DIPHERELINE 22.5 mg Powder

Contents of the leaflet

1. CHARACTERISTICS OF THE MEDICINAL PRODUCT
2. NAME OF THE MEDICINAL PRODUCT
3. QUALITATIVE AND QUANTITATIVE COMPOSITION
4. PHARMACEUTICAL FORM
5. CLINICAL PARTICULARS
6. 1 Therapeutic Indications
7. 2 Posology and Method of Administration
   1. Central Precocious Puberty
8. 3 Contraindications
9. 4 Special Warnings and Precautions for Use
   1. Prostate Cancer
   2. Central Precocious Puberty
10. 5 Interaction with Other Medicinal Products and Other Forms of Interaction
11. 6 Fertility, Pregnancy and Lactation
12. 7 Effects on Ability to Drive and Use Machines
13. 8 Undesirable Effects
14. 9 Overdose
15. PHARMACOLOGICAL PROPERTIES
16. 1 Pharmacodynamic Properties
17. 2 Pharmacokinetic Properties
18. 3 Preclinical Safety Data
19. PHARMACEUTICAL PARTICULARS
20. 1 List of Excipients
21. 2 Incompatibilities
22. 3 Shelf Life
23. 4 Special Precautions for Storage
24. 5 Nature and Contents of Container
25. 6 Special Precautions for Disposal and Preparation of the Medicinal Product
26. MARKETING AUTHORIZATION HOLDER
    1. RESPONSIBLE FOR BATCH RELEASE
27. MARKETING AUTHORIZATION NUMBER
28. DATE OF FIRST AUTHORIZATION
    1. AND DATE OF LAST RENEWAL
29. DATE OF REVISION OF THE TEXT
    1. OF THE SUMMARY OF PRODUCT CHARACTERISTICS

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1. NAME OF THE MEDICINAL PRODUCT

Diphereline SR 22.5 mg, 22.5 mg, powder and solvent for prolonged-release suspension for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains 22.5 mg of triptorelin (Triptorelinum) in the form of triptorelin embonate. After reconstitution in 2 ml of solvent, 1 ml of the prepared suspension contains 11.25 mg of triptorelin. For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for prolonged-release suspension for injection

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Diphereline SR 22.5 mg is indicated for the treatment of locally advanced or metastatic hormone-dependent prostate cancer. Diphereline SR 22.5 mg in combination with radiotherapy is indicated for the treatment of localized or locally advanced hormone-dependent prostate cancer with a high risk of recurrence (see section 5.1). Diphereline SR 22.5 mg is indicated for the treatment of central precocious puberty (CPP) in children from 2 years of age, in whom central precocious puberty has been confirmed by clinical and laboratory findings, and where the onset of puberty has occurred before the age of 8 years in girls and 9 years in boys.

4.2 Posology and Method of Administration

Dosage The recommended dose of Diphereline SR 22.5 mg is 22.5 mg of triptorelin (1 vial) administered every 6 months (every 24 weeks) as a single intramuscular injection. In the treatment of localized or locally advanced hormone-dependent prostate cancer with a high risk of recurrence in combination with radiotherapy or after radiotherapy, clinical data have shown that radiotherapy followed by long-term androgen deprivation is more beneficial than radiotherapy followed by short-term androgen deprivation. See section 5.1. The recommended duration of androgen deprivation in patients with localized or locally advanced hormone-dependent prostate cancer with a high risk of recurrence receiving radiotherapy is 2-3 years. In patients with metastatic castration-resistant prostate cancer who have not undergone surgical castration and are receiving a GnRH agonist, such as triptorelin, and are eligible for treatment with abiraterone acetate or enzalutamide, an androgen receptor inhibitor, GnRH agonist therapy should be continued. Patient with renal or hepatic impairmentIn patients with renal or hepatic impairment, there is no need to modify the dose. Paediatric population

Central Precocious Puberty

Treatment of children with Diphereline SR 22.5 mg should be under the supervision of a paediatric endocrinologist or a paediatrician or endocrinologist with expertise in the treatment of central precocious puberty. Treatment should be discontinued at the onset of physiological puberty in boys and girls. In girls, treatment should not be continued after the bone age has reached 12-13 years. In boys, there are limited data regarding the optimal stopping age based on bone age; however, it is recommended to stop treatment in boys when the bone age reaches 13-14 years. Method of administration Intramuscularly As with other injectable medicinal products, the injection site should be varied periodically. After reconstitution, Diphereline SR 22.5 mg suspension should be administered intramuscularly in a rapid and continuous manner to avoid potential needle blockage. Precautions to be taken before handling or administering the medicinal productDiphereline SR 22.5 mg is intended for intramuscular use only. Since Diphereline SR 22.5 mg is a microgranule suspension, accidental injection into a blood vessel should be avoided. Diphereline SR 22.5 mg must be administered under the supervision of a physician. Instructions for reconstitution of the medicinal product before administration are provided in section 6.6.

4.3 Contraindications

Hypersensitivity to GnRH, its analogues or to any of the excipients listed in section 6.1 (see section 4.8). The use of triptorelin is contraindicated during pregnancy and lactation (see section 4.6).

4.4 Special Warnings and Precautions for Use

The use of GnRH agonists may decrease bone mineral density. In men, initial data suggest that the use of a bisphosphonate in combination with a GnRH agonist may decrease the loss of bone mineral density. Particular caution is required in patients with additional risk factors for osteoporosis (e.g. chronic alcohol abuse, smoking, long-term therapy with drugs that reduce bone mineral density, such as antiepileptic drugs or corticosteroids, a family history of osteoporosis, malnutrition). In rare cases, treatment with GnRH agonists may reveal the presence of a previously unknown pituitary gonadotrophin adenoma. In these patients, an pituitary apoplexy may occur, characterised by sudden headache, vomiting, visual disturbances and ophthalmoplegia. There is an increased risk of depressive episodes (with possible severe depression) in patients undergoing treatment with GnRH agonists, such as triptorelin. Patients should be appropriately informed and treated according to the symptoms that occur. Patients with depression should be closely monitored during therapy. In patients taking anticoagulant drugs, caution is advised when performing intramuscular injections due to the risk of haematoma at the injection site. The safety and efficacy of Diphereline SR 22.5 mg have been established only for intramuscular administration. Subcutaneous administration is not recommended. Seizures have been reported in patients taking GnRH agonists, particularly in children. In some of these patients, there were underlying medical conditions that may have contributed to the seizure (e.g. a history of epilepsy, brain tumours or concomitant use of medicinal products known to cause seizures). Seizures have also been reported in patients without any of these risk factors. This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e. it is essentially sodium-free.

Prostate Cancer

During the initial phase of treatment with triptorelin, as with other GnRH agonists, a transient increase in serum testosterone may occur. As a result, during the first few weeks of treatment, some patients may experience a temporary worsening of symptoms or signs of prostate cancer. During the initial phase of treatment, consideration should be given to the concurrent administration of a suitable anti-androgen to counteract the possible initial worsening of the disease symptoms and biochemical effects of the surge of testosterone. In a small number of patients, a temporary worsening of subjective and objective symptoms of prostate cancer (tumour flare) and an increase in bone pain associated with metastases may occur. These symptoms are usually transient and may be treated symptomatically. As with other GnRH agonists, isolated cases of spinal cord compression or urethral obstruction have been observed. If spinal cord compression or renal impairment occurs, standard treatment of these complications should be instituted, and in severe cases, surgical castration should be considered. Close monitoring of the patient is indicated during the first few weeks of treatment, particularly in patients with metastases in the spine and/or those with urinary obstruction. After surgical castration, triptorelin does not cause further reduction in serum testosterone levels. After achieving castrate levels of testosterone at the end of the first month of treatment, serum testosterone levels remain suppressed as long as patients receive injections every 6 months (24 weeks). The efficacy of treatment can be monitored by measurements of testosterone and prostate-specific antigen levels in serum. Long-term androgen deprivation through either bilateral orchiectomy or GnRH agonist therapy is associated with an increased risk of bone loss and may lead to osteoporosis and increased risk of bone fractures. Androgen deprivation may prolong the QT interval. In patients with a history of or risk factors for QT prolongation, as well as in patients receiving concomitant medicinal products that may prolong the QT interval (see section 4.5), the physician should assess the benefit-risk ratio, including the potential for torsades de pointes-type arrhythmias, prior to prescribing Diphereline SR 22.5 mg. Furthermore, based on epidemiological data, it has been observed that patients may experience metabolic changes (e.g. glucose intolerance, liver steatosis) or an increased risk of cardiovascular diseases during androgen deprivation therapy. However, prospective data do not confirm a link between GnRH agonist therapy and increased cardiovascular mortality. Patients at risk of metabolic or cardiovascular diseases should be carefully assessed before starting treatment and monitored according to their risk factors during androgen deprivation therapy. Administration of triptorelin at therapeutic doses suppresses the pituitary-gonadal axis. Normal function usually recovers after cessation of treatment. Diagnostic tests of gonadal function of the pituitary gland performed during or after treatment with GnRH agonists may give misleading results.

Central Precocious Puberty

Treatment of children with progressive brain tumours should be preceded by a careful assessment of the risk-benefit ratio. Pseudo-precocious puberty (tumour or hypertrophy of the gonads or adrenal glands) and gonadotrophin-independent precocious puberty (toxicosis of the thyroid gland, familial Leydig cell hyperplasia) should be excluded. In girls, initial stimulation of the ovaries after the start of treatment, resulting in a decrease in oestrogen levels, may lead to mild or moderate vaginal bleeding during the first month of treatment. Treatment is long-term and individually adjusted. Diphereline SR 22.5 mg should be administered at regular intervals of 6 months. In exceptional cases, a delay of a few days (169 ± 3 days) in the administration of the medicinal product does not affect the results of treatment. After cessation of treatment, the characteristic signs of puberty will appear. Information on future fertility is still limited; however, it appears that treatment with GnRH agonists does not affect future reproductive function and fertility. In most girls, regular menstrual cycles occur on average 1-2 years after cessation of therapy. During therapy with GnRH agonists for central precocious puberty, a decrease in bone mineral density may occur due to the expected effect of oestrogen suppression. However, after cessation of treatment, bone mass accumulation is preserved, and treatment does not appear to affect peak bone mass in late puberty. After discontinuation of GnRH agonist therapy, slipped capital femoral epiphysis may occur. According to a proposed theory, low oestrogen levels during GnRH agonist therapy weaken the growth plate. The increased growth rate after cessation of treatment results in a decrease in the strength required to displace the growth plate. Idiopathic intracranial hypertension In children and adolescents treated with triptorelin, idiopathic intracranial hypertension (pseudotumour cerebri) has been reported. Patients should be warned about the possibility of signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, vision disturbances and papilloedema. If idiopathic intracranial hypertension occurs, consideration should be given to discontinuing triptorelin.

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction

Caution should be exercised when co-administering triptorelin with medicinal products that affect gonadotrophin secretion in the pituitary gland. Monitoring of hormonal status is recommended. Androgen deprivation may prolong the QT interval; therefore, caution is advised when prescribing Diphereline SR 22.5 mg with other medicinal products that prolong the QT interval or medicinal products that may cause torsades de pointes-type arrhythmias, such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotic medicinal products, etc. (see sections 4.4 and 4.8). Paediatric population Interaction studies have been performed only in adults.

4.6 Fertility, Pregnancy and Lactation

Pregnancy Diphereline SR 22.5 mg is indicated for use in adult men and in children. There are limited data on the use of triptorelin in pregnant women. Diphereline SR 22.5 mg is not indicated for use in women. It must be confirmed that the patient is not pregnant before prescribing Diphereline SR 22.5 mg. Triptorelin must not be used during pregnancy, as the concomitant use of GnRH agonists is associated with a theoretical risk of abortion or fetal abnormality. In women of childbearing potential, before starting treatment, a careful assessment should be made to exclude pregnancy. During treatment, non-hormonal methods of contraception should be used until menses resume. Animal studies have shown effects on reproduction (see section 5.3). Breast-feeding Diphereline SR 22.5 mg is not indicated for use in breast-feeding women.

4.7 Effects on Ability to Drive and Use Machines

The effect on the ability to drive and use machines has not been studied. However, the ability to drive and use machines may be impaired if the patient experiences dizziness, somnolence and visual disturbances, which are adverse reactions of the treatment or the underlying disease.

4.8 Undesirable Effects

General tolerance in men Since patients with locally advanced or metastatic hormone-dependent prostate cancer are generally elderly and may have other diseases typical of this age group, adverse reactions to the medicinal product were reported in more than 90% of patients participating in clinical trials, and the assessment of a causal relationship between the medicinal product and the adverse reaction is difficult. As with other GnRH agonists or surgical castration, the most commonly observed adverse reactions associated with triptorelin treatment were due to its expected pharmacological effects. These reactions included hot flushes and decreased libido. All adverse reactions, except for immune-related allergic reactions (rare) and injection site reactions (<5%), are related to the change in testosterone levels. The following adverse reactions have been reported to be possibly associated with triptorelin. Most of them are known to be associated with either biochemical or surgical castration. The frequency of adverse reactions has been classified as follows: very common (≥1/10); common (≥1/100 to <1>

* After the marketing authorisation of the medicinal product, seizures have been reported in patients taking GnRH agonists, including triptorelin. General information In patients treated with GnRH agonists, an increase in lymphocytes has been reported. This secondary lymphocytosis appears to be related to GnRH agonist-induced castration and may indicate that sex hormones are involved in the involution of the thymus.

4.9 Overdose

The pharmacological properties of the medicinal product Diphereline SR 22.5 mg and its administration route make accidental or intentional overdose unlikely. There are no data on overdose in humans. Animal studies indicate that when higher doses of the medicinal product Diphereline SR 22.5 mg are administered, no other effects are observed except for the intended therapeutic effect on sex hormone levels and the reproductive system. In case of overdose, symptomatic treatment is indicated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

Therapeutic group: hormones and their derivatives, gonadotropin-releasing hormone analogs. ATC code: L02AE04. Mechanism of action and pharmacodynamic effects. Tryptorelin, a GnRH analog administered continuously and in therapeutic doses, acts as a strong inhibitor of gonadotropin secretion. Studies in animals and humans have shown that after administration of tryptorelin, there is an initial and transient increase in circulating luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone in men, and estradiol in women. However, long-term and continuous administration of tryptorelin leads to a decrease in LH and FSH secretion and suppression of steroid synthesis in the testes and ovaries. In men with prostate cancer: Reduction of serum testosterone levels to those normally observed in men undergoing surgical castration occurs within 2 to 4 weeks of starting therapy. The medicinal product Diphereline SR 22.5 mg has been developed to deliver 22.5 mg of tryptorelin over 6 months. After achieving castration levels of testosterone at the end of the first month of treatment, testosterone levels are maintained as long as the patient receives subsequent injections every 24 weeks. This leads to atrophy of accessory sex glands. These effects are usually reversible after discontinuation of the medicinal product. The efficacy of treatment can be monitored by determining serum testosterone levels and prostate-specific antigen (PSA) levels. During clinical trial programs, a 97% median relative reduction in PSA levels at month 6 was demonstrated for the medicinal product Diphereline SR 22.5 mg. In experimental animal models, administration of tryptorelin inhibits the growth of some hormone-sensitive prostate tumors. Clinical efficacy and safety in the treatment of prostate cancer. Administration of the medicinal product Diphereline SR 22.5 mg to patients with advanced prostate cancer in the form of two intramuscular injections (12 months) resulted in achieving castration levels of testosterone in 97.5% of patients after 4 weeks and maintaining castration levels of testosterone in 93.0% of patients from month 2 to month 12 of treatment. In patients with locally advanced prostate cancer, the results of several randomized, long-term clinical trials have shown greater benefits from anti-androgen therapy (ADT) in combination with radiotherapy (RT) compared to radiotherapy alone (RTOG 85-31, RTOG 86-10, EORTC 22863, D’Amico et al., JAMA, 2008). In a randomized phase III clinical trial (EORTC 22961) involving 970 patients with locally advanced prostate cancer (mainly T2c – T4 and a few patients with T1C to T2B with local lymph node disease), 483 were assigned to the short-term androgen suppression group (6 months) in combination with radiotherapy, and 487 to the long-term therapy group, comparing short-term versus long-term hormonal therapy using a non-inferiority analysis. Overall, the total mortality rate at 5 years in the "short-term hormonal therapy" and "long-term hormonal therapy" groups was 19.0% and 15.2%, respectively, and the relative risk was 1.42 (upper one-sided confidence interval (CI) was 1.79 for a confidence level of 95.71%, and two-sided confidence interval (CI) [1.09; 1.85] for a confidence level of 95.71% Borderline significance levels (p-value) when testing differences between groups with different therapies were: 0.65 when testing non-inferiority and 0.0082 in the post-hoc test). The 5-year mortality rate clearly associated with prostate cancer in the "short-term hormonal therapy" and "long-term hormonal therapy" groups was 4.78% and 3.2%, respectively, and the relative risk was 1.71 (95% CI [1.14 to 2.57], p = 0.002). The overall quality of life assessed according to QLQ-C30 did not differ significantly between the two groups (P = 0.37). The indication for use in high-risk localized prostate cancer is based on studies of the results of combining radiotherapy with GnRH analogs. The results of five published clinical trials (EORTC 22863, RTOG 85-31, RTOG 92-02, RTOG 86-10, and D’Amico et al., JAMA, 2008) have shown benefits from combining GnRH analogs with radiotherapy. Among the participants in these studies, it was not possible to distinguish between patients with locally advanced prostate cancer and those with high-risk localized prostate cancer. In patients with castration-resistant prostate cancer, clinical trials have shown a benefit from adding GnRH analogs such as tryptorelin, abiraterone acetate, an androgen biosynthesis inhibitor, or enzalutamide, an androgen receptor inhibitor, to treatment. Clinical efficacy and safety in the treatment of children with precocious puberty. In a non-comparative clinical trial, 44 children with precocious puberty (39 girls and 5 boys) were treated with a total of two intramuscular injections of the medicinal product Diphereline SR 22.5 mg over a period of more than 12 months (48 weeks). Suppression of stimulated LH levels to pre-pubertal levels was achieved in 95.5% of patients after 3 months and in 93.2% and 97.7% of patients after 6 and 12 months, respectively. As a result of treatment, regression or stabilization of secondary sex characteristics and slowing of accelerated bone age and growth were observed. In girls, initial stimulation of the ovaries after starting treatment, resulting in a decrease in estrogen levels, may lead to mild or moderate vaginal bleeding in the first month of treatment.

5.2 Pharmacokinetic Properties

Absorption
After a single intramuscular injection of the medicinal product Diphereline SR 22.5 mg in patients with prostate cancer, the t value was 3 (2-12) hours, and C (0-169 days) was 40.0 (22.2-76.8) ng/ml. In children with precocious puberty, the t value was 4 (2-8) hours, and the C (0-169 days) value was 39.9 (19.1-107.0) ng/ml. Tryptorelin did not accumulate over a 12-month treatment period.
Distribution
The results of pharmacokinetic studies conducted in healthy men indicate that after intravenous administration, tryptorelin is distributed and eliminated according to a 3-compartment model, with half-lives of approximately 6 minutes, 45 minutes, and 3 hours. The volume of distribution at steady state of tryptorelin after intravenous administration of 0.5 mg tryptorelin acetate is approximately 30 l in healthy male volunteers. Since there is no evidence that tryptorelin binds to plasma proteins at clinically significant concentrations, interactions related to the mechanism of displacement from the binding site are unlikely.
Metabolism
No metabolites of tryptorelin have been detected in humans. However, data from pharmacokinetic studies in humans indicate that C-terminal fragments resulting from tissue degradation are either completely broken down within tissues or rapidly broken down in plasma or eliminated by the kidneys.
Elimination
Tryptorelin is eliminated by the kidneys and liver. After intravenous administration of 0.5 mg tryptorelin in healthy male volunteers, 42% of the dose was excreted in the urine as unchanged tryptorelin, which increased to 62% in patients with liver failure. Since the creatinine clearance (Cl) in healthy volunteers was 150 ml/min and only 90 ml/min in patients with liver failure, this indicates that the liver is the main site of tryptorelin elimination. In these healthy volunteers, the actual half-life of tryptorelin was 2.8 hours, and the total clearance of tryptorelin was 212 ml/min, which depended on the combined hepatic and renal elimination. Special populations
After intravenous administration of 0.5 mg tryptorelin in patients with moderate renal impairment (Cl 40 ml/min), the half-life of tryptorelin was 6.7 hours, 7.81 hours in patients with severe renal impairment (Cl 8.9 ml/min), and 7.65 hours in patients with liver function disorders (Cl 89.9 ml/min). The effect of age and race on the pharmacokinetics of tryptorelin has not been systematically studied. However, pharmacokinetic data obtained in healthy male volunteers aged 20 to 22 years with increased creatinine clearance (approximately 150 ml/min) indicate that tryptorelin was eliminated twice as fast in the younger population. This is related to the fact that tryptorelin clearance is correlated with total creatinine clearance, which is known to decrease with age. Due to the wide safety margin of tryptorelin and since the Diphereline SR 22.5 mg preparation is in a prolonged-release form, dose adjustment is not recommended in patients with renal or hepatic impairment. Pharmacokinetic-pharmacodynamic interaction
The interaction between pharmacokinetics and pharmacodynamics of tryptorelin is not simple to evaluate due to its non-linearity and time dependence. Therefore, after single administration in previously untreated patients, tryptorelin induces a dose-dependent increase in LH and FSH responses. After administration of the prolonged-release form, tryptorelin stimulates LH and FSH secretion within the first days after administration, and consequently, testosterone secretion. According to the results of various bioequivalence studies, the maximum increase in testosterone levels is achieved after approximately 4 days with a steady-state C, whose value is independent of the rate of tryptorelin release. This initial response disappears despite continued exposure to tryptorelin, and its place is taken by progressive and steady decrease in testosterone levels. Also, in this case, the magnitude of exposure to tryptorelin may change significantly without affecting changes in testosterone levels.

5.3 Preclinical Safety Data

The toxicity of tryptorelin to organs outside the reproductive system is low. The observed effects were mainly related to the exacerbation of tryptorelin's pharmacological effects. In chronic toxicity studies at clinically relevant doses, tryptorelin induced macro- and microscopic changes in the reproductive organs of male rats, dogs, and monkeys. These changes are believed to be a response to the suppression of gonadal function caused by the pharmacological activity of the active substance. These changes partially regressed after its discontinuation. After subcutaneous administration of tryptorelin at a dose of 10 micrograms/kg body weight to rats on days 6 to 15 of pregnancy, tryptorelin did not exhibit embryotoxic, teratogenic, or any other effects on the development of offspring (F1 generation) or their reproductive capacity. At a dose of 100 micrograms/kg body weight, a reduction in maternal body weight gain and an increased number of resorptions were observed. Tryptorelin is not mutagenic in vitro or in vivo. No oncogenic effect of tryptorelin has been demonstrated in mice at doses up to 6000 micrograms/kg body weight for up to 18 months of treatment. In a 23-month study of carcinogenic effects in rats, nearly 100% incidence of benign pituitary tumors was demonstrated for each dose size, which led to premature death of the animals. The increased incidence of pituitary tumors in rats is commonly associated with treatment with GnRH agonists. The clinical significance of this observation is unknown.

6. PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

Powder:
Copolymer of lactic acid and glycolic acid (PLG 75/25 COOH)
Copolymer of lactic acid and glycolic acid (PLG 85/15 Lauryl ester)
Mannitol
Sodium carmellose
Polysorbate 80
Solvent:
Water for injections

6.2 Incompatibilities

Do not mix the medicinal product with other medicinal products, as compatibility studies have not been conducted.

6.3 Shelf Life

4 years.
Use immediately after reconstitution.
From a microbiological point of view, the ready-to-use suspension for injection should be used immediately after reconstitution. If the suspension for injection is not used immediately after reconstitution, the user is responsible for ensuring appropriate storage conditions until administration, usually not exceeding 24 hours at a temperature of 2 to 8°C.

6.4 Special Precautions for Storage

Do not store above 25°C.
For information on the storage conditions of the medicinal product after reconstitution, see section 6.3.

6.5 Nature and Contents of Container

Vial with powder: a 6 ml clear, pale brown glass type I vial with a bromobutyl rubber stopper, an aluminum cap, and a dark green flip-off cap.
Ampoule with solvent: an ampoule with clear, colorless glass type I containing 2 ml of sterile solvent for suspension and a blister pack containing a syringe and 2 injection needles, all in a cardboard box.

6.6 Special Precautions for Disposal and Preparation of the Medicinal Product

The suspension for injection must be reconstituted under aseptic conditions, using only the solvent provided with the packaging. The instructions for reconstitution provided below and in the package leaflet must be strictly followed.
Using the reconstitution needle (20 G, without a safety device), withdraw the solvent from the ampoule into the provided syringe and transfer it to the vial containing the powder. The suspension should be reconstituted by gently shaking the vial from side to side for a sufficient amount of time to obtain a homogeneous suspension with a milky consistency. Do not invert the vial. Check that there are no residues of unreconstituted powder in the vial. The resulting suspension should be drawn into the syringe without inverting the vial. Then, replace the needle with the injection needle (20 G, equipped with a safety device) and administer the product to the patient. Since the product is in the form of a suspension, it should be administered as soon as possible to prevent sedimentation. For single use only. Dispose of used needles, unused suspension, or any waste according to local regulations. Any unused medicinal product or waste should be disposed of in accordance with national regulations.

7. MARKETING AUTHORIZATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

Ipsen Pharma
65 Quai Georges Gorse
92 100 Boulogne Billancourt
France

8. MARKETING AUTHORIZATION NUMBER

17882

9. DATE OF FIRST AUTHORIZATION

AND DATE OF LAST RENEWAL

Date of first authorization: 02.03.2011
Date of last renewal: 14.02.2020

10. DATE OF REVISION OF THE TEXT

OF THE SUMMARY OF PRODUCT CHARACTERISTICS

• 18.10.2024