Increlex IGF-1 10mg/ml 4ml Vial

$1,170.00

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

INCRELEX 10 mg/ml solution for injection

2. Qualitative and quantitative composition

Each ml contains 10 mg of mecasermin*.

Each vial of 4ml contains 40 mg of mecasermin.

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

Excipient with known effect:

One ml contains 9 mg of benzyl alcohol.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection (injection).

Aqueous, clear and colourless solution.

4. Clinical particulars
4.1 Therapeutic indications

For the long-term treatment of growth failure in children and adolescents from 2 to 18 years 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 2.5th 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.

4.2 Posology and method of administration

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

Posology

The dose should be individualised for each patient. The recommended starting dose of mecasermin is 0.04 mg/kg of body weight twice daily by subcutaneous injection. If no significant adverse reactions 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 patient, 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.

Paediatric population

The safety and efficacy of INCRELEX in children below age of 2 have not been established. No data are available.

Therefore INCRELEX is not recommended in children below age of 2.

Method of administration

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 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 not be administered intravenously.

Precaution to be taken before manipulating or administering the 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 (see section 6.6).

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.

4.3 Contraindications

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

Active or suspected 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.

4.4 Special warnings and precautions for use

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 medicinal products 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 (with the potential to lead to avascular necrosis) 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 hospitalisation 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 without any identified cause may be having an antibody response to injected IGF-1. This may be through the production of anti-IGF IgEs, sustaining antibodies or neutralising antibodies respectively. In such instances, instructions for antibody testing should be considered.

Excipients

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.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Doses of insulin and/or other hypoglycaemic medicinal products may need to be reduced (see section 4.4).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

A negative pregnancy test is recommended for all women of child bearing potential prior to treatment with INCRELEX. It is also recommended that all women of childbearing potential use adequate contraception during treatment.

Pregnancy

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 potential risk for humans is unknown.

INCRELEX should not be used during pregnancy unless clearly necessary.

Breast-feeding

Breast-feeding while taking INCRELEX is not recommended.

Fertility

INCRELEX has been tested in a rat teratology study with no effects on foetus up to 16 mg/kg (20 fold the MRHD based on Body surface Area) and in a rabbit teratology with no effects on foetus at dose of 0.5 mg/kg (2 fold the MRHD based on Body surface Area). INCRELEX has no effects on fertility in rats using intravenous doses 0.25, 1, and 4 mg/day (up to 4 times the clinical exposure with the MRHD based on AUC).

The effects of INCRELEX on unborn child have not been studied. Therefore there is insufficient medical information to determine whether there are significant risks to a foetus. Studies have not been conducted with INCRELEX in nursing mothers. INCRELEX should not be given to pregnant or nursing women. A negative pregnancy test and adequate contraception is required in all pre-menopausal women receiving INCRELEX.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Adverse reaction data was taken from a total of 413 clinical trial patients 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 the clinical trials and occurred in 7 – 9 year old treatment naïve subjects.

During clinical trials in other indications totalling approximately 300 patients, reports of local and/or systemic hypersensitivity were received for 8% of patients. There were also reports of systemic hypersensitivity 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 INCRELEX. No attenuation of growth was observed as a consequence of the development of antibodies.

Tabulated list of adverse reactions

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, adverse reactions are presented in order of decreasing seriousness. Other 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.

Table 1: Adverse reactions

System Organ Class Reactions observed in the clinical trials Reactions observed from the post-marketing environment
Blood and lymphatic system disorders Common:Thymus hypertrophy
Immune system disorders Not known:Systemic hypersensitivity (anaphylaxis, generalized urticaria, angioedema, dyspnoea)Local allergic reactions at the injection site (pruritus, urticaria)
Metabolism and nutrition disorders Very common:HypoglycaemiaCommon:Hypoglycaemic seizure, hyperglycaemia
Psychiatric disorders Uncommon:Depression, nervousness
Nervous system disorders Very common:HeadacheCommon:Convulsions, dizziness, tremor

Uncommon:

Benign intracranial hypertension

Eye disorders Common:Papilloedema
Ear and labyrinth disorders Very common:Otitis mediaCommon:Hypoacusis, ear pain, middle ear effusion
Cardiac disorders Common:Cardiac murmur, tachycardiaUncommon:Cardiomegaly, ventricular hypertrophy, mitral valve incompetence, tricuspid valve incompetence
Respiratory, thoracic and mediastinal disorders Common:Sleep apnoea syndrome, adenoidal hypertrophy, tonsillar hypertrophy, snoring
Gastrointestinal disorders Very common:Vomiting, upper abdominal painCommon:Abdominal pain
Skin and subcutaneous tissue disorders Common:Skin hypertrophy, abnormal hair texture Not known:alopecia
Musculoskeletal and connective tissue disorders Very common:Arthralgia, pain in extremityCommon:Scoliosis, myalgia
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common:Melanocytic naevus
Reproductive system and breast disorders Common:Gynaecomastia
General disorders and administration site conditions Very common:Injection site hypertrophy injection site bruisingCommon:Injection site pain, injection site reaction, injection site haematoma, injection site erythema, injection site induration, injection site haemorrhage, injection site irritation

Uncommon:

Injection site rash, injection site swelling, lipohypertrophy

Investigations Uncommon:Increased weight
Surgical and medical procedures Common:Ear tube insertion

Description of selected adverse reactions

Systemic/local hypersensitivity

Clinical Trial: During clinical trials in other indications (totalling approximately 300 patients) 8% of patients reported local and/or systemic hypersensitivity reactions. All cases were mild or moderate in severity and none was serious.

Post-marketing reports: Systemic hypersensitivity included symptoms such as anaphylaxis, generalised urticaria, angioedema and dyspnoea. The symptoms in the cases indicative of anaphylaxis included hives, angioedema and dyspnoea. Some patients required hospitalisation. Upon re-administration, symptoms did not re-occur in all patients. There were also reports of local allergic reactions at the injection site. Typically these were pruritus and urticaria.

Hypoglycaemia

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

Injection site hypertrophy

This reaction occurred in 71 (17%) subjects from the clinical trials and was generally associated with lack 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 tonsillar growth 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 subjects recovered from the event without sequelae.

Reporting of suspected adverse reactions

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

– In Ireland to HPRA Pharmacovigilance, Earlsfort Terrace, IRL-Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie, E-mail: [email protected]

– In the United Kingdom via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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

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.

Mechanism of action

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 signalling 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.

Pharmacodynamic effects

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 utilisation, 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 and safety

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 92 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. Eighty-three (83) out of 92 patients were naïve to INCRELEX at baseline and 81 completed at least one year of INCRELEX treatment. Baseline characteristics for the 81 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): 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 GH deficiency. 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 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. The height velocities for years 2 through 8 remained statistically 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 was approximately 13 cm (± 8 cm) after an average of 11 years of treatment.