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Myalept

Generic Name: Metreleptin
Class: Leptins

Warning(s)

Warning: Risk of anti-metreleptin antibodies with neutralizing activity and risk of lymphoma.

See full prescribing information for complete boxed warning. 1

Anti-metreleptin antibodies with neutralizing activity have been identified in patients treated with metreleptin. The consequences are not well characterized but could include inhibition of endogenous leptin action and loss of metreleptin efficacy. Worsening metabolic control and/or severe infection have been reported. Test for anti-metreleptin antibodies with neutralizing activity in patients with severe infections or loss of efficacy during metreleptin treatment. Contact Aegerion Pharmaceuticals, Inc. at 1-866-216-1526 for neutralizing antibody testing.1

T-cell lymphoma has been reported in patients with acquired generalized lipodystrophy, both treated and not treated with metreleptin. Carefully consider the benefits and risks of treatment with metreleptin in patients with significant hematologic abnormalities and/or acquired generalized lipodystrophy.1

Metreleptin is available only through a restricted program called the Myalept REMS Program.1

REMS:

FDA approved a REMS for metreleptin to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of metreleptin and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Metreleptin is a recombinant human leptin analog.1

Uses for Myalept

Metreleptin has the following uses:

Metreleptin is a leptin analog indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.1

Metreleptin has the following limitations of use:

The safety and effectiveness of metreleptin for the treatment of complications of partial lipodystrophy have not been established.1

The safety and effectiveness of metreleptin for the treatment of liver disease, including nonalcoholic steatohepatitis (NASH), have not been established.1

Metreleptin is not indicated for use in patients with HIV-related lipodystrophy.1

Metreleptin is not indicated for use in patients with metabolic disease, without concurrent evidence of generalized lipodystrophy.1

Myalept Dosage and Administration

General

Metreleptin is available in the following dosage form(s) and strength(s):

Metreleptin is supplied as a sterile, white, solid, lyophilized cake of 11.3 mg metreleptin per vial to deliver 5 mg per mL when reconstituted with 2.2 mL of bacteriostatic water for injection (BWFI) or preservative-free sterile water for injection (WFI).1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Administer as a subcutaneous injection once daily after the lyophilized cake is reconstituted with BWFI or preservative-free sterile WFI.1

The recommended daily dosages are: 1

  • Body weight 40 kg or less: starting dose 0.06 mg/kg/day, increase or decrease by 0.02 mg/kg to a maximum daily dose of 0.13 mg/kg.1

  • Males greater than 40 kg body weight: starting dose 2.5 mg/day, increase or decrease by 1.25 mg to 2.5 mg/day to a maximum dose of 10 mg/day.1

  • Females greater than 40 kg body weight: starting dose 5 mg/day, increase or decrease by 1.25 mg to 2.5 mg/day to a maximum dose of 10 mg/day.1

Cautions for Myalept

Contraindications

  • General obesity not associated with congenital leptin deficiency.1

  • Hypersensitivity to metreleptin.1

Warnings/Precautions

Risk for Development of Antibodies That Neutralize Endogenous Leptin and/or Metreleptin

Anti-metreleptin antibodies with in vitro neutralizing activity to leptin associated with adverse events consistent with loss of endogenous leptin activity and/or loss of efficacy have been identified in two patients with generalized lipodystrophy treated with metreleptin (severe infections, increases in HbA1c and triglycerides), and in three patients without lipodystrophy who received metreleptin in clinical studies (excessive weight gain, development of glucose intolerance or diabetes mellitus). The clinical implications associated with development of anti-metreleptin antibodies with neutralizing activity are not well characterized at this time due to the small number of reports. Test for anti-metreleptin antibodies with neutralizing activity in patients who develop severe infections or show signs suspicious for loss of metreleptin efficacy during treatment. Contact Aegerion Pharmaceuticals, Inc. at 1-866-216-1526 for neutralizing antibody testing of clinical samples.1

Lymphoma

Three cases of T-cell lymphoma have been reported in the metreleptin lipodystrophy program; all three patients had acquired generalized lipodystrophy. Two of these patients were diagnosed with peripheral T-cell lymphoma while receiving metreleptin. Both had immunodeficiency and significant hematologic abnormalities including severe bone marrow abnormalities before the start of metreleptin treatment. A separate case of anaplastic large cell lymphoma was reported in a patient receiving metreleptin who did not have hematological abnormalities before treatment.1

Lymphoproliferative disorders, including lymphomas, have been reported in patients with acquired generalized lipodystrophy not treated with metreleptin. A causal relationship between metreleptin treatment and the development and/or progression of lymphoma has not been established. Acquired lipodystrophies are associated with autoimmune disorders, and autoimmune disorders are associated with an increased risk of malignancies including lymphomas.1

The benefits and risks of metreleptin treatment should be carefully considered in patients with acquired generalized lipodystrophy and/or those with significant hematologic abnormalities (including leukopenia, neutropenia, bone marrow abnormalities, lymphoma, and/or lymphadenopathy).1

REMS Program

Metreleptin is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS), called the Myalept REMS Program, because of the risks associated with the development of anti-metreleptin antibodies that neutralize endogenous leptin and/or metreleptin and the risk for lymphoma.1

Notable requirements of the Myalept REMS Program include the following: 1

  • Prescribers must be certified with the program by enrolling and completing training.1

  • Pharmacies must be certified with the program and only dispense metreleptin after receipt of the Myalept REMS Prescription Authorization Form for each new prescription.1

Further information is available at or 1-855-6MYALEPT.1

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue (e.g., sulfonylurea) may be necessary in some patients to minimize the risk of hypoglycemia. Closely monitor blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulin secretagogue (e.g., sulfonylurea), when treating with metreleptin.1

Autoimmunity

Leptin plays a role in immune system homeostasis. Acquired lipodystrophies are associated with autoimmune disorders including autoimmune hepatitis and membranoproliferative glomerulonephritis. Cases of progression of autoimmune hepatitis and membranoproliferative glomerulonephritis (associated with massive proteinuria and renal failure) were observed in some patients with acquired generalized lipodystrophy treated with metreleptin. A causal relationship between metreleptin treatment and the development and/or progression of autoimmune disease has not been established. The potential benefits and risks of metreleptin treatment should be carefully considered in patients with autoimmune disease. 1

Hypersensitivity

There have been reports of generalized hypersensitivity (e.g., anaphylaxis, urticaria, generalized rash) in patients taking metreleptin. If a hypersensitivity reaction occurs, instruct the patient to promptly seek medical advice regarding discontinuation of metreleptin.1

Benzyl Alcohol Toxicity

Metreleptin contains benzyl alcohol when reconstituted with BWFI. Metreleptin contains no preservative when reconstituted with preservative-free sterile WFI. Preservative-free sterile WFI is recommended for use in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients, particularly in neonates and premature infants. 1

Specific Populations

Pregnancy

Pregnancy Category C. 1

There is a program that monitors outcomes in women exposed to metreleptin during pregnancy. Women who become pregnant during metreleptin treatment are encouraged to enroll. Patients or their physicians should call 1-855-6MYALEPT to enroll.1

There are no adequate and well-controlled studies of metreleptin in pregnant women. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations and 15% to 20% for pregnancy loss. In a pre- and postnatal development study in mice, administration of metreleptin caused prolonged gestation and dystocia resulting in maternal death during parturition and lower survival of offspring in the immediate postnatal period at doses starting approximately at the maximum recommended clinical dose. Because animal reproduction studies are not always predictive of human response, metreleptin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1

The contribution of metreleptin to obstetrical risks and complications is unknown compared with those already documented in the lipodystrophy patient population (e.g., gestational diabetes, macrosomia, eclampsia, intrauterine growth retardation, intrauterine death, and miscarriage).1

The effects of metreleptin on labor and delivery in pregnant women are unknown. In an in vitro study of human myometrial tissue exposed to a recombinant leptin, human uterine contractility was inhibited. Furthermore, prolonged gestation and dystocia were observed in animal studies with metreleptin.1

Metreleptin administered to pregnant mice during the period of organogenesis was not teratogenic at doses ranging between 7- and 15-fold the maximum recommended clinical dose, based on body surface area of a 20- and 60-kg patient, respectively.1 In a pre- and postnatal development study in mice, metreleptin administered at doses of 3, 10, and 30 mg/kg (approximately 1-, 5-, and 15-fold the clinical dose for a 60-kg subject, based on body surface area) from gestation day 6 to lactation day 21 caused prolonged gestation and dystocia at all doses, starting at approximately the maximum recommended clinical dose. Prolonged gestation resulted in the death of some females during parturition and lower survival of offspring within the immediate postnatal period. Consistent with metreleptin pharmacology, decreased maternal body weight was observed from gestation throughout lactation at all doses and resulted in reduced weight of offspring at birth, which persisted into adulthood. However, no developmental abnormalities were observed and reproductive performance of the first or second generations was not affected at any dose.1 Placental transfer of metreleptin into the fetus was low (approximately 1%) following subcutaneous dosing.1

Nursing Mothers

It is not known if metreleptin is present in human milk. Endogenous leptin is present in human milk. Because of the potential for serious adverse reactions (including possible adverse reactions related to passage of anti-metreleptin antibodies) in nursing infants from metreleptin a decision should be made whether to discontinue nursing or discontinue the drug, taking into account importance of drug to the mother.1

Pediatric Use

The metreleptin study included a total of 35 pediatric patients (73%) with an age range from 1 to 17 years. No clinically meaningful differences were observed in the efficacy and safety of metreleptin between pediatric and adult patients.1

Metreleptin contains benzyl alcohol when reconstituted with BWFI. Metreleptin contains no preservative when reconstituted with preservative-free sterile WFI. Preservative-free sterile WFI is recommended for use in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome" (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.1

Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome," the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. When reconstituted with 2.2 mL of BWFI, metreleptin contains 1.76 mg of benzyl alcohol per mg of metreleptin or 9 mg of benzyl alcohol per mL of reconstituted product. 1

Geriatric Use

Clinical trials of metreleptin did not include sufficient numbers of subjects aged 65 and over (n=1) to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.1

Common Adverse Effects

Most common in clinical trials (≥10%): headache, hypoglycemia, decreased weight, abdominal pain.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Adipocytes store lipids to meet the fuel requirements of non-adipose tissues during fasting. In patients with generalized lipodystrophy, the deficiency of adipose tissue leads to hypertriglyceridemia and ectopic deposition of fat in non-adipose tissues such as liver and muscle, contributing to metabolic abnormalities including insulin resistance. Native leptin is a hormone predominantly secreted by adipose tissue that informs the central nervous system of the status of energy stores in the body. In patients with generalized lipodystrophy, leptin deficiency, resulting from the loss of adipose tissue, contributes to excess caloric intake, which exacerbates the metabolic abnormalities.1

Metreleptin for injection exerts its function by binding to and activating the human leptin receptor (ObR), which belongs to the Class I cytokine family of receptors that signals through the JAK/STAT transduction pathway.1

Advice to Patients

Patient Counseling Information

See FDA-approved Patient Labeling.1

Advise patients that neutralizing antibodies may result in loss in activity of endogenous leptin or loss of efficacy of metreleptin. Advise patients on symptoms or signs that would warrant antibody testing.1

Advise patients that lymphoma has been reported in patients both treated and not treated with metreleptin. Advise patients on symptoms or signs that indicate changes in hematologic status and the importance of routine laboratory assessments and physician monitoring.1

Advise patients that the risk of hypoglycemia is increased when metreleptin is used in combination with insulin or an insulin secretagogue (e.g., sulfonylurea). Explain the symptoms, treatment, and conditions that predispose to development of hypoglycemia to the patient. Advise patients who are taking concomitant insulin, especially those on high doses, or an insulin secretagogue, to closely monitor blood glucose. Hypoglycemia management should be reviewed and reinforced when initiating metreleptin therapy, particularly when concomitantly administered with insulin or an insulin secretagogue.1

Advise patients that worsening of autoimmune disease has been reported during the clinical study of metreleptin. Advise patients with a history of autoimmune disease on symptoms or signs that indicate exacerbation of underlying autoimmune disease and the importance of routine laboratory assessments and physician monitoring.1

Inform patients that hypersensitivity reactions have been reported during use of metreleptin. If symptoms of hypersensitivity reactions occur, patients should seek medical advice.1

Advise nursing mothers that breastfeeding is not recommended with metreleptin use.1

Instructions

Inform patients that each vial of metreleptin requires reconstitution with BWFI or preservative-free sterile WFI, and administration as subcutaneous injection using a syringe and needle. Injections can be given at any time of the day, with or without meals.1

Patients and caregivers should receive proper training in how to prepare and administer the correct dose of metreleptin prior to self-administration. The first dose of metreleptin should be administered by the patient or caregiver under the supervision of a qualified healthcare professional.1

Advise patients on injection technique, dosing regimen, and the importance of proper storage of metreleptin. Care should be taken to avoid intramuscular injection, especially in patients with minimal subcutaneous adipose tissue.1

Advise patients to read the instructions for use for complete administration instructions. The metreleptin medication guide and instructions for use should be reviewed before starting therapy and each time the prescription is refilled.1

When discontinuing metreleptin in patients with a history of pancreatitis and/or severe hypertriglyceridemia, instruct patients to taper their dose over a one-week period. Advise patients that additional monitoring of triglyceride levels and possible initiation or dose adjustment of lipid-lowering medications may be considered.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Metreleptin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Powder, Lyophilized, For Solution

11.3 mg

Myalept

Aegerion Pharmaceuticals Inc.

AHFS Drug Information. © Copyright 2016, Selected Revisions September 1, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Aegerion Pharmaceuticals, Inc. Myalept (metreleptin) SUBCUTANEOUS prescribing information. 2015 Sept.

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