Imcivree

 Patient Selection - POMC, PCSK1, or LEPR Deficiency

• Select patients for treatment with IMCIVREE who have genetically determined or suspected deficiency of POMC, PCSK1, or LEPR [see Clinical Studies ].
• Treat patients with variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS) in the clinical context of the patient [see Clinical Studies ].
• Information on an FDA-approved test for the detection of variants in the POMC, PCSK1, or LEPR is available at http://www.fda.gov/CompanionDiagnostics.

Patient Selection - BBS

Select patients for treatment with IMCIVREE who have a clinical diagnosis of BBS [see Clinical Studies ].

Recommended dosage in Adults and Pediatric Patients 12 Years of Age and Older

In adult and pediatric patients 12 years of age and older, the recommended starting dosage is 2 mg (0.2 mL) injected subcutaneously once daily for 2 weeks, and the recommended target dosage is 3 mg (0.3 mL) injected subcutaneously once daily. Monitor patients for gastrointestinal (GI) adverse reactions [see Adverse Reactions ].

If the starting dosage is:

• Not tolerated, reduce the dosage to 1 mg (0.1 mL) once daily. If the 1 mg once daily dosage is tolerated for at least 1 week, increase the dosage to 2 mg (0.2 mL) once daily.
• Tolerated for 2 weeks, increase the dosage to 3 mg (0.3 mL) once daily. If the 3 mg once daily dosage is not tolerated, decrease the dosage to 2 mg (0.2 mL) once daily.

 Recommended Dosage in Pediatric Patients 6 to Less Than 12 Years of Age

In pediatric patients aged 6 to less than 12 years, the recommended starting dosage is 1 mg (0.1 mL) injected subcutaneously once daily for 2 weeks, and the recommended target dosage is 3 mg (0.3 mL) injected subcutaneously once daily. Monitor patients for GI adverse reactions [see Adverse Reactions ].

If the starting dosage is:

• Not tolerated, reduce the dosage to 0.5 mg (0.05 mL) once daily. If the 0.5 mg once daily dosage is tolerated for at least 1 week, increase the dosage to 1 mg (0.1 mL) once daily.
• Tolerated for 2 weeks, increase the dosage to 2 mg (0.2 mL) once daily. If the 2 mg daily dosage is:          
  1. Not tolerated, reduce the dosage to 1 mg (0.1 mL) once daily.
  2. Tolerated, increase the dosage to 3 mg (0.3 mL) once daily.

Recommended Dosage in Patients with Renal Impairment

Recommended Dosage in Patients with End Stage Renal Disease

IMCIVREE is not recommended for use in patients with end stage renal disease (eGFR less than 15 mL/min/1.73 m2).

Recommended Dosage in Patients with Severe Renal Impairment

For adults and pediatric patients 12 years of age and older with severe renal impairment (estimated glomerular filtration rate [eGFR] of 15 to 29 mL/min/1.73 m2), the recommended starting dosage is 0.5 mg (0.05 mL) injected subcutaneously once daily for 2 weeks, and the recommended target dosage is 1.5 mg (0.15 mL) injected subcutaneously once daily [see Use in Specific Populations and Clinical Pharmacology ]. Monitor patients for GI adverse reactions [see Adverse Reactions ].

If the recommended starting dosage is [see Use in Specific Populations ]:

• Tolerated for 2 weeks, increase the dosage to 1 mg (0.1 mL) once daily. If the 1 mg daily dosage is tolerated for at least 1 week, increase the dosage to 1.5 mg (0.15 mL) once daily.
• Not tolerated, discontinue IMCIVREE.

The use of IMCIVREE in pediatric patients 6 to less than 12 years of age with severe renal impairment is not recommended [see Use in Specific Populations ].

Recommended Dosage in Patients with Mild or Moderate Renal Impairment

The recommended dosage in patients with mild renal impairment (eGFR of 60 to 89 mL/min/1.73 m2) or moderate renal impairment (eGFR of 30 to 59 mL/min/1.73 m2) is the same as in those with normal kidney function [see Dosage and Administration ].

Recommended Monitoring

Obesity Due to POMC, PCSK1, or LEPR Deficiency

• Periodically assess response to IMCIVREE therapy. In pediatric patients, evaluate the impact of weight loss on growth and maturation.
• Evaluate weight loss after 12-16 weeks of treatment. If a patient has not lost at least 5% of baseline body weight or 5% of baseline BMI for patients with continued growth potential, discontinue IMCIVREE as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.

Obesity and a Clinical Diagnosis of BBS

• Periodically assess response to IMCIVREE therapy. In pediatric patients, evaluate the impact of weight loss on growth and maturation.
• Evaluate weight loss after 1 year of treatment. If a patient has not lost at least 5% of baseline body weight or 5% of baseline BMI for patients aged less than 18 years, discontinue IMCIVREE as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.

 Administration Instructions

• Prior to initiation of IMCIVREE, train patients or their caregivers on proper injection technique. Instruct patients to use a 1-mL syringe with a 28- or 29-gauge needle appropriate for subcutaneous injection.
• Remove IMCIVREE from the refrigerator approximately 15 minutes prior to administration. Alternatively, warm IMCIVREE prior to administration by rolling the vial gently between the palms of the hands for 60 seconds.
• Inspect IMCIVREE visually before use. It should appear clear to slightly opalescent, colorless to slightly yellow. Do not use if particulate matter or discoloration is seen.
• Administer IMCIVREE once daily, at the beginning of the day, without regard to meals.
• Inject IMCIVREE subcutaneously in the abdomen, thigh, or arm, rotating to a different site each day. Do not administer IMCIVREE intravenously or intramuscularly.
• If a dose is missed, resume the once daily regimen as prescribed with the next scheduled dose.

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 [see Warnings and Precautions and see Use in Specific Populations ].

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. For the general US population, weight loss offers no potential benefit to a pregnant woman and may result in fetal harm (see Clinical Considerations). In animal reproduction studies, setmelanotide subcutaneously administered to pregnant rats from before mating to the end of organogenesis was not teratogenic at doses 11 times the maximum recommended human dose (MRHD) of 3 mg. Setmelanotide subcutaneously administered to pregnant rabbits during the period of organogenesis was not teratogenic at clinical doses. Setmelanotide administered subcutaneously to pregnant rats during organogenesis through lactation did not result in adverse developmental effects at doses 7 times the MRHD (see Data).

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.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risks

Maternal obesity increases the risk for congenital malformations, including neural tube defects, cardiac malformations, oral clefts, and limb reduction defects. In addition, weight loss during pregnancy may result in fetal harm including increased risk of small for gestational age. Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant women, including those who are already overweight or have obesity, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.

Data

Animal Data

Embryo-fetal development was evaluated in female rats administered setmelanotide subcutaneously during mating to end of major organogenesis (14 days prior to mating to gestation day 17) at doses of 0.5, 3, and 5 mg/kg/day, resulting in exposures up to 11 times the human exposure at MRHD of 3 mg, based on AUC. Dose-related decreases in maternal food intake and body weight gain were observed during the premating period but not during gestation. No evidence of embryo-fetal toxicity was observed.

Embryo-fetal development was evaluated in pregnant rabbits subcutaneously administered setmelanotide during organogenesis (gestation days 7 to 19) at doses of 0.05, 0.1, and 0.2 mg/kg/day, resulting in clinically relevant exposures at the MRHD, based on AUC. Decreases in maternal food consumption and body weight were observed at all doses. Increases in embryo-fetal resorptions and post-implantation losses were observed at ≥0.1 mg/kg/day in the presence of significant maternal toxicity, and fetal body weights were 7% lower than controls at 0.2 mg/kg/day.

Pre- and post-natal development was evaluated in rats subcutaneously administered setmelanotide during organogenesis and continuing to weaning (gestation day 6 to lactation day 21) at doses of 0.5, 3.0, and 5.0 mg/kg/day, which resulted in exposures up to 7 times the human exposure at the MRHD, based on AUC. Pup body weights at birth were 9% lower than controls at 3.0 and 5.0 mg/kg/day, which was consistent with reduced maternal body weight gain and food consumption during gestation. No adverse setmelanotide-related effects on pup survival, growth, maturation, visual function, neurobehavioral performance, or reproductive performance were observed up to the highest dose.

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 [see Warnings and Precautions and see Use in Specific Populations ].

There is no information on the presence of setmelanotide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. However, setmelanotide is present in the milk of rats (see Data). When a drug is present in rat milk, it is likely that the drug will be present in human milk.

Data

Dose-related setmelanotide concentrations were observed in milk 2 hours after subcutaneous injection in the preweaning phase of a pre- and post-natal development study in rats. No quantifiable setmelanotide concentrations were detected in plasma from nursing pups on post-natal Day 11.

Pediatric Use

The safety and effectiveness of IMCIVREE have been established for chronic weight management in pediatric patients aged 6 years and older with obesity due to:

• POMC, PCSK1, or LEPR deficiency with variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS) [see Clinical Studies ]
• BBS [see Clinical Studies ]

Use of IMCIVREE for these indications is supported by evidence from 2 one-year, open-label studies that included 9 pediatric patients with POMC, PCSK1, or LEPR deficiency, and from one 66-week study, which included a 14-week, randomized, double-blind, placebo-controlled period followed by a 52-week open-label period, and included 22 pediatric patients with BBS [see Clinical Studies ].

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. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (IMCIVREE contains 10 mg of benzyl alcohol) [see Warnings and Precautions ].

Geriatric Use

Clinical studies of IMCIVREE did not include patients aged 65 and over. It is not known whether geriatric patients would respond differently than younger adult patients.

Renal Impairment

Patients with severe renal impairment have a higher exposure of setmelanotide relative to patients with normal kidney function. Reduce the recommended starting and target dosage of IMCIVREE in adults and pediatric patients 12 years of age and older with severe renal impairment (eGFR 15-29 mL/min/1.73 m2). The use of IMCIVREE in pediatric patients 6 to less than 12 years of age with severe renal impairment is not recommended [see Dosage and Administration , Clinical Pharmacology ].

The recommended dosage in patients with mild (eGFR of 60-89 mL/min/1.73 m2) or moderate renal impairment (eGFR of 30-59 mL/min/1.73 m2) is the same as those with normal kidney function [see Clinical Pharmacology ].

IMCIVREE is not recommended for use in patients with end stage renal disease (eGFR less than 15 mL/min/1.73 m2).

 Disturbance in Sexual Arousal

Sexual adverse reactions may occur in patients treated with IMCIVREE. Spontaneous penile erections in males (24%) and sexual adverse reactions in females (7% in IMCIVREE-treated patients and 0% in placebo-treated patients from an unapproved population) occurred in clinical studies with IMCIVREE [see Adverse Reactions ].

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

Some drugs that target the central nervous system, such as IMCIVREE, may cause depression or suicidal ideation. Depression (26%) and suicidal ideation (11%) occurred in adults and pediatric patients in IMCIVREE clinical studies [see Adverse Reactions ]. Patients with a history of depression or suicidal ideation may be at increased risk for recurrent episodes while taking IMCIVREE.

Monitor patients for new onset or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors or if clinically significant or persistent depression symptoms occur.

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, have been reported with IMCIVREE. These reactions generally occurred within minutes to hours after injecting IMCIVREE [see Adverse Reactions ]. If hypersensitivity reactions occur, advise patients to promptly seek medical attention and discontinue use of IMCIVREE. IMCIVREE is contraindicated in patients with a prior serious hypersensitivity reaction to setmelanotide or any of the excipients in IMCIVREE.

Skin Pigmentation and Darkening of Pre-Existing Nevi

Generalized increased skin pigmentation occurred in the majority of patients (69%) treated with IMCIVREE in clinical trials [see Adverse Reactions and Clinical Pharmacology ]. IMCIVREE may also cause darkening of pre-existing nevi due to its pharmacologic effect. This effect is reversible upon discontinuation of the drug.

Perform a full body skin examination prior to initiation and periodically during treatment with IMCIVREE to monitor pre-existing and new skin 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, including IMCIVREE. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (IMCIVREE contains 10 mg of benzyl alcohol per mL) [see Use in Specific Populations ].