MYALEPTA Powder for solution for injection Ref.[27914] Active ingredients: Metreleptin

Data from clinical trials do not support safety and efficacy in patients with HIV-related LD.

Hypersensitivity reactions

There have been reports of generalised hypersensitivity (e.g. anaphylaxis, urticaria or generalised rash) in patients using Myalepta. Anaphylactic reactions may follow immediately after administration of the medicine. If an anaphylactic reaction or other serious allergic reaction occurs, administration should be permanently discontinued immediately and appropriate therapy initiated.

Acute pancreatitis associated with discontinuation of Myalepta

Non-compliance with, or abrupt discontinuation of, Myalepta may result in worsening hypertriglyceridaemia and associated pancreatitis, particularly in patients with risk factors for pancreatitis (e.g. history of pancreatitis, severe hypertriglyceridaemia) (see section 4.8). If a patient develops pancreatitis whilst being treated with metreleptin, it is advised that metreleptin be continued uninterrupted, as stopping treatment abruptly may exacerbate the condition. If metreleptin must be stopped for any reason, tapering of the dose over a two-week period is recommended in conjunction with a low fat diet, see section 4.2. During tapering, monitor triglyceride levels and consider initiating or adjusting the dose of lipid-lowering medicinal products as needed. Signs and/or symptoms consistent with pancreatitis should prompt an appropriate clinical evaluation.

Hypoglycaemia with concomitant use of insulin and other anti-diabetics

There is a risk of hypoglycaemia in patients treated with Myalepta who are on anti-diabetic medicinal products, in particular insulin or insulin secretagogues (e.g. sulphonylureas). Large dose reductions of 50% or more of baseline insulin requirements may be needed in the first 2 weeks of treatment. Once insulin requirements have stabilised, dose adjustments of other anti-diabetics may also be needed in some patients to minimise the risk of hypoglycaemia.

Closely monitor blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulin secretagogues and combination treatment. Patients and carers should be advised to be aware of the signs and symptoms of hypoglycaemia.

In clinical studies, hypoglycaemia has been managed with food/drink intake and by modifying the dose of anti-diabetic medicinal product. In case of hypoglycaemic events of a non-severe nature, food intake management may be considered as an alternative to dose-adjustment of anti-diabetics according to the treating physician’s opinion.

Rotation of injection sites is recommended in patients co-administering insulin (or other subcutaneous medicinal products) and Myalepta.

T-cell lymphoma

Cases of T-cell lymphoma (see section 4.8) have been reported while using Myalepta in clinical studies. A causal relationship between the medicinal product treatment and the development and/or progression of lymphoma has not been established.

The benefits and risks of treatment should be carefully considered in patients with acquired generalised LD and/or in patients with significant haematological abnormalities (including leukopenia, neutropenia, bone marrow abnormalities, lymphoma, and/or lymphadenopathy).

Immunogenicity

In clinical trials, antidrug antibodies (ADA) to metreleptin occurred very commonly (88%) in patients. A blocking activity of the reaction between metreleptin and a recombinant leptin receptor has been observed in vitro in the blood of the majority of patients but the impact on the efficacy of metreleptin could not be clearly established (see section 4.8).

In patients with serious and severe infections, continuation of metreleptin should be at the discretion of the prescriber. An association between the development of a blocking activity against metreleptin and serious and severe infections cannot be excluded (see section 4.8).

Though not confirmed in clinical trials, neutralising antibodies could in theory affect the activity of endogenous leptin.

Autoimmune Diseases

Autoimmune disorder progression / flares, including severe autoimmune hepatitis, have been observed in some patients treated with Myalepta but a causal relationship between Myalepta treatment and progression of autoimmune disease has not been established. Close monitoring for underlying autoimmune disorder flares (sudden and severe onset of symptoms) is recommended. The potential benefits and risks of Myalepta treatment should be carefully considered in patients with autoimmune diseases.

Pregnancy

Unplanned pregnancies may occur due to restoration of luteinizing hormone (LH) release, see section 4.6.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium free”.

No interaction studies have been performed in humans.

Leptin is a cytokine and has the potential to alter the formation of cytochrome P450 (CYP450) enzymes. Since it cannot be excluded that metreleptin may reduce exposure to substrates of CYP3A through enzyme induction, the efficacy of hormonal contraceptives may be reduced if co-administered with metreleptin. Therefore, an additional non-hormonal contraceptive method should be considered during treatment. 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 metreleptin, in patients being treated with these types of agents, therapeutic monitoring of effect (e.g., warfarin), or drug concentrations (e.g. cyclosporin or theophylline) should be performed and the individual dose of the agent adjusted as needed. When starting therapy with Myalepta there is a risk of hypoglycaemia in patients who are on anti-diabetic medicinal products, in particular insulin or insulin secretagogues (see section 4.4).

Pregnancy

Myalepta is not recommended during pregnancy and in women of childbearing potential not using contraception. Abortions, stillbirths and preterm deliveries have been reported in women exposed to metreleptin during pregnancy, though there is currently no evidence to suggest a causal relationship with the treatment. Studies in animals have shown some evidence of reproductive toxicity (see section 5.3).

Breast-feeding

It is unknown whether metreleptin or its metabolites are excreted in human milk. Endogenous leptin is present in human milk.

A risk to newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Myalepta therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are data to suggest metreleptin may increase fertility, due to effects on LH, with the consequent potential for unplanned pregnancy (see section 4.4).

Animal studies showed no adverse effects on male or female fertility (see section 5.3).

Myalepta has minor influence on the ability to drive and use machines due to fatigue and dizziness.

Summary of the safety profile

A total of 148 patients with generalised and partial LD received metreleptin during clinical studies.

Safety and efficacy data were analysed in a subgroup of partial LD patients with the following characteristics: 12 years of age and above with leptin levels <12 ng/mL, TG ≥5.65 mmol/l and/or HbA1c ≥8%.

The adverse reactions reported in generalised LD and this subgroup of partial LD patients are listed in Table 7. Additionally, adverse reactions from post-marketing sources are also presented. The most frequently occurring adverse reactions from the clinical studies were hypoglycaemia (14%) and weight decreased (17%).

Tabulated list of adverse reactions

Adverse reactions are classified by MedDRA System Organ Class and absolute frequency in Table 7. Frequencies are defined as very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data). Due to the number of patients with generalised and partial LD treated in clinical trials, it is not possible to detect with certainty, events which occur at a frequency of <1%.

Table 7. Adverse reactions reported with Myalepta in >1 patient during clinical studies in generalised LD and the subgroup of partial LD patients and post-marketing experience:

^* Global post marketing experience

Acute pancreatitis associated with discontinuation of metreleptin

In clinical studies, 6 patients (4 with generalised LD and 2 with partial LD), experienced treatment-emergent pancreatitis. All patients had a history of pancreatitis and hypertriglyceridaemia. Abrupt interruption and/or non-compliance with metreleptin dosing was suspected to have contributed to the occurrence of pancreatitis in 2 patients. The mechanism for pancreatitis in these patients was presumed to be return of hypertriglyceridaemia and therefore increased risk of pancreatitis in the setting of discontinuation of effective therapy for hypertriglyceridaemia.

Hypoglycaemia

Metreleptin may decrease insulin resistance in diabetic patients, resulting in hypoglycaemia in patients with LD and co-existing diabetes. Hypoglycaemia, deemed as related to metreleptin treatment, occurred in 14.2% of patients studied. All reports of hypoglycaemia in patients with generalised LD and in the subgroup of partial LD patients, have been mild in nature with no pattern of onset or clinical sequelae. Generally the majority of events could be managed by food intake with only relatively few modifications of anti-diabetic medicinal product dose occurring.

T-cell lymphoma

Three cases of T-cell lymphoma have been reported while using metreleptin in clinical studies. All three patients had acquired generalised LD. Two of these patients were diagnosed with peripheral T-cell lymphoma while receiving the medicinal product. Both had immunodeficiency and significant haematological abnormalities including severe bone marrow abnormalities before the start of treatment. A separate case of anaplastic large cell lymphoma was reported in a paediatric patient receiving the medicinal product who did not have haematological abnormalities before treatment.

Immunogenicity

In clinical trials (Studies NIH 991265/20010769 and FHA101), the rate of ADAs for generalised LD and the partial LD patients studied and with data available were 88% (65 out of 74 patients). A blocking activity of the reaction between metreleptin and a recombinant leptin receptor has been observed in vitro in the blood of the majority of an extended set of patients (98 out of 102 patients or 96%) but the impact on the efficacy of metreleptin could not be clearly established.

Serious and/or severe infections that were temporally associated with > 80% blocking activity against metreleptin occurred in 5 generalised LD patients. These events included 1 episode in 1 patient of serious and severe appendicitis, 2 episodes in patients of serious and severe pneumonia, a single episode of serious and severe sepsis and non-serious severe gingivitis in 1 patient and 6 episodes of serious and severe sepsis or bacteraemia and 1 episode of non-serious severe ear infection in 1 patient. One serious and severe infection of appendicitis was temporally associated with blocking activity against metreleptin in a patient with partial LD who was not in the subgroup of partial LD patients. Though temporally associated, it is not possible to unequivocally confirm or deny a direct relation to metreleptin treatment based on the currently available body of evidence. LD patients with a blocking activity against metreleptin and concurrent infections responded to standard of care treatment (see section 4.4).

Injection site reactions

Injection site reactions were reported in 3.4% of patients with LD treated with metreleptin. All events reported in clinical studies in patients with LD have been mild or moderate in severity and none have led to treatment discontinuation. Most events occurred during the initial 1-2 months of initiation of treatment.

Paediatric population

Across two completed clinical studies (NIH 991265/20010769 and FHA101), there were 52 paediatric patients (4 in the subgroup of partial LD patients and 48 with generalised LD) enrolled and exposed to metreleptin. Limited clinical data exists in children less than 2 years old for generalised LD patients and less than 12 years old in partial LD patients.

Overall, the safety and tolerability of metreleptin are similar in children and adults.

In generalised LD patients, the overall incidence of adverse reactions was similar regardless of age. Serious adverse reactions were reported in 2 patients, worsening hypertension and anaplastic large cell lymphoma.

In partial LD patients, assessment across age groups is limited, due to the small sample size. No adverse reactions were reported in paediatric patients in the subgroup of partial LD patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system for your country.

United Kingdom: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland: HPRA Pharmacovigilance, Website: www.hpra.ie

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.