Trudhesa Drug Information

is indicated for the acute treatment of migraine with or without aura in adults. TRUDHESA is an ergotamine derivative indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use : TRUDHESA is not indicated for the preventive treatment of migraine or for the management of hemiplegic or basilar migraine.

Limitations of Use TRUDHESA is not indicated for the preventive treatment of migraine. TRUDHESA is not indicated for the management of hemiplegic or basilar migraine.

Dosing Information

The recommended dose of TRUDHESA is 1.45 mg administered as two metered sprays into the nose (one spray of 0.725 mg into each nostril). The dose may be repeated, if needed, a minimum of 1 hour after the first dose. Do not use more than 2 doses of TRUDHESA within a 24-hour period or 3 doses within a 7-day period.

Assessment

Prior to First Dose Prior to initiation of TRUDHESA, a cardiovascular evaluation is recommended . For patients with risk factors predictive of coronary artery disease who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of TRUDHESA take place in the setting of an equipped healthcare facility.

Important

Administration Instructions TRUDHESA is for nasal administration only and must not be injected. TRUDHESA must be assembled prior to use (see Instructions for Use ). Use or discard TRUDHESA within 8 hours once the vial has been opened or the product has been assembled. Prime the assembled TRUDHESA before initial use by releasing 4 sprays.

Use TRUDHESA immediately after priming. Discard TRUDHESA immediately after use. Open and prepare a new TRUDHESA if an additional dose is needed.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Placebo-Controlled Trials with Dihydroergotamine (DHE) Mesylate Nasal Spray Of the 1,796 patients and subjects treated with DHE nasal spray doses 2 mg or less in U.S. and foreign clinical studies, 26 (1.4%) discontinued because of adverse events. The adverse events associated with discontinuation were, in decreasing order of frequency: rhinitis, dizziness, facial edema, and one patient each due to cold sweats, accidental trauma, depression, elective surgery, somnolence, allergy, vomiting, hypotension, and paraesthesia.

Table 1 summarizes the incidence rates of adverse reactions reported by at least 1% of patients who received DHE nasal spray for the treatment of migraine during placebo-controlled, double-blind clinical studies and were more frequent than in those patients receiving placebo. The most commonly reported adverse reactions (greater than 1% of patients who received DHE nasal spray) were rhinitis, nausea, altered sense of taste, application site reactions, dizziness, vomiting, somnolence, pharyngitis, and diarrhea. In most instances these events were transient and self-limited and did not result in patient discontinuation from a study.

Table 1 Adverse Reactions Reported by at Least 1% of the DHE Nasal Spray Treated Patients and Occurred more Frequently than in the Placebo-Group in the Migraine Placebo-Controlled Trials DHE Nasal Spray N=597 % Placebo N=631 % Respiratory System Rhinitis 26 7 Pharyngitis 3 1 Gastrointestinal System Nausea 10 4 Vomiting 4 1 Diarrhea 2 <1 Special Senses, Other Altered Sense of Taste 8 1 Application Site Application Site Reaction 6 2 Central and Peripheral Nervous System Dizziness 4 2 Somnolence 3 2 Body as a Whole, General Hot Flashes 1 <1 Asthenia 1 0 Musculoskeletal System Stiffness 1 <1 Adverse Reactions in Studies with TRUDHESA An open-label study in adults (18 to 66 years of age) was conducted to evaluate the safety and tolerability of TRUDHESA, repeated use of TRUDHESA was allowed over the course of 6 to 12 months. A total of 354 patients with migraine received at least one dose of TRUDHESA. One hundred and eighty-five patients treated on average at least two migraines per month for 6 months, and 55 patients treated on average at least two migraines per month for 12 months. Of the patients who received at least one dose of TRUDHESA, 185 (52.3%) patients experienced local irritative symptoms.

Of these, the most common local irritative symptoms were nasopharyngitis, rhinitis, nasal discomfort, product taste abnormal/dysgeusia, sinusitis, sinus discomfort, olfactory test abnormal, epistaxis, pharyngitis, nasal mucosal disorder, change in smell, ear discomfort, and rhinorrhea.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of dihydroergotamine mesylate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Vasospasm, paresthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating, and pleural and retroperitoneal fibrosis after long-term use of dihydroergotamine. Cases of myocardial infarction and stroke have been reported following the use of dihydroergotamine mesylate .

CYP3A4 Inhibitors

There have been rare reports of serious adverse events in connection with the coadministration of intravenous administration of dihydroergotamine and strong CYP3A4 inhibitors, such as protease inhibitors (e.g., ritonavir, nelfinavir, indinavir), macrolide antibiotics (e.g., erythromycin, clarithromycin), and antifungals (e.g., ketoconazole, itraconazole), resulting in vasospasm that led to cerebral ischemia and/or ischemia of the extremities . The use of strong CYP3A4 inhibitors with dihydroergotamine is contraindicated . Administer moderate CYP3A4 inhibitors (e.g., saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, clotrimazole) with caution.

Triptans Triptans (serotonin 1B/1D receptor agonists) have been reported to cause coronary

artery vasospasm, and its effect could be additive with TRUDHESA. Therefore, triptans and TRUDHESA should not be taken within 24 hours of each other .

Beta Blockers

There have been reports that propranolol may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine.

Vasoconstrictors

TRUDHESA is contraindicated for use with peripheral and central vasoconstrictors because the combination may cause synergistic elevation of blood pressure .

Nicotine Nicotine may provoke vasoconstriction in some patients, predisposing to a greater

ischemic response to ergot therapy .

Selective

Serotonin Reuptake Inhibitors Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HT 1 agonists have been coadministered with selective serotonin reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline).

Pregnancy Risk Summary Available data from published literature indicate an increased risk of preterm delivery with TRUDHESA use during pregnancy. Avoid use of TRUDHESA during pregnancy . Data collected over decades have shown no increased risk of major birth defects or miscarriage with use of dihydroergotamine mesylate during pregnancy. In animal studies, adverse effects on embryofetal development were observed following administration of dihydroergotamine mesylate during pregnancy (decreased fetal body weight and/or skeletal ossification) in rats and rabbits or during pregnancy and lactation in rats (decreased body weight and impaired reproductive function in the offspring) in rats at doses less than those used clinically and which were not associated with maternal toxicity (see Data ). The estimated rate of major birth defects (2.2% to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Intranasal administration of dihydroergotamine mesylate to pregnant rats throughout the period of organogenesis resulted in decreased fetal body weight and/or skeletal ossification at doses of 0.16 mg/day (associated with plasma exposures less than that in humans at the maximum recommended human dose of 2.9 mg) or greater.

A no-effect level for embryofetal toxicity was not identified in rats. Intranasal administration of dihydroergotamine mesylate to pregnant rabbits throughout organogenesis resulted in decreased skeletal ossification at 3.6 mg/day. At the no-effect dose (1.2 mg/day) for adverse effects on embryofetal development in rabbits, plasma exposures (AUC) were less than that in humans at the MRHD. Intranasal administration of dihydroergotamine mesylate to female rats throughout pregnancy and lactation resulted in decreased body weight and impaired reproductive function (decreased mating indices) were observed in the offspring at doses of 0.16 mg/day or greater.

A no-effect dose for adverse developmental effects in rats was not established. Effects on development occurred at doses below those that produced evidence of significant maternal toxicity in these studies. Dihydroergotamine-induced intrauterine growth retardation has been attributed to reduced uteroplacental blood flow resulting from prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

is contraindicated in patients: with concomitant use of strong CYP3A4 inhibitors, such as protease inhibitors (e.g., ritonavir, nelfinavir, or indinavir), macrolide antibiotics (e.g., erythromycin or clarithromycin), and antifungals (ketoconazole or itraconazole) with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia) or patients who have clinical symptoms or findings consistent with coronary artery vasospasm, including Prinzmetal's variant angina with uncontrolled hypertension with peripheral arterial disease with sepsis following vascular surgery with severe hepatic impairment with severe renal impairment with known hypersensitivity to ergot alkaloids with recent use (i.e., within 24 hours) of other 5-HT 1 agonists (e.g., sumatriptan) or ergotamine-containing or ergot-type medications with concomitant use of peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure Concomitant use of strong CYP3A4 inhibitors Patients with ischemic heart disease or coronary artery vasospasm Patients with uncontrolled hypertension, peripheral arterial diseases, sepsis, following vascular surgery, or severe hepatic or renal impairment Patients with hypersensitivity to ergot alkaloids Concomitant use of other 5-HT 1 agonists (e.g., sumatriptan) or ergotamine-containing or ergot-type medications within 24 hours Concomitant use of peripheral and central vasoconstrictors

Symptoms Excessive doses of dihydroergotamine may result in peripheral signs and symptoms

of ergotism. In general, the symptoms of an acute TRUDHESA overdose are similar to those of an ergotamine overdose, although there may be less pronounced nausea and vomiting with TRUDHESA. The symptoms of an ergotamine overdose include the following: numbness, tingling, pain, and cyanosis of the extremities associated with diminished or absent peripheral pulses; respiratory depression; an increase and/or decrease in blood pressure, usually in that order; confusion, delirium, convulsions, and coma; and/or some degree of nausea, vomiting, and abdominal pain. In laboratory animals, dihydroergotamine was lethal when given at intravenous doses of 44 mg/kg in mice, 130 mg/kg in rats, and 37 mg/kg in rabbits.

Treatment Treatment includes discontinuance of the drug, local application of warmth to

the affected area, the administration of vasodilators, and nursing care to prevent tissue damage. Up-to-date information about the treatment of overdosage can often be obtained from a certified Regional Poison Control Center.