SKYTROFA Powder and solvent for solution for injection Ref.[28359] Active ingredients: Lonapegsomatropin

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.

Acute critical illness

In 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 mg or 8 mg somatropin daily (i.e. 37.1–56 mg/week) compared to patients receiving placebo, 42% vs. 19%. As there is no information available on the safety of growth hormone substitution therapy in acutely critically ill patients, the benefits of continued lonapegsomatropin 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 lonapegsomatropin must be weighed against the potential risk involved.

Neoplasm

In patients with previous malignant disease, special attention should be given to signs and symptoms of relapse.

Patients with pre-existing tumours or GHD 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 growth hormone after their first neoplasm.

Intracranial tumours, in particular meningiomas, were the most common form of a second neoplasm reported in patients treated with radiation to the head for their first neoplasm.

Benign intracranial hypertension

In case of severe or recurrent ataxia, 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, 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. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary. Funduscopic examination is recommended at the initiation and periodically during the course of treatment.

Insulin sensitivity

Growth hormone may reduce insulin sensitivity. For patients with diabetes mellitus, the insulin dose may require adjustment after lonapegsomatropin therapy is instituted. Patients with diabetes mellitus, glucose intolerance, or additional risk factors for diabetes mellitus should be monitored closely during lonapegsomatropin therapy (see section 4.5).

Hypoadrenalism

Introduction of growth hormone treatment may result in inhibition of 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD-1) and reduced serum cortisol concentrations. Consequently, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required. 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 lonapegsomatropin treatment (see section 4.5).

Thyroid function

Growth hormone increases the extrathyroidal conversion of T4 to T3 which may result in a reduction in serum T4 and an increase in serum T3 concentrations. Monitoring of thyroid function should therefore be conducted in all patients. In patients with hypopituitarism on standard replacement therapy, the potential effect of lonapegsomatropin treatment on thyroid function must be closely monitored (see section 4.5 and 4.8).

Slipped capital femoral epiphysis

In patients with endocrine disorders, including GHD, slipped epiphyses of the hip may occur more frequently than in the general population. Children with persistent hip/knee pain and/or limping during treatment with lonapegsomatropin should be examined clinically.

Scoliosis

Scoliosis may progress in any child during rapid growth. Because growth hormone treatment increases growth rate, signs and progression of scoliosis should be monitored during treatment. However, growth hormone treatment has not been shown to increase the incidence or severity of scoliosis (see section 4.8).

Pancreatitis

Although rare, pancreatitis should be considered in growth hormone treated children who develop unexplained abdominal pain.

Prader-Willi syndrome

Lonapegsomatropin has not been studied in patients with Prader-Willi syndrome. Lonapegsomatropin 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 GHD. There have been reports of sudden death after initiating therapy with growth hormone in 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.

Leukaemia

Leukaemia has been reported in a small number of GHD patients, some of whom have been treated with somatropin. However, there is no evidence that the leukaemia incidence is increased in growth hormone recipients without predisposing factors.

Use with oral oestrogen containing therapy

Oral oestrogen influences the IGF-1 response to growth hormone. If a female patient taking lonapegsomatropin begins oral oestrogen containing therapy, the dose of lonapegsomatropin may need to be increased to maintain the serum IGF-1 levels within the normal age appropriate range (see section 4.2). Conversely, if a female patient on lonapegsomatropin discontinues oral oestrogen containing therapy, the dose of lonapegsomatropin may need to be reduced to avoid excess of growth hormone and/or adverse reactions (see section 4.5).

Antibodies

Antibodies to lonapegsomatropin were observed in some patients. None of these antibodies were neutralising and there was no apparent clinical impact. However, testing for the presence of antibodies should be considered in patients who fail to respond to therapy.

Glucocorticoid treatment

Concomitant treatment with glucocorticoids inhibits the growth-promoting effects of lonapegsomatropin. Patients with adrenocorticotropic hormone (ACTH) deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth, and patients treated with glucocorticoids should have their growth monitored carefully to assess the potential impact of glucocorticoid treatment on growth.

Growth hormone decreases the conversion of cortisone to cortisol and may unmask previously undiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective (see section 4.4).

Cytochrome P450-metabolised products

Drug-drug interaction studies have not been performed with lonapegsomatropin. Data from interaction studies with somatropin performed in growth hormone deficient children and adults, and healthy elderly men, suggest that somatropin administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes, especially CYP3A and CYP1A2. The clearance of compounds metabolised by CYP 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and ciclosporin) and CYP1A2 (e.g. theophylline) may be increased and could result in lower exposure of these compounds. The clinical significance of this is unknown.

Insulin and/or other hypoglycaemic agents

In patients with diabetes mellitus requiring therapy with a medicinal product (e.g, anti-hyperglycaemic medicinal products), the dose of insulin and/or oral hypoglycaemic medicinal product may require adjustment when lonapegsomatropin therapy is initiated (see section 4.4).

Thyroid hormones

Because growth hormone increases the extrathyroidal conversion of T4 to T3, adjustment of thyroid hormone replacement therapy may be necessary (see section 4.4).

Oral oestrogen therapy

In female patients on oral oestrogen-containing therapy, a higher dose of growth hormone may be required to achieve the treatment goal (see section 4.2 and 4.4).

Pregnancy

There are no or limited amount of data from the use of lonapegsomatropin in pregnant women; published studies with short-acting somatropin use in pregnant women over several decades have not identified any drug-associated risk of major birth defects, miscarriages, or adverse maternal or foetal outcomes.

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Skytrofa is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breastfeeding

There are no data on the presence of lonapegsomatropin in human milk or effect on the breastfed newborns/infants. As lonapegsomatropin is not orally absorbed, it is unlikely to adversely affect the breastfed newborns/infants.

Skytrofa can be used during breastfeeding on strict indication.

Fertility

There are no clinical data on the effect of lonapegsomatropin on fertility. Animal studies are insufficient with respect to fertility (see section 5.3).

Lonapegsomatropin has no or negligible influence on the ability to drive and use machines.

Summary of safety profile

The most frequently reported adverse reactions in clinical trials with lonapegsomatropin were headache (11.1%), arthralgia (4.6%), secondary hypothyroidism (2.6%), and injection site reactions (1.6%). In general, these reactions tended to be transient and severity was mild to moderate.

Tabulated list of adverse reactions

Table 3 below shows adverse reactions which occurred during lonapegsomatropin treatment. The adverse reactions are ranked under headings of MedDRA system organ class and frequency using the following terminology: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and frequency not known (cannot be estimated from the available data).

Table 3. Frequency of adverse reactions in clinical trials:

^a Injection site reactions include hyperaemia, injection site atrophy, injection site pain, injection site urticaria, and localised oedema. The injection site reactions observed with lonapegsomatropin were generally mild and transient.

Description of selected adverse reactions

Immunogenicity

Patients may develop antibodies to lonapegsomatropin. The proportion of patients testing positive for detectable binding antibodies at any time during treatment was low (6.3%) and no patients had neutralising antibodies. No apparent correlation of anti-lonapegsomatropin binding antibodies to adverse events or loss of efficacy was observed. In case of an otherwise unexplained lack of response to lonapegsomatropin treatment, testing for antibodies to lonapegsomatropin should be considered (see section 4.4).

Adverse reactions related to growth hormone pharmacological class

In addition to the above-mentioned adverse drug reactions, those presented below have been reported with other growth hormone-containing products. Frequencies of these adverse events cannot be estimated from the available data (unless otherwise indicated).

Neoplasms benign, malignant and unspecified (including cysts and polyps): leukaemia (see section 4.4).

Metabolism and nutrition disorders: diabetes mellitus type 2 (see section 4.4).

Nervous system disorders: benign intracranial hypertension (see section 4.4), paraesthesia.

Musculoskeletal and connective tissue disorders: myalgia.

Reproductive system and breast disorders: gynaecomastia (frequency: uncommon).

Skin and subcutaneous tissue disorders: skin rash, urticaria and pruritus.

General disorders and administration site conditions: peripheral oedema, facial oedema.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 in Appendix V.

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