- rizatriptan benzoate
POM: Prescription only medicine
This information is intended for use by health professionals
GeneralRizatriptan should not be used prophylactically.The tablets should be swallowed whole with liquid.Effect of food: The absorption of rizatriptan is delayed by approximately 1 hour when administered together with food. Therefore, onset of effect may be delayed when rizatriptan is administered in the fed state (see also Pharmacokinetic Properties, Absorption).
Adults 18 years of age and olderThe recommended dose is 10 mg.Redosing: Doses should be separated by at least two hours; no more than two doses should be taken in any 24-hour period.− For headache recurrence within 24 hours: If headache returns after relief of the initial attack, one further dose may be taken. The above dosing limits should be observed.− After non-response: The effectiveness of a second dose for treatment of the same attack, when an initial dose is ineffective, has not been examined in controlled trials. Therefore, if a patient does not respond to the first dose, a second dose should not be taken for the same attack.Clinical studies have shown that patients who do not respond to treatment of an attack are still likely to respond to treatment for subsequent attacks.Doses should be separated by at least two hours; no more than two doses should be taken in any 24-hour period.
Patients older than 65 yearsThe safety and effectiveness of rizatriptan in patients older than 65 years have not been systematically evaluated.Some patients should receive the lower dose (5 mg) of rizatriptan, in particular the following patient groups:− Patients with mild or moderate renal insufficiency.− Patients with mild to moderate hepatic insufficiency.− Patients on propranolol: Administration of rizatriptan should be separated by at least two hours from administration of propranolol. (See section 4.5).
Children and Adolescents (under 18 years of age)The safety and efficacy of Rizatriptan in children and adolescents under 18 years of age has not yet been established.Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made.
Medication overuse headache (MOH)Prolonged use of any painkiller for headaches can make them worse. If this situation is experienced of suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of MOH should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.Rizatriptan 5 mg Tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine.
FertilityEffects on human fertility have not been investigated. Animal studies only revealed minimal effects on fertility at plasma concentrations far in excess of human therapeutic concentrations (more than 500-fold).
PregnancyThe safety of rizatriptan for the use in human pregnancy has not been established. Animal studies do not indicate harmful effects at dose levels that exceed therapeutic dose levels with respect to the development of the embryo or foetus, or the course of gestation, parturition and post-natal development. Because animal reproductive and developmental studies are not always predictive of human response, Rizatriptan should be used during pregnancy only if clearly needed.
Breast-feedingStudies in rats indicated that very high milk transfer of rizatriptan occurred. Transient, very slight decreases in pre-weaning pup body weights were observed only when the mother's systemic exposure was well in excess of the maximum exposure level for humans. No data exist in humans.Therefore, caution should be exercised when administering rizatriptan to women who are breast-feeding. Infant exposure should be minimised by avoiding breast-feeding for 24 hours after treatment.
Immune system disorders:Rare: Hypersensitivity reaction, anaphylaxis/anaphylactoid reaction.
Psychiatric disorders:Uncommon: Disorientation, insomnia, nervousness.
Nervous system disorders:Common: Dizziness, somnolence, paresthesia, headache, hypaesthesia, decreased mental acuity, tremor. Uncommon: Ataxia, vertigo, dysgeusia/bad taste, Rare: SyncopeNot known: Seizure, serotonin syndrome
Eye disorders:Uncommon: Blurred vision.
Cardiac disorders:Common: Palpitation, tachycardia. Uncommon: arrhythmia, ECG abnormalitiesRare: cerebrovascular accident (most of these adverse reactions have been reported in patients with risk factors predictive of coronary artery disease), bradycardiaNot 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:Common: Hot flushes/flashes.Uncommon: Hypertension.Not known: Peripheral vascular ischaemia.Respiratory, thoracic and mediastinal disorders: Common: Pharyngeal discomfort, dyspnoea. Rare: Wheezing.
Gastrointestinal disorders:Common: Nausea, dry mouth, vomiting, diarrhoea.Uncommon: Thirst, dyspepsia.Not known: ischemic colitis.
Skin and subcutaneous tissue disorders:Common: Flushing, sweating.Uncommon: Pruritus, urticaria, angioedema (e.g. facial oedema, tongue swelling, pharyngeal oedema), (for angioedema see also section 4.4), rash Not known: toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders:Common: Regional heaviness.Uncommon: Neck pain, regional tightness, stiffness, muscle weakness, facial pain, myalgia.
General disorders and administration site conditions:Common: Asthenia/fatigue, pain in abdomen or chest.
Reporting of suspected adverse reactionsReporting 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 at: www.mhra.gov.uk/yellowcard.
AdultsThe efficacy of Rizatriptan Tablets in the acute treatment of migraine attacks was established in four multicentre, placebo-controlled trials that included over 2,000 patients who received Rizatriptan 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 Rizatriptan Tablets were not redosed for the same attack, they were still likely to respond to treatment for a subsequent attack. Rizatriptan Tablets reduced the functional disability and relieved the nausea, photophobia, and phonophobia associated with migraine attacks.Rizatriptan Tablets remain effective in treating menstrual migraine, i.e. migraine that occurs within 3 days before or after the onset of menses.
Adolescents (12 17 years of age)The efficacy of Rizatriptan oral lyophilisates in paediatric patients (12 to 17 years of age) was evaluated in a multicentre, 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 migrane headache initially administered placebo 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 5 mg rizatriptan and patients ≥40 kg received 10 mg 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 Rizatriptan 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 Rizatriptan oral lyophilisates 5 and 10 mg, compared with those who received placebo (39.8% vs. 30.4%, p=0.269).The European Medicines agency has waived the obligation to submit the results of studies with Rizatriptan tablets in all studies of the paediatric population in the treatment of migraine. See section 4.2 for information on paediatric use.'
AbsorptionRizatriptan 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: For the tablets, Tmax is delayed by approximately 1 hour when the tablets are administered in the fed state (See section 4.2).
DistributionRizatriptan is minimally bound (14%) to plasma proteins. The volume of distribution is approximately 140 litres in male subjects, and 110 litres in female subjects.
BiotransformationThe 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.
EliminationFollowing intravenous administration, AUC in men increases proportionally and in women near-proportionally with the dose over a dose range of 10-60 μg/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 patientsThe following data are based on studies with the oral tablet formulation.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.Elderly: The plasma concentrations of rizatriptan observed in elderly subjects (age range 65 to 77 years) after tablet administration were similar to those observed in young adults.Paediatric: 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 tablet 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 after tablet administration 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.
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