Metreleptin (Monograph)

Brand name: Myalept
Drug class: Leptins
Chemical name: N-Methionyl-leptin (human)
Molecular formula: C₇₁₄H₁₁₆₇N₁₉₁O₂₂₁S₆
CAS number: 186018-45-1

Medically reviewed by Drugs.com on Jan 12, 2024. Written by ASHP.

Warning

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for metreleptin to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of metreleptin and consists of the following: communication plan, elements to assure safe use and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/.

Warning

Distribution of metreleptin is restricted. (See REMS under Dosage and Administration.)

Anti-metreleptin antibodies with neutralizing activity identified.
Clinical implications of neutralizing antibodies unknown but may include loss of metreleptin efficacy and/or loss of endogenous leptin activity.
Test for anti-metreleptin antibodies with neutralizing activity in patients who develop severe infections or who show signs suggesting loss of metreleptin efficacy during therapy; contact manufacturer at 866-216-1526 for neutralizing antibody testing of clinical samples. (See Antibody Formation under Cautions and also see Advice to Patients.)

T-cell lymphoma reported in a few patients with acquired generalized lipodystrophy; causal relationship not established.

Consider potential risk and benefit of metreleptin therapy in patients with acquired generalized lipodystrophy and/or serious hematologic abnormalities.

Introduction

Recombinant analog of human leptin.

Uses for Metreleptin

Generalized Lipodystrophy

Replacement therapy as an adjunct to diet for treatment of complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy; designated an orphan drug by FDA for treatment of metabolic disorders secondary to lipodystrophy.

Metreleptin therapy associated with reductions in glycosylated hemoglobin (HbA_1c), fasting glucose, and fasting triglyceride concentrations in patients with generalized lipodystrophy.

Manufacturer states that drug not indicated for use in patients with HIV-related lipodystrophy.

Manufacturer also states that drug not indicated for use in patients with general obesity or metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of congenital or acquired generalized lipodystrophy. (See Contraindications under Cautions.)

Efficacy and safety not established for the treatment of complications of partial lipodystrophy.

Efficacy and safety not established for treatment of liver disease, including nonalcoholic steatohepatitis (NASH).

Metreleptin Dosage and Administration

General

May need to reduce dosage of drugs known to cause hypoglycemia (e.g., insulin or insulin secretagogues, including sulfonylureas). Monitor blood glucose closely in patients receiving concomitant insulin or insulin secretagogues. (See Hypoglycemia with Concomitant use of Insulin or Insulin Secretagogues under Cautions.)
Reduce metreleptin dosage gradually over a one-week period when discontinuing metreleptin in patients with risk factors for pancreatitis. Measure serum triglycerides and monitor for pancreatitis during dosage tapering; may need to initiate or adjust dosage of antilipemic agents.

REMS

Available only through the Myalept REMS program.
Clinicians must enroll in the program and complete training before prescribing metreleptin.
Clinicians must complete a prescription authorization form for each new metreleptin prescription and submit it to the REMS program for certification.
Only certified pharmacies may dispense metreleptin after receipt of the completed prescription authorization form from the REMS program.
Additional information available at [Web] or at 855-6MYALEPT (855-669-2537).

Administration

Administer by sub-Q injection; do not administer IV or IM.

Patient may self-administer drug after instruction by healthcare provider; patient should self-administer first dose under supervision of healthcare provider.

Sub-Q Administration

Administer once daily at the same time each day, without regard to meals.

Inject sub-Q into abdomen, thigh, or upper arm. May use the same area of the body for daily injections; however, rotate injection sites with each dose.

Do not inject into the same site with other medications; do not mix with insulin in the same syringe or vial.

Doses exceeding 1 mL can be administered as 2 injections.

If a dose is missed, administer the missed dose as soon as it is remembered and resume regular schedule the next day. Do not administer 2 doses on same day or increase dose to replace missed dose.

Reconstitution

10–15 minutes before use, remove vial from refrigerator and allow to reach room temperature; do not leave vial at room temperature longer than 4 hours.

Reconstitute vial containing 11.3 mg of metreleptin with 2.2 mL of bacteriostatic water for injection or preservative-free sterile water for injection to provide a solution containing 5 mg/mL of metreleptin. Mix gently; do not shake. For neonates and infants, reconstitute with preservative-free sterile water for injection. (See Pediatric Use under Cautions.)

When reconstituted with bacteriostatic water for injection and then stored at 2–8°C and protected from light, solution may be used for multiple doses within 3 days of reconstitution.

When reconstituted with preservative-free sterile water for injection, administer immediately upon reconstitution and discard any unused solution.

Consult manufacturer-provided patient instructions for use for complete information on storage, reconstitution, and administration.

Dosage

Individualize dosage based on clinical response and tolerability. Dosage is based on weight and/or gender. For male and female patients weighing ≤40 kg at baseline, dosage is based on weight; for patients weighing ≥40 kg at baseline, dosage is based on gender. (See Table 1.)

Pediatric Patients

Generalized Lipodystrophy

Sub-Q

Dosage is based on weight and/or gender. (See Table 1.)

Adults

Generalized Lipodystrophy

Sub-Q

Dosage is based on weight and/or gender. (See Table 1.)

Table 1. Metreleptin Recommended Dosage.1
Baseline Body Weight	Initial Daily Dosage (Injection Volume)	Dosage Adjustments (Injection Volume)	Maximum Daily Dosage (Injection Volume)
≤40 kg (males and females)	0.06 mg/kg (0.012 mL/kg)	0.02 mg/kg (0.004 mL/kg)	0.13 mg/kg (0.026 mL/kg)
Males >40 kg	2.5 mg (0.5 mL)	1.25–2.5 mg (0.25–0.5 mL)	10 mg (2 mL)
Females >40 kg	5 mg (1 mL)	1.25–2.5 mg (0.25–0.5 mL)	10 mg (2 mL)

Prescribing Limits

Pediatric Patients

Generalized Lipodystrophy

Sub-Q

Weight ≤40 kg: 0.13 mg/kg (0.026 mL/kg) daily.

Weight >40 kg: 10 mg (2 mL) daily.

Adults

Generalized Lipodystrophy

Sub-Q

Weight ≤40 kg: 0.13 mg/kg (0.026 mL/kg) daily.

Weight >40 kg: 10 mg (2 mL) daily.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Metreleptin

Contraindications

General obesity not associated with congenital leptin deficiency. (See Antibody Formation under Cautions.)
Hypersensitivity to metreleptin or any ingredient in the formulation

Warnings/Precautions

Warnings

Antibody Formation

Risk of developing anti-metreleptin antibodies with neutralizing activity. Clinical implications not known but such antibodies may lead to loss of metreleptin efficacy and/or loss of endogenous leptin activity.

Test for anti-metreleptin antibodies with neutralizing activity in patients who develop severe infections or loss of metreleptin efficacy. Contact manufacturer at 866-216-1526 for information about neutralizing antibody testing.

Lymphoma

T-cell lymphoma reported in patients with acquired generalized lipodystrophy with or without metreleptin therapy. Causal relationship between metreleptin therapy and the development or progression of lymphoma not established. Acquired lipodystrophies are associated with autoimmune disorders, which are associated with an increased risk of malignancies, including lymphoma.

Carefully consider potential risks and benefits of metreleptin therapy in patients with acquired generalized lipodystrophy and/or serious hematologic abnormalities (including leukopenia, neutropenia, bone marrow abnormalities, lymphoma, and/or lymphadenopathy).

Sensitivity Reactions

Anaphylaxis, urticaria, generalized rash reported. (See Contraindications under Cautions.)

Other Warnings and Precautions

Hypoglycemia with Concomitant use of Insulin or Insulin Secretagogues

Increased risk of hypoglycemia in patients receiving concomitant insulin or insulin secretagogues (e.g., sulfonylureas). Monitor blood glucose closely in patients receiving concomitant insulin therapy, especially in patients taking high dosages, or in those taking insulin secretagogues. Adjust dosage of insulin or insulin secretagogue as necessary; large dosage reductions may be required.

Autoimmunity

Acquired lipodystrophies are associated with autoimmune disorders, including autoimmune hepatitis and membranoproliferative glomerulonephritis. Progression of autoimmune hepatitis and membranoproliferative glomerulonephritis (associated with massive proteinuria and renal failure) reported in some patients with acquired generalized lipodystrophy treated with metreleptin. A causal relationship between metreleptin therapy and the development and/or progression of autoimmune diseases has not been established; however, carefully consider potential risk in patients with autoimmune disease.

Benzyl Alcohol Toxicity

Contains benzyl alcohol when reconstituted with bacteriostatic water for injection. Benzyl alcohol has been associated with serious adverse events and death in pediatric patients, particularly in neonates and premature infants. When prepared for use in neonates and infants, manufacturer recommends reconstitution with preservative-free sterile water for injection. (See Pediatric Use under Cautions and also see Reconstitution under Dosage and Administration.)

Immunogenicity

Potential for immunogenicity. Anti-metreleptin antibodies reported in 84% of patients in generalized lipodystrophy clinical trials. (See Antibody Formation under Cautions.)

Specific Populations

Pregnancy

Category C.

Pregnancy registry at 855-6MYALEPT (855-669-2537).

Lactation

Not known whether metreleptin distributed into human milk; endogenous leptin distributes into milk. Discontinue nursing or the drug.

Pediatric Use

Most patients in principal clinical trial were 1–17 years of age. No overall differences in safety or efficacy relative to adults.

When reconstituted with 2.2 mL of bacteriostatic water for injection, contains 1.76 mg of benzyl alcohol per mg of metreleptin or 9 mg of benzyl alcohol per mL of reconstituted solution. Large amounts (i.e., 100–400 mg/kg daily) of benzyl alcohol associated with toxicity in neonates and low-birth-weight infants. The manufacturer states that usual therapeutic doses of metreleptin deliver substantially lower amounts of benzyl alcohol than those associated with toxicity; however, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Consider the combined daily dose of benzyl alcohol from all sources.

When prepared for use in neonates and infants, reconstitute with preservative-free sterile water for injection. (See Reconstitution under Dosage and Administration.)

Geriatric Use

Insufficient numbers of patients ≥65 years of age to evaluate response relative to younger adults; generally, initiate therapy at lower end of dosage range.

Hepatic Impairment

Efficacy and safety not established in patients with hepatic impairment.

Renal Impairment

Efficacy and safety not established in patients with renal impairment. Renal clearance is the major route of elimination; pharmacokinetics may be altered in renal impairment.

Common Adverse Effects

Headache, hypoglycemia, decreased weight, abdominal pain, arthralgia, dizziness, ear infection, fatigue, nausea, ovarian cyst, upper respiratory tract infection, anemia, back pain, diarrhea, paresthesia, proteinuria, pyrexia.

Drug Interactions

No formal drug interaction studies to date.

Metreleptin Pharmacokinetics

Absorption

Bioavailability

Patients with lipodystrophy: peak plasma concentrations achieved in approximately 4 hours.

Distribution

Extent

Endogenous leptin crosses the blood-brain barrier.

Not known whether distributed into milk; endogenous leptin is distributed into milk.

Elimination

Metabolism

None apparent; formal pharmacokinetic studies lacking.

Elimination Route

Renal excretion.

Half-life

Healthy individuals: 3.8–4.7 hours.

Stability

Storage

Parenteral

Powder for Injection

2–8°C; do not freeze. Store in original carton, protect from light before use. Do not leave at room temperature for more than 4 hours.

Reconstituted Solution

Reconstitution with bacteriostatic water for injection: 2–8°C for up to 3 days; room temperature for up to 4 hours. Protect from light; do not freeze.

Reconstitution with preservative-free water for injection: Use immediately; discard any unused solution.

Actions

Recombinant analog of human leptin; replaces deficient leptin in patients with generalized lipodystrophy.
Binds to and activates leptin receptors; increases insulin sensitivity, improves lipid metabolism, and reduces caloric intake in patients with leptin deficiency.

Advice to Patients

Importance of reading the manufacturer’s medication guide and patient instructions for use before beginning metreleptin therapy and each time the prescription is refilled.
If a dose is missed, administer the missed dose as soon as it is remembered, then resume the regular schedule the next day. Do not exceed the regular daily dose; do not double or increase the dose to replace a missed dose.
Risk of loss of endogenous leptin activity and/or metreleptin efficacy due to neutralizing antibodies. Importance of promptly informing clinician of symptoms that warrant antibody testing (e.g., infection, increased blood glucose or triglycerides).
Possible increased risk of lymphoma. Importance of routine laboratory assessments and monitoring for signs and symptoms that indicate changes in hematologic status.
Increased risk of hypoglycemia in patients taking concomitant insulin and/or insulin secretagogues (e.g., sulfonylureas). Importance of reviewing signs and symptoms of hypoglycemia. Adjustment of insulin and/or insulin secretagogue dosages may be required.
Importance of informing patients that worsening of autoimmune disease has been reported with metreleptin. Importance of routine monitoring of patients with autoimmune disease to detect symptoms that may warrant additional tests.
Importance of informing patients that hypersensitivity reactions (e.g., anaphylaxis, urticaria, generalized rash) have been reported with metreleptin. Importance of informing clinician if hypersensitivity reactions occur.
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed. Encourage women who become pregnant during metreleptin therapy to enroll in the pregnancy monitoring program by calling 855-6MYALEPT (855-669-2537).
Importance of clinicians instructing patients on how to prepare and administer the correct dosage of metreleptin prior to allowing patient self-administration. Patient or caregiver should administer first dose under a clinician's supervision.
Importance of reviewing proper injection technique, dosing regimen, and proper storage of metreleptin; take care to avoid IM injection, especially in patients with minimal sub-Q adipose tissue.
Importance of informing patients with a history of pancreatitis and/or severe hypertriglyceridemia that metreleptin should not be stopped suddenly. When discontinuing metreleptin in patients at risk for pancreatitis, taper the dosage gradually over 1 week. May require additional monitoring of triglyceride concentrations and/or initiation or dose adjustment of lipid-lowering medications.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)

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.