U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  45

 ADVERSE REACTIONS-

 The most common adverse reactions (incidence =23%) were injection site reactions, skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, and spontaneous penile erection 

CONTRAINDICATIONS-                                                                                                      None

WARNINGS AND PRECAUTIONS-                                                                          

 • Disturbance in sexual arousal: Spontaneous penile erections in males and sexual adverse reactions in females occurred with IMCIVREE.

Inform patients that these events may occur and instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention.

 • Depression and suicidal ideation: Depression and suicidal ideation have occurred with IMCIVREE. Monitor patients for new onset or worsening depression.                                    Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors.

 • Skin Pigmentation and Darkening of Pre-Existing Nevi: IMCIVREE may cause generalized increased skin pigmentation and darkening of pre-existing nevi.                     

 Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new pigmentary lesions.

 • Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in neonates and low birth weight infants: IMCIVREE is not approved for use in neonates or infants.     

 Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs. 

• If the starting dose is not tolerated, reduce to 0.5 mg (0.05 mL) once daily dose. If the 0.5 mg once daily dose is tolerated and additional weight loss is desired, titrate to 1 mg (0.1 mL) once daily. 

 • If the 1 mg dose is tolerated, increase the dose to 2 mg (0.2 mL) once daily.

 • If the 2 mg once daily dose is not tolerated, reduce to 1 mg (0.1 mL) once daily. If the 2 mg once daily dose is tolerated and additional weight loss is desired, the dose may be increased to 3 mg (0.3 mL) once daily. 

 DOSAGE FORMS AND STRENGTHS-                                                                                    Injection: 10 mg/mL solution in a 1 mL multiple-dose vial

 PATIENT COUNSELING INFORMATION

Advise the patient or caregiver to read the FDA-approved patient labeling (Instructions for Use).

Spontaneous Penile Erection-                                                                                          Inform male patients that spontaneous erection may occur with IMCIVREE treatment. Advise patients to seek appropriate medical treatment if an erection lasts longer than 4 hours 

Depression and Suicidal Ideation-                                                                                        Inform patients or caregivers that some drugs that target the central nervous system, such as IMCIVREE, may cause depression or suicidal ideation.

Advise patients or caregivers to report any new or worsening symptoms of depression 

Skin Pigmentation and Darkening of Pre-Existing Nevi-                                                   Inform patients or caregivers that skin darkening occurs in the majority of patients treated with IMCIVREE because of its mechanism of action. This change is reversable upon discontinuation of IMCIVREE.

Inform patients or caregivers that they should have a full body skin examination before starting and during treatment with IMCIVREE to monitor these changes.

Pregnancy-                                                                                                                              Advise patients who may become pregnant to inform their healthcare provider of a known or suspected pregnancy.

Lactation-                                                                                                                                    Advise patients that treatment with IMCIVREE is not recommended while breastfeeding 

Administration-                                                                                                                         Instruct patients and caregivers how to prepare and administer the correct dose of IMCIVREE and assess their ability to inject subcutaneously to ensure the proper administration of IMCIVREE.

Instruct patients to use a 1 mL syringe with a 28- or 29-gauge needle appropriate for subcutaneous injection.

Manufactured for: Rhythm Pharmaceuticals, Inc. 222 Berkeley Street, Suite 1200 Boston, MA 02116

12 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                            Setmelanotide is an MC4 receptor agonist with 20-fold less activity at the melanocortin 3 (MC3) and melanocortin 1 (MC1) receptors. MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure.

2. Pharmacodynamics-                                                                                                     

 Energy Expenditure- Short-term administration of IMCIVREE in 12 healthy obese patients increased resting energy expenditure and shifted substrate oxidation to fat.

Blood Pressure and Heart Rate- No clinically significant increases in blood pressure (BP) or heart rate (HR) were observed following administration of IMCIVREE to healthy obese patients or patients with monogenic obesity.

3. Pharmacokinetics- The mean steady state setmelanotide Cmax,ss, AUCtau, and trough concentration for a 3-mg dose administered subcutaneously once daily was 37.9 ng/mL, 495 h*ng/mL, and 6.77 ng/mL, respectively.

Steady-state plasma concentrations of setmelanotide were achieved within 2 days with daily dosing of 1-3 mg setmelanotide.

Absorption-                                                                                                                                  After subcutaneous injection of IMCIVREE, plasma concentrations of setmelanotide reached maximum concentrations at a median tmax of 8 h after dosing.

Distribution-                                                                                                                           The mean apparent volume of distribution of setmelanotide after subcutaneous administration of IMCIVREE 3 mg once daily was estimated from the population pharmacokinetics model to be 48.7 L. Protein binding of setmelanotide is 79.1%.

Elimination-                                                                                                                            The effective elimination half-life (t½) of setmelanotide was approximately 11 hours. The total apparent steady state clearance of setmelanotide following subcutaneous administration of IMCIVREE 3 mg once daily was estimated from the population PK model to be 4.86 L/h.

Metabolism-                                                                                                                         Setmelanotide is expected to be metabolized into small peptides by catabolic pathways.

Excretion-                                                                                                                         Approximately 39% of the administered setmelanotide dose was excreted unchanged in urine during the 24-hour dosing interval following subcutaneous administration of 3 mg once daily.

Specific Populations-                                                                                                            No clinically significant differences in the pharmacokinetics of setmelanotide were observed based on sex. The effect of age 65 years or older, pregnancy, or hepatic impairment on the pharmacokinetics of setmelanotide is unknown.

Pediatric Patients-                                                                                                              IMCIVREE has been evaluated in pediatric patients aged 6 to less than 12 years and aged 12 to 17 years.

For patients aged 12 to 17 years, the setmelanotide AUC and Cmax were 44% and 37% higher, respectively as compared to patients greater than or equal to 17 years. 

Patients with Renal Impairment-                                                                                       Population pharmacokinetic analysis suggests a 19% higher setmelanotide AUC in patients with mild renal impairment as compared to patients with normal renal function 

Drug Interaction Studies -                                                                                                       In vitro assessment of drug-drug interactions Setmelanotide has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 (CYP), transporters and plasma protein binding. In vivo assessment of drug-drug interactions

No clinical studies evaluating the drug-drug interaction potential of setmelanotide have been conducted.

 USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary-                                                                                                  Discontinue IMCIVREE when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. IMCIVREE contains the preservative benzyl alcohol

 Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely.

However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs

There are no available data with IMCIVREE in pregnant women to inform a drug-associated risk for major birth defects and miscarriage, or adverse maternal or fetal outcomes.

The estimated background risk of birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

2. Lactation Risk Summary-                                                                                                Treatment with IMCIVREE is not recommended for use while breastfeeding. IMCIVREE from multiple-dose vials contains the preservative benzyl alcohol.

Because benzyl alcohol is rapidly metabolized by a lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs.

3.Pediatric Use-                                                                                                                         The safety and effectiveness of IMCIVREE for obesity due to POMC, PCSK1, or LEPR deficiency have been established in pediatric patients aged 6 years and older. Use of IMCIVREE for this indication is supported by evidence from 2 open-label studies that included 9 pediatric patients [see Clinical Studies (14)].

The safety and effectiveness of IMCIVREE have not been established in pediatric patients younger than 6 years old.

IMCIVREE is not approved for use in neonates or infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. 

4.Geriatric Use-                                                                                                                      Clinical studies of IMCIVREE did not include patients aged 65 and over. It is not known whether they respond differently from younger patients.

5. Renal Impairment-                                                                                                           Population pharmacokinetic analysis suggests decreased clearance in patients with renal impairment. The majority of patients in the clinical studies had normal renal function. No dose adjustments for patients with mild renal impairment (estimated glomerular filtration rate (eGFR) of 60-89 mL/min/1.73 m2 ) are needed.

 OVERDOSAGE-                                                                                                                        In the event of an overdose initiate appropriate supportive treatment according to the patient’s clinical signs and symptoms.