Rizatriptan

Registered South African indications:

• Migraine

Contraindications

South African recommendations

Oral (tab, waf)

• Hypersensitivity to rizatriptan or any of the ingredients
• Concurrent administration of monoamine oxidase (MAO) inhibitors including linezolid, or use within 2 weeks of discontinuation of MAO inhibitor therapy
• Uncontrolled hypertension
• Established coronary artery disease
• Ischaemic heart disease
  - Angina pectoris
  - History of myocardial infarction
  - History of documented silent ischaemia
• Signs and symptoms of ischaemic heart disease, or Prinzmetal's angina
• Pregnancy
• Lactation
• Not recommended for use in paediatric patients under 18 years of age
• History of stroke or transient ischaemic attack (TIA)
• Peripheral vascular disease, including (but not limited to) ischaemic bowel disease

Oral (odt)

• Hypersensitivity to the active ingredient or any of its excipients
• Concurrent administration of monoamine oxidase (MAO) inhibitors (including linezolid), or use within 2 weeks of discontinuation of MAO inhibitor therapy
• Severe hepatic insufficiency
• Severe renal insufficiency
• Concomitant use of rizatriptan and ergotamine, ergot derivatives (including methysergide), or other 5-HT_1B/1D receptor agonists
• Uncontrolled hypertension
• Established coronary artery disease
• Ischaemic heart disease (angina pectoris, history of myocardial infarction or documented silent ischaemia)
• Signs and symptoms of ischaemic heart disease or Prinzmetal's angina
• Pregnancy
• Lactation
• History of stroke or transient ischaemic attack (TIA)
• Peripheral vascular disease, including (but not limited to) ischaemic bowel disease
• Not recommended for use in paediatric patients under 18 years of age

Recommendations in other jurisdictions

• Hypersensitivity to the active substance or to any of the excipients
• Concurrent administration of monoamine oxidase (MAO) inhibitors or use within two weeks of discontinuation of MAO inhibitor therapy
• Severe hepatic insufficiency
• Severe renal insufficiency
• Patients with a previous cerebrovascular accident (CVA) or transient ischaemic attack (TIA)
• Moderately severe or severe hypertension
• Untreated mild hypertension
• Established coronary artery disease
• 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-HT_1B/1D receptor agonists

Cautions

South African recommendations

• Renal impairment (tab, waf)
• Mild to moderate renal impairment (odt)
• Hepatic impairment (tab, waf)
• Mild to moderate hepatic impairment (odt)
• Administration in those in whom a clear diagnosis of migraine has not been established
• Administration in those with basilar or hemiplegic migraine
• 'Atypical' headaches, i.e. those that might be associated with potentially serious medical conditions (e.g. stroke, ruptured aneurysm) in which cerebrovascular vasoconstriction could be harmful.
• Where chest pain or tightness is experienced (odt)
• Those at risk for coronary artery disease (CAD)
  - Hypertension
  - Diabetics
  - Smokers
  - Those with strong family history for CAD
• Overuse of rizatriptan for 10 or more days per month
• Coadministration with other 5-HT agonists (waf, tab)
• Coadministration within 6hrs of ergotamine-type medications
• Combined use of selective serotonin reuptake inhibitors/serotonin norepinephrine reuptake inhibitors and triptans including rizatriptan
• Coadministration of propranolol
• Phenylketonuric patients (odt, waf)
• Galactose intolerance e.g. galactosaemia (tab)
• Lapp lactase deficiency (tab)
• Glucose-galactose malabsorption (tab)
• Fructose intolerance (tab)
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Mild to moderate renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Basilar or hemiplegic migraine
• "Atypical" headaches associated with serious medical conditions e.g. cerebrovascular accident, ruptured aneurysm
• Unrecognised cardiac disease
• Symptoms of chest pain and tightness which may be intense and involve the throat (thought to indicate ischaemic heart disease)
• Risk factors for coronary artery disease
  - Hypertension
  - Diabetic patients
  - Smokers or users of nicotine substitution therapy
  - Men ≥40 years of age
  - Post-menopausal women
  - Bundle branch block
  - Strong family history of coronary artery disease
• Prolonged use
• Phenylketonuric patients (waf, odt)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab, waf, odt

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Migraine
- Acute attacks with or without aura

• Oral (tab, waf, odt): Initial: 5-10mg; Repeat dose after 2hrs if needed; Max: 30mg/24hrs

- In patients receiving propranolol

• Oral (tab, waf, odt): Initial: 5mg; Repeat dose after 2hrs if needed; Max: 15mg/24hrs (3 doses in any 24hr period)

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Clinical experience has shown that a 10mg dose provides the optimal clinical benefit, but some patients do respond to lower doses. Onset of relief (i.e. reduction of headache pain to mild or none) can occur within 30 minutes after dosing

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For headache recurrence within 24hrs: If headache returns after relief of the initial attack, further doses 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, is not known

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Clinical studies have shown that patients who do not respond to treatment of an attack may respond to treatment for subsequent attacks

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The orodispersible tablet and wafer should be removed from the packaging with dry hands just prior to dosing and placed on the tongue, where it will dissolve and be swallowed with the saliva

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Indications and dosages registered in other jurisdictions

Migraine
- Acute treatment of the headache phase of migraine attacks, with or without aura

• Oral (tab, waf, odt): Initial: 10mg; Repeat dose after 2hrs if needed; Max: 20mg/24hrs

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For headache recurrence within 24hrs: If headache returns after relief of the initial attack, further doses 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

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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

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- Patients on propranolol

• Oral (tab, odt): Initial: 5mg; Repeat dose after 2hrs if needed; Max: 10mg/24hrs

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 Administration of rizatriptan should be separated by at least 2 hours from administration of propranolol

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Some patients should receive the lower (5mg) dose of rizatriptan, in particular the following patient groups:
- patients on propranolol
- patients with mild or moderate renal insufficiency
- patients with mild to moderate hepatic insufficiency
(See special populations)

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Rizatriptan should not be used prophylactically

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The tablets should be swallowed whole with liquid. 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

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The orodispersible tablet should be removed from the aluminium blister with dry hands just prior to dosing and placed on the tongue, where it will dissolve and be swallowed with the saliva. 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

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated

Recommendations in other jurisdictions

• Caution
• The safety of rizatriptan for 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 postnatal development
• Animal reproductive and developmental studies are not always predictive of human response so rizatriptan should be used during pregnancy only if clearly needed

Breastfeeding

South African recommendations

• Contraindicated

Recommendations in other jurisdictions

• Caution; not recommended
• 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 breastfeeding. Infant exposure should be minimised by avoiding breastfeeding for 24 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)

Renal Impairment

South African recommendations

• Caution; no dose adjustment recommended (tab, waf)
  The maximal plasma concentration of rizatriptan in patients with all degrees of renal impairment was similar to that in healthy subjects (tab, waf)
   
• Mild to moderate: Caution; no dose adjustment recommended (odt)
• Severe: Contraindicated (odt)

Recommendations in other jurisdictions

• Mild to moderate: Caution; dose adjustment recommended
  5mg/dose; Max: 10mg/24hrs
• Severe: Contraindicated

Hepatic Impairment

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended (tab, waf)
  Following oral administration in patients with hepatic impairment caused by mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of rizatriptan were similar to those seen in young male and female subjects
• Severe: Caution, no information available (tab, waf)
   
• Mild to moderate: Caution; no dose adjustment recommended (odt)
• Severe: Contraindicated (odt)

Recommendations in other jurisdictions

• Mild to moderate: Caution; dose adjustment recommended
  5mg/dose; Max: 10mg/24hrs
• Severe: Contraindicated

Elderly

South African recommendations

• No dose adjustment recommended

Recommendations in other jurisdictions

• Caution; no information available

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dizziness
• Somnolence
• Paresthesia
• Headache
• Hypoaesthesia
• Decreased mental acuity
• Tremor
• Ataxia
• Syncope
• Seizure
• Serotonin syndrome
• Disorientation
• Insomnia
• Nervousness
• Fatigue

Cardiovascular Disorders

• Palpitation
• Tachycardia
• Myocardial ischaemia or infarction
• Cerebrovascular accident
• Arrhythmia
• ECG abnormalities
• Bradycardia
• Hot flushes
• Hypertension
• Peripheral vascular ischaemia
• Chest pain

Respiratory Disorders

• Pharyngeal discomfort
• Dyspnoea
• Wheezing

Gastrointestinal Disorders

• Nausea and vomiting
• Dry mouth
• Diarrhoea
• Thirst
• Dyspepsia
• Ischaemic colitis
• Abdominal pain

Musculoskeletal Disorders

• Regional heaviness
• Neck pain
• Regional tightness
• Stiffness
• Muscle weakness
• Facial pain
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Flushing
• Sweating
• Pruritus
• Urticaria
• Angioedema
  - Facial oedema
  - Tongue swelling
  - Pharyngeal oedema
• Rash
• Toxic epidermal necrolysis

Immune System Disorders

• Hypersensitivity reaction
• Anaphylaxis/ anaphylactoid reaction

Sensory Disorders

• Blurred vision
• Dysgeusia
• Vertigo

• Ergotamine
• Ergot derivatives
• Methysergide
• Other 5-HT_1B/1D receptor agonists
• Sumatriptan
• Zolmitriptan
• Naratriptan
• Monoamine oxidase inhibitors
• Linezolid
• Beta blockers
• Propranolol
• Selective serotonin reuptake inhibitors
• Serotonin noradrenaline reuptake inhibitors
• CYP2D6 substrates

Other interactions

• St. John's wort (Hypericum perforatum)

None routine. Specific cases may require

• Electrocardiogram (ECG) 
• Cardiovascular evaluation

Additional observations

• Monitor headache severity
• Look for signs/symptoms suggestive of angina

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 binds selectively with high affinity to human 5-HT_1B and 5-HT_1D 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-HT_1B and 5-HT_1D 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-HT_1B and 5-HT_1D 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. 

Tablet 5mg

• Maxalt (MSD) originator

Tablet 10mg

• Maxalt (MSD) originator

Tablet dispersible 5mg

• Rizatriptan Mylan ODT (Mylan)

Tablet dispersible 10mg

• Migrazan ODT (Pharmacare)
• Micrania Melts 10 mg (Pharma Dynamics)
• Rizagran Melt 10 (Sandoz SA)
• Rizatriptan Mylan ODT (Mylan)
• Rizatriptan Unicorn (Sandoz SA)

Wafer 10mg

• Maxalt RPD (MSD) originator