Solriamfetol

Risk Summary

Available data from case reports are not sufficient to determine drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproductive studies, oral administration of solriamfetol during organogenesis caused maternal and fetal toxicities in rats and rabbits at doses ≥4 and 5 times and was teratogenic at doses 19 and ≥5 times, respectively, the maximum recommended human dose (MRHD) of 150 mg based on mg/m² body surface area. Oral administration of solriamfetol to pregnant rats during pregnancy and lactation at doses ≥7 times the MRHD based on mg/m² body surface area resulted in maternal toxicity and adverse effects on fertility, growth, and development in offspring (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Solriamfetol was administered orally to pregnant rats during the period of organogenesis at 15, 67, and 295 mg/kg/day, which are approximately 1, 4, and 19 times the MRHD based on mg/m² body surface area. Solriamfetol at ≥4 times the MRHD caused maternal toxicity that included hyperactivity, significant decreases in body weight, weight gain, and food consumption. Fetal toxicity at these maternally toxic doses included increased incidence of early resorption and post-implantation loss, and decreased fetal weight. Solriamfetol was teratogenic at 19 times the MRHD; it increased the incidence of fetal malformations that included severe sternebrae mal-alignment, hindlimb rotation, bent limb bones, and situs inversus. This dose was also maternally toxic. The no-adverse-effect level for malformation is 4 times and for maternal and embryofetal toxicity is approximately 1 times the MRHD based on mg/m² body surface area.

Solriamfetol was administered orally to pregnant rabbits during the period of organogenesis at 17, 38, and 76 mg/kg/day, which are approximately 2, 5, and 10 times the MRHD based on mg/m² body surface area. Solriamfetol at 10 times the MRHD caused maternal toxicity of body weight loss and decreased food consumption. Solriamfetol was teratogenic at ≥5 times the MRHD, it caused fetal skeletal malformation (slight-to-moderate sternebrae mal-alignment) and decreased fetal weight. The no-adverse-effect level for malformation and fetal toxicity is approximately 2 times and for maternal toxicity is approximately 5 times the MRHD based on mg/m² body surface area.

Solriamfetol was administered orally to pregnant rats during the period of organogenesis from gestation day 7 through lactation day 20 post-partum, at 35, 110, and 350 mg/kg/day, which are approximately 2, 7, and 22 times the MRHD based on mg/m² body surface area. At ≥7 times the MRHD, solriamfetol caused maternal toxicity that included decreased body weight gain, decreased food consumption, and hyperpnea. At these maternally toxic doses, fetal toxicity included increased incidence of stillbirth, postnatal pup mortality, and decreased pup weight. Developmental toxicity in offspring after lactation day 20 included decreased body weight, decreased weight gain, and delayed sexual maturation. Mating and fertility of offspring were decreased at maternal doses 22 times the MRHD without affecting learning and memory. The no-adverse-effect level for maternal and developmental toxicity is approximately 2 times the MRHD based on mg/m² body surface area.

Risk Summary

There are no data available on the presence of solriamfetol or its metabolites in human milk, the effects on the breastfed infant, or the effect of this drug on milk production.

Solriamfetol is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for solriamfetol and any potential adverse effects on the breastfed child from solriamfetol or from the underlying maternal condition.

Clinical Considerations

Monitor breastfed infants for adverse reactions, such as agitation, insomnia, anorexia and reduced weight gain.

Carcinogenesis

Solriamfetol did not increase the incidence of tumors in rats or mice treated orally for up to 101 and 104 weeks at 35, 80, and 200 mg/kg/day (rat), and 20, 65, and 200 mg/kg/day (mouse), respectively. These doses are approximately 2, 6, and 18 times (rat), and 0.4, 2.6, and 7 times (mouse) the MRHD based on AUC.

Mutagenesis

Solriamfetol was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro mammalian chromosomal aberration assay or in the in vivo mouse bone marrow micronucleus assay.

Impairment of Fertility

Solriamfetol did not affect fertility or sperm parameters when administered orally to male rats for 8 weeks at doses of 35 and 110 mg/kg/day, which are approximately 2 and 7 times the MRHD, based on mg/m² body surface area. At 350 mg/kg/day, which is approximately 22 times the MRHD based on mg/m² body surface area, solriamfetol decreased sperm count and sperm concentration without affecting fertility.

Solriamfetol did not affect fertility when administered orally to female rats for 2 weeks premating, during mating, and through gestation day 7 at 15, 67, and 295 mg/kg/day, which are approximately 1, 4, and 19 times the MRHD, based on mg/m² body surface area.

• Blood Pressure and Heart Rate Increases
• Psychiatric Symptoms

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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.

The safety of solriamfetol has been evaluated in 930 patients (ages 18 to 75 years) with narcolepsy or OSA. Among these patients, 396 were treated with solriamfetol in the 12-week placebo-controlled trials at doses of 37.5 mg (OSA only), 75 mg, and 150 mg once daily. Information provided below is based on the pooled 12‑week placebo‑controlled studies in patients with narcolepsy or OSA.

Most Common Adverse Reactions

The most common adverse reactions (incidence ≥5% and greater than placebo) reported more frequently with the use of solriamfetol than placebo in either the narcolepsy or OSA populations were headache, nausea, decreased appetite, anxiety, and insomnia.

Table 1 presents the adverse reactions that occurred at a rate of ≥2% and more frequently in solriamfetol-treated patients than in placebo-treated patients in the narcolepsy population.

Table 1. Adverse Reactions ≥2% in Patients Treated with Solriamfetol and Greater than Placebo in Pooled 12-Week Placebo-Controlled Clinical Trials in Narcolepsy (75 mg and 150 mg):

* “Insomnia” includes insomnia, initial insomnia, middle insomnia, and terminal insomnia. “Anxiety” includes anxiety, nervousness, and panic attack. “Headache” includes headache, tension headache, and head discomfort. “Nausea” includes nausea and vomiting.

Table 2 presents the adverse reactions that occurred at a rate of ≥2% and more frequently in solriamfetol-treated patients than in placebo-treated patients in the OSA population.

Table 2. Adverse Reactions ≥2% in Patients Treated with Solriamfetol and Greater than Placebo in Pooled 12-Week Placebo-Controlled Clinical Trials in OSA (37.5 mg, 75 mg, and 150 mg):

* “Anxiety” includes anxiety, nervousness, and panic attack. “Nausea” includes nausea and vomiting. “Abdominal pain” includes abdominal pain, abdominal pain upper, and abdominal discomfort.

Other Adverse Reactions Observed During the Premarketing Evaluation of Solriamfetol

Other adverse reactions of <2% incidence but greater than placebo are shown below. The following list does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, or 4) which were not considered to have clinically significant implications.

Narcolepsy population:

Psychiatric disorders: agitation, bruxism, irritability

Respiratory, thoracic and mediastinal disorders: cough

Skin and subcutaneous tissue disorders: hyperhidrosis

General disorders and administration site conditions: feeling jittery, thirst, chest discomfort, chest pain

Investigations: weight decreased

OSA population:

Psychiatric disorders: bruxism, restlessness

Nervous system disorders: disturbances in attention, tremor

Respiratory, thoracic and mediastinal disorders: cough, dyspnea

Gastrointestinal disorders: constipation, vomiting

Investigations: weight decreased

Dose-Dependent Adverse Reactions

In the 12-week placebo-controlled clinical trials that compared doses of 37.5 mg, 75 mg, and 150 mg daily of solriamfetol to placebo, the following adverse reactions were dose-related: headache, nausea, decreased appetite, anxiety, diarrhea, and dry mouth (Table 3).

Table 3. Dose-Dependent Adverse Reactions ≥2% in Patients Treated with Solriamfetol and Greater than Placebo in Pooled 12-Week Placebo-Controlled Clinical Trials in Narcolepsy and OSA:

* In OSA only.
** “Headache” includes headache, tension headache, and head discomfort. “Nausea” includes nausea and vomiting.

Adverse Reactions Resulting in Discontinuation of Treatment

In the 12-week placebo-controlled clinical trials, 11 of the 396 patients (3%) who received solriamfetol discontinued because of an adverse reaction compared to 1 of the 226 patients (<1%) who received placebo. The adverse reactions resulting in discontinuation that occurred in more than one solriamfetol-treated patient and at a higher rate than placebo were: anxiety (2/396; <1%), palpitations (2/396; <1%), and restlessness (2/396; <1%).

Increases in Blood Pressure and Heart Rate

Solriamfetol’s effects on blood pressure and heart rate are summarized below. Table 4 shows maximum mean changes in blood pressure and heart rate recorded at sessions where the Maintenance of Wakefulness Test (MWT) was administered. Table 5 summarizes 24-hour ambulatory blood pressure monitoring (ABPM) and ambulatory heart rate monitoring performed in the outpatient setting.

Table 4. Maximal Mean Changes in Blood Pressure and Heart Rate Assessed at MWT Sessions from Baseline through Week 12: Mean (95% CI)*:

SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate

* For study weeks 1, 4, and 12, SBP, DBP, and HR were assessed pre-dose and every 1-2 hours for 10 hours after test drug administration. For all time points at all visits, the mean change from baseline was calculated, by indication and dose, for all patients with a valid assessment. The table shows, by indication and dose, the mean changes from baseline for the week and time point with the maximal change in SBP, DBP, and HR.
** The maximum recommended daily dose is 150 mg. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.

Table 5. Blood Pressure and Heart Rate by 24-hour Ambulatory Monitoring: Mean Change (95% CI) from Baseline at Week 8:

SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate

* Number of patients who had at least 50% valid ABPM readings.
** The maximum recommended daily dose is 150 mg. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.