(zohl mi trip' tan)
P / L : Contraindication - pregnancy; Caution - lactation (breast feeding)
|| See TERMINOLOGY & ABBREVIATIONS ||
|Important Safety Information||
|ATC Classification||N02CC03 - zolmitriptan; Belongs to the class of selective serotonin (5HT1) agonists preparations. Used to relieve migraine.|
|Indication(s)||Zolmitriptan is indicated for the acute treatment of migraine with or without aura in adults. Only use Zolmitriptan if a clear diagnosis of migraine has been established. If a patient has no response to Zolmitriptan treatment for the first migraine attack, reconsider the diagnosis of migraine before Zolmitriptanis administered to treat any subsequent attacks. Zolmitriptan is not indicated for the prevention of migraine attacks. Safety and effectiveness of Zolmitriptan have not been established for cluster headache.|
|Dosage & Administration||
Migraine attack: The recommended starting dose of Zolmitriptan is 1.25 mg or 2.5 mg. The 1.25 mg dose can be achieved by manually breaking the functionally-scored 2.5 mg tablet in half. The maximum recommended single dose of Zolmitriptan is 5 mg.
In controlled clinical trials, a greater proportion of patients had headache response following a 2.5 mg or 5 mg dose than following a 1 mg dose. There was little added benefit from the 5 mg dose compared to the 2.5 mg dose, but adverse reactions were more frequent with the 5 mg dose.
Recurrent attacks: If the migraine has not resolved by 2 hours after taking Zolmitriptan, or returns after a transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose is 10 mg in any 24-hour period.
The safety of Zolmitriptan in the treatment of an average of more than three migraines in a 30-day period has not been established.
Dosing in Patients with Hepatic Impairment
The recommended dose of Zolmitriptan in patients with moderate to severe hepatic impairment is 1.25 mg (one-half of one 2.5 mg Zolmitriptan tablet) because of increased zolmitriptan blood levels in these patients and elevation of blood pressure in some of these patients. Limit the total daily dose in patients with severe hepatic impairment to no more than 5 mg per day.
The use of Zolmitriptan orally disintegrating tablets is not recommended in patients with moderate or severe hepatic impairment because these orally disintegrating tablets should not be broken in half.
May be taken with or without food.
|Special Precautions||May be at risk of certain cerebrovascular events. Cerebral & subarachnoid haemorrhage, stroke & other cerebrovascular events. Symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated w/ other cardiac accessory conduction pathways. Ischaemic heart disease. Patients with or without HTN. Pregnancy & lactation. Childn <12 yr & adolescent 12-17 yr. Elderly >65 yr.|
|Adverse Drug Reactions||
Abdominal pain, dry mouth, nausea, vomiting; muscle weakness, myalgia; sensation abnormalities or disturbances, dizziness, headache, hyperaesthesia, paraesthesia, somnolence, warm sensation; palpitations; asthenia, heaviness, tightness, pain or pressure in throat, neck, limbs or chest.
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
In a long-term, open-label study where patients were allowed to treat multiple migraine attacks for up to 1 year, 8% (167 out of 2,058) withdrew from the trial because of adverse reaction.
The most common adverse reactions (≥5% and >placebo) in these trials were neck/throat/jaw pain, dizziness, paresthesia, asthenia, somnolence, warm/cold sensation, nausea, heaviness sensation, and dry mouth.
Table 1 lists the adverse reactions that occurred in ≥ 2% of the 2,074 patients in any one of the Zolmitriptan 1 mg, 2.5 mg, or 5 mg dose groups in the controlled clinical trials of Zolmitriptan in patients with migraines (Studies 1, 2, 3, 4, and 5). Only adverse reactions that were at least 2% more frequent in a Zolmitriptan group compared to the placebo group are included.
Several of the adverse reactions appear dose related, notably paresthesia, sensation of heaviness or tightness in chest, neck, jaw, and throat, dizziness, somnolence and possibly asthenia and nausea.
Table 1: Adverse Reaction Incidence in Five Pooled Placebo-Controlled Migraine Clinical Trials1
There were no differences in the incidence of adverse reactions in controlled clinical trials in the following subgroups: gender, weight, age, use of prophylactic medications, or presence of aura. There were insufficient data to assess the impact of race on the incidence of adverse reactions.
Less Common Adverse Reactions with Zolmitriptan Tablets
In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled studies, the role of Zolmitriptan in their causation cannot be reliably determined. Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Adverse reaction frequencies were calculated as the number of patients who used Zolmitriptan tablets and reported a reaction divided by the total number of patients exposed to Zolmitriptan tablets (n=4,027). Reactions were further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: infrequent adverse reactions (those occurring in 1/100 to 1/1,000 patients) and rare adverse reactions (those occurring in less than 1/1,000 patients).
General: Infrequent were allergic reactions.
Cardiovascular: Infrequent were arrhythmias, hypertension, and syncope. Rare was tachycardia.
Neurological: Infrequent were agitation, anxiety, depression, emotional lability and insomnia; Rare were amnesia, hallucinations, and cerebral ischemia.
Skin: Infrequent were pruritus, rash and urticaria.
Urogenital: Infrequent were polyuria, urinary frequency and urinary urgency.
Adverse Reactions with Zolmitriptan Oral Disintegrating Tablets
The adverse reaction profile seen with Zolmitriptan oral disintegrating tablets was similar to that seen with Zolmitriptan tablets.
The following adverse reactions were identified during post approval use of Zolmitriptan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The reactions enumerated include all except those already listed in the Clinical Trials Experience section above or the Warnings and Precautions section.
As with other 5-HT1B/1D agonists, there have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving Zolmitriptan. Zolmitriptan is contraindicated in patients with a history of hypersensitivity reaction to Zolmitriptan.
Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and Zolmitriptan within 24 hours of each other is contraindicated.
MAO-A inhibitors increase the systemic exposure of zolmitriptan and its active N-desmethyl metabolite. Therefore, the use of Zolmitriptan in patients receiving MAO-A inhibitors is contraindicated.
Concomitant use of other 5-HT1B/1D agonists (including triptans) within 24 hours of Zolmitriptan treatment is contraindicated because the risk of vasospastic reactions may be additive.
Selective Serotonin Reuptake Inhibitors and Serotonin Norepinephrine Reuptake Inhibitors
Cases of life-threatening serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
Following administration of cimetidine, the half-life and blood levels of zolmitriptan and its active N-desmethyl metabolite were approximately doubled. If cimetidine and Zolmitriptan are used concomitantly, limit the maximum single dose of Zolmitriptan to 2.5 mg, not to exceed 5 mg in any 24-hour period.
|Pregnancy Category (FDA) & use in specific population||
Pregnancy Category C
There are no adequate and well- controlled studies in pregnant women; therefore, Zolmitriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals resulted in embryolethality and fetal abnormalities (malformations and variations) at clinically relevant exposures.
When zolmitriptan was administered to pregnant rats during the period of organogenesis at oral doses of 100, 400, and 1200 mg/kg/day (plasma exposures (AUCs) ≈280, 1100, and 5000 times the human AUC at the maximum recommended human dose (MRHD) of 10 mg/day), there was a dose-related increase in embryolethality. A no-effect dose for embryolethality was not established. When zolmitriptan was administered to pregnant rabbits during the period of organogenesis at oral doses of 3, 10, and 30 mg/kg/day (plasma AUCs ≈1, 11, and 42 times the human AUC at the MRHD), there were increases in embryolethality and in fetal malformations and variations. The no-effect dose for adverse effects on embryo-fetal development was associated with a plasma AUC similar to that in humans at the MRHD. When female rats were given zolmitriptan during gestation, parturition, and lactation at oral doses of 25, 100, and 400 mg/kg/day (plasma AUCs ≈70, 280, and 1100 times that in human at the MRHD), an increased incidence ofhydronephrosis was found in the offspring. The no-effect dose was associated with a plasma AUC ≈280 times that in humans at the MRHD.
It is not known whether zolmitriptan is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Zolmitriptan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
In rats, oral dosing with zolmitriptan resulted in levels in milk up to 4 times higher than in plasma.
The safety and effectiveness in pediatric patients have not been established. Therefore, Zolmitriptan is not recommended for use in patients under 18 years of age.
One randomized, placebo-controlled clinical trial of Zolmitriptan tablets (2.5, 5 and 10 mg) evaluated 696 pediatric patients (aged 12-17 years) with migraines. This study did not demonstrate the efficacy of Zolmitriptan compared to placebo in the treatment of migraine in adolescents. Adverse reactions in the adolescent patients treated with Zolmitriptan were similar in nature and frequency to those reported in clinical trials in adults treated with Zolmitriptan. Zolmitriptan has not been studied in pediatric patients less than 12 years old.
In the postmarketing experience with triptans, including Zolmitriptan, there were no additional adverse reactions seen in pediatric patients that were not seen in adults.
Clinical studies of Zolmitriptan did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) prior to receiving Zolmitriptan.
The pharmacokinetics of zolmitriptan were similar in geriatric patients (aged > 65 years) compared to younger patients.
Patients with Hepatic Impairment
After oral Zolmitriptan administration, zolmitriptan blood levels were increased in patients with moderate to severe hepatic impairment, and significant elevation in blood pressure was observed in some of these patients. Therefore, adjust the Zolmitriptan dose and administer with caution in patients with moderate or severe hepatic impairment.
Mechanism of Action
Zolmitriptan binds with high affinity to human recombinant 5HT1D and 5-HT1B receptors, and moderate affinity for 5-HT1A receptors. The N-desmethyl metabolite also has high affinity for 5-HT1B/1D and moderate affinity for 5-HT1A receptors.
Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of Zolmitriptan for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.
Zolmitriptan is well absorbed after oral administration for both Zolmitriptan tablets and the Zolmitriptan orally disintegrating tablets. Zolmitriptan displays linear kinetics over the dose range of 2.5 to 50 mg.
The AUC and Cmax of zolmitriptan are similar following administration of Zolmitriptan tablets and Zolmitriptan orally disintegrating tablets, but the Tmax is somewhat later with Zolmitriptan, with a median Tmax of 3 hours for Zolmitriptan orally disintegrating tablet compared with 1.5 hours for the Zolmitriptan tablet. The AUC, Cmax, and Tmax for the active N-desmethyl metabolite are similar for the two formulations.
During a moderate to severe migraine attack, mean AUC0-4 and Cmax for zolmitriptan, dosed as a Zolmitriptan tablet, were decreased by 40% and 25%, respectively, and mean Tmax was delayed by one-half hour compared to the same patients during a migraine free period.
Food has no significant effect on the bioavailability of zolmitriptan. No accumulation occurred on multiple dosing.
Mean absolute bioavailability is approximately 40%. The mean apparent volume of distribution is 7.0 L/kg. Plasma protein binding of zolmitriptan is 25% over the concentration range of 10- 1000 ng/mL.
Zolmitriptan is converted to an active N-desmethyl metabolite; the metabolite concentrations are about two-thirds that of zolmitriptan. Because the 5HT1B/1D potency of the metabolite is 2 to 6 times that of the parent compound, the metabolite may contribute a substantial portion of the overall effect after Zolmitriptan administration.
Total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively. About 8% of the dose was recovered in the urine as unchanged zolmitriptan. Indole acetic acid metabolite accounted for 31% of the dose, followed by N-oxide (7%) and N-desmethyl (4%) metabolites. The indole acetic acid and N-oxide metabolites are inactive.
Mean total plasma clearance is 31.5 mL/min/kg, of which one-sixth is renal clearance. The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion.
In patients with severe hepatic impairment, the mean Cmax, Tmax, and AUC0-âˆž of zolmitriptan were increased 1.5-fold, 2-fold (2 vs. 4 hours), and 3-fold, respectively, compared to subjects with normal hepatic function. Seven out of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a 10 mg Zolmitriptan dose. Adjust the Zolmitriptan Dose in patients with moderate or severe hepatic impairment.
Clearance of zolmitriptan was reduced by 25% in patients with severe renal impairment (Clcr ≥ 5 â‰¤ 25 mL/min) compared to subjects with normal renal function (Clcr > = 70 mL/min); no significant change in clearance was observed in patients with moderate renal impairment (Clcr ≥ 26 â‰¤ 50 mL/min).
Zolmitriptan pharmacokinetics in healthy elderly nonmigraineur volunteers (age 65â€“76 years) was similar to those in younger non-migraineur volunteers (age 18 - 39 years).
Mean plasma concentrations of zolmitriptan were up to 1.5 fold higher in females than males.
Retrospective analysis of pharmacokinetic data between Japanese and Caucasians revealed no significant differences.
No differences in the pharmacokinetics of zolmitriptan or its effects on blood pressure were seen in mild to moderate hypertensive volunteers compared with normotensive controls.
Drug Interaction Studies
All drug interaction studies were performed in healthy volunteers using a single 10 mg dose of Zolmitriptan and a single dose of the other drug except where otherwise noted.
Following one week of administration of moclobemide (150 mg twice daily), a specific MAO-A inhibitor, there was an increase of about 25% in both Cmax and AUC for zolmitriptan and a 3-fold increase in the Cmax and AUC of the active Ndesmethyl metabolite of zolmitriptan. MAO inhibitors are contraindicated in Zolmitriptan-treated patients.
Selegiline, a selective MAO-B inhibitor, at a dose of 10 mg/day for 1 week, had no effect on the pharmacokinetics of zolmitriptan and its metabolite.
Following the administration of cimetidine, the half-life and AUC of zolmitriptan (5 mg dose), and its active metabolite, were approximately doubled.
The pharmacokinetics of zolmitriptan, as well as its effect on blood pressure, were unaffected by 4 weeks of pretreatment with oral fluoxetine (20 mg/day).
Cmax and AUC of zolmitriptan were increased 1.5-fold after one week of dosing with propranolol (160 mg/day). Cmax and AUC of the N-desmethyl metabolite were reduced by 30% and 15%, respectively. There were no changes in blood pressure or pulse rate following administration of propranolol with Zolmitriptan.
A single 1 gram dose of acetaminophen did not alter the pharmacokinetics of zolmitriptan and its N-desmethyl metabolite. However, Zolmitriptan administration delayed the Tmax of acetaminophen by one hour.
A single 10 mg dose of metoclopramide had no effect on the pharmacokinetics of zolmitriptan or its metabolites.
Retrospective analysis of pharmacokinetic data across studies indicated that mean Cmax and AUC of zolmitriptan were increased by 30% and 50%, respectively, and Tmax was delayed by one-half hour in women taking oral contraceptives. The effect of Zolmitriptan on the pharmacokinetics of oral contraceptives has not been studied.
The efficacy of Zolmitriptan tablets in the acute treatment of migraine headaches was demonstrated in five randomized, double-blind, placebo-controlled studies (Studies 1, 2, 3, 4, and 5), of which two utilized the 1 mg dose, two utilized the 2.5 mg dose and four utilized the 5 mg dose. In Study 1, patients treated their headaches in a clinic setting. In the other studies, patients treated their headaches as outpatients. In Study 4, patients who had previously used sumatriptan were excluded, whereas in the other studies no such exclusion was applied.
Patients enrolled in these 5 studies were predominantly female (82%) and Caucasian (97%) with a mean age of 40 years (range 12-65). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed at 1, 2, and, in most studies, 4 hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours post-dose. A second dose of Zolmitriptan tablets or other medication was allowed 2 to 24 hours after the initial treatment for persistent and recurrent headache. The frequency and time to use of these additional treatments were also recorded. In all studies, the effect of Zolmitriptan was compared to placebo in the treatment of a single migraine attack.
In all five studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients who received Zolmitriptan tablets at all doses (except for the 1 mg dose in the smallest study) compared to those who received placebo. In Studies 1 and 3, there was a statistically significant greater percentage of patients with headache response at 2 hours in the higher dose groups (2.5 and/or 5 mg) compared to the 1 mg dose group. There were no statistically significant differences between the 2.5 and 5 mg dose groups (or of doses up to 20 mg) for the primary end point of headache response at 2 hours in any study. The results of these controlled clinical studies are summarized in Table 1.
Table 2 : Percentage of Patients with Headache Response (Reduction in Headache Severity from Moderate or Severe Pain to Mild or No Headache) 2 Hours Following Treatment in Studies 1 through 5
The estimated probability of achieving an initial headache response by 4 hours following treatment in pooled Studies 2, 3, and 5 is depicted in Figure 1.
Figure 1 : Estimated Probability of Achieving Initial Headache Response (Reduction in Headache Severity from Moderate or Severe Pain to Mild or No Headache) Within 4 Hours of Treatment in Pooled Studies 2, 3, and 5*
*In this Kaplan-Meier plot, the averages displayed are based on pooled data from 3 placebo controlled, outpatient trials. Patients not achieving headache response or taking additional treatment prior to 4 hours were censored at 4 hours.
For patients with migraine associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of Zolmitriptan tablets as compared with placebo.
Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.
Figure 2 : The Estimated Probability Of Patients Taking A Second Dose Or Other Medication For Migraines Over The 24 Hours Following The Initial Dose Of Study Treatment in Pooled Studies 2, 3, and 5*
*In this Kaplan-Meier plot,patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. The studies did not allow taking additional doses of study medication within 2 hours post-dose.
The efficacy of Zolmitriptan was unaffected by presence of aura; duration of headache prior to treatment; relationship to menses; gender, age, or weight of the patient; pre-treatment nausea or concomitant use of common migraine prophylactic drugs.
Zolmitriptan Orally Disintegrating Tablets
The efficacy of Zolmitriptan 2.5 mg orally disintegrating tablets was demonstrated in a randomized, placebo-controlled trial that was similar in design to the trials of Zolmitriptan tablets. Patients were instructed to treat a moderate to severe headache. Of the 471 patients treated in Study 6, 87% were female and 97% were Caucasian, with a mean age of 41 years (range 18-62).
At 2 hours post-dosing, there was a statistically significant greater percentage of patients treated with Zolmitriptan 2.5 mg with a headache response (reduction in headache severity from moderate or severe pain to mild or no headache) compared to patients treated with placebo (63% vs. 22%). The estimated probability of achieving an initial headache response by 2 hours following treatment with Zolmitriptan orally disintegrating tablets is depicted in Figure 3.
Figure 3 : Estimated Probability of Achieving Initial Headache Response (Reduction in Headache Severity from Moderate or Severe Pain to Mild or No Headache) Within 2 Hours in Study 6*
*In this Kaplan-Meier plotpatients taking additional treatment or not achieving headache response prior to 2 hours were censored at 2 hours.
For patients with migraine-associated photophobia, phonophobia and nausea at baseline, there was a decreased incidence of these symptoms following administration of Zolmitriptan as compared to placebo.
|Brand Name||Manufacturer/Marketer||Composition||Dosage Form||Pack Size & Price|
|MIOTROL||Drug International Ltd||Zolmitriptan INN 2.5mg||Tablet||50's: 500.00 MRP|
|NOMI 2.5||Square Pharmaceuticals Ltd.||Zolmitriptan 2.5mg||Tablet||2x6's: 302.04 MRP|
|Zomitan 2.5||Incepta Pharmaceuticals Limited||Zolmitriptan INN 2.5mg||Film Coated Tablet||10x1's:MRP 250 Tk|