Chemical formula: C₁₉H₁₈F₃N₃O₂ Molecular mass: 377.367 g/mol PubChem compound: 11610526
There are no adequate data on the developmental risk associated with the use of lasmiditan 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.
Published data have suggested that women with migraine may be at increased risk for preeclampsia and gestational hypertension during pregnancy.
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.
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 lasmiditan and any potential adverse effects on the breastfed infant from lasmiditan or from the underlying maternal condition.
No drug-related tumors were observed following oral administration of lasmiditan to TgRasH2 mice at doses of up to 150 (males) or 250 (females) mg/kg/day for 26 weeks or to rats at doses of up to 75 mg/kg/day for 2 years. Plasma exposures (AUC) at the highest dose tested in rats were approximately 15 times that in humans at the maximum recommended human dose (MRHD) of 200 mg/day.
Lasmiditan was negative in in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.
Oral administration of lasmiditan to male (0, 100, 175, or 200 mg/kg/day) or female (0, 100, 150, or 200 mg/kg/day) rats prior to and during mating and continuing in females to Gestation Day 7 resulted in no adverse effects on fertility or reproductive performance. Plasma exposures (AUC) at the highest dose tested (200 mg/kg/day) were approximately 26 times that in humans at the MRHD.
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 lasmiditan has been evaluated in 4,878 subjects who received at least one dose of lasmiditan. In 2 placebo-controlled, Phase 3 trials in adult patients with migraine (Studies 1 and 2), a total of 3,177 patients received lasmiditan 50, 100, or 200 mg. Of the lasmiditan-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 lasmiditan 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:
| Adverse Reaction | Lasmiditan 50 mg N=654 % | Lasmiditan 100 mg N=1265 % | Lasmiditan 200 mg N=1258 % | Placebo N=1262 % |
|---|---|---|---|---|
| Dizziness | 9 | 15 | 17 | 3 |
| Fatiguea | 4 | 5 | 6 | 1 |
| Paresthesiab | 3 | 7 | 9 | 2 |
| Sedationc | 6 | 6 | 7 | 2 |
| Nausea and/or Vomiting | 3 | 4 | 4 | 2 |
| Muscle Weakness | 1 | 1 | 2 | 0 |
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.
The following adverse reactions occurred in less than 2% of lasmiditan-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.
Events of hypersensitivity, including angioedema, rash and photosensitivity reaction, occurred in patients treated with lasmiditan. In controlled trials, hypersensitivity was reported in 0.2% of patients treated with lasmiditan compared to no patients who received placebo. If a serious or severe hypersensitivity reaction occurs, initiate appropriate therapy and discontinue administration of lasmiditan.
Lasmiditan 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 lasmiditan in patients for whom these changes may not be tolerated, including patients taking other medications that lower heart rate.
Lasmiditan 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 lasmiditan 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 lasmiditan compared to a mean increase of 4 mm Hg for placebo. By 2 hours, there were no increases in mean blood pressure with lasmiditan compared to placebo. Lasmiditan has not been well studied in patients with ischemic heart disease. Consider evaluating blood pressure after administration of lasmiditan in patients for whom these changes may not be tolerated.
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