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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.
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
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
0.0015
0.0009
0.0897
0.2135
Height Velocity SDS
53
47
38
19
18
15
12
-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)
+5.1 (3.1)
+3.2 (2.2)
+3.1 (2.4)
+2.5 (2.1)
+2.5 (2.2)
0.0001
+2.7 (1.7)
0.0003
+2.8 (2.7)
0.0041
Height SDS
62
57
51
41
22
-6.7 (1.8)
-5.9 (1.7)
-5.6 (1.8)
-5.3 (1.8)
-5.5 (1.8)
-5.4 (1.8)
-5.2 (2.0)
-5.2 (1.9)
+0.8 (0.5)
+1.1 (0.8)
+1.4 (1.0)
+1.4 (1.1)
+1.4 (1.3)
+1.4 (1.2)
+1.6 (1.1)
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.