Dosage & 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).
The recommended daily dosages are:
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Myalept Prescribing Information
WARNING: RISK OF ANTI-METRELEPTIN ANTIBODIES WITH NEUTRALIZING ACTIVITY AND RISK OF LYMPHOMA
See full prescribing information for complete boxed warning.
Anti-metreleptin antibodies with neutralizing activity have been identified in patients treated with MYALEPT. The consequences are not well characterized but could include inhibition of endogenous leptin action and loss of MYALEPT efficacy. Worsening metabolic control and/or severe infection have been reported. Test for anti-metreleptin antibodies with neutralizing activity in patients with severe infections or loss of efficacy during MYALEPT treatment. Contact Amryt Pharmaceuticals DAC at 1-866-216-1526 for neutralizing antibody testing. ,
T-cell lymphoma has been reported in patients with acquired generalized lipodystrophy, both treated and not treated with MYALEPT. Carefully consider the benefits and risks of treatment with MYALEPT in patients with significant hematologic abnormalities and/or acquired generalized lipodystrophy.
MYALEPT is available only through a restricted program called the MYALEPT REMS PROGRAM.
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.
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.
| Baseline weight | Starting daily dose (injection volume) | Dose adjustments (injection volume) | Maximum daily dose (injection volume) |
|---|---|---|---|
Less than or equal to 40 kg | 0.06 mg/kg | 0.02 mg/kg | 0.13 mg/kg |
Males greater than 40 kg | 2.5 mg | 1.25 mg (0.25 mL) to | 10 mg |
Females greater than 40 kg | 5 mg | 1.25 mg (0.25 mL) to | 10 mg |
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.
| 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.
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 [see How Supplied/Storage and Handling (16.2)].
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 [see How Supplied/Storage and Handling (16.2)]. 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 [see Warnings and Precautions (5.7) and Use in Specific Populations (8.4)]. 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:
- a)
- Remove the vial containing the MYALEPT lyophilized powder from the refrigerator and allow the vial to warm to room temperature prior to use.
- b)
- Visually inspect the vial containing MYALEPT. The cake of lyophilized powder should be intact and white in color.
- c)
- 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.
- d)
- 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.
- e)
- 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.
- f)
- 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.
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:
- a)
- Using a 1-mL or smaller syringe with a needle appropriate for subcutaneous injection, withdraw the prescribed dose of MYALEPT reconstituted solution.
- b)
- Remove any large air pockets or large bubbles from the filled syringe prior to administration. Some small bubbles may remain in the syringe.
- c)
- 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.
- d)
- 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.
- e)
- 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.
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 [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. 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.
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.
For Injection: 11.3 mg of metreleptin supplied in a vial as a sterile, white, solid, lyophilized cake (delivers 5 mg per mL of metreleptin when reconstituted with 2.2 mL of BWFI or WFI).
Pregnancy
Pregnancy Exposure Registry
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 1-855-669-2537 to enroll.
Risk Summary
Available pharmacovigilance reports with the use of MYALEPT 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 (see Clinical Considerations). In an animal reproduction study, no adverse developmental effects were observed with subcutaneous administration of metreleptin to pregnant mice during organogenesis at doses 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, subcutaneous 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 (see Data).
MYALEPT contains benzyl alcohol when reconstituted with BWFI. MYALEPT contains no preservative when reconstituted with WFI. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions (5.7) and Use in Specific Populations (8.4)]. Therefore, if therapy with MYALEPT is needed during pregnancy, consider using preservative-free WFI when reconstituting [see Dosage and Administration (2.2)].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-Associated Maternal and Fetal Risk
Lipodystrophy in pregnancy can result in an increased rate of 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 a published in vitro study of human myometrial tissue exposed to a recombinant leptin, human uterine contractility was inhibited. In animal studies with metreleptin, prolonged gestation and dystocia were observed (see Data).
Data
Animal Data
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.
Lactation
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. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for MYALEPT and any potential adverse effects on the breastfed child from MYALEPT or from the underlying maternal condition.
Pediatric Use
The MYALEPT study included a total of 35 pediatric patients (73%) with an age range from 1 to 17 years [see Clinical Studies (14.1)]. 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.
Geriatric Use
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.
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 [see Warnings and Precautions (5.1)].
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 [see Warnings and Precautions (5.6)].