NutropinAq · 4.4 Special warnings and precautions for use · 1

HOS-084310 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The 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 6 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 reactions Table 1 contains very common (≥ 1/10), common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1,000)

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HOS-084306 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Somatropin should not be used for growth promotion in patients with closed epiphyses. Somatropin must not be used when there is any evidence of activity of a tumour. Intracranial tumours must be inactive and antitumour therapy must be completed prior to starting GH therapy. Treatment should be discontinued if there is evidence of tumour growth. Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open-heart or abdominal surgery, multiple accidental traumas or to treat patients having acute respiratory failure.

HOS-084305 · has-indication-information · PDF-Seite 2

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.

HOS-084308 · has-interaction-information · PDF-Seite 5

Limited published data indicate that growth hormone treatment increases cytochrome P450 mediated antipyrine clearance in man. Monitoring is advisable when somatropin is administered in combination with medicinal products known to be metabolised by CYP450 liver enzymes, such as corticosteroids, sex steroids, anticonvulsants, and cyclosporin. In patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. In addition, patients treated with glucocortocoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses, following initiation of somatropin treatment (see section 4.4). In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral hypoglycemic medicinal product may require adjustment when somatropin therapy is initiated (see section 4.4). 5 In women on oral oestrogen replacement, a higher dose of growth hormone may be required to achieve the treatment goal (see section 4.4).

HOS-084309 · has-pregnancy-information · PDF-Seite 6

Pregnancy There 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-feeding It 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. Fertility The effect of NutropinAq has not been assessed in conventional animal fertility studies (see section 5.3) or clinical studies.

HOS-084307 · has-warning-information · PDF-Seite 3

The maximum recommended daily dose should not be exceeded (see section 4.2). 3 Neoplasm In patients with previous malignant disease, special attention should be given to signs and symptoms of relapse. Patients with pre-existing tumors 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 tumors, 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 syndrome NutropinAq 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 illness The 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 insufficiency Patients 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 hormon

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