AstraZeneca (NYSE: AZN) today announced that the U.S. Food and Drug
Administration (FDA) has approved Myalept™ (metreleptin for injection),
which 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. MYALEPT, a recombinant analog
[laboratory-created form] of human leptin, is the first and only
treatment approved by the FDA for these patients.
AstraZeneca is working to complete the transfer of the Biologics License
Application (BLA) for MYALEPT from Bristol-Myers Squibb Company to
AstraZeneca as part of the acquisition of the diabetes alliance assets
(including MYALEPT and Amylin Pharmaceuticals, LLC), which was completed
on February 1, 2014.
Lipodystrophy is a group of rare syndromes characterized by loss of fat
tissue. In some patients, it is genetic, and in others it may be
acquired for different pathophysiological, and in some cases unknown
reasons. Generalized lipodystrophy is characterized by a widespread loss
of fat tissue under the skin. This loss of fat tissue causes a deficit
in the hormone leptin leading to multiple metabolic complications.
The safety and effectiveness of MYALEPT for the treatment of
complications of partial lipodystrophy or for the treatment of liver
disease, including non-alcoholic steatohepatitis (NASH), have not been
established. MYALEPT is not indicated for use in patients with
HIV-related lipodystrophy or for use in patients with metabolic disease,
including diabetes mellitus and hypertriglyceridemia, without concurrent
evidence of congenital or acquired generalized lipodystrophy.
MYALEPT has Boxed WARNINGS regarding the risk of anti-metreleptin
antibodies with neutralizing activity and risk of lymphoma.
Anti-metreleptin antibodies with neutralizing activity have been
identified in patients treated with MYALEPT. The consequences of these
neutralizing antibodies are not well characterized but could include
inhibition of endogenous leptin action and/or loss of MYALEPT efficacy.
Severe infection and/or worsening metabolic control have been reported.
Healthcare professionals should 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.
T-cell lymphoma has been reported in patients with acquired generalized
lipodystrophy, both treated and not treated with MYALEPT. Healthcare
professionals should carefully consider the benefits and risks of
treatment with MYALEPT in patients with significant hematologic
abnormalities and/or acquired generalized lipodystrophy. Because of
these risks associated with the development of anti-metreleptin
antibodies that neutralize endogenous leptin and/or MYALEPT (metreleptin
for injection) and the risk for lymphoma, MYALEPT is available only
through a restricted program under a Risk Evaluation and Mitigation
Strategy (REMS) called the MYALEPT REMS PROGRAM.
“We are pleased that MYALEPT will be available to patients in the U.S.
MYALEPT is the first approved therapy, as an adjunct to diet, to help
treat the complications of leptin deficiency affecting the lives of
children and adults with generalized lipodystrophy,” said Briggs
Morrison, M.D., executive vice president, Global Medicines Development
and chief medical officer, AstraZeneca. “MYALEPT represents a
significant treatment advancement for people living with this serious
and rare disorder. We are committed to supporting this patient community
and are dedicated to ensuring the appropriate patients who are
prescribed MYALEPT will also have a comprehensive patient support
program available to them.”
MYALEPT is for subcutaneous injection only and is available in an 11.3
mg vial that requires reconstitution.
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. MYALEPT is also contraindicated
in patients with prior severe hypersensitivity reactions to metreleptin
or any of the product components. Known hypersensitivity reactions have
included urticaria and generalized rash.
AstraZeneca is working to make MYALEPT available to patients as soon as
possible in the U.S. MYALEPT has been granted orphan drug status by the
FDA.
INDICATION and IMPORTANT SAFETY INFORMATION
for Myalept™ (metreleptin for injection)
INDICATION
Myalept™ (metreleptin for injection) is a recombinant human 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.
LIMITATIONS OF USE
-
The safety and effectiveness of MYALEPT (metreleptin for injection)
for the treatment of complications of partial lipodystrophy or 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 or in patients with metabolic disease, including
diabetes mellitus and hypertriglyceridemia, without concurrent
evidence of congenital or acquired generalized lipodystrophy.
IMPORTANT SAFETY INFORMATION
WARNING: RISK OF ANTI-METRELEPTIN ANTIBODIES WITH NEUTRALIZING
ACTIVITY AND RISK OF LYMPHOMA
-
Anti-metreleptin antibodies with neutralizing activity have been
identified in patients treated with MYALEPT. The consequences of these
neutralizing antibodies are not well characterized but could include
inhibition of endogenous leptin action and/or loss of MYALEPT
efficacy. Severe infection and/or worsening metabolic control have
been reported. 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
Bristol Myers-Squibb at 1-866-216-1526 for neutralizing antibody
testing of clinical samples
-
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
-
Because of these risks associated with the development of
anti-metreleptin antibodies that neutralize endogenous leptin and/or
MYALEPT and the risk for lymphoma, MYALEPT is available only through a
restricted program under a Risk Evaluation and Mitigation Strategy
(REMS) called the MYALEPT REMS PROGRAM
CONTRAINDICATIONS
MYALEPT (metreleptin for injection) 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
-
Prior severe hypersensitivity reactions to metreleptin or to any of
the product components. Known hypersensitivity reactions have included
urticaria and generalized rash.
WARNINGS AND PRECAUTIONS
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.
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 (metreleptin for injection) 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
Warnings and Precautions section].
Further information is available at www.myaleptrems.com
or 1-855-6MYALEPT.
Hypoglycemia with Concomitant Use with Insulin and Insulin
Secretagogues
Dosages 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 MYALEPT.
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 (metreleptin for injection). 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.
Hypersensitivity
There have been reports of generalized hypersensitivity (e.g., urticaria
or generalized rash) in patients taking MYALEPT. If a hypersensitivity
reaction occurs, patient should promptly seek medical advice regarding
discontinuation of MYALEPT.
Benzyl Alcohol Toxicity
MYALEPT contains benzyl alcohol when reconstituted with Bacteriostatic
Water for Injection (BWFI). The preservative benzyl alcohol has been
associated with serious adverse events and death in pediatric patients,
particularly in neonates and premature infants. Preservative-free Water
for Injection (WFI), that does not contain benzyl alcohol, is
recommended for use in neonates and infants.
ADVERSE REACTIONS
-
In an open label, single arm study (N=48), the most common adverse
reactions reported in ≥5% in patients with generalized lipodystrophy
receiving MYALEPT were:
-
Headache (13%), hypoglycemia (13%), decreased weight (13%),
abdominal pain (10%), arthralgia (8%), dizziness (8%), ear
infection (8%), fatigue (8%), nausea (8%), ovarian cyst (8%),
upper respiratory tract infection (8%), anemia (6%), back pain
(6%), diarrhea (6%), paresthesia (6%), proteinuria (6%), pyrexia
(6%)
-
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
-
Anti-metreleptin antibodies were detected in 84% (36/43) of
generalized lipodystrophy patients studied in the MYALEPT (metreleptin
for injection) trials. The magnitude and persistence of the
observed anti-drug antibody responses is not understood.
Anti-metreleptin antibodies with neutralizing activity associated with
adverse events consistent with loss of endogenous leptin activity
and/or loss of MYALEPT efficacy was observed in 6% (2/33) of the
patients with generalized lipodystrophy tested including severe
infections and worsening of metabolic control (increases in HbA1c
and/or triglycerides) was seen in these two patients.
-
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.
DRUG 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.
USE IN SPECIFIC POPULATIONS
Pregnant Women
-
There are no adequate and well-controlled studies of MYALEPT in
pregnant women. MYALEPT should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus. There is
a program that monitors outcomes in women exposed to MYALEPT during
pregnancy.
-
Disease-Associated Maternal and Fetal Risk: The contribution of
MYALEPT (metreleptin for injection) 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 or Delivery: The effects of MYALEPT on labor and delivery
in pregnant women are unknown.
Nursing Mothers: 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.
Pediatric Use
-
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 (metreleptin for
injection) contains 1.76 mg of benzyl alcohol per mg of
metreleptin or 9 mg of benzyl alcohol per mL of reconstituted product.
ADDITIONAL CONSIDERATIONS
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 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.
Please click
here for US Full Prescribing Information and click
here for Medication Guide for MYALEPT (metreleptin for
injection), including Boxed WARNINGS about the risks of
anti-metreleptin antibodies with neutralizing activity and lymphoma.
Please click
here for Instructions for Use.
About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical business
that focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of cardiovascular,
metabolic, respiratory, inflammation, autoimmune, oncology, infection
and neuroscience diseases. AstraZeneca operates in over 100 countries
and its innovative medicines are used by millions of patients worldwide.
For more information please visit: www.astrazeneca.com.
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