Somatrogon

Drug-drug interaction studies have not been performed with somatrogon. Somatrogon has been shown to induce CYP3A4 mRNA expression in vitro. The clinical significance of this is unknown. Studies with other human growth hormone (hGH) receptor agonists performed in growth hormone deficient children and adults, and healthy elderly men, suggest that administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes, especially CYP3A. The clearance of compounds metabolised by CYP3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and ciclosporin) may be increased and could result in lower exposure of these compounds.

Somatrogon has not been studied in patients with hepatic impairment. No dose recommendation can be made.

Somatrogon has not been studied in patients with renal impairment. No dose recommendation can be made.

In patients with diabetes mellitus requiring medicinal product therapy, the dose of insulin and/or oral/injectable hypoglycaemic medicinal products may require adjustment when somatrogon therapy is initiated.

Oral oestrogen influences the IGF-1 response to growth hormone. If a female patient taking somatrogon begins or discontinues oral oestrogen containing therapy, IGF-1 value should be monitored to determine if the dose of growth hormone should be adjusted to maintain the serum IGF-1 levels within the normal range. In female patients on oral oestrogen-containing therapy, a higher dose of somatrogon may be required to achieve the treatment goal.

Concomitant treatment with glucocorticoids may inhibit the growth-promoting effects of somatrogon. Patients with adrenocorticotropic hormone (ACTH) deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth. Therefore, 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.

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.

There are no data from the use of somatrogon in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Somatrogon is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether somatrogon/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from somatrogon therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The risk of infertility in females or males of reproductive potential has not been studied in humans. In a rat study, the fertility in males and females was not affected.

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

Summary of the safety profile

The commonly reported adverse reactions after treatment with somatrogon are injection site reactions (ISRs) (25.1%), headache (10.7%) and pyrexia (10.2%).

Tabulated list of adverse reactions

Safety data are derived from the phase 2, multi-centre safety and dose-finding study, and the pivotal phase 3, multi-centre non-inferiority study in paediatric patients with GHD (see section 5.1). The data reflect exposure of 265 patients to somatrogon administered once weekly (0.66 mg/kg/week).

Table 1 presents the adverse reactions for somatrogon within the system organ class (SOC). The adverse reactions listed in the table below are presented by SOC and frequency categories, defined using the following convention: 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) or frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1. Adverse reactions:

^a Injection site reactions include the following: injection site pain, erythema, pruritus, swelling, induration, bruising, haemorrhage, warmth, hypertrophy, inflammation, deformation, urticaria.

Description of selected adverse reactions

Injection site reaction

In the phase 3 clinical study, reporting of ISRs was actively solicited during the course of the study. In the majority of cases, local ISRs tended to be transient, occurred mainly in the first 6 months of treatment and were mild in severity; ISRs had a mean onset on the day of the injection and a mean duration of <1 day. Among them, injection site pain, erythema, pruritus, swelling, induration, bruising, hypertrophy, inflammation and warmth were reported in 43.1% of patients treated with somatrogon compared to 25.2% of patients administered daily injections of somatropin.

In the long-term OLE of the clinical phase 3 study, local ISRs were similar in nature and severity, and reported early in subjects switching from somatropin to somatrogon treatment. ISRs were reported in 18.3% of patients originally treated with somatrogon in the main study and continuing treatment in the OLE portion of the study, and likewise, 37% were reported among patients originally treated with somatropin that were switched in the OLE portion of the study to treatment with somatrogon.

Immunogenicity

In the pivotal safety and efficacy study, among 109 subjects treated with somatrogon, 84 (77.1%) tested positive for anti-drug antibodies (ADAs). There were no clinical or safety effects observed with the formation of antibodies.

Other adverse drug reactions for somatropin may be considered class effects, such as:

• Neoplasms benign and malignant
• Metabolism and nutrition disorders: diabetes mellitus type 2.
• Nervous system disorders: benign intracranial hypertension, paraesthesia.
• Musculoskeletal, connective tissue, and bone disorders: myalgia.
• Reproductive system and breast disorders: gynaecomastia.
• Skin and subcutaneous tissue disorders: skin rash, urticaria and pruritus.
• General disorders and administration site conditions: peripheral oedema, facial oedema.
• Gastrointestinal disorders: pancreatitis.

Metacresol

This medicinal product contains metacresol which may contribute to painful injections.