INCRELEX
*Company:
Ipsen Pharmaceuticals LimitedStatus:
No Recent UpdateLegal Category:
Product subject to medical prescription which may not be renewed (A)Active Ingredient(s):
This medicinal product is subject to additional monitoring.
*Additional information is available within the SPC or upon request to the company
Updated on 09 November 2023
File name
231026_ni-ie-pl-clean-36_INC_NIIE.pdf
Reasons for updating
- Change to section 3 - how to take/use
- Change to section 4 - possible side effects
- Change to section 6 - manufacturer
- Change to section 6 - date of revision
- Change to section 7 - Instructions for use
Updated on 09 November 2023
File name
231026_ni-ie-pl-clean-36_INC_NIIE.pdf
Reasons for updating
- Change to section 3 - how to take/use
- Change to section 4 - possible side effects
- Change to section 6 - manufacturer
- Change to section 6 - date of revision
- Change to section 7 - Instructions for use
Updated on 18 November 2021
File name
211111A ni-ie-pl-clean-29_INC.pdf
Reasons for updating
- Change to other sources of information section
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Section 6 of the PIL has been updated to remove the addresses of local representatives
Updated on 16 November 2021
File name
211109A ni-ie-spc-clean_25_INC.pdf
Reasons for updating
- Change to section 3 - Pharmaceutical form
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 6.3 - Shelf life
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
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3 PHARMACEUTICAL FORM
The description of the product has been updated from “Aqueous, clear and colourless solution” to “Colourless to slightly yellow and clear to slightly opalescent liquid”
4.4 Special warnings and precautions for use
Minor correction of wording related to sodium content.
6.3 Shelf life
Change of shelf life from 3 to 5 years.
Updated on 16 November 2021
File name
211109A ni-ie-pl-clean-26_INC.pdf
Reasons for updating
- Change to section 2 - excipient warnings
- Change to section 6 - what the product looks like and pack contents
Updated on 25 August 2021
File name
210816A ni-ie-spc-clean_17_INC.pdf
Reasons for updating
- Change to section 6.5 - Nature and contents of container
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
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Section 6.5 of the SmPC has been updated.
Updated on 20 July 2021
File name
210421A ni-ie-pl-clean_16_INC.pdf
Reasons for updating
- Change to section 4 - how to report a side effect
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The following changes have been made to the PIL:
- Update to section 4 to include the latest QRD text for the "Reporting of side effects" sub-heading
- Update to section 6 to change the contact details for the local representative in Slovakia
Updated on 20 July 2021
File name
210421A ni-ie-spc-clean_15_INC.pdf
Reasons for updating
- Change to Section 4.8 – Undesirable effects - how to report a side effect
- Change to section 9 - Date of first authorisation/renewal of the authorisation
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
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The following changes have been made to the SmPC:
- Section 4.8: The Reporting details section has been updated for Ireland with the latest QRD text
-Section 9: The date of renewal of authorisation has been corrected
Updated on 01 July 2020
File name
180416 INC-IE-000005 Instructions for Use version 5 clean.pdf
Reasons for updating
- Add New Doc
Updated on 01 July 2020
File name
180416 INC-IE-000004 Hypoglycaemia Leaflet version 5 clean.pdf
Reasons for updating
- Add New Doc
Updated on 01 July 2020
File name
200625A INC-IE-000014 Patient Leaflet_V6 clean.pdf
Reasons for updating
- Add New Doc
Free text change information supplied by the pharmaceutical company
Update with respect to the information relating to an adverse event, neoplasia
Updated on 01 July 2020
File name
200625A INC-IE-000012 Increlex Physician Leaflet_V6 clean.pdf
Reasons for updating
- Add New Doc
Free text change information supplied by the pharmaceutical company
Update with respect to the information relating to an adverse event, neoplasia
Updated on 01 July 2020
File name
200625A INC-IE-000016 Dosing Guide_V6 clean.pdf
Reasons for updating
- Replace File
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Update with respect to the information relating to an adverse event, neoplasia
Updated on 08 January 2020
File name
191216A uk-ie-pl-clean_14_INC_UKIE.pdf
Reasons for updating
- Change to section 2 - what you need to know - contraindications
- Change to section 2 - what you need to know - warnings and precautions
- Change to section 3 - overdose, missed or forgotten doses
- Change to section 4 - possible side effects
- Change to section 6 - date of revision
Free text change information supplied by the pharmaceutical company
Update to add neoplasia AE
Updated on 08 January 2020
File name
191216A uk-ie-spc-clean_13_INC_UKIE.pdf
Reasons for updating
- Change to section 4.1 - Therapeutic indications
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
- Change to section 4.9 - Overdose
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
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Type II update to add neoplasia
Updated on 08 December 2019
File name
170914A updated 191206-uk-ie-pl-cl_12_INC_UKIE.pdf
Reasons for updating
- Change to section 2 - what you need to know - warnings and precautions
- Change to section 6 - what the product contains
- Change to other sources of information section
Free text change information supplied by the pharmaceutical company
Update to warning for pregnancy to include standard QRD template wording
Update for excipient warning to include sodium and to update wording for benzyl alcohol
Update to section 6 to reference updated excipient warnings in section 2
Updated on 08 December 2019
File name
170914A updated 191206 uk-ie-spc-cl_11_INC_UKIE.pdf
Reasons for updating
- Change to section 4.1 - Therapeutic indications
- Change to section 4.2 - Posology and method of administration
- Change to section 4.6 - Pregnancy and lactation
- Change to section 4.7 - Effects on ability to drive and use machines
- Change to section 4.8 - Undesirable effects
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 6.3 - Shelf life
- Change to section 6.5 - Nature and contents of container
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Update to section 4.1 to include statement that physician can decide to carry out IGF-1 generation test
Update to section 4.2 to include text for posology for special populations
Update to section 4.6 to update section on breast-feeding
Rewording of section 4.7
Reformating of AEs for immune system disorders in reactions observed from post-marketing in section 4.8.
Inclusion of age range for paediatric patients in first paragraph under clinical efficacy and safety in section 5.1
Removal of statement regarding in-use storage being the responsibility of the user in section 6.3.
Removal of statement relating to appearance of the solution on removal from the fridge in section 6.5.
Updated on 01 August 2019
File name
V5_IE_ INC-IE-000003 Dosing Guide.pdf
Reasons for updating
- Add New Doc
Free text change information supplied by the pharmaceutical company
Version 5 of HCP dosing guide approved 16 April 2018.
Updated on 22 September 2017
Reasons for updating
- New SPC for new product
Legal category:Product subject to medical prescription which may not be renewed (A)
Updated on 22 September 2017
Reasons for updating
- Change to section 2 - Qualitative and quantitative composition
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Section 4: addition of wording relating to the use of antibody testing for allergic reactions for patients treated with IGF-1
Updated on 21 September 2017
File name
PIL_14697_175.pdf
Reasons for updating
- New PIL for new product
Updated on 21 September 2017
Reasons for updating
- Change to section 6 - date of revision
- Change to other sources of information section
Updated on 10 June 2015
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Update of section 4.4 of the SmPC to include information regarding the possible occurrence of avascular necrosis in relation to slipped capital femoral epiphysis.
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.
Updated on 08 May 2015
Reasons for updating
- Change to section 4.8 - Undesirable effects
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
The following AEs can be removed from the SmPC:
Otorrhoea, Retching, Hypertrophy, Injection site fibrosis, Injection site discoloration, Spinal deformity, Dyspnoea, Mouth breathing, Obstructive airway disorder, Adenotonsillectomy and Adenoidectomy, Lymphadenopathy, Atrial hypertrophy, Myopia, Visual acuity reduced, Dysphagia, Asthenia, Lethargy, Chest discomfort, Febrile infection (Pyrexia), Oral candidiasis, Otitis externa, Tonsillitis, Upper Respiratory Tract Infection, Pharyngitis, Increased alanine aminotransferase, Increased aspartate aminotransferase, Obesity, Hyperlipidaemia, Flank pain, Muscle cramp (PT Muscle spasms), Febrile convulsion, Loss of consciousness, Restless leg syndrome, Abnormal behaviour, Disorientation, Sleep terror, Hydronephrosis, Nephrolithiasis, Renal colic, Ovarian cyst, Abnormal respiration (Breath sounds abnormal), Nasal congestion, Nasal turbinate hypertrophy and Acrochordon.
Section 5.1 Pharmacodynamic properties
Further information added to: Clinical efficacy and safety
Section 10: date of Preparation updated 23 April 2015
Updated on 01 May 2015
Reasons for updating
- Change to side-effects
- Addition of manufacturer
Updated on 29 September 2014
Reasons for updating
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
There has been a slight change to the SPC which I recently sent you for Increlex. The change is as follows:
Date of revision of text field has been updated to 15th July 2014.
Updated on 23 September 2014
Reasons for updating
- Addition of black triangle
Updated on 19 September 2014
Reasons for updating
- Addition of black triangle
- Change to section 4.8 - Undesirable effects
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Updated on 19 December 2012
Reasons for updating
- Change to section 4.8 - Undesirable effects
- Change to MA holder contact details
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Updated on 14 December 2012
Reasons for updating
- Change to side-effects
- Change to MA holder contact details
Updated on 27 January 2012
Reasons for updating
- Change to section 4.8 - Undesirable effects
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Updated on 26 January 2012
Reasons for updating
- Change due to user-testing of patient information
- Correction of spelling/typing errors
Updated on 19 June 2011
Reasons for updating
- Change to section 4.8 - Undesirable effects
- Change to section 5.1 - Pharmacodynamic properties
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
4.8 Undesirable effects
An integrated safety database from clinical studies contains 76 subjects with severe Primary IGFD treated for a mean duration of 4.4 years and representing 321 subject-years.
Hypoglycaemia is the most frequently reported adverse drug reaction. The thirty-six subjects (47%) who had one or more episodes of hypoglycaemia included 4 subjects who had hypoglycaemic seizure on one or more occasion. Of the 36 subjects, 12 (33%) had a history of hypoglycaemia prior to beginning treatment. The frequency of hypoglycaemia was highest in the first month of treatment, and episodes were more frequent in younger children. Symptomatic hypoglycaemia was generally avoided when a meal or snack was consumed either shortly before or after the administration of INCRELEX.
Injection site hypertrophy occurred in 24 subjects (32%). This reaction was generally associated with lack of proper rotation of injections. When injections were properly dispersed, the condition resolved.
Tonsillar hypertrophy was noted in 12 (16%) subjects, particularly in the first 1 to 2 years of therapy with lesser tonsillar growth in subsequent years.
Snoring, generally beginning in the first year of treatment, was reported in 17 subjects (22%).
Hypoacusis was reported in 15 subjects (20%).
Intracranial hypertension occurred in three subjects (4%). In two subjects the events resolved without interruption of INCRELEX treatment. INCRELEX treatment was discontinued in the third subject and resumed later at a lower dose without recurrence. Fourteen subjects (18%) had headache considered related to study drug.
During clinical trials in other indications totalling approximately 300 patients,
reports of local and/or systemic hypersensitivity were received for 8% of patients. All
cases were mild or moderate in severity and none was serious.
As with all protein pharmaceuticals, some patients may develop antibodies to INCRELEX. Anti-IGF‑1 antibodies were observed in 11 of 23 children with severe Primary IGFD tested during the first year of therapy. No attenuation of growth was observed as a consequence of the development of antibodies.
Table 1 contains very common (≥ 1/10) and common (≥ 1/100 to < 1/10) adverse reactions for which there is at least a reasonable suspicion of a causal relationship to INCRELEX treatment which occurred in clinical trials. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1: Adverse Drug Reactions in Clinical Trials
System Organ Class |
Adverse Reaction |
|
Very Common |
Common |
|
Investigations
|
|
Cardiac murmur, abnormal tympanometry, abnormal echocardiogram, increased alanine aminotransferase*, increased aspartate aminotransferase*, increased weight
|
Cardiac Disorders
|
|
Cardiomegaly, ventricular hypertrophy, atrial hypertrophy*, tachycardia, tachycardia paroxysmal*, mitral valve incompetence*, tricuspid valve incompetence*
|
Congenital, Familial and Genetic Disorders |
|
Congenital jaw malformation, pigmented naevus*
|
Blood and Lymphatic System Disorders
|
Thymus hypertrophy
|
Lymphadenopathy*
|
Nervous System Disorders
|
Headache
|
Convulsions, febrile convulsion*, benign intracranial hypertension, loss of consciousness*, sleep apnoea syndrome, dizziness, tremor*, restless leg syndrome*
|
Eye Disorders
|
|
Papilloedema, reduced visual acuity*, myopia*
|
Ear and Labyrinth Disorders
|
Hypoacusis
|
Otorrhoea, ear disorder*, middle ear disorder*, tympanic membrane disorder*, ear pain, ear congestion*, fluid in middle ear
|
Respiratory, Thoracic and Mediastinal Disorders
|
Tonsillar hypertrophy, snoring
|
Adenoidal hypertrophy, nasal turbinate hypertrophy*, dyspnoea*, nasal mucosal disorder*, obstructive airway disorder*, abnormal respiration*, nasal congestion, mouth breathing
|
Gastrointestinal Disorders
|
|
Vomiting, retching*, abdominal pain*, upper abdominal pain*, abdominal distension*, dysphagia*
|
Renal and Urinary Disorders |
|
Nephrolithiasis*, hydronephrosis*, renal colic*
|
Skin and Subcutaneous Tissue Disorders
|
|
Skin hypertrophy, acrochordons*, abnormal hair texture*
|
Musculoskeletal and Connective Tissue Disorders
|
|
Arthralgia, pain in extremity, myalgia, scoliosis*, spinal deformity*, soft tissue disorder*, muscle cramp*, flank pain*, musculoskeletal stiffness*
|
Metabolism and Nutrition Disorders |
Hypoglycaemia |
Hypoglycaemic seizure, hyperglycaemia, hyperlipidaemia*, obesity*
|
Infections and Infestations
|
|
Febrile infection*, upper respiratory tract infection*, otitis media, otitis media serous, chronic otitis media serous *, otitis externa*, pharyngitis*, tonsillitis, ear infection, oral candidiasis*
|
Surgical and Medical Procedures
|
|
Adenotonsillectomy*, adenoidectomy, ear tube insertion
|
General Disorders and Administration Site Conditions
|
Injection site hypertrophy
|
Mucosal membrane hyperplasia, hypertrophy, injection site pain, injection site bruising, injection site fibrosis*, injection site reaction*, injection site swelling*, injection site induration*, injection site pigmentation changes*, mucosal oedema*, asthenia*, lethargy*, chest discomfort*
|
Reproductive System and Breast Disorders
|
|
Gynaecomastia, ovarian cyst* |
Psychiatric Disorders
|
|
Depression*, sleep terror, nervousness, abnormal behaviour*, disorientation*
|
* = occurred in only 1 subject (1%) |
The following adverse reactions have been identified during post approval use of
INCRELEX:
-Systemic hypersensitivity: anaphylaxis, generalized urticaria, angioedema, dyspnoea.
-Local allergic reactions at the injection site: pruritus, urticaria.
In the post-marketing setting, the frequency of cases indicative of anaphylaxis was
estimated to be 0.3%. Symptoms included hives, angioedema, and dyspnoea, and
some patients required hospitalization. Upon re-administration, symptoms did not
re-occur in all patients.
Clinical efficacy
Five clinical studies (4 open-label and 1 double-blind, placebo-controlled) were conducted with INCRELEX. Subcutaneous doses of mecasermin, generally ranging from 60 to 120 mg/kg given twice daily (BID), were administered to 76 paediatric subjects with severe Primary IGFD. Patients were enrolled in the studies on the basis of extreme short stature, slow growth rates, low IGF‑1 serum concentrations, and normal GH secretion. Baseline characteristics for the patients evaluated in the primary and secondary efficacy analyses from the combined studies were (mean ± SD): chronological age (years): 6.8 ± 3.8; height (cm): 85.0 ± 15.3; height standard deviation score (SDS): -6.7 ± 1.8; height velocity (cm/yr): 2.8 ± 1.8; height velocity SDS: -3.3 ± 1.7; IGF‑1 (ng/ml): 21.9 ± 24.8; IGF‑1 SDS: ‑4.4 ± 2.0; and bone age (years): 3.9 ± 2.8. Sixty-two subjects had at least one year of treatment. Of these, 53 (85%) had Laron syndrome-like phenotype; 7 (11%) had GH gene deletion, and 1 (2%) had neutralizing antibodies to GH. Thirty-eight (61%) of the subjects were male; 49 (79%) were Caucasian. Fifty-six (90%) of the subjects were prepubertal at baseline.
Annual results for height velocity, height velocity SDS, and height SDS are shown in Table 2. Pre-treatment height velocity data were available for 59 subjects. The height velocities at a given year of treatment were compared by paired t-tests to the pre-treatment height velocities of the same subjects completing that treatment year.
Table 2: Annual Height Results by Number of Years Treated with INCRELEX
|
Pre-Tx |
Year 1 |
Year 2 |
Year 3 |
Year 4 |
Year 5 |
Year 6 |
Year 7 |
Year 8 |
Height Velocity (cm/yr) |
|
|
|
|
|
|
|
|
|
N |
59 |
59 |
54 |
48 |
39 |
21 |
20 |
16 |
14 |
Mean (SD) |
2.8 (1.8) |
8.0 (2.2) |
5.8 (1.4) |
5.5 (1.9) |
4.7 (1.4) |
4.7 (1.6) |
4.8 (1.5) |
4.6 (1.5) |
4.5 (1.2) |
Mean (SD) for change from pre-Tx |
|
+5.2 (2.6) |
+3.0 (2.3) |
+2.6 (2.3) |
+1.6 (2.1) |
+1.5 (1.8) |
+1.5 (1.7) |
+1.0 (2.1) |
+0.9 (2.4) |
P-value for change from pre-Tx [1] |
|
<0.0001 |
<0.0001 |
<0.0001 |
<0.0001 |
0.0015 |
0.0009 |
0.0897 |
0.2135 |
Height Velocity SDS |
|
|
|
|
|
|
|
|
|
N |
59 |
59 |
53 |
47 |
38 |
19 |
18 |
15 |
12 |
Mean (SD) |
-3.3 (1.7) |
1.9 (2.9) |
-0.2 (1.6) |
-0.3 (2.0) |
-0.7 (1.9) |
-0.6 (2.1) |
-0.4 (1.4) |
-0.4 (1.9) |
-0.3 (1.8) |
Mean (SD) for change from pre-Tx P-value for change from pre-Tx [1] |
|
+5.1 (3.1) <0.0001 |
+3.2 (2.2) <0.0001 |
+3.1 (2.4) <0.0001 |
+2.5 (2.1) <0.0001 |
+2.5 (2.2) 0.0001 |
+2.7 (1.7) <0.0001 |
+2.5 (2.1) 0.0003 |
+2.8 (2.7) 0.0041 |
Height SDS |
|
|
|
|
|
|
|
|
|
N |
62 |
62 |
57 |
51 |
41 |
22 |
20 |
16 |
14 |
Mean (SD) |
-6.7 (1.8) |
-5.9 (1.7) |
-5.6 (1.8) |
-5.3 (1.8) |
-5.3 (1.8) |
-5.5 (1.8) |
-5.4 (1.8) |
-5.2 (2.0) |
-5.2 (1.9) |
Mean (SD) for change from pre-Tx P-value for change from pre-Tx [1] |
|
+0.8 (0.5) <0.0001 |
+1.1 (0.8) <0.0001 |
+1.4 (1.0) <0.0001 |
+1.4 (1.1) <0.0001 |
+1.4 (1.3) <0.0001 |
+1.4 (1.2) <0.0001 |
+1.4 (1.1) 0.0001 |
+1.6 (1.1) <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.
Forty-seven subjects were included in an analysis of the effects of INCRELEX on bone age advancement. The mean ± SD change in chronological age was 5.1 ± 3.0 years and the mean ± SD change in bone age was 5.8 ± 2.9 years.
Efficacy is dose dependent. For subjects receiving doses between 100 and 120 μg/kg BID, the mean first year height velocity was approximately 8.7 cm/yr.
Updated on 27 May 2010
Reasons for updating
- Improved electronic presentation
Updated on 26 May 2010
Reasons for updating
- New PIL for new product
Updated on 27 August 2008
Reasons for updating
- New SPC for new product
Legal category:Product subject to medical prescription which may not be renewed (A)