Rizatriptan (Systemic)


VA CLASSIFICATION
Primary: CN105

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antimigraine—

Indications

General considerations
Rizatriptan should be prescribed only for patients who have an established clear diagnosis of migraine {01}.

Accepted

Headache, migraine (treatment)—Rizatriptan is indicated to relieve (abort) acute migraine headaches (with or without aura) {01}.

Unaccepted
Rizatriptan is not recommended for treatment of basilar artery migraine or hemiplegic migraine {01}.

Rizatriptan is not recommended for treatment of cluster headaches {01}. Efficacy and safety of rizatriptan in this condition have not been established {01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Rizatriptan benzoate: 269.4 {01}

Mechanism of action/Effect:

Rizatriptan's mechanism of action has not been established {01}. It is thought that agonist activity at the 5-hydroxytryptamine (5-HT) 1B and 5-HT 1D receptor subtypes provides relief of headaches {01}. Rizatriptan is a highly selective agonist at these receptor subtypes; it has no significant activity at 5-HT 2 or 5-HT 3 receptor subtypes or at adrenergic, dopaminergic, histamine, muscarinic, or benzodiazepine receptors {01}. It has been proposed that constriction of cerebral vessels resulting from 5-HT 1B/1D receptor stimulation reduces the pulsation that may be responsible for the pain of migraine headaches {01}. It has also been proposed that rizatriptan may relieve migraine headaches by decreasing the release of pro-inflammatory neuropeptides {01}.

Absorption:

Oral—Rapid; bioavailability is 45% {01}. Food has no effect on the bioavailability of rizatriptan {01}. However, administering rizatriptan with food will delay by 1 hour the time to reach peak plasma concentration {01}. The rate of absorption is not affected by the presence of a migraine attack {01}.

Protein binding:

Low (14%) {01}.

Biotransformation:

Rizatriptan is metabolized by monoamine oxidase A isoenzyme (MAO-A) to an inactive indole acetic acid metabolite {01}. In addition, several other inactive metabolites are formed {01}. An active metabolite, N-monodesmethyl-rizatriptan, with pharmacological activity similar to that of the parent compound has been identified in small concentrations (14%) in the plasma {01}.

Half-life:

Approximately 2 to 3 hours {01}.

Elimination:
    Renal; following administration of a radiolabeled rizatriptan dose, approximately 82% and 12% of the dose was excreted in the urine and feces, respectively, within 120 hours {01}. Approximately 14% of rizatriptan was excreted in the urine as unchanged and 51% as an indole acetic acid metabolite {01}.


Precautions to Consider

Carcinogenicity/Tumorigenicity

Lifetime carcinogenic studies were done in a 100-week study in mice and a 106-week study in rats receiving doses of rizatriptan of 125 mg per kg of body weight (mg/kg) per day by oral gavage {01}. However, the exposure data were not obtained in these studies {01}. A 5-week study in mice and a 21-week study in rats exposed to the highest dose level of rizatriptan (reflects the area under the plasma concentration–time curve [AUC] exposure of 150 and 240 times the maximum recommended human dose [MRHD], respectively) reported no evidence of tumorigenicity {01}.

Mutagenicity

Rizatriptan demonstrated no mutagenic or clastogenic effects in the microbial mutagenesis (Ames) assay or in the in vitro studies, including mammalian cell mutagenic assay in V-79 Chinese hamster lung cells, alkaline elution assay in rat hepatocytes, chromosomal aberration assay in Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in mouse bone marrow {01}.

Pregnancy/Reproduction
Fertility—
A fertility study in female rats receiving oral doses of rizatriptan of up to 100 mg/kg per day (approximately 225 times the AUC in humans receiving the MRHD) found changes in estrus cyclicity and delays in time to mating {01}. The no-effect dose was 10 mg/kg per day (approximately 15 times the human exposure at the MRHD) {01}. Also, a reproductive study in male rats receiving 250 mg/kg per day (approximately 550 times the human exposure at the MRHD) found no impairment of fertility or reproductive performance {01}.

Pregnancy—
Adequate and well-controlled trials have not been done in pregnant women {01}.

A reproductive study in female rats receiving doses of rizatriptan of up to 10 and 100 mg/kg per day prior to and during mating and throughout gestation and lactation (AUC approximately 15 and 225 times the MRHD, respectively) found reduced birth weights and pre- and post-weaning weight gain in the offspring of the rats {01}. Although there was no apparent maternal toxicity, developmental effects on offspring growth occurred {01}. The developmental no-effect dose of rizatriptan was 2 mg/kg per day (maternal exposure approximately 1.5 times the MRHD) {01}. Since high doses were not evaluated in this reproduction study, the full spectrum of developmental toxicity is unknown {01}. A rat dose-finding study reported an increase in pup mortality at maternally toxic doses (250 mg/kg per day or greater) {01}.

No teratogenic effects were observed in embryofetal developmental studies in pregnant rats and rabbits receiving rizatriptan doses of 100 mg/kg per day and 50 mg/kg per day during organogenesis, respectively {01}. Maternal exposures at the highest doses, approximately 225 and 115 times the human exposure at the MRHD in rats and rabbits, respectively, resulted in decreased fetal weight and maternal weight gain {01}. In both rats and rabbits, the developmental no-effect dose was 10 mg/kg per day (maternal exposure approximately 15 times the MRHD) {01}.

Rizatriptan crosses the placenta in rats and rabbits {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether rizatriptan is distributed into human breast milk {01}. However, rizatriptan is distributed into the milk of rats at a concentration at least fives times greater than the maternal plasma level {01}.

Pediatrics

No information is available on the relationship of age to the effects of rizatriptan in patients up to 18 years of age {01}. Safety and efficacy have not been established {01}.


Geriatrics


Pharmacokinetic studies performed to date have not demonstrated geriatrics-specific problems that would limit the use of rizatriptan in geriatric patients {01}. In patients older than 65 years of age, there was no difference in efficacy or overall side effects compared with younger adults {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Dihydroergotamine or
» Ergotamine or
» Methysergide or
» Other 5-hydroxytryptamine (5HT) agonists such as:
Naratriptan or
Sumatriptan or
Zolmitriptan    (a delay of 24 hours between administration of dihydroergotamine, ergotamine, methysergide, or other 5HT 1 agonists and rizatriptan is recommended because of the possibility of additive and/or prolonged vasoconstriction {01})


Serotonergics (see Appendix II), such as:
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline    (concurrent use may result in weakness, hyperreflexia, and incoordination; monitoring is recommended; a pharmacokinetic study evaluating rizatriptan 10 mg and paroxetine observed no clinical interactions {01})


» Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline    (concurrent use may increase systemic exposure of rizatriptan; rizatriptan should not be taken concurrently with or within 14 days following administration of an MAO inhibitor {01})


Propranolol    (propranolol has been reported to increase the plasma concentration of rizatriptan by 70%; if given concurrently, a 5-mg dose of rizatriptan is recommended and a maximum of three doses in a 24-hour period {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Blood pressure    (may be increased; in healthy volunteers, blood pressure elevations of approximately 2 to 3 mm Hg were observed {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Coronary artery disease, especially:
Angina pectoris or
Myocardial infarction, history of
Myocardial ischemia, silent, documented
Prinzmetal"s angina
» Other conditions in which coronary vasoconstriction would be detrimental    (rizatriptan may cause coronary vasospasms {01})


» Hypertension, uncontrolled    (may be exacerbated {01})


Risk-benefit should be considered when the following medical problems exist
» Coronary artery disease, predisposition to    (rizatriptan may cause serious coronary adverse effects; patients in whom coronary artery disease is a possibility on the basis of age or the presence of other risk factors, such as diabetes, hypercholesterolemia, obesity, a strong family history of coronary artery disease, or tobacco smoking, should be evaluated for the presence of cardiovascular disease before rizatriptan is prescribed; even after a satisfactory evaluation, the advisability of administering the patient"s first dose under medical supervision should be considered {01})


» Hepatic function impairment, moderate or
» Renal function impairment, severe    (studies have shown decreased rizatriptan clearance in patients with moderate hepatic or severe renal disease; caution is recommended {01})


Sensitivity to rizatriptan or aspartame {01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Electrocardiogram (ECG)    (monitoring is recommended for long-term intermittent users of rizatriptan who have risk factors for coronary artery disease {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Chest pain, severe{01}
    
dyspnea{01} (shortness of breath)
    
heaviness, tightness, or pressure in chest and/or neck{01}
    
palpitations{01} (pounding heartbeat)
    
paresthesias{01} (sensation of burning, warmth, heat, numbness, tightness, or tingling)

Incidence less frequent
    
Arrhythmia{01} (irregular heartbeat)
    
bradycardia{01} (slow heartbeat)
    
tachycardia{01} (increased heartbeat)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Asthenia{01} (unusual tiredness or muscle weakness)
    
dizziness{01}
    
dry mouth{01}
    
fatigue{01} (unusual tiredness)
    
hot flashes{01}
    
nausea and/or vomiting{01}
    
somnolence{01} (sleepiness)

Incidence less frequent
    
Arthralgia{01} (joint pain)
    
central nervous system (CNS) effects
including agitation{01}
anxiety{01}
confusion{01}
depression{01}
irritability{01}
    
eye problems
including blurred vision{01}
dry eyes{01}
eye irritation{01}
    
chills{01}
    
constipation{01}
    
diarrhea{01}
    
dyspepsia{01} (heartburn)
    
dysphagia{01} (difficulty swallowing)
    
euphoria{01} (unusual feeling of well-being)
    
flatulence{01} (gas)
    
heat sensitivity{01}
    
hypertension{01} (dizziness; headache, severe or continuing; increased blood pressure)
    
increased sweating{01}
    
increased thirst{01}
    
insomnia (inability to sleep)
    
muscle or joint stiffness, tightness, or rigidity{01}
    
muscle pain or spasms{01}
    
polyuria{01} (sudden, large increase in frequency and quantity of urine)
    
pruritus{01} (itching of the skin)
    
tinnitus (ringing or buzzing in ears)
    
tremor{01} (trembling or shaking of hands or feet)
    
vertigo (feeling of constant movement of self or surroundings)
    
warm and/or cold sensations{01}





Overdose
For specific information on the agents used in the management of rizatriptan overdose, see:    • Charcoal, Activated (Oral-Local) monograph {01}.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
    
Bradycardia{01} (slow heartbeat)
    
dizziness{01}
    
hypertension{01} (dizziness; headache, severe or continuing; increased blood pressure)
    
somnolence{01} (sleepiness)
    
syncope{01} (fainting)
    
vomiting{01}


Treatment of overdose
To decrease absorption—Gastric lavage with activated charcoal may be employed {01}.

Monitoring—Patients should be monitored for at least 12 hours after an overdose {01}.

To enhance elimination—The effectiveness of hemodialysis is unknown {01}.

Supportive care—General supportive measures should be instituted. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Rizatriptan (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to rizatriptan or aspartame

Pregnancy—Rizatriptan crosses the placenta in animals





Breast-feeding—Studies found that rizatriptan was distributed into the milk of lactating rats
Other medications, especially dihydroergotamine, ergotamine, methysergide, monamine oxidase inhibitors, or other 5-hydroxytryptamine agonists
Other medical problems, especially coronary artery disease, predisposition to coronary artery disease, or other conditions that may be adversely affected by coronary artery constriction; hepatic function impairment (moderate); renal function impairment (severe); or hypertension

Proper use of this medication
» Proper administration:

Orally disintegrating tablet—

Remove tablet from blister pack just prior to dosing

Place tablet on tongue; avoid eating, drinking, smoking, or using tobacco while tablet is dissolving

» Not administering if atypical headache symptoms are present; checking with physician instead

Administering after onset of headache pain

Additional benefit may be obtained if the patient lies down in a quiet, dark room after administering medication

» Not taking additional doses if first dose does not provide substantial relief; taking alternate medication as previously advised by physician, then checking with physician as soon as possible

» Taking additional doses, if needed, for return of migraine headache after initial relief was obtained, provided that prescribed limits (quantity used and frequency of administration) are not exceeded

» Compliance with prophylactic therapy, if prescribed

» Proper dosing

» Proper storage

Precautions while using this medication
Avoiding alcohol, which aggravates headaches

» Caution when driving or doing anything else requiring alertness because of possible drowsiness, dizziness, lightheadedness, impairment of physical or mental abilities


Side/adverse effects
Signs of potential side effects, especially chest pain; dyspnea; heaviness, tightness, or pressure in chest and/or neck; palpitations; paresthesias; arrhythmia; bradycardia; and tachycardia


General Dosing Information
The phenylalanine (component of aspartame) in the rizatriptan orally disintegrating tablet should be considered when administering to phenylketonuric patients {01}.


Oral Dosage Forms

Note: The dosing and strengths of the dosage forms available are expressed in terms of rizatriptan base (not the benzoate salt) {01}.


RIZATRIPTAN BENZOATE TABLETS

Usual adult dose
Antimigraine agent
Oral, 5 or 10 mg (base) as a single dose {01}. If necessary, additional doses may be taken at intervals of at least two hours {01}.


Usual adult prescribing limits
30 mg in twenty-four hours {01}.

Usual pediatric dose
Safety and efficacy have not been established in children up to 18 years of age {01}.

Usual geriatric dose
See Usual adult dose {01}.

Strength(s) usually available
U.S.—


5 mg (base) (Rx) [Maxalt{01} (lactose monohydrate) (microcrystalline cellulose) (pregelatinized starch) (ferric acid (red)) (magnesium stearate)]


10 mg (base) (Rx) [Maxalt{01} (lactose monohydrate) (microcrystalline cellulose) (pregelatinized starch) (ferric acid (red)) (magnesium stearate)]

Packaging and storage:
Store at room temperature, preferably between 15 and 30 ºC (59 and 86 ºF) {01}.


RIZATRIPTAN BENZOATE ORALLY DISINTEGRATING TABLETS

Usual adult dose
Antimigraine agent
Oral, 5 or 10 mg (base) as a single dose {01}. If necessary, additional doses may be taken at intervals of at least two hours {01}.


Usual adult prescribing limits
30 mg in twenty-four hours {01}.

Usual pediatric dose
Safety and efficacy have not been established in children up to 18 years of age {01}.

Usual geriatric dose
See Usual adult dose {01}.

Strength(s) usually available
U.S.—


5 mg (base) (Rx) [Maxalt-MLT{01} (orally disintegrating) (gelatin) (mannitol) (glycine) (aspartame (1.05 mg)) (peppermint flavor)]


10 mg (base) (Rx) [Maxalt-MLT{01} (orally disintegrating) (gelatin) (mannitol) (glycine) (aspartame (2.1 mg)) (peppermint flavor)]

Packaging and storage:
Store at room temperature, preferably between 15 and 30 ºC (59 and 86 ºF) {01}.



Developed: 11/11/1998



References
  1. Maxalt package insert (Merck—US), New 6/98, Rec 8/98.
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