MYALEPT

Other Hormones and Agents with Similar Actions

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.

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.

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

hypoglycemia / Early / 13.0-13.0
anemia / Delayed / 6.0-6.0
proteinuria / Delayed / 6.0-6.0
erythema / Early / 4.0-4.0
antibody formation / Delayed / 10.0
hepatitis / Delayed / Incidence not known

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
urticaria / Rapid / 4.0-4.0
skin hyperpigmentation / Delayed / Incidence not known
injection site reaction / Rapid / Incidence not known
rash / Early / Incidence not known

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).

MYALEPT

OTC

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

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.

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.

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.

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

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

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

MYALEPT Subcutaneous Inj Pwd F/Sol: 11.3mg

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

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

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

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

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

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

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

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.

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.