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metreleptin (Myalept)

 

Classes: Leptin Analogs

Dosing and uses of Myalept (metreleptin)

 

Adult dosage forms and strengths

lyophylized powder for reconstitution

  • 11.3mg (5mg/mL when reconstituted with 2.2 mL water for injection)

 

Lipodystrophy

Indicated as replacement therapy (in addition to diet) for the complications of leptin deficiency in patients with congenital generalized or acquired generalized lipodystrophy

Administer by SC injection once daily at the same time each day

≤40 kg (males or females)

  • Initial daily dose: 0.06 mg/kg (0.012 mL/kg) SC
  • Dose adjustments: 0.02 mg/kg (0.004 mL/kg)
  • Maximum daily dose: 0.13 mg/kg (0.026 mL/kg)

Males >40 kg

  • Initial daily dose: 2.5 mg (0.5 mL) SC
  • Dose adjustments: 1.25-2.5 mg (0.25-0.5 mL)
  • Maximum daily dose: 10 mg (2 mL)

Females >40 kg

  • Initial daily dose: 5 mg (1 mL) SC
  • Dose adjustments: 1.25-2.5 mg (0.25-0.5 mL)
  • Maximum daily dose: 10 mg (2 mL)

 

Dosage modifications

Coadministration with insulin or insulin secretagogue (eg, sulfonylurea, meglitinide derivatives): Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue may be necessary in some patients to minimize the risk of hypoglycemia

 

Dosing Considerations

Safety and efficacy not established for

  • Treatment of complications of partial lipodystrophy
  • Treatment of liver disease, including nonalcoholic steatohepatitis (NASH)
  • HIV-related lipodystrophy
  • Use in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of generalized lipodystrophy

Discontinuing due to pancreatitis risk

  • When discontinuing therapy in patients with risk factors for pancreatitis (eg, history of pancreatitis, severe hypertriglyceridemia), taper the dose over a 1-week period
  • During tapering, monitor triglyceride levels and consider initiating or adjusting the dose of lipid-lowering medications as needed
  • Signs and/or symptoms consistent with pancreatitis should prompt an appropriate clinical evaluation

 

Pediatric dosage forms and strengths

lyophylized powder for reconstitution

  • 11.3mg (5mg/mL when reconstituted with 2.2 mL water for injection)

 

Lipodystrophy

Indicated as replacement therapy (in addition to diet) for the complications of leptin deficiency in patients with congenital generalized or acquired generalized lipodystrophy

Administer by SC injection once daily at the same time each day

≤40 kg (males or females)

  • Initial daily dose: 0.06 mg/kg (0.012 mL/kg) SC
  • Dose adjustments: 0.02 mg/kg (0.004 mL/kg)
  • Maximum daily dose: 0.13 mg/kg (0.026 mL/kg)

Males >40 kg

  • Initial daily dose: 2.5 mg (0.5 mL) SC
  • Dose adjustments: 1.25-2.5 mg (0.25-0.5 mL)
  • Maximum daily dose: 10 mg (2 mL)

Females >40 kg

  • Initial daily dose: 5 mg (1 mL) SC
  • Dose adjustments: 1.25-2.5 mg (0.25-0.5 mL)
  • Maximum daily dose: 10 mg (2 mL)

 

Dosage modifications

Coadministration with insulin or insulin secretagogue (eg, sulfonylurea, meglitinide derivatives): Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue may be necessary in some patients to minimize the risk of hypoglycemia

 

Dosing Considerations

Safety and efficacy not established for

  • Treatment of complications of partial lipodystrophy
  • Treatment of liver disease, including nonalcoholic steatohepatitis (NASH)
  • HIV-related lipodystrophy
  • Use in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of generalized lipodystrophy

Discontinuing due to pancreatitis risk

  • When discontinuing therapy in patients with risk factors for pancreatitis (eg, history of pancreatitis, severe hypertriglyceridemia), taper the dose over a 1-week period
  • During tapering, monitor triglyceride levels and consider initiating or adjusting the dose of lipid-lowering medications as needed
  • Signs and/or symptoms consistent with pancreatitis should prompt an appropriate clinical evaluation

 

Myalept (metreleptin) adverse (side) effects

>10%

Headache (13%)

Hypoglycemia (13%)

Decreased weight (13%)

 

1-10%

Abdominal pain (10%)

Arthralgia (8%)

Dizziness (8%)

Ear infection (8%)

Fatigue (8%)

Nausea (8%)

Ovarian cyst (8%)

Upper respiratory tract infection (8%)

Anemia (6%)

Back pain (6%)

Diarrhea (6%)

Paresthesia (6%)

Proteinuria (6%)

Pyrexia (6%)

Antibodies with neutralizing activity (6%)

Injection site erythema and urticaria (4%)

 

Warnings

Black box warnings

Neutralizing antibodies

  • Antimetreleptin antibodies with neutralizing activity have been identified in patients treated with metreleptin
  • The consequences of these neutralizing antibodies are not well characterized but could include inhibition of endogenous leptin action and/or loss of efficacy
  • Severe infection and/or worsening metabolic control reported
  • Test for antimetreleptin antibodies with neutralizing activity in patients who develop severe infections or show signs suspicious for loss of efficacy during treatment

Lymphoma

  • 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 in patients with significant hematologic abnormalities and/or acquired generalized lipodystrophy

Myalept Risk Evaluation and Mitigation Strategy (REMS) Program

  • Because of the risk for autoantibodies and lymphoma, prescribers must be certified with the Myalept REMS Program by enrolling in and completing training
  • Pharmacies must be certified with the program and only dispense metreleptin after receipt of the REMS prescription authorization form for each new prescription

 

Contraindications

Hypersensitivity, including urticaria and generalized rash

General obesity not associated with congenital leptin deficiency; has not been shown to be effective in treating general obesity, and the development of antimetreleptin antibodies with neutralizing activity has been reported in obese patients treated with metreleptin

 

Cautions

For SC injection only; instruct patients and caregivers on the proper SC injection technique (see Administration)

Neutralizing antibody activity to leptin and/or metreleptin may develop, which could result in severe infections or loss of treatment effectiveness (see Black box warnings)

T-cell lymphoma reported in patients with acquired generalized lipodystrophy, both treated and not treated with metreleptin (see Black box warnings)

Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue (eg, sulfonylurea, meglitinide derivatives) may be necessary in some patients to minimize the risk of hypoglycemia (see Dosage modifications)

Hypersensitivity reported; promptly discontinue if hypersensitivity occurs

Benzoyl alcohoL

  • Contains benzyl alcohol when reconstituted with bacteriostatic water for injection
  • Reconstitute with preservative-free water for injection when used in neonates and infants
  • Benzoyl alcohol doses >99 mg/kg/day in neonates and low-birth-weight infants is associated with gasping syndrome
  • Gasping syndrome is characterized by CNS depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine

Autoimmunity

  • Leptin plays a role in immune system homeostasis
  • Acquired lipodystrophies are associated with autoimmune disorders (eg, autoimmune hepatitis, 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

 

Pregnancy and lactation

Pregnancy category: C

Women who become pregnant during treatment are encouraged to enroll in an outcomes monitoring; patients or their physicians should call 1-855-6MYALEPT to enrolL

Lactation: Unknown if distributed in human breast milk; endogenous leptin is present in human milk

Because of the potential for serious adverse reactions (including possible adverse reactions related to passage of antimetreleptin antibodies) in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Myalept (metreleptin)

Mechanism of action

Recombinant analog of the human hormone leptin; binds to and activates the human leptin receptor (ObR), which belongs to the class I cytokine family of receptors that signals through the JAK/STAT transduction pathway

Deficiency of adipose tissue leads to hypertriglyceridemia and ectopic deposition of fat in nonadipose tissues (eg, liver, muscle), contributing to metabolic abnormalities including insulin resistance

Native leptin is a hormone predominantly secreted by adipose tissue that informs the CNS 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

 

Absorption

Peak plasma time: 4-4.3 hr

 

Distribution

Vd: 370, 398, and 463 mL/kg for 0.3, 1, and 3 mg/kg/day doses, respectively

 

Metabolism

No formal metabolism studies have been conducted

Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation

 

Elimination

Half-life: 3.8-4.7 hr

Clearance delayed in presence of leptin antibodies

Excretion: Predominantly renaL

 

Administration

SC Preparation

Remove the vial from the refrigerator and allow vial to warm to room temperature prior to use

Do not use if the white lyophilized cake is discolored

Reconstitute aseptically with 2.2 mL of sterile bacteriostatic water for injection (BWFI) USP (0.9% benzyl alcohol) or 2.2 mL of sterile water for injection (WFI)

For use in neonates and infants, reconstitute with preservative-free sterile WFI (see Cautions)

Slowly inject diluent down the side of the vial; it is normal for some bubbles to form

Gently swirl the contents to reconstitute; do not shake or vigorously agitate

When properly mixed, the reconstituted solution should be clear and free of clumps or dry powder, bubbles, or foam

After reconstitution, the mixture should be clear and colorless; do not use if visible particulates are present in the solution

After reconstitution, the vials should not be frozen (below 0°C) or shaken vigorously; if the reconstituted product is inadvertently frozen, it should be thrown away

 

SC Administration

Instruct patients and caregivers on the proper SC injection technique with care to avoid IM injection in patients with minimal subcutaneous adipose tissue

Never administer IV or Im

Do not mix with insulin; use a separate syringe for each medication

If metreleptin and insulin are administered at the same time of day, they may be injected in the same body area using 2 different injection sites

Can be administered without regard to the timing of meals

If a dose is missed, administer the dose as soon as noticed, and resume the normal dosing schedule the next day

SC injection technique

  • Using a 1-mL syringe with a needle appropriate for SC injection, withdraw the prescribed dose of metreleptin reconstituted solution
  • Remove any large air pockets or large bubbles from the filled syringe prior to administration; some small bubbles may remain in the syringe
  • Administer into the SC tissue of the abdomen, thigh, or upper arm
  • Advise patients to use a different injection site each day when injecting in the same region
  • After choosing an injection site, pinch the skin and at a 45° angle, inject SC
  • Avoid IM injection, especially in patients with minimal subcutaneous adipose tissue
  • Doses exceeding 1 mL can be administered as 2 injections (the total daily dose divided equally) to minimize potential injection-site discomfort due to injection volume
  • When dividing doses due to volume, doses can be administered one after the other

 

Storage

Unopened vials

  • Store refrigerated between 2-8°C (36-46°F) in original carton
  • Do not freeze

Reconstituted vials

  • Reconstituted with water for injection (no preservatives): Use for a single dose and should be administered immediately; unused reconstituted solution cannot be saved for later use and should be discarded
  • Reconstituted with bacteriostatic water for injection: Can be used for multiple doses within 3 days when refrigerated at 2-8°C (36-46°F) and protected from light; do not freeze