Sogroya - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Sogroya 10 mg/1.5 mL solution for injection in pre-filled pen

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One mL of solution contains 6.7 mg of somapacitan*.

Each pre-filled pen contains 10 mg of somapacitan in 1.5 mL solution.

• * Produced by recombinant DNA technology in Escherichia coli followed by attachment of an albumin binding moiety.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear to slightly opalescent, colourless to slightly yellow liquid, essentially free from visible particles.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Sogroya is indicated for the replacement of endogenous growth hormone (GH) in adults with growth hormone deficiency (AGHD).

4.2 Posology and method of administration

Somapacitan should be initiated and monitored by physicians who are appropriately qualified and experienced in the diagnosis and management of adult patients with growth hormone deficiency (e.g. endocrinologists).

Posology

Starting dose

Table 1: Starting dose recommendation _____________­________________________­_______________

AGHD population	Recommended starting dose
Naïve patients Adults (18–60 years) Women on oral oestrogen (irrespective of age) Elderly (>60 years)	1.5 mg/week 2 mg/week 1 mg/week
Patients switching from daily GH medicinal products Adults (18–60 years) Women on oral oestrogen (irrespective of age) Elderly (>60 years)	2 mg/week 4 mg/week 1.5 mg/week

Dose titration

The somapacitan dose must be individually adjusted for each patient. It is recommended to increase the dose gradually with 2–4 weeks intervals in steps from 0.5 mg to 1.5 mg based on the patients’ clinical response and experience of adverse reactions up to a dose of 8 mg somapacitan per week. Serum insulin like growth factor-I (IGF-I) levels (drawn 3–4 days after dosing) can be used as guidance for the dose titration. The IGF-I standard deviation score (SDS) target should aim for the upper normal range not exceeding 2 SDS. IGF-I SDS levels in the target range are usually achieved within 8 weeks of dose titration. Longer dose titration may be necessary in some AGHD patients (see below and section 5.1).

Treatment evaluation

Using IGF-I SDS as a biomarker for dose titration, the aim is to reach IGF-I SDS levels within the age-adjusted upper reference range (IGF-I SDS upper reference range: 0 and +2) within 12 months of titration. If this target range cannot be achieved within this period, or the patient does not obtain the desired clinical response, other treatment options should be considered.

During somapacitan maintenance treatment, evaluation of efficacy and safety should be considered at approximately 6– to 12-month intervals and may be assessed by evaluating biochemistry (IGF-I-, glucose-, and lipid levels), body composition, and body mass index.

Missed dose

Patients who forget a dose are advised to inject somapacitan upon discovery as soon as possible, within 3 days after the missed dose, and then resume their usual once-weekly dosing schedule. If more than 3 days have passed, the dose should be skipped and the next dose should be administered on the regularly scheduled day. If two or more doses have been missed, the dose should be resumed on the regularly scheduled day.

Changing the dosing day

The day of weekly injection can be changed as long as the time between two doses is at least 4 days. After selecting a new dosing day, the once weekly dosing should be continued.

Special populations

Elderly (>60 years of age)

Generally, lower doses of somapacitan may be necessary in older patients. For further information, see section 5.2.

Gender

Men show an increasing IGF-I sensitivity over time. This means that there is a risk that men are overtreated. Women, especially those on oral oestrogen, may require higher doses and a longer titration period than men, see sections 5.1 and 5.2. In women using oral oestrogen, it should be considered to change the route of oestrogen administration (e.g. transdermal, vaginal) see section 4.4.

Renal impairment

No adjustment of the starting dose is required for patients with renal impairment. Patients with renal impairment may need lower doses of somapacitan but since the dose of somapacitan is individually adjusted according to the need of each patient, no further dose adjustment is required, see section 5.2.

Hepatic impairment

No adjustment of the starting dose is required for patients with hepatic impairment. Patients with moderate hepatic impairment may need higher doses of somapacitan but since the dose of somapacitan is individually adjusted according to the need of each patient, no further dose adjustment is required. No information regarding the use of somapacitan in patients with severe hepatic impairment is available. Caution should be exercised if treating these patients with somapacitan, see section 5.2.

Paediatric population

Safety and efficacy of somapacitan in children and adolescents below 18 years have not yet been established. No data are available.

Method of administration

Somapacitan is to be administered once-weekly at any time of the day.

Somapacitan is to be injected subcutaneously in the abdomen or in the thigh. The injection site can be changed without dose adjustment. The injection site should be rotated every week.

The pen delivers doses from 0.05 mg to 4 mg in increments of 0.05 mg (0.075 mL).

For instructions of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Somapacitan 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 somapacitan therapy. Treatment should be discontinued if there is evidence of tumour growth, see section 4.4.

Patients with acute critical illness suffering from complications following open heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions must not be treated with somapacitan (regarding patients undergoing substitution therapy, see section 4.4).

4.4 Special warnings and precautions for use

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.

Adrenocortical insufficiency

Introduction of growth hormone treatment may result in inhibition of 1ipHSD-1 and reduced serum cortisol concentrations. In patients treated with growth hormone, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of growth hormone treatment. It is necessary to monitor patients with known hypoadrenalism for reduced serum cortisol levels and/or for the need of increased doses of glucocorticoid, see section 4.5.

Glucose metabolism impairment

Treatment with growth hormone may decrease insulin sensitivity, particularly at higher doses in susceptible patients and consequently hyperglycaemia may occur in subjects with inadequate insulin secretory capacity. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during growth hormone treatment. Therefore, glucose levels should be monitored periodically in all patients treated with growth hormone, especially in those with risk factors for diabetes mellitus, such as obesity, or a family history of diabetes mellitus. Patients with pre-existing type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during growth hormone therapy. The doses of antihyperglycaemic medicinal products may require adjustment when growth hormone therapy is instituted in these patients.

Neoplasms

There is no evidence for increased risk of new primary cancers in adults treated with growth hormone. In patients in complete remission from malignant diseases or who have been treated for benign tumours, growth hormone therapy has not been associated with an increased relapse rate.

Patients who have achieved complete remission of malignant diseases or who have been treated for benign tumours should be followed closely for relapse after commencement of growth hormone therapy. Growth hormone treatment should be interrupted in case of any development or reoccurrence of malignant or benign tumour.

An overall slight increase in second neoplasms has been observed in childhood cancer survivors treated with growth hormone, with the most frequent being intracranial tumours. The dominant risk factor for secondary neoplasms seems to be prior exposure to radiation.

Benign intracranial hypertension

In the event of severe or recurrent headache, visual symptoms, nausea, and/or vomiting, a fundoscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and if appropriate the growth hormone treatment should be discontinued. At present there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.

Thyroid function

Growth hormone increases the extrathyroidal conversion of T4 to T3 and may as such unmask incipient hypothyroidism. 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.

Use with oral oestrogen

Oral oestrogen influences the IGF-I response to growth hormone including somapacitan.

Women taking any form of oral oestrogen (hormone therapy or contraception) should consider changing the route of oestrogen administration (e.g. transdermal-, vaginal hormone products) or use another form of contraception. If a woman on oral oestrogen is starting somapacitan therapy, higher starting doses and a longer titration period may be required (see section 4.2).

If a woman taking somapacitan begins oral oestrogen therapy, the dose of somapacitan may need to be increased to maintain the serum IGF-I levels within the normal age-appropriate range. Conversely, if a woman on somapacitan discontinues oral oestrogen therapy, the dose of somapacitan may need to be reduced to avoid excess of somapacitan and/or undesirable effects, see sections 4.2 and 4.5.

Lipohypertrophy

When somapacitan is administered at the same site over a long period of time, lipohypertrophy may occur. The injection site should be rotated to reduce the risk, see sections 4.2 and 4.8.

Antibodies

Although no antibodies were observed after treatment with somapacitan, antibodies could be expected as observed with other therapeutic proteins. Testing for presence of anti-somapacitan antibodies should be carried out in patients who fail to respond to therapy.

Acute critical illness

The effect of growth hormone on recovery was studied in two placebo controlled trials involving 522 critical ill adult patients suffering from complications following open heart surgery, abdominal surgery, multiple accidental trauma or acute respiratory failure. Mortality was higher in patients treated with 5.3 or 8 mg growth hormone daily compared to patients receiving placebo, 42% vs 19%.

Based on this information, these types of patients should not be treated with somapacitan. As there is no information available on the safety of growth hormone substitution therapy in acutely critical ill patients, the benefits of continued treatment in this situation should be weighed against the potential risks involved.

Growth hormone deficiency in adults is a lifelong disease and needs to be treated accordingly, however, experience in patients older than 60 years and in patients with more than five years of treatment in adult growth hormone deficiency is still limited.

Paediatric population

Somapacitan should not be administered to patients below 18 years since safety and efficacy of somapacitan in children and adolescents below 18 years have not yet been established.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially sodium-free.

4.5 Interaction with other medicinal products and other forms of interaction

Cytochrome P450 metabolised drugs

Data from an interaction study performed in growth hormone deficient adults suggests that growth hormone administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by cytochrome P450 (e.g. sex steroids, corticosteroids, anticonvulsants and cyclosporine) may be especially increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.

Glucocorticoids

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.

Oral oestrogens

In women on oral oestrogen therapy, a higher dose of somapacitan may be required to achieve the treatment goal, see sections 4.2 and 4.4.

Antihyperglycaemic products

Antihyperglycaemic treatment including insulin may require dose adjustment in case of somapacitan co-administration since somapacitan may decrease insulin sensitivity, see sections 4.4 and 4.8.

Other

The metabolic effects of somapacitan can also be influenced by concomitant therapy with other hormones, e.g. testosterone and thyroid hormones, see section 4.4.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of somapacitan in pregnant women.

Studies in animal have shown reproductive toxicity, see section 5.3.

Sogroya is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether somapacitan/me­tabolites are excreted in human milk.

Available pharmacodynamic/to­xicological data in animals have shown excretion of somapacitan in milk, see section 5.3.

A risk to the breastfed newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Sogroya therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There is no clinical experience with somapacitan use and its potential effect on fertility.

No adverse effects were observed on male and female fertility in rats,see section 5.3.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of safety profile

The commonly reported and serious adverse reactions after treatment with somapacitan are headache (12%), peripheral oedema (4%) and adrenocortical insufficiency (3%).

Tabulated list of adverse reactions

The adverse reactions listed below are based on the compiled safety data from three completed phase 3 trials in patients with AGHD.

The adverse reactions are listed by MedDRA system organ class and frequency category defined as: 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).

Table 2: Adverse reactions

MedDRA system organ class	Very common	Common	Uncommon
Endocrine disorders		Adrenocortical insufficiency Hypothyroidism
Metabolism and nutrition disorders		Hyperglycaemia*
Nervous system disorders	Headache	Paraesthesia	Carpal tunnel syndrome
Skin and subcutaneous tissue disorders		Rash Urticaria	Lipohypertrophy Pruritus
Musculoskeletal and connective tissue disorders		Arthralgia Myalgia Muscle stiffness*	Joint stiffness
General disorders and		Peripheral oedema Fatigue

administration site conditions

Asthenia Injection site reactions*

*In general, these adverse reactions were non-serious, mild or moderate severity and transient

Description of selected adverse reactions

Peripheral oedema

Peripheral oedema was commonly observed (4%). Growth hormone deficient patients are characterised by extracellular volume deficit. When treatment with growth hormone products is initiated, this deficit is corrected. Fluid retention with peripheral oedema may occur. The symptoms are usually transient, dose dependent and may require transient dose reduction.

Adrenocortical insufficiency

Adrenocortical insufficiency was commonly observed (3%), 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

4.9 Overdose

Treatment with growth hormone can lead to an acute overdose with low blood glucose levels initially, followed by high blood glucose levels. These decreased glucose levels have been detected biochemically, but without clinical signs of hypoglycaemia.

Long-term overdosage could result in signs and symptoms consistent with the known effects of human growth hormone excess.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatropin and somatropin agonists, ATC code: H01AC07.

Mechanism of action

Somapacitan is a long-acting recombinant human growth hormone derivative. It consists of 191 amino acids similar to endogenous human growth hormone, with a single substitution in the amino acid backbone (L101C) to which an albumin binding moiety has been attached. The albumin binding moiety (side-chain) consists of a fatty acid moiety and a hydrophilic spacer attached to position 101 of the protein.

The mechanism of action of somapacitan is either directly via the GH-receptor and/or indirectly via IGF-I produced in tissues throughout the body, but predominantly by the liver.

When growth hormone deficiency is treated with somapacitan a normalisation of body composition (i.e., decreased body fat mass, increased lean body mass) and of metabolic action is achieved.

Pharmacodynamic effects

IGF -I

IGF-I is a generally accepted biomarker for efficacy in AGHD.

A dose-dependent IGF-I response is induced following somapacitan administration in AGHD patients. A steady state pattern in IGF-I responses is reached after 1–2 weekly doses.

The IGF-I levels fluctuate during the week. The IGF-I response is maximal after 2 to 4 days.

Compared with daily GH treatment, the IGF-I profile of somapacitan differs, see Figure 1.

Figure 1: Model-derived IGF -I profiles during steady state of somapacitan and somatropin

Clinical efficacy and safety

In a 34-week placebo-controlled (double-blind) and active-controlled (open) trial, 301 treatment-naive adult patients with GHD were randomised (2:1:2) and exposed to once-weekly somapacitan or to placebo or to daily somatropinfor a 34-week treatment period (main phase of the trial). The patient population had a mean age of 45.1 years (range 23–77 years; 41 patients were 65 years or above), 51.7% were females, and 69.7% had adult onset GHD.

A total of 272 AGHD patients who completed the 34-week main phase continued in a 53-week open-label extension period. Subjects on placebo were switched to somapacitan and patients on somatropin were re-randomised (1:1) to either somapacitan or somatropin.

Observed clinical effects for the main endpoints in the main treatment phase (Table 3) and extension treatment phase (Table 4) are presented below.

Table 3: Results at 34 weeks

Change from baseline at 34 weeksa	somapacitan	somatropin	placebo	Difference somapacitan -placebo [95% CI] p-value	Difference somapacitan-somatropin [95% CI]
Number of subjects (N) Truncal fat % (Primary endpoint)	120	119	61	–1.53	1.17
	–1.06	–2.23	0.47	[-2.68; –0.38] 0.0090b	[0.23;2.11]
Visceral adipose tissue (cm2)	–10	–9	3	–14 [-21; –7]	–1 [-7; 4]
Appendicular skeletal muscle mass (g)	558	462	–121	679 [340; 1,019]	96 [-182; 374]
				1144	49
Lean body mass (g)	1,394	1,345	250	[459; 1,829]	[-513;610]
				2.40	0.02
IGF-I SDS level	2.40	2.37	–0.01	[2.09; 2.72]	[-0.23;0.28]

Abbreviations: N = Number of subjects in full analysis set, CI = Confidence interval, DM=Diabetes mellitus. IGF-I SDS: Insulin-like growth factor-I standard deviation score.

a Body composition parameters are based on dual-energy X-ray absorptiometry (DXA) scanning.

b The primary analysis was a comparison of changes from baseline for somapacitan and placebo in truncal fat %. Changes in truncal fat % from baseline to the 34 week’s mea­surements was analysed using an analysis of covariance model with treatment, GHD onset type, sex, region, DM and sex by region by DM interaction as factors and baseline as a covariate incorporating a multiple imputation technique where missing week 34 values were imputed based on data from the placebo group.

Post-hoc subgroup analysis of changes from baseline in truncal fat percentage (%) compared to placebo at week 34 showed an estimated treatment difference (somapacitan-placebo) of –2.49% [-4.19; –0.79] in men, –0.80% [-2.99; 1.39] in women not on oral oestrogen, –1.44% [-3.97; 1.09] in women on oral oestrogen.

Table 4: Results at 87 weeks
Change from baseline at 87 weeksa	somapacitan/ somapacitan	somatropin/ somatropin	placebo/ somapacitan	somatropin/ somapacitan	Difference somapacitan/ somapacitan vs somatropin/so­matropin [95% CI]
Number of subjects (N)	114	52	54	51	1.15
Truncal fat %	–1.51	–2.67	–2.28	–1.35	[-0.10; 2.40]
Visceral adipose tissue (cm2)	–6.64	–6.85	–10.21	–8.77	0.22 [-10; 10]
Appendicular					97.02
skeletal muscle mass (g)	546.11	449.09	411.05	575.80	[-362; 556]
Lean body mass (g)	1,739.05	1,305.73	1,660.56	1,707.82	433.32 [-404; 1271]
a Body composition parameters are based on DXA scanning.

Observed and simulated IGF-I SDS levels in the clinical study

In the main phase of the clinical study IGF-I SDS values of 0 and above were overall achieved in 53% of somapacitan-treated AGHD study patients after an 8-week dose titration period. This proportion was however lower in particular subgroups such as women on oral oestrogen (32%) and patients with childhood-onset (39%) (Table 5). Post-hoc simulation analyses indicated that the proportions of AGHD patients achieving IGF-I SDS levels above 0 are expected to be higher in case somapacitan dose titration beyond 8 weeks would be allowed. In this simulation analysis, it was assumed that somapacitan dose titration was well-tolerated in all patients until the IGF-I SDS target range or a somapacitan dose of 8 mg per week would be achieved.

Table 5 Proportions of somapacitan-treated AGHD patients with IGF-I SDS levels above 0

Women not   Women on    Childhood Subgroups Men      on oral        ora1       onset AGHD oestrogen      oestrogen	Adult onset        All AGHD
Observeda         71%       46%         32%        39% Post hoc Post-hoc         100%       96%         70% 84% simulations	60%     53% 92%     90%

a The trial was designed to titrate towards a IGF-I SDS level above –0.5

Maintenance dose

Maintenance dose varies from person to person and between male and female patients. The average somapacitan maintenance dose observed in the phase 3 clinical trials was 2.4 mg/week.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Sogroya in all subsets of the paediatric population in growth hormone deficiency (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Somapacitan has pharmacokinetic properties compatible with once weekly administration. The reversible binding to endogenous albumin delays elimination of somapacitan and thereby prolongs the in vivo half-life and duration of action.

The pharmacokinetics of somapacitan following subcutaneous administration have been investigated at dose levels from 0.01 to 0.32 mg/kg in healthy adults, and in doses up to 0.12 mg/kg in adults with GHD.

Overall, somapacitan displays non-linear pharmacokinetics, but in the clinically relevant dose range of somapacitan in adults with GHD, somapacitan pharmacokinetics are approximately linear.

Absorption

In adult patients with GHD median tmax ranged from 4 to 24 hours at doses from 0.02 mg/kg/week to 0.12 mg/kg/week.

Steady state exposure was achieved following 1–2 weekly administration.

Absolute bioavailability of somapacitan in humans has not been investigated.

Distribution

Somapacitan is extensively bound (>99%) to plasma proteins and is expected to be distributed like albumin. Based on population PK analyses, the estimated volume of distribution (V/F) was 14.6 L.

Elimination

The terminal half-life was estimated with geometric means ranging from approximately 2 to 3 days at steady state in AGHD patients (doses: 0.02 to 0.12 mg/kg).

Somapacitan will be present in circulation for approximately 2 weeks after the last dose. Little to no accumulation (mean accumulation ratio: 1–2) of somapacitan following multiple dosing has been observed in AGHD patients.

Biotransformation

Somapacitan is extensively metabolised by proteolytic degradation and cleavage of the linker sequence between the peptide and albumin binder.

Somapacitan was extensively metabolised before excretion and no intact somapacitan was found neither in urine, which was the main excretion route (81%), nor in faeces where 13% of somapacitan related material was found, indicating full biotransformation before excretion.

Special populations

Age

Subjects older than 60 years have higher exposure (29%) than younger subjects at the same somapacitan dose. A lower starting dose for subjects above 60 years is described in section 4.2.

Gender

Female subjects and in particular female subjects on oral oestrogen, have lower exposure (53% for females on oral oestrogen and 30 % for females not on oral oestrogen) than male subjects at the same somapacitan dose. A higher starting dose for females on oral oestrogen is described in section 4.2.

Race

There was no difference in somapacitan exposure and IGF-I response between Japanese and White subjects. Despite a higher exposure in Asian Non-Japanese compared to White at the same somapacitan dose, White, Japanese and Asian Non-Japanese needed the same doses to reach similar IGF-I levels. Therefore, there is no dose adjustment recommendation based on race.

Ethnicity

Ethnicity (Hispanic or Latino 4.5% (15 subjects received somapacitan)) was not investigated due to small sample size in the development programme.

Body weight

Despite a higher exposure in subjects with low body weight as compared to subjects with high body weight at the same somapacitan dose, subjects needed the same doses to reach similar IGF-I levels across the body weight range 35 kg to 150 kg. Therefore, there is no dose adjustment recommendation based on body weight.

Renal impairment

A somapacitan dose of 0.08 mg/kg at steady state resulted in higher exposures in subjects with renal impairment, most pronounced in subjects with severe renal impairment and in subjects requiring haemodialysis, where AUC 0–168h ratios to normal renal function were 1.75 and 1.63, respectively. In general, somapacitan exposure tended to increase with decreasing GFR.

Higher IGF-I AUC0–168h levels were observed in subjects with moderate and severe renal impairment and subjects requiring haemodialysis, with ratios to normal renal function of 1.35, 1.40 and 1.24 respectively.

Due to the modest increase observed in IGF-I combined with the low recommended starting doses and the individual dose titration of somapacitan, there is no dose adjustment recommendation in patients with renal impairment.

Hepatic impairment

A somapacitan dose of 0.08 mg/kg at steady state resulted in higher exposure in subjects with moderate hepatic impairment with ratios to normal hepatic function of 4.69 for AUC0–168h and 3.52 for Cmax.

Lower somapacitan stimulated IGF-I levels were observed in subjects with mild and moderate hepatic impairment compared to subjects with normal hepatic function (ratio to normal was 0.85 for mild and 0.75 for moderate).

Due to the modest decrease observed in IGF-I combined with the individual dose titration of somapacitan, there is no dose adjustment recommendation in patients with hepatic impairment.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity or pre- and postnatal development.

No carcinogenicity studies have been performed with somapacitan.

No adverse effects were observed on male and female fertility in rats at a dose resulting in exposure at least 13 and 15-times greater than the expected maximum clinical exposure at 8 mg/week for males and females, respectively. However, irregular female oestrus cycle was seen at all doses treated.

No evidence of foetal harm was identified when pregnant rats and rabbits were administered subcutaneous somapacitan during organogenesis at doses leading to exposures well above expected exposure at the maximum clinical dose of 8 mg/week (at least 18-fold). At high doses leading to exposure at least 130-fold above the expected maximum clinical exposure at 8 mg/week, short/bent/thic­kened long bones were found in pups from female rats receiving somapacitan. Such findings in rats are known to resolve after birth and should be regarded as minor malformations, not permanent abnormalities.

Foetal growth was reduced when pregnant rabbits were dosed with somapacitan subcutaneously at exposures at least 9-fold above the expected exposure at the maximum clinical dose of 8 mg/week.

In lactating rats, somapacitan related material was secreted into milk but to a lower level than observed in plasma (up to 50% of level in plasma).

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Histidine

Mannitol

Poloxamer 188

Phenol

Water for injections

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment).

6.2 Incompatibilities

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

6.3 Shelf life

2 years.

After first opening

6 weeks. Store in a refrigerator (2°C – 8°C).

Do not freeze. Keep away from the freezing element.

Keep Sogroya in the outer carton with the pen cap on to protect from light.

Before and after first opening

If refrigeration is not possible (e.g. during travelling), Sogroya may be kept temporarily at temperatures up to 30°C for up to a total of 72 hours (3 days). Return Sogroya to the refrigerator again after storage at this temperature. If stored out of refrigeration and then returned to refrigeration, the total combined time out of refrigeration should not exceed 3 days, monitor this carefully. The Sogroya pen should be discarded, if it has been kept up to 30°C for more than 72 hours (3 days) or for any period of time kept above 30°C.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze. Keep away from the freezing element.

Keep Sogroya in the outer carton with the pen cap on to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

1.5 mL solution in a glass cartridge (Type I colourless glass) with a plunger made of chlorobutyl rubber and a stopper made of bromobutyl/isoprene rubber sealed with an aluminium cap.

The cartridge is contained in a multidose disposable pen made of polypropylene, polyacetal, polycarbonate and acrylonitrile butadiene styrene and in addition two metal springs.

The cartridge is permanently sealed in a pen-injector.

Pack sizes of 1 pre-filled pen and multipack of 5 (5 packs of 1) pre-filled pen.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The pen is for use by one person only.

Sogroya should not be used if the solution does not appear clear to slightly opalescent, colourless to slightly yellow and free from visible particles.

Sogroya must not be used if it has been frozen.

The cartridge must not be taken out of the pre-filled pen and refilled.

A needle must always be attached before use. Needles must not be re-used. The injection needle should be removed after each injection and the pen should be stored without a needle attached. This may prevent blocked needles, contamination, infection, leakage of solution and inaccurate dosing. In the event of blocked needles, patients must follow the instructions described in the instructions for use accompanying the package leaflet.

Needles are not included. Sogroya pre-filled pen has been tested with 31 Gx6 mm and 32 Gx5 mm disposable needles. Sogroya can be administered with a needle up to a length of 8 mm and as thin as 32 G.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

8. MARKETING AUTHORISATION NUMBERS

EU/1/20/1501/001

EU/1/20/1501/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: