Doliprane

Doliprane is indicated for the acute treatment of migraine with or without aura in adults.

Limitations Of Use

• Use only if a clear diagnosis of migraine has been established. If a patient has no response for the first migraine attack treated with Doliprane, reconsider the diagnosis of migraine before Doliprane is administered to treat any subsequent attacks.
• Doliprane is not indicated for the prevention of migraine attacks.
• Safety and effectiveness of Doliprane have not been established for cluster headache.

Dosing Information

The recommended dose is a single tablet of Doliprane (Dolipranetriptan 2.5 mg) taken orally with fluids.

If the migraine recurs after initial relief, a second tablet may be taken, providing there is an interval of at least 2 hours between doses. The total daily dose of Doliprane should not exceed 3 tablets (3 x 2.5 mg per 24 hour period).

There is no evidence that a second dose of Doliprane is effective in patients who do not respond to a first dose of the drug for the same headache.

The safety of treating an average of more than 4 migraine attacks in a 30-day period has not been established.

Doliprane is contraindicated in patients with:

• Ischemic coronary artery disease (CAD) (e.g. angina pectoris, history of myocardial infarction, or documented silent ischemia), or coronary artery vasospasm, including Prinzmetal's angina.
• Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.
• History of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke.
• Peripheral vascular disease.
• Ischemic bowel disease.
• Uncontrolled hypertension.
• Recent use (i.e., within 24 hours) of another 5-HT1 agonist, an ergotamine containing or ergot-type medication such as dihydroergotamine (DHE) or methysergide.
• Hypersensitivity to Doliprane (angioedema and anaphylaxis seen).

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Myocardial Ischemia, Myocardial Infarction, And Prinzmetal's Angina

Doliprane is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of Doliprane. Some of these reactions occurred in patients without known CAD. Doliprane may cause coronary artery vasospasm (Prinzmetal's angina), even in patients without a history of CAD.

Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving Doliprane. Do not administer Doliprane if there is evidence of CAD or coronary artery vasospasm [ see CONTRAINDICATIONS]. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administrating the first Doliprane dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following Doliprane administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of Doliprane.

Arrhythmias

Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and ventricular fibrillation leading to death have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue Doliprane if these disturbances occur. Doliprane is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.

Chest, Throat, Neck And Jaw Pain/Tightness/Pressure

Sensations of pain, tightness, pressure, and heaviness have been reported in the chest, throat, neck, and jaw after treatment with Doliprane and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of Doliprane is contraindicated in patients with CAD and those with Prinzmetal's angina.

Cerebrovascular Events

Cerebral hemorrhage, subarachnoid hemorrhage, stroke and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not.

Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical of migraine, other potentially serious neurological conditions need to be excluded. Doliprane is contraindicated in patients with a history of stroke or TIA.

Other Vasospasm Reactions

Doliprane, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of a vasospastic reaction following the use of any 5HT1 agonist, rule out a vasospastic reaction before using Doliprane.

Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.

Medication Overuse Headache

Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (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.

Serotonin Syndrome

Serotonin syndrome may occur with Doliprane, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue Doliprane if serotonin syndrome is suspected.

Increase In Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension.

Monitor blood pressure in patients treated with Doliprane. Doliprane is contraindicated in patients with uncontrolled hypertension.

Anaphylactic/Anaphylactoid Reactions

There have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving Doliprane. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Doliprane is contraindicated in patients with a history of hypersensitivity reaction to Doliprane.

Patient Counseling Information

See FDA-Approved Patient Labeling (PATIENT INFORMATION)

Myocardial Ischemia And/Or Infarction, Prinzmetal's Angina, Other Vasospastic Reactions, And Cerebrovascular Events

Inform patients that Doliprane may cause serious cardiovascular adverse reactions such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular reactions can occur without warning symptoms, instruct patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and instruct them to ask for medical advice when observing any indicative sign or symptoms. Instruct patients to seek medical advice if they have symptoms of other vasospastic reactions.

Anaphylactic/Anaphylactoid Reactions

Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving Doliprane. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens.

Medication Overuse Headache

Inform patients that use of drugs to treat acute migraines 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).

Serotonin Syndrome

Inform patients about the risk of serotonin syndrome with the use of Doliprane or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors.

Pregnancy

Inform patients that Doliprane should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Inform patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

The carcinogenic potential of orally administered Dolipranetriptan was evaluated in an 84-week study in mice (4, 13, and 40 mg/kg/day), a 104-week study in rats (8.5, 27 and 85 mg/kg/day), and a 26-week study in p53(+/-) transgenic mice (20, 62.5, 200, and 400 mg/kg/day). Although a maximum tolerated dose was not achieved in the 84-week mouse study and in female rats, plasma exposures at the highest doses studied were higher than that achieved in humans at the maximum recommended human dose (MRHD) of 7.5 mg/day. There were no increases in tumor incidence in the 84-week mouse study at doses producing plasma exposures (AUC) 140 times that in humans at the MRHD. In the rat study, there was a statistically significant increase in the incidence of pituitary adenomas in males only at 85 mg/kg/day, a dose associated with a plasma AUC 250 times that in humans at the MRHD. In the 26-week p53(+/-) transgenic mouse study, the incidence of subcutaneous sarcomas was increased in females at doses of 200 and 400 mg/kg/day.

These sarcomas were associated with subcutaneously implanted animal identification transponders, and are not considered to be relevant to humans. There were no other increases in tumor incidence of any type in any dose group.

Mutagenesis

Dolipranetriptan was clastogenic in human lymphocyte cultures, in the absence of metabolic activation. In the bacterial reverse mutation assay (Ames test), Dolipranetriptan produced an equivocal response in the absence of metabolic activation. Dolipranetriptan was negative in an in vitro mouse lymphoma tk assay and an in vivo mouse bone marrow micronucleus test.

Impairment Of Fertility

Male and female rats were dosed orally with Dolipranetriptan prior to and during mating and in females up to implantation, at doses of 100, 500, and 1000 mg/kg/day (equivalent to approximately 130, 650, and 1300 times the MRHD on a mg/m ² basis). At all dose levels, there was an increase in the number of females that mated on the first day of pairing compared to control animals. This occurred in conjunction with a prolongation of the estrous cycle. In addition, females had a decreased mean number of corpora lutea, and consequently a lower number of live fetuses per litter, which suggested a partial impairment of ovulation. There were no other fertility-related effects.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled trials in pregnant women; therefore, Dolipranetriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When pregnant rats were administered Dolipranetriptan during the period of organogenesis at oral doses of 100, 500 and 1000 mg/kg/day (equivalent to 130, 650 and 1300 times the maximum recommended human dose [MRHD] of 7.5 mg/day on a mg/m² basis) there were dose related increases in incidences of fetuses with dilated ureters, unilateral and bilateral pelvic cavitation, hydronephrosis, and hydroureters. A no-effect dose for renal effects was not established. This signifies a syndrome of related effects on a specific organ in the developing embryo in all treated groups, which is consistent with a slight delay in fetal maturation. This delay was also indicated by a treatment related increased incidence of incomplete ossification of the sternebrae, skull and nasal bones in all treated groups. Reduced fetal weights and an increased incidence of embryolethality were observed in treated rats; an increase in embryolethality occurred in both the embryo-fetal developmental study and in the prenatal-postnatal developmental study. No increase in embryolethality was observed at the lowest dose level studied (100 mg/kg/day, equivalent to 130 times the MRHD on a mg/m² basis). When pregnant rabbits were dosed throughout organogenesis at oral doses up to 80 mg/kg/day (equivalent to 210 times the MRHD on a mg/m² basis), no effects on fetal development were observed.

Nursing Mothers

It is not known whether Dolipranetriptan is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Doliprane, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

In rats, oral dosing with Dolipranetriptan resulted in levels of Dolipranetriptan and/or its metabolites in milk up to four times higher than in plasma.

Pediatric Use

The safety and effectiveness in pediatric patients have not been established. Therefore, Doliprane is not recommended for use in patients under 18 years of age. There are no additional adverse reactions identified in pediatric patients based on postmarketing experience that were not previously identified in adults.

Geriatric Use

Mean blood concentrations of Dolipranetriptan in elderly patients were 1.5-to 2-times higher than those seen in younger adults. No dosage adjustment is necessary.

Patients With Hepatic Impairment

No dosage adjustment is necessary when Doliprane is given to patients with mild to moderate hepatic impairment.

There is no clinical or pharmacokinetic experience with Doliprane in patients with severe hepatic impairment. Because a greater than two-fold increase in AUC is predicted in patients with severe hepatic impairment, there is a greater potential for adverse events in these patients, and Doliprane should therefore be used with caution in that population.

The following adverse reactions are described elsewhere in other sections of the labeling:

• Myocardial ischemia, myocardial infarction, and Prinzmetal's angina
• Arrhythmias
• Chest, throat, neck and/or jaw pain/tightness/pressure
• Cerebrovascular events
• Other vasospasm reactions
• Medication overuse headache
• Serotonin syndrome
• Increases in blood pressure
• Hypersensitivity reactions

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.

Doliprane was evaluated in four randomized, double-blind, placebo-controlled, short-term trials. These trials involved 2392 patients (1554 on Doliprane 2.5 mg and 838 on placebo). In these short-term trials, patients were predominately female (88%) and Caucasian (94%) with a mean age of 42 years (range 18 -69).The treatment-emergent adverse events that occurred most frequently following administration of Doliprane 2.5 mg (i.e., in at least 2% of patients), and at an incidence ≥ 1% greater than with placebo, were dizziness, paresthesia, headache, dry mouth, fatigue, flushing, hot or cold sensation, dyspepsia, skeletal pain, and chest pain. In a long term, open-label study where 496 patients were allowed to treat multiple migraine attacks with Doliprane 2.5 mg for up to 1 year, 5% of patients (n=26) discontinued due to treatment-emergent adverse events.

Table 1 lists treatment-emergent adverse events reported within 48 hours of drug administration that occurred with Doliprane 2.5 mg at an incidence of ≥ 2% and more often than on placebo, in the four placebo-controlled trials. 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 incidence estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ.

Table 1 : Treatment-Emergent Adverse Events Reported within 48 Hours (Incidence ≥ 2% and Greater Than Placebo) of Patients in Four Pooled Placebo-Controlled Migraine Trials

The incidence of adverse events in clinical trials did not increase when up to 3 doses were used within 24 hours. The incidence of adverse events in placebo-controlled clinical trials was not affected by gender, age or concomitant medications commonly used by migraine patients. There were insufficient data to assess the impact of race on the incidence of adverse events.

Other Events Observed In Association With The Administration Of Doliprane

The incidence of frequently reported adverse events in four placebo-controlled trials are presented below. Events are further classified within body system categories. Frequent adverse events are those occurring in at least 1/100 patients.

Central and peripheral nervous system: dysesthesia and hypoesthesia.

Gastrointestinal: vomiting, abdominal pain and diarrhea.

Body as a whole: pain.

Psychiatric: insomnia and anxiety.

Respiratory: sinusitis and rhinitis.

Vision disorders: vision abnormal.

Skin and appendages: sweating increased.

Hearing and vestibular disorders: tinnitus.

Heart rate and rhythm: palpitation.

Postmarketing Experience

The following adverse reactions were identified during post approval use of Doliprane. Because these events 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.

Central and peripheral nervous system: Seizure.

The elimination half-life of Dolipranetriptan is 26 hours. Therefore, monitoring of patients after overdose with Dolipranetriptan should continue for at least 48 hours or while symptoms or signs persist. There is no specific antidote to Dolipranetriptan. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of Dolipranetriptan.

The pharmacokinetics of Dolipranetriptan are similar in migraine patients and healthy subjects.

Absorption

Mean maximum blood concentrations (Cmax) in patients are achieved approximately 2 - 4 hours after administration of a single oral dose of Dolipranetriptan 2.5 mg. The absolute bioavailability of an oral dose of Dolipranetriptan 2.5 mg in healthy subjects is about 20% in males and 30% in females. Food has no significant effect on the bioavailability of Dolipranetriptan, but delays tmax by one hour.

Distribution

Binding of Dolipranetriptan to serum proteins is low (approximately 15%). Reversible binding to blood cells at equilibrium is approximately 60%, resulting in a blood: plasma ratio of about 2:1 in both males and females. The mean steady state volume of distribution of Dolipranetriptan following intravenous administration of 0.8 mg is 4.2 L/kg in males and 3.0 L/kg in females.

Metabolism

in vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of Dolipranetriptan. Following administration of a single oral dose of radiolabeled Dolipranetriptan 2.5 mg to healthy male and female subjects, 32% of the dose was recovered in urine and 62% in feces. Radiolabeled compounds excreted in urine were unchanged Dolipranetriptan, hydroxylated Dolipranetriptan, N-acetyl desmethyl Dolipranetriptan, hydroxylated N-acetyl desmethyl Dolipranetriptan and desmethyl Dolipranetriptan, together with several other minor metabolites. Desmethyl Dolipranetriptan has lower affinity for 5-HT1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown.

Elimination

After an intravenous dose, mean clearance of Dolipranetriptan was 220 and 130 mL/min in males and females, respectively. Renal clearance accounted for about 40% (82 mL/min) and 45% (60 mL/min) of total clearance in males and females, respectively. The mean terminal elimination half-life of Dolipranetriptan in both males and females is approximately 26 hours.