- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Paediatric population- Long-term treatment of children with growth failure due to inadequate endogenous growth hormone secretion.- Long-term treatment of girls from 2 years old with growth failure associated with Turner syndrome.- Treatment of prepubertal children with growth failure associated with chronic renal insufficiency up to the time of renal transplantation.
Adult population- Replacement of endogenous growth hormone in adults with growth hormone deficiency of either childhood or adult-onset etiology. Growth hormone deficiency should be confirmed appropriately prior to treatment. In adults with growth hormone deficiency the diagnosis should be established depending on the etiology:Adult-onset: The patient must have growth hormone deficiency as a result of hypothalamic or pituitary disease, and at least one other hormone deficiency diagnosed (except for prolactin). Test for growth hormone deficiency should not be performed until adequate replacement therapy for other hormone deficiencies have been instituted. Childhood-onset: Patients who have had growth hormone deficiency as a child should be retested to confirm growth hormone deficiency in adulthood before replacement therapy with NutropinAq is started.
PosologyThe NutropinAq dosage and administration schedule should be individualised for each patient.
Growth failure in children due to inadequate growth hormone secretion0.025 - 0.035 mg/kg bodyweight given as a daily subcutaneous injection.Somatropin therapy should be continued in children and adolescents until their epiphysis are closed.
Growth failure associated with Turner syndromeUp to 0.05 mg/kg bodyweight given as a daily subcutaneous injection.Somatropin therapy should be continued in children and adolescents until their epiphysis are closed.
Growth failure associated with chronic renal insufficiencyUp to 0.05 mg/kg bodyweight given as a daily subcutaneous injection.Somatropin therapy should be continued in children and adolescents until their epiphysis are closed, or up to the time of renal transplantation.
Growth hormone deficiency in adultsAt the start of somatropin therapy, low initial doses of 0.15 - 0.3 mg are recommended, given as a daily subcutaneous injection. The dose should be adjusted stepwise, controlled by serum Insulin-like Growth Factor-1 (IGF-I) values. The recommended final dose seldom exceeds 1.0 mg/day. In general, the lowest efficacious dose should be administered. In older or overweight patients, lower doses may be necessary.
Method of administrationThe solution for injection should be administered subcutaneously each day. The site of injection should be changed.
Precaution to be taken before manipulating or administering the productNutropinAq is supplied as a multi-dose solution. After removal from the refrigerator, if the solution is cloudy, the content must not be injected. Gently swirl. Do not shake vigorously as it could denature the protein. NutropinAq is intended for use only with the NutropinAq Pen. For instructions for use and handling of the medicinal product, see section 6.6.
NeoplasmIn patients with previous malignant disease, special attention should be given to signs and symptoms of relapse.Patients with pre-existing tumours or growth hormone deficiency secondary to an intracranial lesion should be examined routinely for progression or recurrence of the underlying disease process. In childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their first neoplasm. Intracranial tumours, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm, were the most common of these second neoplasms.
Prader-Willi syndromeNutropinAq is not indicated for the long-term treatment of paediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome, unless they also have a diagnosis of growth hormone deficiency. There have been reports of sleep apnoea and sudden death after initiating therapy with growth hormone in paediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnoea, or unidentified respiratory infection.
Acute critical illnessThe effects of growth hormone on recovery were studied in two placebo-controlled clinical trials involving 522 adult patients who were critically ill due to complications following open-heart or abdominal surgery, multiple accidental traumas, or who were having acute respiratory failure. Mortality was higher (41.9 % vs. 19.3 %) among growth hormone treated patients (doses 5.3 - 8 mg/day) compared to those receiving placebo.The safety of continuing somatropin treatment in patients with acute critical illness in intensive care units due to complications following open-heart or abdominal surgery, multiple accidental trauma or acute respiratory failure receiving replacement doses for approved indications has not been established. Therefore, the benefit-risk assessment for continuing treatment should be performed carefully.
Chronic renal insufficiencyPatients with growth hormone failure secondary to CRI should be examined periodically for evidence of progression of renal osteodystrophy. Slipped capital femoral epiphyses and aseptic necrosis of the femoral head may be seen in children with advanced renal osteodystrophy and in growth hormone deficiency, and it is uncertain whether these problems are affected by GH therapy. Physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in patients treated with NutropinAq.
ScoliosisScoliosis 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.
Glycaemic controlBecause somatropin may reduce insulin sensitivity, patients should be monitored for evidence of glucose intolerance. For patients with diabetes mellitus, the insulin dose may require adjustment after NutropinAq therapy is instituted. Patients with diabetes or glucose intolerance should be monitored closely during somatropin therapy. Somatropin therapy is not indicated in diabetic patients with active proliferative or severe non-proliferative retinopathy.
Intracranial hypertensionIntracranial hypertension with papilloedema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with somatropin. Symptoms usually occur within the first eight weeks of the initiation of NutropinAq therapy. In all reported cases, intracranial hypertension-associated signs and symptoms resolved after reduction of the somatropin dose or termination of the therapy. Funduscopic examination is recommended at the initiation and periodically during the course of treatment.
HypothyroidismHypothyroidism may develop during treatment with somatropin, and untreated hypothyroidism may prevent optimal response to NutropinAq. Therefore, patients should have periodic thyroid function tests and should be treated with thyroid hormone when indicated. Patients with severe hypothyroidism should be treated accordingly prior to the start of NutropinAq therapy.
Renal transplantationSince somatropin therapy following renal transplantation has not been adequately tested, NutropinAq treatment should be terminated after that surgery.
Glucocorticoids useConcomitant treatment with glucocorticoids inhibits the growth-promoting effects of NutropinAq. Patients with ACTH deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth. The use of NutropinAq in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated.
LeukaemiaLeukaemia has been reported in a small number of growth hormone deficient patients treated with growth hormone. A causal relationship to somatropin therapy has not been established.
Pancreatitis in childrenChildren treated with somatropin have an increased risk of developing pancreatitis compared to adults treated with somatropin. Although rare, pancreatitis should be considered in somatropin-treated children who develop abdominal pain. Excipients This medicinal product contains less than 1 mmol sodium (23 mg) per cartridge, i.e. essentially 'sodium- free'.
PregnancyThere are no or limited data from the use of somatropin in pregnant women. Thus, the risk for humans is unknown. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).Somatropin is not recommended during pregnancy and should be discontinued if pregnancy occurs. During pregnancy, maternal somatropin will largely be replaced by placental growth hormone.
Breast-feedingIt is unknown whether somatropin/metabolites are excreted in human milk. No animal data are available.Caution should be exercised while breast-feeding during treatment with NutropinAq.
FertilityThe effect of NutropinAq has not been assessed in conventional animal fertility studies (see section 5.3) or clinical studies.
Summary of the safety profileThe adverse reactions reported in both adults and children receiving Nutropin, NutropinAq, Nutropin Depot or Protropin (somatrem) are listed in the table below, based on experience from clinical trials all approved indications (642 patients) and post-marketing sources which included a surveillance survey (National Cooperative Growth Study [NCGS] in 35,344 patients). Approximately 2.5 % of patients from the NCGS have experienced drug related adverse reactions. The most frequently reported adverse reactions from the pivotal and supportive clinical trials were hypothyroidism, impaired glucose tolerance, headache, hypertonia, arthralgia, myalgia, peripheral oedema, oedema, asthenia, injection site reaction and the presence of drug specific antibodies.The most serious adverse reactions from the pivotal and supportive clinical trials were neoplasm and intracranial hypertension.Neoplasms (malignant and benign) were reported in both the pivotal and supportive clinical trials and in the post-marketing surveillance survey (see sections 4.3 and 4.4). The majority of neoplasms reported were recurrence of previous neoplasms and second neoplasms.Intracranial hypertension was reported in the post-marketing surveillance survey. It is typically associated with papilloedema, visual changes, headache, nausea, and/or vomiting and symptoms usually occur within eight weeks of initiation of therapy with NutropinAq. NutropinAq reduces insulin sensitivity; glucose tolerance impairment was reported in both the pivotal and supportive clinical trials and the post-marketing surveillance survey. Events of diabetes mellitus and hyperglycaemia were reported in the post-marketing surveillance survey (see section 4.4). Injection site reactions such as haemorrhage, atrophy, urticaria and pruritus were reported in the pivotal and supportive clinical trials and/or the post-marketing surveillance survey. These events can be avoided by correct injection technique and rotation of injection sites.A small percentage of patients may develop antibodies to the protein somatropin. The binding capacity of growth hormone antibodies was lower than 2 mg/l in NutropinAq subjects tested, which has not been associated with adversely affected growth rate.
Tabulated summary of adverse reactionsTable 1 contains very common (≥ 1/10), common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1,000) adverse reactions which occurred in clinical trials and a post-marketing surveillance survey. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Other adverse reactions have been identified during post approval use of NutropinAq. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.
|System Organ Class||Reactions observed in Pivotal and Supportive Clinical Trials (in 642 patients)||Reactions observed from the postmarketing environment|
|Neoplasms benign, malignant and unspecified (including cysts and polyps)||Uncommon: Neoplasm malignant, neoplasm benign||Rare: Neoplasm malignant recurrence, melanocytic naevus|
|Blood and lymphatic system disorders||Uncommon: Anaemia|
|Endocrine disorders||Common: Hypothyroidism||Rare: Hypothyroidism|
|Metabolism and nutrition disorders||Common: Glucose tolerance impaired Uncommon: Hypoglycaemia, hyperphosphatemia||Rare: Diabetes mellitus, hyperglycaemia, hypoglycaemia, glucose tolerance impaired|
|Psychiatric disorders||Uncommon: Personality disorder||Rare: Abnormal behaviour, depression, insomnia|
|Nervous system disorders||Common: Headache, hypertonia, Uncommon: Carpal tunnel syndrome, somnolence, nystagmus||Uncommon: Headache Rare: Benign intracranial hypertension, intracranial pressure increased, migraine, carpal tunnel syndrome, paraesthesia, dizziness|
|Eye disorders||Uncommon: Papilloedema, diplopia||Rare: Papilloedema, vision blurred|
|Ear and labyrinth disorders||Uncommon: Vertigo|
|Cardiac disorders||Uncommon: Tachycardia|
|Vascular disorders||Uncommon: Hypertension||Rare: Hypertension|
|Respiratory thoracic and mediastinal disorders||Rare: Tonsillar hypertrophy Uncommon: Adenoidal hypertrophy|
|Gastrointestinal disorders||Uncommon: Abdominal pain, vomiting, nausea, flatulence||Rare: Abdominal pain, diarrhoea, nausea, vomiting|
|Skin and subcutaneous tissue disorders||Uncommon: Exfoliative dermatitis, skin atrophy, skin hypertrophy, hirsutism, lipodystrophy, urticaria||Rare: Generalised pruritus, urticaria, rash|
|Musculoskeletal and connective tissue disorders||Very common in adults, common in children: Arthralgia, myalgia Uncommon: Muscle atrophy, bone pain||Uncommon: Slipped capital femoral epiphysis, scoliosis progression, arthralgia Rare: Bone development abnormal, osteochondrosis, muscular weakness, pain in extremity|
|Renal and urinary disorders||Uncommon: Urinary incontinence, pollakiuria, polyuria, urine abnormality|
|Reproductive system and breast disorders||Uncommon: Uterine haemorrhage, genital discharge||Rare: Gynaecomastia|
|General disorders and administration site conditions||Very common in adults, common in children: Peripheral oedema, oedema Common: Asthenia, injection site reaction Uncommon: Injection site haemorrhage, injection site atrophy, injection site mass, hypertrophy||Uncommon: Peripheral oedema, oedema, injection site reaction (irritation, pain) Rare: Asthenia, face oedema, fatigue, irritability, pain, pyrexia, injection site reaction (haemorrhage, haematoma, atrophy, urticaria, pruritus, swelling, erythema)|
|Investigations||Common: Drug specific antibody present||Rare: Blood glucose increased, weight increased|
Description of selected adverse reactions
NeoplamsThere is a risk of neoplasia due to treatment with GH. The underlying risk varies according to the underlying cause for growth hormone deficiency (e.g. secondary to intracranial lesion), associated co-morbidities and treatment(s) undertaken. NutropinAq therapy must not be initiated when there is evidence of tumour activity. Patients with pre-existing tumours or growth hormone deficiency secondary to an intracranial lesion should be examined routinely for progression or recurrence of the underlying disease process. Treatment must be discontinued if there is evidence of tumour growth.
Intracranial hypertensionIn all reported cases, intracranial hypertension associated signs and symptoms resolved after reduction of the NutropinAq dose or termination of therapy (see section 4.4). Fundoscopic examination is recommended at the initiation and periodically during the course of treatment.
HypothyroidismHypothyroidism may develop during treatment with NutropinAq and untreated hypothyroidism may prevent optimal response to NutropinAq. Patients should have periodic thyroid function tests and should be treated with thyroid hormone when required. Patients with pre-existing hypothyroidism should be treated prior to the start of NutropinAq therapy.
Glycaemic controlAs NutropinAq may reduce insulin sensitivity, patients should be monitored for evidence of glucose intolerance. For patients with diabetes mellitus, the dose of insulin may need adjustment after NutropinAq therapy is initiated. Patients with diabetes or glucose intolerance should be monitored closely during somatropin therapy.
Injection site reactionsInjection site reactions may be avoided by using the correct injection technique and rotation of injection sites.
Slipped capital femoral epiphysisPatients with endocrinological disorders are more prone to develop a slipped capital femoral epiphysis.
Indication-specific adverse drug reactions from clinical trials
Children with growth failure due to inadequate growth hormone secretion (n=236)Common: central nervous system neoplasm (2 patients experienced a recurrent medulloblastoma, 1 patient experienced a histiocytoma). See also section 4.4.
Girls with growth failure associated with Turner syndrome (n=108)Common: menorrhagia.
Children with growth failure associated with chronic renal insufficiency (n=171)Common: renal failure, peritonitis, osteonecrosis, blood creatinine increase.Children with chronic renal insufficiency receiving NutropinAq are more likely to develop intracranial hypertension, although children with organic GHD and Turner syndrome also have an increased incidence. The greatest risk is at the beginning of treatment.
Adults with growth hormone deficiency (n=127)Very common: paraesthesia.Common: hyperglycaemia, hyperlipidaemia, insomnia, synovial disorder, arthrosis, muscular weakness, back pain, breast pain, gynaecomastia.
Reporting of suspected adverse reactionsReporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system:Yellow Card SchemeTel: Freephone 0808 100 3352Website: www.mhra.gov.uk/yellowcard.
SymptomsAcute overdose could lead to hyperglycaemia. Long-term overdose could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone.
ManagementTreatment is symptomatic and supportive. There is no antidote for somatropin overdose. It is recommended to monitor thyroid function following an overdose.
Mechanism of actionSomatropin stimulates growth rate and increases adult height in children who lack endogenous growth hormone and in children who have growth failure due to Turner Syndrome or CRI. Treatment of growth hormone deficient adults with somatropin results in reduced fat mass, increased lean body mass and increased spine bone mineral density. Metabolic alterations in these patients include normalisation of IGF-I serum levels.
Pharmacodynamic effectsIn vitro and in vivo preclinical and clinical tests have demonstrated that somatropin is therapeutically equivalent to human growth hormone of pituitary origin.Actions that have been demonstrated for human growth hormone include:
Tissue Growth1. Skeletal growth: growth hormone and its mediator IGF-I stimulate skeletal growth in growth hormone deficient children by an effect on the epiphyseal plates of long bones. This results in a measurable increase in body length until these growth plates fuse at the end of puberty.2. Cell growth: Treatment with somatropin results in an increase in both the number and size of skeletal muscle cells.3. Organ growth: Growth hormone increases the size of internal organs, including kidneys, and increases red blood cell mass.
Protein metabolismLinear growth is facilitated in part by growth hormone-stimulated protein synthesis. This is reflected by nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood urea nitrogen during growth hormone therapy.
Carbohydrate metabolismPatients with inadequate growth hormone secretion sometimes experience fasting hypoglycaemia that is improved by treatment with somatropin. Growth hormone therapy may decrease insulin sensitivity and impair glucose tolerance.
Mineral metabolismSomatropin induces retention of sodium, potassium and phosphorus. Serum concentration of inorganic phosphorus are increased in patients with growth hormone deficiency after NutropinAq therapy due to metabolic activity associated with bone growth and increased tubular reabsorption in the kidney. Serum calcium is not significantly altered by somatropin. Adults with growth hormone deficiency show low bone mineral density and in the childhood-onset patient, NutropinAq has been shown to increase spine bone mineral density in a dose-dependent manner.
Connective tissue metabolismSomatropin stimulates the synthesis of chondroitin sulphate and collagen as well as the urinary excretion of hydroxyproline.
Body compositionAdult growth hormone deficient patients treated with somatropin at a mean dosage of 0.014 mg/kg bodyweight daily demonstrate a decrease in fat mass and increase in lean body mass. When these alterations are coupled with the increase in total body water and bone mass, the overall effect of somatropin therapy is to modify body composition, an effect that is maintained with continued treatment.
Clinical efficacy and safety
Growth failure in childrenTwo pivotal, open label, uncontrolled, multicentre studies have been conducted, one exclusively in previously untreated patients (n=67), and the other in previously untreated patients (n=63) and in children previously treated with somatropin (n=9). The dose in both studies was 0.043 mg/kg/day, administered subcutaneously (s.c.). Doses used in these US based studies are consistent with the US approved dose regimen. Of the 139 patients included, 128 completed the first 12 months of therapy, with an average treatment time of 3.2 and 4.6 years and a total exposure of 542 patient years. In both studies there was a significant improvement in growth rate in the naïve patients, increasing from 4.2 to 10.9 cm/year in one study and from 4.8 to 11.2 cm/year in the other at 12 months. The growth rate decreased after the first year in both studies, but continued to be greater than pretreatment levels for up to 48 months treatment (7.1 cm/year). The height standard deviation score (SDS) improved each year, increasing from -3.0 to -2.7 at baseline to -1.0 to -0.8 at Month 36. The improvements in growth were not accompanied by undue advancement of bone age, which would jeopardise future growth potential. Predicted adult height (PAH) increased from 157.7-161.0 cm at baseline to 161.4-167.4 cm at Month 12 and 166.2-171.1 cm at Month 36. Supportive data are provided by two other studies, in which patients were given a dose of 0.3 or 0.6 mg/kg/week either as a daily injection or three times per week, or 0.029 mg/kg/day. The data on growth rate and height SDS were broadly similar to those observed in the pivotal studies. For 51 patients who achieved near-adult height after an average duration of treatment of 6 years in males and 5 years in females, the mean near-adult height SDS was -0.7 in males and -1.2 in females. IGF-I levels increased from a baseline of 43 ng/ml to 252 ng/ml at 36 months, which approximate to the normal levels expected in children of this age. The most common adverse events (AEs) observed in the pivotal studies were infection, headache, otitis media, fever, pharyngitis, rhinitis and gastroenteritis and vomiting.
Growth failure associated with chronic renal insufficiencyTwo pivotal, multicentre, controlled studies have been conducted in patients with growth failure associated with chronic renal insufficiency (CRI). Each study had a two year treatment period which included a placebo arm, followed by an open label uncontrolled extension in which all patients received somatropin. The dose was 0.05 mg/kg/day s.c. in both studies. The results of both studies were similar.In total, 128 patients received somatropin over the 24 month controlled phase of the 2 studies, and 139 patients were treated with somatropin in the open extension phases. Overall, 171 patients were exposed to somatropin for an average of 3.5 or 2.8 years.Both studies demonstrated a statistically significant increase in growth rate compared to placebo over the first year (9.1-10.9 cm/year vs 6.2-6.6 cm/year), which decreased slightly in the second year (7.4-7.9 cm/year vs 5.5-6.6 cm/year). There was also a significant increase in height SDS in somatropin-treated patients, from -2.9 to -2.7 at baseline to -1.6 to -1.4 at 24 months. Height gains were maintained in the patients treated for 36 or 48 months. A total of 58% and 65% of somatropin-treated patients, who were below normal range at baseline, had reached heights within the normal range by Month 24.The results to Month 60 show continued improvement, and more patients reached height SDS in the normal range. The average change in height SDS after 5 years of treatment was close to 2 standard deviations (SDs). A statistically significant increase in mean PAH SDS was observed, from -1.6 or -1.7 at baseline to -0.7 or -0.9 at Month 24. This continued to increase in those patients treated for 36 and 48 months. IGF-I levels, which were low at study entry, were restored to within the normal range with somatropin therapy. The most frequently reported AEs were associated with both NutropinAq and placebo and were fever, infection, vomiting, cough increased, pharyngitis, rhinitis and otitis media. There was a high incidence of urinary tract infections.
Growth failure associated with Turner SyndromeOne pivotal, multicentre, open label, controlled study has been conducted in Turner Syndrome. Patients received an s.c. dose of 0.125 mg/kg three times a week or 0.054 mg/kg/day, both regimens giving a cumulative weekly dose of approximately 0.375 mg/kg. Patients under 11 years of age were also randomised to receive oestrogen therapy, either in late (aged 15 years) or early (aged 12 years) adolescence. A total of 117 patients were treated with somatropin; 36 received somatropin 0.125 mg/kg three times a week and 81 patients received 0.054 mg/kg somatropin daily. The average treatment time was 4.7 years in the somatropin three times a week group and 4.6 years in the somatropin daily group.Growth rate increased significantly from 3.6-4.1 cm/year at baseline to 6.7-8.1 cm/year at Month 12, 6.7-6.8 cm/year at Month 24 and 4.5-5.1 cm/year at Month 48. This was accompanied by a significant increase in height SDS from -0.1 to 0.5 at baseline to 0.0 to 0.7 at Month 12 and 1.6 to 1.7 at Month 48. Compared with matched historical controls, early somatropin therapy (mean duration of 5.6 years) combined with oestrogen replacement at age 12 years resulted in an adult height gain of 5.9 cm (n=26), whereas girls who initiated oestrogen at age 15 years (mean duration of somatropin therapy 6.1 years) had a mean adult height gain of 8.3 cm (n=29). Thus, the greatest improvement in adult height was observed in patients who received early GH treatment and oestrogen after age 14 years.The most commonly reported AEs were flu syndrome, infection, headache, pharyngitis, rhinitis and otitis media. These events are expected in children and were mild/moderate AEs.
Growth hormone deficiency in adultsTwo pivotal, multicentre, placebo-controlled, double-blind studies have been conducted in patients diagnosed with adult growth hormone deficiency (AGHD), one in adult-onset AGHD (n=166) and the other in childhood-onset AGHD (n=64). The dose of somatropin was 0.0125 mg/kg/day sc in adult-onset AGHD and 0.0125 or 0.025 mg/kg/day in childhood-onset AGHD.In both studies, somatropin treatment resulted in significant changes compared to placebo in total body % fat (-6.3 to -3.6 vs +0.2 to-0.1), trunk % fat (-7.6 to -4.3 vs +0.6 to 0.0) and total body % lean (+3.6 to +6.4 vs -0.2 to +0.2). These changes were highly significant at the 12-month time point in both studies, and at the 24-month time point in the childhood-onset study. At the 12-month time point, the percentage change was higher in the childhood-onset study than in the adult-onset study. No significant changes in bone mineral density (BMD) were observed in adult-onset AGHD patients, however in the childhood-onset study, all groups had an increase in BMD at 24 months, although there was no statistically significant dose response for total body BMD. Lumbar spine BMD had statistically significant increases in both treated groups, and the increase was dose dependent. Supporting data from a study on adult-onset GHD patients were generally consistent with those of the pivotal studies, with some improvements in BMD. The most frequently reported AEs in the two pivotal studies were headache, oedema, arthralgia/arthrosis, tenosynovitis, paraesthesia and allergic reaction/rash. The incidence of these AEs was also high in the placebo groups.
IntroductionThe pharmacokinetic properties of NutropinAq have only been investigated in healthy adult males.
General characteristicsAbsorption: The absolute bioavailability of recombinant human growth hormone after subcutaneous administration is about 80%. Distribution: Animal studies with somatropin showed that growth hormone localises to highly perfused organs, particularly the liver and kidney. The volume of distribution at steady state for somatropin in healthy adult males is about 50 ml/kg bodyweight, approximating the serum volume.Biotransformation: Both the liver and the kidney have been shown to be important protein catabolising organs for growth hormone. Animal studies suggest that the kidney is the dominant organ of clearance. Growth hormone is filtered at the glomerulus and reabsorbed in the proximal tubules. It is then cleaved within renal cells into its constituent amino acids, which return to the systemic circulation.Elimination: After subcutaneous bolus administration, the mean terminal half-life t½ of somatropin is about 2.3 hours. After intravenous bolus administration of somatropin, the mean terminal half-life t½β or t½γ is about 20 minutes and the mean clearance is reported to be in the range of 116 - 174 ml/h/kg.Available literature data suggest that somatropin clearance is similar in adults and children.
Special populationInformation about the pharmacokinetics of somatropin in elderly and paediatric populations, in different races or genders and in patients with renal or hepatic impairment is incomplete.
Paediatric populationAvailable literature data suggests that somatropin clearances are similar in adults and children.
Older peopleLimited published data suggest that the plasma clearance and average steady-state plasma concentration of somatropin may not be different between young and elderly patients.
RaceReported values for half-lives for endogenous GH in normal adult black males are not different from observed values for normal adult white males. No data for other races are available.
Growth hormone deficiencyClearance and mean terminal half-life t½ of somatropin in adult and paediatric growth hormone deficient patients are similar to those observed in healthy subjects.
Renal impairmentChildren and adults with chronic renal failure and end-stage renal disease tend to have decreased clearance compared to normal subjects. Endogenous growth hormone production may also increase in some individuals with end-stage renal disease. However, no somatropin accumulation has been reported in children with chronic renal failure or end-stage renal disease dosed with current regimens.
Turner syndromeLimited published data for exogenously-administered somatropin suggest absorption and elimination half-lives and time of maximum concentration tmax in Turner patients are similar to those observed in both normal and growth hormone deficient populations.
Hepatic impairmentIn patients with severe liver dysfunction a reduction in somatropin clearance has been noted. The clinical significance of this decrease is unknown.
GenderNo gender-specific pharmacokinetic studies have been done with NutropinAq. The available literature indicates that the pharmacokinetics of somatropin are similar in men and women.
Carcinogenic potentialCarcinogenicity and genotoxicity studies have not been conducted with Nutropin Aq. In genotoxicity studies with other recombinant growth hormone preparations, there was no evidence of gene mutation in bacterial reverse mutation assays, chromosomal damage in human lymphocyte and mouse bone marrow cells, gene conversion in yeast or unscheduled DNA synthesis in human carcinoma cells. In carcinogenicity studies testing biologically recombinant active growth hormone in rats and mice, no increase in the incidence of tumors was shown.
Toxicity to reproduction and developmentNo conventional reproduction studies were performed. Somatropin is known to be associated with inhibition of the reproduction in male and female rats at doses of 3 IU/kg/day (1 mg/kg/day) or more, with reduced copulation and conception rates, lengthened or absent oestrous cycles, and at 10 IU/kg/day (3.3 mg/kg/day). Long-term treatment of monkeys during pregnancy and lactation and of newborn animals until adolescence, sexual maturity and reproduction did not indicate substantial disturbances of fertility, pregnancy, delivery, nursing or development of progeny.
Environmental Risk Assessment (ERA)Under the proposed indications, the use of somatropin is not expected to result in an unacceptable risk to the environment.
Instructions for use and handlingNutropinAq is supplied as a multi-dose solution. After removal from the refrigerator, if the solution is cloudy, the content must not be injected. Gently swirl. Do not shake vigorously as it could denature the protein. NutropinAq is intended for use only with the NutropinAq Pen. Wipe the rubber seal of the NutropinAq with rubbing alcohol or an antiseptic solution to prevent contamination of the contents by microorganisms that may be introduced by repeated needle insertions. It is recommended that NutropinAq be administered using sterile, disposable needles.The NutropinAq Pen allows for administration of a minimum dose of 0.1 mg to a maximum dose of 4.0 mg, in 0.1 mg increments. A cartridge that is in the pen should not be removed during injections.
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