How to use Increlex in the treatment of severe primary IGF-1 deficiency
- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
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.
PosologyThe 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 populationThe 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 administrationINCRELEX 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 productThe 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.
Women of childbearing potential / Contraception in males and femalesA 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.
PregnancyThere 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-feedingBreast-feeding while taking INCRELEX is not recommended.
FertilityINCRELEX has been tested in a rat teratology study with no effects on ftus 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.
Summary of the safety profileAdverse 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 reactionsTable 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: Hypoglycaemia Common: Hypoglycaemic seizure, hyperglycaemia|
|Psychiatric disorders||Uncommon: Depression, nervousness|
|Nervous system disorders||Very common: Headache Common: Convulsions, dizziness, tremor Uncommon: Benign intracranial hypertension|
|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, 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 pain Common: 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 extremity Common: 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 bruising Common: 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 hypersensitivityClinical Trial: During clinical trials in other indications (totaling 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, generalized urticaria, angioedema and 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. There were also reports of local allergic reactions at the injection site. Typically these were pruritus and urticaria.
HypoglycaemiaOf 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 hypertrophyThis 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 hypertrophyThis was noted in 38 (9%) subjects, particularly in the first 1 to 2 years of therapy with lesser tonsillar growth in subsequent years.
SnoringThis occurred generally in the first year of treatment, and was reported in 30 subjects (7%).
Intracranial hypertension/increased intracranial pressureThis 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 reactionsReporting 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@example.com.- In the United Kingdom via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Mechanism of actionInsulin-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 effectsThe following actions have been demonstrated for endogenous human IGF-1:
Tissue GrowthSkeletal 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 MetabolismIGF-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 MetabolismCirculating IGF-1 plays an important role in the acquisition and maintenance of bone mass. IGF-1 increases bone density.
Clinical efficacy and safetyFive 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.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)|
|Mean (SD)||2.6 (1.7)||8.0 (2.3)||5.9 (1.7)||5.5 (1.8)||5.2 (1.5)||4.9 (1.5)||4.8 (1.4)||4.3 (1.5)||4.4 (1.5)|
|Mean (SD) for change from pre-Tx||+5.4 (2.6)||+3.2 (2.6)||+2.8 (2.4)||+2.5 (2.5)||+2.1 (2.1)||+1.9 (2.1)||+1.4 (2.2)||+1.3 (2.8)|
|P-value for change from pre-Tx ||<0.0001||<0.0001||<0.0001||<0.0001||<0.0001||<0.0001||0.0042||0.0486|
|Height Velocity SDS|
|Mean (SD)||-3.4 (1.6)||1.7 (2.8)||-0.0 (1.7)||-0.1 (1.9)||-0.2 (1.9)||-0.3 (1.7)||-0.2 (1.6)||-0.5 (1.7)||-0.2 (1.6)|
|Mean (SD) for change from pre-Tx||+5.2 (2.9)||+3.4 (2.4)||+3.3 (2. 3)||+3.2 (2.1||+3.2 (2.1)||+3.3 (2.0)||+3.0 (2.1)||+3.3 (2.7)|
|P-value for change from pre-Tx ||<0.0001||<0.0001||<0.0001||<0.0001||<0.0001||<0.0001||<0.0001||<0.0003|
|Mean (SD)||-6.9 (1.8)||-6.1 (1.8)||-5.6 (1.7)||-5.3 (1.7)||-5.1 (1.7)||-5.0 (1.7)||-4.9 (1.6)||-4.9 (1.7)||-5.1 (1.7)|
|Mean (SD) for change from pre-Tx||+0.8 (0.6)||+1.2 (0.9)||+1.4 (1.1)||+1.6 (1.2)||+1.7 (1.3)||+1.8 (1.1)||+1.7 (1.0)||+1.7 (1.0)|
|P-value for change from pre-Tx ||<0.0001||<0.0001||<0.0001||<0.0001||<0.0001||<0.0001||0.0001||<0.0001|
AbsorptionThe 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%.
DistributionIn 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.
BiotransformationBoth the liver and the kidney have been shown to metabolise IGF-1.
EliminationThe mean terminal t1/2 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.
ElderlyThe pharmacokinetics of INCRELEX have not been studied in subjects greater than 65 years of age.
ChildrenThe pharmacokinetics of INCRELEX have not been studied in subjects younger than 12 years of age.
GenderIn 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.
RaceNo information is available.
Renal impairmentNo studies have been conducted in children with renal impairment.
Hepatic impairmentNo studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of mecasermin.
Toxicity to reproductionIn 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.
Carcinogenic potentialMecasermin 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.
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.
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Patient information about severe primary IGF-1 deficiency and how Increlex can help
Introduction to Increlex and information on how to administer the product and safety issues relating to use
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