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Pharmaceutical Approval Update June 2019

Michele B. Kaufman PharmD, BCGP, RPh

Sunosi (solriamfetol) tablets for oral use

Manufacturer: Jazz Pharmaceuticals, Inc., Palo Alto, California

Date of Approval: March 20, 2019

Indication: Solriamfetol is a dopamine and norepinephrine reuptake inhibitor (DNRI) indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA).

Limitations of use. Solriamfetol is not indicated to treat the underlying airway obstruction in OSA. Ensure that the obstruction is treated (e.g., with continuous positive airway pressure [CPAP]) for at least one month prior to initiating solriamfetol for excessive daytime sleepiness. Modalities to treat the underlying airway obstruction should be continued during treatment with solriamfetol, as the drug is not a substitute for these.

Drug Class: Dopamine and norepinephrine reuptake inhibitor (DNRI)

Uniqueness of Drug: Solriamfetol is the first DNRI approved for treating excessive daytime sleepiness associated with OSA or narcolepsy. For patients with narcolepsy or OSA, excessive daytime sleepiness can negatively affect their daily lives at home or work, or their daily activities. At present, the controlled-substance schedule is pending. This is usually available within 90 days of a drug’s approval by the Food and Drug Administration.

Warnings and Precautions

Blood pressure and heart-rate increases. Patients should have their blood pressure and heart rate monitored prior to initiating therapy and periodically throughout treatment. Blood pressure should be controlled before and during therapy. Exercise caution when treating patients at a higher risk of major adverse cardiovascular events, particularly patients with known cardiovascular disease, cerebrovascular disease, or pre-existing hypertension, and patients at an advanced age. Avoid using solriamfetol in patients with unstable cardiovascular disease, serious heart arrhythmias, or other serious heart problems. Solriamfetol should be used cautiously with other drugs that increase blood pressure and heart rate.

Psychiatric symptoms. Solriamfetol should be used with caution in patients with a history of psychosis or bipolar disorders. Consider dose reduction or discontinuation of solriamfetol if psychiatric symptoms develop. Psychiatric adverse reactions observed in clinical trials include anxiety, insomnia, and irritability.

Other drug interactions. Dopaminergic drugs that increase dopamine levels or bind to dopamine receptors could result in pharmacodynamic interactions with solriamfetol. These possible interactions have not been evaluated. Therefore, dopaminergic drugs should be used with caution when concomitantly administered with solriamfetol.

Michele B. Kaufman, PharmD, BCGP, RPh

Use in Specific Populations

Pregnancy. There is a pregnancy registry for solriamfetol because of fetal animal toxicity.

Lactation. Solriamfetol is present in rat’s 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 the underlying maternal condition. Breastfed infants should be monitored for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

Contraindications: Solriamfetol is contraindicated in patients receiving concomitant treatment with a monoamine oxidase inhibitor (MAOI) or within 14 days following discontinuation of an MAOI because of the risk of hypertensive reaction. Potential outcomes include myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, stroke, renal failure, and death.

Availability and Storage: Solriamfetol is available as 75-mg and 150-mg yellow oblong tablets in bottles of 30 and 100. It should be stored at a room temperature of 68° to 77°F (temperature excursions between 59° and 86°F are permitted).

Dosing and Administration: Solriamfetol should be administered once daily on awakening. Avoid administration within nine hours of planned bedtime as the drug could interfere with sleep. The dose may be increased at intervals of at least three days. The maximum dose is 150 mg once daily. For patients with narcolepsy, the starting dose is 75 mg once daily; for patients with OSA, the starting dose is 37.5 mg once daily.

Renal dosing

  • Moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2): start dosing at 37.5 mg once daily. Based on efficacy and tolerability, the dose may be increased to a maximum of 75 mg once daily after at least seven days.
  • Severe renal impairment (eGFR 15–29 mL/min/1.73 m2): administer 37.5 mg once daily. The maximum recommended daily dose is 37.5 mg.
  • End-stage renal disease (eGFR < 15 mL/min/1.73 m2): solriamfetol use is not recommended.

Commentary: Solriamfetol’s efficacy and safety was based on data from four phase 3, randomized, placebo-controlled trials in the Treatment of Obstructive sleep apnea and Narcolepsy Excessive Sleepiness (TONES) program. Solriamfetol was evaluated in more than 900 adults with excessive daytime sleepiness associated with narcolepsy or OSA. The drug was shown to maintain its effect relative to placebo after six months’ use. At week 12, solriamfetol 150 mg in narcolepsy patients and all doses in OSA patients demonstrated improvement in wakefulness compared to placebo. This was assessed in test sessions 1 (approximately one hour post-dose) through 5 (approximately nine hours post-dose) of the Maintenance of Wakefulness Test. In addition, 68% to 74% of patients treated with 75 mg solriamfetol and 78% to 90% of patients treated with 150 mg solriamfetol reported an overall clinical improvement in their condition. This was assessed by the Patient Global Impression of Change scale. The most common adverse reactions in clinical trials were anxiety, decreased appetite, headache, and nausea.

Source: Jazz Pharmaceuticals Inc., SunosiTM prescribing information

Zulresso (brexanolone) injection, for intravenous use

Manufacturer: Sage Therapeutics, Inc., Cambridge, Massachusetts

Date of Approval: March 19, 2019

Indication: Brexanolone is a neuroactive steroid gamma-aminobutyric acid A (GABA-A) receptor positive modulator for the treatment of postpartum depression (PPD) in adults.

Drug Class: GABA-A receptor modulator antidepressant

Uniqueness of Drug: Postpartum depression is a major depressive episode that occurs after childbirth, although symptoms can start during pregnancy. Like other forms of depression, PPD is distinguished by sadness and/or loss of interest in enjoyable activities, anxiety, and anhedonia. It can present with symptoms such as cognitive impairment, feelings of worthlessness or guilt, suicidal ideation, withdrawing from friends or family, difficulty bonding with one’s new baby, and thinking about harming oneself or, more rarely, the baby. It is estimated that PPD affects approximately one in nine women who have given birth in the United States. Without proper screening, up to half of PPD cases could remain undiagnosed. This is the first drug to receive FDA approval specifically to treat PPD. Brexanolone received a priority review and also was granted breakthrough therapy status.

Warning and Precautions

Boxed warning. Excessive sedation and sudden loss of consciousness (LOC)

Patients are at risk of excessive sedation or sudden LOC during brexanolone administration. Because of the risk of serious harm, patients must be monitored for excessive sedation and sudden LOC and have continuous pulse oximetry monitoring. Patients must be accompanied during interactions with their child(ren). Brexanolone is only available through a restricted program called Zulresso REMS (risk evaluation and mitigation strategy).

Suicidal thoughts and behaviors. Consider changing the therapeutic regimen, including discontinuing brexanolone, in patients whose PPD becomes worse or who experience emergent suicidal thoughts and behaviors.

Contraindications: None

Use in Special Populations: Brexanolone can cause fetal harm, and should not be used in patients with end-stage renal disease.

Availability, Dosage, and Administration: Brexanolone injection is available as a single-dose vial of 100 mg/20 mL (5 mg/mL), which must be diluted prior to administration. Undiluted brexanolone should be stored at 36°F to 46°F and be protected from light. It should not be frozen. Brexanolone should be prepared and stored in polyolefin, non-DEHP, non–latex-only bags. Diluted brexanolone in the infusion bag can be used at room temperature for up to 12 hours. If the product is not used immediately after dilution, it should be stored under refrigerated conditions for up to 96 hours. Each 60-hour infusion will require the preparation of at least five infusion bags.


  • 0–4 hours, initiate with a dosage of 30 mcg/kg/hour;
  • 4–24 hours, increase dosage to 60 mcg/kg/hour;
  • 24–52 hours, increase dosage to 90 mcg/kg/hour (a reduction in dosage to 60 mcg/kg/hour may be considered during this time period for patients who do not tolerate the 90-mcg/kg/hour infusion);
  • 52–56 hours, decrease dosage to 60 mcg/kg/hour;
  • 56–60 hours, decrease dosage to 30 mcg/kg/hour.

Brexanolone is administered as a continuous intravenous (IV) infusion over a total of 60 hours (2.5 days). Because of the risk of serious harm from LOC, patients must be continuously monitored for excessive sedation and also have continuous pulse oximetry monitoring. While receiving the infusion, patients must be accompanied during interactions with their child(ren). The REMS states that patients will be counseled on the risks of brexanolone treatment and instructed that they must be monitored for these effects at a health care facility for the entire 60-hour duration of the infusion. Patients should not drive, operate machinery, or perform other dangerous activities until feelings of sleepiness from the treatment have completely dissipated.

Commentary: Brexanolone’s efficacy was assessed in two double-blind, placebo-controlled clinical trials wherein patients received a 60-hour continuous IV infusion of brexanolone or placebo. Patients were then followed for four weeks. One study included patients with severe PPD and the other included patients with moderate PPD. The primary efficacy endpoint was the change from baseline in depressive symptoms as measured by a depression rating scale. In both studies, brexanolone demonstrated superiority to placebo in improving depressive symptoms at the end of the first infusion. Improvement was also observed at the end of the 30-day follow-up period. The most common adverse reactions in clinical trials included dry mouth, flushing, LOC, and sleepiness.

Sources: Sage Therapeutics, Inc., ZulressoTM prescribing information; Sage Therapeutics press release, March 19, 2019

Mayzent (siponimod) tablets for oral use

Manufacturer: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey

Date of Approval: March 26, 2019

Indication: Siponimod is indicated for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

Drug Class: Sphingosine 1-phosphate receptor modulator

Uniqueness of Drug: Siponimod is the first and only treatment specifically approved for patients with active SPMS in more than 15 years. In addition, siponimod is approved across the MS spectrum, which includes patients with CIS, RRMS, and active SPMS, with most patients not requiring a first-dose observation.

Warnings and Precautions

Infections. As siponimod can increase infection risk, patients should be monitored throughout treatment. Siponimod should not be started in patients with an active infection. Before treatment begins, obtain a complete blood count.

Macular edema. An ophthalmic evaluation is recommended before starting treatment and if there is any vision change while taking siponimod. Patients with diabetes mellitus and uveitis may be at an increased risk.

Bradyarrhythmia and atrioventricular conduction delays. Siponimod may result in a transient heart-rate decrease. Consider resting heart rate with concomitant beta-blocker use; a cardiologist consultation should be obtained prior to using siponimod with other agents that cause bradycardia.

Respiratory effects. Siponimod can cause declines in pulmonary function. Pulmonary function should be assessed (e.g., spirometry) if clinically indicated.

Liver injury. Liver enzyme tests should be obtained prior to starting siponimod. Patients with severe hepatic impairment should be closely monitored. If significant liver injury occurs, siponimod should be discontinued.

Blood pressure increases. Monitor blood pressure during treatment due to a heightened risk of blood pressure increases.

Fetal risk. Women of childbearing potential should use effective contraception while taking siponimod and for 10 days after stopping the drug.

Contraindications: Siponimod is contraindicated in the following:

  • patients with a CYP2C9*3/*3 genotype;
  • patients who have had a myocardial infarction (MI), unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, and/or Class III/IV heart failure in the last six months; and
  • patients who have Mobitz type II second-degree/third-degree atrioventricular (AV) block, or sick sinus syndrome, unless they have a functioning pacemaker.
  • Drug Interactions

    • CYP2C9 and CYP3A4 inhibitors. Increase in siponimod exposure; concomitant use of siponimod with moderate CYP2C9 inhibitors and moderate/strong CYP3A4 inhibitors is not recommended.
    • CYP2C9 and CYP3A4 inducers. Decrease in siponimod exposure; concomitant use of siponimod with moderate CYP2C9 inducers and strong CYP3A4 inducers is not recommended.
    • Vaccines. Avoid the use of live attenuated vaccines during treatment and for up to four weeks after completion of treatment with siponimod.

    Availability, Dosage, and Administration: Siponimod is available as 0.25-mg and 2-mg tablets. First-dose monitoring is recommended in patients with sinus bradycardia, first-degree/second-degree [Mobitz type I] AV block, or a history of MI or heart failure. Assessments are required prior to starting siponimod therapy. Titration is required upon therapy initiation with the recommended maintenance dose of 2 mg. The recommended maintenance dose is 1 mg in patients with a CYP2C9 *1/*3 or *2/*3 genotype.

    Commentary: The efficacy of siponimod was assessed in a randomized, double-blind, parallel-group, placebo-controlled, time-to-event study in patients (N = 1,651) with SPMS who had evidence of disability progression in the prior two years, no evidence of relapse in the three months prior to study enrollment, and an Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5 at study entry. Patients were randomized to receive either once-daily siponimod 2 mg or placebo, starting with a dose titration. Evaluations were performed at baseline, at every three months during the study, and at the time of a suspected relapse. Evaluations of magnetic resonance imaging (MRI) scans were performed at baseline and every 12 months. The primary study endpoint was the time to three-month confirmed progression in disability. The fraction of patients with confirmed progression of disability was statistically significantly lower in the siponimod-treated group than in the placebo-treated group. Siponimod patients also had a decreased number of relapses compared with placebo patients. Siponimod must be dispensed with a Patient Medication Guide, because of the warnings and precautions noted in the section above. Prior to commencing treatment with siponimod, patients should have a complete blood count and their liver enzymes checked. Both blood pressure and liver enzymes should also be monitored throughout treatment. As macular edema can occur, patients should inform their health care team if they experience vision changes. Siponimod can also cause transient bradycardia and lung function decline. The most common adverse reactions reported in clinical trials were headache, hypertension, and transaminase increases.

    Source: Novartis Pharmaceuticals Corporation, Mayzent® prescribing information

    Author bio: 
    Dr. Kaufman is a freelance medical writer living in New York City and a pharmacist in the New York–Presbyterian Lower Manhattan Hospital Pharmacy Department.