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WARNING
PERIPHERAL ISCHEMIA FOLLOWING COADMINISTRATION WITH STRONG CYP3A4 INHIBITORS
Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of dihydroergotamine with strong CYP3A4 inhibitors. Because CYP3A4 inhibition elevates the serum levels of dihydroergotamine, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of TRUDHESA with strong CYP3A4 inhibitors is contraindicated [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS].
TRUDHESA (dihydroergotamine mesylate) nasal spray is a single-dose, drug-device combination product containing a dihydroergotamine mesylate drug constituent and a nasal spray device constituent.
The chemical name for dihydroergotamine mesylate is ergotaman-3', 6', 18-trione, 9,10-dihydro- 12'-hydroxy-2'-methyl-5'- (phenylmethyl)-, (5'a)-, monomethanesulfonate. Its molecular weight is 679.78, and its molecular formula is C33H37N5O5•CH4O3S.
The chemical structure is:
 |
The drug constituent is a dihydroergotamine mesylate solution. Each milliliter (mL) of solution contains dihydroergotamine mesylate 4.0 mg (equivalent to 3.43 mg dihydroergotamine), and the following inactive ingredients: caffeine (10.0 mg), carbon dioxide (q.s.), dextrose (50.0 mg), and water (q.s. to 1.0 mL).
TRUDHESA nasal spray, after assembly and priming, delivers 0.725 mg dihydroergotamine mesylate per spray. A total dose of 1.45 mg of dihydroergotamine mesylate is delivered in 2 sprays. The nasal spray device contains hydrofluoroalkane-134a (HFA) propellant.
TRUDHESA is indicated for the acute treatment of migraine with or without aura in adults.
TRUDHESA is not indicated for the preventive treatment of migraine.
TRUDHESA is not indicated for the management of hemiplegic or basilar migraine.
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.
Prior to initiation of TRUDHESA, a cardiovascular evaluation is recommended [see WARNINGS AND PRECAUTIONS]. 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.
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.
TRUDHESA (dihydroergotamine mesylate) nasal spray is a single-dose, drug-device combination product containing a vial of dihydroergotamine mesylate with a clear and colorless to faintly yellow solution and an intranasal delivery device. Each spray delivers 0.725 mg of dihydroergotamine mesylate.
TRUDHESA (dihydroergotamine mesylate) nasal spray (0.725 mg per spray) is supplied as a package of 4 single-dose units (NDC 77530-725-04). Each single-dose unit contains:
Store TRUDHESA at controlled room temperature, 20°C to 25°C (68°F to 77°F), with excursions allowed between 15°C to 30°C (59°F to 86°F). Do not refrigerate or freeze.
Manufactured by: Mipharm, S.p.A. Milano, Italy. Revised: Sep 2021
The following clinically significant adverse reactions are described elsewhere in the labeling:
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.
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 (13), dizziness (2), facial edema (2), 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, doubleblind 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 selflimited 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 |
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 [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS]. The use of strong CYP3A4 inhibitors with dihydroergotamine is contraindicated [see CONTRAINDICATIONS]. Administer moderate CYP3A4 inhibitors (e.g., saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, clotrimazole) with caution.
Triptans (serotonin [5-HT] 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 [see CONTRAINDICATIONS].
There have been reports that propranolol may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine.
TRUDHESA is contraindicated for use with peripheral and central vasoconstrictors because the combination may cause synergistic elevation of blood pressure [see WARNINGS AND PRECAUTIONS].
Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy [see WARNINGS AND PRECAUTIONS].
Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HT1 agonists have been coadministered with selective serotonin reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline).
TRUDHESA contains dihydroergotamine (as the mesylate salt), which is not a controlled substance.
Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Currently available data have not demonstrated drug abuse with dihydroergotamine. However, cases of drug abuse in patients on other forms of ergot therapy have been reported.
Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Currently available data have not demonstrated physical or psychological dependence with dihydroergotamine. However, cases of psychological dependence in patients on other forms of ergot therapy have been reported.
Included as part of the "PRECAUTIONS" Section
Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of dihydroergotamine with strong CYP3A4 inhibitors, including protease inhibitors, macrolide antibiotics, and antifungals. Because CYP3A4 inhibition elevates the serum levels of dihydroergotamine, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of TRUDHESA with strong CYP3A4 inhibitors is contraindicated [see CONTRAINDICATIONS and DRUG INTERACTIONS].
The potential for adverse cardiac adverse reactions exists with TRUDHESA treatment. Serious adverse cardiac events, including some that have been fatal, have occurred following use of dihydroergotamine mesylate. These events have included acute myocardial infarction, lifethreatening disturbances of cardiac rhythm (e.g., ventricular tachycardia and ventricular fibrillation), coronary artery vasospasm, and transient myocardial ischemia.
Prior to initiation of TRUDHESA, a cardiovascular evaluation is recommended to determine if the patient is free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. If, during the cardiovascular evaluation, the patient's medical history (including risk factors), or electrocardiographic investigation, findings are consistent with coronary artery vasospasm or myocardial ischemia, TRUDHESA should not be administered [see CONTRAINDICATIONS].
For patients with risk factors predictive of coronary artery disease (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of coronary artery disease, females who are surgically or physiologically postmenopausal, or males who are over 40 years of age) 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, unless the patient has previously received dihydroergotamine mesylate. During the interval immediately following the first use of TRUDHESA, an electrocardiogram is recommended in those patients with risk factors because ischemia can occur in the absence of clinical symptoms.
The potential for adverse cerebrovascular adverse reactions exists with TRUDHESA treatment. Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with dihydroergotamine mesylate; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the dihydroergotamine mesylate having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). Discontinue TRUDHESA if a cerebrovascular event is suspected.
TRUDHESA, like other ergot alkaloids, may cause vasospastic reactions other than coronary artery vasospasm. Myocardial, peripheral vascular, and colonic ischemia have been reported with dihydroergotamine mesylate.
Dihydroergotamine mesylate associated vasospastic phenomena may also cause muscle pains, numbness, coldness, pallor, and cyanosis of the digits. In patients with compromised circulation, persistent vasospasm may result in gangrene or death. TRUDHESA should be discontinued immediately if signs or symptoms of vasoconstriction develop.
Patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud's syndrome, following the use of any 5-HT agonist, including TRUDHESA, should be evaluated by a healthcare provider.
Significant elevation in blood pressure has been reported on rare occasions in patients with and without a history of hypertension treated with dihydroergotamine mesylate. TRUDHESA is contraindicated in patients with uncontrolled hypertension [see CONTRAINDICATIONS].
An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5- HT1 agonist in a study evaluating subjects undergoing cardiac catheterization.
Overuse of acute migraine drugs (e.g., ergotamines, triptans, opioids, or a combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (i.e., medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients including withdrawal of the overused drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
Based on the mechanism of action of dihydroergotamine and findings from the published literature, TRUDHESA may cause preterm labor. Avoid use of TRUDHESA during pregnancy [see Use In Specific Populations]
The potential for fibrotic complications exists with TRUDHESA treatment. There have been reports of pleural and retroperitoneal fibrosis in patients following prolonged daily use of dihydroergotamine mesylate. Rarely, prolonged daily use of other ergot alkaloid drugs has been associated with cardiac valvular fibrosis. Rare cases have also been reported in association with the use of dihydroergotamine mesylate; however, in those cases, patients also received drugs known to be associated with cardiac valvular fibrosis.
Administration of TRUDHESA should not exceed the dosing guidelines and should not be used for chronic daily administration [see DOSAGE AND ADMINISTRATION].
Local irritative symptoms were reported in 52% of patients treated with at least one dose of TRUDHESA in an open-labeled trial, which allowed repeated use of TRUDHESA over 6 to 12 months. The most common local irritative symptoms (at least 1% of patients) were nasopharyngitis (21%), rhinitis (19%), nasal discomfort (7%), product taste abnormal/dysgeusia (6%), sinusitis (5%), sinus discomfort (4%), olfactory test abnormal [defined based on a change in score at a prespecified threshold on the University of Pennsylvania Smell Identification Test (UPSIT)] (4%), epistaxis (3%), pharyngitis (3%), nasal mucosal disorder (2%), change in smell (1%), ear discomfort (1%), and rhinorrhea (1%). If a severe local irritation event occurs for no other attributable reasons, TRUDHESA should be temporarily suspended until the event resolves. If the event does not resolve, or it recurs with re-challenge, TRUDHESA should be discontinued permanently. Administration of TRUDHESA should not exceed the dosing guidelines and should not be used for chronic daily administration [see DOSAGE AND ADMINISTRATION].
Nasal tissue in animals treated with dihydroergotamine mesylate daily showed mild mucosal irritation characterized by mucous cell and transitional cell hyperplasia and squamous cell metaplasia. Changes in rat nasal mucosa at 64 weeks were less severe than at 13 weeks. Local effects on respiratory tissue after chronic intranasal dosing in animals have not been evaluated.
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Inform patients that serious and/or life-threatening peripheral ischemia (cerebral ischemia and/or ischemia of the extremities) has been associated with the coadministration of dihydroergotamine mesylate and strong CYP3A4 inhibitors, such as macrolide antibiotics and protease inhibitors [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS].
Inform patients of the risk for serious cardiac, cerebrovascular, and other vasospasm related events. Advise patients to notify their healthcare provider if they develop any risk factors or symptoms while taking TRUDHESA. Inform patients that nicotine may provoke vasoconstriction predisposing to a greater ischemic response [see WARNINGS AND PRECAUTIONS].
Inform patients that use of drugs to treat migraine attacks for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see WARNINGS AND PRECAUTIONS].
Advise patients to notify their healthcare provider if they have bothersome local irritation [see WARNINGS AND PRECAUTIONS].
Advise patients to inform their healthcare providers if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see DRUG INTERACTIONS].
Advise patients of the risk for preterm birth. Advise women to inform their healthcare provider if they are pregnant or intend to become pregnant [see WARNINGS AND PRECAUTIONS, Use In Specific Populations]
Advise patients not to breastfeed during treatment with TRUDHESA [see Use In Specific Populations].
Advise patients that TRUDHESA must be assembled prior to use and that, prior to administration, the device must be primed (i.e., pumped 4 times). Instruct patients to use or discard TRUDHESA within 8 hours once the vial has been opened or the product has been assembled.
Assessment of the carcinogenic potential of dihydroergotamine mesylate in mice and rats has not been assessed.
Dihydroergotamine mesylate was negative in an in vitro mutagenicity (Ames) assay and positive in in vitro chromosomal aberration (V79 Chinese hamster cell assay with metabolic activation, and human peripheral blood lymphocyte) assays. Dihydroergotamine was negative in in vivo micronucleus assays in mouse and hamster.
There was no evidence of impairment of fertility in rats given intranasal doses of dihydroergotamine mesylate up to 1.6 mg/day, which was associated with plasma exposures (AUC) approximately 3 times that in humans at the maximum recommended human dose of 2.9 mg/day.
Available data from published literature indicate an increased risk of preterm delivery with TRUDHESA use during pregnancy. Avoid use of TRUDHESA during pregnancy [see WARNINGS AND PRECAUTIONS]. 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.
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 [AUC] less than that in humans at the maximum recommended human dose [MRHD] 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.
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 diarrhea, vomiting, weak pulse, and unstable blood pressure in breastfed infants exposed to ergotamine. TRUDHESA 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 TRUDHESA and for 3 days after the last dose. Breast milk supply during this time should be pumped and discarded.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of TRUDHESA and other dihydroergotamine mesylate products did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. 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.
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 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.
TRUDHESA is contraindicated in patients:
Dihydroergotamine binds with high affinity to 5-HT1Dα and 5-HT1Dβ receptors. The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effects at 5-HT1δ receptors.
Significant elevation in blood pressure has been reported in patients with and without a history of hypertension [see WARNINGS AND PRECAUTIONS].
Dihydroergotamine possesses oxytocic properties [see WARNINGS AND PRECAUTIONS].
The mean time from dosing to maximum plasma concentration following TRUDHESA administration was approximately 0.5 hours.
Dihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters.
Metabolism
Four dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite, 8'-ß-hydroxy dihydroergotamine, exhibits affinity equivalent to its parent for adrenergic and 5-HT receptors and demonstrates equivalent potency in several venoconstrictor activity models, in vivo and in vitro. The other metabolites, i.e., dihydrolysergic acid, dihydrolysergic amide, and a metabolite formed by oxidative opening of the proline ring, are of minor importance. Following nasal administration, total metabolites represent only 20% to 30% of plasma AUC. The systemic clearance of dihydroergotamine mesylate following intravenous and intramuscular administration is 1.5 L/min. Quantitative pharmacokinetic characterization of the four metabolites has not been performed.
Excretion
The major excretory route of dihydroergotamine is via the bile in the feces. The total body clearance is 1.5 L/min, which reflects mainly hepatic clearance. Only 6% to 7% of unchanged dihydroergotamine is excreted in the urine after intramuscular injection. The renal clearance (0.1 L/min) is unaffected by the route of dihydroergotamine administration.
The mean apparent half-life of TRUDHESA nasal administration in healthy subjects is approximately 12 hours.
No studies have been conducted on the effect of renal or hepatic impairment, gender, race, ethnicity, or pregnancy on dihydroergotamine pharmacokinetics [see CONTRAINDICATIONS, Use In Specific Populations].
Rare reports of ergotism have been obtained from patients treated with dihydroergotamine and macrolide antibiotics (e.g., clarithromycin, erythromycin) and from patients treated with dihydroergotamine and protease inhibitors (e.g., ritonavir), presumably due to inhibition of CYP3A metabolism of ergotamine [see CONTRAINDICATIONS].
The pharmacokinetics of dihydroergotamine did not appear to be significantly affected by the concomitant use of a local vasoconstrictor.
Multiple oral doses of the β-adrenoceptor antagonist propranolol, used for migraine prophylaxis, had no significant influence on the Cmax, tmax, or AUC of dihydroergotamine doses up to 4 mg. However, propranolol may potentiate the vasoconstrictive action of ergotamine [see DRUG INTERACTIONS].
The effect of oral contraceptives on the pharmacokinetics of TRUDHESA has not been studied.
The efficacy of TRUDHESA is based on the relative bioavailability of TRUDHESA nasal spray compared to dihydroergotamine mesylate nasal spray in healthy subjects.
The clinical studies described below were conducted using dihydroergotamine mesylate nasal spray.
The efficacy of dihydroergotamine mesylate nasal spray for the acute treatment of migraine headaches was evaluated in four randomized, double-blind, placebo controlled studies in the U.S. The patient population for the trials was predominantly female (87%) and Caucasian (95%) with a mean age of 39 years (range 18 to 65 years). Patients treated a single moderate to severe migraine headache with a single dose of study medication and assessed pain severity over the 24 hours following treatment. Headache response was determined 0.5, 1, 2, 3 and 4 hours after dosing and was defined as a reduction in headache severity to mild or no pain. In studies 1 and 2, a four-point pain intensity scale was utilized; in studies 3 and 4, a five-point scale was used to record pain response. Although rescue medication was allowed in all four studies, patients were instructed not to use them during the four hour observation period. In studies 3 and 4, a total dose of 2 mg was compared to placebo. In studies 1 and 2, doses of 2 and 3 mg were evaluated, and showed no advantage of the higher dose for a single treatment. In all studies, patients received a regimen consisting of 0.5 mg in each nostril, repeated in 15 minutes (and again in another 15 minutes for the 3 mg dose in studies 1 and 2).
The percentage of patients achieving headache response 4 hours after treatment was significantly greater in patients receiving 2 mg doses of dihydroergotamine mesylate nasal spray compared to those receiving placebo in 3 of the 4 studies (see Table 2 and Table 3 and Figure 1 and Figure 2).
Table 2 Studies 1 and 2: Percentage of Patients with Headache Responsea 2 and 4 Hours Following a Single Treatment of Study Medication (Dihydroergotamine Mesylate Nasal Spray or Placebo)
| N | 2 hours | 4 hours | ||
| Study 1 | Dihydroergotamine mesylate nasal spray | 105 | 61%** | 70%** |
| Placebo | 98 | 23% | 28% | |
| Difference from Placebo | 37% | 42% | ||
| Study 2 | Dihydroergotamine mesylate nasal spray | 103 | 47% | 56%* |
| Placebo | 102 | 33% | 35% | |
| Difference from Placebo | 14% | 21% | ||
| aHeadache response was defined as a reduction in headache severity to mild or no pain. Headache response was based on pain intensity as interpreted by the patient using a four-point pain intensity scale. *p value < 0.01 **p value < 0.001 |
||||
Table 3 Studies 3 and 4: Percentage of Patients with Headache Responsea 2 and 4 Hours Following a Single Treatment of Study Medication (Dihydroergotamine Mesylate Nasal Spray or Placebo)
| N | 2 hours | 4 hours | ||
| Study 3 | Dihydroergotamine mesylate nasal spray | 50 | 32 | 48%* |
| Placebo | 50 | 20% | 22% | |
| Difference from Placebo | 12% | 26% | ||
| Study 4 | Dihydroergotamine mesylate nasal spray | 47 | 30% | 47% |
| Placebo | 50 | 20% | 30% | |
| Difference from Placebo | 10% | 17% | ||
| aHeadache response was defined as a reduction in headache severity to mild or no pain. Headache response was evaluated on a five-point scale that included pain response. *p value < 0.01 |
||||
The Kaplan-Meier plots below (Figure 1 and Figure 2) provides an estimate of the probability that a patient will have responded to a single 2 mg dose of dihydroergotamine mesylate nasal spray as a function of the time elapsed since initiation of treatment.
Figure 1 Estimated Probability of a Patient Responding During the Four Hours Following a Single 2 mg Dose of Dihydroergotamine Mesylate Nasal Spray as a Function of the Time Elapsed Since Initiation of Treatment*
 |
| *The figure shows the probability over time of obtaining a response following treatment with dihydroergotamine mesylate nasal spray. Headache response was based on pain intensity as interpreted by the patient using a fourpoint pain intensity scale. Patients not achieving response within 4 hours were censored to 4 hours. |
Figure 2 Estimated Probability of a Patient Responding to Dihydroergotamine Mesylate Nasal Spray During the Four Hours Following Dosing*
 |
| *The figure shows the probability over time of obtaining a response following treatment with dihydroergotamine mesylate nasal spray. Headache response was evaluated on a five-point scale that included pain response. Patients not achieving response within 4 hours were censored to 4 hours. |
For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was a lower incidence of these symptoms at 2 and 4 hours following administration of dihydroergotamine mesylate nasal spray compared to placebo.
Patients were not allowed to use additional treatments for 8 hours prior to study medication dosing and during the 4-hour observation period following study treatment. Following the 4-hour observation period, patients were allowed to use additional treatments. For all studies, the estimated probability of patients using additional treatments for their migraines over the 24 hours following the single 2 mg dose of study treatment is summarized in Figure 3 below.
Figure 3 Estimated Probability of a Patient Using Additional Treatments for Migraine Over the 24 Hours Following Either Dihydroergotamine Mesylate Nasal Spray 2 mg (or Placebo)*
 |
| *Kaplan-Meier plot based on data obtained from all studies with patients not using additional treatments censored to 24 hours. All patients received a single treatment of study medication for their migraine attack. The plot also includes patients who had no response to the initial dose. |
Neither age nor sex appear to affect the patient's response to dihydroergotamine mesylate nasal spray. The racial distribution of patients was insufficient to determine the effect of race on the efficacy of dihydroergotamine mesylate nasal spray.
TRUDHESA™
(true - deh - sa)
(dihydroergotamine mesylate) nasal spray
What is the most important information I should know about TRUDHESA?
TRUDHESA can cause serious side effects, including:
Do not take medicines known as strong CYP3A4 inhibitors, such as:
These are not all of the medicines that could affect how TRUDHESA works. Your healthcare provider can tell you if it is safe to take TRUDHESA with other medicines.
What is TRUDHESA?
TRUDHESA is a prescription medicine used for the acute treatment of migraine with or without aura in adults.
It is not known if TRUDHESA is safe and effective in children.
Do not take TRUDHESA if you:
Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take TRUDHESA with other medicines.
Before you take TRUDHESA, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Your healthcare provider will decide if you can take TRUDHESA with your other medicines.
Especially tell your healthcare provider if you take:
These are not all of the medicines that could affect how TRUDHESA works. Your healthcare provider can tell you if it is safe to take TRUDHESA with other medicines.
How should I take TRUDHESA?
What are the possible side effects of TRUDHESA?
TRUDHESA can cause serious side effects, including:
See "What is the most important information I should know about TRUDHESA?"
TRUDHESA is not for people with risk factors for heart disease unless a heart exam is done and shows no problem. You have a higher risk for heart disease if you:
The most common side effects of TRUDHESA include:
These are not all the possible side effects TRUDHESA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store TRUDHESA?
Keep TRUDHESA away from heat and light.
Keep TRUDHESA and all medicines out of the reach of children.
Do not throw TRUDHESA into fire or incinerators as the canister inside the device may explode.
General information about the safe and effective use of TRUDHESA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRUDHESA for a condition for which it was not prescribed. Do not give TRUDHESA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TRUDHESA that is written for health professionals.
What are the ingredients in TRUDHESA?
Active ingredient: Dihydroergotamine mesylate
Inactive ingredients: Caffeine, carbon dioxide, dextrose, and water. The nasal spray device canister contains hydrofluoroalkane-134a (HFA) propellant. The vial stopper is not made with natural rubber latex. TRUDHESA is a trademark of Impel NeuroPharma Inc.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
INSTRUCTIONS FOR USE
Trudhesa™
(true-deh-sa)
(dihydroergotamine mesylate)
nasal spray
For Nasal Use Only
Introduction
Read this Instructions for Use before you start to use Trudhesa and each time you get a prescription refill.There may be new information.
This information does not take the place of talking with your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about Trudhesa when you start taking it and at regular checkups.
It is important to follow these directions accurately in order to receive the correct dose.Contact your healthcare provider if you have any questions about how to use this product.
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Nasal Spray Device Parts
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Glass Vial Parts
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Important Information You Need To Know Before Dosing with Trudhesa
Storing Trudhesa
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Preparing to Dose with Trudhesa
Step 1:Gather and Check Supplies
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Step 2: Remove Blue Plastic Cover,Metal Foil and Grey Rubber Stopper from Glass Vial
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Step 3: Remove the clear Plastic Cover from the Nasal Spray Device
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Step 4: Screw the Glass Vial into the Nasal Spray Device
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Step 5: Prime the Nasal Spray Device by Pumping Four Times with Fingers and Thumb
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Important Tip: The purpose of priming is to bring the medicine to the tip of the spray nozzle. If you do not prime the nasal spray device,you will not get your correct dose of medicine.
Always prime the nasal spray device before use by pumping exactly 4 times.
During priming, make sure to aim the nozzle away from your face and anything thay you do not want coming into contact with the spray of medicine.
Using Trudhesa
Step 6: Position the Nasal Spray Device
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Step 7:Spray the First Spray into 1 Nostril
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Step 8:Spray the Second Spray into Other Nostril
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Important Tip: A complete dose is 2 sprays;1 spray in each nostril.
Do nottake more than 2 doses within a 24-hour period. Do nottake more than 3 doses in a 7-day period.Please refer to the prescribing information for more information.
Sniffing while or after dosing is not necessary.However,sniffing will not hurt you or make the medicine less effective.
Important Frequently Asked Questions(FAQs)
Question: Can I save medicine by skipping the 4 pumps in "Step 5:Prime the Nasal Spray Device"?
Answer: No Skipping the 4 pumps to prime the nasal spray device can result in you not getting your correct dose of medicine.
Qestion: When I first pumped the nasal spray device to prime nothing seemed to happen.Why?
Answer: The purpose of priming is to bring the medicine up to the tip of the nozzle. Even though you may not see or hear anything on your first pump or two, the pumping action will move the medicine from the glass vial through the inside of the nasal spray device and into the nozzle.You should see a spray by your fourth pump attempt.Always prime by pumping exactly 4 times prior to dosing.
Question: Can I reuse the nasal spray device with a new glass vial?
Answer:No,The nasal spray device is for one-time use only and must be thrown away after you have closed(1 spray in each nostril).This is because the device may clog.After dosing,leave the glass vial screwed onto the nasal spray device and throw away the assembled nasal spray device into the trash. Do not recycle any part of the product.
Question: Can I use the medicine that remains in the glass vial for a later dose?
Answer: No,Although it is nrmal for some medicine to remain in the glass vial, it can not be used for later dosing.Any leftover medicine will become ineffective.
Question: What happens if I sparay more than one time in the same nostril?
Answer: A complete and correct dose is one spray into each nostril.Do not dose in you other nostril if you already sprayed two times in one nostril.Talk to your healthcare provider if you have moderate to severe irritaiton in you nose or changes in smell.
Question: How soon can I take another dose if I am not getting relief from my migraine?
Answer: You can take another dose ar least 1 hour after youar first dose if your symptoms persist.Do not take more than 2 doses within a 24-hour period.Do nottake more than 3 doses in a 7-day period.Please refer to the prescribing information for more information.
This Instructions for Use has been approved by the U.S.Food and Drug Administration.
