Metreleptin Shionogi

Patients With Generalized Lipodys trophy

Metreleptin Shionogi (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.

Sections or subsections omitted from the full prescribing information are not listed.

Limitations Of Use

• The safety and effectiveness of Metreleptin Shionogi for the treatment of complications of partial lipodystrophy have not been established.
• The safety and effectiveness of Metreleptin Shionogi for the treatment of liver disease, including nonalcoholic steatohepatitis (NASH), have not been established.
• Metreleptin Shionogi is not indicated for use in patients with HIV-related lipodystrophy.
• Metreleptin Shionogi 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]), Metreleptin Shionogi dosage may be decreased or increased to the maximum dosage listed in Table 1.

Table 1: Metreleptin Shionogi Recommended Dosage

Metreleptin Shionogi should be administered once daily at the same time every day. Metreleptin Shionogi 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.

Metreleptin Shionogi Preparation And Storage

Healthcare practitioners should provide proper training to patients and caregivers regarding how to prepare and administer the correct dose of Metreleptin Shionogi prior to self-use. The patients and caregivers should prepare and administer the first dose of Metreleptin Shionogi 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.

Metreleptin Shionogi 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, Metreleptin Shionogi 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. 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. When reconstituted in sterile WFI, Metreleptin Shionogi 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:

1. Remove the vial containing the Metreleptin Shionogi lyophilized powder from the refrigerator and allow the vial to warm to room temperature prior to use.
2. Visually inspect the vial containing Metreleptin Shionogi. The cake of lyophilized powder should be intact and white in color.
3. 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 Metreleptin Shionogi with other diluents.
4. Inject the BWFI or WFI into the vial containing the lyophilized powder of Metreleptin Shionogi, slowly injecting down the side of the vial. It is normal for some bubbles to form.
5. 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 Metreleptin Shionogi 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.
6. Regarding the compatibility of Metreleptin Shionogi reconstituted solution with other solutions:
   • Do not mix with, or transfer into, the contents of another vial of Metreleptin Shionogi.
   • Do not add other medications, including insulin. Use a separate syringe for insulin injections.

See the Metreleptin Shionogi Instructions for Use for complete administration instructions. The instructions can also be found at www.Metreleptin Shionogi.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 Metreleptin Shionogi intravenously or intramuscularly.

Instruct patients to follow the recommended injection technique:

1. Using a 1-mL syringe with a needle appropriate for subcutaneous injection, withdraw the prescribed dose of Metreleptin Shionogi reconstituted solution.
2. Remove any large air pockets or large bubbles from the filled syringe prior to administration. Some small bubbles may remain in the syringe.
3. Administer Metreleptin Shionogi 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 Metreleptin Shionogi reconstituted solution subcutaneously. Avoid intramuscular injection, especially in patients with minimal subcutaneous adipose tissue.
4. 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.

Do not mix Metreleptin Shionogi with insulin. Use a separate syringe for each medication. If Metreleptin Shionogi 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 Metreleptin Shionogi Instructions for Use for complete administration instructions. The instructions can also be found at www.Metreleptin Shionogi.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. Closely monitor blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulin secretagogue (e.g., sulfonylurea) when treating with Metreleptin Shionogi.

Discontinuation In Patients At Risk For Pancreatitis

When discontinuing Metreleptin Shionogi 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

Metreleptin Shionogi is contraindicated in patients with general obesity not associated with congenital leptin deficiency. Metreleptin Shionogi 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 Shionogi.

Hypersensitivity

Metreleptin Shionogi 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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk For Development Of Antibodies That Neutralize Endogenous Leptin And/Or Metreleptin Shionogi

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 Metreleptin Shionogi (severe infections, increases in HbA1c and triglycerides), and in three patients without lipodystrophy who received Metreleptin Shionogi 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 Metreleptin Shionogi efficacy during treatment. Contact Aegerion Pharmaceuticals, Inc. at 1-866-216-1526 for neutralizing antibody testing of clinical samples.

Lymphoma

Three cases of T-cell lymphoma have been reported in the Metreleptin Shionogi lipodystrophy program; all three patients had acquired generalized lipodystrophy. Two of these patients were diagnosed with peripheral T-cell lymphoma while receiving Metreleptin Shionogi. Both had immunodeficiency and significant hematologic abnormalities including severe bone marrow abnormalities before the start of Metreleptin Shionogi treatment. A separate case of anaplastic large cell lymphoma was reported in a patient receiving Metreleptin Shionogi who did not have hematological abnormalities before treatment.

Lymphoproliferative disorders, including lymphomas, have been reported in patients with acquired generalized lipodystrophy not treated with Metreleptin Shionogi. A causal relationship between Metreleptin Shionogi 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 Metreleptin Shionogi 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).

Metreleptin Shionogi REMS Program

Metreleptin Shionogi is available only through a restricted distribution program under a REMS, called the Metreleptin Shionogi REMS Program, because of the risks associated with the development of anti-metreleptin antibodies that neutralize endogenous leptin and/or Metreleptin Shionogi and the risk for lymphoma.

Notable requirements of the Metreleptin Shionogi 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 Metreleptin Shionogi after receipt of the Metreleptin Shionogi REMS Prescription Authorization Form for each new prescription.

Further information is available at www.Metreleptin Shionogirems.com or 1-855-6Metreleptin Shionogi.

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. Closely monitor blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulin secretagogue (e.g., sulfonylurea), when treating with Metreleptin Shionogi.

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 Metreleptin Shionogi. A causal relationship between Metreleptin Shionogi treatment and the development and/or progression of autoimmune disease has not been established. The potential benefits and risks of Metreleptin Shionogi treatment should be carefully considered in patients with autoimmune disease.

Hypersensitivity

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

Benzyl Alcohol Toxicity

Metreleptin Shionogi contains benzyl alcohol when reconstituted with BWFI. Metreleptin Shionogi 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.

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 Metreleptin Shionogi. Advise patients on symptoms or signs that would warrant antibody testing.

Risk Of Lymphoma

Advise patients that lymphoma has been reported in patients both treated and not treated with Metreleptin Shionogi.

Advise patients on symptoms or signs that indicate changes in hematologic status and the importance of routine laboratory assessments and physician monitoring.

Risk Of Hypoglycemia

Advise patients that the risk of hypoglycemia is increased when Metreleptin Shionogi 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 Metreleptin Shionogi therapy, particularly when concomitantly administered with insulin or an insulin secretagogue.

Risk Of Autoimmune Disease

Advise patients that worsening of autoimmune disease has been reported during the clinical study of Metreleptin Shionogi. 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.

Risk Of Hypersensitivity Reactions

Inform patients that hypersensitivity reactions have been reported during use of Metreleptin Shionogi. If symptoms of hypersensitivity reactions occur, patients should seek medical advice.

Nursing Mothers

Advise nursing mothers that breastfeeding is not recommended with Metreleptin Shionogi use.

Instructions

• Inform patients that each vial of Metreleptin Shionogi 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 Metreleptin Shionogi prior to self-administration. The first dose of Metreleptin Shionogi 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 Metreleptin Shionogi. 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 Metreleptin Shionogi Medication Guide and Instructions for Use should be reviewed before starting therapy and each time the prescription is refilled.
• When discontinuing Metreleptin Shionogi 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 lipidlowering medications may be considered.

Nonclinical Toxicology

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

Pregnancy Category C

There is a program that monitors outcomes in women exposed to Metreleptin Shionogi during pregnancy. Women who become pregnant during Metreleptin Shionogi treatment are encouraged to enroll. Patients or their physicians should call 1-855-6Metreleptin Shionogi to enroll.

Risk Summary

There are no adequate and well-controlled studies of Metreleptin Shionogi 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, Metreleptin Shionogi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Disease-Associated Maternal And Fetal Risk

The contribution of Metreleptin Shionogi 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 Metreleptin Shionogi 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).

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.

Nursing Mothers

It is not known if Metreleptin Shionogi 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 Metreleptin Shionogi a decision should be made whether to discontinue nursing or discontinue the drug, taking into account importance of drug to the mother.

Pediatric Use

The Metreleptin Shionogi study 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 of Metreleptin Shionogi between pediatric and adult patients.

Metreleptin Shionogi contains benzyl alcohol when reconstituted with BWFI. Metreleptin Shionogi 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, Metreleptin Shionogi 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 Metreleptin Shionogi 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.

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 Metreleptin Shionogi was evaluated in 48 patients with generalized lipodystrophy in a single-arm, open-label study. 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 2.

Table 2: Adverse Reactions of 5% or Greater Incidence in Patients with Generalized Lipodys trophy Receiving Metreleptin Shionogi in an Open-Label, Single-Arm Study

In patients with generalized lipodystrophy receiving Metreleptin Shionogi 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.

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 Metreleptin Shionogi 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 Metreleptin Shionogi 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 HbA1c and/or triglycerides). Test for anti-metreleptin antibodies with neutralizing activity in patients who develop severe infections or show signs suspicious for loss of Metreleptin Shionogi efficacy during treatment. Contact Aegerion Pharmaceuticals, Inc. 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.

There were no reports of overdose in the lipodystrophy clinical trial program of Metreleptin Shionogi. In the event of an overdose, patients should be monitored and appropriate supportive treatment be initiated as dictated by the patient's clinical status.

Clinical studies in patients with generalized lipodystrophy suggest that Metreleptin Shionogi increases insulin sensitivity and reduces food intake. Improvements in insulin sensitivity and reductions in food intake are consistent with lower HbA1c, fasting glucose, and fasting triglyceride values that were seen in the Metreleptin Shionogi clinical trial.

There are limited data on the pharmacokinetics of metreleptin in patients with generalized lipodystrophy, and therefore, no formal exposure-response analysis has been performed. It should be noted that the leptin assay measures both endogenous leptin as well as exogenously administered metreleptin.

Absorption

Peak serum leptin concentration (Cmax) occurred approximately 4.0 to 4.3 hours after subcutaneous administration of single doses ranging from 0.1 to 0.3 mg/kg in healthy subjects. In a supportive trial in lipodystrophy patients, the median Tmax of metreleptin was 4 hours (range: 2 to 8 hours; N=5) following single-dose administration of metreleptin.

Distribution

In studies of healthy adult subjects, following intravenous administration of metreleptin, leptin volume of distribution was approximately 4 to 5 times plasma volume; volumes (Vz) (mean ± SD) were 370 ± 184 mL/kg, 398 ± 92 mL/kg, and 463 ± 116 mL/kg for 0.3, 1.0, and 3.0 mg/kg/day doses, respectively.

Metabolism And Elimination

No formal metabolism studies have been conducted with metreleptin. Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. Following single subcutaneous doses of 0.01 to 0.3 mg/mL metreleptin in healthy subjects, the half-life was 3.8 to 4.7 hours. The clearance of metreleptin is expected to be delayed in the presence of leptin antibodies.