MYALEPTA 5.8mg powder for injection medication leaflet

Myalepta 3 mg powder for solution for injection.

Myalepta 5.8 mg powder for solution for injection.

Myalepta 11.3 mg powder for solution for injection.

Myalepta 3 mg powder for solution for injection

Each vial contains 3 mg of metreleptin*.

After reconstitution with 0.6 mL water for injections (see section 6.6), each mL contains 5 mg ofmetreleptin.

Myalepta 5.8 mg powder for solution for injection

Each vial contains 5.8 mg of metreleptin*.

After reconstitution with 1.1 mL water for injections (see section 6.6), each mL contains 5 mg ofmetreleptin.

Myalepta 11.3 mg powder for solution for injection

Each vial contains 11.3 mg of metreleptin*.

After reconstitution with 2.2 mL water for injections (see section 6.6), each mL contains 5 mg ofmetreleptin.

*Metreleptin is a recombinant human leptin analogue (produced in Escherichia coli cells byrecombinant DNA technology to form recombinant methionyl-human leptin).

For the full list of excipients, see section 6.1.

Powder for solution for injection (powder for injection).

White lyophilised cake or powder.

Myalepta is indicated as an adjunct to diet as a replacement therapy to treat the complications of leptindeficiency in lipodystrophy (LD) patients:

* with confirmed congenital generalised LD (Berardinelli-Seip syndrome) or acquired generalised

LD (Lawrence syndrome) in adults and children 2 years of age and above

* with confirmed familial partial LD or acquired partial LD (Barraquer-Simons syndrome), inadults and children 12 years of age and above for whom standard treatments have failed toachieve adequate metabolic control.

Treatment should be initiated and monitored by a healthcare professional experienced in the diagnosisand management of metabolic disorders.

The recommended daily dose of metreleptin is based on body weight as provided in Table 1.

In order to ensure patients and carers understand the correct dose to be injected, the prescriber shouldprescribe the appropriate dose both in milligrams and the volume in millilitres. In order to avoidmedication errors including overdose, dose calculation and dose adjustment guidelines below shouldbe followed. A review of the patient’s self-administration technique is recommended every 6 monthswhilst using Myalepta.

Actual body weight at initiation of treatment should always be used when calculating the dose.

Table 1 Metreleptin recommended dose

Baseline weight Starting daily dose Dose adjustments Maximum daily dose(injection volume) (injection volume) (injection volume)

Males and females ≤ 40 kg 0.06 mg/kg 0.02 mg/kg 0.13 mg/kg(0.012 mL/kg) (0.004 mL/kg) (0.026 mL/kg)

Males > 40 kg 2.5 mg 1.25 mg (0.25 mL) to 10 mg(0.5 mL) 2.5 mg (0.5 mL) (2 mL)

Females > 40 kg 5 mg 1.25 mg (0.25 mL) to 10 mg(1 mL) 2.5 mg (0.5 mL) (2 mL)

Based on clinical response (e.g. inadequate metabolic control) or other consideration (e.g. tolerabilityissues, excessive weight loss especially in paediatric patients), the dose may be decreased, or increasedto the maximum dose listed in Table 1. The maximum tolerated dose may be less than the maximumdaily dose, outlined in Table 1, as evidenced by excessive weight loss, even if metabolic response isincomplete.

A minimum clinical response is defined as at least:

* 0.5% HbA1c reduction and/or 25% reduction in insulin requirementsand/or

* 15% reduction in triglycerides (TGs)

If clinical response is not seen after 6 months of treatment the physician should ensure that the patientis compliant with the administration technique, is receiving the correct dose and is adherent to diet. Adose increase before stopping treatment should be considered.

Metreleptin dose increases in adults and children based on incomplete clinical response can beconsidered after a minimum of 6 months of treatment, allowing for lowering concomitant insulin, oralanti-diabetic and/or lipid lowering medication.

Reductions in HbA1c and TG may not be seen in children as metabolic abnormalities may not bepresent at the start of treatment. It is anticipated that most children will require increasing per kg dose,especially as they reach puberty. Increasing abnormalities of TG and HbA1c may be seen which mayrequire a dose increase. Dose adjustments in children without metabolic abnormalities shouldprimarily be made according to weight change.

Dose increases should not be made more frequently than every 4 weeks. Dose decreases based onweight loss may be made weekly.

There is a risk of hypoglycaemia in patients treated with Myalepta who are on anti-diabetic therapy.

Large dose reductions of 50% or more of baseline insulin requirements may be needed in the initialphases of treatment. Once insulin requirements have stabilised, dose adjustments of other anti-diabetictherapies may also be needed in some patients to minimise the risk of hypoglycaemia (see section 4.4and 4.8).

Discontinuation in patients at risk for pancreatitis

When discontinuing Myalepta in patients with risk factors for pancreatitis (e.g. history of pancreatitis,severe hypertriglyceridaemia), tapering of the dose over a two-week period is recommended inconjunction with a low-fat diet. During tapering, monitor triglyceride levels and consider initiating oradjusting the dose of lipid-lowering medicinal products as needed. Signs and/or symptoms consistentwith pancreatitis should prompt an appropriate clinical evaluation (see section 4.4).

If a patient misses a dose, the dose should be administered as soon as the omission is noticed and thenormal dosing schedule resumed the next day.

Clinical trials of metreleptin did not include sufficient numbers of patients aged 65 and older todetermine whether they respond differently from younger patients. In general, dose selection andmodification for an elderly patient should be cautious, although no specific dose adjustment isrecommended.

Metreleptin has not been studied in patients with impaired renal or hepatic function. No doserecommendations can be made.

The safety and efficacy of metreleptin in children aged 0 to 2 years with generalised LD and childrenaged 0 to 12 years with partial LD has not been established. Very limited data are available forchildren, especially less than 6 years, with generalised LD.

Subcutaneous use.

Healthcare professionals should provide patients and carers with training on the reconstitution of theproduct and proper subcutaneous injection technique, so as to avoid intramuscular injection in patientswith minimal subcutaneous adipose tissue.

Patients and/or carers should prepare and administer the first dose of the medicinal product under thesupervision of a qualified healthcare professional.

The injection should be administered at the same time every day. It can be administered any time ofthe day without regard to the timing of meals.

The reconstituted solution should be injected into the abdomen, thigh or upper arm tissue. It isrecommended that patients should use a different injection site each day when injecting in the sameregion. Doses exceeding 1 mL can be administered as two injections (the total daily dose dividedequally) to minimise potential injection site discomfort due to injection volume. When dividing dosesdue to volume, doses can be administered one after the other at different injection sites.

When small doses/volumes are prescribed (e.g. in children), the vials will remain almost completelyfilled with product after withdrawal of the required dose. Remaining reconstituted product should bediscarded after use.

For instructions on reconstitution of the medicinal product before administration, see section 6.6 andthe information intended for patients in the package leaflet (section 7).

Table 2 Starting dose calculation

Weight and gender Starting dose calculation

For males and females Weight (kg) x 0.06 mg/kg = Individual patient daily starting dose in mg≤ 40 kg once daily dose Weight (kg) x 0.012 mL/kg = Individual patient daily starting volume to injectin mL

Example:25 kg patient is initiated at 0.06 mg/kg of Myalepta. The individual patientdose = 1.5 mg25 kg patient is initiated at 0.012 mL/kg = 0.3 mL of Myalepta solution toinject

For males > 40 kg once Individual patient once daily dose in mg = 2.5 mgdaily dose Amount to inject once daily dose = 0.5 mL

For females > 40 kg Individual patient once daily dose in mg = 5 mgonce daily dose Amount to inject once daily dose = 1 mL

Table 3 Required syringe for Myalepta reconstitution with water for injection

Syringe Needle gauge and length

Myalepta 3 mg powder for solution for injection1.0 mL 21 gauge40 mm needle

Myalepta 5.8 mg powder for solution for injection3.0 mL 21 gauge40 mm needle

Myalepta 11.3 mg powder for solution for injection3.0 mL 21 gauge40 mm needle

Table 4 Required administration syringe per Myalepta dose

Syringe Needle gauge and length Myalepta dose range to be administered0.3 mL U100 Insulin 31 gauge For doses of:

Syringe 8 mm needle ≤ 1.5 mg/≤ 0.3 mL volume daily1.0 mL 30 gauge For doses of:13 mm needle > 1.5 mg - 5 mg/0.3 - 1.0 mL volume daily3.0 mL 30 gauge For doses of:13 mm needle > 5 mg - 10 mg/> 1.0 mL volume daily

For patients weighing less than 40 kg, actual body weight at initiation of therapy should be used tocalculate dose; of these, in patients weighing less than or equal to 25 kg, refer to Table 5 for thestarting dose.

Table 5 Conversion table for the 0.3 mL U100 insulin syringe

Rounded ‘Unit’

Weight of child Dose of Actual amount measurement

Myalepta of solution* amount ofsolution volume in 0.3 mLsyringe to inject9 kg 0.54 mg 0.108 mL 0.10 mL 1010 kg 0.60 mg 0.120 mL 0.12 mL 1211 kg 0.66 mg 0.132 mL 0.13 mL 1312 kg 0.72 mg 0.144 mL 0.14 mL 1413 kg 0.78 mg 0.156 mL 0.15 mL 1514 kg 0.84 mg 0.168 mL 0.16 mL 1615 kg 0.90 mg 0.180 mL 0.18 mL 1816 kg 0.96 mg 0.192 mL 0.19 mL 1917 kg 1.02 mg 0.204 mL 0.20 mL 2018 kg 1.08 mg 0.216 mL 0.21 mL 2119 kg 1.14 mg 0.228 mL 0.22 mL 2220 kg 1.20 mg 0.240 mL 0.24 mL 2421 kg 1.26 mg 0.252 mL 0.25 mL 2522 kg 1.32 mg 0.264 mL 0.26 mL 2623 kg 1.38 mg 0.276 mL 0.27 mL 2724 kg 1.44 mg 0.288 mL 0.28 mL 2825 kg 1.50 mg 0.300 mL 0.30 mL 30

*Note: Initial and dose increments should be rounded down to the nearest 0.01 mL

The once daily dose of Myalepta can be increased by increments as shown in Table 6 to a maximumdaily dose.

Table 6 Dose adjustment calculation

Adjust doseas follows Action(if necessary)

Weight (kg) x 0.02 mg/kg = amount of dose adjustment in mg

Total daily volume to be injected is total dose in mg divided by 5.

Example: A 15 kg patient is initiated at 0.06 mg/kg of Myalepta. The

Males and females individual patient dose = 0.9 mg. A dose increment of 0.02 mg/kg increases≤ 40 kg the daily dose to 0.08 mg/kg = 1.2 mg. Total daily volume to be injected istotal dose in mg divided by 5, in this case it is 1.2 mg/5 = 0.24 mL whichequals 24 units on the 0.3 mL insulin syringe.

The maximum daily dose in males and females is 0.13 mg/kg or 0.026 mL/kginjection volume.

For all patients weighing more than 40 kg an incremental adjustment increasein daily dose would be 1.25 mg or 0.25 mL injection volume.

Total daily volume to be injected is total dose in mg divided by 5.

Both males andfemales > 40 kg Example: A male patient is initiated at 2.5 mg of Myalepta daily. A doseincrement of 1.25 mg increases the daily dose to 3.75 mg.

Total daily volume to be injected is 3.75 mg/5 = 0.75 mL.

The maximum daily dose in males and females is 10 mg or 2 mL injectionvolume.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

There have been reports of generalised hypersensitivity (e.g. anaphylaxis, urticaria or generalised rash)in patients using Myalepta (see section 4.8). Anaphylactic reactions may follow immediately afteradministration 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 worseninghypertriglyceridaemia and associated pancreatitis, particularly in patients with risk factors forpancreatitis (e.g. history of pancreatitis, severe hypertriglyceridaemia) (see section 4.8). If a patientdevelops pancreatitis whilst being treated with metreleptin, it is advised that metreleptin be continueduninterrupted, as stopping treatment abruptly may exacerbate the condition. If metreleptin must bestopped for any reason, tapering of the dose over a two-week period is recommended in conjunctionwith a low fat diet, see section 4.2. During tapering, monitor triglyceride levels and consider initiatingor adjusting the dose of lipid-lowering medicinal products as needed. Signs and/or symptomsconsistent 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 medicinalproducts, in particular insulin or insulin secretagogues (e.g. sulphonylureas). Large dose reductions of50% or more of baseline insulin requirements may be needed in the first 2 weeks of treatment. Onceinsulin requirements have stabilised, dose adjustments of other anti-diabetics may also be needed insome patients to minimise the risk of hypoglycaemia.

Blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulinsecretagogues and combination treatment should be closely monitored. Patients and carers should beadvised to be aware of the signs and symptoms of hypoglycaemia.

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

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

T-cell lymphoma

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

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

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 beenobserved in vitro in the blood of the majority of patients but the impact on the efficacy of metreleptincould not be clearly established (see section 4.8).

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

Serious and severe infections

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

Autoimmune diseases

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

Unplanned pregnancies may occur due to restoration of luteinizing hormone (LH) release, see section4.6.

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 CYP3Athrough enzyme induction, the efficacy of hormonal contraceptives may be reduced if co-administeredwith metreleptin (see section 4.6). Therefore, an additional non-hormonal contraceptive method shouldbe considered during treatment. The effect of metreleptin on CYP450 enzymes may be clinicallyrelevant 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 ortheophylline) should be performed and the individual dose of the agent adjusted as needed. Whenstarting therapy with Myalepta there is a risk of hypoglycaemia in patients who are on anti-diabeticmedicinal products, in particular insulin or insulin secretagogues (see section 4.4).

Female patients of childbearing potential should be advised to use adequate contraception, ifnecessary, during treatment with metreleptin. Concomitant administration of Myalepta with hormonalcontraceptives may decrease hormonal contraceptives bioavailability (see section 4.5). Women shouldbe counselled to use an alternative non-hormonal method of contraception when Myalepta is used withhormonal contraceptives.

Myalepta is not recommended during pregnancy and in women of childbearing potential not usingcontraception. Abortions, stillbirths and preterm deliveries have been reported in women exposed tometreleptin during pregnancy, though there is currently no evidence to suggest a causal relationshipwith the treatment. Studies in animals have shown some evidence of reproductive toxicity (seesection 5.3).

It is unknown whether metreleptin or its metabolites are excreted in human milk. Endogenous leptin ispresent 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 oftherapy for the woman.

There are data to suggest metreleptin may increase fertility, due to effects on LH, with the consequentpotential 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.

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 followingcharacteristics: 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 mostfrequently occurring adverse reactions from the clinical studies were hypoglycaemia (14%) and weightdecreased (17%).

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 (≥ 1/1,000to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimatedfrom available data). Due to the number of patients with generalised and partial LD treated in clinicaltrials, 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 ingeneralised LD and the subgroup of partial LD patients and post-marketing experience

System Organ Class Very common Common Frequency not known*

Infections and infestations Influenza, Pneumonia

Immune system disorders Anaphylactic reaction

Metabolism and nutrition Hypoglycaemia Decreased appetite Diabetes mellitus,disorders Hyperphagia, Insulinresistance

Nervous system disorders Headache

Cardiac disorders Tachycardia

Vascular disorders Deep vein thrombosis

Respiratory, thoracic and Cough, Dyspnoeamediastinal disorders Pleural effusion

Gastrointestinal disorders Abdominal pain, Abdominal pain upper,

Nausea Diarrhoea, Pancreatitis,

Skin and subcutaneous tissue Alopecia Pruritus, Rash, Urticariadisorders

Musculoskeletal and Arthralgia, Myalgiaconnective tissue disorders

Reproductive system and Menorrhagiabreast disorders

System Organ Class Very common Common Frequency not known*

General disorders and Fatigue, Injection Fat tissue increased,administration site conditions site bruising, Injection site

Injection site haemorrhage, Injectionerythema, Injection site pain, Injection sitesite reaction pruritus, Injection siteswelling, Malaise,

Peripheral swelling

Investigations Weight Neutralising Blood glucose abnormal,decreased antibodies Blood triglyceridesincreased, Drug specificantibody present,

Glycosylatedhaemoglobin increased,

Weight increased

*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), experiencedtreatment-emergent pancreatitis. All patients had a history of pancreatitis and hypertriglyceridaemia.

Abrupt interruption and/or non-compliance with metreleptin dosing was suspected to have contributedto the occurrence of pancreatitis in 2 patients. The mechanism for pancreatitis in these patients waspresumed to be return of hypertriglyceridaemia and therefore increased risk of pancreatitis in thesetting of discontinuation of effective therapy for hypertriglyceridaemia.

Metreleptin may decrease insulin resistance in diabetic patients, resulting in hypoglycaemia in patientswith 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 LDand in the subgroup of partial LD patients, have been mild in nature with no pattern of onset or clinicalsequelae. Generally the majority of events could be managed by food intake with only relatively fewmodifications 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. Allthree 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 significanthaematological abnormalities including severe bone marrow abnormalities before the start oftreatment. A separate case of anaplastic large cell lymphoma was reported in a paediatric patientreceiving the medicinal product who did not have haematological abnormalities before treatment.

In clinical trials (Studies NIH 991265/20010769 and FHA101), the rate of ADAs for generalised LDand the partial LD patients studied and with data available were 88% (65 out of 74 patients). Ablocking activity of the reaction between metreleptin and a recombinant leptin receptor has beenobserved in vitro in the blood of the majority of an extended set of patients (98 out of 102 patients or96%) 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 againstmetreleptin occurred in 5 generalised LD patients. These events included 1 episode in 1 patient ofserious and severe appendicitis, 2 episodes in patients of serious and severe pneumonia, a singleepisode of serious and severe sepsis and non-serious severe gingivitis in 1 patient and 6 episodes ofserious 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 activityagainst 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 tometreleptin treatment based on the currently available body of evidence. LD patients with a blockingactivity against metreleptin and concurrent infections responded to standard of care treatment (seesection 4.4).

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

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

In partial LD patients, assessment across age groups is limited, due to the small sample size. Noadverse reactions were reported in paediatric patients in the subgroup of partial LD patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In one post-marketing case, an infant was exposed to a 10-fold overdose of metreleptin for 8 months.

In this case, prolonged overdose was associated with severe anorexia causing vitamin and zincdeficiencies, iron deficiency anaemia, protein calorie malnutrition, and poor weight gain, whichresolved following supportive treatment and dose adjustment.

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactionsand supportive treatment initiated.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, amino acids andderivatives, ATC code: A16AA07

Metreleptin mimics the physiological effects of leptin by binding to and activating the human leptinreceptor, which belongs to the Class I cytokine family of receptors that signals through the JAK/STATtransduction pathway.

Only the metabolic effects of metreleptin have been studied. No effects on the distribution ofsubcutaneous fat are expected.

The efficacy and safety of treatment with metreleptin was evaluated in an open-label, single-arm study(Study NIH 991265/20010769) in patients with congenital or acquired generalised LD or familial oracquired partial LD. Patients were eligible for inclusion if they were > 6 months old, with a leptinlevel of < 12 ng/mL, and had at least 1 of the following 3 metabolic abnormalities:● Presence of diabetes mellitus, or● Fasting insulin concentration > 30 μU/mL, or● Fasting TG concentration > 2.26 mmol/L or postprandially elevated triglycerides> 5.65 mmol/L

The co-primary efficacy endpoints in this study were defined as:● Actual change from baseline in HbA1c at Month 12, and● Percent change from baseline in fasting serum TGs at Month 12

Study NIH 991265/20010769 was conducted over 14 years, with the primary efficacy assessmentsbeing made in both generalised LD and partial LD patients after 12 months of treatment. Multipledosing regimens were explored during the NIH study, which led to the posology recommended insection 4.2.

Concomitant anti-diabetic and lipid-lowering dose regimens were not held constant during the study,but analyses showed no significant difference in efficacy between patients who had no increases oradditions to their anti-diabetic or lipid-lowering treatments versus the overall study population.

Generalised LD

Of the 66 generalised LD patients enrolled, 45 (68%) had congenital generalised LD and 21 (32%) hadacquired generalised LD. Overall, 51 (77%) patients were female, 31 (47%) were Caucasian, 11 (17%)

Hispanic, and 16 (24%) Black. The median age at baseline was 15 years (range: 1-68 years), with 45(68%) patients being less than 18 years of age. The median fasting leptin concentration at baseline was1.0 ng/mL in males (range: 0.3-3.3 ng/mL) and 1.1 ng/mL in females (range: 0.2-5.3 ng/mL) using the

LINCO RIA test method.

The median duration of metreleptin treatment was 4.2 years (range: 3.4 months-13.8 years). Themedicinal product was administered subcutaneously either once daily or twice daily (in two equaldoses). The weighted average daily dose (i.e., the average dose taking into account duration oftreatment at different doses) for the 48 patients with baseline body weight greater than 40 kg was2.6 mg for males and 5.2 mg for females during the first year of treatment, and 3.7 mg for males and6.5 mg for females over the entire study period. For the 18 patients with baseline body weight lessthan or equal to 40 kg, the weighted average daily dose was 2.0 mg for males and 2.3 mg for femalesin the first year of treatment, and 2.5 mg for males and 3.2 mg for females over the entire study period.

Table 8 Primary outcome results in an open-label, single-arm study (NIH 991265/20010769) inevaluable patients with generalised LD treated with metreleptin at 12 months

Parameter n Baseline Change from baseline at month 12

HbA1c (%) 59

Mean (SD) 8.6 (2.33) -2.2 (2.15)

P < 0.001

Fasting TGs (mmol/L) 58

Mean (SD) 14.7 (25.6) -32.1% (71.28)

P 0.001

SD = standard deviation

Among 45 patients with generalised LD who had a baseline HbA1c of 7% or greater and dataavailable at Month 12, the mean (SD) baseline HbA1c was 9.6% (1.63) and the mean reduction in

HbA1c at Month 12 was 2.8%. Among 24 patients with generalised LD who had a baseline TG level5.65 mmol/L or greater and data available at month 12, the mean (SD) baseline TG level was31.7 mmol/L (33.68) and the mean percent reduction in triglycerides at month 12 was 72%.

Among the 39 patients with generalised LD who were receiving insulin at baseline, 16 (41%) wereable to discontinue insulin use altogether after starting metreleptin. Most of these patients (13 of 16)were able to stop insulin use within the first year of metreleptin. For the 32 patients with generalised

LD who were receiving oral anti-diabetic medicinal products at baseline, 7 (22%) were able todiscontinue their use. A total of 8 (24%) of the 34 patients with generalised LD who were receivinglipid-lowering therapies at baseline discontinued their use during metreleptin treatment.

There was evidence of improvement in renal and hepatic function in patients with generalised LDtreated with metreleptin. In 24 patients with renal data available, the mean change at Month 12 inprotein excretion rate versus baseline (1,675.7 mg/24hr) was -906.1 mg/24 hr. In 43 patients withhepatic data available, the mean changes at Month 12 in alanine aminotransferase, versus baseline(112.5 U/L) was -53.1 U/L, and aspartate aminotransferase versus baseline (75.3 U/L) was -23.8 U/L.

Partial LD subgroup

A subgroup of partial LD patients is analysed for whom TG ≥ 5.65 mmol/L and/or HbA1c ≥ 6.5% atbaseline. Of the 31 partial LD subgroup patients evaluated, 27 (87%) had familial partial LD and 4(13%) had acquired partial LD. Overall, 30 (97%) patients were female, 26 (84%) were Caucasian, 2(7%) Hispanic, and 0 Black. The median age at baseline was 38 years (range: 15-64 years), with 5(16%) patients being less than 18 years of age. The median fasting leptin concentration at baseline was5.9 ng/mL (1.6-16.9) using the LINCO RIA test method.

The median duration of metreleptin treatment was 2.4 years (range: 6.7 months-14.0 years). Themedicinal product was administered subcutaneously either once daily or twice daily (in two equaldoses). The weighted average daily dose (i.e., the average dose taking into account duration oftreatment at different doses) for all 31 patients with baseline body weight greater than 40 kg was7.0 mg during the first year of treatment, and 8.4 mg over the entire study period.

Table 9 Primary outcome results in study (NIH 991265/20010769) of evaluable patients in thepartial LD subgroup treated with metreleptin at 12 months

Parameter n Baseline Change from baseline at month 12

HbA1c (%) 27

Mean (SD) 8.8 (1.91) -0.9 (1.23)

P < 0.001

Fasting Triglycerides (mmol/L) 27

Mean (SD) 15.7 (26.42) -37.4% (30.81)

P < 0.001

SD = standard deviation

Among 15 patients in the partial LD subgroup who had a baseline TG level 5.65 mmol/L or greaterand data available at Month 12, the mean (SD) baseline triglyceride level was 27.6 mmol/L (32.88)and the mean percent reduction in TGs at Month 12 was 53.7%.

Among 18 patients in the partial LD subgroup who had a baseline HbA1c level 8% or greater and dataavailable at Month 12, the mean (SD) baseline HbA1c level was 9.9% (1.59) and the mean reductionin HbA1c at Month 12 was 1.3%.

In the generalised LD group, the number of patients according to age group was as follows: 5 patients< 6 years (including a single patient < 2 years), 12 patients ≥ 6 to < 12 years and 28 patients aged ≥ 12to < 18 years; in the partial LD subgroup, there were no patients < 12 years of age and 4 patients ≥ 12to < 18 years.

In the generalised LD group, mean decreases from baseline in HbA1c were noted in all age groups≥ 6 years; the mean decreases to Month 12/last observation carried forward LOCF were similar in thetwo older age groups (-1.1% and -2.6%). Mean change among the 5 patients < 6 years of age was0.2%. These differences across age groups are likely related to differences in mean HbA1c at baseline,which was in the normal range for patients < 6 years (5.7%) and lower in patients ≥ 6 to < 12 years(6.4%) compared to the older age group (9.7%). Mean decreases from baseline to Month 12/LOCF in

TGs for the generalised LD group were noted in all age groups with larger mean changes observed inthe older age group (-42.9%) compared to the younger age groups (-10.5% and -14.1%).

Among the 4 patients in the partial LD subgroup between 12 and 18 years of age, mean change to

Month 12/LOCF for HbA1c was -0.7% and for TGs was -55.1%.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Myalepta in one or more subsets of the paediatric population in the treatment of lipodystrophy (seesection 4.2 for information on paediatric use).

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct.

The European Medicines Agency will review any new information which may become available everyyear and this SmPC will be updated as necessary.

There are limited data on the pharmacokinetics of metreleptin in patients with lipodystrophy andtherefore no formal exposure-response analysis has been performed.

Peak serum leptin (endogenous leptin and metreleptin) concentration (Cmax) occurred approximately4.0 hours after subcutaneous administration of single doses ranging from 0.1 to 0.3 mg/kg in healthyadult subjects. In a supportive trial in LD patients, the median Tmax was 4 hours (range: 2 to 6 hours;

N = 5) following single-dose administration of metreleptin.

In studies of healthy adult subjects, following intravenous administration of metreleptin, leptin volumeof distribution (endogenous leptin and metreleptin) was approximately 4 to 5 times plasma volume;volumes (mean ± SD) were 370 ± 184 mL/kg, 398 ± 92 mL/kg, and 463 ± 116 mL/kg for 0.3, 1.0, and3.0 mg/kg/day doses, respectively.

No formal metabolism studies have been conducted.

Non-clinical data indicate renal clearance is the major route of metreleptin elimination, with noapparent contribution of systemic metabolism or degradation. Following single subcutaneous doses of0.01 to 0.3 mg/kg metreleptin in healthy adult subjects, the half-life was 3.8 to 4.7 hours. After IVadministration, metreleptin clearance was shown to be 79.6 mL/kg/h in healthy volunteers. Theclearance of metreleptin appears to be delayed in the presence of ADAs. A higher accumulation isobserved with higher ADA levels. Dose adjustments should be made based on clinical response (seesection 4.4).

No formal pharmacokinetic studies were conducted in patients with hepatic impairment.

No formal pharmacokinetic studies were conducted in patients with renal impairment. Non-clinicaldata indicate renal clearance is the major route of metreleptin elimination, with no apparentcontribution of systemic metabolism or degradation. Hence, the pharmacokinetics may be altered inpatients with renal impairment.

Age, gender, race, body mass index

Specific clinical studies have not been conducted to assess the effect of age, gender, race, or bodymass index on the pharmacokinetics of metreleptin in patients with lipodystrophy.

Non-clinical data based on conventional studies of safety pharmacology, repeated dose toxicity andgenotoxicity reveal no risks additional to those attributed to an excess of the expectedpharmacodynamic responses, such as loss of appetite and body weight.

Two-year carcinogenicity studies in rodents have not been conducted. Metreleptin exhibits nogenotoxic potential and no proliferative or preneoplastic lesions were observed in mice or dogsfollowing treatment up to 6 months.

Reproductive toxicity studies conducted in mice have revealed no adverse effects on mating, fertilityor embryo-foetal development up to the maximum tested dose, approximately, 15-fold the maximumrecommended clinical dose, based on body surface area of a 60 kg patient.

In a pre- and postnatal development study in mice, metreleptin caused prolonged gestation anddystocia at all tested doses, starting at, approximately, a dose identical to the maximum recommendedclinical dose, based on body surface area of a 60 kg patient. Prolonged gestation resulted in the deathof some females during parturition and lower survival of offspring within the immediate postnatalperiod. These findings are considered to be related indirectly to metreleptin pharmacology, resulting innutritional deprivation of treated animals, and also possibly, due to an inhibitory effect on spontaneousand oxytocin-induced contractions, as has been observed in strips of human myometrium exposed toleptin. Decreased maternal body weight was observed from gestation throughout lactation at all dosesand resulted in reduced weight of offspring at birth, which persisted into adulthood. However, nodevelopmental abnormalities were observed and reproductive performance of the first or secondgenerations was not affected at any dose.

Reproductive toxicity studies have not included toxicokinetics analysis. However, separate studiesrevealed that exposure of the mouse foetus to metreleptin was low (< 1%) after subcutaneousadministration of metreleptin to pregnant mice. The AUC exposure of pregnant mice wasapproximately 2 to 3 times greater than observed in non-pregnant mice after 10 mg/kg subcutaneousadministration of metreleptin. A 4 to 5-fold increase in the t1/2 values was also observed in pregnantmice compared to non-pregnant mice. The greater metreleptin exposure and longer t1/2 observed in thepregnant animals may be related to a reduced elimination capacity by binding to soluble leptinreceptor found at higher levels in pregnant mice.

No studies with direct administration of metreleptin to juvenile animals have been conducted.

However, in published studies, leptin treatment of euleptinaemic prepubertal female mice has led to anearlier onset of puberty.

Glycine

Sucrose

Polysorbate 20

Glutamic acid

Sodium Hydroxide (for pH adjustment)

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

4 years.

Following reconstitution with water for injections, the medicinal product must be used immediatelyand cannot be stored for future use.

Store in a refrigerator (2 °C-8 °C). Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Myalepta 3 mg powder for solution for injection

Type I glass vial (3 mL) with a chlorobutyl rubber stopper and an aluminium seal/red plastic flip-offcap.

Myalepta 5.8 mg powder for solution for injection

Type I glass vial (3 mL) with a chlorobutyl rubber stopper and an aluminium seal/blue plastic flip-offcap.

Myalepta 11.3 mg powder for solution for injection

Type I glass vial (5 mL) with a chlorobutyl rubber stopper and an aluminium seal/white plastic flip-offcap.

Pack sizes of 1 or 30 vials.

Not all pack sizes may be marketed.

The patient will receive a carton containing 1 or 30 vials of Myalepta, depending on the pack size,which should be stored in a refrigerator until the day of use.

The patient will also receive separately the solvent for reconstitution (i.e. water for injection), thesyringes/needles for reconstitution, the syringes/needles for administration, the cleansing alcoholswabs, and a sharps disposal container.

Instructions for reconstitution1. Remove the vial from the refrigerator and allow the vial to warm for 10 minutes to reach roomtemperature (20 °C-25 °C) prior to reconstitution.2. Visually inspect the vial containing the medicinal product. The cake of lyophilised powdershould be intact and white in colour.3. Reconstitution:

Myalepta 3 mg powder for solution for injection

Using a 1 mL syringe with a 21-gauge or smaller diameter needle, withdraw 0.6 mL of water forinjection. Do not reconstitute with other diluents.

Myalepta 5.8 mg powder for solution for injection

Using a 3 mL syringe with a 21-gauge or smaller diameter needle, withdraw 1.1 mL of water forinjection. Do not reconstitute with other diluents.

Myalepta 11.3 mg powder for solution for injection

Using a 3 mL syringe with a 21-gauge or smaller diameter needle, withdraw 2.2 mL of water forinjection. Do not reconstitute with other diluents.

4. Insert the needle into the vial containing the lyophilized powder, through the centre of thestopper and direct the stream of solvent to the wall of the vial to avoid excessive foaming.

5. Remove the needle and syringe from the vial and gently swirl the contents to reconstitute, untilthe liquid is clear. Do not shake or vigorously agitate. The reconstituted solution will take lessthan 5 minutes to become clear. When properly mixed, the Myalepta reconstituted solutionshould be clear, colourless, and free of clumps or dry powder, bubbles or foam. Do not use thesolution if discoloured or cloudy, or if particulate matter remains.

6. After reconstitution, each mL contains 5 mg of metreleptin.7. For instructions on administration, see section 4.2.

Myalepta reconstituted with water for injection is for single use only and should be administeredimmediately.

Unused reconstituted solution cannot be stored for later use. Any unused medicinal product or wastematerial should be disposed of in accordance with local requirements.

Chiesi Farmaceutici S.p.A.

Via Palermo 26/A43122 Parma

Italy

Myalepta 3 mg powder for solution for injection

EU/1/18/1276/003

EU/1/18/1276/004

Myalepta 5.8 mg powder for solution for injection

EU/1/18/1276/005

EU/1/18/1276/006

Myalepta 11.3 mg powder for solution for injection

EU/1/18/1276/001

EU/1/18/1276/002

Date of first authorisation: 30 July 2018

Date of latest renewal: 31 March 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.