1 contains rizatriptan benzoate, a selective
5-hydroxytryptamine1B/1D (5-HT1B/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.
Registered trademark of MERCK & CO., Inc. COPYRIGHT © 1998,
2006 MERCK & CO., Inc. All rights reserved
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
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 AUC0-âˆž and
Cmax of rizatriptan (10 mg orally) were about 30% and 11%
higher in females as compared to males, respectively, while Tmax 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 AUC0-âˆž 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.
Race: Pharmacokinetic data revealed no significant
differences between African American and Caucasian subjects.
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
Cmax 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
* p value less than 0.05 in comparison with placebo
â€ p value less than 0.05 in comparison with 5 mg
â€¡ Results for initial headache only.
Comparisons of drug performance based upon results obtained
in different clinical trials are never reliable. Because studies are conducted
at different times, with different samples of patients, by different
investigators, employing different criteria and/or different interpretations of
the same criteria, under different conditions (dose, dosing regimen, etc.),
quantitative estimates of treatment response and the timing of response may be
expected to vary considerably from study to study.
The estimated probability of achieving an initial headache response within 2
hours following treatment is depicted in Figure 1.
Figure 1: Estimated Probability of Achieving an
Initial Headache Response by 2 Hours† â€
For patients with migraine-associated photophobia, phonophobia, and nausea at
baseline, there was a decreased incidence of these symptoms following
administration of MAXALT compared to placebo.
Two to 24 hours following the initial dose of study treatment, patients were
allowed to use additional treatment for pain response in the form of a second
dose of study treatment or other medication. The estimated probability of
patients taking a second dose or other medication for migraine over the 24 hours
following the initial dose of study treatment is summarized in Figure 2.
Figure 2: Estimated Probability of Patients Taking a
Second Dose of MAXALT Tablets or Other Medication for Migraines Over the 24
Hours Following the Initial Dose of Study Treatment† â€ â€
Efficacy was unaffected by the presence of aura; by the gender, or age of the
patient; or by concomitant use of common migraine prophylactic drugs (e.g.,
beta-blockers, calcium channel blockers, tricyclic antidepressants) or oral
contraceptives. In two additional similar studies, efficacy was unaffected by
relationship to menses. There were insufficient data to assess the impact of
race on efficacy.
In a single study in adolescents (n=291), there were no statistically
significant differences between treatment groups. The headache response rates at
2 hours were 66% and 56% for MAXALT 5 mg Tablets and placebo,
Table 2: Response Rates 2 Hours Following Treatment of Initial Headache