Title: Triptan Class Review SBAR: Situation-Background-Assessment-Recommendation Initiation and Feedback Phase Situation: Triptans, also called serotonin 5-hydroxytryptamine (5-HT)(1B/1D) agonists, are used to treat migraine and certain other headaches. The cause of migraine is not known. Scientists have several theories to explain how triptans work. There is currently a wide variety of triptans on the Trinity Health formulary and this class has never been standardized of what agents are necessary to manage migraine while a patient is in the hospital. Background: Many patients suffer from migraine headaches; characterized by intense headaches, nausea, vomiting, and sensitivity to light, sound or movements as defined by the International Headache Society. Migraine attacks last from four to 72 hours and are preceded or accompanied by transient focal neurological symptoms known as aura in 10% to 20% of patients. More common in women than men, migraines are costly in terms of health care resources, lost productivity and impact on quality of life. Triptans have become the treatment of choice for moderate to severe migraine attacks. There are a wide variety of triptans available and within the amount of triptans available, there are different formulations. Further, some triptans have a niche in particular types of migraines (i.e. refractory, menstrual migraine). The objective of this monograph was to evaluate the safety and efficacy of the triptan class and identify the cost effective agents necessary to manage migraine. Assessment: There is little variation in the safety and efficacy between the various triptans that are available. Trinity Health has many of the different triptans currently on formulary. Triptans do not have black box warnings, however, there are a few contraindications that are similar across the board. Class adverse effects of triptans include tingling, flushing, dizziness, drowsiness, fatigue, and heaviness, tightness, or pressure in the chest, angina, myocardial infarction, cardiac arrhythmia, stroke, seizure, and death have occurred rarely with triptans. Compared to all other triptans, sumatriptan has more severe adverse effects. Sumatriptan also comes in many different formulations that include intranasal, auto and jet injectors, and oral tablets. A triptan should generally not be used within 24 hours of another triptan or an ergot because vasoconstriction could be additive; cases of serotonin syndrome reported with SSRIs and SNRIs, but risk is low. Recommendation: Formulary Non-Formulary Sumatriptan tablets Eletriptan Sumatriptan subcutaneous injection Frovatriptan Rizatriptan tablets Almotriptan Naratriptan Sumatriptan Nasal Spray Zolmitriptan

Establish a therapeutic interchange for patients coming in on Non-Formulary triptans to sumatriptan 50 mg PO once PRN migraine, may repeat once. Prescribers may select a lower or higher dose of sumatriptan if they prefer. References/Citations: See monograph

Submitted by: Rachael Lu, PharmD, BCPS CEC/CLG/CSG: Pharmacy CLG – Trinity Health Pharmacy and Therapeutics Committee Date 2-25-2019

Title: Triptan Class Review Final Decision and Action Planning Phase CEC Decision for Implementation: what do the leaders need to know

1. What were final decisions? Would include any changes to the recommendations out for feedback

• Pharmacy and Therapeutics Committee (1-29-19) supported recommendation to: Formulary Non-Formulary Sumatriptan tablets Eletriptan Sumatriptan subcutaneous injection

Frovatriptan

Rizatriptan tablets Almotriptan Naratriptan Sumatriptan Nasal Spray Zolmitriptan

Establish a therapeutic interchange for patients coming in on Non-Formulary triptans to sumatriptan 50 mg PO once PRN migraine, may repeat once. Prescribers may select a lower or higher dose of sumatriptan if they prefer.

2. Who owns the next steps? • ICS team in collaboration with TIS 3. Estimated timeframe… • Target implementation prior to Epic implementation. 4. Which functional groups will be involved in the implementation? • Nursing, Prescribers, Pharmacists 5. Regional ICLT to communicate to functional leads and areas.

Teams Actions When CMO Share background and decision with medical

staff for support, awareness and understanding.

Upon receipt of information

CNO Share background and decision with nursing staff for support, awareness, and understanding.

Upon receipt of information

Pharmacy Work with ICS to remove non-formulary triptans from formulary and manage non-formulary triptans with manual therapeutic interchanges.

Prior to Epic implementation.

Informatics Coordinate efforts with ICS team to manage change toward removal of non-formulary triptans from local formulary

Prior to Epic Implementation.

Finalized by: Rachael Lu, PharmD, BCPS CEC/CLG/CSG: Trinity Health Pharmacy and Therapeutics Committee Date 1-29-2019

Triptans Class Formulary Review December 10, 2018

St. Joseph Mercy Oakland

Agents in Class Triptans are first-line agents for the acute treatment of migraines. This review will focus on the different formulations of triptans available on the market. 1,2

Table 1: Triptan Agents Brand name Generic name Formulation Available doses

Summary Recommendations approved Pharmacy and Therapeutics Committee 1-29-19 Recommendation to Committee Formulary Non-Formulary Sumatriptan tablets Eletriptan Sumatriptan subcutaneous injection Frovatriptan Rizatriptan tablets Almotriptan Naratriptan Sumatriptan Nasal Spray Zolmitriptan

Establish a therapeutic interchange for patients coming in on Non-Formulary triptans to sumatriptan 50 mg PO once PRN migraine, may repeat once. Prescribers may select a lower or higher dose of sumatriptan if they prefer. Key Findings: Triptan therapy should be individualized to each patient’s needs and preferences through consideration of efficacy, potential AEs, drug-drug interactions, and cost. According to the various studies, eletriptan and rizatriptan are most efficacious of the triptans and other methods of migraine relief. Rizatriptan, however, is utilized more frequently throughout Trinity Health and is also lower in cost. At this time, there does not seem to be a need for eletriptan as it is more costly and not utilized as often. Sumatriptan should remain on formulary due to low cost and variety of formulations available, however, sumatriptan nasal spray has a greater role in the outpatient setting and should be non-formulary. Due to low utilization at our health system, high cost, available dosage forms, and lack of efficacy in clinical trials, consider removing frovatriptan, almotriptan, and naratriptan from formulary. Zolmitriptan should also be removed from formulary due to its similar efficacy to sumatriptan. RHM Feedback 17 RHM provided feedback Do not support recommendation – 1 RHM Support Recommendation – 15 RHM

Draft_Review_Comments triptans 1-23-19.xl

Imitrex 3-9

Imitrex STATdose system Onzetra Xsail Sumavel DosePro Zembrace SymTouch Alsuma

Sumatriptan Tablet Intranasal solution (Imitrex) Subcutaneous (Imitrex) Autoinjector solution Jet-injector solution

Imitrex: 25 mg, 50 mg, 100 mg Imitrex: 5 mg/actuation, 20 mg/actuation Imitrex: 6 mg/0.5 mL Alsuma: 6 mg/0.5 mL Imitrex STATdose system: 4 mg/0.5 mL; 6 mg/0.5 mL Zembrace SymTouch: 3 mg/0.5 mL Sumavel DosePro: 4 mg/0.5 mL

Relpax 10 Eletriptan Tablet 20 mg 40 mg

Frova 11 Frovatriptan Tablet 2.5 mg Amerge 12 Naratriptan Tablet 1 mg

2.5 mg Maxalt 13

Maxalt MLT Rizatriptan Tablet

ODT 5 mg,10 mg 5 mg, 10 mg

Axert 14 Almotriptan Tablet 6.25 mg 12.5 mg

Zomig 15, 17

Zomig ZMT Zolmitriptan Tablet

Nasal ODT

2.5, 5 mg 2.5, 5 mg 2.5, 5 mg

*Generic sumatriptan available for all formulations except Jet-injector Mechanism of action 17,18

Selective 5-HT1B and 5-HT1D receptor agonist on intracranial blood vessels and sensory nerves of the trigeminal system that cause vasoconstriction and reduce neurogenic inflammation associated with antidromic neuronal transmission correlating with the relief of migraines.

Pharmacokinetics 3-17

Table 2: Pharmacokinetics of Triptans Onset of

action Distribution Bioavailability Metabolism Half-life Excretion

Sumatriptan Oral: ~30 Intranasal sol: 15-30 SubQ: ~10

Oral, intranasal powder and solution: 2.7 L/kg SubQ: 50 L

Solution 17%, Powder 19% Oral: 15%; SubQ: 97% ± 16%; Note: Sumavel DosePro is bioequivalent to sumatriptan SubQ injection via needle when administered into the thigh or abdomen

Hepatic to inactive metabolite Monoamine oxidase Extensive first-pass metabolism following oral administration Hepatic impairment: oral bioavailability markedly increases

1-4 hours Oral: urine (60%); feces (~40%) Intranasal: urine (42%) SubQ: urine (38%)

Eletriptan 1.5-2 hours

138 L ~50%, increased with high-fat meal

Hepatic via CYP3A4 Forms one active metabolite Mild to moderate hepatic impairment results in increase in half life and AUC

~4 Elderly: 4.5-5.7 Metabolite~ 13

Renal and non-renal

Frovatriptan 2-4 hours Male: 4.2 L/kg Female: 3 L/kg

Male: ~20% Female: ~30%

Primarily hepatic via CYP1A2

~26 hours Feces (62%) Urine (32%)

Naratriptan ~1-2 hours

170 L ~70% Hepatic via CYP

6 hours Moderate renal impairment: 11 hours (range:7-20 hours)

Urine (50% as unchanged drug; 30% as metabolites)

Hepatic impairment: 8-16 hours

Rizatriptan ~2 hours Females: 110 L Males: 140 L

~45% Monoamine oxidase-A (MAO-A) Significant first pass metabolism

2-3 hours Urine (82%) Feces (12%)

Almotriptan 1-3 hours 180 to 200 L ~70% MAO-A oxidative deamination CYP3A/2D6 to inactive metabolites

3-5 hours Urine (75%) Feces: (~13%)

Zolmitriptan Tablet: 1.5 hours ODT and nasal spray: 3 hours

Oral: 7 L/kg Nasal spray: 8.4 L/kg

Oral: 40 % Nasal spray: 10.2%

Converted to an active N-desmethyl metabolite (2-6 times more potent than zolmitriptan at 5-HT1B and 5-HT1D receptors)

3 hours Urine: 60-65% Feces: 30%

Black Box Warnings 3-17 Not applicable to any of the triptan medications and their different formulations Contraindications 3-17

• Familial hemiplegic migraine • Basilar migraine • Ischemic stroke • Ischemic heart disease • Prinzmetals angina • Uncontrolled hypertension • Combination with monoamine oxidase inhibitors or ergot compounds • Pregnancy

Warnings/Precautions 3-17

Table 3: Precautions for Triptans Suma-

triptan Ele- triptan

Frova- triptan

Nara- triptan

Riza- triptan

Almo- triptan

Zolmi- triptan

Anaphylactic reactions X X X X X Cardiac events: coronary artery vasospasm, ischemia, MI, ventricular tachycardia/fibrillation, cardiac arrest, death

X X X X X X X

Cerebrovascular events: cerebral/subarachnoid hemorrhage, stroke

X X X X X X X

CNS depression: dizziness, weakness, drowsiness

X X

Elevated blood pressure X X X X X X X Ocular effects: transient and permanent blindness (rare)

X X

Visual effect: partial vision loss and transient blindness

X X X X

Serotonin syndrome X X Vasospasm-related events: Peripheral vascular ischemia, GI vascular ischemia and infarction, splenic infarction, and Raynaud syndrome

X X X X X X X

Headaches with use >10 days per month

X X X X

Special Populations 18-23

Table 4: Special populations Pregnancy Breast-Feeding

considerations Pediatrics Geriatrics

Sumatriptan Pregnancy Category C If treatment for cluster headaches is needed during pregnancy, sumatriptan may be used if first-line options fail.

Following oral, subcutaneous, or intranasal administration, manufacturers recommend withholding breastfeeding for 12 hours after the maternal dose.

Results of clinical studies are mixed with regards to efficacy with oral and subcutaneous sumatriptan doses; however, sumatriptan nasal spray is effective for the acute treatment of migraines in adolescent patients

Safety and efficacy in elderly (>65 years) has not been established Not recommended due to cardiovascular risk

Eletriptan Pregnancy Category C No data available. Until additional information is available, other agents are preferred for the initial treatment of migraine in pregnancy.

The manufacturer recommends that caution be exercised when administering eletriptan to breastfeeding women as drug is present in breast milk

Safety and efficacy not established Not recommended for use in patients under 18 years of age.

Safety and efficacy in elderly >65 years of age have not been established Use lowest recommended doses initially

Frovatriptan Naratriptan Rizatriptan

Pregnancy Category C No data available. Until additional information is available, other agents are preferred for the initial treatment

Unknown if present in breast milk The decision to breastfeed during therapy should consider the risk of infant exposure, benefits of breastfeeding, and

Safety and efficacy not established Not recommended for use in patients under 18 years of age.

Use with caution due to cardiovascular risk in elderly patients

of migraine in pregnancy.

benefits of treatment to the mother.

Almotriptan Pregnancy Category C No data available. Until additional information is available, other agents are preferred for the initial treatment of migraine in pregnancy.

Unknown if present in breast milk The decision to breastfeed during therapy should consider the risk of infant exposure, benefits of breastfeeding, and benefits of treatment to the mother.

The pharmacokinetics of almotriptan has not been evaluated in pediatrics patients FDA approved in ages 12-17 years old

Use with caution due to cardiovascular risk in elderly patients

Zolmitriptan Pregnancy Category C No data available. Until additional information is available, other agents are preferred for the initial treatment of migraine in pregnancy.

Unknown if present in breast milk The decision to breastfeed during therapy should consider the risk of infant exposure, benefits of breastfeeding, and benefits of treatment to the mother.

Nasal spray: Acute treatment of migraine with or without aura (FDA approved in ages ≥12 years and adults)

Oral: Acute treatment of migraine with or without aura (FDA approved in adults)

Use with caution due to cardiovascular risk in elderly patients

Adverse Reactions 3-17

Table 5: Adverse Reactions with Triptans Frovatriptan Zolmitriptan Sumatriptan >10% Not applicable GI: Unpleasant taste (nasal:

adults: 17% to 21%; children & adolescents: 6% to 10%)

Injection -CNS: tingling (14%), dizziness and vertigo (<12%) -Local: injection site reaction (59%) Nasal -GI: Dysgeusia (≤25%), nausea and vomiting (≤14%) -Respiratory: Nasal discomfort (≤11%)

1-10% -CV: flushing (4%), chest pain (2%), palpitations (1%) -CNS: dizziness (8%), fatigue (5%), headache, paresthesia (4%), drowsiness (>2%), anxiety (1%), dysesthesia, hypoesthesia, insomnia, pain (1%)

CV: Chest pain (oral: 2% to 4%), chest pressure (nasal: 1% to <2%), facial edema, palpitations (nasal: 1% to <2%), cardiac arrhythmia, hypertension, syncope, tachycardia (≤1%) CNS: Dizziness (adults: 6% to 10%; children & adolescents: 2%), paresthesia (5% to 10%),

Injection -CV: flushing (7%), chest discomfort (5%), chest pressure (2%) -CNS: burning sensation, pressure (7%), numbness, paresthesia (5%), sedation (<3%), headache (2%) -Dermatologic: Diaphoresis (2%) -GI: Nausea and vomiting (4%) -Neuromuscular & skeletal: Neck pain, neck stiffness (≤5%), weakness (5%), myalgia (2%)

- Dermatologic: diaphoresis (1%) -GI: xerostomia (3%), nausea (>2%), dyspepsia (2%), abdominal pain, diarrhea, vomiting (1%) -Neuromuscular and skeletal: musculoskeletal pain (3%) -Ophthalmic: visual disturbance (1%) - Otic: tinnitus (1%) -Respiratory: rhinitis, sinusitis (1%)

drowsiness (4% to 8%), local alterations in temperature sensations (oral: 5% to 7%), sensation of pressure (oral: hyperesthesia (nasal: 1% to 5%), (1% to 5%), flushing sensation (nasal: 4%), pain (nasal: 2% to 4%), vertigo (oral: 2%), chills (nasal: 1% to <2%), depersonalization (nasal: 1% to <2%), headache (1% to <2%), agitation, amnesia, anxiety, depression (≤1%), emotional lability (oral: ≤1%), insomnia, nervousness (nasal: ≤1%) Dermatologic: Diaphoresis (oral: 2% to 3%), pruritus, skin rash, urticaria (≤1%) GI: Nausea (adults: 4% to 9%; children & adolescents: 2%), xerostomia (2% to 5%), dyspepsia (oral: 2% to 3%), dysphagia (1% to 2%), abdominal pain (nasal: 1% to <2%), vomiting (1% to <2%) Local: Local pain (4% to 10%; neck/throat/jaw), application site irritation (nasal: 3%) Neuromuscular & skeletal: Weakness (oral: 5% to 9%; nasal: 3%), arthralgia, myalgia (nasal: 1% to <2%) Respiratory: Nasal discomfort (nasal: 3%), constriction of the pharynx (nasal: 2%), pressure on pharynx (nasal: 1% to <2%), bronchitis, cough, dyspnea, epistaxis, laryngeal edema, pharyngitis, rhinitis, sinusitis (nasal: ≤1%)

-Respiratory: Nasal discomfort, sinus discomfort (≤2%), bronchospasm (1%) Nasal -CNS: Localized numbness, nasal cavity pain, paresthesia (≤5%), dizziness (≤2%), vertigo (≤2%), localized burning (1%) -Local: irritation (≤5%) -Respiratory: Rhinorrhea, sore nose (≤5%), nasal signs and symptoms, sinus discomfort (≤4%), rhinitis (2%) Tablet -CV: Hot and cold flashes (3%), chest pain/pressure (≤2%) -CNS: Pain (≤8%), sensation of pressure (≤8%), paresthesia (3% to 5%), fatigue (≤3%), malaise (≤3%), vertigo (2%) -Gastrointestinal: Sore throat (≤3%) -Local: Local pain (2%) -Neuromuscular & skeletal: Jaw pain and neck pain (≤3%) -Respiratory: Pharyngeal edema (≤3%)

Naratriptan Rizatriptan Almotriptan Eletriptan >10% Not applicable Not applicable Not applicable Not applicable 1-10% -CNS: pain (4%),

fatigue (2%), -CV: chest pain (<3%), flushing, palpitations (>1%)

-CNS: Drowsiness

-CV: chest pain (2-4%), palpitations

dizziness, drowsiness, paresthesia (1-2%), hot and cold flashes, sensation of pressure, vertigo (1%) -GI: nausea (4-5%), vomiting (1%), xerostomia (1%) -Neuromuscular and skeletal: neck pain (2%) -Ophthalmic: photophobia (1%) -Respiratory: constriction of pharynx (2%), ENT infection (1%)

-CNS: dizziness (4-9%), drowsiness (4-8%), fatigue (4-7%), paresthesia (3-4%), pain (3%), feeling of heaviness, headache (<2%), euphoria, hypoesthesia (>1%) -GI: nausea (4-6%), xerostomia (3%), sore throat, (<2%), abdominal distress, diarrhea, vomiting (>1%) - Neuromuscular and skeletal: weakness (4-7%), jaw pain/pressure, neck pain/pressure (<2%) -Respiratory: pharyngeal edema, pressure on pharynx (<2%), dyspnea (>1%)

(≤5%), dizziness (≤4%), headache (≤2%) -GI: Nausea (1% to 3%), vomiting (≤2%), xerostomia (1%) -Neuromuscular and skeletal: Paresthesia (≤1%)

-CNS: dizziness, drowsiness (6 - 7%), headache -Dermatologic: diaphoresis -GI: nausea (8%), xerostomia (3-4%), abdominal pain (2%), dyspepsia (2%), dysphagia (1-2%) -Neuromuscular and skeletal: weakness (4-10%), back pain -Respiratory: pharyngitis

Drug Interactions 3-17

Table 6: Drug Interactions with Triptans Sumatriptan Eletriptan Frovatriptan Naratriptan Monitor therapy: Anti-emetics Antipsychotics Droxidopa Metaxalone Methylphenidate Metoclopramide Opioid analgesic Tramadol Serotonin modulators Avoid combination: Dapoxetine Ergot derivative Methylene blue MOA-inhibitors Seretonin 5-HT1D receptor agonists

Monitor therapy: Anti-emetics Antipsychotics Ceritinib Droxidopa Fosaprepitant Metaxalone Methylphenidate Metoclopramide Opioid analgesic Palbociclib Serotonin modulators Simeprevir Tedizolid Tramadol Consider therapy modification: MOA-inhibitors Moderate CYP3A4 inhibitors Linezolid Stiripentol Avoid combination: Conivaptan Strong CYP3A4 inhibitors Dapoxetine Ergot derivatives Fusidic acid Idelalisib Methylene blue

Monitor therapy: Anti-emetics Antipsychotics Droxidopa Metaxalone Methylphenidate Metoclopramide Opioid analgesic Serotonin modulators Tedizolid Tramadol Consider therapy modification: MOA-inhibitors Linezolid Avoid combination: Dapoxetine Ergot derivative

Monitor therapy: Anti-emetics Antipsychotics Droxidopa Metaxalone Methylphenidate Metoclopramide Opioid analgesic Serotonin modulators Tedizolid Tramadol Consider therapy modification: MOA-inhibitors Linezolid Avoid combination: Dapoxetine Ergot derivative Methylene blue

Rizatripan Almotriptan Zolmitriptan Monitor therapy: Anti-emetics Antipsychotics Droxidopa Metaxalone Methylphenidate Metoclopramide Opioid analgesics Serotonin modulators Tramadol Consider therapy modification: Propranolol Avoid combination: Dapoxetine Ergot derivative Methylene blue MOA-inhibitors

Monitor therapy: Anti-emetics Antipsychotics Droxidopa Metaxalone Methylphenidate Metoclopramide Opioid analgesics Serotonin modulators Tramadol Consider therapy modification: Strong CYP3A4 inhibitors Avoid combination: Dapoxetine Ergot derivative Methylene blue MOA-inhibitors

Monitor therapy: Anti-emetics Antipsychotics Droxidopa Metaxalone Methylphenidate Metoclopramide Propranolol Tramadol Consider therapy modification: Cimetidine Avoid combination: Dapoxetine Ergot derivative Methylene blue MOA-inhibitors

Recommended Monitoring 3-17

Efficacy: Headache severity Safety: Signs/symptoms suggestive of angina; blood pressure, heart rate, and/or ECG with first dose in patients with likelihood of unrecognized coronary disease, such as patients with significant hypertension, hypercholesterolemia, obese patients, patients with diabetes, smokers with other risk factors or strong family history of coronary artery disease; signs/symptoms of serotonin syndrome and hypersensitivity reactions Dosing 3-17

Table 7: Adult and Pediatric Dosing of Triptans Adult dosing Pediatric dosing Sumatriptan Migraine

Oral Single dose of 25, 50, or 100 mg taken with fluids. If satisfactory response not achieved within 2 hours, a second dose may be administered. Doses of 50 or 100 mg are equally effective. Maximum 24h dose: 200 mg Intranasal solution: A single dose of 5 mg, 10 mg, or 20 mg administered in one nostril. If headache has not resolved within 2 hours or returns, the dose may be repeated once after 2 hours, Maximum 24h dose: 40 mg Subcutaneous: Alsuma and Imitrex: 6 mg; if side effects are limiting, lower dose at 1-5 mg Sumavel: 6 mg, if side effects dose limiting, use 4 mg

Migraine Intranasal 5, 10, or 20 mg administered in one nostril as a single dose Oral Age ≤17 years: Limited data available; efficacy results variable Age >18 years: Single dose of 25, 50, or 100 mg taken with fluids. If satisfactory response not achieved within 2 hours, a second dose may be administered. Doses of 50 or 100 mg are equally effective. Maximum 24h dose: 200 mg Subcutaneous: Age ≥6 years and ≤17 years: 3 to 6 mg single dose Age >18

May repeat if needed >1 hour after initial dose (Maximum 24h dose: two 6 mg injections) Zembrace: 3 mg; repeat up to 4 injections if needed Maximum 24h dose: 12 mg Cluster headache Subcutaneous (excluding Zembrace) Initial: 6 mg; may repeat if needed ≥1 hour after initial dose

Imitrex, Sumavel: Initial: 6 mg; if side effects are dose limiting, use lower doses: Imitrex: 1 to 5 mg or Sumavel: 4 mg. May repeat if needed ≥1 hour after initial dose Maximum 24h dose: 6 mg Zembrace: Initial: 3 mg; after 1 hour may repeat dose if needed up to 4 injections separated by at least 1 hour Maximum 24h dose: 12 mg

Eletriptan Acute migraine: Initial: 20 to 40 mg as a single dose (maximum: 40 mg/dose); If headache improves but returns, dose may be repeated after 2 hours have elapsed since first dose (maximum: 80 mg/day)

Not recommended for use in patients under 18 years of age

Frovatriptan Migraine 2.5 mg; if headache recurs, a second dose may be administered after 2 hours have elapsed since the first dose Maximum 24h dose: 7.5 mg

Not recommended for use in patients under 18 years of age

Naratriptan Acute migraine Initial: 1 to 2.5 mg; if headache recurs or does not fully resolve, second dose may be administered after 4 hours Maximum 24h dose: 5 mg Menstrual migraine (off-label) 1 mg twice daily beginning 2-3 days prior to expected onset of symptoms Continue for total of 5-6 days

Not recommended for use in patients under 18 years of age

Rizatriptan Migraine: 5-10 mg; repeat after 2 hours if relief not established Maximum 24h dose: 5 mg

Not recommended for use in patients under 18 years of age

Almotriptan Migraine 6.25-12.5 mg in a single dose; repeat dose after 2 hours Maximum 24h dose: 25 mg

Children >12 years: Refer to adult dosing

Zolmitriptan Cluster headache, treatment (off-label): Nasal inhalation: 2.5 or 5 mg dose per nasal spray Oral: 5 to 10 mg at the onset of cluster headache Maximum 24h dose: 10 mg Migraine: Nasal inhalation: 2.5 mg Oral: 1.25-2.5 mg ODT: 2.5 mg May repeat in 2 hours if migraine has not resolved Maximum 24h dose: 10 mg

Migraine: Nasal inhalation only 2.5 mg; may repeat in 2 hours if migraine headache has not resolved Maximum 24h dose: 10 mg Dose adjustment for concomitant therapy with cimetidine: single dose 2.5 mg Maximum 24h dose 5 mg

Menstrual migraine, prophylaxis (off-label use): Oral: 2.5 mg 2-3 times daily starting 2 days prior to expected onset of menses and continued through to 5 days after the onset of menses (7 days total) Dose adjustment for concomitant therapy with cimetidine: Oral: single dose 2.5 mg Maximum 24h dose 5 mg

Clinical Studies/Comparative Efficacy Placebo Controlled and Head-to-Head Trials A cross-over, double blind, randomized, multicenter trial evaluated the consistency of efficacy and safety of oral sumatriptan in 233 patients suffering from migraines. The patients received 50 mg oral sumatriptan or placebo for the treatment of 12 migraine attacks. Within each group of 4 attacks, three were treated with sumatriptan and one was treated with placebo. Overall, the efficacy rate was statistically significant for sumatriptan against placebo at 2 or 4 hours (2 hours: sumatriptan 60%, p < 0.001; 4 hours sumatriptan 79%, p < 0.001). Oral sumatriptan was similarly effective at relieving the associated symptoms and at reducing clinical disability in most attacks. The incidence of adverse events did not differ between treatment groups. 24

A randomized, parallel-group, double-blind, placebo-controlled trial investigated the use of oral naratriptan 2.5 mg in non-responders to oral sumatriptan. Participants at 57 different sites in the U.S. had had an unsatisfactory response to sumatriptan, had a history of migraine for at least 1 year, and had experienced at least one migraine attack in each of the 2 months preceding the study. The objective of this study was to determine whether patients who responded poorly to sumatriptan would respond to naratriptan. Naratriptan was superior to placebo for relief of migraine pain at 4 hours (P <.001), and that it was superior to placebo in patients with no pain at 4 hours (P = 0.022) and for headache relief at 2 hours (P = .005); however, it did not achieve statistical significance in patients with no pain at 2 hours. No significant AEs occurred. 25

A randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of oral almotriptan (12.5 mg and 25 mg) versus sumatriptan 100 mg and placebo in 668 migraine patients ages 18 to 65 years. Those whose migraine onset occurred before age 50 years had at least a 1-year history of up to six migraine attacks per month, with at least 24 hours between attacks. Almotriptan 12.5 mg was tolerated to the same degree as placebo and was significantly better tolerated than sumatriptan (P <.001) when the incidence of AEs was considered. There was no statistically significant difference in the incidence of AEs between almotriptan 25 mg and sumatriptan 100 mg. 26

Head-to-head trials assessing the efficacy of eletriptan 40 mg compared with sumatriptan 100 mg were conducted. 2,906 adults who experienced up to six migraine attacks, with or without aura, per month, were included in these trials. Eletriptan use resulted in significantly higher headache-response rates versus sumatriptan at both 1 hour and 2 hours (P <.0001), as well as higher pain-free response rates at 2 hours versus sumatriptan and placebo (P <.0001). Eletriptan showed superior efficacy compared with sumatriptan across all clinically relevant outcomes. Both eletriptan and sumatriptan were well tolerated, and reported AEs were mild and transient. Regarding AEs, eletriptan demonstrated tolerability comparable to that of placebo, with the exception of asthenia. In summary, the use of eletriptan to treat an acute attack was associated with a significantly higher probability of response compared with sumatriptan. 27

Meta-analysis: 2013 28

Two-hour outcomes 24-hour sustained outcomes Comparison Pain-free

response Headache response

Pain-free response

Headache response

Placebo vs Eletriptan (40 mg) Sumatriptan (50 mg)

4.95 (3.75-6.59) 3.24 (2.66-3.97)

4.69 (3.91-5.59) 2.88 (2.45-3.39)

3.66 (2.63-5.15) 1.94 (1.43-2.63)

3.65 (2.76-5.10) 2.16 (1.68-2.79)

Rizatriptan (10 mg) Almotriptan (2.5 mg) Zolmitriptan (12.5 mg) Naratriptan (2.5 mg) Frovatriptan (2.5 mg)

4.44 (3.51-5.69) 2.45 (1.77-3.39) 3.40 (2.54-4.53) 1.68 (1.04-2.72) 3.52 (2.25-5.66)

3.87 (3.26-4.60) 2.87 (2.20-3.73) 3.80 (3.05-4.77) 2.24 (1.61-3.13) 2.21 (1.63-2.99)

2.85 (2.00-4.10) 2.98 (1.97-4.51) 3.36 (2.28-4.96) 1.37 (0.64-2.83) ------

1.92 (1.40-2.67) 2.44 (1.59-3.91) 2.61 (1.89-3.74) 2.01 (1.17-3.52) -----

Eletriptan (40 mg) vs. Sumatriptan (50 mg) Rizatriptan (10 mg) Almotriptan (2.5 mg) Zolmitriptan (12.5 mg) Naratriptan (2.5 mg) Frovatriptan (2.5 mg)

1.53 (1.16-2.01) 1.12 (0.80-1.55) 2.03 (1.38-2.96) 1.46 (1.02-2.09) 2.95 (1.78-4.90) 1.41 (0.82-2.37)

1.64 (1.29-2.03) 1.21 (0.95-1.54) 1.63 (1.19-2.23) 1.23 (0.93-1.61) 2.09 (1.46-2.99) 2.12 (1.48-3.01)

1.89 (1.37-2.62) 1.28 (0.78-2.10) 1.22 (0.74-2.06) 1.09 (0.70-1.70) 2.68 (1.36-5.59) -----

1.69 (1.38-2.17) 1.88 (1.23-3.01) 1.50 (0.83-2.58) 1.39 (0.96-2.06) 1.82 (1.12-2.99) ----

Sumatriptan (50 mg) vs. Rizatriptan (10 mg) Almotriptan (2.5 mg) Zolmitriptan (12.5 mg) Naratriptan (2.5 mg) Frovatriptan (2.5 mg)

0.73 (0.56-0.94) 1.32 (0.95-1.84) 0.95 (0.69-1.32) 1.93 (1.17-3.17) 0.92 (0.55-1.49)

0.75 (0.60-0.93) 1.00 (0.76-1.34) 0.58 (0.76-0.98) 1.29 (0.89-1.86) 1.30 (0.92-1.84)

0.67 (0.42-1.09) 0.65 (0.39-1.09) 0.58 (0.36-0.93) 1.46 (0.68-3.08)

1.13 (0.74-1.69) 0.89 (0.52-1.47) 0.82 (0.57-1.47) 1.08 (0.63-1.81)

Rizatriptan (10 mg) vs. Almotriptan (2.5 mg) Zolmitriptan (12.5 mg) Naratriptan (2.5 mg) Frovatriptan (2.5 mg)

1.85 (1.24-2.67) 1.31 (0.92-1.87) 2.65 (1.61-4.38) 1.26 (0.74-2.10)

1.34 (0.99-1.84) 1.02 (0.77-1.33) 1.73 (1.20-2.47) 1.75 (1.23-2.49)

0.95 (0.56-1.68) 0.84 (0.5-1.46) 2.09 (0.94-4.88)

0.79 (0.44-1.33) 0.73 (0.45-1.17) 0.97 (0.49-1.77)

Almotriptan (2.5 mg) vs. Zolmitriptan (12.5 mg) Naratriptan (2.5 mg) Frovatriptan (2.5 mg)

1.04 (0.61-1.79) 2.10 (1.10-4.12) 1.44 (0.83-2.53)

0.58 (0.39-0.84) 0.98 (0.63-1.55) 0.77 (0.52-1.16)

0.89 (0.58-1.36) 2.19 (0.97-2.19)

0.93 (0.53-1.64) 1.21 (0.61-2.64)

Zolmitriptan (12.5 mg) vs. Naratriptan (2.5 mg) Frovatriptan (2.5 mg)

0.72 (0.49-1.06) 0.69 (0.39-1.20)

0.75 (0.55-1.02) 1.29 (0.86-1.93)

2.46 (2.46-5.53)

1.32 (0.71-2.35)

Naratriptan (2.5 mg) vs. Frovatriptan (2.5 mg)

0.96 (0.56-1.64)

1.71 (1.18-2.51)

Two-hour outcomes 24-hour sustained outcomes

Triptan Pain-free response (%)

Headache response (%)

Pain-free response (%)

Headache response (%)

Eletriptan 68.7 71.6 54.1 87.8 Sumatriptan 0.0 0.0 0.0 0.0 Rizatriptan 22.6 15.7 9.2 0.1 Almotriptan 0.0 0.0 10.4 3.5 Zolmitriptan 0.7 12.6 26.1 7.7 Naratriptan 0.0 0.1 0.2 0.9 Frovatriptan 8.0 0.0

Summary of 2013 meta-analysis: This meta-analysis from 2013 included only double-blind, randomized clinical trials comparing triptans to either placebo or another triptan. The primary outcomes were pain-free response at two hours and 24-hour sustained pain-free response. Secondary outcomes were headache response at two hours and 24-hour sustained headache response. According to the following trials, all triptans were significantly superior to placebo for all outcomes, with the exception of naratriptan for 24-hour sustained pain-free response. Eletriptan consistently had the highest odds ratio of producing 2 hour pain relief, two-hour headache response, 24-hour sustained pain relief, and 24-hour sustained headache response. Rizatriptan appears to offer the second most favorable treatment outcome at two hours, but does not maintain the same degree of efficacy at 24 hours’ efficacy. Zolmitriptan and high-dose

sumatriptan offer the third highest chance of pain-free response and headache response, and appear to maintain their efficacy at 24 hours. Meta-analysis: 2016 29

Comparison 1h-pain free

1h-pain relief

2h-pain free

2h-pain relief

2h-nausea absence

Rescue medication

Recurrence All- adverse event

Nausea

Sumatriptan vs. placebo

2.89 (1.74, 4.81)

1.71 (1.34, 2.19)

2.93 (2.49, 3.44)

1.94 (1.76, 2.14)

1.08 (0.90, 1.30)

0.62 (0.54, 0.71)

1.34 (1.1, 1.63)

1.88 (1.59, 2.23)

1.83 (1.45, 2.32)

Zolmitriptan vs. placebo

2.45 (2.08, 2.9)

1.94 (1.73, 2.18)

2.75 (2.06, 3.68)

2.17 (1.88, 2.50)

1.44 (1.29, 1.62)

0.56 (0.51, 0.62)

1.09 (0.67, 1.76)

1.94 (1.49, 2.53)

2.17 (1.51, 3.12)

Almotriptan vs. placebo

1.99 (0.99, 3.99)

1.32 (0.89, 1.94)

1.66 (1.09, 2.53)

1.57 (1.29, 1.90)

1.37 (0.97, 1.93)

0.53 (0.23, 1.21)

1.58 (0.87, 2.84)

1.48 (0.94, 2.33)

0.57 (0.21, 1.53)

Rizatriptan vs. placebo

3.25 (1.79, 5.90)

1.71 (1.21, 2.43)

5.36 (4.09, 7.04)

2.12 (1.74, 2.58)

1.39 (1.24, 1.55)

0.60 (0.42, 0.87)

1.43 (1.14, 1.8)

1.68 (1.44, 1.96)

1.24 (0.88, 1.76)

Naratriptan vs. placebo

3.50 (0.43, 28.8)

1.72 (1.16, 2.56)

2.75 (1.66, 4.56)

1.99 (1.50, 2.62)

1.25 (1.00, 1.57)

0.52 (0.38, 0.71)

1.02 (0.61, 1.7)

1.81 (1.10, 2.98)

1.00 (0.25, 4.08)

Eletriptan vs. placebo

18.4 (4.54, 74.9)

3.63 (2.23, 5.92)

7.41 (5.16, 10.63)

2.70 (2.23, 3.27)

1.30 (1.11, 1.53)

0.38 (0.30, 0.48)

1.52 (1.16, 0.75)

0.91 (0.75, 1.11)

0.19 (0.04, 0.85)

Zolmitriptan vs. sumatriptan

0.86 (0.66, 1.12)

1.01 (0.88, 1.14)

0.97 (0.82, 1.14)

1.00 (0.90, 1.11)

- 0.97 (0.68, 1.40)

1.06 (0.89, 1.26)

1.08 (0.97, 1.21)

1.11 (0.70, 1.76)

Almotriptan vs. sumatriptan

- 0.98 (0.78, 1.22)

0.79, 0.64, 0.97)

1.02 (0.85, 1.24)

1.03 (0.85, 1.25)

1.13 (0.93, 1.37)

1.16 (0.9, 1.5)

0.52 (0.37, 0.73)

0.64 (0.32, 1.30)

Rizatriptan vs. sumatriptan

1.49 (1.16, 1.91)

1.11 (0.95, 1.30)

1.20 (1.08, 1.34)

1.03 (0.91, 1.16)

1.08 (0.96, 1.23)

0.90 (0.63, 1.28)

1.07 (0.93, 1.24)

0.88 (0.75, 1.04)

0.74 (0.55, 1.00)

Naratriptan vs. sumatriptan

- 0.98 (0.63, 1.50)

0.96 (0.56, 1.62)

0.96 (0.56, 1.62)

1.02 (0.78, 1.33)

1.35 (0.79, 2.31)

0.61 (0.47, 0.79)

0.94 (0.70, 1.26)

0.78 (0.26, 2.28)

Eletriptan vs. sumatriptan

1.42 (0.93, 2.15)

1.29 (1.05, 1.58)

1.35 (1.10, 1.65)

1.12 (0.96, 1.31)

1.09 (0.94, 1.27)

0.74 (0.59, 0.93)

0.94 (0.75, 1.18)

0.83 (0.69, 1.01)

-

Almotriptan vs. zolmitriptan

- - 0.90 (0.73, 1.11)

0.93 (0.77, 1.12)

- 0.99 (0.74, 1.32)

1.07 (0.8, 1.42)

- 1.18 (0.52, 2.65)

Rizatriptan vs. zolmitriptan

1.22 (0.73, 2.02)

1.20 (0.73, 2.02)

1.22 (0.90, 1.66)

1.05 (0.81, 1.35)

1.12 (0.87, 1.44)

- 0.96 (0.68, 1.36)

0.89 (0.63, 1.27)

-

Eletriptan vs. zolmitriptan

1.59 (0.96, 2.64)

1.39 (1.06, 1.81)

1.93 (1.50, 2.49)

1.13 (0.93, 1.38)

1.10 (0.91, 1.34)

- 0.92 (0.68, 1.23)

1.08 (0.85, 1.37)

-

Naratriptan vs. rizatriptan

0.35 (0.14, 0.84)

0.73 (0.49, 1.08)

0.46 (0.31, 0.69)

0.70 (0.51, 0.97)

0.86 (0.63, 1.18)

- 0.63 (0.41, 0.96)

0.70 (0.44, 1.09)

0.47 (0.17, 1.28)

Summary of 2016 meta-analysis:

This meta-analysis included randomized, double blind clinical trials that compared the various triptans to placebo, each other and NSAIDs. Eletriptan and rizatriptan are superior to sumatriptan, zolmitriptan, almotriptan, ibuprofen and aspirin with respect to pain-relief. When analyzing 2 h-nausea-absence, rizatriptan has a better efficacy than sumatriptan, while other treatments indicate no distinctive difference compared with placebo. Furthermore, sumatriptan demonstrates a higher incidence of all-adverse-event compared with NSAIDs and almotriptan. In conclusion, eletriptan was found to be the most suitable therapy for migraine from a comprehensive point of view. Trinity Health Triptan Utilization (July 2017-July 2018)

Triptan Cost at SJMO

Triptan NDC/UPC Acq Cost Sumatriptan 25 mg tab X9 UD 62756-0520-69 4.66 USD/1 Ea Sumatriptan 50 mg tab X9 UD 62756-0521-69 3.45 USD/ 1 Ea Sumatriptan 5 mg Nasal Spray X6 Unknown 269.81 USD/1 Ea Sumatriptan 20 mg Nasal Spray X6 Unknown 221.89 USD/1 Ea Sumatriptan 6 mg/0.5 mL SDV X5 Unknown 21.25 USD/1 Ea Almotriptan 6.25 mg tab X6 UD 00378-5245-85 134.59 USD/ 1 Ea Almotriptan 12.5 mg tab X12 UD 00378-5246-85 259.47 USD/ 1 Ea Frovatriptan Succinate 2.5 mg tab X9 BP

68462-0694-97 215.53 USD/ 1 Ea

Eletriptan Hydrobromide 20 mg tab 6 UD

00093-8310-18 60.99 USD/1 Ea

Eletriptan Hydrobromide 40 mg tab 6 UD

00093-8311-18 54.46 USD/1 Ea

Naratriptan 1 mg tab 9 UD 00054-0278-03 13.31 USD/1 Ea Naratriptan 2.5 mg tab 9 UD 42043-0131-09 9.21 USD/1 Ea

CDM Desc (Stmt Billed) CDM Desc Total Volume

Total IP Volume

Total OP Volume

Total ED Volume

NARATRIPTAN TAB 2.5MG NARATRIPTAN TAB 2.5MG 60 60

SUMATRIPTAN NAS SPRY 5MG SUMATRIPTAN NAS SPRY 5MG 4 2 2

SUMATRIPTAN TAB 25MG SUMATRIPTAN TAB 25MG 1771 1455 266 50 SUMATRIPTAN TAB 50MG SUMATRIPTAN TAB 50MG 3122 2459 554 109 ZOLMITRIPTAN TAB 2.5MG ZOLMITRIPTAN TAB 2.5MG 25 20 5 SUMATRIPTAN SUCCINATE INJ 6MG SUMATRIPTAN VIAL 6MG 1083 397 97 589

SUMATRIPTAN NAS SPRY 20MG 6PK SUMATRIPTAN NAS SPRY 20MG 6PK 19 18 1

ELETRIPTAN TAB 40MG ELETRIPTAN TAB 40MG 6 4 2 RIZATRIPTAN TAB 5MG RIZATRIPTAN TAB 5MG 90 77 13 ELETRIPTAN TAB 20MG ELETRIPTAN TAB 20MG 23 23 0 RIZATRIPTAN TAB 10MG RIZATRIPTAN TAB 10MG 41 21 2 18 RIZATRIPTAN TAB SOL 5MG RIZATRIPTAN TAB SOL 5MG 67 34 33 SUMATRIPTAN TAB 100MG SUMATRIPTAN TAB 100MG 77 66 8 3

RIZATRIPTAN TAB SOL 10MG RIZATRIPTAN TAB SOL 10MG 19 5 1 137

SUMATRIPTAN SUCCINATE INJ 6MG SUMATRIPTAN SUCCINATE INJ 6MG 13 13

Rizatriptan Benz 5 mg ODT tab 9 UD

65862-0625-90 9.69 USD/1 Ea

Rizatriptan Benz 10 mg ODT tab 9 UD

65862-0626-90 11.37 USD/1 Ea

Zolmitriptan 2.5 mg tab X6 UD 65862-0914-69 3.64 USD/1 Ea Zolmitriptan 5 mg tab X3 UD 27241-0022-38 4.61 USD/1 Ea

Conclusion There is little variation in the safety and efficacy between the various triptans that are available. Trinity Health has many of the different triptans currently on formulary. Triptans do not have black box warnings, however, there are a few contraindications that are similar across the board. Class adverse effects of triptans include tingling, flushing, dizziness, drowsiness, fatigue, and heaviness, tightness, or pressure in the chest, angina, myocardial infarction, cardiac arrhythmia, stroke, seizure, and death have occurred rarely with triptans. Compared to all other triptans, sumatriptan has more severe adverse effects. Sumatriptan also comes in many different formulations that include intranasal, auto and jet injectors, and oral tablets. A triptan should generally not be used within 24 hours of another triptan or an ergot because vasoconstriction could be additive; cases of serotonin syndrome reported with SSRIs and SNRIs, but risk is low. Recommendations Triptan therapy should be individualized to each patient’s needs and preferences through consideration of efficacy, potential AEs, drug-drug interactions, and cost. According to the various studies, eletriptan and rizatriptan are most efficacious of the triptans and other methods of migraine relief. Rizatriptan, however, is utilized more frequently throughout Trinity Health and is also lower in cost. At this time, there does not seem to be a need for eletriptan as it is more costly and not utilized as often. Sumatriptan should remain on formulary due to low cost and variety of formulations available, however, sumatriptan nasal spray has a greater role in the outpatient setting and should be non-formulary. Due to low utilization at our health system, high cost, available dosage forms, and lack of efficacy in clinical trials, consider removing frovatriptan, almotriptan, and naratriptan from formulary. Zolmitriptan should also be removed from formulary due to its similar efficacy to sumatriptan. Summary of recommendations

Formulary Non-Formulary • Sumatriptan tablets • Eletriptan • Sumatriptan subcutaneous injection • Frovatriptan • Rizatriptan tablets • Almotriptan • Naratriptan • Sumatriptan Nasal Spray

• Zolmitriptan

• Establish a therapeutic interchange for patients coming in on Non-Formulary triptans to sumatriptan 50

mg PO once PRN migraine, may repeat once. Prescribers may select a lower or higher dose of sumatriptan if they prefer.

References

1. American Academy of Neurology and the American Headache Society, "Evidence-Based Guideline Update: Pharmacologic Treatment for Episodic Migraine Prevention in Adults,” April 2012

2. American Headache Society, “The Acute Treatment of Migraine in Adults: The American Headache Society Evidence Assessment of Migraine Pharmacotherapies,” 2015

3. Imitrex injection (sumatriptan) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; July 2018.

4. Imitrex injection (sumatriptan) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; July 2018.

5. Imitrex (sumatriptan) nasal spray [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; December 2017.

6. Imitrex tablets (sumatriptan) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; November 2013.

7. Imitrex (sumatriptan) [product monograph]. Mississauga, Ontario, Canada: GlaxoSmithKline; April 2018. 8. Onzetra Xsail (sumatriptan nasal powder) [prescribing information]. Aliso Viejo, CA: Avanir

Pharmaceuticals; January 2016. 9. Zembrace SymTouch (sumatriptan succinate) [prescribing information]. San Diego, CA: Dr. Reddy’s; March

2017. 10. Relpax (eletriptan) [prescribing information]. New York, NY: Pfizer; November 2013. 11. Apo-Frovatriptan (frovatriptan) [product monograph]. Toronto, Ontario, Canada: Apotex Inc.; June 2014. 12. Amerge (naratriptan) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; November

2016. 13. Maxalt and Maxalt-MLT (rizatriptan) [prescribing information]. Whitehouse Station, NJ: Merck; March

2015. 14. Axert (almotriptan) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals Inc; May 2017. 15. Zomig and Zomig-ZMT tablets (zolmitriptan) [prescribing information]. Hayward, CA: AstraZeneca; June

2018. 16. Zomig nasal spray (zolmitriptan) [prescribing information]. Hayward, CA: AstraZeneca; November 2016. 17. Martin GR, Robertson AD, MacLennan SJ, et al. Receptor specificity and trigemino-vascular inhibitory

actions of a novel 5-HT1b/1d receptor partial agonist, 311C90 (zolmitriptan)®. BrJ Pharmacol 1997; 121: 157–64

18. Jürgens TP, Schaefer C, and May A, "Treatment of Cluster Headache in Pregnancy and Lactation," Cephalalgia, 2009, 29(4):391-400.[PubMed 19170693]

19. MacGregor EA. Migraine in pregnancy and lactation. Neurol Sci. 2014;35(Suppl 1):61-64. doi: 10.1007/s10072-014-1744-2.[PubMed 24867839]

20. Lewis D, Ashwal S, Hershey A, et al, "Practice Parameter: Pharmacological Treatment of Migraine Headache in Children and Adolescents: Report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society," Neurology, 2004, 63(12):2215-24.[PubMed 15623677]

21. Källén B, Nilsson E, Otterblad Olausson P. Delivery outcome after maternal use of drugs for migraine: a register study in sweden. Drug Saf. 2011;34(8):691-703.[PubMed 21751829]

22. MacGregor EA, "Headache in Pregnancy," Neurol Clin, 2012, 30(3):835-66.[PubMed 22840792] +all triptans 23. Nezvalová-Henriksen K, Spigset O, and Nordeng HM, "Errata in 'Triptan Exposure During Pregnancy and

the Risk of Major Congenital Malformations and Adverse Pregnancy Outcomes: Results From the Norwegian Mother and Child Cohort Study,'" Headache, 2012, 52(8):1319-20.[PubMed 22946832] )

24. Bussone G, Manzoni GC, Cortelli P, et al. Efficacy and tolerability of sumatriptan in the treatment of multiple migraine attacks. Neurol Sci. 2000;21:272-278.

25. Stark, S, Spierings ELH, McNeal S, et al. Naratriptan efficacy in migraineurs who respond poorly to oral sumatriptan. Headache. 2000;40:513-520.

26. Dowson AJ, Massiou H, Laínez JM, Cabarrocas X. Almotriptan is an effective and well-tolerated treatment for migraine pain: results of a randomized, double blind, placebo-controlled clinical trial. Cephalalgia. 2002;22:453-461.

27. Diener HC, Ryan R, Sun W, Hettiarachchi J. The 40-mg dose of eletriptan: comparative efficacy and tolerability versus sumatriptan 100 mg. Eur J Neurol. 2004;11:125-134.

28. Thorlund, Kristian, et al. "Comparative efficacy of triptans for the abortive treatment of migraine: a multiple treatment comparison meta-analysis." Cephalalgia 34.4 (2014): 258-267.

29. Xu, Haiyang, et al. "Network meta-analysis of migraine disorder treatment by NSAIDs and triptans." The journal of headache and pain 17.1 (2016): 113.