DRUG INTERACTIONS-(details)

1. Monoamine Oxidase (MAO) Inhibitors -                                                                  Do not administer SUNOSI concomitantly with MAOIs or within 14 days after discontinuing MAOI treatment. Concomitant use of MAO inhibitors and noradrenergic drugs may increase the risk of a hypertensive reaction.

Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure 

2. Drugs that Increase Blood Pressure and/or Heart Rate-                                  Concomitant use of SUNOSI with other drugs that increase blood pressure and/or heart rate has not been evaluated, and such combinations should be used with caution 

3 Dopaminergic Drugs-                                                                                              Dopaminergic drugs that increase levels of dopamine or that bind directly to dopamine receptors might result in pharmacodynamic interactions with SUNOSI. Interactions with dopaminergic drugs have not been evaluated with SUNOSI. Use caution when concomitantly administering dopaminergic drugs with SUNOSI.

BRIEF SUMMARY

SUNOSOL- (Mar 2019)

Indn-    Excessive sleepnesness in adult patients with narcolepsy or                                              obstructive sleep apnea

Comp- 75mg tablets Starting dose for patients with narcolepsy:    75 mg once daily. Starting dose for patients with OSA: 37.5 mg once daily. Dose may be increased at intervals of at least 3 days. Maximum dose is 150 mg once daily.

ADR-  Most common adverse reactions (=5% and greater than placebo): headache, nausea, decreased appetite, insomnia, and anxiety.

CI- Concurrent treatment with a monoamine oxidase inhibitor (MAOI) or use of an MAOI within the preceding 14 days.

 WARNINGS -

 Blood Pressure and Heart Rate Increases: Measure heart rate and blood pressure prior to initiating and periodically throughout treatment. Control hypertension before and during therapy. Avoid use in patients with unstable cardiovascular disease, serious heart arrhythmias, or other serious heart problems

Pat Inform-   

Potential for Abuse and Dependence-                                                                            Advise patients that it  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  drug  as recommended in the Medication Guide.

Primary OSA Therapy Use -                                                                                           Inform patients thatI 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 .

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U.S. FDA APPROVED  DRUGS DURING 2019

Sr.No-  5

HIGHLIGHTS OF PRESCRIBING INFORMATION-

 These highlights do not include all the information needed to use                         SUNOSI™ safely and effectively.                                                                                    See full prescribing information for SUNOSI. SUNOSI (solriamfetol) tablets, for oral use, [controlled substance schedule pending]

Initial U.S. Approval: [pending controlled substance scheduling]

INDICATIONS AND USAGE -

SUNOSI 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-                                                                                                        SUNOSI is not indicated to treat the underlying airway obstruction in OSA. Ensure that the underlying airway obstruction is treated (e.g., with continuous positive airway pressure (CPAP)) for at least one month prior to initiating SUNOSI for excessive daytime sleepiness. Modalities to treat the underlying airway obstruction should be continued during treatment with SUNOSI. SUNOSI is not a substitute for these modalities.

ADVERSE REACTIONS-

 Most common adverse reactions (=5% and greater than placebo): headache, nausea, decreased appetite, insomnia, and anxiety.

 CONTRAINDICATIONS-

 Concurrent treatment with a monoamine oxidase inhibitor (MAOI) or use of an MAOI within the preceding 14 days.

 WARNINGS AND PRECAUTIONS-

 Blood Pressure and Heart Rate Increases: Measure heart rate and blood pressure prior to initiating and periodically throughout treatment. Control hypertension before and during therapy. Avoid use in patients with unstable cardiovascular disease, serious heart arrhythmias, or other serious heart problems

 Psychiatric Symptoms: Use caution in treating patients with a history of psychosis or bipolar disorders. Consider dose reduction or discontinuation of SUNOSI if psychiatric symptoms develop. (

 DOSAGE AND ADMINISTRATION -

 Administer once daily upon awakening. Avoid administration within 9 hours of planned bedtime because of the potential to interfere with sleep.

 Starting dose for patients with narcolepsy:                                                                      75 mg once daily.

 Starting dose for patients with OSA: 37.5 mg once daily.

 Dose may be increased at intervals of at least 3 days.

 Maximum dose is 150 mg once daily.

Renal impairment

 Moderate impairment: Starting dose is 37.5 mg once daily. o May increase to 75 mg once daily after at least 7 days. ? Severe impairment: Starting dose and maximum dose is 37.5 mg once daily. ? End stage renal disease (ESRD): Not recommended. FULL

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). 

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 [see Indications and Usage (1)]. 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

Distributed by: Jazz Pharmaceuticals, Inc. Palo Alto, CA 94304 Protected by U.S. patent numbers: 8440715, 8877806, and 960491

CLINICAL PHARMACOLOGY 12.1 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 12 Reference ID: 4577845 efficacy could be mediated through its activity as a dopamine and norepinephrine reuptake inhibitor (DNRI). 12.2 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). These heart rate effects impact the interpretability of the QTc effects, particularly in the 900 mg group. In this study, solriamfetol 300 mg did not prolong the QTcF interval to a clinically relevant extent. 12.3 Pharmacokinetics Solriamfetol exhibits linear kinetics over the dose range of 42 to 1008 mg (approximately 0.28 to 6.7 times the maximum recommended dosage). Steady state is reached in 3 days, and once-daily administration is expected to result in minimal accumulation (1.06 times single-dose exposure). 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. 13 Reference ID: 4577845 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 ) are summarized in Figure 1. 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)]. An average of 21% of solriamfetol was removed by hemodialysis. In general, median Tmax values were not affected by renal impairment. 14 Reference ID: 4577845 Figure 1. Effect of Renal Impairment on Solriamfetol Pharmacokinetics 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 ba

DRUG INTERACTIONS-(details)

7.1 Monoamine Oxidase (MAO) Inhibitors Do not administer SUNOSI concomitantly with MAOIs or within 14 days after discontinuing MAOI treatment. Concomitant use of MAO inhibitors and noradrenergic drugs may increase the risk of a hypertensive reaction. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4)]. 8 Reference ID: 4577845 7.2 Drugs that Increase Blood Pressure and/or Heart Rate Concomitant use of SUNOSI with other drugs that increase blood pressure and/or heart rate has not been evaluated, and such combinations should be used with caution [see Warnings and Precautions (5.1)].

7.3 Dopaminergic Drugs Dopaminergic drugs that increase levels of dopamine or that bind directly to dopamine receptors might result in pharmacodynamic interactions with SUNOSI. Interactions with dopaminergic drugs have not been evaluated with SUNOSI. Use caution when concomitantly administering dopaminergic drugs with SUNOSI.

8 USE IN SPECIFIC POPULATIONS 8.1 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. 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 9 Reference ID: 4577845 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 postimplantation loss, and decreased fetal weight. Solriamfetol was teratogenic at 19 times the MRHD; it increased the incidence of fetal malformations that included severe sternebrae malalignment, 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. 8.2 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. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Clinical studies of SUNOSI in pediatric patients have not been conducted. 10 Reference ID: 4577845 8.5 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 [see Dosage and Administration (2.5)]. 8.6 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 9.1 Controlled Substance SUNOSI contains solriamfetol. (Controlled substance schedule to be determined after review by the Drug Enforcement Administration). 9.2 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 Drug Liking scores similar to or lower than phentermine. In this crossover study, elevated mood was reported by 2.4% of placebo-treated subjects, 8 to 24% of SUNOSI-treated subjects, and 10 to 18% of phentermine-treated subjects. A ‘feeling of relaxation’ was reported in 5% of placebo-treated subjects, 5 to 19% of SUNOSI-treated subjects and 15 to 20% of phentermine-treated subjects. Physicians should carefully evaluate patients for a recent history of drug abuse, especially those with a history of stimulant (e.g., methylphenidate, amphetamine, or cocaine) or alcohol abuse, and follow such patients closely, observing them for signs of misuse or abuse of SUNOSI (e.g., incrementation of doses, drug-seeking behavior). 11 Reference ID: 4577845 9.3 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.

10 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 Certified Poison Control Center at 1-800-222-1222 for latest recommendations. 11 DESCRIPTION SUNOSI contains solriamfetol, a dopamine and norepinephrine reuptake inhibitor (DNRI). Solriamfetol is a phenylalanine derivative with the systematic name (R)-2- amino-3-phenylpropylcarbamate hydrochloride. The molecular formula is C10H15N2O2Cl, and the molecular weight is 230.69. The chemical structure is: