SKYTROFA 3mg powder + solvent for injection medication leaflet

Skytrofa 3 mg powder and solvent for solution for injection in cartridge

Skytrofa 3.6 mg powder and solvent for solution for injection in cartridge

Skytrofa 4.3 mg powder and solvent for solution for injection in cartridge

Skytrofa 5.2 mg powder and solvent for solution for injection in cartridge

Skytrofa 6.3 mg powder and solvent for solution for injection in cartridge

Skytrofa 7.6 mg powder and solvent for solution for injection in cartridge

Skytrofa 9.1 mg powder and solvent for solution for injection in cartridge

Skytrofa 11 mg powder and solvent for solution for injection in cartridge

Skytrofa 13.3 mg powder and solvent for solution for injection in cartridge

Skytrofa consists of somatropin transiently conjugated to a methoxypolyethylene glycol carrier(mPEG) via a proprietary TransCon Linker. The strength of Skytrofa always indicates the quantity ofthe somatropin moiety.

Skytrofa 3 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 3 mg of somatropin* equivalent to 8.6 mg of lonapegsomatropinand 0.279 mL of solvent. After reconstitution the concentration based on somatropin** proteinis 11 mg/mL.

Skytrofa 3.6 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 3.6 mg of somatropin* equivalent to 10.3 mg oflonapegsomatropin and 0.329 mL of solvent. After reconstitution the concentration based onsomatropin** protein is 11 mg/mL.

Skytrofa 4.3 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 4.3 mg of somatropin* equivalent to 12.3 mg oflonapegsomatropin and 0.388 mL of solvent. After reconstitution the concentration based onsomatropin** protein is 11 mg/mL.

Skytrofa 5.2 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 5.2 mg of somatropin* equivalent to 14.8 mg oflonapegsomatropin and 0.464 mL of solvent. After reconstitution the concentration based onsomatropin** protein is 11 mg/mL.

Skytrofa 6.3 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 6.3 mg of somatropin* equivalent to 18 mg oflonapegsomatropin and 0.285 mL of solvent. After reconstitution the concentration based onsomatropin** protein is 22 mg/mL.

Skytrofa 7.6 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 7.6 mg of somatropin* equivalent to 21.7 mg oflonapegsomatropin and 0.338 mL of solvent. After reconstitution the concentration based onsomatropin** protein is 22 mg/mL.

Skytrofa 9.1 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 9.1 mg of somatropin* equivalent to 25.9 mg oflonapegsomatropin and 0.4 mL of solvent. After reconstitution the concentration based onsomatropin** protein is 22 mg/mL.

Skytrofa 11 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 11 mg of somatropin* equivalent to 31.4 mg oflonapegsomatropin and 0.479 mL of solvent. After reconstitution the concentration based onsomatropin** protein is 22 mg/mL.

Skytrofa 13.3 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 13.3 mg of somatropin* equivalent to 37.9 mg oflonapegsomatropin and 0.574 mL of solvent. After reconstitution the concentration based onsomatropin** protein is 22 mg/mL.

* The strength indicates the quantity of the somatropin moiety without consideration of themPEG-linker.

** Produced in Escherichia coli cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection (injection).

White to off-white powder.

The solvent is a clear and colourless solution.

Growth failure in children and adolescents aged from 3 years up to 18 years due to insufficientendogenous growth hormone secretion (growth hormone deficiency [GHD]).

Treatment should be initiated and monitored by physicians who are qualified and experienced in thediagnosis and management of paediatric patients with GHD.

The amount and concentration of lonapegsomatropin is always expressed in terms of mg somatropinreferring to the content of the somatropin moiety and not including mPEG-linker in order to preventmedication errors when patients switch from daily somatropin therapy.

The posology and administration should be individualised for each patient.

The recommended starting dose of Skytrofa is 0.24 mg somatropin/kg body weight, given onceweekly. The recommended starting dose strengths for such a dose by weight range can be found in

Table 1.

Table 1 Recommended dose for patients by weight, when prescribed doses of 0.24 mgsomatropin/kg/week

Weight (kg) Somatropin dose strength11.5 - 13.9 3 mg14 - 16.4 3.6 mg16.5 - 19.9 4.3 mg20 - 23.9 5.2 mg24 - 28.9 6.3 mg29 - 34.9 7.6 mg35 - 41.9 9.1 mg42 - 50.9 11 mg51 - 60.4 13.3 mg60.5 - 69.9 15.2 mg (using two dual-chamber cartridges of 7.6 mg each)70 - 84.9 18.2 mg (using two dual-chamber cartridges of 9.1 mg each)85 - 100 22 mg (using two dual-chamber cartridges of 11 mg each)

If prescribing a dose other than 0.24 mg somatropin/kg/week, calculate the total weekly dose (in mgsomatropin) and select the appropriate dose strength as follows:

* Total weekly dose (mg somatropin) = prescribed dose (mg somatropin/kg) x patient’s bodyweight (kg)

* Round the total weekly dose (mg somatropin) to the closest dose strength while also consideringtreatment goals and clinical response.

Starting dose for patients switching from daily somatropin medicinal products

If changing therapy to once-weekly lonapegsomatropin from daily somatropin, there should be atleast 8 hours between the final dose of once-daily somatropin and the first dose of lonapegsomatropin.

In children switching from daily somatropin, physicians may adjust the starting dose taking intoconsideration the current somatropin dose, individual clinical response, and clinical considerationsspecific to the patient.

For children switching from daily somatropin medicinal products at a weekly dose equal to or greaterthan 0.24 mg somatropin/kg body weight, the recommended starting dose of lonapegsomatropinis 0.24 mg somatropin/kg body weight (Table 1).

For children switching from daily somatropin medicinal products at a weekly dose less than 0.24 mgsomatropin/kg body weight, use the previously prescribed weekly dose as the recommended startingdose of lonapegsomatropin (see equation above).

Dose titration

The dose of lonapegsomatropin should be individually adjusted for each patient based on clinicalresponse, adverse reactions, and/or serum insulin-like growth factor-1 (IGF-1) concentrations outsidethe targeted range. Available somatropin dose strengths can be found in section 1.

Average IGF-1 standard deviation score (SDS) levels (drawn 4-5 days after dosing) can be used asguidance for dose titration (Table 2). It is necessary to wait a minimum of 2 weeks after initiation oflonapegsomatropin or after any dose change before assessing the resulting IGF-1 SDS levels. Doseadjustments should be targeted to achieve average IGF-1 SDS levels in the normal range, i.e.between -2 and +2 (preferably close to 0 SDS).

IGF-1 SDS levels may vary over time, and therefore routine monitoring of serum IGF-1 SDS levelsthroughout the course of treatment is recommended, especially during puberty.

Table 2 Recommended change in somatropin dose strength for average IGF-1 SDScategories

Average IGF-1 SDS range Recommended change in somatropin dose(drawn on post-dose day 4-5) strength> +4 Reduce by 3 dose strengths+3 to +4 Reduce by 2 dose strengths+2 to +3 Reduce by 1 dose strength

- 2 to +2 No change< -2 Increase by 1 dose strength

Treatment evaluation

Evaluation of efficacy and safety should be considered at approximately 6- to 12-month intervals andmay be assessed by evaluating auxological parameters, biochemistry (IGF-1, hormones, glucose, andlipid levels), and pubertal status. More frequent evaluations should be considered during puberty.

Treatment should be discontinued in patients with annualised height velocity < 2 cm/year, final heightachievement, height velocity SDS < + 1 after the first year of treatment, or in case bone age is> 14 years (girls) or > 16 years (boys) which corresponds to the closure of the epiphyseal growthplates.

Once the epiphyses are fused, patients should be clinically re-evaluated for the need for growthhormone treatment.

Oral oestrogen therapy

Females on oral oestrogen-containing therapy may require a higher dose of growth hormone toachieve the treatment goal (see section 4.4).

If a dose is missed, it should be administered as soon as possible and no more than 2 days after themissed dose. If more than 2 days have passed, the missed dose should be skipped, and the next doseshould be administered on the regularly scheduled day. In each case, patients can then resume theirregular once-weekly dosing schedule.

The day of weekly injection can be changed to a different day of the week. Lonapegsomatropin can beadministered 2 days before or 2 days after the scheduled dosing day. It should be ensured that at least5 days will pass between the last dose and the newly-established regular once-weekly dosing day.

No information in patients with renal impairment is available and dose recommendations cannot begiven.

No information in patients with hepatic impairment is available and dose recommendations cannot begiven.

The safety and efficacy of lonapegsomatropin in children under 3 years of age has not beenestablished. Currently available data are described in section 5.1 but no recommendation on aposology can be made.

Each injection should be administered subcutaneously once-weekly in the abdomen, buttock or thigh.

The site of administration should be varied to prevent lipoatrophy.

Lonapegsomatropin is intended to be administered after reconstitution of the powder for solution forinjection with the enclosed solvent. Lonapegsomatropin should be administered by means of the

Skytrofa Auto-Injector. The patient and caregiver should receive training to ensure understanding ofthe administration procedure by means of the device in order to be allowed to (self)-injectlonapegsomatropin.

The reconstituted solution should be colourless and clear to opalescent and free or practically free ofvisible particles (see section 6.6).

For instructions on reconstitution of the medicinal product before administration, see section 6.6 andthe instructions included at the end of the package leaflet.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (seesection 4.4).

Somatropin must not be used when there is any evidence of activity of a tumour (see section 4.4).

Intracranial tumours must be inactive and anti-tumour therapy must be completed prior to startinggrowth hormone therapy. Treatment should be discontinued if there is evidence of tumour growth.

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

Lonapegsomatropin must not be used for growth promotion in children with closed epiphyses.

In order to improve the traceability of biological medicinal products, the name and the batch numberof 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 with5.3 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 inacutely critically ill patients, the benefits of continued lonapegsomatropin treatment in this situationshould be weighed against the potential risks involved. In all patients developing other or similar acutecritical illness, the possible benefit of treatment with lonapegsomatropin must be weighed against thepotential risk involved.

Neoplasm

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

Patients with pre-existing tumours or GHD secondary to an intracranial lesion should be examinedroutinely for progression or recurrence of the underlying disease process.

In childhood cancer survivors, an increased risk of a second neoplasm has been reported in patientstreated with growth hormone after their first neoplasm. Intracranial tumours, in particularmeningiomas, were the most common form of a second neoplasm reported in patients treated withradiation to the head for their first neoplasm.

Anaphylactic reactions including angioedema have been reported with the use of lonapegsomatropin.

Inform patients and caregivers that such reactions can occur, particularly after first dose, and thatprompt medical attention should be sought if a sudden serious hypersensitivity reaction occurs. If ahypersensitivity reaction occurs, the use of lonapegsomatropin should be discontinued (seesection 4.3).

Benign intracranial hypertension

In case of severe or recurrent ataxia, headache, visual problems, nausea and/or vomiting, a funduscopyfor papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranialhypertension should be considered and, if appropriate, growth hormone treatment should bediscontinued. At present there is insufficient evidence to give specific advice on the continuation ofgrowth hormone treatment in patients with resolved intracranial hypertension. If growth hormonetreatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.

Funduscopic examination is recommended at the initiation and periodically during the course oftreatment.

Insulin sensitivity

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

Hypoadrenalism

Introduction of growth hormone treatment may result in inhibition of 11β-Hydroxysteroiddehydrogenase type 1 (11βHSD-1) and reduced serum cortisol concentrations. Consequently,previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoidreplacement may be required. In addition, patients treated with glucocorticoid replacement therapy forpreviously 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 reductionin serum T4 and an increase in serum T3 concentrations. Monitoring of thyroid function shouldtherefore be conducted in all patients. In patients with hypopituitarism on standard replacementtherapy, the potential effect of lonapegsomatropin treatment on thyroid function must be closelymonitored (see section 4.5 and 4.8).

Slipped capital femoral epiphysis and osteonecrosis

In patients with endocrine disorders, including GHD, slipped epiphyses of the hip may occur morefrequently than in the general population. Osteonecrosis has been reported in patients treated withother growth hormone products. Children with persistent hip/knee pain and/or limping duringtreatment with lonapegsomatropin should be examined clinically.

Scoliosis

Scoliosis may progress in any child during rapid growth. Because growth hormone treatment increasesgrowth 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 (seesection 4.8).

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

Prader-Willi syndrome

Lonapegsomatropin has not been studied in patients with Prader-Willi syndrome. Lonapegsomatropinis not indicated for the long-term treatment of paediatric patients who have growth failure due togenetically confirmed Prader-Willi syndrome unless they also have a diagnosis of GHD. There havebeen 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 ofupper 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 treatedwith somatropin. However, there is no evidence that the leukaemia incidence is increased in growthhormone recipients without predisposing factors.

Use with oral oestrogen containing therapy

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

Antibodies

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

Glucocorticoid treatment

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

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

Cytochrome P450-metabolised products

Drug-drug interaction studies have not been performed with lonapegsomatropin. Data from interactionstudies with somatropin performed in growth hormone deficient children and adults, and healthyelderly men, suggest that somatropin administration may increase the clearance of compounds knownto be metabolised by cytochrome P450 isoenzymes, especially CYP3A and CYP1A2. The clearance ofcompounds metabolised by CYP 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants andciclosporin) and CYP1A2 (e.g. theophylline) may be increased and could result in lower exposure ofthese 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-hyperglycaemicmedicinal products), the dose of insulin and/or oral hypoglycaemic medicinal product may requireadjustment when lonapegsomatropin therapy is initiated (see section 4.4).

Thyroid hormones

Because growth hormone increases the extrathyroidal conversion of T4 to T3, adjustment of thyroidhormone 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 berequired to achieve the treatment goal (see section 4.2 and 4.4).

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 notidentified any drug-associated risk of major birth defects, miscarriages, or adverse maternal or foetaloutcomes.

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

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

Skytrofa can be used during breastfeeding on strict indication.

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

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

The most frequently reported adverse reactions in clinical trials with lonapegsomatropin wereheadache (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.

Table 3 below shows adverse reactions which occurred during lonapegsomatropin treatment. Theadverse reactions are ranked under headings of MedDRA system organ class and frequency using thefollowing 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

System organ class Very common Common Uncommon

Immune system disorders Anaphylactic reactionb

Endocrine disorders Secondary Secondary adrenocorticalhypothyroidism insufficiency

Nervous system disorders Headache

Musculoskeletal and Arthralgia Scoliosisconnective tissue Arthritisdisorders Growing pains

Reproductive system and Gynaecomastiabreast disorders

General disorders and Injection site reactionsaadministration siteconditionsa Injection site reactions include hyperaemia, injection site atrophy, injection site pain, injection siteurticaria, and localised oedema. The injection site reactions observed with lonapegsomatropin weregenerally mild and transient.

b Anaphylactic reactions reported with lonapegsomatropin included angioedema (see section 4.4).

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

Adverse reactions related to growth hormone pharmacological class

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

* Neoplasms benign, malignant and unspecified (including cysts and polyps): leukaemia (seesection 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Acute overdose could lead initially to hypoglycaemia and subsequently to hyperglycaemia. Long-termoverdose could result in signs and symptoms of gigantism.

Treatment is symptomatic and supportive. There is no antidote for somatropin overdose.

It is recommended to monitor thyroid function following an overdose.

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatropin andsomatropin agonists, ATC Code: H01AC09.

Lonapegsomatropin is a long-acting ‘prodrug’ of somatropin. Lonapegsomatropin consists of theparent drug, somatropin, that is transiently conjugated to a methoxypolyethylene glycol carrier(4 x 10 kDa mPEG) via a proprietary TransCon Linker. The carrier has a shielding effect thatminimizes renal excretion and receptor-mediated clearance of lonapegsomatropin. After subcutaneousadministration, lonapegsomatropin releases fully active somatropin via autocleavage of the TransCon

Linker. Somatropin (191 amino acids) has the same mode of action and distribution as dailysomatropin, but with a once-weekly subcutaneous injection.

Somatropin binds to a dimeric hGH receptor in the cell membrane of target cells resulting inintracellular signal transduction and a host of pharmacodynamic effects. Somatropin has direct tissueand metabolic effects, and indirect effects mediated by IGF-1, including stimulation of chondrocytedifferentiation and proliferation, stimulation of hepatic glucose output, protein synthesis and lipolysis.

Somatropin stimulates skeletal growth in paediatric patients with GHD as a result of effects on thegrowth plates (epiphyses) of bones.

Somatropin released from lonapegsomatropin produces a dose linear IGF-1 response, with a change indose of 0.02 mg somatropin/kg resulting in an approximate change in average weekly IGF-1 standarddeviation score (SDS) of 0.17.

At steady-state, IGF-1 SDS levels peaked approximately 2 days post-dose, with the average weekly

IGF-1 SDS coinciding with approximately 4.5 days post-dose (Figure 1). IGF-1 SDS levels were inthe normal range for GHD patients for the majority of the week, similar to daily somatropin.

Figure 1 Mean (±SE) IGF-1 SDS at steady-state in children with GHD after administration ofonce-weekly lonapegsomatropin 0.24 mg somatropin/kg/week

The efficacy and safety of once-weekly lonapegsomatropin were evaluated in phase 3 clinical trialsthat included 306 paediatric patients with GHD.

heiGHt trial:

In a 52-week multi-centre randomised, open-label, active-controlled, parallel-group phase 3 clinicaltrial, 161 treatment-naïve, prepubertal paediatric patients with GHD were randomised to once-weeklylonapegsomatropin (N=105) or daily somatropin (N=56), both at a total weekly dose of0.24 mg somatropin/kg. The patients ranged in age from 3.2 to 13.1 years with a mean of 8.5 years.

Most (N=132 (82%)) subjects were male. The patients had a mean baseline height SDS of -2.93. Theprimary efficacy endpoint was annualised height velocity (AHV) at week 52. Treatment withonce-weekly lonapegsomatropin for 52 weeks resulted in a non-inferior AHV compared to dailysomatropin (Table 4). Also, changes in the height standard deviation score (SDS) (change frombaseline) tended to be larger for once-weekly lonapegsomatropin compared to daily somatropin(Table 4). Changes in AHV and height SDS tended to be larger for lonapegsomatropin compared tothose of somatropin from week 26 through the end of the trial at week 52.

The mean (SD) ratio of bone age to chronological age advanced similarly in both arms from baselineto week 52: 0.69 (0.16) to 0.75 (0.15) with once-weekly lonapegsomatropin and 0.70 (0.14) to0.76 (0.14) with daily somatropin.

Table 4 Growth and IGF-1 response at week 52 in paediatric treatment-naïve patients with

GHD (Intention-to-treat analysis)

Once-weekly Daily somatropin Estimate oflonapegsomatropin (N=56) treatment difference(N=105) (0.24 mg (lonapegsomatropin(0.24 mg somatropin/kg/week) minus somatropin)somatropin/kg/week)

AHV (cm/year)a, LS 11.2 10.3 0.9bmean (95% CI) (10.7-11.6) (9.7-10.9) (0.2-1.5)

Height SDS, change 1.10 0.96 0.14dfrom baselinec, LS mean (1.02-1.18) (0.85-1.06) (0.03-0.26)(95% CI)

IGF-1 SDS categorye, %< 0 23.1% 40.7% Not analysed0 to +2 69.2% 57.4%+2 to +3 7.7% 1.9%>+3 0 0a AHV: The estimates of LS mean and 95% CI are from an ANCOVA model that included baselineage, peak growth hormone levels (log transformed) at stimulation test, baseline height SDS -average SDS of parental height as covariates, and treatment and gender as factors. Missing data areimputed with multiple imputation method.

b p=0.0088 (2-sided) for superiorityc Height SDS, change from baseline: The estimates of LS mean and 95% CI are from an ANCOVAmodel that included baseline age, peak growth hormone levels (log transformed) at stimulation testand baseline height SDS as covariates, and treatment and gender as factors.

d p=0.0149 (2-sided)e Average level at week 52

In an open-label extension trial, patients from the heiGHt trial who continued treatment withlonapegsomatropin had an increase in height SDS of 1.61 from baseline to week 104. Patients whoswitched from daily somatropin to lonapegsomatropin at week 52 had an increase in height SDSof 1.49 from baseline to week 104.

Supportive evidence

Evidence from additional clinical trials with lonapegsomatropin supports the long-term clinicalefficacy of lonapegsomatropin treatment.

fliGHt trial:

In a 26-week single-arm open-label clinical trial evaluating lonapegsomatropin 0.24 mgsomatropin/kg/week in 146 paediatric GHD patients aged 1 to 17 years old, of whom 143 had receivedprior daily somatropin treatment for mean (SD) 1.1 (0.7) years, the mean (SD) annualised heightvelocity was 9 (2.7) cm/year and the mean (SD) change from trial baseline in height SDS was0.28 (0.25). Patient and caregiver preference were evaluated at week 13. 84% of patients and 90% ofcaregivers preferred once-weekly lonapegsomatropin over their prior daily somatropin.

Table 5 Average IGF-1 SDS levels at baseline and week 26 in paediatrictreatment-experienced patients with GHD (intention-to-treat analysis)

Baseline Week 26

Average IGF-1 SDS (N=143) (N=139)category n (%) n (%)< 0 37 (25.9) 13 (9.4)0 to +2 74 (51.7) 71 (51.1)+2 to +3 27 (18.9) 33 (23.7)> +3 5 (3.5) 22 (15.8)enliGHten trial:

In a long-term open-label extension trial, which enrolled patients from the heiGHt trial and fliGHttrial, patients (N=298) who continued treatment with lonapegsomatropin had a mean (SD) height SDSat extension trial baseline of -1.56 (0.88) and at week 208 (the last visit for which adequate data areavailable) -0.39 (0.90), corresponding to a mean (SD) change of +1.24 (0.65).

The pharmacokinetics following administration of lonapegsomatropin was assessed after single dosein a total of 73 healthy adults in 2 trials. In addition, PK in paediatrics with GHD was evaluated basedon intense sampling at week 13 in 11 subjects and sparse sampling in 109 subjects across 2 trials.

Demographic details are provided in Table 6 for the subjects included in the pharmacokineticevaluation of lonapegsomatropin.

Table 6 Demography of subjects in pharmacokinetic evaluation of lonapegsomatropin

Category Healthy adults Children with GHD

N 73 109

Male/Female 55/19 87/22

American Indian or Alaska Native 0 0

Asian 10 1

Black or African American 13 2

Native Hawaiian or Other Pacific Islander 0 0

White 49 104 (11 with intense PK sampling)

Other/Multiple 1 2

Hispanic or Latino 23 5

Not Hispanic or Latino 50 104

Following subcutaneous dose administration, lonapegsomatropin releases somatropin in a controlledmanner that follows first-order kinetics.

In paediatric GHD patients, following subcutaneous dose administration of lonapegsomatropin0.24 mg somatropin/kg/week, the observed mean (CV%) steady state peak serum concentration (Cmax)of lonapegsomatropin was 1230 (86.3) ng somatropin/mL at median Tmax of 25 hours, and for releasedsomatropin Cmax was 15.2 (83.4) ng/mL with a median time to reach Cmax of 12 hours. The mean(CV%) somatropin exposure over the one-week dose interval (area under the curve) was500 (83.8) h*ng/mL. Accumulation of lonapegsomatropin or somatropin following repeat doseadministration was not observed.

In paediatric GHD patients, injections were rotated between the abdomen, buttock, and thigh. Noapparent association of administration site with somatropin exposure was observed.

The absolute bioavailability of lonapegsomatropin following subcutaneous dose administration has notbeen investigated.

In paediatric GHD patients, the mean (CV%) steady state apparent volume of distribution oflonapegsomatropin after subcutaneous administration of 0.24 mg somatropin/kg/week was0.13 (109) L/kg. Somatropin released from lonapegsomatropin is expected to have a similar volume ofdistribution as endogenous growth hormone.

The metabolic fate of somatropin involves protein catabolism in both the liver and kidneys.

Excretion

In paediatric GHD patients, the mean (CV%) steady state apparent clearance of lonapegsomatropinafter subcutaneous administration of 0.24 mg somatropin/kg/week was 3.2 (67) mL/h/kg with a mean(±SD) observed half-life of 30.7 (± 12.7) hours. The apparent half-life of somatropin released fromlonapegsomatropin was approximately 25 hours.

No sex-specific pharmacokinetic studies have been done with lonapegsomatropin. The availableliterature indicates that the pharmacokinetics of somatropin is similar in males and females.

Based on a population pharmacokinetic analysis, age, sex, race/ethnicity, and body weight do not havea clinically meaningful effect on the pharmacokinetics.

No studies in patients with renal or hepatic impairments have been conducted with lonapegsomatropin(see section 4.2). A reduction in somatropin clearance following administration of daily somatropinhas been noted in patients with severe liver and kidney dysfunction. The clinical significance of thisdecrease is unknown. The pharmacokinetics of the mPEG carrier of lonapegsomatropin is expected tobe dependent on renal function but has not been assessed in patients with renal impairment.

Lonapegsomatropin has not been studied in patients below 6 months of age (see section 4.2).

Non-clinical data reveal no special hazard for humans based on safety pharmacology, repeated dosetoxicity, genotoxicity, and carcinogenicity.

Reproductive toxicology studies performed in rats and histopathological evaluation of reproductiveorgans in monkeys administered subcutaneous lonapegsomatropin at doses up to 20-fold the clinicaldose of 0.24 mg somatropin/kg/week did not induce adverse effects on male and female fertility or onreproductive organs. Due to antibody formation impairing exposure in rats, no firm conclusion can bemade with respect to the relevance for human fertility.

No embryonic or foetal development toxicities occurred in rats administered subcutaneouslonapegsomatropin at doses up to 13-fold the clinical dose of 0.24 mg somatropin/kg/week. Due tointermittent exposure no firm conclusion can be made with respect to the embryo-foetal developmentstudy in rats.

An embryo-foetal development toxicity study in rabbits has shown foetal abnormalities andembryo-foetal mortality at 1.5-fold and 6-fold, the clinical dose of 0.24 mg somatropin/kg/week,respectively, and possibly caused by maternal toxicity. The clinical relevance of these findings isuncertain.

In a pre- and postnatal developmental study in rats there were no adverse effects on thepregnant/lactating female or on development of the conceptus and the offspring following exposure ofthe female from implantation through weaning to subcutaneous doses of a structurally relatedtransiently pegylated somatropin prodrug up to 13-fold the clinical dose of 0.24 mgsomatropin/kg/week.

mPEG exposure

At about 10 times the human exposure to the mPEG component of lonapegsomatropin, vacuolationoccurs in choroid plexus (CP) epithelial cells of cynomolgus monkeys after one year of exposure. Atabout 34 times the human exposure to mPEG, a slight increase in the number of animals with vacuoleswas seen in CP epithelial cells of monkeys. The vacuolation was not associated with adversemorphological changes or clinical signs. Vacuolation of cells is considered an adaptive response.

Therefore, this is not considered as a possible adverse effect in humans at the therapeutic dose.

Succinic acid

Trehalose dihydrate

Trometamol

Water for injections

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

Unopened5 years when stored in a refrigerator (2°C - 8°C).

Alternatively, Skytrofa may be stored at temperatures ≤30°C for up to 6 months. Within the 6 months,the medicinal product can be returned to refrigeration (2°C - 8°C).

Record the date on the carton when the medicinal product was first removed from the refrigerator.

Discard the medicinal product when 6 months have passed.

Chemical and physical in-use stability has been demonstrated for reconstituted product storedfor 4 hours at temperatures ≤30°C.

From a microbiological point of view, the product should be used immediately after reconstitution. Ifnot used immediately, in-use storage times and conditions prior to use are the responsibility of the userand should not exceed 4 hours at temperatures ≤30°C.

Store in refrigerator (2°C - 8°C). Do not freeze.

Store in the original package in order to protect from light.

For alternative storage conditions at temperatures ≤30°C, see section 6.3.

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

Glass cartridge (Type I glass) with two chambers separated by a rubber stopper (bromobutyl). Thecartridge is closed by a rubber stopper (bromobutyl) in one end and by a rubber closure disc(bromobutyl) in the other end. The cartridge is mounted in a plastic needle adaptor.

Each pack contains 4 single-use dual-chamber cartridges packed in individual blisters and 6 disposableinjection needles 0.25 mm x 4 mm (31G x 5/32”). Each dual-chamber cartridge has a specific labelwith assigned two-colour coding ribbons that is only used by the Auto-Injector to select the correctreconstitution settings. Strength colours are indicated on the carton and blister foil and should be usedto differentiate the individual strengths.

Skytrofa 3 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 3 mg of somatropin as powder in the first chamberand 0.279 mL of solvent in the second chamber. The cartridge two-colour label (bottom/top) isyellow/green. The strength colour on the carton and blister is light apricot.

Skytrofa 3.6 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 3.6 mg of somatropin as powder in the first chamber and0.329 mL of solvent in the second chamber. The cartridge two-colour label (bottom/top) isyellow/cyan. The strength colour on the carton and blister is cyan.

Skytrofa 4.3 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 4.3 mg of somatropin as powder in the first chamber and0.388 mL of solvent in the second chamber. The cartridge two-colour label (bottom/top) isyellow/pink. The strength colour on the carton and blister is dark grey.

Skytrofa 5.2 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 5.2 mg of somatropin as powder in the first chamber and0.464 mL of solvent in the second chamber. The cartridge two-colour label (bottom/top) is green/pink.

The strength colour on the carton and blister is yellow.

Skytrofa 6.3 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 6.3 mg of somatropin as powder in the first chamber and0.285 mL of solvent in the second chamber. The cartridge two-colour label (bottom/top) iscyan/yellow. The strength colour on the carton and blister is orange.

Skytrofa 7.6 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 7.6 mg of somatropin as powder in the first chamber and0.338 mL of solvent in the second chamber. The cartridge two-colour label (bottom/top) is cyan/pink.

The strength colour on the carton and blister is dark purple.

Skytrofa 9.1 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 9.1 mg of somatropin as powder in the first chamber and 0.4 mLof solvent in the second chamber. The cartridge two-colour label (bottom/top) is pink/yellow. Thestrength colour on the carton and blister is golden brown.

Skytrofa 11 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 11 mg of somatropin as powder in the first chamberand 0.479 mL of solvent in the second chamber. The cartridge two-colour label (bottom/top) ispink/green. The strength colour on the carton and blister is dark blue.

Skytrofa 13.3 mg powder and solvent for solution for injection in cartridge

Each dual-chamber cartridge contains 13.3 mg of somatropin as powder in the first chamber and0.574 mL of solvent in the second chamber. The cartridge two-colour label (bottom/top) is pink/cyan.

The strength colour on the carton and blister is dark red.

Handling

If refrigerated, keep at room temperature for 15 minutes before use.

Each Skytrofa dual-chamber cartridge containing the powder and solvent for solution for injection isfor single-use only and must only be used with the supplied injection needles and the Skytrofa

Auto-Injector. The Skytrofa Auto-Injector is not included in this pack. The powder for solution forinjection must be reconstituted with the enclosed solvent by a Skytrofa Auto-Injector after attachingthe needle to the dual-chamber cartridge.

The reconstituted solution should be colourless and clear to opalescent and free or practically free ofvisible particles. The solution may occasionally contain air bubbles. If the solution contains particles,it must not be injected.

Following reconstitution, Skytrofa is administered subcutaneously (automatically dosed) by the

Skytrofa Auto-Injector.

Skytrofa is dosed as a full single-dose (total use).

Read the instructions for use for preparing Skytrofa provided at the end of the package leaflet and theinstructions for use provided with the Skytrofa Auto-Injector before use.

The patient should be advised to discard the cartridge and injection needle after each injection. Anyunused medicinal product or waste material should be disposed in accordance with local requirements.

Ascendis Pharma Endocrinology Division A/S

Tuborg Boulevard 12

DK-2900 Hellerup

Denmark

EU/1/21/1607/001

EU/1/21/1607/002

EU/1/21/1607/003

EU/1/21/1607/004

EU/1/21/1607/005

EU/1/21/1607/006

EU/1/21/1607/007

EU/1/21/1607/008

EU/1/21/1607/009

Date of first authorisation: 11 January 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.