Rizatriptan 10mg Orodispersible Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Rizatriptan 10mg orodispersible tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Rizatriptan 10mg orodispersible tablets
Each tablet contains 14.53 mg of rizatriptan benzoate equivalent to 10.0mg Rizatriptan.
Excipients with known effect: aspartame 2.90 mg.
For a full list of excipients see section 6.1.
3 PHARMACEUTICAL FORM
Orodispersible tablet
10 mg orodispersible tablets are white, round, biconvex tablets, with a score line in one side and dimensions 10.0±0.1mm and 2.9±0.2mm in thickness. The orodispersible tablets are not intended to be divided.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Acute treatment of the headache phase of migraine attacks, with or without aura. Rizatriptan should not be used prophylactically.
4.2 Posology and method of administration
Adults 18 years of age and older The 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.
Some patients should receive the lower (5 mg) dose of rizatriptan, in particular the following patient groups:
• patients on propranolol. Administration of rizatriptan should be separated by at least two hours from administration of propranolol. (See section 4.5)
• patients with mild or moderate renal insufficiency.
• patients with mild to moderate hepatic insufficiency.
Doses should be separated by at least two hours; no more than two doses should be taken in any 24-hour period.
Patiens older than 65 years
The safety and efficacy of rizatriptan in patients older than 65 years have not been systematically evaluated.
Paediatric patients
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.
Rizatriptan orodispersible tablets need not be taken with liquid. The orodispersible tablets are not intended to be divided.
Method of administration
The orodispersible tablet can be used in situations in which liquids are not available, or to avoid the nausea and vomiting that may accompany the ingestion of tablets with liquids.
4.3 Contraindications
• Hypersensitivity to rizatriptan or to any of the excipients listed in section 6.1.
• Concurrent administration of monoamine oxidase (MAO) inhibitors or use within two weeks of discontinuation of MAO inhibitor therapy. (See section 4.5)
• Rizatriptan is contraindicated in patients with severe hepatic or severe renal insufficiency.
• Rizatriptan is contraindicated in patients with a previous cerebrovascular accident (CVA) or transient ischaemic attack (TIA).
• Moderately severe or severe hypertension, or untreated mild hypertension.
• Established coronary artery disease, including ischaemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischaemia), signs and symptoms of ischaemic heart disease, or Prinzmetal's angina.
• Peripheral vascular disease.
• Concomitant use of rizatriptan and ergotamine, ergot derivatives (including methysergide), or other 5-HT1B/1D receptor agonists. (See section 4.5).
4.4 Special warnings and precautions for use
Rizatriptan should only be administered to patients in whom a clear diagnosis of
migraine has been established. Rizatriptan should not be administered to patients with basilar or hemiplegic migraine.
Rizatriptan should not be used to treat 'atypical' headaches, i.e. those that might be associated with potentially serious medical conditions, (e.g. CVA, ruptured aneurysm) in which cerebrovascular vasoconstriction could be harmful.
Rizatriptan can be associated with transient symptoms including chest pain and tightness which may be intense and involve the throat (see section 4.8). Where such symptoms are thought to indicate ischaemic heart disease, no further dose should be taken and appropriate evaluation should be carried out.
As with other 5-HT1B/1D receptor agonists, rizatriptan should not be given, without prior evaluation, to patients in whom unrecognised cardiac disease is likely or to patients at risk for coronary artery disease (CAD) [e.g. patients with hypertension, diabetics, smokers or users of nicotine substitution therapy, men over 40 years of age, post-menopausal women, patients with bundle branch block, and those with strong family history for CAD]. Cardiac evaluations may not identify every patient who has cardiac disease and, in very rare cases, serious cardiac events have occurred in patients without underlying cardiovascular disease when 5-HT1 agonists have been administered. Those in whom CAD is established should not be given rizatriptan.
(See section 4.3).
5-HT1B/1D receptor agonists have been associated with coronary vasospasm. In rare cases, myocardial ischaemia or infarction have been reported with 5-HT1B/1D receptor agonists including rizatriptan (see section 4.8).
Other 5-HT1B/1D agonists, (e.g. sumatriptan) should not be used concomitantly with rizatriptan (See section 4.5).
It is advised to wait at least six hours following use of rizatriptan before administering ergotamine-type medications, (e.g. ergotamine, dihydro-ergotamine or methysergide). At least 24 hours should elapse after the administration of an ergotamine-containing
preparation before rizatriptan is given. Although additive vasospastic effects were not observed in a clinical pharmacology study in which 16 healthy males received oral rizatriptan and parenteral ergotamine, such additive effects are theoretically possible, (see section 4.3)
Serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) has been reported following concomitant treatment with triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin noradrenaline reuptake inhibitors (SNRIs). These reactions can be severe. If concomitant treatment with rizatriptan and an SSRI or SNRI is clinically warranted, appropriate observation of the patient is advised, particularly during treatment initiation, with dose increases, or with addition of another serotonergic medication (see section 4.5).
Undesirable effects may be more common during concomitant use of triptans (5-HT1B/1D agonists) and herbal preparations containing St John's wort (Hypericum perforatum).
Angioedema (e.g. facial oedema, tongue swelling and pharyngeal oedema) may occur in patients treated with triptans, among which rizatriptan. If angioedema of the tongue or pharynx occurs, the patient should be placed under medical supervision until symptoms have resolved. Treatment should promptly be discontinued and replaced by an agent belonging to another class of active substances.
The potential for interaction should be considered when rizatriptan is administered to patients taking CYP 2D6 substrates (see section 4.5)
Medication overuse headache (MOH)
Prolonged use of any painkiller for headaches can make them worse. If this situation is experienced or 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 orodispersible tablets contain aspartame, a source of phenylalanine. Phenylalanine may be harmful for people with phenylketonuria.
4.5 Interaction with other medicinal products and other forms of interaction
Ergotamine, ergot derivatives (including methysergide), other 5 HT 1B/1D receptor agonists: Due to an additive effect, the concomitant use of rizatriptan and ergotamine, ergot derivatives (including methysergide), or other 5 HT 1B/1D receptor agonists (e.g. sumatriptan, zolmitriptan, naratriptan) increase the risk of coronary artery vasoconstriction and hypertensive effects. This combination is contraindicated (see section 4.3).
Monoamine oxidase inhibitors: Rizatriptan is principally metabolised via monoamine oxidase, 'A' subtype (MAO-A). Plasma concentrations of rizatriptan and its active N-monodesmethyl metabolite were increased by concomitant administration of a selective, reversible MAO-A inhibitor. Similar or greater effects are expected with non-selective, reversible (e.g. linezolid) and irreversible MAO inhibitors. Due to a risk of coronary artery vasoconstriction and hypertensive episodes, administration of rizatriptan to patients taking inhibitors of MAO is contraindicated. (See section 4.3)
Beta-blockers: Plasma concentrations of rizatriptan may be increased by concomitant administration of propranolol. This increase is most probably due to first-pass metabolic interaction between the two active substances, since MAO-A plays a role in the metabolism of both rizatriptan and propranolol. This interaction leads to a mean increase in AUC and Cmax of 70-80%. In patients receiving propranolol, the 5 mg dose of 'Rizatriptan' should be used. (See section 4.2)
In a drug-interaction study, nadolol and metoprolol did not alter plasma concentrations of rizatriptan.
Selective Serotonin Reuptake Inhibitors (SSRIs) /Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) and Serotonin Syndrome: There have been reports describing patients with symptoms compatible with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of selective serotonin reuptake inhibitors (SSRIs) or serotonin noradrenaline reuptake inhibitors (SNRIs) and triptans (see section 4.4).
In vitro studies indicate that rizatriptan inhibits cytochrome P450 2D6 (CYP 2D6). Clinical interaction data are not available. The potential for interaction should be considered when rizatriptan is administered to patients taking CYP 2D6 substrates.
4.6 Fertility, pregnancy and lactation
Fertility
Effects 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).
Use during pregnancy
The 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.
Use during lactation
Studies 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.
4.7 Effects on ability to drive and use machines
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Rizatriptan has minor influence on the ability to drive and use machines.
Migraine or treatment with rizatriptan may cause somnolence in some patients. Dizziness has also been reported in some patients receiving rizatriptan. Patients should, therefore, evaluate their ability to perform complex tasks during migraine attacks and after administration of rizatriptan.
4.8 Undesirable effects
Rizatriptan (as the tablet and orodispersible tablet formulation) was evaluated in 8630 adult patients for up to one year in controlled clinical studies. The most common undesirable 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 to <1/10]; Uncommon: [>1/1,000 to <1/100]; Rare [>1/10,000 to <1/1,000]; Very rare [<1/10,000], not known [cannot be estimated from the available data]).
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, dysguesia/ bad taste.
Rare: syncope
Not known: seizure, serotonin syndrome.
Eye disorders:
Uncommon: blurred vision.
Cardiac disorders:
Common: palpitation, tachycardia.
Uncommon: arrhythmia, ECG abnormalities
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 heart 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 (for angioedema see also section 4.4).
Musculoskeletal and connective tissue disorders:
Common: regional heaviness.
Uncommon: neck pain, facial pain, regional tightness, stiffness, muscle weakness, 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).
4.9 Overdose
Rizatriptan 40 mg (administered as either a single tablet dose or as two doses with a two-hour interdose interval) has been administered in over 300 adult 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 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 'Rizatriptan'. 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: analgesics, antimigraine preparations; selective serotonin (5HTi) agonists
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, 5HT3; 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
Orodispersible tablets
The efficacy of rizatriptan orodispersible tablets in the acute treatment of migraine attacks was established in two multicentre, randomised, placebo-controlled trials that were similar in design to the trials of rizatriptan orodispersible tablets. In one study (n=311), by two hours post-dosing, relief rates in patients treated with rizatriptan orodispersible tablets were approximately 66% for rizatriptan 5 mg and 10 mg, compared to 47% in the placebo group. In a larger study (n=547), by two hours postdosing, relief rates were 59% in patients treated with rizatriptan orodispersible tablets 5 mg, and 74% after 10 mg, compared to 28% in the placebo group. Rizatriptan orodispersible tablets also relieved the disability, nausea, photophobia, and phonophobia which accompanied the migraine episodes. A significant effect on pain relief was observed as early as 30 minutes post-dosing in one of the two clinical trials for the 10 mg dose (see section 5.2 Absorption).
Based on studies with the oral tablet, rizatriptan remains effective in treating menstrual migraine, i.e. migraine that occurs within 3 days before or after the onset of menses.
Rizatriptan orodispersible tablets enables migraine patients to treat their migraine attacks without having to swallow liquids. This may allow patients to administer their medication earlier, for example, when liquids are not available, and to avoid possible worsening of GI symptoms by swallowing liquids.
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 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 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 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 subsets of the paediatric population in the treatment of migraine. See section 4.2 for information on paediatric use.
5.2 Pharmacokinetic properties
Absorption
Rizatriptan is rapidly and completely absorbed following oral administration.
Orodispersible tablets: The mean oral bioavailability of the lingual tablet is approximately 40-45%, and mean peak plasma concentrations (Cmax) are reached in approximately 1.6-2.5 hours (Tmax). The time to maximum plasma concentration following administration of rizatriptan as the lingual tablet formulation is delayed by 30-60 minutes relative to the tablet
Effect of food: The effect of food on the absorption of rizatriptan from the orodispersible tablet 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 orodispersible tablet is administered after meals. (See section 4.2).
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 sulfate 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 pg/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
The 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.
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 1060 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.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development and pharmacokinetics and metabolism.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose,
Maize starch
Silica colloidal anhydrous Aspartame (E951)
Mint powder consisting of:
-mint oil,
-terpeneless mint oil -eucalyptol, menthone,
-isomenthone,
-methyl acetate -menthol
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
Do not store above 30°C
6.5 Nature and contents of container
Rizatriptan is supplied in PA/AL/PVC-Aluminum blisters. Packs of 2, 3, 6, 12 or 18 orodispersible tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Aspire Pharma Limited Bellamy House Winton Road Petersfield Hampshire GU32 3HA
MARKETING AUTHORISATION NUMBER(S)
8
PL 35533/0003
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
31/05/2014
10 DATE OF REVISION OF THE TEXT
31/05/2014