4.1. Therapeutic indications

Acute treatment of the headache phase of migraine attacks, with or without aura, in adults.

4.2. Posology and method of administration

Posology

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.

Paediatric population

Children and Adolescents (under 18 years of age)

The safety and efficacy of rizatriptan in children and adolescents under 18 years of age have not been established.

Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made.

Elderly

The safety and effectiveness of rizatriptan in patients older than 65 years have not been systematically evaluated.

Method of Administration

Rizatriptan 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 section 5.2).

4.3. Contraindications

• Hypersensitivity to the active substance 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. Patients 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 medicines (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 medicine (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, including 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 medicines.

4.5. Interaction with other medicinal products and other forms of interaction

Ergotamine, ergot derivatives (including methysergide), other 5-HT1B/1D receptor agonists

Due to an additive effect, the concomitant use of rizatriptan and ergotamine, ergot derivatives (including methysergide), or other 5-HT1B/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 medicine 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

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative toxicity following first trimester exposure. Animal studies do not indicate reproductive toxicity (see section 5.3).

There is limited data in relation to use of rizatriptan in the second and third trimester of pregnancy. Use of rizatriptan may be considered during pregnancy, if clinically necessary.

Breast-feeding

Rizatriptan is excreted in low concentration in human milk with an average relative infant dose less than < 1 % (less than 6% in worst case scenario based on Cmax in breastmilk). Caution should be exercised when administering rizatriptan to women who are breast-feeding. Infant exposure may be minimised by avoiding breast-feeding for 12 hours after treatment.

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).

4.7. Effects on 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 oral lyophilisate formulation) was evaluated in 8,630 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 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:

Common: insomnia

Uncommon: disorientation, nervousness

Nervous system disorders:

Common: dizziness, somnolence, paresthesia, 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

Gastrointestinal disorders:

Common: nausea, dry mouth, vomiting, diarrhoea, dyspepsia

Uncommon: thirst

Not known: ischaemic colitis

Skin and subcutaneous tissue disorders:

Common: flushing

Uncommon: pruritus, urticaria, angioedema (e.g. facial oedema, tongue swelling, pharyngeal oedema) (for angioedema see section 4.4), rash, sweating

Not 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) or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Rizatriptan 40 mg (administered as either a single tablet 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 side 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 overdose. 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.