METRELEPTIN: 1,136 Adverse Event Reports & Safety Profile

MYALEPT (metreleptin) for injection is a recombinant human leptin analog for injection that binds to and activates the leptin receptor. Metreleptin (recombinant methionyl-human leptin) is produced in E. coli and differs from native human leptin by the addition of a methionine residue at its amino terminus. Metreleptin is a 147-amino acid, nonglycosylated, polypeptide with one disulfide bond between Cys-97 and Cys-147 and a molecular weight of approximately 16.15 kDa. MYALEPT is supplied as a sterile, white, solid, lyophilized cake containing 11.3 mg that is reconstituted with 2.2 mL of BWFI or WFI to a final formulation of 5 mg/mL metreleptin for subcutaneous injection. Inactive ingredients are: glutamic acid (1.47 mg/mL), glycine (20 mg/mL), polysorbate 20 (0.1 mg/mL), and sucrose (10 mg/mL), pH 4.25.

AND USAGE MYALEPT is a leptin analog indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. ( 1 ) Limitations of Use The safety and effectiveness of MYALEPT for the treatment of complications of partial lipodystrophy have not been established. ( 1 ) The safety and effectiveness of MYALEPT for the treatment of liver disease, including nonalcoholic steatohepatitis (NASH), have not been established. ( 1 ) MYALEPT is not indicated for use in patients with HIV-related lipodystrophy. ( 1 ) MYALEPT is not indicated for use in patients with metabolic disease, without concurrent evidence of generalized lipodystrophy. ( 1 )

1.1 Patients with Generalized Lipodystrophy MYALEPT (metreleptin) for injection is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. Limitations of Use The safety and effectiveness of MYALEPT for the treatment of complications of partial lipodystrophy have not been established. The safety and effectiveness of MYALEPT for the treatment of liver disease, including nonalcoholic steatohepatitis (NASH), have not been established. MYALEPT is not indicated for use in patients with HIV-related lipodystrophy. MYALEPT is not indicated for use in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of congenital or acquired generalized lipodystrophy.

AND ADMINISTRATION Administer as a subcutaneous injection once daily after the lyophilized cake is reconstituted with Bacteriostatic Water for Injection (BWFI) or preservative-free sterile Water for Injection (WFI). ( 2.1 ) The recommended daily dosages are: Body weight 40 kg or less: starting dose 0.06 mg/kg/day, increase or decrease by 0.02 mg/kg to a maximum daily dose of 0.13 mg/kg. ( 2.1 ) Males greater than 40 kg body weight: starting dose 2.5 mg/day, increase or decrease by 1.25 mg to 2.5 mg/day to a maximum dose of 10 mg/day. ( 2.1 ) Females greater than 40 kg body weight: starting dose 5 mg/day, increase or decrease by 1.25 mg to 2.5 mg/day to a maximum dose of 10 mg/day. ( 2.1 )

2.1 Recommended Dosing See Table 1 for the recommended daily dose and maximum recommended daily dose in adults and pediatric patients. Based on clinical response (e.g., inadequate metabolic control) or other considerations (e.g., tolerability issues, excessive weight loss [especially in pediatric patients]), MYALEPT dosage may be decreased or increased to the maximum dosage listed in Table 1.

Table

1: MYALEPT Recommended Dosage Baseline weight Starting daily dose (injection volume) Dose adjustments (injection volume) Maximum daily dose (injection volume) Less than or equal to 40 kg (males and females) 0.06 mg/kg (0.012 mL/kg) 0.02 mg/kg (0.004 mL/kg) 0.13 mg/kg (0.026 mL/kg) Males greater than 40 kg 2.5 mg (0.5 mL) 1.25 mg (0.25 mL) to 2.5 mg (0.5 mL) 10 mg (2 mL) Females greater than 40 kg 5 mg (1 mL) 1.25 mg (0.25 mL) to 2.5 mg (0.5 mL) 10 mg (2 mL) In pediatric patients, small volumes for administration can result in medication errors when measured incorrectly [see Dosage and Administration (2.3) , Adverse Reactions (6.3) ] .

Table

2 provides example doses and volumes by weight . For patients using insulin syringes, the volume conversion is 100 Units/mL.

Table

2: Example Dosing Chart for Patients Less than or Equal to 40 kg Weight Starting Dose Dose Adjustment Maximum Dose 5 kg 0.30 mg (0.06 mL or 6 Units) 0.10 mg (0.02 mL or 2 Units) 0.65 mg (0.13 mL or 13 Units) 10 kg 0.60 mg (0.12 mL or 12 Units) 0.20 mg (0.04 mL or 4 Units) 1.3 mg (0.26 mL or 26 Units) 15 kg 0.90 mg (0.18 mL or 18 Units) 0.30 mg (0.06 mL or 6 Units) 1.95 mg (0.39 mL or 39 Units) 20 kg 1.2 mg (0.24 mL or 24 Units) 0.40 mg (0.08 mL or 8 Units) 2.6 mg (0.52 mL or 52 Units) 25 kg 1.5 mg (0.3 mL or 30 Units) 0.50 mg (0.1 mL or 10 Units) 3.25 mg (0.65 mL or 65 Units) 30 kg 1.8 mg (0.36 mL or 36 Units) 0.60 mg (0.12 mL or 12 Units) 3.9 mg (0.78 mL or 78 Units) 35 kg 2.1 mg (0.42 mL or 42 Units) 0.70 mg (0.14 mL or 14 Units) 4.55 mg (0.91 mL or 91 Units) 40 kg 2.4 mg (0.48 mL or 48 Units) 0.80 mg (0.16 mL or 16 Units) 5.2 mg (1.03 mL or 103 Units) MYALEPT should be administered once daily at the same time every day. MYALEPT can be administered any time of day without regard to the timing of meals. Instruct patients that if a dose is missed, administer the dose as soon as noticed, and resume the normal dosing schedule the next day.

2.2 MYALEPT Preparation and Storage Healthcare practitioners should provide proper training to patients and caregivers regarding how to prepare and administer the correct dose of MYALEPT prior to self-use. The patients and caregivers should prepare and administer the first dose of MYALEPT under the supervision of a qualified healthcare professional. Instruct patients to store the vials of lyophilized powder in their carton in the refrigerator as soon as received <span class="opacity-50 text-xs">[see How Supplied/Storage and Handling (16.2) ]</span>. MYALEPT can be reconstituted aseptically with 2.2 mL of sterile Bacteriostatic Water for Injection (BWFI), USP (0.9% benzyl alcohol), or with 2.2 mL of sterile Water for Injection (WFI). When reconstituted in BWFI, MYALEPT solution can be used within 3 days when stored in the refrigerator between 36°F and 46°F (2°C and 8°C) and protected from light <span class="opacity-50 text-xs">[see How Supplied/Storage and Handling (16.2) ]</span>. Discard unused reconstituted solution after 3 days. Attach the supplied sticker to the vial and enter the discard date. For use in neonates and infants, reconstitute with preservative-free sterile WFI <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) and Use in Specific Populations (8.4) ]</span>. When reconstituted in sterile WFI, MYALEPT should be administered immediately. Unused reconstituted solution cannot be saved for later use and should be discarded. Reconstitution of the Lyophilized Powder Instruct patients to follow the directions below for reconstitution of the lyophilized powder: Remove the vial containing the MYALEPT lyophilized powder from the refrigerator and allow the vial to warm to room temperature prior to use. Visually inspect the vial containing MYALEPT. The cake of lyophilized powder 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 (WFI). Do not reconstitute MYALEPT with other diluents. Inject the BWFI or WFI into the vial containing the lyophilized powder of MYALEPT, slowly injecting down the side of the vial. It is normal for some bubbles to form. Remove the needle and syringe from the vial and gently swirl the contents to reconstitute. Do not shake or vigorously agitate. When properly mixed, the MYALEPT reconstituted solution should be clear and free of clumps or dry powder, bubbles or foam. Do not use the solution if discolored or cloudy, or if particulate matter remains. Regarding the compatibility of MYALEPT reconstituted solution with other solutions: Do not mix with, or transfer into, the contents of another vial of MYALEPT. Do not add other medications, including insulin. Use a separate syringe for insulin injections. See the MYALEPT Instructions for Use for complete administration instructions. The instructions can also be found at www.myalept.com .

2.3 Administration Instructions Healthcare practitioners should instruct patients and caregivers on the proper subcutaneous injection technique with care to avoid intramuscular injection in patients with minimal subcutaneous adipose tissue. Never administer MYALEPT intravenously or intramuscularly. Instruct patients to follow the recommended injection technique: Using a 1-mL or smaller syringe with a needle appropriate for subcutaneous injection, withdraw the prescribed dose of MYALEPT reconstituted solution. Remove any large air pockets or large bubbles from the filled syringe prior to administration. Some small bubbles may remain in the syringe. Administer MYALEPT into the subcutaneous tissue of the abdomen, thigh or upper arm. Advise patients to use a different injection site each day when injecting in the same region. After choosing an injection site, pinch the skin and at a 45-degree angle, inject the MYALEPT reconstituted solution subcutaneously. Avoid intramuscular injection, especially in patients with minimal subcutaneous adipose tissue. Doses exceeding 1 mL can be administered as two 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. In pediatric patients, small volumes for administration can result in medication errors when measured incorrectly. Smaller syringe sizes may be more appropriate for pediatric patients weighing less than or equal to 25 kg. Ensure the proper size syringe is selected.

Table

2 provides example doses and volumes by weight [see Dosage and Administration (2.1) , Adverse Reactions (6.3) ]. Do not mix MYALEPT with insulin. Use a separate syringe for each medication. If MYALEPT and insulin are administered at the same time of day, they may be injected in the same body area using two different injection sites. See the MYALEPT Instructions for Use for complete administration instructions. The instructions can also be found at www.myalept.com .

2.4 Dosage Adjustments of Medications Known to Cause Hypoglycemia Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue (e.g., sulfonylurea) may be necessary in some patients to minimize the risk of hypoglycemia <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) and Adverse Reactions (6.1) ]</span>. Closely monitor blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulin secretagogue (e.g., sulfonylurea) when treating with MYALEPT.

2.5 Discontinuation in Patients at Risk for Pancreatitis When discontinuing MYALEPT therapy in patients with risk factors for pancreatitis (e.g., history of pancreatitis, severe hypertriglyceridemia), tapering of the dose over a one-week period is recommended. During tapering, monitor triglyceride levels and consider initiating or adjusting the dose of lipid-lowering medications as needed. Signs and/or symptoms consistent with pancreatitis should prompt an appropriate clinical evaluation.

General obesity not associated with congenital leptin deficiency. ( 4.1 ) Hypersensitivity to metreleptin. ( 4.2 )

4.1 General Obesity MYALEPT is contraindicated in patients with general obesity not associated with congenital leptin deficiency. MYALEPT 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 MYALEPT <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>.

4.2 Hypersensitivity MYALEPT is contraindicated in patients with prior severe hypersensitivity reactions to metreleptin or to any of the product components. Known hypersensitivity reactions have included anaphylaxis, urticaria and generalized rash <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6) ]</span>.

REACTIONS Most common in clinical trials (≥10%): headache, hypoglycemia, decreased weight, abdominal pain. ( 5.4 , 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi Farmaceutici S.p.A. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Open-Label, Single-Arm Study The safety of MYALEPT was evaluated in 48 patients with generalized lipodystrophy in a single-arm, open-label study <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span>. The median duration of exposure in this trial was 2.7 years with a range of 3.6 months to 10.9 years. The most frequent adverse reactions are summarized in Table 3.

Table

3: Adverse Reactions of 5% or Greater Incidence in Patients with Generalized Lipodystrophy Receiving MYALEPT in an Open-Label, Single-Arm Study All Subjects N=48 (%) 1. Hypoglycemic events were assessed as mild, moderate, severe, or life threatening based on the protocol specified definitions: Mild: Documentation of low plasma glucose values with no symptoms; Moderate: Presence of clinical symptoms requiring ingestion of glucose, self-alleviated; Severe: Presence of neuroglycopenic symptoms requiring assistance from others for alleviation; Life threatening: Loss of consciousness and/or requiring intervention by administration of intravenous glucose or intramuscular glucagon.

Headache

6 (13)

Hypoglycemia

1 6 (13) Decreased weight 6 (13) Abdominal pain 5 (10)

Arthralgia

4 (8)

Dizziness

4 (8) Ear infection 4 (8)

Fatigue

4 (8)

Nausea

4 (8) Ovarian cyst 4 (8) Upper respiratory tract infection 4 (8)

Anemia

3 (6) Back pain 3 (6)

Diarrhea

3 (6)

Paresthesia

3 (6)

Proteinuria

3 (6)

Pyrexia

3 (6) In patients with generalized lipodystrophy receiving MYALEPT in this study, less common adverse reactions included injection-site erythema and urticaria (N=2 [4%]). Six patients (13%) had 7 adverse reactions of hypoglycemia, 6 of which occurred in the setting of concomitant insulin use, with or without oral antihyperglycemic agents. Two patients (4%) had events of pancreatitis, both of whom had a medical history of pancreatitis.

6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Anti-metreleptin antibodies were detected in 84% (36/43) of generalized lipodystrophy patients studied in the MYALEPT trials. Total anti-metreleptin antibody titers ranged between 1:5 and 1:1,953,125. The incompleteness of the current immunogenicity database precludes understanding of the magnitude and persistence of the observed anti-drug antibody responses. Anti-metreleptin antibodies with neutralizing activity associated with adverse events consistent with loss of endogenous leptin activity and/or loss of MYALEPT efficacy were observed in 6% (2/33) of the patients with generalized lipodystrophy tested. Adverse events reported in these two patients included severe infections and worsening of metabolic control (increases in HbA 1c and/or triglycerides). Test for anti-metreleptin antibodies with neutralizing activity in patients who develop severe infections or show signs suspicious for loss of MYALEPT efficacy during treatment.

Contact Chiesi

Farmaceutici S.p.A. at 1-866-216-1526 for testing of clinical samples. 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, resulting in potential underestimation of the number of samples positive for anti-metreleptin antibodies with neutralizing activity. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to metreleptin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of MYALEPT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Incorrect dose administered, accidental overdose <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.3) ]</span> Injection site reaction, including inflammation and hyperpigmentation

AND PRECAUTIONS Anti-metreleptin antibodies with neutralizing activity: Could inhibit endogenous leptin action and/or result in loss of MYALEPT efficacy. Test for neutralizing antibodies in patients with severe infections or loss of efficacy during MYALEPT treatment. ( 5.1 ) T-cell lymphoma: Carefully consider benefits and risks of treatment with MYALEPT in patients with significant hematologic abnormalities and/or acquired generalized lipodystrophy. ( 5.2 ) Hypoglycemia: A dose adjustment, including possible large reductions, of insulin or insulin secretagogue may be necessary. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. ( 5.4 ) Autoimmunity: Autoimmune disorder progression has been observed in patients treated with MYALEPT. Carefully consider benefits and risks of MYALEPT treatment in patients with autoimmune disease. ( 5.5 ) Hypersensitivity: Hypersensitivity reactions (e.g., anaphylaxis, urticaria or generalized rash) have been reported. Patient should promptly seek medical advice regarding suspected reactions. ( 5.6 )

Benzyl Alcohol

Toxicity: Preservative-free sterile WFI recommended for neonates and infants. ( 5.7 )

5.1 Risk for Development of Antibodies that Neutralize Endogenous Leptin and/or MYALEPT Anti-metreleptin antibodies with in vitro neutralizing activity to leptin associated with adverse events consistent with loss of endogenous leptin activity and/or loss of efficacy have been identified in two patients with generalized lipodystrophy treated with MYALEPT (severe infections, increases in HbA 1c and triglycerides), and in three patients without lipodystrophy who received MYALEPT in clinical studies (excessive weight gain, development of glucose intolerance or diabetes mellitus). The clinical implications associated with development of anti-metreleptin antibodies with neutralizing activity are not well characterized at this time due to the small number of reports. Test for anti-metreleptin antibodies with neutralizing activity in patients who develop severe infections or show signs suspicious for loss of MYALEPT efficacy during treatment.

Contact Chiesi

Farmaceutici S.p.A. at 1-866-216-1526 for neutralizing antibody testing of clinical samples [see Adverse Reactions (6.2) ].

5.2 Lymphoma Three cases of T-cell lymphoma have been reported in the MYALEPT lipodystrophy program; all three patients had acquired generalized lipodystrophy. Two of these patients were diagnosed with peripheral T-cell lymphoma while receiving MYALEPT. Both had immunodeficiency and significant hematologic abnormalities including severe bone marrow abnormalities before the start of MYALEPT treatment. A separate case of anaplastic large cell lymphoma was reported in a patient receiving MYALEPT who did not have hematological abnormalities before treatment. Lymphoproliferative disorders, including lymphomas, have been reported in patients with acquired generalized lipodystrophy not treated with MYALEPT. A causal relationship between MYALEPT treatment and the development and/or progression of lymphoma has not been established. Acquired lipodystrophies are associated with autoimmune disorders, and autoimmune disorders are associated with an increased risk of malignancies including lymphomas. The benefits and risks of MYALEPT treatment should be carefully considered in patients with acquired generalized lipodystrophy and/or those with significant hematologic abnormalities (including leukopenia, neutropenia, bone marrow abnormalities, lymphoma, and/or lymphadenopathy).

5.3 MYALEPT REMS Program MYALEPT is available only through a restricted distribution program under a REMS, called the MYALEPT REMS Program, because of the risks associated with the development of anti-metreleptin antibodies that neutralize endogenous leptin and/or MYALEPT and the risk for lymphoma <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1, 5.2) ]</span>. Notable requirements of the MYALEPT REMS Program include the following: Prescribers must be certified with the program by enrolling and completing training. Pharmacies must be certified with the program and only dispense MYALEPT after receipt of the MYALEPT REMS Prescription Authorization Form for each new prescription. Further information is available at www.myaleptrems.com or 1-855-669-2537.

5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue (e.g., sulfonylurea) may be necessary in some patients to minimize the risk of hypoglycemia <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) and Adverse Reactions (6.1) ]</span>. Closely monitor blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulin secretagogue (e.g., sulfonylurea), when treating with MYALEPT.

5.5 Autoimmunity Leptin plays a role in immune system homeostasis. Acquired lipodystrophies are associated with autoimmune disorders including autoimmune hepatitis and membranoproliferative glomerulonephritis. Cases of progression of autoimmune hepatitis and membranoproliferative glomerulonephritis (associated with massive proteinuria and renal failure) were observed in some patients with acquired generalized lipodystrophy treated with MYALEPT. A causal relationship between MYALEPT treatment and the development and/or progression of autoimmune disease has not been established. The potential benefits and risks of MYALEPT treatment should be carefully considered in patients with autoimmune disease.

5.6 Hypersensitivity There have been reports of generalized hypersensitivity (e.g., anaphylaxis, urticaria or generalized rash) in patients taking MYALEPT. If a hypersensitivity reaction occurs, instruct the patient to promptly seek medical advice regarding discontinuation of MYALEPT.

5.7 Benzyl Alcohol Toxicity MYALEPT contains benzyl alcohol when reconstituted with BWFI. MYALEPT contains no preservative when reconstituted with sterile Water for Injection (WFI). Preservative-free WFI is recommended for use in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients, particularly in neonates and premature infants <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span>.

INTERACTIONS No formal drug interaction studies were performed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. This should be taken into account when prescribing concomitant drugs metabolized by CYP450 (e.g., oral contraceptives and drugs with a narrow therapeutic index). The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of MYALEPT, in patients being treated with these types of agents, therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the agent adjusted as needed.