Maxalt 5 MG Disintegrating Oral Tablet
WARNINGS
MAXALT 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: Because of the potential of this class of compounds (5-HT 1B/1D agonists) to cause coronary vasospasm, MAXALT should not be given to patients with documented ischemic or vasospastic coronary artery disease (see CONTRAINDICATIONS ).
It is strongly recommended that rizatriptan not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) 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.
The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best.
If, during the cardiovascular evaluation, the patient’s medical history, electrocardiographic or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, rizatriptan should not be administered (see CONTRAINDICATIONS ).
For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of rizatriptan take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received rizatriptan.
Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following MAXALT, in these patients with risk factors.
It is recommended that patients who are intermittent long-term users of MAXALT and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use MAXALT.
The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to rizatriptan.
Cardiac Events and Fatalities Associated with 5-HT 1 Agonists: Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following the administration of rizatriptan.
Life-threatening disturbances of cardiac rhythm and death have been reported within a few hours following the administration of other 5-HT 1 agonists.
Considering the extent of use of 5-HT 1 agonists in patients with migraine, the incidence of these events is extremely low.
MAXALT can cause coronary vasospasm.
Because of the close proximity of the events to MAXALT use, a causal relationship cannot be excluded.
In the cases where there has been known underlying coronary artery disease, the relationship is uncertain.
Premarketing experience with rizatriptan: Among the 3700 patients with migraine who participated in premarketing clinical trials of MAXALT, one patient was reported to have chest pain with possible ischemic ECG changes following a single dose of 10 mg.
Postmarketing experience with rizatriptan: Serious cardiovascular events have been reported in association with the use of MAXALT.
The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by rizatriptan or to reliably assess causation in individual cases.
Cerebrovascular Events and Fatalities Associated with 5-HT 1 Agonists: Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5-HT 1 agonists; and some have resulted in fatalities.
In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not.
It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).
Other Vasospasm-Related Events: 5-HT 1 agonists may cause vasospastic reactions other than coronary artery vasospasm.
Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported with 5-HT 1 agonists.
Increase in Blood Pressure: Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients receiving 5-HT 1 agonists with and without a history of hypertension.
In healthy young male and female subjects who received maximal doses of MAXALT (10 mg every 2 hours for 3 doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed.
Rizatriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS ).
An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT 1 agonist in a study evaluating subjects undergoing cardiac catheterization.
Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome may occur with triptans, including MAXALT treatment, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
If concomitant treatment with rizatriptan and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) (see PRECAUTIONS, Drug Interactions ).
DRUG INTERACTIONS
Drug Interactions (See also 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.
OVERDOSAGE
No overdoses of MAXALT were reported during clinical trials.
Rizatriptan 40 mg (administered as either a single dose or as two doses with a 2-hour interdose interval) was generally well tolerated in over 300 patients; dizziness and somnolence were the most common drug-related adverse effects.
In a clinical pharmacology study in which 12 subjects received rizatriptan, at total cumulative doses of 80 mg (given within four hours), two subjects experienced syncope and/or bradycardia.
One subject, a female aged 29 years, developed vomiting, bradycardia, and dizziness beginning three hours after receiving a total of 80 mg rizatriptan (administered over two hours); a third degree AV block, responsive to atropine, was observed an hour after the onset of the other symptoms.
The second subject, a 25 year old male, experienced transient dizziness, syncope, incontinence, and a 5-second systolic pause (on ECG monitor) immediately after a painful venipuncture.
The venipuncture occurred two hours after the subject had received a total of 80 mg rizatriptan (administered over four hours).
In addition, based on the pharmacology of rizatriptan, hypertension or other more serious cardiovascular symptoms could occur after overdosage.
Gastrointestinal decontamination, (i.e., gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with MAXALT.
Clinical and electrocardiographic monitoring should be continued for at least 12 hours, even if clinical symptoms are not observed.
The effects of hemo- or peritoneal dialysis on serum concentrations of rizatriptan are unknown.
DESCRIPTION
MAXALT COPYRIGHT © 1998, 2006 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved 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 C 15 H 19 N 5 •C 7 H 6 O 2 , 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 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.
image of structural formula
CLINICAL STUDIES
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 postdose 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 4 controlled studies using the marketed formulation are summarized in Table 1.
Table 1: Response Rates 2 Hours Following Treatment of Initial Headache Study Placebo MAXALT Tablets 5 mg MAXALT Tablets 10 mg 1 35% (n=304) 62% p value < 0.05 in comparison with placebo (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) 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 †† 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 ††† 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, respectively.
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.
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 the 2 controlled studies using the marketed formulation are summarized in Table 2.
Table 2: Response Rates 2 Hours Following Treatment of Initial Headache Study Placebo MAXALT-MLT 5 mg MAXALT-MLT 10 mg 1 47% (n=98) 66% p value < 0.01 in comparison with placebo (n=100) 66% (n=113) 2 28% (n=180) 59% (n=181) 74% , (n=186) The estimated probability of achieving an initial headache response by 2 hours following treatment with MAXALT-MLT is depicted in Figure 3.
Figure 3: Estimated Probability of Achieving an Initial Headache Response with MAXALT-MLT by 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 ‡‡
HOW SUPPLIED
No.
3732 — MAXALT Tablets, 5 mg, are pale pink, capsule-shaped, compressed tablets coded MRK on one side and 266 on the other.
They are supplied as follows: NDC 0006-0266-18, carton of 18 tablets.
No.
3733 — MAXALT Tablets, 10 mg, are pale pink, capsule-shaped, compressed tablets coded MAXALT on one side and MRK 267 on the other.
They are supplied as follows: NDC 0006-0267-18, carton of 18 tablets.
No.
3800 — MAXALT-MLT Orally Disintegrating Tablets, 5 mg, are white to off-white, round lyophilized orally disintegrating tablets debossed with a modified triangle on one side, and measuring 10.0-11.5 mm (side-to-side) with a peppermint flavor.
Each orally disintegrating tablet is individually packaged in a blister inside an aluminum pouch (sachet).
They are supplied as follows: NDC 0006-3800-18, 6 x unit of use carrying case of 3 orally disintegrating tablets (18 tablets total).
No.
3801 — MAXALT-MLT Orally Disintegrating Tablets, 10 mg, are white to off-white, round lyophilized orally disintegrating tablets debossed with a modified square on one side, and measuring 12.0-13.8 mm (side-to-side) with a peppermint flavor.
Each orally disintegrating tablet is individually packaged in a blister inside an aluminum pouch (sachet).
They are supplied as follows: NDC 0006-3801-18, 6 x unit of use carrying case of 3 orally disintegrating tablets (18 tablets total).
Storage Store MAXALT Tablets at room temperature, 15-30°C (59-86°F).
Dispense in a tight container, if product is subdivided.
Store MAXALT-MLT Orally Disintegrating Tablets at room temperature, 15-30°C (59-86°F).
The patient should be instructed not to remove the blister from the outer aluminum pouch until the patient is ready to consume the orally disintegrating tablet inside.
MAXALT Tablets are manufactured for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA By: MSD, Ltd.
Cramlington, Northumberland, NE23 3JU, UK MAXALT-MLT Orally Disintegrating Tablets are manufactured for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA By: Catalent UK Swindon, Zydis Ltd.
Swindon, Wiltshire, SN5 8RU, UK US Patent No.: 5,298,520 Issued August 2010 9652508
GERIATRIC USE
Geriatric Use The pharmacokinetics of rizatriptan were similar in elderly (aged ≥ 65 years) and in younger adults.
Because migraine occurs infrequently in the elderly, clinical experience with MAXALT is limited in such patients.
In clinical trials, there were no apparent differences in efficacy or in overall adverse experience rates between patients under 65 years of age and those 65 and above (n=17).
MECHANISM OF ACTION
Mechanism of Action Rizatriptan binds with high affinity to human cloned 5-HT 1B and 5-HT 1D receptors.
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 activity at 5-HT 2 , 5-HT 3 , alpha- and beta-adrenergic, dopaminergic, histaminergic, muscarinic or benzodiazepine receptors.
Current theories on the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of vasoactive and pro-inflammatory peptides from sensory nerve endings in an activated trigeminal system.
The therapeutic activity of rizatriptan in migraine can most likely be attributed to agonist effects at 5-HT 1B/1D receptors on the extracerebral, intracranial blood vessels that become dilated during a migraine attack and on nerve terminals in the trigeminal system.
Activation of these receptors results in cranial vessel constriction, inhibition of neuropeptide release and reduced transmission in trigeminal pain pathways.
INDICATIONS AND USAGE
MAXALT is indicated for the acute treatment of migraine attacks with or without aura in adults.
MAXALT is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see CONTRAINDICATIONS ).
Safety and effectiveness of MAXALT have not been established for cluster headache, which is present in an older, predominantly male population.
PEDIATRIC USE
Pediatric Use Safety and effectiveness of rizatriptan in pediatric patients have not been established; therefore, MAXALT is not recommended for use in patients under 18 years of age.
The efficacy of MAXALT Tablets (5 mg) in patients aged 12 to 17 years was not established in a randomized placebo-controlled trial of 291 adolescent migraineurs (see Clinical Studies ).
Adverse events observed were similar in nature to those reported in clinical trials in adults.
Postmarketing experience with other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults.
The long-term safety of rizatriptan in pediatric patients has not been studied.
PREGNANCY
Pregnancy: Pregnancy Category C In a general reproductive study in rats, birth weights and pre- and post-weaning weight gain were reduced in the offspring of females treated prior to and during mating and throughout gestation and lactation with doses of 10 and 100 mg/kg/day.
Maternal drug exposures (AUC) at these doses were approximately 15 and 225 times, respectively, the exposure in humans receiving the maximum recommended daily dose (MRDD) of 30 mg.
In a pre- and post-natal developmental toxicity study in rats, an increase in mortality of the offspring at birth and for the first three days after birth, a decrease in pre- and post-weaning weight gain, and decreased performance in a passive avoidance test (which indicates a decrease in learning capacity of the offspring) were observed at doses of 100 and 250 mg/kg/day.
The no-effect dose for all of these effects was 5 mg/kg/day, approximately 7.5 times the exposure in humans receiving the MRDD.
With doses of 100 and 250 mg/kg/day, the decreases in average weight of both the male and female offspring persisted into adulthood.
All of these effects on the offspring in both reproductive toxicity studies occurred in the absence of any apparent maternal toxicity.
In embryofetal development studies, no teratogenic effects were observed when pregnant rats and rabbits were administered doses of 100 and 50 mg/kg/day, respectively, during organogenesis.
Fetal weights were decreased in conjunction with decreased maternal weight gain at the highest doses (maternal exposures approximately 225 and 115 times the human exposure at the MRDD in rats and rabbits, respectively).
The developmental no-effect dose in these studies was 10 mg/kg/day in both rats and rabbits (maternal exposures approximately 15 times human exposure at the MRDD).
Toxicokinetic studies demonstrated placental transfer of drug in both species.
There are no adequate and well-controlled studies in pregnant women; therefore, rizatriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to MAXALT while pregnant.
Healthcare providers are encouraged to report any prenatal exposure to MAXALT by calling the Pregnancy Registry at (800) 986-8999.
NUSRING MOTHERS
Nursing Mothers It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when MAXALT is administered to women who are breast-feeding.
Rizatriptan is extensively excreted in rat milk, at a level of 5-fold or greater than maternal plasma levels.
INFORMATION FOR PATIENTS
Information for Patients Migraine or treatment with MAXALT may cause somnolence in some patients.
Dizziness has also been reported in some patients receiving MAXALT.
Patients should, therefore, evaluate their ability to perform complex tasks during migraine attacks and after administration of MAXALT.
Physicians should instruct their patients to read the patient package insert before taking MAXALT.
See the accompanying PATIENT INFORMATION leaflet.
Patients should be cautioned about the risk of serotonin syndrome with the use of rizatriptan or other triptans, especially during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) (see WARNINGS ).
DOSAGE AND ADMINISTRATION
In controlled clinical trials, single doses of 5 and 10 mg of MAXALT Tablets or MAXALT-MLT were effective for the acute treatment of migraines in adults.
There is evidence that the 10-mg dose may provide a greater effect than the 5-mg dose (see CLINICAL PHARMACOLOGY, Clinical Studies ).
Individuals may vary in response to doses of MAXALT Tablets.
The choice of dose should therefore be made on an individual basis, weighing the possible benefit of the 10-mg dose with the potential risk for increased adverse events.
Redosing: Doses should be separated by at least 2 hours; no more than 30 mg should be taken in any 24-hour period.
The safety of treating, on average, more than four headaches in a 30-day period has not been established.
Patients receiving propranolol: In patients receiving propranolol, the 5-mg dose of MAXALT should be used, up to a maximum of 3 doses in any 24-hour period.
(See CLINICAL PHARMACOLOGY, Drug Interactions .) For MAXALT-MLT Orally Disintegrating Tablets, administration with liquid is not necessary.
The orally disintegrating tablet is packaged in a blister within an outer aluminum pouch.
Patients should be instructed not to remove the blister from the outer pouch until just prior to dosing.
The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where it will dissolve and be swallowed with the saliva.