Increlex

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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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 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. 
 
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 confirmed 
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 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. In some cases, when deemed necessary, the physician may 
decide to assist in the diagnosis by performing an IGF-I generation test. 
 
4.2 Posology and method of administration 
 
Treatment with mecasermin should be directed by physicians who are experienced in the diagnosis and 
management of patients with growth disorders. 
 
 
 



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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 twice daily should not be exceeded as this may 
increase the risk of neoplasia (see section 4.3, 4.4 and 4.8).  
 
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 twice daily (BID). 

Paediatric population 
 
The safety and efficacy of mecasermin in children below age of 2 have not been established (see section 5.1). 
No data are available. 
Therefore, this medicinal product is not recommended in children below age of 2. 
 
Special Populations 
Hepatic impairment 
There are limited data concerning the pharmacokinetics of mecasermin in children with hepatic impairment, in 
this specific population of severe primary IGFD patients. It is recommended that the dose be individualised for 
each patient as described under posology 
 
Renal impairment 
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 be individualised for each 
patient as described under posology 
 
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, this medicinal product 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 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. 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. 
 
INCRELEX is contraindicated in children and adolescents with active or suspected neoplasia, or any 
condition 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. 
 
4.4 Special warnings and precautions for use 



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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 malignant tumours. 
 
There have been post-marketing reports of both benign and malignant neoplasms in children and adolescents 
who have received treatment with INCRELEX.  These cases represented a variety of different 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 unapproved uses or at higher than recommended 
doses.  Current knowledge of IGF-1 biology suggests that IGF-1 plays a role in malignancies in all organs 
and tissues. Physicians should therefore be vigilant of any symptoms of potential malignancy.  
If benign or malignant neoplasia develops, INCRELEX treatment should be discontinued definitely and 
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 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 mecasermin 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 this medicinal product. 
 
Echocardiogram is recommended before initiation of mecasermin 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 this medicinal product. 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 mecasermin, 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 mecasermin 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 mecasermin treatment. 
Any patient with the onset of a limp or complaint of hip or knee pain should be evaluated. 
 



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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-1 IgEs, sustaining 
antibodies or neutralizing 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’. 
 
Traceability 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded 
 
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 
mecasermin. 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. 
 
This medicinal product should not be used during pregnancy unless clearly necessary. 
 
Breast-feeding 
Breast-feeding while taking INCRELEX is not recommended, because there is insufficient information on 
the excretion of mecasermin in human milk. 
 
Fertility 
Mecasermin has been tested in a rat teratology study with no effects on fœtus up to 16 mg/kg (20 fold the 
maximum recommended human dose (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). Mecasermin 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). 



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The effects of mecasermin on the 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 mecasermin in breast-feeding 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 
 
INCRELEX may have a major influence on the ability to drive or use machines in case of a hypoglycaemic 
episode. Hypoglycaemia is a very common adverse reaction. 
 
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 totaling 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 mecasermin. 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. As these reactions are reported voluntarily from a population of uncertain size, 
it is not possible to reliably estimate their frequency (not known). 

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  



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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 
 
 

Not known: Benign and malignant 
neoplasms 

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 
 
Neoplasms 
There have been post-marketing reports of benign and malignant neoplasms in children and adolescents who 
have received treatment with INCRELEX. These cases represented a variety of different malignancies and 
included rare malignancies usually not seen in children (see section 4.4 and 4.3). 
 
 



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Systemic/local hypersensitivity 
Clinical Trial 
During clinical trials in other indications (totaling approximately 300 patients) 8% of patients reported a 
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. 
 
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 listed in Appendix V. 
 
4.9 Overdose 
 
Acute overdose could lead to hypoglycaemia. 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. 
 
Long-term overdose may result in signs and symptoms of acromegaly or gigantism.  Overdosing may lead 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 is restarted, 
the dose should not exceed the recommended daily dosage (see section 4.2) 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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 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 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; age 
range (years): 1.7 to 17.5; 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 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 



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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) 
         

N 75 75 63 62 60 53 39 25 19 
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 [1] 

 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0042 0.0486 

Height Velocity SDS          
N 75 75 62 62 58 50 37 22 15 

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 
P-value for change 

from pre-Tx [1] 

 +5.2 
(2.9) 

<0.0001 

+3.4 
(2.4) 

<0.0001 

+3.3  
(2. 3) 

<0.0001 

+3.2 
(2.1) 

<0.0001 

+3.2 
(2.1) 

0.0001 

+3.3 
(2.0) 

<0.0001 

+3.0 
(2.1) 

<0.0001 

+3.3 
(2.7) 

0.0003 

Height SDS          
N 81 81 67 66 64 57 41 26 19 

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 
P-value for change 

from pre-Tx [1] 

 +0.8 
(0.6) 

<0.0001 

+1.2 
(0.9) 

<0.0001 

+1.4 
(1.1) 

<0.0001 

+1.6 
(1.2) 

<0.0001 

+1. 7 
(1.3) 

<0.0001 

+1. 8 
(1.1) 

<0.0001 

+1. 7 
(1.0) 

0.0001 

+1.7 
(1.0) 

<0.0001 

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 in bone 
age was comparable to the mean increase in chronological age; for these subjects, there does not appear 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 one adverse 
event during the course of the studies. There was no death during the studies. No subject discontinued the 
studies due to adverse events. 
 
Hypoglycaemia was the most frequently reported adverse event and a proper attention has to be given to 
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 information on 
this medicinal product.  



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The European Medicines Agency will review any new information which may become available every year 
and this SmPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
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. 
 
Biotransformation 
Both the liver and the kidney have been shown to metabolise IGF-1.   
 
Elimination 
The 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. 
 
Special populations 
 
Elderly 
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 adolescents 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 impairment 
No studies have been conducted in children with renal impairment.   
 
Hepatic impairment 
No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of 
mecasermin. 



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5.3 Preclinical safety data 
 
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: 
 
Toxicity to reproduction 
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. 
 
Carcinogenic potential 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Benzyl alcohol 
Sodium chloride 
Polysorbate 20 
Glacial acetic acid 
Sodium acetate 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
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 medicinal product may be stored for a maximum of 
30 days at 2°C to 8°C.  
 



13 

6.4 Special precautions for storage 
 
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. 
 
6.5 Nature and contents of container 
 
5 ml vial (type I glass) closed with a stopper (bromobutyl/isoprene polymer) and a seal (lacquered plastic). 
 
Each vial contains 4 ml of solution. 
 
Pack size of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
INCRELEX is supplied as a multi-dose solution. 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Ipsen Pharma 
65, quai Georges Gorse 
92100 Boulogne-Billancourt  
France 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/402/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 03 August 2007 
Date of latest renewal: 03 August 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

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


14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 
BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 

USE  
 

  C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

  E. SPECIFIC OBLIGATION TO COMPLETE POST-
AUTHORISATION MEASURES FOR THE MARKETING 
AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES 

 
 



15 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER 
RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Lonza AG  
Lonzastrasse  
CH-3930 Visp  
Switzerland 
 
 
Name and address of the manufacturer responsible for batch release 
 
Beaufour Ipsen Industrie 
Rue d'Ethe Virton 
28100 Dreux 
France 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent 
updates published on the European medicines web-portal. 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 

OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency;  
• Whenever the risk management system is modified, especially as the result of new information being 

received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same 
time. 
 
• Additional risk minimisation measures 
 
The MAH must ensure that, at launch, all physicians who are expected to prescribe INCRELEX are 
provided with a “physician information pack” containing the following: 



16 

• Product information 
• Physician information about INCRELEX (information card, dosing guide, and a dose calculator) 
• Patient information pack 

 
The physician information about INCRELEX should contain the following key elements: 
 

• To document severe primary IGF-1 deficiency diagnosis. 
• To educate parents on the signs, symptoms and treatment of hypoglycaemia, including injection of 

glucagon. 
• To advise parents regarding the benefit of INCRELEX versus the increased risk of benign and 

malignant neoplasia. 
• INCRELEX is contraindicated in case of active or suspected neoplasia, or any condition or medical 

history which increases the risk of benign or malignant neoplasia , and therapy should be 
discontinued definitely if evidence of neoplasia develops. 

• To document assessment of patient history and risk factors for malignancy to ensure 
contraindications are excluded. 

• To inform parents that they should monitor for development of any new growth or signs and 
symptoms potentially related to benign or malignant neoplasm and report immediately to an 
appropriate healthcare professional in case of suspicion. 

• To prevent overdose by strictly following the label and manage any overdose effects by 
discontinuation of the treatment or dose reduction 

• That patients should have examinations of the ears, nose and throat periodically and at the 
occurrence of clinical symptoms to rule out such potential complications or to initiate appropriate 
treatment. 

• To perform a routine funduscopic examination prior to beginning treatment and periodically during 
treatment or at the occurrence of clinical symptoms. 

• Slipped capital femoral epiphysis and progression of scoliosis can occur in patients who experience 
rapid growth. These conditions should be monitored during INCRELEX treatment. 

• To inform parents and patients that systemic allergic reactions are possible and that if this occurs 
treatment should be interrupted, and prompt medical attention should be sought. 

• Immunogenicity sampling information. 
 
The patient information about INCRELEX should contain the following information: 
 

• That INCRELEX should be administered shortly before or after a meal or snack because it has 
insulin-like hypoglycaemic effects. 

• The signs and symptoms of hypoglycaemia. Instructions on the treatment of hypoglycaemia. That 
parents and caregivers should always ensure that the child has a source of sugar. Instructions on the 
administration of glucagon should severe hypoglycaemia occur. 

• INCRELEX should not be administered if the patient is unable to eat for any reason. The dose of 
INCRELEX should not be doubled to make up for one or more omitted doses. 

• To avoid engaging in any high-risk activities (such as vigorous physical activity) within 2 - 3 hours 
after dosing, particularly at the initiation of INCRELEX treatment, until a well-tolerated dose of 
INCRELEX has been established. 

• The patients or parents should report immediately to the appropriate healthcare professional as soon 
as there is a suspicion of the patient developing a benign or malignant neoplasm. 

• Instructions to change and rotate the site of injection for each injection to avoid the development of 
lipohypertrophy. 

• Instructions to report the onset or worsening of snoring that may indicate an increase in growth of 
tonsils and/or adenoids following the beginning of treatment with INCRELEX.  

• To report the onset of severe headache, blurred vision and associated nausea and vomiting to their 
physician. 

• To report any onset of a limp or complaint of hip or knee pain to their physician so it can be 
evaluated. 

 



17 

In addition there will be a dosing guide, and a dose calculator, for use by physician and patients to include 
information on the individualised dose escalation to minimise the risk of medication errors and 
hypoglycaemia. 
 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR 

THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES 
 
This being an approval under exceptional circumstances and pursuant to Article 14(8) of Regulation (EC) No 
726/2004, the MAH shall conduct, within the stated timeframe, the following measures: 
 
 
 
Description Due date 

To perform one long-term safety study where mecasermin treatment is initiated in 
early phase of childhood and continued to adulthood in order to investigate: 
 

• Long-term toxicity in patients undergoing developmental changes  
• Possible occurrence of malignancies as well as other risks 

 
 The interim reports will be submitted every two years until the final patient 

is followed for 5 years. 

Final report by 
2023 



18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



20 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
INCRELEX 10 mg/ml solution for injection 
mecasermin  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml contains 10 mg of mecasermin. 
Each vial contains 40 mg of mecasermin. 
 
 
3. LIST OF EXCIPIENTS 
 
Other ingredients: benzyl alcohol, sodium chloride, polysorbate 20, glacial acetic acid, sodium acetate and 
water for injections. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection. 
One multi-use vial of 4 ml. 
40mg/4ml 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
  
 
8. EXPIRY DATE 
 
EXP 
After first opening, use within 30 days. 
 



21 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Keep vial in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Ipsen Pharma 
65, quai Georges Gorse 
92100 Boulogne-Billancourt  
France  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/402/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
INCRELEX 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN:  
 



22 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
INCRELEX 10 mg/ml injection  
mecasermin 
SC 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
Lot 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
40mg/4ml 
 
 
6. OTHER 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



24 

 
Package leaflet: Information for the user 

 
INCRELEX 10 mg/ml solution for injection 

Mecasermin 
 

This medicine is subject to additional monitoring. This will allow quick identification of new safety 
information. You can help by reporting any side effects you may get. See the end of section 4 for how to 
report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains important 

information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What INCRELEX is and what it is used for  
2. What you need to know before you use INCRELEX 
3. How to use INCRELEX  
4. Possible side effects  
5. How to store INCRELEX 
6. Contents of the pack and other information 
 
1. What INCRELEX is and what it is used for 
 

- INCRELEX is a liquid that contains mecasermin which is a man-made insulin-like growth factor-1 
(IGF-1), which is similar to the IGF-1 made by your body. 

- It is used to treat children and adolescents from 2 to 18 years old who are very short for their age 
because their bodies do not make enough IGF-1. This condition is called primary IGF-1 deficiency. 

 
2. What you need to know before you use INCRELEX   
 
Do not use INCRELEX 
- If you currently have any tumour or growth, either cancerous or non-cancerous 
- if you have had cancer in the past 
- if you have any conditions which may increase the risk of cancer 
- if you are allergic to mecasermin or any of the other ingredients of this medicine (listed in section 6). 
- in premature babies or neonates because it contains benzyl alcohol. 
 
Warnings and precautions  
There is an increased risk of tumours and growths (both cancerous and non-cancerous) in children and 
adolescents treated with INCRELEX.  If any new growth, skin lesion or any unexpected symptom occurs 
during treatment or after treatment, see your doctor immediately since mecasermin may play a role in cancer 
development.  
 
Talk to your doctor or pharmacist before using INCRELEX 
- if you have a curved spine (scoliosis). You should be monitored for progression of scoliosis. 
- if you develop a limp or hip or knee pain 
- if you have enlarged tonsils (tonsillar hypertrophy). You should have examinations periodically. 
- if you have symptoms of increased pressure in the brain (intracranial hypertension), such as visual 

changes, headache, nausea and/or vomiting, contact the doctor for advice. 



25 

- if you have a localised reaction at the injection site or generalised allergic reaction with INCRELEX. 
Call the doctor as soon as possible if you get a localised rash. Get medical help immediately if you have 
a generalised allergic reaction (hives, trouble breathing, faintness or collapse and feeling generally 
unwell). 

- if you have finished growing (the bone growth plates are closed). In this case INCRELEX cannot help 
you grow and should not be used. 

 
 
Children under 2 years old 
 
The use of this medicine has not been studied in children under 2 years of age and is therefore not 
recommended. 
 
Other medicines and INCRELEX 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
 
Especially tell the doctor if you take insulin or other anti-diabetes medicines. A dose adjustment may be 
needed for these medicines. 
 
Pregnancy, breast-feeding and fertility 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor for advice before using this medicine. 
 
A negative pregnancy test is recommended for all women of child bearing potential prior to treatment with 
mecasermin. It is also recommended that all women of childbearing potential use adequate contraception 
during treatment. 
 
Mecasermin therapy should be discontinued if pregnancy occurs. 
 
Mecasermin should not be administered to a breast-feeding mother. 
 
Driving and using machines 
 
Mecasermin may cause hypoglycaemia (very common side effect, see section 4) that may impair your ability 
to drive and use machines because your ability to concentrate or react may be reduced. 
 
You should avoid engaging in any high-risk activities (e.g., driving, etc.) within 2-3 hours after dosing, 
particularly at the start of INCRELEX treatment, until a dose of INCRELEX has been found which does not 
cause side effects that make these activities risky. 
 
INCRELEX contains benzyl alcohol and sodium 
 
INCRELEX contains benzyl alcohol as a preservative which may cause toxic reactions and allergic 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’. 
 
3. How to use INCRELEX 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you 
are not sure. 
 
The typical dose is 0.04 to 0.12 mg/kg of patient weight administered twice a day. See the ‘Instructions for 
Use’ at the end of this leaflet. 
 



26 

Inject INCRELEX just under your skin shortly before or after a meal or snack because it may have insulin-
like hypoglycaemic effects and so it may decrease blood sugar levels (see hypoglycaemia in section 4). Do 
not inject your dose of INCRELEX if you cannot eat for any reason. Do not make up the missed dose by 
giving two doses the next time. The next dose should be taken as usual, with a meal or snack. 
 
Inject INCRELEX just below the skin in your upper arm, upper leg (thigh), stomach area (abdomen), or 
buttocks. Never inject it into a vein or muscle. Change the injection site for each injection. 
 
Only use INCRELEX that is clear and colourless. 
 
Treatment with mecasermin is a long-term therapy. For further information ask the doctor. 
 
If you use more INCRELEX than you should 
 
Mecasermin, like insulin, may lower blood sugar levels (see hypoglycaemia in section 4). 
 
If more INCRELEX than recommended was injected, contact your doctor immediately. 
 
Acute overdose could lead to hypoglycaemia (low blood sugar).  
 
Treatment of acute overdose of mecasermin should be directed at reversing hypoglycaemia. Sugar-
containing fluids or food should be consumed. If the patient is not awake or alert enough to drink sugar-
containing fluids, an injection of glucagon into the muscle may be necessary to reverse the low blood sugar. 
Your doctor or nurse will instruct you how to give the injection of glucagon. 
 
Long-term overdose may result in enlargement of certain body parts (e.g., hands, feet, parts of the face) or 
excessive growth of the whole body. If you suspect long-term overdose, contact your doctor immediately. 
 
If you forget to use INCRELEX 
 
Do not use a double dose to make up for a forgotten dose. 
If a dose is skipped, the next dose should not be made larger to compensate. The next dose should be taken 
as usual, with a meal or snack. 
 
If you stop using INCRELEX 
 
A disruption or early ending of treatment with mecasermin may impair the success of the growth therapy. 
Please ask the doctor for advice before stopping the treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. If you get any 
side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. 
 
The most frequently occurring side effects with mecasermin are: low blood sugar (hypoglycemia), vomiting, 
injection site reactions, headache and middle ear infections. Serious allergic reactions have also been 
reported with INCRELEX. If you develop any of these events, please follow the advice given for each event 
in the sections below.  
 
Frequency not known (frequency cannot be estimated from the available data) 
Cancerous and non-cancerous tumours 
An increase in both cancerous and non-cancerous tumours has been reported in patients treated with 
INCRELEX.  The risk of such tumours may be higher if INCRELEX is used for condition other than what is 
stated in Section 1 or used at higher than recommended dose as per Section 3.  
 



27 

Serious allergic reactions (anaphylaxis) 
Generalised hives, difficulty in breathing, dizziness, swelling of the face and/or throat have been reported 
following mecasermin use. Stop INCRELEX immediately and seek urgent medical advice if you develop a 
serious allergic reaction. 
Local allergic reactions at the injection site (itching, hives) have also been reported. 
 
Hair loss (alopecia) 
Hair loss has also been reported following mecasermin use. 
 
Very common (may affect more than 1 in 10 people) 
Low blood sugar (hypoglycaemia)  
Mecasermin may lower blood sugar levels. Signs of low blood sugar are: dizziness, tiredness, restlessness, 
hunger, irritability, trouble concentrating, sweating, nausea and fast or irregular heartbeats.  
 
Severe hypoglycaemia may cause unconsciousness, seizures/fits or death. Stop INCRELEX immediately and 
seek urgent medical advice if you develop seizures/fits or become unconscious.  
 
If you take INCRELEX, you should avoid participating in high risk activities (such as vigorous physical 
activity) within 2 to 3 hours after INCRELEX injection, especially at the beginning of INCRELEX 
treatment. 

 
Before beginning treatment with INCRELEX the doctor or nurse will explain to you how to treat 
hypoglycaemia. You should always have a source of sugar such as orange juice, glucose gel, sweets, or milk 
available in case symptoms of hypoglycaemia occur. For severe hypoglycaemia, if you are not responsive 
and cannot drink sugar-containing fluids, you should give an injection of glucagon. The doctor or nurse will 
instruct you how to give the injection. Glucagon raises the blood sugar when it is injected. It is important that 
you have a well-balanced diet including protein and fat such as meat and cheese in addition to sugar-
containing foods. 
 
Injection site hypertrophy (tissue at injection site increases in size) and bruising 
These can be avoided by changing the injection site at each injection (injection site rotation).  
 
Digestive system  
Vomiting and pain in the upper belly have occurred with mecasermin treatment. 
 
Infections 
Infections of the middle ear have been observed in children with mecasermin treatment.  
 
Musculoskeletal system 
Joint pains and pains in the limbs have occurred with mecasermin treatment.  
 
Nervous system 
Headache has occurred with mecasermin treatment. 
 
Common (may affect up to 1 in 10 people) 
Seizures 
Seizures (fits) have been observed with mecasermin treatment. 
Dizziness and tremor have also been reported with mecasermin treatment. 
 
Heart abnormalities  
A fast heart rate and abnormal heart sounds have been reported with mecasermin treatment. 
 
Increased blood sugar (hyperglycaemia) 
Increased blood sugar has also been observed with mecasermin treatment. 
 



28 

Enlarged tonsils/adenoids 
Mecasermin may enlarge your tonsils/adenoids. Some signs of enlarged tonsils/adenoids include: snoring, 
difficulty breathing or swallowing, sleep apnoea (a condition where breathing stops briefly during sleep), or 
fluid in the middle ear, as well as infections of the ear. Sleep apnea can cause excessive daytime sleepiness. 
Call the doctor should these symptoms bother you. The doctor should regularly examine your 
tonsils/adenoids.  
 
Enlarged thymus 
An enlarged thymus (a specialized organ of the immune system) has been observed with mecasermin 
treatment. 
 
Papilloedema 
A swelling at the back of the eye (due to increased pressure within the brain) may be observed by a doctor or 
optician during mecasermin treatment.  
 
Hypoacusis (hearing loss) 
Hypoacusis (hearing loss), ear pain and fluid in the middle ear have been observed with mecasermin 
treatment. Tell the doctor if you develop hearing problems. 
 
Worsened scoliosis (caused by rapid growth) 
If you have scoliosis, you will need to be checked often for an increase in the curve of the spine.  
Pain in muscles has also been seen with mecasermin treatment. 
 
Reproductive system 
Breast enlargement has been observed with mecasermin treatment. 
 
Digestive system  
Pain in the belly has occurred with mecasermin treatment. 
 
Skin and hair changes 
Skin thickening, moles and abnormal hair texture have been seen with mecasermin treatment. 
 
Reactions at the injection site 
Reactions including pain, irritation, bleeding, bruising, redness and hardening have been reported with 
INCRELEX treatment. Injection site reactions can be avoided by changing the injection site at each injection 
(injection site rotation). 
 
Uncommon (may affect up to 1 in 100 people)  
Increased pressure in the brain (intracranial hypertension) 
INCRELEX can sometimes cause a temporary increase in pressure within the brain. The symptoms of 
intracranial hypertension can include visual changes, headache, nausea and/or vomiting. Tell the doctor 
immediately if you have any of these symptoms. Your doctor can check to see if intracranial hypertension is 
present. If it is present, your doctor may decide to temporarily reduce or discontinue mecasermin therapy. 
Mecasermin may be started again after the episode is over.  
 
Heart abnormalities 
In some patients treated with mecasermin, an ultrasound examination of the heart (echocardiogram) showed 
an increased size of the heart muscle and abnormalities of heart valve function. Your doctor may perform an 
echocardiogram before, during and after mecasermin treatment.  
 
Reactions at the injection site 
Reactions including rash, swelling and fatty lumps have been reported with INCRELEX treatment. Injection 
site reactions can be avoided by changing the injection site at each injection (injection site rotation). 
 
Weight increase 
Weight increase has been observed with mecasermin treatment. 
 



29 

Other uncommon side effects seen with mecasermin treatment include depression, nervousness. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 
 
5. How to store INCRELEX 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and label after EXP. The expiry 
date refers to the last day of the month. 
 
Store in a refrigerator (2°C - 8°C). Do not freeze.  
Keep the vial in the outer carton in order to protect from light.  
After first use, the vial may be stored for up to 30 days at 2°C to 8ºC. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment. 
 
6. Contents of the pack and other information 
 
What INCRELEX contains  
- The active substance is mecasermin. One ml contains 10 mg of mecasermin. Each vial contains 40 mg 

of mecasermin. 
- The other ingredients are: benzyl alcohol, sodium chloride, polysorbate 20, glacial acetic acid, sodium 

acetate and water for injections (see section 2 "INCRELEX contains benzyl alcohol and sodium"). 
 
What INCRELEX looks like and contents of the pack 
 
INCRELEX is a clear and colourless solution for injection (injection) supplied in a glass vial closed with a 
stopper and a seal. The vial contains 4 ml of solution.  
 
Pack size of 1 vial. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Ipsen Pharma 
65, quai Georges Gorse 
92100 Boulogne-Billancourt  
France  
 
Manufacturer: 
Beaufour Ipsen Industrie 
Rue d'Ethe Virton 
28100 Dreux 
France  
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien,  
Luxembourg/Luxemburg 
Ipsen NV 

Italia 
Ipsen SpA 
Via del Bosco Rinnovato n. 6 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


30 

Guldensporenpark 87 
B-9820 Merelbeke 
België /Belgique/Belgien  
Tél/Tel: + 32 9 243 96 00 
 

Milanofiori Nord Palazzo U7 
20090 Assago (Mi) 
Tel: + 39 - 02 - 39 22 41 

România, България 
Ipsen Pharma 
Str. Grigore Alexandrescu nr. 59, clădirea HQ  
Sector 1, 010623, Bucureşti,  
România 
Tel/Тел.: + 40 (021) 231 27 20  
 

Latvija 
Ipsen Pharma pārstāvniecība Latvijā 
Kalnciema iela 33-5 
Rīga LV 1046 
Tel: +371 67622233 
 

Česká republika 
Ipsen Pharma, s.r.o. 
Olbrachtova 2006/9, 
140 00 Praha 4  
Tel: + 420 242 481 821 
 

Lietuva, Hrvatska 
Ipsen Pharma Lietuvos filialas 
9-ojo Forto 47  
LT-48100 Kaunas 
Tel. + 370 37 337854 
 

Danmark, Norge, Suomi/Finland, Sverige, 
Ísland 
Institut Produits Synthèse (IPSEN) AB 
Kista Science Tower 
Färögatan 33 
SE- 164 51 Kista 
Sverige/Ruotsi/Svíþjóð 
Tlf/Puh/Tel/Sími: +46 8 451 60 00 
 

Magyarország 
Ipsen Pharma SAS Magyarországi  
Kereskedelmi Képviselet 
Árbóc utca 6. 
H-1133  Budapest 
Tel.: + 36 1 555 5930 

Deutschland, Österreich 
Ipsen Pharma GmbH 
Einsteinstrasse 174  
D-81677 München 
Tel.: +49 89 262043289 

Nederland 
Ipsen Farmaceutica B.V. 
Taurusavenue 33 B 
NL-2132 LS Hoofddorp 
Tel: + 31 23 55 41 600 
 

Eesti 
Centralpharma Communications OÜ 
Selise 26-11, 13522, Tallinn 
Tel: +372 6015540  
 

Polska 
Ipsen Poland Sp. z o.o. 
Al. Jana Pawła II 29 
PL-00-867 Warszawa 
Tel.: + 48 (0) 22 653 68 00 
 



31 

Ελλάδα, Κύπρος, Malta 
Ipsen Μονοπρόσωπη EΠΕ  
Αγ. Δημητρίου 63 
Άλιμος  
GR-17456 Αθήνα  
Ελλάδα 
Τηλ: + 30 - 210 - 984 3324 
 

Portugal 
Ipsen Portugal - Produtos Farmacêuticos S.A. 
Alameda Fernão Lopes, no 16A – 1ºB 
  
P-1495 - 190 Algés 
Tel: + 351 - 21 - 412 3550 

España 
Ipsen Pharma S.A. 
Torre Realia, Plaza de Europa, 41-43   
08908 L’Hospitalet de Llobregat  
Barcelona 
Tel: + 34 - 936 - 858 100 
 

Slovenija 
PharmaSwiss d.o.o. 
 Brodišče 32 SI-1236 Trzin 
Tel: + 386 1 236 47 00 

France 
Ipsen Pharma 
65 quai Georges Gorse 
F-92100 Boulogne-Billancourt 
Tél: + 33 - 1 - 58 33 50 00 
 

United Kingdom 
Ipsen Ltd. 
190 Bath Road 
Slough, Berkshire  
SL1 3XE  
Tel: + 44  - (0)1753 - 62 77 00 
 

Ireland 
Ipsen Pharmaceuticals Ltd. 
Blanchardstown Industrial Park 
Blanchardstown 
IRL-Dublin 15 
Tel: + 353 - 1 - 809 8200 
 

Slovenská republika 
Liek s.r.o. 
Hviezdoslavova 19 
SK-90301 Senec 
Tel: + 421 245 646 322 
 

 
This leaflet was last revised in  
 
This medicine has been authorised under ‘exceptional circumstances’. This means that because of the rarity 
of this disease it has been impossible to get complete information on this medicine. 
The European Medicines Agency will review any new information on this medicine every year and this 
leaflet will be updated as necessary. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
<-----------------------------------------------------------------------------------------------------------------------------> 
 
 

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


32 

INSTRUCTIONS FOR USE 
 
INCRELEX should be administered using sterile disposable syringes and injection needles which could be 
provided by your doctor, pharmacist or nurse. The syringes should be of small enough volume that the 
prescribed dose can be withdrawn from the vial with reasonable accuracy. 
 
Preparing the dose 
 
1. Wash your hands before getting INCRELEX ready for your injection. 
 
2. Use a new disposable needle and syringe every time you give a dose. Use syringes and needles only 

once. Throw them away properly in a sharps container (such as a biohazard container), hard plastic 
container (such as a detergent bottle), or metal container (such as an empty coffee can). Never share 
needles and syringes. 

 
3. Check the liquid to make sure it is clear and colourless. Do not use after the expiry date (which is 

stated on the label after EXP and it refers to the last day of the month) or if it is cloudy or if you see 
bits. If a vial freezes, dispose appropriately. Ask your pharmacist how to throw away medicines you 
no longer use. 

 
4. If you are using a new vial, remove the protective cap. Do not remove the rubber stopper. 
 
5. Wipe the rubber stopper of the vial with an alcohol swab to prevent contamination of the vial by germs 

that may be introduced by repeated needle insertions (see Figure 1). 
 

 
 

 

Figure 1: Wipe top 
with alcohol 



33 

 
6. Before putting the needle into the vial, pull back on plunger to draw air into the syringe equal to the 

prescribed dose. Put the needle through the rubber top of the vial and push the plunger to inject air 
into the vial (see Figure 2). 

 
 
 

 
 
 
 
 
 
 
 
 
 

 
7. Leave the syringe in the vial and turn both upside down. Hold the syringe and vial firmly (see Figure 

3). 
 
   

 
 
 
 
 
 
 

Figure 2: Inject air 
into vial 

Figure 3: Prepare for 
extraction 



34 

 
8.  Make sure the tip of the needle is in the liquid (see Figure 4). Pull the plunger to withdraw the correct 

dose into the syringe (see Figure 5). 
 
          
 

                           
 
 
             
    
 
 
 
9.  Before you take the needle out of the vial, check the syringe for air bubbles. If bubbles are in the 

syringe, hold the vial and syringe with needle straight up and tap the side of the syringe until the 
bubbles float to the top. Push the bubbles out with the plunger and draw liquid back in until you have 
the correct dose (see Figure 6). 

 
 

        
             
     
 
 
 
 
 
 
 

Figure 4: Tip in 
liquid   

Figure 5: Extract 
correct dose  

Figure 6: Remove air bubbles 
and refill syringe 



35 

10.  Remove the needle from the vial and replace the protective cap. Do not let the needle 
touch anything. You are now ready to inject (see Figure 7). 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injecting the dose: 
 
Inject INCRELEX as instructed by the doctor. 
Do not give the injection if you are unable to eat shortly before or after the injection. 
 
1. Decide on an injection area – upper arm, thigh, buttock, or abdomen (see below). The injection site 

should be changed for each injection (rotate the injection site). 
 

                                                            
 
 
 
2. Use alcohol or soap and water to clean the skin where you are going to inject you. The injection site 

should be dry before you inject. 

Figure 7: Ready to 
inject 

Upper arm Thigh Buttock Abdomen  



36 

3. Lightly pinch the skin. Insert the needle in the way the doctor showed you. Release the skin (see 
Figure A). 

 
 
 
 
 
 
 
 
 
 
 
 
 
4. Slowly push in the plunger of the syringe all the way, making sure you have injected all the liquid. 

Pull the needle straight out and gently press on the spot where you injected you with gauze or a cotton 
ball for a few seconds. Do not rub the area (see Figure B). 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. Follow the doctor’s instructions for throwing away the needle and syringe. Do not recap the syringe. 

Used needle and syringe should be placed in a sharps container (such as a biohazard container), hard 
plastic container (such as a detergent bottle), or metal container (such as an empty coffee can). Such 
containers should be sealed and disposed of properly in the way your doctor described. 

 

Figure A: Lightly pinch 
the skin and inject as 
instructed 

Figure B: Press (don’t rub) 
with gauze or cotton 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES
	A. LABELLING
	B. PACKAGE LEAFLET