Enjenla

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENJENLA (NGENLA)

Composition:

Active substance: somatrogon;

1 ml of solution contains somatrogon 20 mg or 50 mg;

1 pre-filled pen contains 24 mg of somatrogon in 1.2 ml of solution or 60 mg of somatrogon in 1.2 ml of solution;

Excipients: trisodium citrate dihydrate; citric acid monohydrate; L-histidine, sodium chloride, m-cresol, poloxamer 188, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear solution, colorless to slightly yellowish, with pH 6.6.

Pharmacotherapeutic group. Pituitary and hypothalamic hormones and their analogues, somatropin and somatropin agonists. ATC code H01AC08.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Somatrogon is a glycoprotein with an amino acid sequence of human chorionic gonadotropin (hCG) containing one copy of the C-terminal peptide (CTP) from the beta-chain of hCG at the N-terminus and two copies of CTP (in tandem) at the C-terminus. The glycosylation domains and CTP determine the half-life of somatrogon, allowing once-weekly administration of the drug.

Somatrogon binds to the growth hormone (GH) receptor and initiates a signaling cascade that leads to changes in growth and metabolism. According to the GH signaling cascade, binding of somatrogon results in activation of the STAT5b signaling pathway and increases serum insulin-like growth factor-1 (IGF-1) concentration. IGF-1 concentrations have been shown to increase in a dose-dependent manner during somatrogon therapy, which partially mediates the clinical effect. As a result, GH and IGF-1 stimulate metabolic changes, linear growth, and increase growth velocity in children with growth hormone deficiency (GHD).

Pharmacodynamic Effects

In clinical studies, somatrogon increased IGF-1 concentrations. Pharmacodynamic assessments performed approximately 96 hours after drug administration to determine the standard deviation score (SDS) of mean IGF-1 concentration over the dosing interval showed normalization of IGF-1 levels in patients after one month of therapy.

Water and mineral metabolism

Somatrogon induces phosphorus retention in the body.

Clinical Efficacy and Safety

The safety and efficacy of somatrogon for the treatment of children and adolescents aged 3 years and older with GHD were evaluated in two multicenter, randomized, open-label, controlled clinical studies. Both studies had a 12-month core period during which once-weekly somatrogon was compared to daily somatropin, followed by an open-label extension period during which all patients received once-weekly somatrogon. The primary efficacy endpoint for both studies was annual growth velocity after 12 months of therapy. Both studies also assessed other endpoints reflecting catch-up growth, such as change in height SDS from baseline and height SDS.

In a pivotal multicenter Phase 3 non-inferiority study, the safety and efficacy of somatrogon at a dose of 0.66 mg/kg/week were compared to somatropin at 0.034 mg/kg/day in 224 prepubertal children with GHD. The mean age in the treatment groups was 7.7 years (minimum age 3.01, maximum 11.96), 40.2% of patients were aged 3 to 7 years inclusive, and 59.8% were aged 7 years and older; 71.9% of patients were male and 28.1% were female. In this study, 74.6% of patients were of Caucasian origin, 20.1% were of Mongoloid origin, and 0.9% were African American. Baseline disease characteristics were balanced between the two treatment groups. Approximately 68% of patients had a peak plasma GH level of at most 7 ng/mL, and their mean height was below –2 SDS.

Once-weekly administration of somatrogon was not inferior in its effect on growth velocity at 12 months compared to once-daily somatropin (see Table 1). Once-weekly administration of somatrogon also resulted in an increase in IGF-1 concentration SDS from a mean value of –1.95 at baseline to a mean value of 0.65 at 12 months.

In an open-label extension of the pivotal phase 3 study, a total of 91 patients received somatrogon at a dose of 0.66 mg/kg/week for at least 2 years, with growth data collected. After 2 years, a rapid increase in height SDS from baseline was observed (the overall change in mean height SDS (SD) was 1.38 (0.78), with a median of 1.19 (range: 0.2 to 4.9)).

In a multicenter phase 2 study evaluating safety and dose-finding, 31 patients received somatrogon at doses up to 0.66 mg/kg/week for up to 7.7 years. At the final assessment, height SDS (mean (SD)) was -0.39 (0.95), and the cumulative change in growth velocity SDS (mean (SD)) from baseline was 3.37 (1.27).

Treatment burden

In a randomized, open-label, crossover phase 3 study involving 87 children with GHD, the burden of therapy with weekly somatrogon (0.66 mg/kg/week) was compared to daily somatropin. In the weekly somatrogon group, significant therapy burden reduction (decreased difficulty) for the patient, therapy burden reduction (decreased difficulty) for the caregiver, greater convenience for the patient, greater intention to adhere to treatment, and greater overall benefits for the patient were observed.

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Enjaymo in all pediatric subgroups of patients for long-term treatment of children with growth disturbance due to growth hormone deficiency (see section "Posology and method of administration").

Pharmacokinetics

The pharmacokinetics (PK) of somatrogon were evaluated using a population approach in 42 children (age range 3 to 15.5 years) with GHD.

Absorption

After subcutaneous injection, serum concentrations of somatrogon increased slowly, reaching peak levels between 6 and 18 hours post-dose.

In children with GHD, exposure to somatrogon increases proportionally with dose when administered at doses of 0.25 mg/kg/week, 0.48 mg/kg/week, and 0.66 mg/kg/week. Following once-weekly administration, somatrogon does not accumulate in the body. In children with GHD, the peak steady-state concentration, determined using population PK modeling, was 636 ng/mL following a dose of 0.66 mg/kg/week. Patients with positive anti-ALZ test results had approximately 45% higher steady-state mean concentrations.

Distribution

In children with GHD, the apparent central volume of distribution, estimated in the population PK study, was 0.728 L/kg, and the apparent peripheral volume of distribution was 0.165 L/kg.

Biotransformation

Metabolism of somatrogon is considered to occur via classical protein catabolism, followed by recycling of amino acids and return to the systemic circulation.

Elimination

In pediatric patients with GHD, the apparent clearance, estimated in the population PK study, was 0.0317 L/h/kg. Patients with positive anti-ALZ test results had approximately 25.8% lower apparent clearance.

With an estimated effective half-life of 28.2 hours from the population PK study, somatrogon is expected to remain in circulation for approximately 6 days after the last dose.

Special patient groups

Age, race, gender, body weight

According to population PK analysis, age, gender, race, and ethnicity do not have a clinically significant impact on the pharmacokinetics of somatrogon in pediatric patients with GHD. Exposure to somatrogon decreases with increasing body weight. However, the somatrogon dose of 0.66 mg/kg/week provides adequate systemic exposure for safe and effective outcomes across the body weight range evaluated in clinical studies.

Preclinical safety data

Preclinical data obtained from standard safety pharmacology and repeated-dose toxicity studies indicate no special hazard for humans.

Reproductive and developmental toxicity studies were conducted in rats subcutaneously administered somatrogon at doses up to 30 mg/kg (equivalent to exposure levels approximately 14 times higher than those in humans at the maximum recommended dose, based on AUC).

Somatrogon increased the duration of the estrous cycle, copulatory interval, and number of corpora lutea in female rats, but did not affect mating performance, fertility, or early embryonic development.

No adverse effects of somatrogon on embryofetal development were observed.

In a prenatal and postnatal development study, somatrogon increased mean body weight in first-generation (F1) offspring (both sexes) and increased the mean copulatory interval in F1 females following administration of the highest dose (30 mg/kg). These changes were consistent with prolonged estrous cycle duration; however, no treatment-related adverse effects on mating performance were observed.

Clinical characteristics

Indications

Enjenla is indicated for the treatment of children and adolescents aged 3 years and older with growth failure due to inadequate secretion of growth hormone.

Contraindications

Hypersensitivity to somatrogon (see section "Special precautions") or to any of the excipients of the medicinal product.

Somatrogon must not be used in the presence of signs of active malignancy based on experience with daily administration of growth hormone (GH) preparations. Intracranial tumors must be inactive and antineoplastic therapy must be completed prior to initiating growth hormone (GH) therapy. Treatment should be discontinued if there are signs of tumor growth (see section "Special precautions").

Somatrogon must not be used to stimulate growth in children with closed epiphyses.

Somatrogon must not be administered to patients with acute critical illness due to complications following open-heart surgery, abdominal surgery, multiple accidental traumas, acute respiratory failure, or similar conditions (for patients undergoing replacement therapy, see section "Special precautions").

Interaction with other medicinal products and other forms of interaction

Interaction studies involving children have not been conducted.

Glucocorticoids

Concomitant treatment with glucocorticoids may suppress the growth-promoting effect of somatrogon. In patients with adrenocorticotropic hormone (ACTH) deficiency, replacement therapy with glucocorticoids should be carefully adjusted to avoid growth suppression. Therefore, growth in patients receiving glucocorticoids should be closely monitored to assess the potential impact of glucocorticoid therapy on growth.

Growth hormone reduces the conversion of cortisone to cortisol and may unmask previously undiagnosed central hypoadrenalism or lead to inefficacy of low replacement doses of glucocorticoids (see section "Special precautions").

Insulin and hypoglycemic medicinal products

Patients with diabetes mellitus requiring pharmacological therapy may require adjustment of insulin and/or oral or injectable hypoglycemic agents at the initiation of somatrogon therapy (see section "Special precautions").

Thyroid hormone preparations

Treatment with daily growth hormone administration may unmask previously undiagnosed or subclinical central hypothyroidism. There may be a need for initiation or adjustment of replacement therapy with thyroxine (see section "Special precautions").

Oral estrogen therapy

Female patients receiving oral estrogen therapy may require higher doses of somatrogon to achieve treatment goals (see section "Special precautions").

Drugs metabolized by cytochrome P450

Drug interaction studies with somatrogon have not been conducted. Somatrogon has been shown to induce CYP3A4 mRNA expression in vitro. The clinical significance of this observation is unknown. Studies with other human growth hormone receptor agonists in children and adults with growth hormone deficiency, as well as in healthy elderly men, indicate that administration of these agents may increase the clearance of compounds known to be metabolized by cytochrome P450 isoenzymes, particularly CYP3A. The clearance of compounds metabolized by CYP3A4 (e.g., sex steroids, corticosteroids, anticonvulsants, and cyclosporine) may be increased, potentially leading to reduced exposure to these medicinal products.

Special precautions for use

Traceability

In order to improve traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded in the patient documentation.

Hypersensitivity

Serious systemic hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported with daily administration of growth hormone products. If a serious hypersensitivity reaction occurs, somatropin should be discontinued immediately; appropriate treatment should be initiated in accordance with standard medical practice, and the patient should be monitored until signs and symptoms resolve (see section "Contraindications").

Hypoadrenalism

Published data indicate that patients receiving daily growth hormone therapy who have pituitary hormone deficiency or are at risk for developing such deficiency may be at risk for decreased serum cortisol levels and/or manifestation of central (secondary) hypoadrenalism. Additionally, patients receiving glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in maintenance or stress doses after initiation of somatropin treatment (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be monitored for decreased serum cortisol levels and/or the need for increased glucocorticoid dosing in patients with diagnosed hypoadrenalism (see section "Interaction with other medicinal products and other forms of interaction").

Thyroid function disorders

Growth hormone enhances extrathyroidal conversion of T4 to T3 and may unmask pre-existing hypothyroidism. Patients with known hypothyroidism should receive appropriate treatment prior to initiation of somatropin therapy, based on clinical evaluation. Since hypothyroidism affects the body's response to growth hormone therapy, patients should have regular monitoring of thyroid function and receive thyroid hormone replacement therapy if indicated (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Prader–Willi syndrome

The use of somatropin in patients with Prader–Willi syndrome has not been studied. Somatropin is not indicated for long-term treatment of pediatric patients with short stature due to genetically confirmed Prader–Willi syndrome, except when they also have growth hormone deficiency. There have been reports of sudden death after initiation of growth hormone therapy in children with Prader–Willi syndrome who had one or more risk factors: severe obesity, upper airway obstruction, sleep apnea, or undiagnosed respiratory infection.

Glucose metabolism disorders

Treatment with growth hormone products may reduce insulin sensitivity and lead to hyperglycemia. Additional monitoring should be considered for patients receiving somatropin who have impaired glucose tolerance or additional risk factors for developing diabetes mellitus. For patients with diabetes mellitus receiving somatropin therapy, dose adjustments of hypoglycemic agents may be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Neoplasia

Particular attention should be paid to signs and symptoms of recurrence when treating patients with a history of malignancy. Patients with existing tumors or secondary growth hormone deficiency due to intracranial lesions should undergo regular monitoring for progression or recurrence of the underlying disease. An increased risk of second neoplasia has been reported in patients treated with somatropin after childhood cancer. Intracranial tumors, particularly meningiomas, in patients who received cranial irradiation for the first neoplasm, were the most common of these second neoplasms.

Benign intracranial hypertension

Intracranial hypertension (IH) with papilledema, ataxia, visual disturbances, headache, nausea, and/or vomiting has been reported in a small number of patients receiving growth hormone therapy. Fundoscopy is recommended at the start of treatment and as clinically indicated. Somatropin should be temporarily discontinued in patients with clinical or fundoscopic signs of IH. There is currently insufficient evidence to provide specific recommendations on continuing growth hormone therapy after resolution of IH symptoms. If somatropin therapy is resumed, monitoring for signs and symptoms of IH is required.

Acute critical illness

In critically ill adult patients with complications following open-heart surgery, abdominal surgery, multiple accidental traumas, or acute respiratory failure, mortality was higher in those receiving somatropin at doses of 5.3 or 8 mg per day (i.e., 37.1–56 mg/week) compared to placebo: 42% versus 19%. Given this information, such patients should not be treated with somatropin. As there is no available safety data on growth hormone replacement therapy in patients with acute critical illness, the benefits of continuing somatropin therapy in such situations should be weighed against potential risks. For all patients who develop another or similar acute critical illness, the potential benefit of somatropin treatment should be carefully evaluated against the potential risk.

Pancreatitis

Although pancreatitis is rare in patients receiving growth hormone products, this diagnosis should be considered if severe abdominal pain occurs during somatropin therapy.

Scoliosis

Since somatropin increases the rate of growth, signs of development or progression of scoliosis should be monitored during treatment.

Epiphyseal disorders

Disorders at the epiphyses, including slipped capital femoral epiphysis, may occur more frequently in patients with endocrine disorders or rapid growth. Any child who develops limping or complains of hip or knee pain during treatment should be carefully evaluated.

Oral estrogen therapy

Oral estrogens affect the IGF-1 response to growth hormone. If a patient receiving somatropin starts or stops oral estrogen therapy, IGF-1 levels should be monitored to determine whether growth hormone dose adjustment is needed to maintain serum IGF-1 concentrations within the normal range (see section "Method of administration and dosage"). Patients receiving oral estrogen therapy may require higher doses of somatropin to achieve treatment goals (see section "Interaction with other medicinal products and other forms of interaction").

Excipients

Sodium content

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

Myositis is a very rare adverse reaction that may be related to the preservative metacresol. Myositis should be considered in the differential diagnosis if myalgia or excessive pain at the injection site occurs. If confirmed, growth hormone products not containing metacresol should be used.

Use during pregnancy or breastfeeding

Pregnancy

There are no data on the use of somatropin in pregnant women. Animal studies have shown no direct or indirect harmful effects on reproductive function (see section "Preclinical safety data").

Enjenla is not recommended for use in pregnant women or in women of reproductive potential who are not using contraception.

Breastfeeding

It is unknown whether somatropin or its metabolites are excreted in human breast milk. A risk to newborns and infants cannot be excluded. The decision on whether to discontinue breastfeeding or to discontinue/abstain from somatropin therapy should be made taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Reproductive function

The risk of infertility in women or men with reproductive potential has not been studied. In rat studies, no impairment of reproductive function was observed in males or females (see section "Preclinical safety data").

Ability to affect reaction speed when driving or operating machinery

Enjenla has no or negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Treatment should be initiated and monitored by physicians qualified and experienced in the diagnosis and treatment of children with growth hormone deficiency (GHD).

Dosage

The recommended dose is 0.66 mg/kg body weight administered once weekly by subcutaneous injection.

Each prefilled pen allows setting and administration of the dose prescribed by the physician. The dose may be rounded up or down at the discretion of the physician familiar with the individual needs of the patient. If doses exceeding 30 mg are required (i.e., patient body weight exceeds 45 kg), two injections should be administered.

Initial dose for patients switching from daily growth hormone therapy

For patients transitioning from daily growth hormone therapy to somatrogon administered once weekly, treatment may be initiated at a dose of 0.66 mg/kg/week the day after the last daily injection.

Dose titration

If necessary, the somatrogon dose may be adjusted based on growth velocity, adverse reactions, patient body weight, and serum insulin-like growth factor 1 (IGF-1) concentration.

When monitoring IGF-1 levels, blood samples should always be collected 4 days after the previous dose. Dose adjustments should aim to achieve a mean standard deviation score (SDS) of serum IGF-1 within the normal range, i.e., between –2 and +2 (preferably close to 0 SDS).

For patients whose serum IGF-1 concentration exceeds the age- and sex-matched reference mean by more than 2 SDS, the somatrogon dose should be reduced by 15%. Some patients may require multiple dose reductions.

Evaluation and discontinuation of treatment

The efficacy and safety of somatrogon treatment should be evaluated approximately every 6–12 months. This evaluation may include auxological parameters, biochemical markers (IGF-1, hormone, and glucose concentrations), and pubertal status. Regular monitoring of serum IGF-1 SDS values is recommended throughout the treatment course. During puberty, evaluations should be performed more frequently.

Treatment should be discontinued if signs of epiphyseal plate closure are present (see section "Contraindications"). Therapy should also be discontinued in patients who have reached or nearly reached final height, i.e., annual growth velocity less than 2 cm/year or bone age exceeding 14 years in girls and 16 years in boys.

Missed dose

Patients should adhere to their regular dosing day. If a dose is missed, somatrogon should be administered as soon as possible within 3 days of the missed dose, after which the regular once-weekly dosing schedule should be resumed. If more than 3 days have passed, the missed dose should be skipped and the next dose administered on the scheduled day. In either case, patients may resume their regular once-weekly dosing schedule.

Changing the day of administration

The day of weekly administration may be changed if necessary, but the interval between two doses must be at least 3 days. After selecting a new administration day, continue weekly administration on that day.

Special patient populations

Elderly patients

The safety and efficacy of somatrogon in patients over 65 years of age have not been established. Data are lacking.

Renal impairment

The use of somatrogon in patients with renal impairment has not been studied. No dosage recommendations can be provided.

Hepatic impairment

The use of somatrogon in patients with hepatic impairment has not been studied. No dosage recommendations can be provided.

Pediatric population

The safety and efficacy of somatrogon in neonates, infants, and children under 3 years of age have not been established. Data are lacking.

Method of administration

Somatrogon is administered as a subcutaneous injection.

Somatrogon should be injected under the skin of the abdomen, thigh, buttocks, or shoulder. The injection site should be rotated systematically within the area for each administration. Injections into the shoulder or buttocks should be performed by a caregiver.

Both the patient and the caregiver should be trained in the injection procedure to enable self-administration.

If multiple injections are required to administer the full dose, they should be given at different body sites.

Somatrogon should be administered once weekly, on the same day each week, at any time of day.

Enjelna, solution for injection in a prefilled pen, 24 mg.

The prefilled pen allows administration of doses from 0.2 to 12 mg of somatrogon in 0.2 mg increments (0.01 mL).

Enjelna, solution for injection in a prefilled pen, 60 mg.

The prefilled pen allows administration of doses from 0.5 to 30 mg of somatrogon in 0.5 mg increments (0.01 mL).

Special precautions for handling and disposal of waste

The solution should be clear, colorless to slightly yellow, and free of particles. Do not inject the medicinal product if it is cloudy, dark yellow, or contains foreign particles. Do not shake, as shaking may damage the product.

Each prefilled pen of Enjelna is intended for use by a single patient only. Under no circumstances should the prefilled pen of Enjelna be used by another person, even if the needle is changed.

The prefilled pen should be used only within 28 days after first use. Do not use after the expiry date.

This medicinal product must not be frozen or exposed to heat (temperatures above 32°C). If the product has been frozen or exposed to heat, it should be disposed of.

Preparation of the dose

The pen can be used immediately after removal from the refrigerator. For more comfortable injection, the prefilled pen containing sterile somatrogon solution may be warmed to room temperature (not exceeding 32°C) for up to 30 minutes. The solution in the pen should be inspected for flakes, particles, or discoloration. The pen must not be shaken. If flakes, particles, or discoloration are observed, the pen must not be used.

Administration

The selected injection site should be prepared according to the instructions for use. It is recommended to rotate the injection site systematically within the area for each administration. Always replace the cap on the prefilled pen after each injection. After each use, return Enjelna to the refrigerator. Always attach a new needle before each use. Needles must not be reused. The injection needle should be removed after each injection, and the pen should be stored without the needle attached. This helps prevent needle clogging, contamination, infection, leakage of solution, and inaccurate dosing.

In case of needle blockage (i.e., liquid does not appear at the needle tip), patients should follow the instructions described in the section "Patient information."

Sterile needles, not included in the packaging, are required for administration. Enjelna can be administered using needles ranging from 4 to 8 mm in length and 30 to 32G in gauge.

Instructions for preparation and administration of the product are provided in the "Method of administration" section.

Disposal

Any unused medicinal product and waste material should be disposed of in accordance with local requirements. The prefilled pen should be disposed of if it is empty, has been exposed to temperatures above 32°C, has been out of the refrigerator for more than 4 hours during each use, has been used 5 times, or more than 28 days have passed since first use, even if unused product remains. After proper administration of all doses, a small amount of sterile somatrogon solution may remain in the pen. Patients should be instructed not to use the remaining solution and to dispose of the pen appropriately.

Patient information

Instructions for use of the 24 mg or 60 mg injection pen

• Enjelna for injection is a multi-dose prefilled pen containing 24 mg or 60 mg of the drug.
• Enjelna may be administered by the patient, caregiver, physician, or nurse. Do not self-administer Enjelna until you have been shown the correct injection technique. You must also read and understand the instructions for use. If your doctor or nurse determines that you or your caregiver can administer Enjelna at home, you must receive training on the proper preparation and administration of this medicinal product. It is important that you read, understand, and follow these instructions to correctly administer Enjelna. It is important to speak with your doctor or nurse to ensure you understand all instructions regarding Enjelna dosing.
• To help remember when to administer Enjelna, you may mark your calendar in advance. Contact your doctor or nurse if you or your caregiver have any questions about the correct way to administer Enjelna.
• Each turn (click) of the dose selector on the prefilled pen containing 24 mg of drug increases the dose by 0.2 mg. Doses from 0.2 to 12 mg can be administered in a single injection. If your dose exceeds 12 mg, you will need to administer multiple injections.

Each turn (click) of the dose selector on the prefilled pen containing 60 mg of drug increases the dose by 0.5 mg. Doses from 0.5 to 30 mg can be administered in a single injection. If your dose exceeds 30 mg, you will need to administer multiple injections.

• After proper administration of all doses, a small amount of drug may remain in the pen. This is normal. Patients must not attempt to use the remaining solution and should dispose of the pen properly.
• Do not share your pen with other people, even if the needle is changed. You may transmit serious infections to others or acquire serious infections from them.
• Always use a new needle for each injection. This reduces the risk of infection, contamination, leakage of drug, and needle blockage, which may lead to incorrect dosing.
• Do not shake the pen. Shaking may damage the medicinal product.
• The pen is not recommended for use by blind patients or patients with visual impairments unless assisted by someone trained in the correct administration of this medicinal product.

Below is a detailed description of the administration steps for the 24 mg pen. When using the 60 mg pen, the same steps should be followed.

Preparing for Injection

Step 1. Prepare

• Wash and dry your hands.
• You may use the pen immediately after removing it from the refrigerator. For a more comfortable injection, allow the pen to reach room temperature for 30 minutes (see "Storage conditions").
• Check the name, concentration, and label of the medicine on your pen to ensure it is the medicine prescribed by your doctor.
• Check the expiry date on the pen label. Do not use the medicine if the expiry date has passed.
• Do not use your pen if:
  • its contents have been frozen or exposed to heat (temperatures above 32°C), or more than 28 days have passed since first use of the pen (see "Storage conditions");
  • the pen has been dropped;
  • the pen appears cracked or damaged.
• Do not remove the cap from the pen until you are ready to inject.

Step 2. Choose and clean the injection site

• Enjenla should be injected subcutaneously into the abdomen, thighs, buttocks, or shoulders.
• Select the best injection site according to your doctor's or nurse's recommendations.
• If more than one injection is needed to administer the full dose, administer them into different sites.
• Avoid areas near bones or areas with bruises, redness, ulcers, or lumps, as well as those with scars or signs of skin disease.
• Clean the injection site with an alcohol swab.
• Allow the area to dry.
• Do not touch the injection site after cleaning.

Step 3. Check the medication

• Remove the pen cap and keep it for reattaching after the injection.
• Inspect the medication inside the cartridge holder.
• Ensure the solution is clear and colorless to pale yellow. Do not inject the medication if it is cloudy or dark yellow.
• Make sure there are no flakes or particles in the solution. Do not inject the medication if it contains flakes or particles.

Note. The presence of one or more air bubbles in the medication is normal.

Step 4. Attach the needle

• Take a new needle and remove the protective paper.
• Hold the needle aligned with the pen, keeping both the needle and pen straight.
• Gently press and then screw the needle onto the pen.

Do not overtighten.

Note. Handle carefully to avoid attaching the needle at an angle, which may cause leakage of the medication.

Caution! Needles are sharp at both ends. Handle with care to avoid accidental needlestick injury (to yourself or others).

Step 5. Remove the outer needle cap

• Remove the outer needle cap.
• Be sure to keep the outer needle cap. You will need it later to remove the needle.

Note. After removing the outer cap, you should see the inner needle cap. If not, try reattaching the needle.

Note. If you are using a needle with a safety shield, refer to the needle instructions for proper use.

Step 6. Remove the inner needle cap

• Carefully remove the inner needle cap to expose the needle.
• Dispose of the inner needle cap in a sharps container. It will not be needed anymore.

Note. If you are using a needle with a safety shield, refer to the needle instructions for proper use.

Setting up a new pen (initial preparation) — for first use of a new pen only

You must set up (initially prepare) each new pen before first use.

• This setup is performed before the first use of each new pen.
• The purpose of setting up a new pen is to remove air bubbles and ensure that you receive the required dose.

Important! Skip steps A to B if you have already set up the pen.

Step A. Set the dose selector

• Turn the dose selector to 0.4 for the 24 mg pen or to 1.0 for the 60 mg pen.

Note. If you have turned the dose selector too far, you can turn it back.

Step B. Tap the cartridge holder

• Hold the pen with the needle pointing upwards so that air bubbles can rise.
• Gently tap the cartridge holder to allow air bubbles to move upwards.

Important! Perform Step B even if you do not see air bubbles.

Step C. Press the button and check for fluid flow

• Press the injection button until it stops and the dose window shows «0».
  • Check for fluid at the needle tip. If fluid appears, your pen is primed.
  • Always ensure a drop of fluid appears before each injection. If no fluid appears, repeat steps A to B.
    • If no fluid appears after repeating steps A to B five times, attach a new needle and try once more.

Do not use the pen if no fluid drop appears. Contact your doctor or nurse and use a new pen.

Setting the prescribed dose

Step 7. Select the dose

• Turn the dose selector to set the dose.
  • You can increase or decrease the dose by turning the dose selector in either direction.
  • The dose selector turns in increments of 0.2 mg at a time for the pen containing 24 mg, or 0.5 mg at a time for the pen containing 60 mg.
  • For the pen containing 24 mg of medication, you can set a dose of up to 12 mg for a single injection; for the pen containing 60 mg of medication, you can set a dose of up to 30 mg for a single injection.
  • The dose window displays the dose in milligrams (mg).
• Always check the dose window to make sure you have set the correct dose.

Important! Do not press the injection button while adjusting the dose.

What should I do if I cannot set the required dose?

• If your dose exceeds 12 mg or 30 mg, you will need to administer multiple injections.
• With a single injection, you can deliver from 0.2 to 12 mg using the pen containing 24 mg, or from 0.5 to 30 mg using the pen containing 60 mg.
  • If you need help dividing your dose correctly, consult your doctor or nurse.
  • Use a new needle for each injection (see "Step 4. Attach the needle").
  • If you usually require 2 injections to receive your full dose, make sure to administer the second dose.

What should I do if there is not enough medication left in the pen?

• If your pen contains less than 12 mg or 30 mg of medication, the dose selector will stop, and the remaining amount of medication will be displayed in the dose window.
• If there is not enough medication in your pen to administer the full dose, you may:
  • inject the amount remaining in your pen, then prepare a new pen to receive the full dose.

Remember to subtract the dose you have already administered.

For example, if your dose is 3.8 mg and you can only set the dose selector to 1.8 mg, you should inject an additional 2.0 mg using a new pen. Or, if your dose is 21.5 mg and you can only set the dose selector to 17 mg, you should inject an additional 4.5 mg using a new pen.

• take a new pen and administer the full dose.

Administering the Dose

Step 8. Insert the needle

• Hold the pen so you can see the numbers in the dose window.
• Insert the needle directly into the skin.

Step 9. Administer the medication

• Keep the needle in the same position in the skin.
• Press the injection button until it stops and "0" appears in the dose window.

Step 10. Count to 10

• Continue pressing the injection button, counting to 10. This will ensure you receive the full dose of the medicine.
• After counting to 10, release the injection button and slowly withdraw the pen from the injection site by pulling the needle straight out.

Note. You may see a drop of medicine at the tip of the needle. This is normal and does not affect the dose you have just received.

Step 11. Replace the outer needle cap

• Carefully place the outer needle cap back onto the needle.
• Press the outer needle cap firmly until it clicks into place.

Caution! Never attempt to reattach the inner needle cap to the needle. You may accidentally prick yourself with the needle.

Note. If you are using a needle with a safety shield, refer to the needle instructions for proper use.

Step 12. Remove the needle

• Unscrew the needle with the cap from the pen.
• Gently pull until the needle with the cap comes off.

Note. If the needle does not detach, replace the outer needle cap and try again. Apply pressure while unscrewing the needle.

Dispose of used pen needles in a sharps container according to your doctor’s, nurse’s, or pharmacist’s instructions and in accordance with local health and safety regulations. Keep the sharps container out of the reach of children. Do not reuse needles.

Step 13. Replace the pen cap

• Replace the cap back onto the pen.
• Do not place the cap onto the pen while a needle is still attached.
• If there is medicine remaining in your pen, store it in the refrigerator between uses (see section “Storage conditions”).

Step 14. After the injection

• Gently press a clean cotton ball or gauze pad against the injection site and hold for a few seconds.
• Do not rub the injection site. You may have slight bleeding at the site. This is normal.
• If needed, you may apply a small bandage to the injection site.
• If your pen is empty or more than 28 days have passed since the first use, dispose of it even if there is unused medicine remaining. Dispose of it in a sharps container.
• To help remember when to dispose of the pen, you may write the date of first use on the pen label below:

Date of first use / /

Children

The medicine can be used in pediatric practice.

Overdose

Single doses of somatrogen exceeding 0.66 mg/kg/week have not been studied. Based on experience with daily administration of growth hormone-containing medicines, short-term overdose may initially cause hypoglycemia, followed by hyperglycemia. Prolonged overdose may lead to signs and symptoms of gigantism and/or acromegaly, consistent with the effects of excess growth hormone.

Treatment of somatrogen overdose should consist of general supportive measures.

Adverse Reactions

Summary of safety profile

The most common adverse reactions following somatrogon treatment are injection site reactions (ISRs) (25.1%), headache (10.7%), and pyrexia (10.2%).

List of adverse reactions

Safety data were obtained from a multicenter phase 2 dose-finding and safety study, as well as from a pivotal multicenter phase 3 non-inferiority study in pediatric patients with growth hormone deficiency (see section "Pharmacodynamics"). The data reflect the use of somatrogon once weekly (0.66 mg/kg/week) in the treatment of 265 patients.

Below is a list of adverse reactions to somatrogon by system organ classes, categorized according to standard frequency categories: 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 group, adverse reactions are listed in order of decreasing severity.

Blood and lymphatic system disorders. Common: anaemia, eosinophilia.

Endocrine disorders. Common: hypothyroidism; uncommon: adrenal insufficiency.

Nervous system disorders. Very common: headache.

Eye disorders. Common: allergic conjunctivitis.

Skin and subcutaneous tissue disorders. Uncommon: generalized rash.

Musculoskeletal and connective tissue disorders. Common: arthralgia; limb pain.

General disorders and administration site conditions. Very common: injection site reactions; pyrexia.

Description of individual adverse reactions

Injection site reactions

In a phase 3 clinical trial, injection site reactions (ISRs) were actively solicited throughout the study. Most ISRs were transient, occurring primarily within the first 6 months of therapy and were mild in severity; ISRs typically occurred on the day of injection and had a median duration of less than 1 day. Among these, pain, erythema, pruritus, swelling, induration, bruising, hypertrophy, inflammation, and increased skin temperature at the injection site were observed in 43.1% of patients receiving somatrogon, compared with 25.2% of patients receiving daily somatropin injections.

In the long-term open-label extension of the phase 3 clinical study, local ISRs were similar in nature and severity. Reports occurred at the beginning of therapy in patients switching from somatropin to somatrogon. ISRs were recorded in 18.3% of patients who initially received somatrogon in the main study and continued treatment during the extension, and similarly, 37% were recorded in patients who initially received somatropin and were switched to somatrogon during the extension study.

Immunogenicity

In the pivotal safety and efficacy study of 109 patients receiving somatrogon, 84 (77.1%) tested positive for anti-drug antibodies (ADAs). No clinical effects or impact on safety were observed following antibody formation.

Other adverse reactions associated with somatropin can be considered effects typical of this class of drugs, including:

• benign and malignant neoplasms (see section "Special precautions");
• metabolic and nutritional disorders: type 2 diabetes mellitus (see section "Special precautions");
• nervous system disorders: benign intracranial hypertension (see section "Special precautions"), paresthesia;
• musculoskeletal and connective tissue disorders: myalgia;
• reproductive system and breast disorders: gynecomastia;
• skin and subcutaneous tissue disorders: skin rash, urticaria, and pruritus;
• general disorders and administration site conditions: peripheral edema, facial swelling;
• gastrointestinal disorders: pancreatitis (see section "Special precautions").

Metacresol

This medicinal product contains metacresol, which may cause pain during injections (see section "Special precautions").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Keep out of the reach of children.

Prior to first use, store in a refrigerator (from 2 to 8 °C). An unopened pen may be temporarily stored for up to 4 hours at temperatures up to 32 °C.

After first use, the storage period is 28 days. Store in a refrigerator (from 2 to 8 °C). Do not freeze. Store the medicinal product in the pen with the cap attached to protect from light.

The Enjenla medicinal product may be kept at room temperature (up to 32 °C) for up to 4 hours during each injection, up to a maximum of 5 times. After each use, return the pen containing Enjenla to the refrigerator. Avoid exposure to temperatures above 32 °C and do not leave the medicinal product at room temperature for more than 4 hours during each use.

The pen containing Enjenla should be discarded if it has been used 5 times, if it has been exposed to temperatures above 32 °C, or if it has been out of the refrigerator for more than 4 hours during any single use.

Incompatibilities.

Since compatibility studies have not been conducted, this medicinal product must not be mixed with other medicinal products.

Packaging.

1 pre-filled pen containing a cartridge in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Pfizer Manufacturing Belgium NV.

Manufacturer's location and address of place of business.

Reitseweg 12, Puurs-Sint-Amands, 2870, Belgium.