Sumatriptan

Sumatriptan is a an Antimigraine Agent belonging to pharmacology class of Serotonin 5-HT1B, 1D Receptor Agonist Class

Sumatriptan can be used in the treatment of Cluster headache, acute and Migraine, moderate to severe, acute treatment.

It is Rapidly but incompletely absorbed from the gastrointestinal tract (oral). Bioavailability: Approx 14-15% (oral); 19% (intranasal powder); approx 16% or 58-87% (intranasal spray [varies on brand formulation]); 97% ± 16% (SC). Time to peak plasma concentration: Approx 2-2.5 hours (oral); approx 45 minutes (intranasal powder); median 10 minutes or approx 1.5 hours (intranasal spray [varies on brand formulation]); 12 (range: 4-25) minutes (SC) and Crosses the placenta and enters breast milk (small amounts). Volume of distribution (central): 50 L (SC). Volume of distribution (apparent): 2.7 L/kg (oral, intranasal). Plasma protein binding: 14-21% which get metabolized in the liver into inactive indole acetic acid metabolite; further converted via ester glucuronide conjugation. May be metabolized primarily by monoamine oxidase type A isoenzyme. Undergoes extensive first-pass metabolism and get excreted Via urine (Approx 60%; predominantly as indole acetic acid metabolite, 3% as unchanged drug); faeces (approx 40%). Intranasal: Via urine (42% as indole acetic acid metabolite; 3% as unchanged drug). SC: Via urine (38% as indole acetic acid metabolite; 22% as unchanged drug). Elimination half-life: Approx 2 hours (range: 1-4 hours).

The common side effects associated with Sumatriptan include Sensation of heaviness, pressure, pain and tightness in the chest, throat, jaw or neck; peripheral vascular ischemia, colonic ischemia (with abdominal pain and bloody diarrhea), splenic infarction, Raynaud’s syndrome; exacerbation of headache.

Sumatriptan is available in the form of tablets, injectable solution.

The molecule is available in India, USA, Japan, Germany.

Selective agonist for serotonin (5-HT_1B and 5-HT_1D receptors) on intracranial blood vessels and sensory nerves of the trigeminal system; causes vasoconstriction and reduces neurogenic inflammation associated with antidromic neuronal transmission correlating with relief of migraine

The Tmax of Sumatriptan was about 2-2.5 hours.

Onset of Action was about 30 minutes.

Sumatriptan is available in tablet, Injectable solution

Oral: May administer without regard to meals.

Subcutaneous: Not for IM or IV use. Needle penetrates ¹/₄ inch of skin; use in areas of the body with adequate skin and subcutaneous thickness (lateral thigh or upper arm). In patients receiving doses other than 4 or 6 mg, use the 6 mg single-dose vial instead of the autoinjector device.

Sumatriptan can be used in the treatment of Cluster headache, acute and Migraine, moderate to severe, acute treatment. It is also used to treat Cyclic vomiting syndrome (migraine associated), abortive therapy.

Sumatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

Sumatriptan is approved for use in the following clinical indications

Cluster headache, acute: Subcutaneous :Acute treatment of cluster headache episodes in adults as monotherapy or in combination with 100% oxygen.

Migraine, moderate to severe, acute treatment: Intranasal, Oral, Subcutaneous: Acute treatment of migraine with or without aura in adults.

• Although not approved there have been certain off labelled uses documented for Sumatriptan which include:

Cyclic vomiting syndrome (migraine associated), abortive therapy.

Cluster headache, acute: Note: As monotherapy or in combination with 100% oxygen. Some experts recommend initial treatment with only 100% oxygen if available. Limit use to <10 days per month to avoid medication-overuse headache.

SUBCUTANEOUS (preferred route): Initial: 6 mg once; a lower dose of 3 mg may be effective in select patients. If initial dose was effective but headache recurs, may repeat a dose (usually same as first dose) after ≥1 hour; some experts recommend waiting ≥2 hours before repeating a dose . Maximum dose: 6 mg per dose; 12 mg in 24 hours.

Intranasal (alternative route) (off-label): Solution: Initial: 20 mg once in single nostril contralateral to side of headache . If initial dose was effective but headache recurs, may repeat the dose after ≥2 hours. Maximum dose: 40 mg in 24 hours.

Note: When treating acute cluster headache, following initiation of medication(s) for prevention of cluster headaches, patients with ≥2 headaches per day may temporarily receive >2 doses of sumatriptan per day (either Subcutaneous or intranasal at usual dose and interval) until prophylaxis becomes effective, according to some experts..

Cyclic vomiting syndrome (migraine associated), abortive therapy (off-label use): Note: To be administered during the prodrome or shortly after vomiting begins (eg, within 30 to 45 minutes); may be used alone for relatively mild or infrequent episodes. If symptoms are frequent or severe, may be used in conjunction with ongoing prophylactic therapy.

Intranasal: 20 mg; may repeat after 2 hours in patients with no or partial response (maximum: 6 doses/week).

SUBCUTANEOUS: 6 mg; may repeat after 1 hour in patients with no or partial response (maximum: 6 doses/week).

Migraine, moderate to severe, acute treatment:

Note: Administration early in the course of a migraine attack, at the first sign of pain, may improve response to treatment. Some experts recommend a large initial dose, as it may be more effective than multiple smaller doses. When attack is complicated by vomiting or severe nausea, a nonoral preparation may be more effective. Limit use to <10 days per month to avoid medication-overuse headache.

Oral: 50 to 100 mg as a single dose. If symptoms persist or return, may repeat dose (usually same as first dose) after ≥2 hours. Maximum dose: 100 mg/dose; 200 mg per 24 hours.

Intranasal:

Solution: Usual: 20 mg as a single dose in 1 nostril; if symptoms persist or return, may repeat dose after ≥2 hours. Maximum dose: 40 mg per 24 hours.

Powder, breath-activated: 22 mg as a single dose; using product-specific device, give as one 11 mg capsule insufflated in each nostril. If symptoms persist or return, may repeat dose after ≥2 hours. Maximum dose: 44 mg per 24 hours. Refer to product-specific administration instructions.

Spray: 10 mg as a single dose in 1 nostril. If symptoms persist or return, may repeat dose after ≥1 hour. Maximum dose: 30 mg per 24 hours. May also administer at least 1 hour following a dose of another sumatriptan product (use following another 5-HT₁ agonist is contraindicated).

SUBCUTANEOUS: Usual: 6 mg once. If symptoms persist or return, may repeat dose (usually same as first dose) after ≥1 hour. If 6 mg was not tolerated, subsequent doses of 1 to 5 mg may provide sufficient relief with better tolerability. Maximum dose: 6 mg/dose; 12 mg per 24 hours.

Tablet:

25 mg, 50 mg, 100 mg

Injectable solution:

• 6mg/0.5mL vial, 3mg/0.5mL, 4mg/0.5mL

Tablet, Injectable Solution.

• Dose Adjustment in Hepatic Patient:

Mild to moderate hepatic impairment:

Oral: Bioavailability of oral sumatriptan is increased with liver disease. If treatment is needed, do not exceed single doses of 50 mg.

Intranasal: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). However, dosage adjustment not expected due to extensive non-hepatic metabolism to inactive agents.

SUBCUTANEOUS: No dosage adjustment necessary.

Severe hepatic impairment: Oral, intranasal, and subcutaneous (Imitrex and Sumatriptan injection) formulations are contraindicated in severe hepatic impairment.

• Dose Adjustment in Pediatric Patient:

Migraine: Limited data available: Note: Results of clinical studies are mixed with regards to efficacy, particularly with oral and Subcutaneous sumatriptan doses.

Intranasal:

Children 5 to 12 years: Intranasal: 5 mg, 10 mg, or 20 mg administered in one nostril as a single dose as soon as possible after the onset of migraine; dose should be selected on an individual basis. A double-blind, placebo-controlled study of 129 patients (mean age: 12.4 years; range: 8 to 17 years) used a weight-based dosing regimen: Body weight: 20 to 39 kg: 10 mg/dose; body weight ≥40 kg: 20 mg/dose; however, relatively few children <12 years of age were included in the study . A small, randomized, double-blind, placebo-controlled study of 14 children (age range: 6 to 9 years; median: 8.2 years) used intranasal doses of 20 mg/dose . A small, retrospective review of 10 children (age range: 5 to 12 years; mean: 9.9 years) used intranasal doses of 5 mg (n=2) or 20 mg (n=8) .

Children ≥12 years and Adolescents: Intranasal: 10 mg or 20 mg administered in one nostril as a single dose as soon as possible after the onset of migraine; a lower dose of 5 mg as a single dose may also be effective; dose should be selected on an individual basis .

Oral:

Note: According to the manufacturer, efficacy of oral sumatriptan monotherapy was not established in five controlled trials in adolescent patients; frequency of adverse events was dose-related and age-dependent (ie, younger patients reported more adverse events). Guidelines do not recommend oral sumatriptan alone due to very low confidence in efficacy; however, the combination product of sumatriptan and naproxen is recommended in patients ≥12 years of age .

Children ≥10 years and Adolescents: Oral: 25 mg or 50 mg as a single dose administered within 30 minutes of headache onset. There was no statistically significant improvement in pain relief at 2 hours; however, some improvement was noted .

Subcutaneous:

Children ≥6 years and Adolescents: Subcutaneous: 3 to 6 mg as a single dose. An open-label prospective trial of 17 children 6 to 16 years with juvenile migraine used Subcutaneous doses of 6 mg in 15 patients weighing 30 to 70 kg, and 3 mg/dose in two children weighing 22 kg and 30 kg. Another open-label prospective trial in 50 consecutive children (ages 6 to 18 years) with severe migraine used Subcutaneous doses of 0.06 mg/kg/dose. Relief was reported as good/excellent in 84% of the patients; 16% reported fair to poor relief; additional studies are needed.

Cyclic vomiting syndrome (CVS), abortive therapy: Limited data available:

Note: Based on efficacy data in adolescents and extrapolation from migraine efficacy in children, sumatriptan could be considered for treatment in children <12 years of age with refractory CVS using migraine treatment doses. Dosing for individuals ≥12 years of age is below; for dosing in younger children, refer to Migraine dosing.

Intranasal: Nasal solution: Children ≥12 years and Adolescents: Intranasal: 20 mg administered as a single dose in 1 nostril; doses should be administered as soon as possible after the onset of prodromal symptoms. If there is no response or partial response to the first dose, may consider repeating after 1 to 2 hours.

Subcutaneous: Adolescents: Subcutaneous: 3 to 6 mg as a single dose; doses should be administered as soon as possible after the onset of prodromal symptoms. If there is no response or partial response to the first dose, some experts recommend repeating after 1 to 2 hours

The dietary restriction should be individualized as per patient requirements.

Sumatriptan may be contraindicated in the following conditions:-

Hypersensitivity (eg, angioedema, anaphylaxis) to sumatriptan or any component of the formulation; ischemic heart disease or signs or symptoms of ischemic heart disease (coronary artery vasospasm, Prinzmetal angina, angina pectoris, MI, silent myocardial ischemia); history of cerebrovascular syndromes (including strokes, transient ischemic attacks), history of hemiplegic or basilar migraine; peripheral vascular disease (including ischemic bowel disease); uncontrolled hypertension; use within 24 hours of ergotamine derivatives; use within 24 hours of another 5-HT₁ agonist; concurrent administration or within 2 weeks of discontinuing an MAO type A inhibitors; Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders; severe hepatic impairment.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Disease-related concerns:

• Hepatic impairment: Use oral formulations of sumatriptan with caution (and with dosage limitations) in patients with mild to moderate hepatic impairment where treatment is necessary and advisable. Presystemic clearance of orally administered sumatriptan is reduced in hepatic impairment, leading to increased plasma concentrations; dosage reduction of the oral product is recommended. Non-oral routes of administration (intranasal, subcutaneous) do not undergo similar hepatic first-pass metabolism and are not expected to result in significantly altered pharmacokinetics in patients with hepatic impairment. Use of the oral, intranasal, Imitrex, and Sumatriptan injectable is contraindicated in severe hepatic impairment.

• Seizure disorders: Use with caution in patients with history of seizure disorder or in patients with a lowered seizure threshold; seizures have been reported after sumatriptan administration in patients with or without a history of seizures.

Special populations:

• Older adult: Use with caution; perform a cardiovascular evaluation prior to initiation of therapy in older adult patients with cardiovascular risk factors (eg, diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) and periodically during intermittent long-term use.

Dosage form specific issues:

• Latex: The packaging (needle cover of prefilled syringe) may contain dry natural rubber, which is a derivative of latex.

Other warnings/precautions:

• Appropriate use: Only indicated for the acute treatment of migraine or cluster headache (depending on product); not indicated for migraine or cluster headache prophylaxis, or for the treatment of hemiplegic or basilar migraine. Acute migraine agents (eg, 5-HT₁ agonists, opioids, ergotamine, or a combination of the agents) used for 10 or more days per month may lead to worsening of headaches (medication overuse headache); withdrawal treatment may be necessary in the setting of overuse. If a patient does not respond to the first dose, the diagnosis of migraine or cluster headache should be reconsidered; rule out underlying neurologic disease in patients with atypical headache and in patients with no prior history of migraine or cluster headache.

There is no sufficient scientific evidence traceable regarding use and safety of Sumatriptan in concurrent use with alcohol.

Sumatriptan is present in breast milk.

Data related to the presence of sumatriptan in breast milk are available from 2 studies.

• Sumatriptan 6 mg SUBQ was administered as a single dose to 5 women (mean duration of lactation 22.2 weeks) and milk concentrations were measured over 8 hours. The mean maximum concentration of sumatriptan in breast milk was 87.2 mcg/L (range: 61.9 to 112.5 mcg/L). The median half-life in breast milk was 2.2 hours and the maximum milk concentrations occurred between 1.7 and 3.5 hours after the maternal dose. Using the cumulative excretion of sumatriptan, authors of the study calculated the relative infant dose (RID) of sumatriptan to be 3.5% of the weight-adjusted maternal dose.

Pregnancy

Pregnancy Category C: There are no adequate and well-controlled trials in pregnant women. In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal. Sumatriptan tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Increased incidence of adverse events with St. John's wort..

The adverse reactions related to Sumatriptan can be categorized as

Common Adverse effects: Sensation of heaviness, pressure, pain and tightness in the chest, throat, jaw or neck; peripheral vascular ischaemia, colonic ischaemia (with abdominal pain and bloody diarrhea, splenic infarction, Raynaud’s syndrome; exacerbation of headache

Less Common Adverse effects: Nausea, vomiting; dysgeusia (intranasal). General disorders and administration site conditions: Injection site reactions (e.g. pain, burning, stinging, swelling, erythema, bruising, bleeding); pain, heat or cold sensation, pressure or tightness; malaise, fatigue.

Rare Adverse effects: Hypertensive Crisis, Seizures.

The clinically relevant drug interactions of Sumatriptan is briefly summarized here

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 sumatriptan tablets within 24 hours of each other is contraindicated.

Monoamine Oxidase-A Inhibitors

MAO-A inhibitors increase systemic exposure by 7-fold. Therefore, the use of sumatriptan tablets in patients receiving MAO-A inhibitors is contraindicated.

Other 5-HT1 Agonists

Because their vasospastic effects may be additive, co-administration of sumatriptan tablets and other 5-HT 1 agonists (e.g., triptans) within 24 hours of each other is contraindicated.

Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome

Cases of serotonin syndrome have been reported during co-administration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors.

The common side of Sumatriptan include the following

Sensation of heaviness, pressure, pain and tightness in the chest, throat, jaw or neck; peripheral vascular ischemia, colonic ischemia (with abdominal pain and bloody diarrhea), splenic infarction, Raynaud’s syndrome; exacerbation of headache or medica.

Pregnancy Category C: There are no adequate and well-controlled trials in pregnant women. In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal. Sumatriptan tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral administration of sumatriptan to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day, or approximately 3 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m 2 basis. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 (approximately 2 times the MRHD on a mg/m2 basis) and 0.75 mg/kg/day, respectively.

Oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day, or approximately 2 times the MRHD on a mg/m 2 basis. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day, or approximately 3 times the MRHD on a mg/m2 basis. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day, or approximately 5 times the MRHD on a mg/m2 basis.

Labor and Delivery

There is no FDA guidance on use of Sumatriptan (oral) during labor and delivery.

Nursing Mothers

Sumatriptan is excreted in human milk following subcutaneous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan tablets.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Sumatriptan tablets are not recommended for use in patients younger than 18 years of age.

Two controlled clinical trials evaluated sumatriptan nasal spray (5 to 20 mg) in 1,248 adolescent migraineurs aged 12 to 17 years who treated a single attack. The trials did not establish the efficacy of sumatriptan nasal spray compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These trials did not establish the efficacy of oral sumatriptan compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older adolescents.

Post-marketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal sumatriptan are not presently available.

Geriatric Use

Clinical trials of sumatriptan tablets did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. 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 CAD) prior to receiving sumatriptan tablets.

Gender

There is no FDA guidance on the use of Sumatriptan (oral) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Sumatriptan (oral) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Sumatriptan (oral) in patients with renal impairment.

Hepatic Impairment

The maximum single dose in patients with mild to moderate hepatic impairment should not exceed 50 mg. Sumatriptan tablets are contraindicated in patients with severe hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Sumatriptan (oral) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Sumatriptan (oral) in patients who are immunocompromised.

Pharmacodynamics:

Sumatriptan is an agonist of serotonin or 5-hydroxytryptamine 1 (5-HT₁) receptor subtype. It relieves migraine by selectively acting at 5-HT_1B and 5-HT_1D receptors in intracranial blood vessels and sensory nerves of trigeminal system, thereby causing vasoconstriction and inhibition of neurogenic inflammation..

Pharmacokinetics:

Absorption: Rapidly but incompletely absorbed from the gastrointestinal tract (oral). Bioavailability: Approx 14-15% (oral); 19% (intranasal powder); approx 16% or 58-87% (intranasal spray [varies on brand formulation]); 97% ± 16% (SC). Time to peak plasma concentration: Approx 2-2.5 hours (oral); approx 45 minutes (intranasal powder); median 10 minutes or approx 1.5 hours (intranasal spray [varies on brand formulation]); 12 (range: 4-25) minutes (SC).

Distribution: Crosses the placenta and enters breast milk (small amounts). Volume of distribution (central): 50 L (SC). Volume of distribution (apparent): 2.7 L/kg (oral, intranasal). Plasma protein binding: 14-21%.

Metabolism: Metabolized in the liver into inactive indole acetic acid metabolite; further converted via ester glucuronide conjugation. May be metabolised primarily by monoamine oxidase type A isoenzyme. Undergoes extensive first-pass metabolism.

Excretion: Oral: Via urine (Approx 60%; predominantly as indole acetic acid metabolite, 3% as unchanged drug); faeces (approx 40%). Intranasal: Via urine (42% as indole acetic acid metabolite; 3% as unchanged drug). SC: Via urine (38% as indole acetic acid metabolite; 22% as unchanged drug). Elimination half-life: Approx 2 hours (range: 1-4 hours).

1. https://www.uptodate.com/contents/Sumatriptan -drug-information?search=Sumatriptan &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Sumatriptan _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Sumatriptan ?type=full&mtype=generic#mechanism-of-action