istrative Site Conditions: lipohypertrophy, bruising
Infections and Infestations: otitis media, serous otitis media
Respiratory, Thoracic and Mediastinal Disorders: snoring, tonsillar hypertrophy
Nervous System Disorders: headache, dizziness, convulsions
Gastrointestinal Disorders: vomiting
Ear and Labyrinth Disorders: hypoacusis, fluid in middle ear, ear pain, abnormal tympanometry
Cardiac Disorders: cardiac murmur
Musculoskeletal and Connective Tissue Disorders: arthralgia, pain in extremity
Blood and Lymphatic System Disorders: thymus hypertrophy
Surgical and Medical Procedures: ear tube insertion
Hypoglycemia was reported by 30 subjects (42%) at least once during their course of therapy. Most cases of hypoglycemia were mild or moderate in severity. Five subjects had severe hypoglycemia (requiring assistance and treatment) on one or more occasions and 4 subjects experienced hypoglycemic seizures/loss of consciousness on one or more occasion. Of the 30 subjects reporting hypoglycemia, 14 (47%) had a history of hypoglycemia prior to treatment. The frequency of hypoglycemia was highest in the first month of treatment, and episodes were more frequent in younger children. Symptomatic hypoglycemia was generally avoided when a meal or snack was consumed either shortly (i.e., 20 minutes) before or after the administration of INCRELEX®.
Tonsillar hypertrophy was noted in 11 (15%) subjects in the first 1 to 2 years of therapy with lesser tonsillar growth in subsequent years. Tonsillectomy or tonsillectomy/adenoidectomy was performed in 7 subjects; 3 of these had obstructive sleep apnea, which resolved after the procedure in all three cases.
Intracranial hypertension occurred in three subjects. 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.
Mild elevations in the serum AST and LDH were found in a significant proportion of patients before and during treatment. Rise in levels of these serum enzymes did not lead to treatment discontinuation. ALT elevations were occasionally noted during treatment.
Renal and splenic lengths (measured by ultrasound) increased rapidly on INCRELEX® treatment during the first years of therapy. This lengthening slowed down subsequently; though in some patients, renal and/or splenic length reached or surpassed the 95th percentile. Renal function (as defined by serum creatinine and calculated creatinine clearance) was normal in all patients, irrespective of renal growth.
Elevations in cholesterol and triglycerides to above the upper limit of normal were observed before and during treatment.
Echocardiographic evidence of cardiomegaly/valvulopathy was observed in a few individuals without associated clinical symptoms. The relation of these cardiac changes to drug treatment cannot be assessed due to underlying disease and the lack of a control group.
Thickening of the soft tissues of the face was observed in several patients and should be monitored during INCRELEX® treatment.
6.2 ImmunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be in |
