Maxalt (Rizatriptan Benzoate): Side Effects, Interactions, Warning, Dosage & Uses

Rizatriptan binds with high affinity to human cloned 5-HT1B/1D
receptors. MAXALT presumably exerts its therapeutic effects in the treatment of
migraine headache by binding to 5-HT1B/1D receptors located on intracranial
blood vessels and sensory nerves of the trigeminal system.

Rizatriptan is completely absorbed following oral
administration. The mean oral absolute bioavailability of the MAXALT Tablet is
about 45%, and mean peak plasma concentrations (Cmax) are reached in approximately
1-1.5 hours (Tmax). The presence of a migraine headache did not appear to
affect the absorption or pharmacokinetics of rizatriptan. Food has no
significant effect on the bioavailability of rizatriptan but delays the time to
reach peak concentration by an hour. In clinical trials, MAXALT was administered
without regard to food.

The bioavailability and Cmax of rizatriptan were similar
following administration of MAXALT Tablets and MAXALT-MLT Orally Disintegrating
Tablets, but the rate of absorption is somewhat slower with MAXALT-MLT, with Tmax
delayed by up to 0.7 hour. AUC of rizatriptan is approximately 30% higher in
females than in males. No accumulation occurred on multiple dosing.

The mean volume of distribution is approximately 140
liters in male subjects and 110 liters in female subjects. Rizatriptan is
minimally bound (14%) to plasma proteins.

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

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

The plasma half-life of rizatriptan in males and females
averages 2-3 hours.

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.

Special Populations

Geriatric: 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).

Pediatric: The pharmacokinetics of rizatriptan was
determined in pediatric migraineurs 6 to 17 years of age. Exposures following
single dose administration of 5 mg MAXALT-MLT to pediatric patients weighing
20-39 kg (44-87 lb) or 10 mg MAXALT-MLT to pediatric patients weighing
≥40 kg (88 lb) were similar to those observed following single dose
administration of 10 mg MAXALT-MLT to adults.

Gender: The mean AUC0-∞ 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
subjects with normal hepatic function; plasma concentrations of rizatriptan
were approximately 30% greater in patients with moderate hepatic insufficiency.

Renal impairment: In patients with renal
impairment (creatinine clearance 10-60 mL/min/1.73 m²), the AUC AUC0-∞ of
rizatriptan was not significantly different from that in subjects with normal
renal function. In hemodialysis patients, (creatinine clearance < 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.

[See also 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 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
and DRUG INTERACTIONS].

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

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, DRUG INTERACTIONS, and PATIENT INFORMATION].

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.

Clinical Studies

The efficacy of MAXALT Tablets was established in four
multicenter, randomized, placebo-controlled trials. Patients enrolled in these
studies were primarily female (84%) and Caucasian (88%), with a mean age of 40
years (range of 18 to 71). Patients were instructed to treat a moderate to
severe headache. Headache response, defined as a reduction of moderate or
severe headache pain to no or mild headache pain, was assessed for up to 2
hours (Study 1) or up to 4 hours after dosing (Studies 2, 3 and 4). Associated
symptoms of nausea, photophobia, and phonophobia and maintenance of response up
to 24 hours post-dose were evaluated. A second dose of MAXALT Tablets was
allowed 2 to 24 hours after dosing for treatment of recurrent headache in
Studies 1 and 2. Additional analgesics and/or antiemetics were allowed 2 hours
after initial treatment for rescue in all four studies.

In all studies, the percentage of patients achieving
headache response 2 hours after treatment was significantly greater in patients
who received either MAXALT 5 or 10 mg compared to those who received placebo.
In a separate study, doses of 2.5 mg were not different from placebo. Doses
greater than 10 mg were associated with an increased incidence of adverse
effects. The results from the four controlled studies are summarized in Table
2.

Table 2: Response Rates 2 Hours Following Treatment of
Initial Headache in Studies 1, 2, 3, and 4

Study Placebo MAXALT Tablets 5 mg MAXALT Tablets 10 mg
1 35% (n=304) 62%* (n=458) 71%*,† (n=456)
2* 37% (n=82) 77%* (n=320)
3 23% (n=80) 63%* (n=352)
4 40% (n=159) 60%* (n=164) 67%* (n=385)
*p-value < 0.05 in comparison with placebo.
†p-value < 0.05 in comparison with 5 mg.
‡Results for initial headache only.

Comparisons of drug performance based upon results
obtained in different clinical trials may not be 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 in pooled Studies 1, 2, 3,
and 4 is depicted in Figure 1.

Figure 1: Estimated Probability of Achieving an
Initial Headache Response by 2 Hours in Pooled Studies 1, 2, 3, and 4*

*Figure 1 shows the Kaplan-Meier plot of the probability
over time of obtaining headache response (no or mild pain) following treatment
with MAXALT or placebo. The averages displayed are based on pooled data from 4 placebo-controlled,
outpatient trials providing evidence of efficacy (Studies 1, 2, 3, and 4 ).
Patients taking additional treatment or not achieving headache response prior
to 2 hours were censored at 2 hours.

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 in Pooled Studies 1, 2, 3, and 4*

*This Kaplan-Meier plot is based on data obtained in 4
placebo-controlled outpatient clinical trials (Studies 1, 2, 3, and 4 ).
Patients not using additional treatments were censored at 24 hours. The plot
includes both patients who had headache response at 2 hours and those who had
no response to the initial dose. Remedication was not allowed within 2 hours
post-dose.

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.

MAXALT-MLT Orally Disintegrating Tablets

The efficacy of MAXALT-MLT was established in two
multicenter, randomized, placebo-controlled trials that were similar in design
to the trials of MAXALT Tablets (Studies 5 and 6). Patients were instructed to
treat a moderate to severe headache. Patients treated in these studies were
primarily female (88%) and Caucasian (95%), with a mean age of 42 years (range
18-72).

In both studies, the percentage of patients achieving
headache response 2 hours after treatment was significantly greater in patients
who received either MAXALT-MLT 5 or 10 mg compared to those who received
placebo. The results from Studies 5 and 6 are summarized in Table 3.

Table 3: Response Rates 2 Hours Following Treatment of
Initial Headache in Studies 5 and 6

Study Placebo MAXALT-MLT 5 mg MAXALT-MLT 10 mg
5 47% (n=98) 66%* (n=100) 66%* (n=113)
6 28% (n=180) 59%* (n=181) 74%*,†(n=186)
*p-value < 0.01 in comparison with placebo.
†p-value < 0.01 in comparison with 5 mg.

The estimated probability of achieving an initial
headache response by 2 hours following treatment with MAXALT-MLT in pooled
Studies 5 and 6 is depicted in Figure 3.

Figure 3: Estimated Probability of Achieving an
Initial Headache Response with MAXALT-MLT  by 2 Hours in Pooled Studies 5 and 6*

*Figure 3 shows the Kaplan-Meier plot of the probability
over time of obtaining headache response (no or mild pain) following treatment
with MAXALT-MLT or placebo. The averages displayed are based on pooled data from
2 placebo-controlled, outpatient trials providing evidence of efficacy (Studies
5 and 6). Patients taking additional treatment or not achieving headache
response prior to 2 hours were censored at 2 hours.

For patients with migraine-associated photophobia and
phonophobia at baseline, there was a decreased incidence of these symptoms
following administration of MAXALT-MLT as 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 4.

Figure 4: Estimated Probability of Patients Taking a
Second Dose of MAXALT-MLT or Other Medication for Migraines Over the 24 Hours
Following the Initial Dose of Study Treatment in Pooled Studies 5 and 6*

*This Kaplan-Meier plot is based on data obtained in 2
placebo-controlled outpatient clinical trials (Studies 5 and 6). Patients not
using additional treatments were censored at 24 hours. The plot includes both
patients who had headache response at 2 hours and those who had no response to
the initial dose. Remedication was not allowed within 2 hours post-dose.

Pediatric Patients 6 To 17 Years Of Age

The efficacy of MAXALT-MLT in pediatric patients 6 to 17
years was evaluated in a multicenter, randomized, double-blind,
placebo-controlled, parallel group clinical trial (Study 7). Patients had to have
at least a 6-month history of migraine attacks (with or without aura) usually
lasting 3 hours or more (when untreated). The patient population was
historically non-responsive to NSAIDs and acetaminophen therapy.

Patients were instructed to treat a single migraine
attack with headache pain of moderate to severe intensity. The treatment phase
of the study had two stages. Stage 1 was used to identify placebo
nonresponders, who then entered into Stage 2, in which patients were randomized
to MAXALT-MLT or placebo. Using a weight-based dosing strategy, patients 20 kg
to < 40 kg (44 lb to < 88 lb) received MAXALT-MLT 5 mg or placebo, and
patients ≥40 kg (88 lb) received MAXALT-MLT 10 mg or placebo.

The mean age for the studied patient population was 13
years. Sixty-one percent of the patients were Caucasian, and fifty-six percent
of the patients were female. The percentage of patients achieving the primary
efficacy endpoint of no headache pain at 2 hours after treatment was
significantly greater in patients who received MAXALT-MLT, compared with those
who received placebo (33% vs. 24%).  Study 7 results are summarized in Table 4.

Table 4: Response Rates 2 Hours Following Treatment of
Initial Headache in Pediatric Patients 6 to 17 Years of Age in Study 7

Endpoint Placebo MAXALT-MLT p-Value
No headache pain at 2 hours post-dose 24% (n/m=94/388) 33% (n/m=126/382) 0.01
n = Number of evaluable patients with no headache pain at
2 hours post-dose.
m = Number of evaluable patients in population.

The observed percentage of pediatric patients achieving
no headache pain within 2 hours following initial treatment with MAXALT-MLT is
shown in Figure 5.

Figure 5: Observed Percentage of Patients Reporting No
Headache Pain by 2 Hours Post-Dose in Study 7

The prevalence of the exploratory endpoints of absence of
migraine-associated symptoms (nausea, photophobia, and phonophobia) at 2 hours
after taking the dose was not statistically significantly different between
patients who received MAXALT-MLT and those who received placebo.

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