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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 HbA1c 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 Aegerion Pharmaceuticals, Inc. at 1-866-216-1526 for neutralizing antibody testing of clinical samples [see ADVERSE REACTIONS].
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).
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 [see paragraphs above].
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 1-855-6MYALEPT.
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 [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS]. 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.
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.
There have been reports of generalized hypersensitivity (e.g., 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.
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 [see Use In Specific Populations].
Patient Counseling Information
See FDA-approved Patient Labeling (Medication Guide).
Risk of Neutralizing Antibodies
Advise patients that neutralizing antibodies may result in loss in activity of endogenous leptin or loss of efficacy of MYALEPT. Advise patients on symptoms or signs that would warrant antibody testing [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
Risk of Lymphoma
Advise patients that lymphoma has been reported in patients both treated and not treated with MYALEPT. Advise patients on symptoms or signs that indicate changes in hematologic status and the importance of routine laboratory assessments and physician monitoring [see WARNINGS AND PRECAUTIONS].
Risk of Hypoglycemia
Advise patients that the risk of hypoglycemia is increased when MYALEPT is used in combination with insulin or an insulin secretagogue (e.g., sulfonylurea). Explain the symptoms, treatment, and conditions that predispose to development of hypoglycemia to the patient. Advise patients who are taking concomitant insulin, especially those on high doses, or an insulin secretagogue, to closely monitor blood glucose. Hypoglycemia management should be reviewed and reinforced when initiating MYALEPT therapy, particularly when concomitantly administered with insulin or an insulin secretagogue [see WARNINGS AND PRECAUTIONS].
Risk of Autoimmune Disease
Advise patients that worsening of autoimmune disease has been reported during the clinical study of MYALEPT. Advise patients with a history of autoimmune disease on symptoms or signs that indicate exacerbation of underlying autoimmune disease and the importance of routine laboratory assessments and physician monitoring [see WARNINGS AND PRECAUTIONS].
Risk of Hypersensitivity Reactions
Inform patients that hypersensitivity reactions have been reported during use of MYALEPT. If symptoms of hypersensitivity reactions occur, patients should seek medical advice [see WARNINGS AND PRECAUTIONS].
Advise nursing mothers that breastfeeding is not recommended with MYALEPT use [see Use In Specific Populations].
- Inform patients that each vial of MYALEPT requires reconstitution with BWFI or preservative-free WFI, and administration as subcutaneous injection using a syringe and needle. Injections can be given at any time of the day, with or without meals.
- Patients and caregivers should receive proper training in how to prepare and administer the correct dose of MYALEPT prior to self-administration. The first dose of MYALEPT should be administered by the patient or caregiver under the supervision of a qualified healthcare professional.
- Advise patients on injection technique, dosing regimen, and the importance of proper storage of MYALEPT. Care should be taken to avoid intramuscular injection, especially in patients with minimal subcutaneous adipose tissue.
- Advise patients to read the Instructions for Use for complete administration instructions. The MYALEPT Medication Guide and Instructions for Use should be reviewed before starting therapy and each time the prescription is refilled.
- When discontinuing MYALEPT in patients with a history of pancreatitis and/or severe hypertriglyceridemia, instruct patients to taper their dose over a one-week period. Advise patients that additional monitoring of triglyceride levels and possible initiation or dose adjustment of lipid-lowering medications may be considered [see DOSAGE AND ADMINISTRATION].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year carcinogenicity studies in rodents have not been conducted with metreleptin. No proliferative or preneoplastic lesions were observed in mice or dogs following treatment up to six months. However, leptin is reported in the literature to promote cell proliferation in vitro and tumor progression in some mouse models of cancer.
Metreleptin was not mutagenic in the Ames bacterial mutagenicity assay or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells and human peripheral blood lymphocytes. Metreleptin was not mutagenic or clastogenic in an in vivo mouse micronucleus assay.
In a fertility study in mice, metreleptin had no adverse effects on mating, fertility, or early embryonic development at doses ranging between 7 and 15 times the maximum recommended clinical dose based on body surface area of a 20-and 60-kg patient, respectively.
Use In Specific Populations
Pregnancy Category C
There is a program that monitors outcomes in women exposed to MYALEPT during pregnancy. Women who become pregnant during MYALEPT treatment are encouraged to enroll. Patients or their physicians should call 1-8556MYALEPT to enroll.
There are no adequate and well-controlled studies of MYALEPT in pregnant women. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations and 15% to 20% for pregnancy loss. In a pre-and postnatal development study in mice, administration of metreleptin caused prolonged gestation and dystocia resulting in maternal death during parturition and lower survival of offspring in the immediate postnatal period at doses starting approximately at the maximum recommended clinical dose. Because animal reproduction studies are not always predictive of human response, MYALEPT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Disease-Associated Maternal and Fetal Risk
The contribution of MYALEPT to obstetrical risks and complications is unknown compared with those already documented in the lipodystrophy patient population (e.g., gestational diabetes, macrosomia, eclampsia, intrauterine growth retardation, intrauterine death, and miscarriage).
Labor and Delivery
The effects of MYALEPT on labor and delivery in pregnant women are unknown. In an in vitro study of human myometrial tissue exposed to a recombinant leptin, human uterine contractility was inhibited. Furthermore, prolonged gestation and dystocia were observed in animal studies with metreleptin (see below).
Metreleptin administered to pregnant mice during the period of organogenesis was not teratogenic at doses ranging between 7-and 15-fold the maximum recommended clinical dose, based on body surface area of a 20-and 60-kg patient, respectively.
In a pre-and postnatal development study in mice, metreleptin administered at doses of 3, 10, and 30 mg/kg (approximately 1-, 5-, and 15-fold the clinical dose for a 60-kg subject, based on body surface area) from gestation day 6 to lactation day 21 caused prolonged gestation and dystocia at all doses, starting at approximately the maximum recommended clinical dose. Prolonged gestation resulted in the death of some females during parturition and lower survival of offspring within the immediate postnatal period. Consistent with metreleptin pharmacology, 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. However, no developmental abnormalities were observed and reproductive performance of the first or second generations was not affected at any dose.
Placental transfer of metreleptin into the fetus was low (approximately 1%) following subcutaneous dosing.
It is not known if MYALEPT is present in human milk. Endogenous leptin is present in human milk. Because of the potential for serious adverse reactions (including possible adverse reactions related to passage of anti-metreleptin antibodies) in nursing infants from MYALEPT a decision should be made whether to discontinue nursing or discontinue the drug, taking into account importance of drug to the mother [see ADVERSE REACTIONS and Nonclinical Toxicology].
The MYALEPT study included a total of 35 pediatric patients (73%) with an age range from 1 to 17 years [see Clinical Studies]. No clinically meaningful differences were observed in the efficacy and safety of MYALEPT between pediatric and adult patients.
MYALEPT contains benzyl alcohol when reconstituted with BWFI. MYALEPT contains no preservative when reconstituted with 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, particularly in pediatric patients. The “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) has been associated with benzyl alcohol dosages > 99 mg/kg/day in neonates and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.
Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. When reconstituted with 2.2 mL of BWFI, MYALEPT contains 1.76 mg of benzyl alcohol per mg of metreleptin or 9 mg of benzyl alcohol per mL of reconstituted product.
Clinical trials of MYALEPT did not include sufficient numbers of subjects aged 65 and over (n=1) to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 9/15/2015
Additional Myalept Information
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