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    Other Hormones and Preparations with Similar Actions

    BOXED WARNING

    Bone marrow suppression, leukopenia, lymphoma, neutropenia, new primary malignancy, requires an experienced clinician

    Carefully consider the benefits and risks of metreleptin treatment in patients with acquired generalized lipodystrophy or those with significant hematologic abnormalities (including leukopenia, neutropenia, bone marrow suppression or abnormalities, lymphoma, and/or lymphadenopathy). Although a causal relationship has not been established, 3 cases of new primary malignancy (i.e., T-cell lymphoma) had been reported in the Myalept lipodystrophy program at the time of FDA-approval; all 3 patients had acquired generalized lipodystrophy. Two patients were diagnosed with peripheral T-cell lymphoma while receiving metreleptin; both had immunodeficiency and significant hematologic abnormalities prior to treatment. A separate case of anaplastic large cell lymphoma was reported in a patient receiving metreleptin who did not have hematological abnormalities before treatment. Lymphoproliferative disorders, including lymphomas, have also been reported in patients with acquired generalized lipodystrophy not treated with metreleptin. Acquired lipodystrophies are associated with autoimmune disorders, and autoimmune disorders are associated with an increased risk of malignancy. Because of the possible risk for lymphoma and the known risk of anti-metreleptin antibodies that neutralize endogenous leptin, administration requires an experienced clinician who is registered with the Myalept REMS Program.

    Anti-metreleptin antibodies, infection

    Anti-metreleptin antibodies with neutralizing activity have been identified in patients treated with metreleptin. The clinical consequences of these neutralizing antibodies are not fully understood but could include inhibition of endogenous leptin activity and/or loss of metreleptin efficacy. Severe infection and/or worsening metabolic control have been reported in patients with generalized lipodystrophy who developed anti-metreleptin antibodies; excessive weight gain and development of glucose intolerance or diabetes have been reported in patients without lipodystrophy who received the drug. Test for anti-metreleptin antibodies in patients who develop severe infections or show signs of loss of efficacy during treatment. Contact the manufacturer at 1-866-216-1526 for neutralizing antibody testing of clinical samples. Because of the risk for developing neutralizing antibodies, metreleptin is only available through a restricted distribution program (Myalept REMS Program).

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant human leptin analog
    Used to treat complications of leptin deficiency in patients with congenital generalized or acquired generalized lipodystrophy
    Only available through Myalept REMS Program because of risks of neutralizing antibodies and lymphoma

    COMMON BRAND NAMES

    MYALEPT

    HOW SUPPLIED

    MYALEPT Subcutaneous Inj Pwd F/Sol: 11.3mg

    DOSAGE & INDICATIONS

    For the treatment of complications due to leptin deficiency in patients with congential or acquired generalized lipodystrophy.
    Subcutaneous dosage
    Male Adults, Adolescents, and Children weighing more than 40 kg

    2.5 mg/day (0.5 mL) subcutaneously initially. Increase or decrease dose by 1.25 to 2.5 mg/day (0.25 to 0.5 mL) as clinically indicated. Do not exceed 10 mg/day (2 mL/day). Administer once daily at the same time every day. The dosage may be decreased or increased based on clinical response and tolerability. Dose selection for geriatric patients should be cautious, usually starting at the low end of the dosing range.

    Female Adults, Adolescents, and Children weighing more than 40 kg

    5 mg/day (1 mL) subcutaneously initially. Increase or decrease dose by 1.25 to 2.5 mg/day (0.25 to 0.5 mL) as clinically indicated. Do not exceed 10 mg/day (2 mL/day). Administer once daily at the same time every day. The dosage may be decreased or increased based on clinical response and tolerability. Dose selection for geriatric patients should be cautious, usually starting at the low end of the dosing range.

    Adults, Adolescents, Children, Infants, and Neonates weighing 40 kg or less

    0.06 mg/kg/day (0.012 mL/kg) subcutaneously, initially. Increase or decrease dose by 0.02 mg/kg/day (0.004 mL/kg) based on clinical response and tolerability. Do not exceed 0.13 mg/kg/day (0.026 mL/kg/day). Administer once daily at the same time every day. Dose selection for geriatric patients should be cautious, usually starting at the low end of the dosing range.

    MAXIMUM DOSAGE

    Adults

    > 40 kg: 10 mg/day (2 ml) SC.
    <= 40 kg: 0.13 mg/kg/day (0.026 ml/kg) SC.

    Geriatric

    > 40 kg: 10 mg/day (2 ml) SC.
    <= 40 kg: 0.13 mg/kg/day (0.026 ml/kg) SC.

    Adolescents

    > 40 kg: 10 mg/day (2 ml) SC.
    <= 40 kg: 0.13 mg/kg/day (0.026 ml/kg) SC.

    Children

    > 40 kg: 10 mg/day (2 ml) SC.
    <= 40 kg: 0.13 mg/kg/day (0.026 ml/kg) SC.

    Infants

    0.13 mg/kg/day (0.026 ml/kg) SC.

    Neonates

    0.13 mg/kg/day (0.026 ml/kg) SC.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Provide proper training to patients and caregivers regarding how to prepare and administer the correct dose of metreleptin prior to self-use.
    The patient or caregiver should prepare and administer the first dose of metreleptin under the supervision of a qualified healthcare provider.

    Subcutaneous Administration

    Reconstitution
    Remove the vial from the refrigerator and allow it to warm to room temperature prior to use.
    Visually inspect the vial; the cake of lyophilized power should be intact and white in color.
    Using a 3 ml syringe with a 22 gauge or smaller diameter needle, withdraw 2.2 ml of sterile Bacteriostatic Water for Injection (BWFI) or preservative-free Sterile Water for Injection (SWI). Do not reconstitute with other diluents.
    For neonates and infants, reconstitute with preservative-free Sterile Water for Injection (SWI) only.
    Inject the BWFI or SWI into the vial containing the lyophilized powder of metreleptin, slowly injecting down the side of the vial. It is normal for some bubbles to form.
    After removing the needle and syringe from the vial, gently swirl the contents to reconstitute. Do not shake or vigorously agitate. The reconstituted solution should be clear and free of clumps or dry powder, bubbles or foam. Do not use the solution if it is discolored or cloudy, or if particulate matter remains.
    Do not mix with, or transfer into, the contents of another vial of metreleptin. Do not add other medications, including insulin. Use a separate syringe for insulin injections.
    Storage: Store vials in the refrigerator between 2—8 degrees C (36—46 degrees F) and protect from light. Keep vials in the carton when not in use. Do not freeze; if the reconstituted product is inadvertently frozen, it should be discarded.
    After reconstitution using preservative-free Sterile Water for Injection (SWI):
    Administer immediately after preparation; discard unused reconstituted solution.
    After reconstitution using Bacteriostatic Water for Injection:
    The reconstituted solution can be left in the original vial at room temperature for up to 4 hours prior to administration, but any unused solution should then be discarded and not stored.
    If placed in the refrigerator and protected from light shortly after reconstitution, the solution may be stored at 2—8 degrees C (36—46 degrees F), but must be used or discarded within 3 days.
    When counseling patients for self-use, instruct them to write the discard date (2 calendar days after the date of reconstitution) on the provided sticker and attach to the vial before placing in the refrigerator. The vial should be thrown away after administration of the dose on the "discard date".
     
    Subcutaneous Injection
    Use a 1 ml syringe to withdraw the prescribed dose of metreleptin reconstituted solution. Remove any large air pockets or large bubbles from the filled syringe prior to administration.
    Administer metreleptin into the subcutaneous tissue of the abdomen, thigh, or upper arm. A different injection site should be used each day.
    After choosing and cleaning an injection site, pinch the skin and inject the dose subcutaneously at a 45 degree angle. Avoid intramuscular 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.
    If metreleptin and insulin are administered at the same time of day, they may be injected in the same general area of the body using separate syringes and 2 different injection sites.
    Administer at the same time every day. May be given without regard to meals.

    STORAGE

    MYALEPT:
    - Avoid use of product if it has been frozen
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Store in outer carton when not in use
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Metreleptin is contraindicated in patients with a prior severe hypersensitivity reaction to metreleptin or any of the product components.

    Obesity

    Metreleptin is contraindicated in patients with general obesity not associated with congential leptin deficiency. Metreleptin has not been shown to be effective in treating general obesity, and the development of anti-metreleptin antibodies with neutralizing activity has been reported in obese patients treated with metreleptin.

    Bone marrow suppression, leukopenia, lymphoma, neutropenia, new primary malignancy, requires an experienced clinician

    Carefully consider the benefits and risks of metreleptin treatment in patients with acquired generalized lipodystrophy or those with significant hematologic abnormalities (including leukopenia, neutropenia, bone marrow suppression or abnormalities, lymphoma, and/or lymphadenopathy). Although a causal relationship has not been established, 3 cases of new primary malignancy (i.e., T-cell lymphoma) had been reported in the Myalept lipodystrophy program at the time of FDA-approval; all 3 patients had acquired generalized lipodystrophy. Two patients were diagnosed with peripheral T-cell lymphoma while receiving metreleptin; both had immunodeficiency and significant hematologic abnormalities prior to treatment. A separate case of anaplastic large cell lymphoma was reported in a patient receiving metreleptin who did not have hematological abnormalities before treatment. Lymphoproliferative disorders, including lymphomas, have also been reported in patients with acquired generalized lipodystrophy not treated with metreleptin. Acquired lipodystrophies are associated with autoimmune disorders, and autoimmune disorders are associated with an increased risk of malignancy. Because of the possible risk for lymphoma and the known risk of anti-metreleptin antibodies that neutralize endogenous leptin, administration requires an experienced clinician who is registered with the Myalept REMS Program.

    Anti-metreleptin antibodies, infection

    Anti-metreleptin antibodies with neutralizing activity have been identified in patients treated with metreleptin. The clinical consequences of these neutralizing antibodies are not fully understood but could include inhibition of endogenous leptin activity and/or loss of metreleptin efficacy. Severe infection and/or worsening metabolic control have been reported in patients with generalized lipodystrophy who developed anti-metreleptin antibodies; excessive weight gain and development of glucose intolerance or diabetes have been reported in patients without lipodystrophy who received the drug. Test for anti-metreleptin antibodies in patients who develop severe infections or show signs of loss of efficacy during treatment. Contact the manufacturer at 1-866-216-1526 for neutralizing antibody testing of clinical samples. Because of the risk for developing neutralizing antibodies, metreleptin is only available through a restricted distribution program (Myalept REMS Program).

    Autoimmune disease, hepatitis

    Leptin is involved in immune system homeostasis. Acquired lipodystrophies are associated with autoimmune disease or disorders including autoimmune hepatis and membranoproliferative glomerulonephritis. Cases of progression of autoimmune hepatitis and membranoproliferative glomerulonephritis (associated with massive proteinuria and renal failure) have occurred in 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; however, the potential benefits and risks should be considered prior to initiating treatment in patients with autoimmune disease.

    Diabetes mellitus, hypoglycemia

    Monitor patients with diabetes mellitus closely while they are receiving metreleptin. Adjustments in their medication regimens may be necessary; some patients may require large reductions of insulin or insulin secretagogues (e.g., sulfonylureas) to minimize the risk of hypoglycemia. Monitor blood glucose closely in patients on concomitant insulin therapy, especially those on high doses, or an insulin secretagogue while treating with metreleptin. Counsel patients to be particularly watchful for symptoms of hypoglycemia and to check their blood glucose more frequently and contact their prescriber if such symptoms occur.

    Abrupt discontinuation, hypertriglyceridemia, pancreatitis

    Avoid abrupt discontinuation of metreleptin therapy in patients with risk factors for pancreatitis (e.g., history of pancreatitis, severe hypertriglyceridemia); tapering of the dose over a 1 week period is recommended. During tapering, monitor triglyceride levels and consider initiating or adjusting the dose of lipid-lowering medications as needed. Counsel patients about signs and symptoms of pancreatitis, and instruct them to seek medical attention immediately if such signs or symptoms occur. Any signs or symptoms of pancreatitis warrant prompt clinical evaluation.

    Labor, pregnancy

    Adequate and well-controlled studies of metreleptin have not been performed in pregnant women. According to the manufacturer, metreleptin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproduction studies in mice, metreleptin was not teratogenic when given at doses ranging from 7- to 15-fold the maximum recommended clinical dose based on body surface area of a 20- and 60- kg patient, respectively during the period of organogenesis. In a pre- and postnatal development study in mice, administration of metreleptin from day 6 to lactation day 21 caused prolonged gestation and dystocia resulting in maternal death of some females during parturition and lower survival of offspring in the immediate postnatal periods at doses starting approximately at the maximum recommended clinical dose. 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. No developmental abnormalities were observed and reproductive performance of the 1st or 2nd generations was not affected at any dose. Placental transfer of metreleptin into the fetus was low (approximately 1%) after SC dosing. 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. To monitor fetal outcomes of pregnant women exposed to metreleptin, the manufacturer maintains a Myalept Registry that collects data on pregnant women treated with metreleptin. Physicians are encouraged to register patients by calling 1-855-6MYALEPT.

    Breast-feeding

    It is not known whether metreleptin is present in human milk, but endogenous leptin is present in human milk. Because of the potential for serious adverse reactions of metreleptin, including possible adverse reactions related to passage of anti-metreleptin antibodies, in a breast-feeding infant, a decision should be made whether to discontinue nursing or discontinue the drug.

    Infants, neonates

    Use only preservative-free Sterile Water for Injection to reconstitute metreleptin doses for neonates and infants. Metreleptin solution contains benzyl alcohol when reconstituted with Bacteriostatic Water for Injection (BWFI), but metreleptin contains no preservative when reconstituted with Sterile Water for Injection. Administration of parenteral solutions containing benzyl alcohol have been associated with fatal '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) in neonates and low birthweight infants.

    Geriatric

    Clinical studies of metreleptin did not include sufficient numbers of geriatric patients aged 65 years or over (n = 1) to determine whether they respond differently from younger patients. In general, dosage selection and titration for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / 4.0-4.0
    new primary malignancy / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known

    Moderate

    hypoglycemia / Early / 13.0-13.0
    anemia / Delayed / 6.0-6.0
    proteinuria / Delayed / 6.0-6.0
    antibody formation / Delayed / 10.0
    hepatitis / Delayed / Incidence not known

    Mild

    headache / Early / 13.0-13.0
    weight loss / Delayed / 13.0-13.0
    abdominal pain / Early / 10.0-10.0
    infection / Delayed / 8.0-8.0
    dizziness / Early / 8.0-8.0
    nausea / Early / 8.0-8.0
    arthralgia / Delayed / 8.0-8.0
    fatigue / Early / 8.0-8.0
    fever / Early / 6.0-6.0
    diarrhea / Early / 6.0-6.0
    paresthesias / Delayed / 6.0-6.0
    back pain / Delayed / 6.0-6.0
    injection site reaction / Rapid / 4.0-4.0
    urticaria / Rapid / 4.0-4.0
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Acetohexamide: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Carbamazepine: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving carbamazepine, drug concentration monitoring should be performed and the carbamazepine dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as carbamazepine.
    Chlorpropamide: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Conjugated Estrogens: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Conjugated Estrogens; Bazedoxifene: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Conjugated Estrogens; Medroxyprogesterone: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Cyclosporine: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving cyclosporine, drug concentration monitoring should be performed and the cyclosporine dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as cyclosporine.
    Dextromethorphan; Quinidine: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving quinidine, drug concentration monitoring should be performed and the quinidine dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as quinidine.
    Dienogest; Estradiol valerate: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Diethylstilbestrol, DES: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Dihydroergotamine: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and dihydroergotamine concomitantly; the precise effect of metreleptin on the metabolism of dihydroergotamine is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, such as dihydroergotamine.
    Disopyramide: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving disopyramide, drug concentration and clinical monitoring should be performed and the disopyramide dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as disopyramide.
    Drospirenone; Estradiol: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Drospirenone; Ethinyl Estradiol: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Esterified Estrogens: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Esterified Estrogens; Methyltestosterone: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Estradiol: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Estradiol; Levonorgestrel: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Estradiol; Norethindrone: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Estradiol; Norgestimate: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Estrogens: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Estropipate: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Desogestrel: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Norethindrone: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Norgestimate: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethinyl Estradiol; Norgestrel: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Ethosuximide: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving ethosuximide, drug concentration monitoring should be performed and the ethosuximide dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as ethosuximide.
    Fentanyl: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and fentanyl concomitantly; fentanyl dosage should be carefully selected and titrated. Upon initiation or discontinuation of metreleptin, carefully monitor patients for therapeutic and adverse effects of fentanyl and adjust the dosage as necessary. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as fentanyl.
    Glimepiride: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Glimepiride; Pioglitazone: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Glimepiride; Rosiglitazone: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Glipizide: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Glipizide; Metformin: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Glyburide: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Glyburide; Metformin: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Insulins: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Meglitinides: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulin secretagogue therapy (i.e., nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Mestranol; Norethindrone: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and oral contraceptives concomitantly; the precise effect of metreleptin on hormone metabolism is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index.
    Metformin; Repaglinide: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulin secretagogue therapy (i.e., nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Nateglinide: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulin secretagogue therapy (i.e., nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Pimozide: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and pimozide concomitantly. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as pimozide. Upon initiation or discontinuation of metreleptin, therapeutic or drug concentration monitoring should be performed if possible, and the dosage of pimozide adjusted as needed.
    Quinidine: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving quinidine, drug concentration monitoring should be performed and the quinidine dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as quinidine.
    Repaglinide: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulin secretagogue therapy (i.e., nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Sirolimus: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving sirolimus, drug concentration monitoring should be performed and the sirolimus dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as sirolimus.
    Sulfonylureas: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Tacrolimus: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving tacrolimus, drug concentration monitoring should be performed and the tacrolimus dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as tacrolimus.
    Theophylline, Aminophylline: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving theophylline, drug concentration monitoring should be performed and the theophylline dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as theophylline.
    Tolazamide: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Tolbutamide: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Warfarin: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving warfarin, more frequent INR monitoring should be performed; warfarin dosage adjustments may be necessary. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as warfarin.

    PREGNANCY AND LACTATION

    Pregnancy

    It is not known whether metreleptin is present in human milk, but endogenous leptin is present in human milk. Because of the potential for serious adverse reactions of metreleptin, including possible adverse reactions related to passage of anti-metreleptin antibodies, in a breast-feeding infant, a decision should be made whether to discontinue nursing or discontinue the drug.

    MECHANISM OF ACTION

    Lipodystrophies are acquired or inherited disorders characterized by the selective loss of adipose tissue. They are a heterogenous group of disorders with unique clinical presentations and underlying pathologies. Some lipodystrophies are generalized, while others affect a smaller portion of the body. Adipocytes store lipids to meet energy requirements of non-adipose tissues during fasting. Native human leptin is a hormone predominately secreted by adipose tissue that regulates energy homeostasis and metabolic function. Circulating levels of leptin closely correlate with the amount of adipose tissue present. In patients with generalized lipodystrophy, the deficiency of adipose tissue leads to hypertriglyceridemia and fat deposition in non-adipose tissues such as liver and muscle, contributing to metabolic abnormalities including insulin resistance. In patients with generalized lipodystrophy, leptin deficiency contributes to excess caloric intake, which exacerbates the metabolic abnormalities. Metreleptin is a recombinant human leptin analog that 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. Clinical studies in patients with generalized lipodystrophy suggest that metreleptin increases insulin sensitivity and reduces food intake, resulting in reductions in HbA1c, fasting glucose, and fasting triglyceride values.

    PHARMACOKINETICS

    Metreleptin is administered via subcutaneous injection. Pharmacokinetic data in patients with generalized lipodystrophy are limited; no formal exposure-response analysis was performed prior to FDA-approval. Metreleptin has a large volume of distribution (Vd). After IV administration of single doses, the Vd was approximately 4—5 times plasma volume in healthy adults; mean volumes were 370 +/- 184 ml/kg, 398 +/- 92 ml/kg, and 463 +/- 116 ml/kg for 0.3, 1, and 3 mg/kg/day doses, respectively. No formal metabolism studies have been conducted; however, nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent systemic metabolism. The clearance is expected to be delayed in the presence of leptin antibodies.
     
    NOTE: The leptin assay measures both endogenous leptin as well as exogenously administered metreleptin.
     
    Affected cytochrome P450 enzymes: none

    Subcutaneous Route

    After single doses ranging from 0.1—0.3 mg/kg SC in healthy subjects, the Cmax occurred approximately 4—4.3 hours after administration; the median Tmax was 4 hours (range: 2—8 hours) in a supportive trial in 5 lipodystrophy patients. After single subcutaneous doses of 0.01—0.3 mg/kg SC in healthy subjects, the t1/2 was 3.8—4.7 hours.