NGENLA Solution for injection Ref.[49626] Active ingredients: Somatrogon

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.

Hypersensitivity

Serious systemic hypersensitivity reactions (e.g. anaphylaxis, angioedema) have been reported with daily growth hormone medicinal products. If a serious hypersensitivity reaction occurs, use of somatrogon should be immediately discontinued; patients should be treated promptly per standard of care and monitored until signs and symptoms resolve (see section 4.3).

Hypoadrenalism

Based on published data patients receiving daily growth hormone therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatrogon treatment (see section 4.5). Patients should be monitored for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism (see section 4.5).

Thyroid function

Growth hormone increases the extrathyroidal conversion of T4 to T3 and may unmask incipient hypothyroidism. Patients with pre-existing hypothyroidism should be treated accordingly prior to the initiation of treatment with somatrogon as indicated based on clinical evaluation. As hypothyroidism interferes with the response to growth hormone therapy, patients should have their thyroid function tested regularly and should receive replacement therapy with thyroid hormone when indicated (see sections 4.5 and 4.8).

Prader-Willi syndrome

Somatrogon has not been studied in patients with Prader-Willi syndrome. Somatrogon 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 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.

Glucose metabolism

Treatment with growth hormone medicinal products may reduce insulin sensitivity and induce hyperglycaemia. Additional monitoring should be considered in patients treated with somatrogon who have glucose intolerance, or additional risk factors for diabetes. In patients treated with somatrogon who have diabetes mellitus, hypoglycaemic medicinal products might require adjustment (see section 4.5).

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.

Benign intracranial hypertension

Intracranial hypertension (IH) with papilledema, ataxia, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with growth hormone medicinal products. Funduscopic examination is recommended at the initiation of treatment and as clinically warranted. In patients with clinical or funduscopic evidence of IH, somatrogon should be temporarily discontinued. At present there is insufficient evidence to give specific advice on the continuation of growth hormone treatment in patients with resolved IH. If treatment with somatrogon is restarted, monitoring for signs and symptoms of IH is necessary.

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%. Based on this information, these types of patients should not be treated with somatrogon. As there is no information available on the safety of growth hormone substitution therapy in acutely critically ill patients, the benefits of continued somatrogon 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 somatrogon must be weighed against the potential risk involved.

Pancreatitis

Although rare in patients treated with growth hormone medicinal products, pancreatitis should be considered in somatrogon-treated patients who develop severe abdominal pain during treatment.

Scoliosis

Because somatrogon increases growth rate, signs of development or progression of scoliosis should be monitored during treatment.

Epiphyseal disorders

Epiphyseal disorders, including slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders or in patients undergoing rapid growth. Any paediatric patient with the onset of a limp or complaints of hip or knee pain during treatment should be carefully evaluated.

Oral oestrogen therapy

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 (see section 4.2). In female patients on oral oestrogen-containing therapy, a higher dose of somatrogon may be required to achieve the treatment goal (see section 4.5).

Excipients

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium free’.

Metacresol

Myositis is a very rare adverse event that may be related to the preservative metacresol. In the case of myalgia or disproportionate pain at injection site, myositis should be considered and if confirmed, other growth hormone medicinal products without metacresol should be used.

No interactions studies in paediatrics have been performed.

Glucocorticoids

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 (see section 4.4).

Insulin and hypoglycaemic medicinal products

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 (see section 4.4).

Thyroid medicinal products

Treatment with daily growth hormone may unmask previously undiagnosed or subclinical central hypothyroidism. Thyroxine replacement therapy may need to be initiated or adjusted (see section 4.4).

Oral oestrogen therapy

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

Cytochrome P450 metabolised products

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.

Pregnancy

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 (see section 5.3). Ngenla is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

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 (see section 5.3).

Ngenla 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: (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, 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 (see section 4.4).

Metacresol

This medicinal product contains metacresol which may contribute to painful injections (see section 4.4).

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.