Ipsen Pharmaceuticals Ltd

INCRELEX 10 mg/ml solution for injection.

Each ml contains 10 mg of mecasermin.

Each vial contains 40 mg of mecasermin.

Mecasermin is a recombinant DNA-derived human insulin-like growth factor-1(IGF-1) produced in Escherichia coli.

Excipients:

One ml contains 9 mg of benzyl alcohol.

For a full list of excipients, see section 6.1.

Solution for injection.

Aqueous, clear and colourless solution.

For the long-term treatment of growth failure in children and adolescents with severe primary insulin-like growth factor-1 deficiency (Primary IGFD).

Severe Primary IGFD is defined by:

• height standard deviation score –3.0 and

• basal IGF-1 levels below the 2.5^th percentile for age and gender and

• GH sufficiency.

• Exclusion of secondary forms of IGF-1 deficiency, such as malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids.

Severe Primary IGFD includes patients with mutations in the GH receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects; they are not GH deficient, and therefore, they cannot be expected to respond adequately to exogenous GH treatment. It is recommended to confirm the diagnosis by conducting an IGF-1 generation test.

Treatment with INCRELEX should be directed by physicians who are experienced in the diagnosis and management of patients with growth disorders.

The dose should be individualised for each patient. The recommended starting dose of mecasermin is 0.04 mg/kg twice daily by subcutaneous injection. If no significant treatment-related adverse events occur for at least one week, the dose may be raised in increments of 0.04 mg/kg to the maximum dose of 0.12 mg/kg given twice daily. Doses greater than 0.12 mg/kg given twice daily have not been evaluated in children with severe Primary IGFD.

If the recommended dose is not tolerated by the subject, treatment with a lower dose can be considered. Treatment success should be evaluated based on height velocities. The lowest dose that was associated with substantial growth increases on an individual basis was 0.04 mg/kg BID.

INCRELEX should be administered shortly before or after a meal or snack. If hypoglycaemia occurs with recommended doses, despite adequate food intake, the dose should be reduced. If the patient is unable to eat, for any reason, INCRELEX should be withheld. The dose of mecasermin should never be increased to make up for one or more omitted doses.

Injection sites should be rotated to a different site with each injection.

INCRELEX should be administered using sterile disposable syringes and injection needles. The syringes should be of small enough volume that the prescribed dose can be withdrawn from the vial with reasonable accuracy.

INCRELEX is not recommended for use in children below age 2 due to a lack of data on safety and efficacy (see section 5.1).

Hypersensitivity to the active substance or to any of the excipients.

Intravenous administration.

Active or suspected neoplasia. Therapy should be discontinued if evidence of neoplasia develops.

Benzyl alcohol must not be given to premature babies or neonates.

Thyroid and nutritional deficiencies should be corrected before initiating INCRELEX treatment.

INCRELEX is not a substitute for GH treatment.

INCRELEX should not be used for growth promotion in patients with closed epiphyses.

INCRELEX should be administered shortly before or after a meal or snack, because it may have insulin-like hypoglycaemic effects. Special attention should be paid to young children, children with a history of hypoglycaemia and children with inconsistent food intake. Patients should avoid engaging in any high-risk activities within 2-3 hours after dosing, particularly at the initiation of INCRELEX treatment, until a well tolerated dose of INCRELEX has been established. If a person with severe hypoglycemia is unconscious or otherwise unable to ingest food normally, an injection of glucagon may be required. Persons with a history of severe hypoglycemia should have glucagon available. At the time of initial prescription, physicians should educate parents on the signs, symptoms and treatment of hypoglycaemia, including injection of glucagon.

Doses of insulin and/or other hypoglycaemic agents may need to be reduced for diabetic subjects using INCRELEX.

Echocardiogram is recommended before initiation of INCRELEX treatment in all patients. Patients who terminate treatment should also have an echocardiogram. Patients with abnormal echocardiogram findings or cardiovascular symptoms should be followed regularly with echocardiogram procedures.

Lymphoid tissue (e.g., tonsillar) hypertrophy associated with complications, such as snoring, sleep apnoea, and chronic middle-ear effusions have been reported with the use of INCRELEX. Patients should have examinations periodically and at the occurrence of clinical symptoms to rule out such potential complications or to initiate appropriate treatment.

Intracranial hypertension (IH) with papilloedema, visual changes, headache, nausea and/or vomiting has been reported in patients treated with INCRELEX, as has been reported with therapeutic GH administration. IH-associated signs and symptoms resolved after interruption of dosing. Funduscopic examination is recommended at the initiation, periodically during the course of INCRELEX therapy and at the occurrence of clinical symptoms.

Slipped capital femoral epiphysis and progression of scoliosis can occur in patients who experience rapid growth. These conditions and other symptoms and signs known to be associated with GH treatment in general should be monitored during INCRELEX treatment. Any patient with the onset of a limp or complaint of hip or knee pain should be evaluated.

In post-marketing experience in patients treated with INCRELEX, cases of hypersensitivity, urticaria, pruritus and erythema have been reported. These have been observed both as being systemic and/or local to the injection site. A small number of cases indicative of anaphylaxis requiring hospitalization have been reported. Parents and patients should be informed that such reactions are possible and that if a systemic allergic reaction occurs, treatment should be interrupted and prompt medical attention should be sought.

Treatment should be reconsidered if after a year patients remain non-responsive.

Persons who have allergic reactions to injected IGF-1, who have unexpectedly high blood values of IGF-1 after injection, or who fail to show a growth response may be having an antibody response to injected IGF-1. In such instances, follow the instructions for antibody testing.

INCRELEX contains 9 mg/ml benzyl alcohol as a preservative.

Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

No interaction studies have been performed.

A negative pregnancy test and education about adequate contraception are recommended for all women of child bearing potential prior to treatment with INCRELEX.

There are no adequate data for the use of mecasermin in pregnant women.

Animal studies are insufficient with respect to pregnancy (see section 5.3). The potential risk for humans is unknown.

INCRELEX should not be used during pregnancy unless clearly necessary.

Breast-feeding while taking INCRELEX is not recommended.

No studies on the effects on the ability to drive and use machines have been performed. However, hypoglycaemia may impair the ability to drive or use machines.

An integrated safety database from clinical studies contains 76 subjects with severe Primary IGFD treated for a mean duration of 4.4 years and representing 321 subject-years.

Hypoglycaemia is the most frequently reported adverse drug reaction. The thirty-six subjects (47%) who had one or more episodes of hypoglycaemia included 4 subjects who had hypoglycaemic seizure on one or more occasion. Of the 36 subjects, 12 (33%) had a history of hypoglycaemia prior to beginning treatment. The frequency of hypoglycaemia was highest in the first month of treatment, and episodes were more frequent in younger children. Symptomatic hypoglycaemia was generally avoided when a meal or snack was consumed either shortly before or after the administration of INCRELEX.

Injection site hypertrophy occurred in 24 subjects (32%). This reaction was generally associated with lack of proper rotation of injections. When injections were properly dispersed, the condition resolved.

Tonsillar hypertrophy was noted in 12 (16%) subjects, particularly in the first 1 to 2 years of therapy with lesser tonsillar growth in subsequent years.

Snoring, generally beginning in the first year of treatment, was reported in 17 subjects (22%).

Hypoacusis was reported in 15 subjects (20%).

Intracranial hypertension occurred in three subjects (4%). In two subjects the events resolved without interruption of INCRELEX treatment. INCRELEX treatment was discontinued in the third subject and resumed later at a lower dose without recurrence. Fourteen subjects (18%) had headache considered related to study drug.

During clinical trials in other indications totalling approximately 300 patients, reports of local and/or systemic hypersensitivity were received for 8% of patients. All cases were mild or moderate in severity and none was serious.

As with all protein pharmaceuticals, some patients may develop antibodies to INCRELEX. Anti-IGF-1 antibodies were observed in 11 of 23 children with severe Primary IGFD tested during the first year of therapy. No attenuation of growth was observed as a consequence of the development of antibodies.

Table 1 contains very common ( 1/10) and common ( 1/100 to < 1/10) adverse reactions for which there is at least a reasonable suspicion of a causal relationship to INCRELEX treatment which occurred in clinical trials. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Adverse Drug Reactions in Clinical Trials

The following adverse reactions have been identified during post approval use of INCRELEX. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.

-Systemic hypersensitivity: anaphylaxis, generalized urticaria, angioedema, dyspnoea

The symptoms in the cases indicative of anaphylaxis included hives, angioedema and dyspnoea. Some patients required hospitalization. Upon re-administration, symptoms did not re-occur in all patients.

-Local allergic reactions at the injection site: pruritis, urticaria.

No case of overdose has been reported.

Acute overdose could lead to hypoglycaemia. Long-term overdose may result in signs and symptoms of acromegaly or gigantism.

Treatment of acute overdose of mecasermin should be directed at alleviating any hypoglycaemic effects. Oral glucose or food should be consumed. If the overdose results in loss of consciousness, intravenous glucose or parenteral glucagon may be required to reverse the hypoglycaemic effects.

Pharmacotherapeutic group:          Somatropin and agonists, ATC code: H01AC03

This medicinal product has been authorised under “Exceptional Circumstances”.

This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.

The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.

Mecasermin is a human insulin-like growth factor-1 (rhIGF-1) produced by recombinant DNA technology. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges and a molecular weight of 7649 daltons. The amino acid sequence of the product is identical to that of endogenous human IGF-1. The rhIGF-1 protein is synthesised in bacteria (E. coli) that have been modified by the addition of the gene for human IGF-1.

Insulin-like growth factor-1 (IGF-1) is the principal hormonal mediator of statural growth. Under normal circumstances, growth hormone (GH) binds to its receptor in the liver and other tissues, and stimulates the synthesis/secretion of IGF-1. In target tissues the Type 1 IGF-1 receptor, which is homologous to the insulin receptor, is activated by IGF-1, leading to intracellular signaling which stimulates multiple processes leading to statural growth. The metabolic actions of IGF-1 are in part directed at stimulating the uptake of glucose, fatty acids, and amino acids so that metabolism supports growing tissues.

The following actions have been demonstrated for endogenous human IGF-1:

Tissue Growth

• Skeletal growth is accomplished at the epiphyseal plates at the ends of a growing bone. Growth and metabolism of epiphyseal plate cells are directly stimulated by GH and IGF-1.

• Organ growth: treatment of IGF-1 deficient rats with rhIGF-1 results in whole body and organ growth.

• Cell growth: IGF-1 receptors are present on most types of cells and tissues. IGF-1 has mitogenic activity that leads to an increased number of cells in the body.

Carbohydrate Metabolism

IGF-1 suppresses hepatic glucose production, stimulates peripheral glucose utilization, and can reduce blood glucose and cause hypoglycaemia.

IGF-1 has inhibitory effects on insulin secretion.

Bone/Mineral Metabolism

Circulating IGF-1 plays an important role in the acquisition and maintenance of bone mass. IGF-1 increases bone density.

Clinical efficacy

Five clinical studies (4 open-label and 1 double-blind, placebo-controlled) were conducted with INCRELEX. Subcutaneous doses of mecasermin, generally ranging from 60 to 120 μg/kg given twice daily (BID), were administered to 76 paediatric subjects with severe Primary IGFD. Patients were enrolled in the studies on the basis of extreme short stature, slow growth rates, low IGF-1 serum concentrations, and normal GH secretion. Baseline characteristics for the patients evaluated in the primary and secondary efficacy analyses from the combined studies were (mean ± SD): chronological age (years): 6.8 ± 3.8; height (cm): 85.0 ± 15.3; height standard deviation score (SDS): -6.7 ± 1.8; height velocity (cm/yr): 2.8 ± 1.8; height velocity SDS: -3.3 ± 1.7; IGF-1 (ng/ml): 21.9 ± 24.8; IGF-1 SDS: -4.4 ± 2.0; and bone age (years): 3.9 ± 2.8. Sixty-two subjects had at least one year of treatment. Of these, 53 (85%) had Laron syndrome-like phenotype; 7 (11%) had GH gene deletion, and 1 (2%) had neutralizing antibodies to GH. Thirty-eight (61%) of the subjects were male; 49 (79%) were Caucasian. Fifty-six (90%) of the subjects were prepubertal at baseline.

Annual results for height velocity, height velocity SDS, and height SDS are shown in Table 2. Pre-treatment height velocity data were available for 59 subjects. The height velocities at a given year of treatment were compared by paired t-tests to the pre-treatment height velocities of the same subjects completing that treatment year.

Table 2: Annual Height Results by Number of Years Treated with INCRELEX

Forty-seven subjects were included in an analysis of the effects of INCRELEX on bone age advancement. The mean ± SD change in chronological age was 5.1 ± 3.0 years and the mean ± SD change in bone age was 5.8 ± 2.9 years.

Efficacy is dose dependent. For subjects receiving doses between 100 and 120 μg/kg BID, the mean first year height velocity was approximately 8.7 cm/yr.

GENERAL CHARACTERISTICS

Absorption

The absolute subcutaneous bioavailability of mecasermin in severe Primary IGFD subjects has not been determined. The bioavailability of mecasermin after subcutaneous administration in healthy subjects has been reported to be approximately 100%.

Distribution

In blood, IGF-1 is bound to six IGF binding proteins (IGFBPs), with ~80% bound as a complex with IGFBP-3 and an acid-labile subunit. IGFBP-3 is reduced in subjects with severe Primary IGFD, resulting in increased clearance of IGF-1 in these subjects relative to healthy subjects. The total IGF-1 volume of distribution (mean ± SD) after subcutaneous administration of INCRELEX in 12 subjects with severe Primary IGFD is estimated to be 0.257 (± 0.073) l/kg at a mecasermin dose of 0.045 mg/kg, and is estimated to increase as the dose of mecasermin increases. Limited information is available on the concentration of unbound IGF-1 after the administration of INCRELEX.

Metabolism

Both the liver and the kidney have been shown to metabolise IGF-1.

Excretion

The mean terminal t_1/2 of total IGF-1 after single subcutaneous administration of 0.12 mg/kg in three paediatric subjects with severe Primary IGFD is estimated to be 5.8 hours. Clearance of total IGF-1 is inversely proportional to serum IGFBP-3 levels and total IGF-1 systemic clearance (CL/F) is estimated to be 0.04 l/hr/kg at 3 mg/l IGFBP-3 in 12 subjects.

CHARACTERISTICS IN SPECIAL POPULATIONS

Geriatric

The pharmacokinetics of INCRELEX have not been studied in subjects greater than 65 years of age.

Children

The pharmacokinetics of INCRELEX have not been studied in subjects younger than 12 years of age.

Gender

In children over 12 years old with Primary IGFD and in healthy adults there were no apparent differences between males and females in the pharmacokinetics of INCRELEX.

Race

No information is available.

Renal insufficiency

No studies have been conducted in children with renal impairment.

Hepatic insufficiency

No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of mecasermin.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity or genotoxicity.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

Reproductive toxicity

In rats and rabbits reproductive toxicity was studied after intravenous but not after subcutaneous application (the normal clinical route). These studies did not indicate direct or indirect harmful effects with respect to fertility and pregnancy, but due to the different route of application the relevance of these findings is unclear. Placental transfer of mecasermin was not studied.

Carcinogenesis

Mecasermin was administered subcutaneously to Sprague Dawley rats at doses of 0, 0.25, 1, 4, and 10 mg/kg/day for up to 2 years. An increased incidence of adrenal medullary hyperplasia and pheochromocytoma was observed in male rats at doses of 1 mg/kg/day and above ( 1 times the clinical exposure with the maximum recommended human dose [MRHD] based on AUC) and female rats at all dose levels ( 0.3 times the clinical exposure with the MRHD based on AUC).

An increased incidence of keratoacanthoma in the skin was observed in male rats at doses of 4 and 10 mg/kg/day ( 4 times the exposure with the MRHD based on AUC). An increased incidence of mammary gland carcinoma in both male and female rats was observed in animals treated with 10 mg/kg/day (7 times the exposure with the MRHD based on AUC). Excess mortality secondary to IGF-1 induced hypoglycaemia was observed in the carcinogenesis studies.

Benzyl alcohol

Sodium chloride

Polysorbate 20

Glacial acetic acid

Sodium acetate

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

3 years

After opening:

Chemical and physical in-use stability has been demonstrated for 30 days at 2°C to 8°C.

From a microbiological point of view, once opened, the product may be stored for a maximum of 30 days at 2°C to 8°C. Other in-use storage times and conditions are the responsibility of the user.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

4 ml of solution in a 5 ml vial (type I glass) closed with a latex-free stopper (bromobutyl/isoprene polymer) and a seal (lacquered plastic).

Pack size of 1 vial.

INCRELEX is supplied as a sterile solution with preservative for multiple use.

The solution should be clear immediately after removal from the refrigerator. If the solution is cloudy, or contains particulate matter, it must not be injected.

Any unused product or waste material should be disposed of in accordance with local requirements.

Ipsen Pharma

65, quai Georges Gorse

92100 Boulogne-Billancourt

France

EU/1/07/402/001

Date of first authorisation: 03/08/2007

July 2010