INCRELEX 10mg / ml injectible solution medication leaflet

INCRELEX 10 mg/ml solution for injection

Each ml contains 10 mg of mecasermin*.

Each vial of 4 ml contains 40 mg of mecasermin*.

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

Escherichia coli.

One ml contains 9 mg of benzyl alcohol.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Colourless to slightly yellow and clear to slightly opalescent liquid.

For the long-term treatment of growth failure in children and adolescents from 2 to 18 years withconfirmed 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 2.5th percentile for age and gender and

* GH sufficiency.

* Exclusion of secondary forms of IGF-1 deficiency, such as malnutrition, hypopituitarism,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 signalingpathway, and IGF-1 gene defects; they are not GH deficient, and therefore, they cannot be expected torespond adequately to exogenous GH treatment. In some cases, when deemed necessary, the physicianmay decide to assist in the diagnosis by performing an IGF-I generation test.

Treatment with mecasermin should be directed by physicians who are experienced in the diagnosisand management of patients with growth disorders.

The dose should be individualised for each patient. The recommended starting dose of mecasermin is0.04 mg/kg of body weight twice daily by subcutaneous injection. If no significant adverse reactionsoccur for at least one week, the dose may be raised in increments of 0.04 mg/kg to the maximum doseof 0.12 mg/kg given twice daily. Doses greater than 0.12 mg/kg twice daily should not be exceeded asthis may increase the risk of neoplasia (see section pct. 4.3, pct. 4.4 and 4.8).

If the recommended dose is not tolerated by the patient, treatment with a lower dose can beconsidered. Treatment success should be evaluated based on height velocities. The lowest dose thatwas associated with substantial growth increases on an individual basis was 0.04 mg/kg twice daily(BID).

The safety and efficacy of mecasermin in children below age of 2 have not been established (seesection 5.1). No data are available.

Therefore, this medicinal product is not recommended in children below age of 2.

There are limited data concerning the pharmacokinetics of mecasermin in children with hepaticimpairment, in this specific population of severe primary IGFD patients. It is recommended that the dosebe individualised for each patient as described under posology

There are limited data concerning the pharmacokinetics of mecasermin in children with renal impairment,in this specific population of severe primary IGFD patients. It is recommended that the dose beindividualised for each patient as described under posology

INCRELEX should be administered by subcutaneous injection shortly before or after a meal or snack.

If hypoglycaemia occurs with recommended doses, despite adequate food intake, the dose should bereduced. If the patient is unable to eat, for any reason, this medicinal product should be withheld.

Pre-prandial glucose monitoring is recommended at treatment initiation and until a well-tolerated doseis established. If frequent symptoms of hypoglycaemia or severe hypoglycaemia occur, blood glucosemonitoring should continue regardless of pre-prandial condition and if possible, in case ofhypoglycaemic symptoms.

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 to help prevent lipohypertrophy.

INCRELEX should not be administered intravenously.

Precaution to be taken before manipulating or administering the medicinal product

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.

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

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

INCRELEX is contraindicated in children and adolescents with active or suspected neoplasia, or anycondition or medical history which increases the risk of benign or malignant neoplasia.

Therapy should be discontinued if evidence of neoplasia develops.

As INCRELEX contains benzyl alcohol, it must not be given to premature babies or neonates.

Benign and malignant neoplasms

There is an increased risk of benign and malignant neoplasia in children and adolescents treated with

INCRELEX, since IGF-1 plays a role in the initiation and progression of benign and malignanttumours.

There have been post-marketing reports of both benign and malignant neoplasms in children andadolescents who have received treatment with INCRELEX. These cases represented a variety ofdifferent malignancies and included rare malignancies usually not seen in children (see section 4.8).

The increased risk of neoplasia may be higher in patients who receive INCRELEX for unapproveduses or at higher than recommended doses. Current knowledge of IGF-1 biology suggests that IGF-1plays a role in malignancies in all organs and tissues. Physicians should therefore be vigilant of anysymptoms of potential malignancy.

If benign or malignant neoplasia develops, INCRELEX treatment should be discontinued definitelyand appropriate expert medical care sought.

Mecasermin is not a substitute for GH treatment.

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

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

Doses of insulin and/or other hypoglycaemic medicinal products may need to be reduced for diabeticsubjects using this medicinal product.

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

Lymphoid tissue (e.g., tonsillar) hypertrophy associated with complications, such as snoring, sleepapnoea, and chronic middle-ear effusions have been reported with the use of this medicinal product.

Patients should have examinations periodically and at the occurrence of clinical symptoms to rule outsuch potential complications or to initiate appropriate treatment.

Intracranial hypertension (IH) with papilloedema, visual changes, headache, nausea and/or vomitinghas been reported in patients treated with mecasermin, as has been reported with therapeutic GHadministration. IH-associated signs and symptoms resolved after interruption of dosing. Funduscopicexamination is recommended at the initiation, periodically during the course of mecasermin therapyand at the occurrence of clinical symptoms.

Slipped capital femoral epiphysis (with the potential to lead to avascular necrosis) and progression ofscoliosis can occur in patients who experience rapid growth. These conditions and other symptomsand signs known to be associated with GH treatment in general should be monitored duringmecasermin treatment. Any patient with the onset of a limp or complaint of hip or knee pain should beevaluated.

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/orlocal to the injection site. A small number of cases indicative of anaphylaxis requiring hospitalisationhave been reported. Parents and patients should be informed that such reactions are possible and that ifa systemic allergic reaction occurs, treatment should be interrupted and prompt medical attentionshould 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 without any identified cause may behaving an antibody response to injected IGF-1. This may be through the production of anti-IGF-1

IgEs, sustaining antibodies or neutralizing antibodies respectively. In such instances, instructions forantibody testing should be considered.

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 3years old.

This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded

No interaction studies have been performed.

Doses of insulin and/or other hypoglycaemic medicinal products may need to be reduced (see section4.4).

A negative pregnancy test is recommended for all women of child bearing potential prior to treatmentwith mecasermin. It is also recommended that all women of childbearing potential use adequatecontraception during treatment.

There are no or limited amount of data for the use of mecasermin in pregnant women.

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). The potentialrisk for humans is unknown.

This medicinal product should not be used during pregnancy.

Breast-feeding while taking INCRELEX is not recommended, because there is insufficientinformation on the excretion of mecasermin in human milk.

Mecasermin has been tested in a rat teratology study with no effects on fœtus up to 16 mg/kg (20 foldthe maximum recommended human dose (MRHD) based on body surface area) and in a rabbitteratology with no effects on foetus at dose of 0.5 mg/kg (2 fold the MRHD based on body surfacearea). Mecasermin has no effects on fertility in rats using intravenous doses 0.25, 1, and 4 mg/day (upto 4 times the clinical exposure with the MRHD based on AUC).

The effects of mecasermin on the unborn child have not been studied. Therefore there is insufficientmedical information to determine whether there are significant risks to a foetus. Studies have not beenconducted with mecasermin in breast-feeding mothers. INCRELEX should not be given to pregnant ornursing women. A negative pregnancy test and adequate contraception is required in all pre-menopausal women receiving INCRELEX.

INCRELEX may have a major influence on the ability to drive or use machines in case of ahypoglycaemic episode. Hypoglycaemia is a very common adverse reaction.

Adverse reaction data was taken from a total of 413 clinical trial patients with IGFD, including 92patients with severe primary IGFD. Data was also collected from post-marketing sources.

The most frequently reported adverse reactions from the clinical trials were headache (44%),hypoglycaemia (28%), vomiting (26%), injection site hypertrophy (17%), and otitis media (17%).

Intracranial hypertension/increased intracranial pressure occurred in 4 (0.96%) of patients from theclinical trials and occurred in 7 - 9 year old treatment naïve subjects.

During clinical trials in other indications totaling approximately 300 patients, reports of local and/orsystemic hypersensitivity were received for 8% of patients. There were also reports of systemichypersensitivity from post-marketing use, of which some cases were indicative of anaphylaxis. Post-marketing reports of local allergic reactions were also received.

Some patients may develop antibodies to mecasermin. No attenuation of growth was observed as aconsequence of the development of antibodies.

Table 1 contains very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1000, <1/100) adverse reactions which occurred in clinical trials. Within each frequency grouping, adversereactions are presented in order of decreasing seriousness. Other adverse reactions have beenidentified during post approval use of INCRELEX. As these reactions are reported voluntarily from apopulation of uncertain size, it is not possible to reliably estimate their frequency (not known).

Table 1: Adverse reactions

Reactions observed in the Reactions observed from the

System Organ Class clinical trials post-marketing environment

Blood and lymphatic system Common: Thymus hypertrophydisorders

Immune system disorders Not known: Systemichypersensitivity (anaphylaxis,generalized urticaria,angioedema, dyspnoea), localallergic reactions at the injectionsite (pruritus, urticaria)

Metabolism and nutrition Very common: Hypoglycaemiadisorders Common: Hypoglycaemicseizure, hyperglycaemia

Psychiatric disorders Uncommon: Depression,nervousness

Nervous system disorders Very common: Headache

Common: Convulsions,dizziness, tremor

Uncommon: Benign intracranialhypertension

Eye disorders Common: Papilloedema

Ear and labyrinth disorders Very common: Otitis media

Common: Hypoacusis, ear pain,middle ear effusion

Cardiac disorders Common: Cardiac murmur,tachycardia

Uncommon: Cardiomegaly,ventricular hypertrophy, mitralvalve incompetence, tricuspidvalve incompetence

Respiratory, thoracic and Common: Sleep apnoeamediastinal disorders syndrome, adenoidalhypertrophy, tonsillarhypertrophy, snoring

Gastrointestinal disorders Very common: Vomiting, upperabdominal pain

Common: Abdominal pain

Skin and subcutaneous tissue Common: Skin hypertrophy, Not known: alopeciadisorders abnormal hair texture

Musculoskeletal and Very common: Arthralgia, painconnective tissue disorders in extremity

Common: Scoliosis, myalgia

Neoplasms benign, malignant Common: Melanocytic naevus Not known: Benign andand unspecified (incl cysts and malignant neoplasmspolyps)

Reproductive system and Common: Gynaecomastiabreast disorders

General disorders and Very common: Injection siteadministration site conditions hypertrophy, injection sitebruising

Common: Injection site pain,injection site reaction, injectionsite haematoma, injection siteerythema, injection siteinduration, injection sitehaemorrhage, injection siteirritation

Uncommon: Injection site rash,injection site swelling,lipohypertrophy

Investigations Uncommon: Increased weight

Surgical and medical Common: Ear tube insertionprocedures

Neoplasms

There have been post-marketing reports of benign and malignant neoplasms in children andadolescents who have received treatment with INCRELEX. These cases represented a variety ofdifferent malignancies and included rare malignancies usually not seen in children (see section 4.4 and4.3).

Systemic/local hypersensitivity

Clinical Trial

During clinical trials in other indications (totaling approximately 300 patients) 8% of patients reporteda local and/or systemic hypersensitivity reactions. All cases were mild or moderate in severity andnone was serious.

Post-marketing reports

Systemic hypersensitivity included symptoms such as anaphylaxis, generalized urticaria, angioedemaand dyspnoea. The symptoms in the cases indicative of anaphylaxis included hives, angioedema anddyspnoea. Some patients required hospitalization. Upon re-administration, symptoms did not re-occurin all patients. There were also reports of local allergic reactions at the injection site. Typically thesewere pruritus and urticaria.

Of the 115 (28%) subjects who experienced one or more episode of hypoglycaemia, 6 subjectsexperienced a hypoglycaemic seizure on one or more occasion. Symptomatic hypoglycaemia wasgenerally avoided when a meal or snack was consumed either shortly before or after the administrationof INCRELEX.

Injection site hypertrophy

This reaction occurred in 71 (17%) subjects from the clinical trials and was generally associated withlack of proper rotation of injections. When injections were properly dispersed, the condition resolved.

Tonsillar hypertrophy

This was noted in 38 (9%) subjects, particularly in the first 1 to 2 years of therapy with lesser tonsillargrowth in subsequent years.

Snoring

This occurred generally in the first year of treatment and was reported in 30 subjects (7%).

Intracranial hypertension/increased intracranial pressure

This occurred in 4 subjects (0.96%); in two subjects INCRELEX was discontinued and not restarted;in two subjects the event did not recur after restarting INCRELEX at a reduced dose. All 4 subjectsrecovered from the event without sequelae.

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.

Acute overdose could lead to hypoglycaemia. Treatment of acute overdose of mecasermin should bedirected at alleviating any hypoglycaemic effects. Oral glucose or food should be consumed. If theoverdose results in loss of consciousness, intravenous glucose or parenteral glucagon may be requiredto reverse the hypoglycaemic effects.

Long-term overdose may result in signs and symptoms of acromegaly or gigantism. Overdosing maylead to supraphysiological IGF-1 levels and may increase the risk of benign and malignant neoplasm.

In case of an acute or a chronic overdose, Increlex must be discontinued immediately. If Increlex isrestarted, the dose should not exceed the recommended daily dosage (see section 4.2)

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatropin andsomatropin agonists, ATC code: H01AC03

Mecasermin is a human insulin-like growth factor-1 (rhIGF-1) produced by recombinant DNAtechnology. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfidebridges and a molecular weight of 7649 daltons. The amino acid sequence of the product is identical tothat of endogenous human IGF-1. The rhIGF-1 protein is synthesised in bacteria (E. coli) that havebeen 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. Undernormal circumstances, growth hormone (GH) binds to its receptor in the liver and other tissues andstimulates the synthesis/secretion of IGF-1. In target tissues the Type 1 IGF-1 receptor, which ishomologous to the insulin receptor, is activated by IGF-1, leading to intracellular signalling whichstimulates multiple processes leading to statural growth. The metabolic actions of IGF-1 are in partdirected at stimulating the uptake of glucose, fatty acids, and amino acids so that metabolism supportsgrowing 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 andmetabolism 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 mitogenicactivity 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 reduceblood 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-1increases bone density.

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 twicedaily (BID), were administered to 92 paediatric subjects with severe Primary IGFD. Patients wereenrolled in the studies on the basis of extreme short stature, slow growth rates, low IGF-1 serumconcentrations and normal GH secretion. Eighty-three (83) out of 92 patients were naïve to

INCRELEX at baseline and 81 completed at least one year of INCRELEX treatment. Baselinecharacteristics for the 81 patients evaluated in the primary and secondary efficacy analyses from thecombined studies were (mean ± SD): chronological age (years): 6.8 ± 3.8; age range (years): 1.7 to17.5; height (cm): 84.1 ± 15.8; height standard deviation score (SDS): -6.9 ± 1.8; height velocity(cm/yr): 2.6 ± 1.7; height velocity SDS: -3.4 ± 1.6; IGF-1 (ng/ml): 24.5 ± 27.9; IGF-1 SDS: -4.2 ± 2.0;and bone age (years): 3.8 ± 2.8. Of these, 72 (89%) had Laron syndrome-like phenotype; 7 (9%) had

GH gene deletion, 1 (1%) had neutralizing antibodies to GH and 1 (1%) had isolated genetic GHdeficiency. Forty-six (57%) of the subjects were male; 66 (81%) were Caucasian. Seventy-four (91%)of the subjects were prepubertal at baseline.

Annual results for height velocity, height velocity SDS, and height SDS until year 8 are shown in

Table 2. Pre-treatment height velocity data were available for 75 subjects. The height velocities at agiven year of treatment were compared by paired t-tests to the pre-treatment height velocities of thesame subjects completing that treatment year. The height velocities for years 2 through 8 remainedstatistically greater than baseline. For the 21 treatment naïve subjects with near-adult height, the mean(± SD) of the difference between observed increase in height versus that expected from Laron wasapproximately 13 cm (± 8 cm) after an average of 11 years of treatment.

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

Pre-Tx Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8

Height Velocity(cm/yr)

N 75 75 63 62 60 53 39 25 19

Mean (SD) 2.6 (1.7) 8.0 5.9 5.5 5.2 4.9 4.8 4.3 4.4(2.3) (1.7) (1.8) (1.5) (1.5) (1.4) (1.5) (1.5)

Mean (SD) for +5.4 +3.2 +2.8 +2.5 +2.1 +1.9 +1.4 +1.3change from pre-Tx (2.6) (2.6) (2.4) (2.5) (2.1) (2.1) (2.2) (2. 8)

P-value for change <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0042 0.0486from pre-Tx [1]

Height Velocity SDS

N 75 75 62 62 58 50 37 22 15

Mean (SD) -3.4 (1.6) 1.7 -0.0 -0.1 -0.2 -0.3 -0. 2 -0. 5 -0.2(2.8) (1.7) (1.9) (1.9) (1.7) (1. 6) (1.7) (1.6)

Mean (SD) for +5.2 +3.4 +3.3 +3.2 +3.2 +3.3 +3.0 +3.3change from pre-Tx (2.9) (2.4) (2. 3) (2.1) (2.1) (2.0) (2.1) (2.7)

P-value for change <0.0001 <0.0001 <0.0001 <0.0001 0.0001 <0.0001 <0.0001 0.0003from pre-Tx [1]

Height SDS

N 81 81 67 66 64 57 41 26 19

Mean (SD) -6.9 (1.8) -6.1 -5.6 -5.3 -5.1 -5.0 -4.9 -4.9 -5.1(1.8) (1.7) (1.7) (1.7) (1.7) (1.6) (1.7) (1.7)

Mean (SD) for +0.8 +1.2 +1.4 +1.6 +1. 7 +1. 8 +1. 7 +1.7change from pre-Tx (0.6) (0.9) (1.1) (1.2) (1.3) (1.1) (1.0) (1.0)

P-value for change <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0001 <0.0001from pre-Tx [1]

Pre-Tx = Pre-treatment; SD = Standard Deviation; SDS = Standard Deviation Score[1] P-values for comparison versus pre-Tx values were computed using paired t-tests.

For subjects with bone age available for at least 6 years after treatment initiation, the mean increase inbone age was comparable to the mean increase in chronological age; for these subjects, there does notappear to be any clinically significant advance of bone age relative to chronological age.

Efficacy is dose dependent. The dose of 120 μg/kg given subcutaneously (SC) and twice daily (BID)was associated with the greatest growth responses.

Among all subjects included for safety evaluation (n=92), 83% of the subjects reported at least oneadverse event during the course of the studies. There was no death during the studies. No subjectdiscontinued the studies due to adverse events.

Hypoglycaemia was the most frequently reported adverse event and a proper attention has to be givento meals in relation to dosing.

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 informationon this medicinal product.

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

The absolute subcutaneous bioavailability of mecasermin in severe Primary IGFD subjects has notbeen determined. The bioavailability of mecasermin after subcutaneous administration in healthysubjects has been reported to be approximately 100%.

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-1volume of distribution (mean ± SD) after subcutaneous administration of INCRELEX in 12 subjectswith severe Primary IGFD is estimated to be 0.257 (± 0.073) l/kg at a mecasermin dose of0.045 mg/kg, and is estimated to increase as the dose of mecasermin increases. Limited information isavailable on the concentration of unbound IGF-1 after the administration of INCRELEX.

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

The mean terminal t1/2 of total IGF-1 after single subcutaneous administration of 0.12 mg/kg in threepaediatric subjects with severe Primary IGFD is estimated to be 5.8 hours. Clearance of total IGF-1 isinversely proportional to serum IGFBP-3 levels and total IGF-1 systemic clearance (CL/F) isestimated to be 0.04 l/hr/kg at 3 mg/l IGFBP-3 in 12 subjects.

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

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

In adolescents with Primary IGFD and in healthy adults there were no apparent differences betweenmales and females in the pharmacokinetics of INCRELEX.

No information is available.

No studies have been conducted in children with renal impairment.

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

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

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

Toxicity to reproduction

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

Carcinogenic potential

Mecasermin was administered subcutaneously to Sprague Dawley rats at doses of 0, 0.25, 1, 4, and10 mg/kg/day for up to 2 years. An increased incidence of adrenal medullary hyperplasia andpheochromocytoma was observed in male rats at doses of 1 mg/kg/day and above (≥ 1 times theclinical exposure with the maximum recommended human dose [MRHD] based on AUC) and femalerats 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 and10 mg/kg/day (≥ 4 times the exposure with the MRHD based on AUC). An increased incidence ofmammary gland carcinoma in both male and female rats was observed in animals treated with10 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 medicinalproducts.

5 years

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 medicinal product may be stored for amaximum of 30 days at 2°C to 8°C.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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

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

5 ml vial (type I glass) closed with a stopper (chloro-butyl/isoprene polymer) and a seal (Colouredplastic).

Each vial contains 4 ml of solution.

Pack size of 1 vial.

INCRELEX is supplied as a multi-dose solution.

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

Ipsen Pharma65, quai Georges Gorse92100 Boulogne-Billancourt

France

EU/1/07/402/001

Date of first authorisation: 03 August 2007

Date of latest renewal: 16 June 2017

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

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