NUTROPINAQ Solution for injection Ref.[27676] Active ingredients: Somatropin

The maximum recommended daily dose should not be exceeded (see section 4.2).

Neoplasm

In 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 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 hormone deficiency, and it is uncertain whether these problems are affected by GH therapy.

Slipped capital femoral epiphysis

In patients with endocrine disorders, including growth hormone deficiency, slipped epiphyses of the hip may occur more frequently than in the general population. A patient treated with somatropin who develops a limp or complains of hip or knee pain should be evaluated by a physician.

Scoliosis

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.

Glycaemic control

Because 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 hypertension

Intracranial 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.

Hypothyroidism

Hypothyroidism 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 transplantation

Since somatropin therapy following renal transplantation has not been adequately tested, NutropinAq treatment should be terminated after that surgery.

Glucocorticoids use

Concomitant 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.

Leukaemia

Leukaemia 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

Although rare, pancreatitis should be considered in somatropin-treated patients who develop abdominal pain, especially in children.

Use with oral oestrogen therapy

If a woman taking NutropinAq begins oral oestrogen therapy, the dose of NutropinAq may need to be increased to maintain the serum IGF-1 levels within the normal age appropriate range. Conversely, if a woman on NutropinAq discontinues oral oestrogen therapy, the dose of NutropinAq may need to be reduced to avoid excess of growth hormone and/or side effects (see section 4.5).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per cartridge, i.e. essentially "sodium- free‟.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

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 glucocorticoid 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 hypoglycaemic medicinal product may require adjustment when somatropin therapy is initiated (see section 4.4).

In women on oral oestrogen replacement, a higher dose of growth hormone may be required to achieve the treatment goal (see section 4.4).

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.

Somatropin has no known effect on the ability to drive or to use machines.

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 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) 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.

Description of selected adverse reactions

Neoplasm

There 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 hypertension

In 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.

Hypothyroidism

Hypothyroidism 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 control

As 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 reactions

Injection site reactions may be avoided by using the correct injection technique and rotation of injection sites.

Slipped capital femoral epiphysis

Patients with endocrinological disorders are more prone to develop a slipped capital femoral epiphysis.

Indication-specific adverse drug reactions from clinical trials

Paediatric population

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.

Adult population

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 reactions

Reporting 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 listed below:

In Ireland to HPRA Pharmacovigilance, Earlsfort Terrace, IRL-Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie, E-mail: medsafety@hpra.ie

In the United Kingdom via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.