REYVOW Tablet Ref.[10110] Active ingredients: Lasmiditan

5.1 Driving Impairment

REYVOW may cause significant driving impairment. In a driving study, administration of single 50 mg, 100 mg, or 200 mg doses of REYVOW significantly impaired subjects' ability to drive [see Clinical Studies (14.2)]. Additionally, more sleepiness was reported at 8 hours following a single dose of REYVOW compared to placebo. Advise patients not to engage in potentially hazardous activities requiring complete mental alertness, such as driving a motor vehicle or operating machinery, for at least 8 hours after each dose of REYVOW. Patients who cannot follow this advice should not take REYVOW. Prescribers and patients should be aware that patients may not be able to assess their own driving competence and the degree of impairment caused by REYVOW.

5.2 Central Nervous System Depression

REYVOW may cause central nervous system (CNS) depression, including dizziness and sedation [see Adverse Reactions (6.1)].

Because of the potential for REYVOW to cause sedation, other cognitive and/or neuropsychiatric adverse reactions, and driving impairment, REYVOW should be used with caution if used in combination with alcohol or other CNS depressants [see Drug Interactions (7.1)]. Patients should be warned against driving and other activities requiring complete mental alertness for at least 8 hours after REYVOW is taken [see Warnings and Precautions (5.1)].

5.3 Serotonin Syndrome

In clinical trials, reactions consistent with serotonin syndrome were reported in patients treated with REYVOW who were not taking any other drugs associated with serotonin syndrome. Serotonin syndrome may also occur with REYVOW during coadministration with serotonergic drugs [e.g., 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 signs (e.g., hyperreflexia, incoordination), and/or gastrointestinal signs and 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 REYVOW if serotonin syndrome is suspected.

5.4 Medication Overuse Headache

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.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Driving Impairment [see Warnings and Precautions (5.1)]
• Central Nervous System Depression [see Warnings and Precautions (5.2)]
• Serotonin Syndrome [see Warnings and Precautions (5.3)]
• Medication Overuse Headache [see Warnings and Precautions (5.4)]

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety of REYVOW has been evaluated in 4,878 subjects who received at least one dose of REYVOW. In 2 placebo-controlled, Phase 3 trials in adult patients with migraine (Studies 1 and 2), a total of 3,177 patients received REYVOW 50, 100, or 200 mg [see Clinical Studies (14.1)]. Of the REYVOW-treated patients in these 2 studies, approximately 84% were female, 78% were White, 18% were Black, and 18% were of Hispanic or Latino ethnicity. The mean age at study entry was 42.4 years (range 18 to 81).

Long-term safety was assessed for 2,030 patients, dosing intermittently for up to 12 months in a long-term safety study. Of these, 728 patients were exposed to 100 mg or 200 mg for at least 3 months, 361 patients were exposed to these doses for at least 6 months, and 180 patients were exposed to these doses for at least 12 months, all of whom treated at least 2 migraine attacks per month on average. In that study, 14% (148 out of 1,039) in the 200 mg dose group, and 11% (112 out of 991) in the 100 mg dose group withdrew from the trial because of an adverse event. The most common adverse event resulting in discontinuation in the long-term safety study (greater than 2%) was dizziness.

Table 1 shows adverse reactions that occurred in at least 2% of patients treated with REYVOW and more frequently than in patients who received placebo in Studies 1 and 2. The most common adverse reactions (at least 5%) were dizziness, fatigue, paresthesia, and sedation.

Table 1. Adverse Reactions Occurring in ≥2% and at a Frequency Greater than Placebo in Studies 1 and 2:

^a Fatigue includes the adverse reaction related terms asthenia and malaise.
^b Paresthesia includes the adverse reaction related terms paresthesia oral, hypoesthesia, and hypoesthesia oral.
^c Sedation includes the adverse reaction related term somnolence.

Less Common Adverse Reactions

The following adverse reactions occurred in less than 2% of REYVOW-treated patients but more frequently than in patients receiving placebo: vertigo, incoordination, lethargy, visual impairment, feeling abnormal, palpitations, anxiety, tremor, restlessness, sleep abnormalities including sleep disturbance and abnormal dreams, muscle spasm, limb discomfort, cognitive changes, confusion, euphoric mood, chest discomfort, speech abnormalities, dyspnea, and hallucinations.

Hypersensitivity

Events of hypersensitivity, including angioedema, rash and photosensitivity reaction, occurred in patients treated with REYVOW. In controlled trials, hypersensitivity was reported in 0.2% of patients treated with REYVOW compared to no patients who received placebo. If a serious or severe hypersensitivity reaction occurs, initiate appropriate therapy and discontinue administration of REYVOW.

Vital Sign Changes

Heart Rate Decrease

REYVOW was associated with mean decreases in heart rate of 5 to 10 beats per minute (bpm) while placebo was associated with mean decreases of 2 to 5 bpm. Consider evaluating heart rate after administration of REYVOW in patients for whom these changes may not be tolerated, including patients taking other medications that lower heart rate [see Drug Interactions (7.3)].

Blood Pressure Increase

REYVOW may increase blood pressure following a single dose. In non-elderly healthy volunteers there was a mean increase from baseline in ambulatory systolic and diastolic blood pressure of approximately 2 to 3 mm Hg one hour after administration of 200 mg REYVOW compared to a mean increase of up to 1 mm Hg for placebo. In healthy volunteers over 65 years of age, there was a mean increase from baseline in ambulatory systolic blood pressure of 7 mm Hg one hour after administration of 200 mg REYVOW compared to a mean increase of 4 mm Hg for placebo. By 2 hours, there were no increases in mean blood pressure with REYVOW compared to placebo. REYVOW has not been well studied in patients with ischemic heart disease. Consider evaluating blood pressure after administration of REYVOW in patients for whom these changes may not be tolerated.

7.1 CNS Depressants

Concomitant administration of REYVOW and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of REYVOW to cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions, REYVOW should be used with caution if used in combination with alcohol or other CNS depressants [see Warnings and Precautions (5.2)].

7.2 Serotonergic Drugs

Concomitant administration of REYVOW and drugs (e.g., SSRIs, SNRIs, TCAs, MAO inhibitors, trazodone, etc.), over-the counter medications (e.g., dextromethorphan), or herbal supplements (e.g., St. John’s Wort) that increase serotonin may increase the risk of serotonin syndrome [see Warnings and Precautions (5.3)]. Use REYVOW with caution in patients taking medications that increase serotonin.

7.3 Heart Rate Lowering Drugs

REYVOW has been associated with a lowering of heart rate [see Adverse Reactions (6.1)]. In a drug interaction study, addition of a single 200 mg dose of REYVOW to propranolol decreased heart rate by an additional 5 beats per minute compared to propranolol alone, for a mean maximum of 19 beats per minute. Use REYVOW with caution in patients taking concomitant medications that lower heart rate if this magnitude of heart rate decrease may pose a concern.

7.4 P-gp and Breast Cancer Resistant Protein (BCRP)

REYVOW inhibits P-gp and BCRP in vitro. Concomitant use of REYVOW and drugs that are P-gp or BCRP substrates should be avoided.

Risk Summary

There are no adequate data on the developmental risk associated with the use of REYVOW in pregnant women. In animal studies, adverse effects on development (increased incidences of fetal abnormalities, increased embryofetal and offspring mortality, decreased fetal body weight) occurred at maternal exposures less than (rabbit) or greater than (rat) those observed clinically (see Data).

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated rates 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.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data have suggested that women with migraine may be at increased risk for preeclampsia and gestational hypertension during pregnancy.

Data

Animal Data

Oral administration of lasmiditan (0, 100, 175, or 250 mg/kg/day) to pregnant rats throughout organogenesis resulted in increases in skeletal variations at the mid and high doses and reduced fetal body weight at the high dose. The high dose was associated with maternal toxicity. At the no-effect dose (100 mg/kg/day) for adverse effects on embryofetal development in rats, plasma exposure (AUC) was approximately 10 times that in humans at the MRHD.

Oral administration of lasmiditan (0, 50, 75, or 115 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in malformations (skeletal and visceral), increases in skeletal variations and embryofetal mortality, and decreased fetal body weight at the highest dose tested, which was associated with maternal toxicity. Plasma exposure (AUC) at the no-effect dose (75 mg/kg/day) for adverse effects on embryofetal development in rabbits was less than that in humans at the MRHD.

Oral administration of lasmiditan (0, 100, 150, or 225 mg/kg/day) to rats throughout pregnancy and lactation resulted in increases in stillbirth and neonatal mortality at the highest dose tested, which was associated with maternal toxicity and delayed parturition. Plasma exposure (AUC) at the no-effect dose (150 mg/kg/day) for adverse effects on pre- and postnatal development was approximately 16 times that in humans at the MRHD.

Risk Summary

There are no data on the presence of lasmiditan in human milk, the effects of lasmiditan on the breastfed infant, or the effects of lasmiditan on milk production. Excretion of lasmiditan and/or metabolites into milk, at levels approximately 3 times those in maternal plasma, was observed in lactating rats following oral administration of lasmiditan.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for REYVOW and any potential adverse effects on the breastfed infant from REYVOW or from the underlying maternal condition.

Safety and effectiveness in pediatric patients have not been established.

In controlled clinical trials, dizziness occurred more frequently in patients who were at least 65 years of age (19% for REYVOW, 2% for placebo) compared to patients who were less than 65 years of age (14% for REYVOW, 3% for placebo). A larger increase in systolic blood pressure also occurred in patients 65 years of age and older compared to patients who were less than 65 years of age [see Adverse Reactions (6.1)]. Clinical studies of REYVOW did not include sufficient numbers of subjects aged 65 and over to determine whether there is a difference in efficacy in these patients compared to younger subjects. However, in clinical pharmacology studies, no clinically relevant effect on exposure to REYVOW was observed in elderly subjects [see Clinical Pharmacology (12.3)]. 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.

No dosage adjustment is needed for patients with mild or moderate hepatic impairment (Child-Pugh A or B). REYVOW has not been studied in patients with severe hepatic impairment (Child-Pugh C) and its use in these patients is not recommended.

REYVOW contains lasmiditan, a Schedule V controlled substance.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. In a human abuse potential (HAP) study in recreational poly-drug users (n=58), single oral therapeutic doses (100 and 200 mg) and a supratherapeutic dose (400 mg) of REYVOW were compared to alprazolam (2 mg) (C-IV) and placebo. With all doses of REYVOW, subjects reported statistically significantly higher “drug liking” scores than placebo, indicating that REYVOW has abuse potential. In comparison to alprazolam, subjects who received REYVOW reported statistically significantly lower “drug liking” scores. In the HAP study, euphoric mood occurred to a similar extent with REYVOW 200 mg, REYVOW 400 mg, and alprazolam 2 mg (43-49%). A feeling of relaxation was noted in more subjects on alprazolam (22.6%) than with any dose of REYVOW (7-11%).

Phase 2 and 3 studies indicate that, at therapeutic doses, REYVOW produced adverse events of euphoria and hallucinations to a greater extent than placebo. However these events occur at a low frequency (about 1% of patients).

Evaluate patients for risk of drug abuse and observe them for signs of lasmiditan misuse or abuse.

Physical withdrawal was not observed in healthy subjects following abrupt cessation after 7 daily doses of lasmiditan 200 mg or 400 mg.