Metreleptin is a recombinant human leptin analog approved as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. It is not approved for the treatment of complications of partial lipodystrophy or HIV-related lipodystrophy. Metreleptin is produced in E. coli and contains an additional methionine residue at its amino terminus, making it slightly different than native human leptin. Lipodystrophies are acquired or inherited disorders characterized by the selective loss of adipose tissue. Affected patients are predisposed to insulin resistance, including diabetes mellitus, dyslipidemia, hypertriglyceridemia, and hepatic steatosis. The hormone leptin has a central role in energy homeostasis; serum leptin levels are proportional to adipocyte mass. In an open-label, single-arm study of 48 patients (median age = 15 years; range, 1-68 years), metreleptin treatment resulted in reductions in HbA1c, fasting glucose, and triglycerides from baseline values. At 12 months, patients receiving metreleptin (n = 35) had a mean decrease of 2% from their mean baseline HbA1c of 8.7%. The mean baseline fasting glucose (n = 37) was 174 mg/dl, and the mean reduction was 49 mg/dl. The median baseline fasting triglycerides (n = 36) was 348 mg/dl, which decreased by a median of 185 mg/dl. The weighted average daily dose for patients weighing > 40 kg was 2.6 mg/day SC for males and 4.6 mg/day for females during the first year of therapy and 3.2 mg/day (males) and 6.3 mg (females) over the entire study period. The median treatment duration was 2.7 years (range, 3.6 months-10.9 years). Due to the risk of anti-metreleptin antibodies with neutralizing activity and the possible increased risk of lymphoma, metreleptin is available only through a restricted program called the Myalept REMS Program. The FDA approved metreleptin in February 2014.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific 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.
Ear infection (8%), upper respiratory tract infection (8%), and fever (6%) were reported during a single-arm, open-label study of 48 patients with generalized lipodystrophy. Severe infection may be a sign developing anti-metreleptin antibodies with neutralizing activity. Any patient who presents with a severe infection should be tested for anti-metreleptin antibodies. The manufacturer can be contacted at 1-866-216-1526 for testing of clinical samples.
Anti-metreleptin antibodies with neutralizing activity to leptin were detected in 6% (2/33) of the patients with generalized lipodystrophy who were tested in clinical trials. These 2 patients experienced adverse events consistent with the loss of endogenous leptin activity and loss of metreleptin efficacy (i.e., severe infections and worsening of metabolic control [increase in HbA1c and triglycerides]). In addition, 3 patients without lipodystrophy who received metreleptin in clinical trials developed excessive weight gain, glucose intolerance, and diabetes. Because the number of patients who have developed neutralizing antibodies is small, the clinical implications have not been fully characterized. Patients who develop severe infections or show signs suspicious for loss of metreleptin efficacy should be tested for anti-metreleptin antibodies with neutralizing activity. The manufacturer can be contacted at 1-866-216-1526 for testing of clinical samples. In clinical trials, anti-metreleptin antibodies were detected in 84% (36/43) of patients who received metreleptin for generalized lipodystrophy. Total anti-metreleptin antibody titers ranged from 1:5 to 1:1,1953,125. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. The immunogenicity assays utilized in clinical trials lacked sensitivity; the number of samples positive for anti-metreleptin antibodies with neutralizing activity could have been underestimated. Additionally, several factors can influence the incidence of antibody positivity including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. Comparison of the incidence of antibodies to metreleptin with the incidence of antibodies to other products may be misleading.
Although a causal relationship has not been established, cases of new primary malignancy have been reported with metreleptin use. At the time of FDA-approval, 3 cases of T-cell lymphoma had been reported in the Myalept lipodystrophy program; 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 the initiation of metreleptin therapy. 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, metreleptin is only available through the Myalept REMS Program.
Hypoglycemia occurred in 6 of 48 (13%) patients with generalized lipodystrophy in pre-marketing clinical trials of metreleptin. 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.
In a single-arm, open-label study of metreleptin in 48 patients with generalized lipodystrophy, headache (13%) and dizziness (8%) were among the most commonly reported adverse events. Anemia occurred in 6% of patients.
Gastrointestinal (GI) adverse effects associated with metreleptin use include: abdominal pain (10%), diarrhea (6%), and nausea (8%). Weight loss is also a common effect (13%). In one trial of 48 patients with generalized lipodystrophy, 2 patients (4%) developed pancreatitis; both had a medical history of pancreatitis. When discontinuing metreleptin in patients with risk factors for pancreatitis, 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. 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.
During an open-label single-arm study of metreleptin in 48 patients with generalized lipodystrophy, arthralgia (8%), back pain (6%), fatigue (8%), and paresthesias (6%) were reported. Ovarian cyst was detected in 8% of patients (4 of 36 females).
Generalized hypersensitivity reactions, including urticaria and rash, have occurred with metreleptin use. Instruct patients to seek medical advice promptly if symptoms of a hypersensitivity reaction occur. In a clinical trial of 48 patients with generalized lipodystrophy, injection site erythema and urticaria each occurred in 4% of patients. Injection site reaction, including inflammation and skin hyperpigmentation, were reported during postmarketing use.
During a clinical trial of 48 patients with generalized lipodystrophy, proteinuria occurred in 6% of patients. In addition, cases of progression of autoimmune hepatitis and membranoproliferative glomerulonephritis, associated with massive proteinuria and renal failure (unspecified), have been observed in some patients with acquired generalized lipodystrophy who received metreleptin; however, a causal relationship between metreleptin therapy and the development of these conditions has not been found. Acquired lipodystrophies are associated with autoimmune disorders, including autoimmune hepatitis and membranoproliferative glomerulonephritis; it has not been determined whether metreleptin therapy increases this risk.
Metreleptin is contraindicated in patients with a prior severe hypersensitivity reaction to metreleptin or any of the product components.
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.
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 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).
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.
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.
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.
Available pharmacovigilance reports with the use of metreleptin in pregnant women are insufficient to evaluate for any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. These reports describe similar adverse pregnancy outcomes as those documented in women with lipodystrophy. 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 the reproductive performance of the 1st or 2nd generations was not affected at any dose. The placental transfer of metreleptin into the fetus was low (approximately 1%) after subcutaneous dosing. The effects of metreleptin on labor and obstetric delivery in pregnant women are unknown; in an in vitro study of human myometrial tissue exposed to 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 1-855-669-2537.
There are no available data on the presence of metreleptin in human milk; however, endogenous leptin is present in human milk. There are no available data on the effects of metreleptin on the breastfed infant or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.
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.
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.
General dosing information:
-Limitations of use: Metreleptin is not approved for the treatment of complications of partial lipodystrophy; for the treatment of liver disease, including nonalcoholic steatohepatitis (NASH); for use in patients with HIV-related lipodystrophy; or in patients with metabolic disease, without concurrent evidence of lipodystrophy (generalized).
-Metreleptin should be administered once daily at the same time every day. It can be administered any time of day without regard to the timing of meals.
-When discontinuing metreleptin therapy in patients with risk factors for pancreatitis, taper the dosage over one week. Monitor triglyceride levels and initiate or adjust lipid-lowering therapy as indicated. Promptly evaluate any patient with signs or symptoms of pancreatitis.
-If a dose is missed, administer the dose as soon as noticed, and resume the normal dosing schedule the next day.
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 Limits:
-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.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
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.
Conjugated Estrogens: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Conjugated Estrogens; Bazedoxifene: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Conjugated Estrogens; Medroxyprogesterone: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
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.
Desogestrel; Ethinyl Estradiol: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
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: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
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: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Drospirenone; Ethinyl Estradiol: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Elagolix; Estradiol; Norethindrone acetate: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Esterified Estrogens: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Esterified Estrogens; Methyltestosterone: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Estradiol: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Estradiol; Levonorgestrel: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Estradiol; Norethindrone: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Estradiol; Norgestimate: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Estradiol; Progesterone: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Estrogens affected by CYP3A inducers: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Estropipate: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Ethinyl Estradiol; Norelgestromin: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Ethinyl Estradiol; Norgestrel: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
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.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Etonogestrel; Ethinyl Estradiol: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
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.
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.
Insulin Aspart: (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.
Insulin Aspart; Insulin Aspart Protamine: (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.
Insulin Degludec: (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.
Insulin Degludec; Liraglutide: (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.
Insulin Detemir: (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.
Insulin Glargine: (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.
Insulin Glargine; Lixisenatide: (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.
Insulin Glulisine: (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.
Insulin Lispro: (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.
Insulin Lispro; Insulin Lispro Protamine: (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.
Insulin, Inhaled: (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.
Isophane Insulin (NPH): (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.
Levonorgestrel; Ethinyl Estradiol: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
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.
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.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Norethindrone; Ethinyl Estradiol: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
Norgestimate; Ethinyl Estradiol: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
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.
Pioglitazone; 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.
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.
Regular Insulin: (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.
Regular Insulin; Isophane Insulin (NPH): (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.
Relugolix; Estradiol; Norethindrone acetate: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
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.
Segesterone Acetate; Ethinyl Estradiol: (Major) Concurrent use of metreleptin with estrogens may produce unpredictable effects, including a decrease in estrogen efficacy or an increase in estrogen-related adverse effects. Women taking both estrogens and metreleptin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed metreleptin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of metreleptin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect or an increase in adverse effects while on metreleptin, with dose adjustments made based on clinical response. Estrogens are CYP3A4 substrates and metreleptin may alter the formation of CYP enzymes. Concurrent administration may increase or decrease estrogen elimination.
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.
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.
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.
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
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
No formal pharmacokinetic studies were conducted for metreleptin prior to FDA-approval in patients with hepatic impairment.
Renal Impairment
No formal pharmacokinetic studies were conducted for metreleptin prior to FDA-approval in patients with renal impairment. Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. Therefore, the pharmacokinetics of metreleptin may be altered in subjects with renal impairment.
Pediatrics
Specific clinical studies have not been conducted to assess the effect of age on the pharmacokinetics of metreleptin in patients with generalized lipodystrophy. Clinical evaluation of metreleptin 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 between pediatric and adult patients.
Geriatric
Specific clinical studies have not been conducted to assess the effect of age on the pharmacokinetics of metreleptin in patients with generalized lipodystrophy. Clinical evaluation of metreleptin did not include sufficient numbers of subjects aged 65 and over (n = 1) to determine whether they respond differently from younger subjects.
Gender Differences
Specific clinical studies have not been conducted to assess the effect of gender differences on the pharmacokinetics of metreleptin in patients with generalized lipodystrophy.
Ethnic Differences
Specific clinical studies have not been conducted to assess the effect of ethnic differences on the pharmacokinetics of metreleptin in patients with generalized lipodystrophy.
Obesity
Specific clinical studies have not been conducted to assess the effect of body mass index on the pharmacokinetics of metreleptin in patients with generalized lipodystrophy.