U.S. FDA APPROVED  DRUGS DURING 2019

Sr.No- 5

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling 

Potential for Abuse and Dependence Advise patients that SUNOSI is a federally controlled substance because it has the potential to be abused 

Advise patients to keep their medication in a secure place and to dispose of unused SUNOSI as recommended in the Medication Guide.

Primary OSA Therapy Use                                                                                       Inform patients that SUNOSI is not indicated to treat the airway obstruction in OSA and they should use a primary OSA therapy, such as CPAP, as prescribed to treat the underlying obstruction . SUNOSI is not a substitute for primary OSA therapy. 

Blood Pressure and Heart Rate                                                                               Increases Instruct patients that SUNOSI can cause elevations of their blood pressure and pulse rate and that they should be monitored for such effects 

Psychiatric Symptoms                                                                                                 Instruct patients to contact their healthcare provider if they experience, anxiety, insomnia, irritability, agitation, or signs of psychosis or bipolar disorders 

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

For more information, visit www.SUNOSI.com Distributed by: Jazz Pharmaceuticals, Inc. Palo Alto, CA 94304 Protected by U.S. patent numbers: 8440715, 8877806, and 9604917

 CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                                               The mechanism of action of solriamfetol to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea is unclear. However, its efficacy could be mediated through its activity as a dopamine and norepinephrine reuptake inhibitor (DNRI).

2. Pharmacodynamics                                                                                       Solriamfetol binds to the dopamine transporter and norepinephrine transporter with low affinity (Ki=14.2 µM and 3.7 µM, respectively), and inhibits the reuptake of dopamine and norepinephrine with low potency (IC50 =2.9 µM and 4.4 µM, respectively).

Solriamfetol has no appreciable binding affinity for the serotonin transporter (Ki=81.5 µM) and does not inhibit serotonin reuptake (IC50 > 100 µM). Solriamfetol has no appreciable binding affinity to dopamine, serotonin, norepinephrine, GABA, adenosine, histamine, orexin, benzodiazepine, muscarinic acetylcholine, or nicotinic acetylcholine receptors.

Cardiac Electrophysiology                                                                                          The effect of solriamfetol 300 mg and 900 mg (twice and six times the maximum recommended dose, respectively) on the QTc interval was evaluated in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy subjects.

A large increase in heart rate was observed in both solriamfetol treatment groups (mean change from baseline in HR of 21 and 27 bpm in the 300 and 900 mg groups, respectively, compared with 8 bpm in the placebo group).

Absorption                                                                                                                         The oral bioavailability of solriamfetol is approximately 95%. Peak plasma concentration of solriamfetol occurs at a median Tmax of 2 hours (range 1.25 to 3.0 hours) post-dose under fasted conditions.

Effect of Food                                                                                                             Ingestion of solriamfetol with a high-fat meal resulted in minimal change in Cmax and AUCinf; however, a delay of approximately 1 hour in Tmax was observed.

Distribution                                                                                                                     The apparent volume of distribution of solriamfetol is approximately 199 L. Plasma protein binding ranged from 13.3% to 19.4% over solriamfetol concentration range of 0.059 to 10.1 mcg/mL in human plasma. The mean blood-to-plasma concentration ratio ranged from 1.16 to 1.29. 

Elimination                                                                                                                Solriamfetol exhibits first-order elimination after oral administration. The apparent mean elimination half-life is about 7.1 hours.

Metabolism                                                                                                          Solriamfetol is minimally metabolized in humans.

Excretion                                                                                                               Approximately 95% of the dose was recovered in urine as unchanged solriamfetol, and 1% or less of the dose was recovered as the minor inactive metabolite N-acetyl solriamfetol in a mass balance study.

Renal clearance (18.2 L/h) represented the majority of apparent total clearance (19.5 L/h). Active tubular secretion is likely involved in the renal elimination of the parent drug.

Specific Populations Population                                                                                  PK analysis indicated that age, gender, and race do not have clinically relevant effects on the pharmacokinetics of solriamfetol. No dose adjustments were made in clinical studies that enrolled patients ages 65 and above.

Patients with Renal Impairment                                                                             Exposures to solriamfetol in patients with renal impairment compared to subjects with normal renal function (eGFR = 90 mL/min/1.73 m2 ) 

 The half-life of solriamfetol was increased approximately 1.2-, 1.9-, and 3.9-fold in patients with mild (eGFR 60-89 mL/min/1.73 m2 ), moderate (eGFR 30–59 mL/min/1.73 m2 ), or severe (eGFR <30 mL/min/1.73 m2 ) renal impairment, respectively.

Exposure (AUC) and half-life of solriamfetol was significantly increased in patients with ESRD (eGFR <15 mL/min/1.73 m2 ) [see Use in Specific Populations (8.6)].

Drug Interaction Studies                                                                                                 In Vitro Studies CYP and UGT Enzymes: Solriamfetol was minimally metabolized in vitro. Solriamfetol is not an inhibitor of CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. It does not induce CYP1A2, 2B6, 3A4, or UGT1A1 enzymes at clinically relevant concentrations.

Transporter Systems: Solriamfetol is a low-avidity substrate of OCT2, MATE1, OCTN1, and OCTN2. Solriamfetol is a weak inhibitor of OCT2 (IC50 of 146 µM) and MATE1 (IC50 of 211 µM), and is not an inhibitor of OCT1, MATE2-K, OCTN1, or OCTN2.

Solriamfetol does not appear to be a substrate or inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, or OAT3. Based on in vitro data, clinically significant PK drug interactions with major CYPs and transporters are not expected in patients taking SUNOSI.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SUNOSI during pregnancy.

Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-877-283-6220 or contacting the company at www.SunosiPregnancyRegistry.com.

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.

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.

2. Lactation 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 SUNOSI and any potential adverse effects on the breastfed child from SUNOSI or from the underlying maternal condition.

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

3 Pediatric Use                                                                                                             Safety and effectiveness in pediatric patients have not been established. Clinical studies of SUNOSI in pediatric patients have not been conducted.

4. Geriatric Use                                                                                                               Of the total number of patients in the narcolepsy and OSA clinical studies treated with SUNOSI, 13% (123/930) were 65 years of age or over. No clinically meaningful differences in safety or effectiveness were observed between elderly and younger patients. Solriamfetol is predominantly eliminated by the kidney.

Because elderly patients are more likely to have decreased renal function, dosing may need to be adjusted based on eGFR in these patients. Consideration should be given to the use of lower doses and close monitoring in this population 

5. Renal Impairment-                                                                                                      Dosage adjustment is not required for patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m2 ).

Dosage adjustment is recommended for patients with moderate to severe renal impairment (eGFR 15-59 mL/min/1.73 m2 ). SUNOSI is not recommended for patients with end stage renal disease (eGFR <15 mL/min/1.73 m2 )

[see Dosage and Administration (2.5), Warnings and Precautions (5.1, 5.2), Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

1. Controlled Substance-                                                                                              SUNOSI contains solriamfetol. (Controlled substance schedule to be determined after review by the Drug Enforcement Administration).

2. Abuse -                                                                                                                        SUNOSI has potential for abuse. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect.

The abuse potential of SUNOSI 300 mg, 600 mg, and 1200 mg (two, three, and four times the maximum recommended dose, respectively) was assessed relative to phentermine, 45 mg and 90 mg, (a Schedule IV controlled substance) in a human abuse potential study in individuals experienced with the recreational use of stimulants. Results from this clinical study demonstrated that SUNOSI produced

3. Dependence-                                                                                                                   In a long-term safety and maintenance of efficacy study, the effects of abrupt discontinuation of SUNOSI were evaluated following at least 6 months of SUNOSI use in patients with narcolepsy or OSA.

The effects of abrupt discontinuation of SUNOSI were also evaluated during the twoweek safety follow-up periods in the Phase 3 studies.

There was no evidence that abrupt discontinuation of SUNOSI resulted in a consistent pattern of adverse events in individual subjects that was suggestive of physical dependence or withdrawal.

 OVERDOSAGE-

A specific reversal agent for SUNOSI is not available. Hemodialysis removed approximately 21% of a 75 mg dose in end stage renal disease patients. Overdoses should be managed with primarily supportive care, including cardiovascular monitoring. Consult with a C