Melanocortin 4 Receptor Agonist

Imcivree

Approved 25 Nov 2020SubcutaneousSolution

Indications

IMCIVREE is indicated to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged [ see Dosage and Administration (2.1) ]: 4 years and older with acquired hypothalamic obesity (HO) 2 years and older with syndromic or monogenic obesity due to: o Bardet-Biedl syndrome (BBS) o Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS).

IMCIVREE is a melanocortin 4 (MC4) receptor agonist indicated to reduce excess body weight and maintain reduction long term in adults and pediatric patients aged (1): 4 years and older with acquired hypothalamic obsesity (HO). 2 years and older with Bardet-Biedl syndrome (BBS). 2 years and older with pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by an genetic test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS).

Limitations of Use: IMCIVREE is not indicated for the treatment of patients with the following conditions as IMCIVREE would not be expected to be effective: Obesity due to suspected POMC, PCSK1, or LEPR-deficiency with POMC , PCSK1 , or LEPR variants classified as benign or likely benign. ( 1 ) Other types of obesity not related to acquired HO, BBS or POMC, PCSK1 or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity.

( 1 )

1.1Limitations of Use:

IMCIVREE is not indicated for the treatment of patients with the following conditions as IMCIVREE would not be expected to be effective:

Obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign.
Other types of obesity not related to acquired HO, BBS, or POMC, PCSK1, or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity

Contraindications

Indications

( 1 )

1.1Limitations of Use:

IMCIVREE is not indicated for the treatment of patients with the following conditions as IMCIVREE would not be expected to be effective:

Obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign.
Other types of obesity not related to acquired HO, BBS, or POMC, PCSK1, or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity

Warnings and precautions

Disturbance in Sexual Arousal: Spontaneous penile erections in males and sexual adverse reactions in females have occurred. Inform patients that these events may occur and instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention. ( 5.1 ) Depression and Suicidal Ideation: Depression and suicidal ideation have occurred. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors.

Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors, or clinically significant or persistent depression symptoms occur. ( 5.2 ) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. If suspected, advise patients to promptly seek medical attention and discontinue IMCIVREE. ( 5.3 ). Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and Development of New Melanocytic Nevi: Generalized increased skin pigmentation, darkening of pre-existing nevi, and development of new nevi have occurred.

Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new pigmentary lesions. ( 5.4 ) Acute Adrenal Insufficiency in Patients with Acquired HO : Monitor patients for signs of acute adrenal insufficiency. ( 5.5 ) Sodium Imbalance in Patients with Acquired HO and Central Diabetes Insipidus : Monitor patients for signs and symptoms of hyponatremia and hypernatremia.

(5.6)

5.1Disturbance in Sexual Arousal

Sexual adverse reactions may occur in patients treated with IMCIVREE. Spontaneous penile erections and increased frequency of penile erections in males occurred in clinical trials with IMCIVREE [see Adverse Reactions (6.1)]. Inform patients that these events may occur and instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention.

5.2Depression and Suicidal Ideation

Some drugs that target the central nervous system, such as IMCIVREE, may cause depression or suicidal ideation [see Adverse Reactions (6.1) ]. 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.

5.3Hypersensitivity 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 ( 6.2 )]. 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.

5.4Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and Development of New Melanocytic Nevi Generalized

or focal increases in skin pigmentation occurred in the majority of IMCIVREE-treated patients in clinical trials [ see Adverse Reactions (6.1) and Clinical Pharmacology (12.1) ]. This effect is reversible upon discontinuation of the drug. IMCIVREE may also cause the development of new melanocytic nevi or darkening of pre-existing nevi due to its pharmacologic effect. Perform a full body skin examination prior to initiation and periodically during treatment with IMCIVREE to monitor pre-existing and new skin pigmented lesions.

5.5 Acute Adrenal Insufficiency in Patients with Acquired HO In a clinical trial of adults and pediatric patients aged 4 years and older with acquired HO and secondary adrenal insufficiency, serious adverse reactions related to acute adrenal insufficiency were reported by 5% of IMCIVREE-treated patients and no placebo-treated patients. In patients with secondary adrenal insufficiency, monitor for clinical signs of acute adrenal insufficiency.

5.6 Sodium Imbalance in Patients with Acquired HO and Central Diabetes Insipidus In a clinical trial of adults and pediatric patients aged 4 years and older with acquired HO and concomitant central diabetes insipidus (DI)/arginine vasopressin (AVP) deficiency, hyponatremia was reported in 6% of IMCIVREE-treated patients and 2% of placebo-treated patients, and hypernatremia was reported in 5% of IMCIVREE-treated patients and 4% of placebo-treated patients.

In patients with acquired HO and concomitant DI/AVP deficiency, monitor serum sodium levels with changes in fluid intake and hydration status. Adjust the doses of concomitant therapies for DI/AVP deficiency as needed.

Pregnancy and breastfeeding

8.1Pregnancy 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. 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 Risk 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 until 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.

Adverse reactions

The following clinically significant adverse reactions are described elsewhere in the labeling: Disturbance in Sexual Arousal [see Warnings and Precautions (5.1)] Depression and Suicidal Ideation [see Warnings and Precautions (5.2)] Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and Development of New Melanocytic Nevi [see Warnings and Precautions (5.4)] Acute Adrenal Insufficiency in Patients with Acquired HO [ see Warnings and Precautions (5.5) ] Sodium Imbalance in Patients with Acquired HO and Central Diabetes Insipidus [ see Warnings and Precautions (5.6) ] Most common adverse reactions (incidence ≥20% in at least 1 indication) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at 1-833-789-6337 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Acquired HO (Adults and Pediatric Patients Aged 4 Years and Older) The safety of IMCIVREE was evaluated in a randomized, double-blind, placebo-controlled clinical trial which included a dose titration period of 4 to 8 weeks and a 52-week treatment period, in 142 patients aged 4 years and older with acquired HO (Trial 1) [see Clinical Studies (14.1)] .

The trial duration was 56 to 60 weeks. Table 5 summarizes the adverse reactions that occurred in 5% or more of the IMCIVREE-treated patients and more frequently than placebo-treated patients in Trial 1. Other Adverse Reactions in Patients Aged 4 Years and Older with Acquired HO Disturbance in Sexual Arousal Spontaneous penile erections and increased frequency of penile erections were reported in 7% of IMCIVREE-treated patients and 4% of placebo-treated patients.

Acute Adrenal Insufficiency Serious adverse reactions related to acute adrenal insufficiency were reported by 5% of IMCIVREE-treated patients and no placebo-treated patients. Sodium Imbalance Among patients with acquired HO and concomitant central diabetes insipidus (DI)/arginine vasopressin (AVP) deficiency, hyponatremia was reported in 6% of IMCIVREE-treated patients and 2% of placebo-treated patients, and hypernatremia was reported in 5% of IMCIVREE-treated patients and 4% of placebo-treated patients.

Bardet-Biedl Syndrome (Adults and Pediatric Patients Aged 6 Years and Older) The safety of IMCIVREE was evaluated in a clinical trial, which included a 14‑week, randomized, double-blind, placebo-controlled period followed by a 52-week open-label treatment period, in 44 patients aged 6 years and older with obesity and a clinical diagnosis of BBS (Trial 2) [see Clinical Studies (14.2)] . The trial duration was 66 weeks.

During the 14-week placebo-controlled period in Trial 2, the most common reported adverse reactions in IMCIVREE-treated patients when compared to placebo-treated patients were hyperpigmentation disorders (67% vs 0%, respectively) and vomiting (11% vs 0%, respectively). Adverse reactions were also evaluated during the 52-week active-treatment period, defined as the period from randomization to Week 52 in patients initially randomized to IMCIVREE, and from Week 14 to Week 66 in patients initially randomized to placebo.

Table 6 summarizes the adverse reactions that occurred in 2 or more IMCIVREE-treated patients in Trial 2 during the 52-week active treatment period. POMC, PCSK1, and LEPR Deficiency (Adults and Pediatric Patients Aged 6 Years and Older) The safety of IMCIVREE was evaluated in two 52-week, open-label clinical trials of 27 patients aged 6 years and older with obesity due to POMC, PCSK1, or LEPR deficiency with POMC , PCSK1 , or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (Trial 3 and Trial 4) [see Clinical Studies (14.3)] .

Table 7 summarizes the adverse reactions that occurred in the open-label trials during the first 52 weeks of treatment in 3 or more patients treated with IMCIVREE. POMC, PCSK1, and LEPR Deficiency and BBS (Pediatric Patients Aged 2 to less than 6 Years) The safety of IMCIVREE was evaluated in one 52-week, open-label clinical trial of 12 patients aged 2 to less than 6 years with obesity due to POMC, PCSK1, or LEPR deficiency with POMC , PCSK1 , or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance, or obesity due to BBS (Trial 5) [see Clinical Studies (14.4)] .

No patients with PCSK1 were enrolled in the trial. Table 8 summarizes the adverse reactions that occurred in the open-label trial during 52 weeks of treatment in 3 or more patients treated with IMCIVREE. Other Adverse Reactions in Patients Aged 2 to less than 6 Years with Obesity due to POMC or LEPR Deficiency or BBS Disturbance in Sexual Arousal Spontaneous penile erections were reported in 8% of IMCIVREE-treated patients.

Depression Depressed mood was reported in 8% of IMCIVREE-treated patients image description image description image description image description

6.2Postmarketing Experience

The following adverse reactions have been identified during post-approval use of IMCIVREE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity, including anaphylaxis

Imcivree

Indications

1.1Limitations of Use:

Contraindications

Two medicines in one question?

Imcivree

Indications

1.1Limitations of Use:

Contraindications

Two medicines in one question?

Warnings and precautions

5.1Disturbance in Sexual Arousal

5.2Depression and Suicidal Ideation

5.3Hypersensitivity Reactions

5.4Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and Development of New Melanocytic Nevi Generalized

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Discontinue

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Official product information

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