Section 2: Qualitative and Quantitative Composition: Phrase added ‘produced by recombinant DNA technology in mammalian cells’.
Section 3: Pharmaceutical Form: description added ‘white lyophilized powder and clear colourless solvent’.
Section 4.1: Therapeutic indications: addition of the indications, ‘growth disturbance (current height SDS < -2.5 and parental adjusted height SDS < -1) in short children born small for gestational age (SGA) with a birth weight and/or length below – 2 SD, who failed to show catch-up growth (HV SDS < 0 during the last year) by 4 years of age or later’
Section 4.2: Posology and method of administration: Addition of dosage regimen and treatment period guidelines for growth failure in short children born small for gestational age (SGA).
Section 4.3 Contraindications: Addition of the following contraindication ‘Patients with acute critical illness suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions should not be treated with Somatropin. (Regarding patients undergoing Somatropin therapy and becoming critically ill, see 4.4 “Special warnings and special precautions for use“.)
Section 4.4: Special warning and special precautions for use: the following warnings and precautions have been added.
‘Somatropin may induce a state of insulin resistance, which can result in hyperinsulinism and in some patients hyperglycemia. To detect insulin resistance, patients should be monitored for evidence of glucose intolerance’.
‘Stable background retinopathy should not lead to discontinuation of Somatropin replacement therapy. In case of development of preproliferative changes and the presence of proliferative retinopathy Somatropin replacement therapy should be discontinued’.
‘Fluid retention is expected during growth hormone replacement therapy in adults’.
‘Slipped capital femoral epiphysis is often associated with endocrine disorders such as GHD and hypothyroidism, and with growth spurts. In children treated with growth hormone, slipped capital femoral epiphysis may either be due to underlying endocrine disorders or to the increased growth velocity caused by the treatment. Growth spurts may increase the risk of joint-related problems, the hip joint being under particular strain during the prepubertal growth spurt’.
‘In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.
For SGA patients it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, increased body mass index, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered’.
‘For SGA patients it is recommended to measure IGF-I level before start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the IGF-I/IGFBP-3 ratio could be taken into account to consider dose adjustment’.
‘Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore not recommended to initiate treatment near onset of puberty. Experience with SGA patients with Silver-Russel syndrome is limited’.
‘Some of the height gain obtained with treating short children born SGA with Somatropin may be lost if treatment is stopped before final height is reached’.
‘Cases of sleep apnoea and sudden death in patients with Prader-Willi-Syndrome under treatment with Somatropin have been reported. Saizen is not indicated for the treatment of patients with Prader-Willi-Syndrome’.
The existing special precaution regarding the appearance of hypothyroidism has been replaced with the following: ‘During treatment with Somatropin an enhanced T4 to T3 conversion has been found which may result in a reduction in serum T4 and an increase in serum T3 concentrations. In general, the peripheral thyroid hormone levels have remained within the reference ranges for healthy subjects. The effects of Somatropin on thyroid hormone levels may be of clinical relevance in patients with central subclinical hypothyroidism in whom overt hypothyroidism theoretically may develop. Conversely, in patients receiving replacement therapy with thyroxine mild hyperthyroidism may occur. It is therefore particularly advisable to test thyroid function after starting treatment with Somatropin and after dose adjustments’.
Section 4.5 Interaction with other medicinal products and other forms of interaction:
The following interaction information has been added:
‘Somatropin has been reported to induce a modest reduction of serum cortisol levels in GH deficient patients receiving adrenal substitution treatment. Therefore, it is recommended to monitor serum cortisol levels in patients on corticosteroid replacement therapy in whom Somatropin therapy is started and adjust the dose of corticosteroids if necessary’.
‘Published in vitro data indicate that growth hormone may be an inducer of cytochrome P450 3A4. The clinical significance of this observation is unknown. However, when Somatropin is administered in combination with drugs known to be metabolised by CYP P450 3A4 hepatic enzymes, it is advisable to monitor the clinical effectiveness of such drugs’.
Section 4.6 Pregnancy and Lactation: The pregnancy statement has been replaced with the following: ‘For Saizen no clinical data on exposed pregnancies are available. Thus, the risk for humans is unknown. Although animal studies do not point to a potential risk during pregnancy, Saizen should be discontinued if pregnancy occurs’.
Section 4.8 Undesirable Effects: The following additional information has been included regarding undesirable events: ‘Fluid retention is expected during growth hormone replacement therapy in adults. Oedema, joint swelling, arthralgias, myalgias and paresthesias may be clinical manifestations of fluid retention. However, these symptoms / signs are usually transient and dose dependent.’ Paragraph deleted: ‘Epiphysiolysis at the site of the hip joint may occur. A child with an unexplained limp should be examined.’
The listing of adverse events reported is updated presented by body system and frequency. Adverse events added include localized lipoatrophy, stiffness, paresthesia, carpel tunnel syndrome, idiopathic intracranial hypertension, hypothyroidism, insulin resistance added.
Section 4.9 Overdose: Statement long term overdosage could result in signs and symptoms of gigantism and / or acromegaly deleted. Statement added ‘Somatropin overdose is likely to cause manifestations of fluid retention’.
Section 5.1 Pharmacodynamic properties: Two paragraphs relating to clinical trials conducted with Saizen in SGA added.
Section 6.3 Shelf life: Sentence ‘The reconstituted solution for injection is stable for 28 days’ has been amended to read, ‘After reconstitution, the product may be stored for a maximum of 28 days in a refrigerator (2°C to 8°C).’
Section 6.4 Special precautions for storage: the statement ‘Store the reconstituted product at 2ºC to 8ºC in the cartridge’ has been amended to ‘Store the reconstituted product in a refrigerator (2°C to 8°C).’
Section 6.5 Nature and contents of container: Reference to inclusion of plunger rods has been removed. Statement added ‘The vials and cartridges are closed by rubber stoppers’.
Section 6.6 Instructions for use, handling and disposal: Typo corrected in the first paragraph.
Section 8 Irish Product Authorisation Number removed.
Section 9 Date of First Authorisation / Renewal of Authorisation: Date of renewal amended to ‘19 April 2005’.
Section 10 Date of Revision of the Text: Amended to ‘April 2005’.
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