24 Jun 2009

GENOTROPIN (Somatropin) - United Kingdom

Updated: 24 Jun 2009

GENOTROPIN

Children Growth disturbance due to insufficient secretion of growth hormone (growth hormone deficiency, GHD) and growth disturbance associated with Turner syndrome or chronic renal insufficiency. 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 –2SD, who failed to show catch-up growth (HV SDS < 0 during the last year) by 4 years of age or later. Prader-Willi syndrome (PWS), for improvement of growth and body composition.

The diagnosis of PWS should be confirmed by appropriate genetic testing. Adults Replacement therapy in adults with pronounced growth hormone deficiency. Adult Onset: Patients who have severe growth hormone deficiency associated with multiple hormone deficiencies as a result of known hypothalamic or pituitary pathology and who have at least one known deficiency of a pituitary hormone not being prolactin.

These patients should undergo an appropriate dynamic test in order to diagnose or exclude a growth hormone deficiency. Childhood Onset: Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes. Patients with childhood onset GHD should be re-evaluated for growth hormone secretory capacity after completion of longitudinal growth. In patients with a high likelihood for persistent GHD, i.e. a congenital cause or GHD secondary to a pituitary/hypothalamic disease or insult, an IGF-I SDS <- 2 off growth hormone treatment for at least 4 weeks should be considered sufficient evidence of profound GHD. All other patients will require IGF-I assay and one growth hormone stimulation test

GENOTROPIN Description, Presentation and Dosage

GENOTROPIN Description

GENOTROPIN Drug Class Description

Growth hormones.

GENOTROPIN Drug Description

Genotropin 5.3 mg powder and solvent for solution for injection. Genotropin 12 mg powder and solvent for solution for injection.

GENOTROPIN Generic Name

Somatropin

GENOTROPIN Presentation

GENOTROPIN Presentation

Powder and solvent for solution for injection. In the two-chamber cartridge there is a white powder in the front compartment and a clear solution in the rear compartment.

GENOTROPIN Manufacturer

Pharmacia Limited

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GENOTROPIN Dosage

GENOTROPIN Adult Dosage

The dosage and administration schedule should be individualised.

The injection should be given subcutaneously and the site varied to prevent lipoatrophy.

Growth disturbance due to insufficient secretion of growth hormone in children: Generally a dose of 0.025 - 0.035 mg/kg body weight per day or 0.7 - 1.0 mg/m2 body surface area per day is recommended. Even higher doses have been used.

Where childhood onset GHD persists into adolescence, treatment should be continued to achieve full somatic development (e.g. body composition, bone mass). For monitoring, the attainment of a normal peak bone mass defined as a T score> −1 (i.e. standardized to average adult peak bone mass measured by dual energy X-ray absorptiometry taking into account sex and ethnicity) is one of the therapeutic objectives during the transition period. For guidance on dosing see adult section below.

Prader-Willi syndrome, for improvement of growth and body composition in children: Generally a dose of 0.035 mg/kg body weight per day or 1.0 mg/m2 body surface area per day is recommended. Daily doses of 2.7 mg should not be exceeded. Treatment should not be used in children with a growth velocity less than 1 cm per year and near closure of epiphyses.

Growth disturbance due to Turner syndrome: A dose of 0.045 - 0.050 mg/kg body weight per day or 1.4 mg/m2 body surface area per day is recommended.

Growth disturbance in chronic renal insufficiency: A dose of 1.4 mg/m2 body surface area per day (approximately 0.045 - 0.050 mg/kg body weight per day) is recommended. Higher doses can be needed if growth velocity is too low. A dose correction can be needed after six months of treatment.

Growth disturbance in short children born small for gestational age (SGA): A dose of 0.035 mg/kg body weight per day (1 mg/m2 body surface area per day) is usually recommended until final height is reached. Treatment should be discontinued after the first year of treatment if the height velocity SDS is below +1. Treatment should be discontinued if the height velocity is < 2 cm/year and, if confirmation is required, bone age is> 14 years (girls) or> 16 years (boys), corresponding to closure of the epiphyseal growth plates.

Dosage Recommendations for Paediatric Patients

< Indication mg/kg body weight mg/m2body surface area
  dose per day dose per day
Growth hormone deficiency in children 0.025 - 0.035 0.7 - 1.0
Prader-Willi Syndrome in children 0.035 1.0
Turner syndrome 0.045 - 0.050 1.4
Chronic renal insufficiency 0.045 - 0.050 1.4
Children born small for gestational age (SGA) 0.035 1.0

Growth hormone deficient adult patients: In patients who continue growth hormone therapy after childhood GHD, the recommended dose to restart is 0.2 – 0.5 mg/day. The dose should be gradually increased or decreased according to individual patient requirements as determined by the IGF-I concentration.

In patients with adult-onset GHD, therapy should start with a low dose, 0.15 - 0.3 mg per day. The dose should be gradually increased according to individual patient requirements as determined by the IGF-I concentration.

In both cases treatment goal should be insulin-like growth factor-I (IGF-I) concentrations within 2 SDS from the age corrected mean. Patients with normal IGF-I concentrations at the start of the treatment should be administered growth hormone up to an IGF-I level into upper range of normal, not exceeding the 2 SDS. Clinical response and side effects may also be used as guidance for dose titration. It is recognised that there are patients with GHD who do not normalize IGF-I levels despite a good clinical response, and thus do not require dose escalation. The daily maintenance dose seldom exceeds 1.0 mg per day. Women may require higher doses than men, with men showing an increasing IGF-I sensitivity over time.

This means that there is a risk that women, especially those on oral oestrogen replacement are under-treated while men are over-treated. The accuracy of the growth hormone dose should therefore be controlled every 6 months. As normal physiological growth hormone production decreases with age, dose requirements are reduced. In patients above 60 years, therapy should start with a dose of 0.1 - 0.2 mg per day and should be slowly increased according to individual patient requirements. The minimum effective dose should be used. Daily maintenance dose in these patients seldom exceeds 0.5 mg per day.

GENOTROPIN Child Dosage

Growth hormone deficiency, normally 0.07 - 0.1 i.u./kg (0.025 - 0.035mg/kg) daily by subcutaneous injection. Turner syndrome, 0.14 i.u./kg (0.045 - 0.050mg/kg) daily by subcutaneous injection. Renal insufficiency, 0.14 i.u./kg (0.045 - 0.050mg/kg) daily by subcutaneous injection, increase dose if necessary. Dose adjustment may be required after 6 months. Vary injection site.

GENOTROPIN Precautions, Reactions and Contraindications

GENOTROPIN Special Precautions

GENOTROPIN Special Precautions

Diagnosis and therapy with Genotropin should be initiated and monitored by physicians who are appropriately qualified and experienced in the diagnosis and management of patients with the therapeutic indication of use.

Myositis is a very rare adverse event that may be related to the preservative metacresol. In the case of myalgia or disproportionate pain at the injection site, myositis should be considered and, if confirmed, a Genotropin presentation without metacresol should be used.

Somatropin may induce a state of insulin resistance and in some patients hyperglycaemia. Therefore patients should be observed for evidence of glucose intolerance. In rare cases the diagnostic criteria for diabetes mellitus type II may be fulfilled as a result of the somatropin therapy, but risk factors such as obesity (including obese PWS patients), family history, steroid treatment, or pre-existing impaired glucose tolerance have been present in most cases where this has occurred. In patients with an already manifest diabetes mellitus, the anti-diabetic therapy might require adjustment when somatropin is instituted.

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 hypothyroidism theoretically may develop. Conversely, in patients receiving replacement therapy with thyroxin, mild hyperthyroidism may occur. It is therefore particularly advisable to test thyroid function after starting treatment with somatropin and after dose adjustments.

In growth hormone deficiency secondary to treatment of malignant disease, it is recommended to pay attention to signs of relapse of the malignancy.

In patients with endocrine disorders, including growth hormone deficiency, slipped epiphyses of the hip may occur more frequently than in the general population. Children limping during treatment with somatropin should be examined clinically.

In case of severe or recurrent headache, visual problems, nausea and/or vomiting, a funduscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and, if appropriate, the growth hormone treatment should be discontinued. At present there is insufficient evidence to give specific advice on the continuation of growth hormone treatment in patients with resolved intracranial hypertension. However, clinical experience has shown that reinstitution of the therapy is often possible without recurrence of the intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.

Experience in patients above 80 years is limited. Elderly patients may be more sensitive to the action of Genotropin, and therefore may be more prone to develop adverse reactions.

In patients with PWS, treatment should always be in combination with a calorie-restricted diet.

There have been reports of fatalities associated with the use of growth hormone in paediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity (those patients exceeding a weight/height of 200%), history of respiratory impairment or sleep apnoea, or unidentified respiratory infection. Patients with one or more of these factors may be at increased risk.

Before initiation of treatment with somatropin in patients with Prader-Willi syndrome, signs for upper airway obstruction, sleep apnoea, or respiratory infections should be assessed.

If during the evaluation of upper airway obstruction, pathological findings are observed, the child should be referred to an ENT specialist for treatment and resolution of the respiratory disorder prior to initiating growth hormone treatment.

Sleep apnoea should be assessed before onset of growth hormone treatment by recognised methods such as polysomnography or overnight oxymetry, and monitored if sleep apnoea is suspected.

If during treatment with somatropin patients show signs of upper airway obstruction (including onset of or increased snoring), treatment should be interrupted, and a new ENT assessment performed.

All patients with Prader-Willi syndrome should be monitored if sleep apnoea is suspected.

Patients should be monitored for signs of respiratory infections, which should be diagnosed as early as possible and treated aggressively.

All patients with Prader-Willi syndrome should also have effective weight control before and during growth hormone treatment.

Scoliosis is common in patients with PWS. Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitored during treatment. However, growth hormone treatment has not been shown to increase the incidence or severity of scoliosis.

Experience with prolonged treatment in adults and in patients with PWS is limited.

In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.

In SGA children it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk of diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered.

In SGA children it is recommended to measure the 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 in patients with Silver-Russell syndrome is limited.

Some of the height gain obtained with treating short children born SGA with growth hormone may be lost if treatment is stopped before final height is reached.

In chronic renal insufficiency, renal function should be below 50 percent of normal before institution of therapy. To verify growth disturbance, growth should be followed for a year preceding institution of therapy. During this period, conservative treatment for renal insufficiency (which includes control of acidosis, hyperparathyroidism and nutritional status) should have been established and should be maintained during treatment. The treatment should be discontinued at renal transplantation.

To date, no data on final height in patients with chronic renal insufficiency treated with Genotropin are available.

The effects of Genotropin on recovery were studied in two placebo controlled trials involving 522 critically ill adult patients suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma or acute respiratory failure. Mortality was higher in patients treated with 5.3 or 8 mg Genotropin daily compared to patients receiving placebo, 42% vs. 19%. Based on this information, these types of patients should not be treated with Genotropin. As there is no information available on the safety of growth hormone substitution therapy in acutely critically ill patients, the benefits of continued treatment in this situation should be weighed against the potential risks involved.

In all patients developing other or similar acute critical illness, the possible benefit of treatment with Genotropin must be weighed against the potential risk involved.

GENOTROPIN Adverse Reactions

GENOTROPIN Adverse Reactions

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Patients with growth hormone deficiency are characterised by extracellular volume deficit. When treatment with somatropin is started, this deficit is rapidly corrected. In adult patients, adverse effects related to fluid retention such as peripheral oedema, stiffness in the extremities, arthralgia, myalgia and paraesthesia are common. In general, these adverse effects are mild to moderate, arise within the first months of treatment and subside spontaneously or with dose reduction.

The incidence of these adverse effects is related to the administered dose, the age of patients and possibly inversely related to the age of patients at the onset of growth hormone deficiency. In children, such adverse effects are uncommon.

Transient local skin reactions at the injection site in children are common.

Rare cases of diabetes mellitus type II have been reported.

Rare cases of benign intracranial hypertension have been reported.

Carpal tunnel syndrome is an uncommon event among adults.

Somatropin has given rise to the formation of antibodies in approximately 1% of patients. The binding capacity of these antibodies has been low and no clinical changes have been associated with their formation.

  Common >1/100, <1/10 Uncommon>1/1000, <1/100 Rare>1/10,000, < 1/1000 Very rare <1/10,000
Neoplasms, benign and malignant       Leukaemia
Immune system disorders Formation of antibodies      
Endocrine disorders     Diabetes mellitus type II  
Nervous system disorders In adults paraesthesia In adults carpal tunnel syndrome. In children paraesthesia Benign intracranial hypertension  
Skin and subcutaneous tissue disorders In children transient local skin reactions      
Musculoskeletal, connective tissue and bone disorders In adults stiffness in the extremities, arthralgia, myalgia In children stiffness in the extremities, arthralgia, myalgia    
General disorders and administration site disorders In adults peripheral oedema In children peripheral oedema    

Somatropin has been reported to reduce serum cortisol levels, possibly by affecting carrier proteins or by increased hepatic clearance. The clinical relevance of these findings may be limited. Nevertheless, corticosteroid replacement therapy should be optimised before initiation of Genotropin therapy.

Very rare cases of leukaemia have been reported in growth hormone deficient children treated with somatropin, but the incidence appears to be similar to that in children without growth hormone deficiency.

In the post-marketing experience rare cases of sudden death have been reported in patients affected by Prader-Willi syndrome treated with somatropin, although no causal relationship has been demonstrated.

GENOTROPIN Contraindications

GENOTROPIN Contraindications

Genotropin should not be used when there is any evidence of tumour activity and anti-tumour therapy must be completed prior to starting therapy.

Genotropin should not be used for growth promotion in children with closed epiphyses.

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 Genotropin. 

Hypersensitivity to the active substance or to any of the excipients.

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