Dihydroergotamine

Caution should be exercised in patients with renal impairment who are not on dialysis. The dose should be reduced accordingly and appropriate monitoring may be indicated.

Patients with mild to moderate hepatic impairment should be monitored appropriately and the dose should be reduced accordingly.

Treatment should be discontinued if numbness occurs in the extremities.

Dihydroergotamine reduces the effects of glycerol trinitrate (nitroglycerin).

Patients with a history of drug-induced fibrous tissue disorders such as retroperitoneal and pleural fibrosis should be closely monitored.

Risk Summary

Available data from published literature indicate an increased risk of preterm delivery with dihydroergotamine use during pregnancy. Avoid use of dihydroergotamine during pregnancy. Data collected over decades have shown no increased risk of major birth defects or miscarriage with the use of dihydroergotamine during pregnancy.

In animal reproduction studies, adverse effects on development were observed following intranasal 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) at doses that 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 and greater. A no-effect level for adverse effects on embryofetal development 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. The no-effect dose for adverse effects on embryofetal development in rabbits was 1.2 mg/day.

Intranasal administration of dihydroergotamine mesylate to female rats throughout pregnancy and lactation resulted in decreased body weight and impaired reproductive function (decreased mating indices) in the offspring at doses of 0.16 mg/day or greater. A no-effect dose for adverse effects on pre- and postnatal development in rats was not established. Effects on offspring development occurred at doses below those that produced evidence of 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.

There are no data on the presence of dihydroergotamine in human milk; however, ergotamine, a related drug, is present in human milk. There are reports of vomiting, diarrhea, weak pulse, and unstable blood pressure in breastfed infants exposed to ergotamine. Dihydroergotamine may reduce milk supply because it may decrease prolactin levels. Because of the potential for reduced milk supply and serious adverse events in the breastfed infant, including diarrhea, vomiting, weak pulse, and unstable blood pressure, advise patients not to breastfeed during treatment with dihydroergotamine and for 3 days after the last dose. Breast milk supply during this time should be pumped and discarded.

Carcinogenesis

In a 2-year mouse carcinogenicity study, subcutaneous (SC) administration of dihydroergotamine mesylate (0, 0.5, 1.5 or 5 mg/kg/day) resulted in an increased incidence of fibrosarcoma at the injection sites in males and females at the high dose. The higher dose not associated with an increase in tumors (1.5 mg/kg/day) is approximately 2 times the recommended human dose (RHD) of 3 mg/day SC on a body surface area (mg/m²) basis.

In a 2-year rat carcinogenicity study, intranasal administration of dihydroergotamine mesylate (0, 0.4, 0.8 or 1.6 mg/day for 13 weeks, followed by 0, 0.08, 0.24 or 0.8 mg/day for the remainder of the study) did not result in an increase in tumors.

Mutagenesis

Dihydroergotamine mesylate was clastogenic in two in vitro chromosomal aberration assays, the V79 Chinese hamster cell assay with metabolic activation and the cultured human peripheral blood lymphocyte assay. There was no evidence of mutagenic potential when dihydroergotamine mesylate was tested in the presence or absence of metabolic activation in two gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/HGPRT assay) and in an assay for DNA damage (the rat hepatocyte unscheduled DNA synthesis test). Dihydroergotamine was not clastogenic in the in vivo mouse and hamster micronucleus tests.

Impairment of Fertility

There was no evidence of impairment of fertility in rats given intranasal doses of dihydroergotamine mesylate nasal spray up to 1.6 mg/day (associated with mean plasma dihydroergotamine mesylate exposures [AUC] approximately 9 to 11 times those in humans receiving the MRDD of 4 mg).

During clinical studies and the foreign postmarketing experience with dihydroergotamine mesylate nasal spray there have been no fatalities due to cardiac events.

Serious cardiac events, including some that have been fatal, have occurred following use of dihydroergotamine mesylate injection, but are extremely rare. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation.

Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate.

Incidence in Controlled Clinical Trials

Of the 1,796 patients and subjects treated with dihydroergotamine mesylate 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 13, dizziness 2, facial edema 2, and one each due to cold sweats, accidental trauma, depression, elective surgery, somnolence, allergy, vomiting, hypotension, and paraesthesia.

The most commonly reported adverse events associated with the use of dihydroergotamine mesylate nasal spray during placebo-controlled, double-blind studies for the treatment of migraine headache and not reported at an equal incidence by placebo-treated patients were rhinitis, altered sense of taste, application site reactions, dizziness, nausea, and vomiting. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ.

Dihydroergotamine mesylate nasal spray was generally well tolerated. In most instances these events were transient and self-limited and did not result in patient discontinuation from a study. The following table summarizes the incidence rates of adverse events reported by at least 1% of patients who received dihydroergotamine mesylate nasal spray for the treatment of migraine headaches during placebo-controlled, double-blind clinical studies and were more frequent than in those patients receiving placebo.

Table 3. Adverse events reported by at least 1% of the dihydroergotamine mesylate nasal spray treated patients and occurred more frequently than in the placebo-group in the migraine placebo-controlled trials:

Other Adverse Events During Clinical Trials

In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. Because the reports include events observed in open and uncontrolled studies, the role of dihydroergotamine mesylate nasal spray in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used dihydroergotamine mesylate nasal spray in placebo-controlled trials and reported an event divided by the total number of patients (n=1796) exposed to dihydroergotamine mesylate nasal spray. All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; and rare adverse events are those occurring in fewer than 1/1,000 patients.

Skin and Appendages

Infrequent: petechia, pruritus, rash, cold clammy skin.

Rare: papular rash, urticaria, herpes simplex.

Musculoskeletal

Infrequent: cramps, myalgia, muscular weakness, dystonia.

Rare: arthralgia, involuntary muscle contractions, rigidity.

Central and Peripheral Nervous System

Infrequent: confusion, tremor, hypoesthesia, vertigo.

Rare: speech disorder, hyperkinesia, stupor, abnormal gait, aggravated migraine.

Autonomic Nervous System

Infrequent: increased sweating.

Special Senses

Infrequent: sense of smell altered, photophobia, conjunctivitis, abnormal lacrimation, abnormal vision, tinnitus, earache.

Rare: eye pain.

Psychiatric

Infrequent: nervousness, euphoria, insomnia, concentration impaired.

Rare: anxiety, anorexia, depression.

Gastrointestinal

Infrequent: abdominal pain, dyspepsia, dysphagia, hiccup.

Rare: increased salivation, esophagospasm.

Cardiovascular

Infrequent: edema, palpitation, tachycardia.

Rare: hypotension, peripheral ischemia, angina.

Respiratory System

Infrequent: dyspnea, upper respiratory tract infections.

Rare: bronchospasm, bronchitis, pleural pain, epistaxis.

Urinary System

Infrequent: increased frequency of micturition, cystitis.

Reproductive, Female

Rare: pelvic inflammation, vaginitis.

Body as a Whole – General

Infrequent: feeling cold, malaise, rigors, fever, periorbital edema.

Rare: flu-like symptoms, shock, loss of voice, yawning.

Application Site

Infrequent: local anesthesia.

Post-introduction Reports

Voluntary reports of adverse events temporally associated with dihydroergotamine products used in the management of migraine that have been received since the introduction of the injectable formulation are included in this section save for those already listed above. Because of their source (open and uncontrolled clinical use), whether or not events reported in association with the use of dihydroergotamine are causally related to it cannot be determined. There have been reports of pleural and retroperitoneal fibrosis in patients following prolonged daily use of injectable dihydroergotamine mesylate. dihydroergotamine mesylate nasal spray is not recommended for prolonged daily use.