ZOLMitriptan 5 MG Oral Tablet
DRUG INTERACTIONS
7 7.1 Ergot-containing Drugs 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 [see Contraindications (4) ].
7.2 MAO-A Inhibitors 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 [see Contraindications (4) and Clinical Pharmacology (12.3) ].
7.3 5-HT1B/1D Agonists Concomitant use of other 5-HT 1B/1D agonists(including triptans)within 24 hours of zolmitriptan treatment is contraindicated because the risk of vasospastic reactions may be additive [see Contraindications (4) ].
7.4 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)[see Warnings and Precautions(5.7) ].
7.5 Cimetidine Following administration of cimetidine, the half-life and blood levels of zolmitriptan and its active N-desmethyl metabolite were approximately doubled [see Clinical Pharmacology (12.3) ].
If cimetidine and zolmitriptan are used concomitantly, limit the maximum single dose of zolmitriptan tablets to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ].
OVERDOSAGE
10 There is no experience with acute overdose of zolmitriptan.
Clinical study subjects who received single 50 mg oral doses of zolmitriptan commonly experienced sedation.
There is no specific antidote to zolmitriptan.
In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.
The elimination half-life of zolmitriptan is 3 hours [see Clinical Pharmacology (12.1) ]; therefore, monitor patients after overdose with zolmitriptan for at least 15 hours or until symptoms or signs resolve.
It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of zolmitriptan.
DESCRIPTION
11 Zolmitriptan tablets and zolmitriptan orally disintegrating tablets contain zolmitriptan, which is a selective 5-hydroxytryptamine 1B/1D (5HT 1B/1D )receptor agonist.
Zolmitriptan is chemically designated as(S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5yl]methyl]-2-oxazolidinone and has the following chemical structure: The molecular formula is C 16 H 21 N 3 O 2 , representing a molecular weight of 287.36.
Zolmitriptan is a white to almost white powder that is readily soluble in water.
Zolmitriptan tablets are available as 2.5 mg (yellow and functionally-score) and 5 mg (pink, not scored) film-coated tablets for oral administration.
The film-coated tablets contain anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, yellow iron oxide (2.5 mg tablet), red iron oxide (5 mg tablet) and polyethylene glycol.
Zolmitriptan orally disintegrating tablets are available as 2.5 mg and 5 mg white uncoated tablets.
The orally disintegrating tablets contain mannitol, microcrystalline cellulose, crospovidone, aspartame [see Warnings and Precautions ( 5.9 )] , colloidal silicon dioxide, magnesium stearate and orange flavor.
zolmitriptan-structure.jpg
CLINICAL STUDIES
14 Zolmitriptan Tablets 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 to 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 2.
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 Placebo Zolmitriptan Tablets 1 mg Zolmitriptan Tablets 2.5 mg Zolmitriptan Tablets 5 mg Study 1 * 16% (n † =19) 27% (n=22) NA ‡ 60% §¶ (n=20) Study 2 19% (n=88) NA NA 66% § (n=179) Study 3 34% (n=121) 50% § (n=140) 65% §¶ (n=260) 67% §¶ (n=245) Study 4 # 44% (n=55) NA NA 59% § (n=491) Study 5 36% (n=92) NA 62% § (n=178) NA * Study 1 was the only study in which patients treated the headache in a clinic setting.
† n = number of patients randomized ‡ NA = not applicable § P<0.05 in comparison with placebo.
¶ P<0.05 in comparison with 1 mg.
# Study 4 was the only study where patients were excluded who had previously used sumatriptan.
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 (Study 6) 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 to 62).
At 2 hours post-dosing, there was a statistically significant greater percentage of patients treated with zolmitriptan 2.5 mg orally disintegrating tablets 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 plot, patients 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.
Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment 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 in Study 6 is summarized in Figure 4.
Figure 4 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 Study 6* * In this Kaplan-Meier plot, patients not taking 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.
Taking another dose of study medication was allowed 2 hours post-dose in Study 6.
In contrast to studies of zolmitriptan tablets (Studies 1, 2, 3, 4, and 5), Study 6 allowed re-dosing of zolmitriptan oral disintegrating tablets prior to 4 hours.
fig1 fig-2 fig3 fig4
HOW SUPPLIED
16 /STORAGE AND HANDLING 2.5 mg Tablets – Yellow, biconvex, round, film-coated, functionally-scored tablets containing 2.5 mg of zolmitriptan identified with “CL 82” and break line on one side are supplied in : Bottle of 90 tablets NDC 33342-112-10 Cartons of 100 (10×10) unit dose blister tablets NDC 33342-112-12 Cartons of 6 (2×3) unit dose blister tablets NDC 33342-112-74 Cartons of 3 (1×3) unit dose blister tablets NDC 33342-112-52 5 mg Tablets – Pink, biconvex, round, film-coated tablets containing 5 mg of zolmitriptan identified with “CL 83” debossed on one side and plain on other side are supplied in: Bottle of 90 tablets NDC 33342-113-10 Cartons of 100 (10×10) unit dose blister tablets NDC 33342-113-12 Cartons of 6 (2×3) unit dose blister tablets NDC 33342-113-74 Cartons of 3 (1×3) unit dose blister tablets NDC 33342-113-52 2.5 mg Orally disintegrating tablets – White to off white, round, flat faced,uncoated, bevelled tablet containing 2.5 mg of zolmitriptan identified with a debossed “CL 84” on one side and plain on other side are supplied as follows: Bottles of 90 tablets NDC 33342-139-10 Carton of 100 (10 x 10) unit dose blister tablets NDC 33342-139-12 Cartons of 6 (2×3) unit dose blister tablets NDC 33342-139-74 Cartons of 3 (1×3) unit dose blister tablets NDC 33342-139-52 5 mg Orally disintegrating tablets – White to off white, flat faced, round, uncoated, bevelled tablet containing 5 mg of zolmitriptan identified with a debossed “CL 85” on one side and plain on the other are supplied as follows: Bottles of 90 tablets NDC 33342-140-10 Carton of 100 (10 x 10) unit dose blister tablets NDC 33342-140-12 Cartons of 6 (2×3) unit dose blister tablets NDC 33342-140-74 Cartons of 3 (1×3) unit dose blister tablets NDC 33342-140-52 Store both zolmitriptan tablets and zolmitriptan orally disintegrating tablets at 68°F to 77°F (20°C to 25°C) [see USP Controlled Room Temperature.] and away from children.
Protect from moisture.
Discard when expired.
GERIATRIC USE
8.5 Geriatric Use 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 [see Warnings and Precautions(5.1) ].
The pharmacokinetics of zolmitriptan were similar in geriatric patients(aged > 65 years)compared to younger patients [see Clinical Pharmacology(12.3) ].
DOSAGE FORMS AND STRENGTHS
3 DOSAGE FORMS & STRENGTHS 2.5 mg Tablets: Light yellow, biconvex, round film-coated, scored tablets containing 2.5 mg of zolmitriptan with “CL 82” debossed on one side and breakline on other side.
5 mg Tablets: Pink, biconvex, film-coated tablets containing 5 mg of zolmitriptan identified with “CL 83” debossed on one side and plain on other side.
2.5 mg Orally disintegrating tablets: White to off white, round, flat faced, uncoated, bevelled tablet containing 2.5 mg of zolmitriptan identified with a debossed “CL 84” on one side and plain on other side.
5 mg Orally disintegrating tablets: White to off white, flat faced, round, uncoated, bevelled tablet containing 5 mg of zolmitriptan identified with a debossed “CL 85” on one side and plain on the other side.
Tablets: 2.5 mg functionally-scored ( 3 ) Tablets: 5 mg(not scored)( 3 ) Orally Disintegrating Tablets: 2.5 mg and 5 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Zolmitriptan binds with high affinity to human recombinant 5HT 1D and 5-HT 1B receptors, and moderate affinity for 5-HT 1A receptors.
The N-desmethyl metabolite also has high affinity for 5-HT 1B/1D and moderate affinity for 5-HT 1A 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-HT 1B/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.
INDICATIONS AND USAGE
1 INDICATIONS & USAGE Zolmitriptan is indicated for the acute treatment of migraine with or without aura in adults.
Limitations of Use 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 zolmitriptan are 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.
Zolmitriptan is a serotonin(5-HT) 1B/1D receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults ( 1 ) Limitations of Use : Use only after a clear diagnosis of migraine has been established ( 1 ) Not indicated for the prophylactic therapy of migraine ( 1 ) Not indicated for the treatment of cluster headache ( 1 )
PEDIATRIC USE
8.4 Pediatric Use 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 to 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.
PREGNANCY
8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of zolmitriptan in pregnant women.
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 (see Data).
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
The estimated rates of major birth defects (2.2%-2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.
Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.
Data Animal Data 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 embryofetal 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 of hydronephrosis was found in the offspring.
The no-effect dose was associated with a plasma AUC ≈280 times that in humans at the MRHD.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Myocardial Ischemia/Infarction, and Prinzmetal’s Angina : Perform cardiac evaluation in patients with multiple cardiovascular risk factors ( 5.1 ) Arrhythmias : Discontinue zolmitriptan if occurs ( 5.2 ) Chest/Throat/Neck/Jaw Pain, Tightness, and Pressure : Generally not associated with myocardial ischemia; evaluate for CAD in patients at high risk ( 5.3 ) Cerebral Hemorrhage, Subarachnoid Hemorrhage, and Stroke : Discontinue zolmitriptan if occurs ( 5.4 ) Gastrointestinal Ischemic Reactions and Peripheral Vasospastic Reactions : Discontinue zolmitriptan if occurs ( 5.5 ) Medication Overuse Headache : Detoxification may be necessary ( 5.6 ) Serotonin Syndrome : Discontinue zolmitriptan if occurs ( 5.7 , 7.4 ) Patients with Phenylketonuria : Zolmitriptan orally disintegrating tablets contains phenylalanine ( 5.9 ) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina Zolmitriptan is contraindicated in patients with ischemic or vasospastic coronary artery disease(CAD).
There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of zolmitriptan.
Some of these reactions occurred in patients without known CAD.
5-HT 1 agonists including zolmitriptan may cause coronary artery vasospasm(Prinzmetal’s Angina), even in patients without a history of CAD.
Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors(e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD)prior to receiving zolmitriptan.
Do not administer zolmitriptan if there is evidence of CAD or coronary artery vasospasm [see Contraindications(4) ].
For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administrering the first zolmitriptan dose in a medically-supervised setting and performing an electrocardiogram (ECG)immediately following zolmitriptan administration.
For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of zolmitriptan.
5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and ventricular fibrillation leading to death have been reported within a few hours following the administration of 5-HT 1 agonists.
Discontinue zolmitriptan if these disturbances occur.
Zolmitriptan is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Contraindications(4) ].
5.3 Chest, Throat, Neck and Jaw Pain/Tightness/Pressure As with other 5-HT 1 agonists, sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with zolmitriptan and is usually non-cardiac in origin.
However, perform a cardiac evaluation if these patients are at high cardiac risk.
5-HT 1 agonists including zolmitriptan are contraindicated in patients with CAD or Prinzmetal’s variant angina [see Contraindications (4) ].
5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities.
In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not.
As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine, exclude other potentially serious neurological conditions.
Zolmitriptan is contraindicated in patients with a history of stroke or transient ischemic attack [see Contraindications (4) ].
5.5 Other Vasospasm Reactions 5-HT 1 agonists, including zolmitriptan, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome.
In patients who experience symptoms or signs suggestive of a vasospastic reaction following the use of any 5-HT 1 agonist, rule out a vasospastic reaction before receiving additional zolmitriptan doses [see Contraindications (4) ].
Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists.
Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists has not been clearly established.
5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache).
Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks.
Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
5.7 Serotonin Syndrome Serotonin syndrome may occur with triptans, including zolmitriptan tablet and zolmitriptan orally disintegrating tablets, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.5) ].
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The onset of symptoms usually rapidly occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication.
Discontinue zolmitriptan if serotonin syndrome is suspected [see Drug Interactions (7.4) ] 5.8 Increase in Blood Pressure Significant elevations in systemic blood pressure have been reported in patients treated with 5-HT 1 agonists including patients without a history of hypertension; very rarely, these increases in blood pressure have been associated with serious adverse reactions.
In healthy subjects treated with 5 mg of zolmitriptan, an increase of 1 and 5 mm Hg in the systolic and diastolic blood pressure, respectively, was seen.
In a study of patients with moderate to severe liver impairment, 7 of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a dose of 10 mg of zolmitriptan.
As with all triptans, blood pressure should be monitored in zolmitriptan-treated patients.
Zolmitriptan is contraindicated in patients with uncontrolled hypertension [see Contraindications (4) ].
5.9 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU).
Zolmitriptan orally disintegrating tablets contain phenylalanine (a component of aspartame).
Each 2.5 mg orally disintegrating tablet contains 2.1 mg phenylalanine.
Each 5 mg orally disintegrating tablet contains 4.2 mg phenylalanine.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).
Myocardial Ischemia and/or Infarction, Prinzmetal’s angina, Other Vasospastic Reactions, and Cerebrovascular Events.
Inform patients that zolmitriptan may cause serious cardiovascular adverse reactions such as myocardial infarction or stroke, which may result in hospitalization and even death.
Although serious cardiovascular reactions can occur without warning symptoms, instruct patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and instruct them to ask for medical advice when observing any indicative sign or symptoms.
Instruct patients to seek medical advice if they have symptoms of other vasospastic reactions [see Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.5 ) ].
Medication Overuse Headache Inform patients that use of drugs to treat acute migraines for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use(e.g., by keeping a headache diary)[see Warnings and Precautions(5.6) ].
Serotonin Syndrome Inform patients about the risk of serotonin syndrome with the use of zolmitriptan or other triptans,-particularly during combined use with selective serotonin reuptake inhibitors(SSRIs)or serotonin norepinephrine reuptake inhibitors(SNRIs)[see Warnings and Precautions(5.7) ].
Pregnancy Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant.
Lactation Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations(8.2) ].
Handling of Zolmitriptan Orally Disintegrating Tablets Inform patients not to break zolmitriptan orally disintegrating tablets.
Inform patients that the orally disintegrating tablets are packaged in a blister.
Instruct patients not to remove the orally disintegrating tablets from the blister until just prior to dosing.
Instruct patients that prior to dosing, peel open the blister pack and place the orally disintegrating tablet on the tongue, where it will dissolve and be swallowed with the saliva [see Dosage and Administration ( 2.2 ) ].
Patients with Phenylketonuria Inform patients with phenylketonuria (PKU) that zolmitriptan orally disintegrating tablets contains phenylalanine (a component of aspartame) [see Warnings and Precautions ( 5.9 )].
Manufactured For : Macleods Pharma USA, Inc.
Plainsboro, NJ 08536 Manufactured by : Macleods Pharmaceuticals Ltd.
Baddi, Himachal Pradesh, India.(IND) Revised 01/2019
DOSAGE AND ADMINISTRATION
2 DOSAGE & ADMINISTRATION Recommended starting dose: 1.25 mg or 2.5 mg ( 2.1 ) Maximum single dose: 5 mg ( 2.1 ) May repeat dose after 2 hours if needed; not to exceed 10 mg in any 24 hour period ( 2.1 ) Do not break zolmitriptan orally disintegrating tablets ( 2.2 ) Moderate or Severe Hepatic Impairment: 1.25 mg recommended ( 2.3 , 8.6 ) 2.1 Dosing Information The recommended starting dose of zolmitriptan tablets are 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 tablets are 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.
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.
2.2 Administration of Zolmitriptan Orally Disintegrating Tablets Instruct patients not to break zolmitriptan orally disintegrating tablets because they are not functionally-scored.
Administration with liquid is not necessary.
Orally disintegrating tablets are packaged in a blister pack.
Instruct patients not to remove the tablet from the blister until just prior to dosing.
Subsequently, instruct patients to peel the blister pack open, and to place the orally disintegrating tablet on the tongue, where it will dissolve and it will be swallowed with the saliva.
2.3 Dosing in Patients with Hepatic Impairment The recommended dose of zolmitriptan tablets 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 are not recommended in patients with moderate or severe hepatic impairment because these orally disintegrating tablets should not be broken in half [see Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )].
2.4 Dosing in Patients taking Cimetidine If Zolmitriptan tablets are co-administered with cimetidine, limit the maximum single dose of zolmitriptan to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Drug Interactions (7.5), Clinical Pharmacology (12.3)].