Agents for Migraine - Information Summary
Drug Name:Agents for Migraine - Information Summary
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Patient Information
Pharmacology/ Pharmacokinetics
Interaction with Food
Pregnancy and lactation
Drug Interaction:
Agents for Migraine include-
Ergotamine derivatives
Dihydrergotamine mesylate, Ergotamine tartarate, Methysergide maleate
Agents for Migraine include-
Serotonin 5-HT1 agonists
Almotriptan, Eletriptan, Frovatriptan, Naratripptan, Rizatriptan, Sumatriptan, Zolmitriptan
Drug interactions- Summary
Cimetidine +
Zolmitriptan
Following coadministration with cimetidine the half life and AUC of a 5mg dose
of zolmitriptan and its active metabolite were approximately doubled
Potent CYP3A4 inhibitors e.g ketoconazole/itraconazole/nefazodone/ troleandomycin,
clarithromycin/ rotonavir/nelfinavir + Almotriptan/ Electriptan
Coadmin. of almotriptan and ketoconazole (400mg/day for 3 days) resulted
in an increase in AUC and maximal plasma concentration of almotriptan.
Do not use electriptan within 72 hurs of treatment with potent CYP3A4 inhibitors
MAOIs + Almotriptan/ Rizatriptan /Sumitriptan /Zolmitriptan
Use of certain 5-HT1 agonists cocurrently with or within 2 weeks following
discontinuing an MAOI is contraindicated. It is necessary to use such
agents together, naratriptan, eletriptan, and fravotriptan appear to be
less likely to interact with MAOIs.
Almotriptan, /Frovatriptan,/Naratriptan,/Rizatriptan/Sumitriptan,/Zolmitriptan +
SSRIs. /Fluoxetine/fluvoxetine /paroxetine,/ serataline
Reports of weakness, hyperflexia, and incordination with
combined use of SSRIs. If concomitant use is clinically warranted,
observe the patient carefully. No interaction was observed when
Rizatriptan was coadministerd with paroxetine.
Fluoxetine had not effect on almotriptan, but clearance,
Ergot alkaloids/ (dihydroergotamine/methysergide ) + 5-HT1 agonists
Risk of vasopatic recations may ber increased . Use of 5-HT1 agonists
within 24 hours of treatment with an ergot containg medication is
contraindicated.
5-HT1 agonists + Ergot alkaloids/ (dihydroergotamine/methysergide )
Risk of vasospatic recations may be increased. Co-administration
of two 5-HT1 agonists within 24 hours is contraindicated
Sibutramine + Naratriptan /Rizatriptan/ Sumatriptan/ Zolmitriptan
a (serotonin syndrome ) including CNS irritability , motor weakness,
shivering , myoclonus , and altered consciousness may occur.
Co-administration is not recommended. Monitor the patient for adverse
effects if concurrent use cannot be avoided.
Propranolol + Rizatriptan
Coadministration of 240mg/day propranolol and a single
dose of 10mg rizatriptan in healthy subjects
Propranolol + Zolmitriptan
Cmax and AUC of zolmitriptan increased 1.5 fold but decreased for the
N-desmethyl metabolite. No effects on blood pressure or pulse rate
were observed
Propranolol + Frovatriptan
Propranolol increased the AUC of 2.5mg frovatripotan in males by 60%
and in females by 29%. The Cmax of frovatriptan was increased by 23%
in males and 16% in females in the presence of propranolol.
Propranolol + Eletriptan
Cmax and AUC of eritriptan were increased by 10% and 33% respy.
in the presence propranolol . No interactive increase in blood pressure
were observed
Oral contraceptives +Frovatriptan
Mean Cmax and AUC of frovatriptan are 30% higher in these subjects
taking oral contraceptives compared with those not taking oral
contraceptives
Indication:
Migraine treatment
Agents for Migraine include-
Ergotamine derivatives Dihydrergotamine mesylate, Ergotamine tartarate, Methysergide maleate
Agents for Migraine include-
Serotonin 5-HT1 agonists Almotriptan, Eletriptan, Frovatriptan, Naratripptan, Rizatriptan, Sumatriptan, Zolmitriptan
Adverse Reaction:
Serious coronary vasospasm , transient mycardial ischemia, ventricullar fibrillation/ tachycardia, and MI have been associated with 5-HT1 agonists.
Oral - these agents have been well tolerated. Across all doses, most adverse reactions are mild and transcient and did not lead to long lasting effects.
ALMOTRIPTAN -
Cardiovascular-
Palpitations, tachycardia, vasodilation 1%) hypertension, sycope
(less than 0.1%)
CNS-
Dizziness, somlolence, ( 1% to more) anxiety, CNS stimulation, hypesthesia, insomnia,
restlessness, shakiness, tremor, vertigo 1% abnormal coordination, change in dreams,
depressive symptoms, euphoria, hyperflexia, hypertonia, impaired concentrations, nervousness, neuropathy,,nightmares ( less than 0.1%)
Dermatologic-
Dermatitis, diaphoresis, eryhmea, pruritus, rash 1% photosensitivity
reactions ( less than 0.1% )
GI-
Diarrhea, dyspepsia, vomiting abdominal cramps, s or pain colitis, esophageal reflux,
gastritis, gastroenteritis, increased salivation, increased thirst.
Metabolic-
Hyperglycemia, increased serum CPK, hypercholesrolemia, increase GGT
Musculoskeletal-
Muscular weakness, myalgia, athlagia, arthiritis, myopathy
Respiratory-
Bronchitis, dyspnea, epistaxis, pharnygnitis, rhinitis, sinusitis, hyperventilation,
sneezing
Special senses-
conjuntivitis, ear pain, eye irritation, taste alteration., dry eyes, eye pain, otistis
otitis media, tinnitus
Miscellaneous-
Headache, asthenia, back pain, chest pain, chills, dysmennorrhea, fatigue,
neck pain, rigid back, fever
Contra-Indications:
Injectable preparation used IV-
Potential to cause coronary vasospasm,patients with ischemic heart disease ( angina pectoris ), history of MI , strokes, ischemic attacks
TIAs or documented silent ischemia
Prinzmetal variant angina or significant underlying cardiovascular disease
Concurrent use of ( within 24 hours of ) ergot containing prepn or ergot type medications such as dihydroergotamine or methysergide.
Concurrent monoamine oxidase inhibitors MAOI therapy ( or within 2 weeks of discontinuing an MAOI ( except eletriptan )
Naratriptan and sumitriptan - cerbrovascular or peripheral vascular syndromes, severe impairment, ( child Pugh grade C) severe renal impairment (Ccr less than 15mL/min ( naratriotan only)
Frovatriotan and eletriptan - peripheral vascular disease
Eletriptan - severe hepatic impairment
Warnings/precautions-
Risk of myocardial ischemia or MI and other adverse cardiac events-
because of the potential of these compounds to cause coronary vasospasm, do not give these agents to patients with documented ischemic or vasopastic coronary artery disease
It is strongly recommended that 5-HT1 agonists not be given to patients in whom unrecognized coronary artery disease CAD is predicted by the presence of risk factors eg. hypertension, hyperchloesrolemia, smoking, obesity, diabetes, strong family history of CAD, female with surgical or physilogical menopause or male older than 40 years of age) .
Patients with symptomatic Wolff- Parkinson -
White syndrome or arrhythmias associated with cardiac accessory conduction pathway disorders should not receive zolmitriptan
Cardiac events and fatalities associated with 5-HT1 agonists-
Serious adverse cardiac events including acute MI , life threatening disturbances of cardiac
rhythm, and death have been reported within few hours following admin. of 5- HT1 agonists.
Considering the use of 5 - HT1 agonists in patients with migraine , the incidence of these events is extremely low.
Cerbrovascular events and fatalities with 5-HT1 agonists-
Cerebral hemorrhage , subarachnoid hemorrhage , stroke, and other cerebrovascular events have been reported in patients treated with 5-Ht1 agonists and some have resulted in fatalites.
It should be noted that patients with migraine may be at increased risk of certain cerebrovacular events eg. stroke, hemorrhage, TIA
Increase in blood pressure- significant increase in blood pressure including hypertensive crisis have been reported on rare occassions in patients with a history of with or without hypertension trreated with 5HT1 agonists.
5-HT1 agonists are contraindicated in patients with uncontrolled hypertension.
Renal function impairment-
Use rizatriptan and sumitriptan with caution in dialysis patients becausec of decrease in clearance
Hepatic function impairment-
Administer with caution to patients with diseases that may alter the absorption,metabolism,
or excretion of drugs.
Phtosensitivity-
Photosensitization may occur. Caution patients to take protective measures
Pregnancy -Use during pregnancy only if the potential benefits justifies the potential risk to the fetus
Lactation-
Sumatriptan and eletriptan are excreted in human breast milk.
Naratriptan -related material is excreted in milk of rats.
Rizatriptan is extensively excreted in rat milk at a level 5-fold or greater than matenal plasms levels
Frovatriptan and its metabolites are excreted in the milk of lactating rats with maximum concentration being 4 fold than seen in blood.
Excercise caution when administering to a nursing woman
Children-
Safety and efficacy have not beenestablished.
Elderly-
Pharmacokinetics disposition of 5-HT1 agonists in the elderly is similar to that seen in younger adults.
Patient Information:
Injection- sumitriptan-
Instruct patients who are advised to self administer sumatriptan in medically unsupervised situations,on the proper use of the product prior to doing so for the first time, including loading the auto-injector and discarding empty syringes
For adults the usual dose is a single injection given just below the skin.
Administer as soon as migraine symptoms appear, but it may given at any time during the attack.
A second injection can be given if symptoms of migraine return.
Do not use more than 2 injections/24 hours and allow at least 1 hour between each dose.
The patient may experience pain or redness at the site of injection, but this usually lasts less than
1 hour.
Intranasal- for adults,
Usual dose is a single nasal spray into 1 nostril.
If headache returns, a second nasal spray may be given 2 hours after the first spray.
For any attack where the patient has no response to the first nasal spray, do not use a second nasal spray without consulting a physician
Do not administer more than 40mg sumatriptan or more than 10mg zolmitriptan nasal spray in any 24 hour period.
Oral-
Take a single dose with fluids as soon as symptoms of migraine appear.
A second dose may be taken if symptoms return, but no sooner than 2 hours ( sumatriptan,
zolmitriptan, eletriptan ) or 4 hours ( naratriptan, ) following the first dose.
For a given attack if there is no response to the first dose do not take a second dose without first consulting a physician.
Do not take more than 200mg sumatriptan, more than 5mg naratriptan, more than 10mg zolmitriptan or more than 80mg eletriptan in any 24 hours period.
Tell a physician if the patient has risk factors for heart disease (eg. high blood pressure,
high cholesterol, obesity, diabetes, smoking, strong family history of heart disease or stroke,a male over 40 years of age postmenopausal women )
These agents are intended to relieve migraine but not to prevent or reduce the number of attacks.
Use only to treat an actual migraine attack or cluster headache ( sumatriptan inj only )
Instruct patients not to use these agents if they are pregnant, think that they might be pregnant,are trying to become pregnant, or not taking adequate contraception , unless they have discussed this with their physician
If pain, tightness, pressure or heaviness in the chest , throat, neck or jaw occurs when using these agents, instruct patients to discuss it with a physician before using more.
If the chest pain is severe or does not go away, instruct patients to immediately call a physician
If sudden or severe abdominal pain occurs following naratriptan or sumatriptan admin.,
instruct patient to immediately call a physician
If shortness of breath, wheezing ,heart throbbing, swelling of eye lids, face or lips, skin rash,
skin lumps, or hives occur, advice patients to immediately tell a physician .
Instruct patients not to take additional dose unless directed by the physician.
If feelings of tingling, heat, flushing ( redness of face lasting for a short time) heaviness, pressure,drowsiness, dizziness, tiredness, or sickness develop, instruct patients to tell a physician
Migraine or treatment with Rizatriptan may cause somnolence in some patients. Dizziness also has been reported.
Evalute ability to perform complex tasks during migraine and after administration of Rizatriptan.
Instruct patiens not to remove the blister from the outer pouch until just prior to dosing
zolmitriptan or rizatriptan orally -disintegrating tablets.
Instruct patients to peel blister packs open with dry hands and to place orally-disintegrating
tablets on the tongue,where it will dissolve and be swalllowed with the saliva.
Photosensitization ( photoallergy or photoxicity ) may occur.
Therefore, caution patients to take protective measures (ie. sunscreens, protective clothing ) against exposure to sunlight or ultraviolet light until tolerance is determined
Pharmacology/ Pharmacokinetics:
Pharmacology-
Sumatriptan, naratriptan, zolmitriptan, rizatriptan, frovatriptan, eletriptan and almotriptan are selective
5-hydroxytryptamine1 (5-HT1 or serotonin ) receptor agonists
Pharmacokinetics-
Renal Function Impairment--
Zolmitriptan -Clearance of zolmitriptan was reduced by 25% in patients with severe renal impairment ( Ccr approx 5 to 25mL/min. No significant change was observed in those with moderate renal
impairment
Naratriptan - Clearance of naratriptan was reduced by 50% in patients with moderate renal impairment ( Ccr 18 to 39 mL/min. resultiing in an increase in mean half life from 6 hours ( healthy ) to 11 hours (range 7 to 20 hours).
Rizatriptan- in hemodialysis patients ( Ccr less than 2mL/min/ 1.73m2 ) the AUC for rizatripotan was approximately 44% greater than that in patients with normal renal function.
Amlotriptan - Clearance of amlotriptan was approximately 65% lower in patients with severe renal impairment ( Ccr between 10 and 30mL/min ) and approximately 40% lower in patients with moderate renal impairment ( Ccr between 31 and 71 mL/min).
Frovatriptan - because less than 10% of frovatriptan is partially impaired patients excreted in urine after an oral dose, it is unlikely that the exposure of frovatriptan will be affected by renal impairment.
The pharmacokinetics frovatriptan following a single oral dose of 2.5mg was not different in patients with renal impairment
Hepatic Function Impairment-
liver plays an important role in presystemic clearance of 5-HT1 agonists. Accodingly the bioavailability may be markedly increased in patientsdwith liver disease.
Sumatriptan -Oral - in a small study of hepatically impaired patients, sumatriptan AUC and Cmax increased by approximately 70% and Tmax decreased by 40 minutes.
Zolmitriptan - in severely hepatically impaired patients, the mean Cmx and Tmax and AUC of zolmitriptan were increased 1.5, 2 and 3 fold respy.
Administer zolmitriptan with caution in patients with liver disease, generally using doses less than 2.5mg
Rizatriptan- following oral admin in patients with hepatic impairment caused by mild to moderate alcoholic cirrhosis of the liver , plasma concn. of rizatriptan were similar in patients with mild to hepatic insufficiency compared with a control group of healthy subjects, plasma concentration of rizatriptan were approx. 30% greater in patients with moderate hepatic insufficiency.
Almotriptan- the pharmacokinetics of almotripotan have not been assessed in this population.
Based on mechanisms of almotriptan clearance the maximum decrease expected because the hepatic impairment would be 60%
Eletriptan - the effects of severe effects of hepatic impairment on eletriptan metabolism have not been evaluated.
Elderly- there is stastically significant increase in electriptan half life )
betrween elderly 65 to 93 years of age and younger adults subjects ( 18 to 45 years of age )
Interaction with Food:
Food has significant effect on oral 5-HT1 agonists bioavailability, but delays sumatriptans Tmax by aaproximately 30 minutes and rizatriptans time to reach peak concentration by 1 hour. AUC and Cmax of eletriptan are increased approximately 20% to 30% following oral admin. of a high fat meal.
Pregnancy and lactation:
Pregnancy-
There are no adequate and well controlled studies in pregnant women
Use during pregnancy only if the potential benefits justifies the potential risk to the fetus
Lactation-
Sumatriptan and eletriptan are excreted in human breast milk.
Lactating rats dosed with zolmitriptan had milk levels equivalent to maternal plasma levels at 1 hour
and 4 times higher than plasma levels at 4 hours
Naratriptan -related material is excreted in milk of rats.
Rizatriptan is extensively excreted in rat milk at a level 5-fold or greater than matenal plasms levels
Frovatriptan and its metabolites are excreted in the milk of lactating rats with maximum concentration
being 4 fold than seen in blood.
Excercise caution when administering to a nursing woman
Children-
safety and efficacy have not beenestablished.
Elderly-
Pharmacokinetics disposition of 5-HT agonists in the elderly is similar to that seen in younger adults.