Rizatriptan 40 mg (administered as either a single dose or as two doses with a two-hour interdose interval) was generally well tolerated in over 300 adult patients; dizziness and somnolence were the most common drug-related adverse effects.
In a clinical pharmacology study in which 12 adult 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 five-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. Gastro-intestinal decontamination (e.g. 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 haemo- or peritoneal dialysis on serum concentrations of rizatriptan are unknown.
3 years.
Not applicable.
Lactose monohydrate, microcrystalline cellulose (E460a), starch, pregelatinised, iron oxide red (E172) and magnesium stearate (E572).
MAXALT (as the tablet and oral lyophilisate formulation) was evaluated in 8630 adult patients for up to one year in controlled clinical studies. The most common side effects evaluated in clinical studies were dizziness, somnolence, and asthenia/fatigue. The following side effects have been evaluated in clinical studies and/or reported in post-marketing experience:
(Very common [> 1/10]; Common [>1/100, <1/10]; Uncommon [>1/1000, <1/100]; Rare [>1/10,000 <1/1,000]; Very rare [< 1/10000], not known [cannot be estimated from the available data]).
Immune system disorders:
Rare: hypersensitivity reaction, anaphylaxis/anaphylactoid reaction.
Pyschiatric disorders:
Common: insomnia
Uncommon: disorientation, nervousness.
Nervous system disorders:
Common: dizziness, somnolence, paraesthesia, headache, hypoaesthesia, decreased mental acuity.
Uncommon: ataxia, vertigo, dysgeusia/bad taste, tremor, syncope
Not known: seizure, serotonin syndrome.
Eye disorders:
Uncommon: blurred vision.
Cardiac disorders:
Common: palpitation.
Uncommon: arrhythmia, ECG abnormalities, tachycardia
Rare: cerebrovascular accident (most of these adverse reactions have been reported in patients with risk factors predictive of coronary artery disease), bradycardia
Not known: myocardial ischaemia or infarction (most of these adverse reactions have been reported in patients with risk factors predictive of coronary artery disease)
Vascular disorders:
Uncommon: hypertension, hot flushes/flashes
Not known: peripheral vascular ischaemia.
Respiratory, thoracic and mediastinal disorders:
Common: pharyngeal discomfort
Uncommon: dyspnoea
Rare: wheezing.
Gastro-intestinal disorders:
Common: nausea, dry mouth, vomiting, diarrhoea, dyspepsia
Uncommon: thirst,
Not known: ischemic colitis.
Skin and subcutaneous tissue disorders:
), rash, sweatingNot known: toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders:
Common: regional heaviness, neck pain, stiffness
Uncommon: regional tightness, muscle weakness, facial pain, myalgia.
General disorders and administration site conditions:
Common: asthenia/fatigue, pain in abdomen or chest.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website www.mhra.gov.uk/yellowcard.
Preclinical data indicate no risk for humans based on conventional studies of repeat dose toxicity, genotoxicity, carcinogenic potential, reproductive and developmental toxicity, safety pharmacology, and pharmacokinetics and metabolism.
Pharmacotherapeutic group: antimigraine preparations, selective serotonin (5HT1) agonist, ATC-code: N02C C04.
Mechanism of action: Selective Serotonin (5-HT 1B/1D) agonists
Rizatriptan binds selectively with high affinity to human 5-HT1B and 5-HT1D receptors and has little or no effect or pharmacological activity at 5-HT2, 5-HT3; adrenergic alpha1, alpha2 or beta; D1, D2, dopaminergic, histaminic H1; muscarinic; or benzodiazepine receptors.
The therapeutic activity of rizatriptan in treating migraine headache may be attributed to its agonist effects at 5-HT1B and 5-HT1D receptors on the extracerebral intracranial blood vessels that are thought to become dilated during an attack and on the trigeminal sensory nerves that innervate them. Activation of these 5-HT1B and 5-HT1D receptors may result in constriction of pain producing intracranial blood vessels and inhibition of neuropeptide release that leads to decreased inflammation in sensitive tissues and reduced central trigeminal pain signal transmission.
Pharmacodynamic effects
Adults
The efficacy of MAXALT Tablets in the acute treatment of migraine attacks was established in four multicentre, placebo-controlled trials that included over 2,000 patients who received MAXALT 5 or 10 mg for up to one year. Headache relief occurred as early as 30 minutes following dosing, and response rates (i.e. reduction of moderate or severe headache pain to no or mild pain) two hours after treatment were 67-77% with the 10-mg tablet, 60-63% with the 5-mg tablet, and 23-40% with placebo. Although patients who did not respond to initial treatment with MAXALT were not redosed for the same attack, they were still likely to respond to treatment for a subsequent attack. MAXALT reduced the functional disability and relieved the nausea, photophobia, and phonophobia associated with migraine attacks.
MAXALT remains effective in treating menstrual migraine, i.e. migraine that occurs within 3 days before or after the onset of menses.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with MAXALT tablets in all subsets of the paediatric population in the treatment of migraine.
Adolescents (12-17 years of age)
The efficacy of MAXALT oral lyophilisates in paediatric patients (12 to 17 years of age) was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel group study (n=570). The patient population was required to be historically non-responsive to NSAIDs and acetaminophen therapy. Patients with a qualifying migraine headache initially administered placebo or rizatriptan within 30 minutes of onset. Following the 15 minute placebo run-in, subjects who did not respond to placebo then treated a single migraine attack with placebo or rizatriptan. Using a weight-based dosing strategy, patients 20 kg to <40 kg received 5mg rizatriptan and patients >40 kg received 10mg rizatriptan.
In this enriched population study, a difference of 9% between active treatment and placebo was observed for the primary efficacy endpoint of pain freedom (reduction from moderate or severe pain to no pain) 2 hours after treatment (31% under rizatriptan vs. 22% for placebo (p=0.025)). No significant difference for the secondary endpoint of pain relief (reduction from moderate or severe pain to mild or no pain) was found.
Children (6-11 years of age)
The efficacy of MAXALT oral lyophilisates was also evaluated in paediatric patients 6 to 11 years of age in the same acute placebo-controlled clinical trial (n=200). The percentage of patients achieving pain freedom 2 hours after treatment was not statistically significantly different in patients who received MAXALT oral lyophilisates 5 and 10 mg, compared with those who received placebo (39.8% vs. 30.4%, p=0.269).
Absorption
Rizatriptan is rapidly and completely absorbed following oral administration. The mean oral bioavailability of the tablet is approximately 40-45%, and mean peak plasma concentrations (Cmax) are reached in approximately 1-1.5 hours (Tmax). Administration of an oral tablet dose with a high-fat breakfast had no effect on the extent of rizatriptan absorption, but absorption was delayed for approximately one hour.
Effect of Food: The effect of food on the absorption of rizatriptan from the oral lyophilisate has not been studied. For the rizatriptan tablets, Tmax is delayed by approximately 1 hour when the tablets are administered in the fed state. A further delay in the absorption of rizatriptan may occur when the oral lyophilisate is administered after meals.
Distribution
Rizatriptan is minimally bound (14%) to plasma proteins. The volume of distribution is approximately 140 litres in male subjects, and 110 litres in female subjects.
Biotransformation
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 pharmacologically active. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5-HT1B/1D receptors, is formed to a minor degree, but does not contribute significantly to the pharmacodynamic activity of rizatriptan. 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 include the N-oxide, the 6-hydroxy compound, and the sulphate conjugate of the 6-hydroxy metabolite. None of these minor metabolites is pharmacologically active. Following oral administration of 14C-labelled rizatriptan, rizatriptan accounts for about 17% of circulating plasma radioactivity.
Elimination
Following intravenous administration, AUC in men increases proportionally and in women near-proportionally with the dose over a dose range of 10-60 1g/kg. Following oral administration, AUC increases near-proportionally with the dose over a dose range of 2.5-10 mg. The plasma half-life of rizatriptan in males and females averages 2-3 hours. The plasma clearance of rizatriptan averages about 1,000-1,500 mL/min in males and about 900-1,100 mL/min in females; about 20-30% of this is renal clearance. Following an oral dose of 14C-labelled rizatriptan, about 80% of the radioactivity is excreted in urine, and about 10% of the dose is excreted in faeces. This shows that the metabolites are excreted primarily via the kidneys.
Consistent with its first pass metabolism, approximately 14% of an oral dose is excreted in urine as unchanged rizatriptan while 51% is excreted as indole acetic acid metabolite. No more than 1% is excreted in urine as the active N-monodesmethyl metabolite.
If rizatriptan is administered according to the maximum dosage regimen, no drug accumulation in the plasma occurs from day to day.
Characteristics in Patients
Patients with a migraine attack: A migraine attack does not affect the pharmacokinetics of rizatriptan.
Gender: The AUC of rizatriptan (10 mg orally) was about 25% lower in males as compared to females, Cmax was 11% lower, and Tmax occurred at approximately the same time. This apparent pharmacokinetic difference was of no clinical significance.
Older people: The plasma concentrations of rizatriptan observed in elderly subjects (age range 65 to 77 years) were similar to those observed in young adults.
Paediatric population: A pharmacokinetics study of rizatriptan (as the oral lyophilisates formulation) was conducted in paediatric migraineurs 6 to 17 years of age. The mean exposures following a single dose administration of 5 mg rizatriptan oral lyophilisates to paediatric patients weighing 20-39 kg or 10 mg rizatriptan oral lyophilisates to paediatric patients weighing >40 kg were respectively 15% lower and 17% higher compared to the exposure observed following single dose administration of 10 mg rizatriptan oral lyophilisates to adults. The clinical relevance of these differences is unclear.
Hepatic impairment (Child-Pugh's score 5-6): Following oral administration in patients with hepatic impairment caused by mild alcoholic cirrhosis of the liver, plasma concentrations of rizatriptan were similar to those seen in young male and female subjects. A significant increase in AUC (50%) and Cmax (25%) was observed in patients with moderate hepatic impairment (Child-Pugh's score 7). Pharmacokinetics were not studied in patients with Child-Pugh's score >7 (severe hepatic impairment).
Renal impairment: In patients with renal impairment (creatinine clearance 10-60 mL/min/1.73 m2), the AUC of rizatriptan was not significantly different from that in healthy subjects. In haemodialysis patients (creatinine clearance <10 mL/min/1.73 m2), the AUC for rizatriptan was approximately 44% greater than that in patients with normal renal function. The maximal plasma concentration of rizatriptan in patients with all degrees of renal impairment was similar to that in healthy subjects.
20 March 2014
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK
Do not store above 30°C.
All aluminium blister push through, packs of 2, 3, 6, 12 or 18 tablets.
Not all pack sizes may be marketed.
Tablet 5 mg PL 00025/0369
Tablet 10 mg PL 00025/0370
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.
Any unused product or waste material should be disposed of in accordance with local requirements.
Date of first authorisation: June 1998
Date of latest renewal: 12 May 2014
