patients, (creatinine clearance less than 2 mL/min/1.73 m²), however, the AUC for rizatriptan was approximately 44% greater than that in patients with normal renal function. (See PRECAUTIONS.)

Race: Pharmacokinetic data revealed no significant differences between African American and Caucasian subjects.

PRECAUTIONS, Drug Interactions.)

Monoamine oxidase inhibitors: Rizatriptan is principally metabolized via monoamine oxidase, "A" subtype (MAO-A). Plasma concentrations of rizatriptan may be increased by drugs that are selective MAO-A inhibitors (e.g., moclobemide) or nonselective MAO inhibitors [type A and B] (e.g., isocarboxazid, phenelzine, tranylcypromine, and pargyline). In a drug interaction study, when MAXALT 10 mg was administered to subjects (n=12) receiving concomitant therapy with the selective, reversible MAO-A inhibitor, moclobemide 150 mg t.i.d., there were mean increases in rizatriptan AUC and C_max of 119% and 41% respectively; and the AUC of the active N-monodesmethyl metabolite of rizatriptan was increased more than 400%. The interaction would be expected to be greater with irreversible MAO inhibitors. No pharmacokinetic interaction is anticipated in patients receiving selective MAO-B inhibitors. (See CONTRAINDICATIONS; PRECAUTIONS, Drug Interactions.)

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

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

Paroxetine: In a study of the interaction between the selective serotonin reuptake inhibitor (SSRI) paroxetine 20 mg/day for two weeks and a single dose of MAXALT 10 mg in healthy subjects (n=12), neither the plasma concentrations of rizatriptan nor its safety profile were affected by paroxetine (see WARNINGS and PRECAUTIONS, Information for Patients).

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

Table 1: Response Rates 2 Hours Following Treatment of Initial Headache