Update to add neoplasia AE

Type II update to add neoplasia

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

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.

Version 5 of HCP dosing guide approved 16 April 2018.

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. 

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

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.   

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

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 = 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.