Instructions for use Leuprorelin-Vista implant 11.25 mg syringe applicator No. 1
Composition
active ingredient: leuprorelin acetate;
1 implant contains leuprorelin acetate 11.25 mg, equivalent to 10.72 mg leuprorelin; excipients: Resomer® R202H (Poly-D, L-lactide), Resomer® RG502H (Poly(lactide-co-glycolide)).
Dosage form
Implant.
Main physicochemical properties: implant visible in implant holder. Dimensions: length about 17.8 mm, width about 1.5 mm.
Functionality: after actuating the applicator, an undamaged cylindrical rod of white to off-white color emerges from the needle.
Pharmacotherapeutic group
Gonadotropin-releasing hormone analogues.
ATX code L02A E02.
Pharmacological properties
Pharmacodynamics
The active substance of the drug - leuprorelin acetate - is a synthetic analogue of the natural hypothalamic gonadotropin-releasing hormone (LHRH), which controls the secretion of gonadotropin hormones - luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the anterior pituitary gland. These hormones stimulate the synthesis of steroids by the gonads.
Unlike physiological LHG, which is released by the hypothalamus in a pulsatile manner, leuprorelin acetate (also called an LHG agonist) provides a continuous blockade of the LHG receptors of the pituitary gland throughout the treatment period, as a result of which the pituitary gland ceases to perceive and respond to the initial short-term stimulation (downregulation). As a result of the reverse inhibition of pituitary gonadotropin secretion, testosterone levels decrease, which affects the growth of prostate cancer tissue. Under normal circumstances, this tissue is stimulated by dihydrotestosterone, which is released in response to the decrease in testosterone levels in prostate cells.
Continuous administration of leuprorelin acetate results in a reduction in the number and sensitivity (so-called downregulation) of pituitary receptors and, as a result, a decrease in the levels of LH, FSH and DHT. This, in turn, causes a decrease in testosterone levels to the castrate range. Animal studies have demonstrated an antiandrogenic effect and inhibition of prostate carcinoma growth.
According to experimental and clinical studies, a three-month course of treatment with leuprorelin acetate after initial stimulation provides a decrease in gonadotropin secretion. In men, subcutaneous administration of leuprorelin acetate initially causes an increase in LH and FSH levels, which is accompanied by a temporary increase in testosterone and dihydrotestosterone levels. Due to the short-term deterioration of the clinical picture in the first 3 weeks of treatment, which was observed in isolated cases, men with prostate cancer may be prescribed additional antiandrogens at the initial stage of treatment. Long-term administration of leuprorelin acetate, on the contrary, causes a decrease in LH and FSH levels. Androgen levels in men decrease to values that are recorded after surgical removal of both testicles. These changes usually occur 2-3 weeks after the start of therapy and persist throughout the entire course of further treatment. Also, when considering treatment with leuprorelin acetate, it is necessary to assess the hormonal sensitivity of the prostate cancer tissue and the potential therapeutic benefits of orchiectomy. If necessary, orchiectomy can be replaced by 3-month doses of leuprorelin acetate. According to the data obtained, castrate testosterone levels can be maintained for more than 5 years with continuous administration of leuprorelin acetate.
Clinical efficacy.
Clinical trials in patients with metastatic, castration-resistant prostate cancer have shown benefit from additional dosing of agents such as androgen synthesis inhibitors (e.g., abiraterone acetate), antiandrogens (e.g., enzalutamide), taxanes (e.g., docetaxel or cabazitaxel), or radiotherapeutic agents (e.g., radium-223) in addition to a hypothalamic gonadotropin-releasing hormone such as leuprorelin acetate. Pharmacokinetics.
After injection of the implant, a continuous release of leuprorelin acetate (the active ingredient of the drug) from the lactic acid polymer begins, which lasts up to 3 months. Over time, the polymer is absorbed in a similar way to surgical suture material.
Distribution and output.
The volume of distribution of leuprorelin in men is 36 L, the total clearance is 139.6 ml/min. Repeated administration leads to a permanent decrease in testosterone levels to castrate (sterile) levels, in the absence of a temporary increase in testosterone levels that occurs after the first injection.
Patients with renal/hepatic impairment.
In patients with impaired renal or hepatic function, leuprorelin levels were found to be similar to those in patients with normal renal and hepatic function. Some patients with chronic renal failure had higher serum leuprorelin levels. However, this observation is unlikely to be of clinical significance.
Bioavailability
The relative bioavailability after 84 days is 84.6%, calculated based on comparison with the AUC of intravenous injection of leuprorelin acetate 1 mg.
Indication
Determining the hormonal sensitivity of prostate cancer to assess the need for hormone suppression/hormone ablation interventions.
Treatment of hormone-dependent advanced prostate cancer and treatment of high-risk localized prostate cancer and locally advanced prostate cancer in combination with radiation.
Contraindication
Hypersensitivity to leuprorelin acetate, other gonadotropin-releasing hormone (GnRH) agonists or to any of the excipients of the medicinal product.
Patients who have previously undergone orchiectomy (like other GnRH agonists, it does not cause a further decrease in serum testosterone levels after surgical castration).
· Hormone-independent tumors.
· Contraindicated for women and children.
Special safety precautions
Use only if the package with the syringe applicator is intact. Use immediately after opening the package.
Interaction with other medicinal products and other types of interactions
Interactions with other drugs are unknown.
Since antiandrogen therapy may prolong the QT interval, the possibility of concomitant use of Leuprorelin-Vista with drugs that prolong the QT interval or can induce torsade de pointes, such as antiarrhythmic drugs of class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibulitide), methadone, moxifloxacin, neuroleptics and others should be carefully evaluated (see section "Special instructions").
Application features
Patients with hypertension require close monitoring. There is an increased risk of depression (which may be serious), symptoms of emotional lability such as crying, irritability, impatience, anger and aggression in patients taking gonadotropin-releasing hormone antagonists. Patients should be informed of this risk and appropriate medical care should be provided if such symptoms occur.
In the post-marketing period, there have been reports of seizures in patients receiving leuprorelin acetate; these events have been reported in adults with or without a history of epilepsy, seizure disorders or risk factors for seizures. At the beginning of treatment, a transient increase in serum testosterone levels is common, which may be accompanied by a temporary exacerbation of certain clinical symptoms (new or worsening of ostalgia, urinary obstruction with associated complications, spinal cord compression, myasthenia gravis, lymphedema). With continued treatment with the drug, complications usually resolve spontaneously. Allergic and anaphylactic reactions, including both local reactions at the injection site and systemic reactions, may occur. At the initial stage of treatment, additional appropriate antiandrogens may be considered to reduce the severity of possible complications (initial increase in testosterone and exacerbation of clinical symptoms).
The success of therapy should be regularly monitored by clinical tests (digital rectal examination of the prostate, ultrasound, skeletal scintigraphy, computed tomography) and analyses of phosphatase levels and/or prostate-specific antigen (PSA) and testosterone concentrations in serum.
Hypogonadism resulting from long-term treatment with LHRH analogues and/or orchiectomy may lead to osteoporosis with an increased risk of fractures. The development of osteoporosis is more pronounced after orchiectomy (with increased cortisol levels) than after administration of LHRH analogues.
In high-risk patients, additional administration of bisphosphonates may prevent bone demineralization.
Patients with brain or spinal cord metastases, neurological disorders, and urinary tract obstruction require very close monitoring, especially during the first few weeks of treatment. In isolated cases, spinal cord compression and renal failure have been observed in such patients.
When using the drug Leuprorelin-Vista, doping tests may show a positive result.
Altered glucose tolerance has been observed in some patients treated with LHRH analogues. Patients with diabetes should be monitored during treatment with the drug.
Antiandrogen therapy may prolong the QT interval.
In patients with a history of QT prolongation (or with corresponding risk factors), as well as in patients receiving concomitant medications that may prolong the QT interval (see section “Interaction with other medicinal products and other forms of interaction”), physicians should assess the risk-benefit ratio, including the possibility of torsade de pointes, before initiating treatment.
Use during pregnancy or breastfeeding
The drug Leuprorelin-Vista is not intended for use in women and is contraindicated during pregnancy and breastfeeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
Due to the occurrence of fatigue in some patients, sometimes very severe, especially at the initial stage of treatment, which may be due to the underlying tumor disease, the drug, even when used correctly, may inhibit the sharpness of reactions and negatively affect the ability to drive a car and work with complex mechanical equipment. Alcohol enhances this negative effect. The possibility of adverse reactions from the nervous system and the organs of vision should also be taken into account.
Method of administration and doses
The recommended dose is 1 implant every 3 months. If there is no temporary improvement or positive dynamics, it is not recommended to continue treatment.
In exceptional cases, the use of the drug is postponed for a period of up to 4 weeks; the therapeutic effect does not decrease in most patients.
The drug should be administered by a physician experienced in anticancer therapy. The implant is inserted subcutaneously in the abdomen, avoiding accidental intra-arterial administration.
Instructions for use:
Read these instructions carefully as the syringe supplied with this medicine may be different from the ones the patient has used before.
1. Disinfect the injection site on the anterior abdominal wall below the navel line.
2. Remove the syringe from the sterile pouch and check for the presence of the implant in the chamber (see boxed area). If necessary, hold the syringe against the light or gently shake it.
3. Pull the syringe plunger all the way out until the entire line is visible in the second window.
Caution: The plunger can only be pushed forward to insert the implant if it has been fully withdrawn previously.
4. Remove the protective cap from the needle.
5. Hold the syringe body with one hand. With the other hand, pinch the skin of the patient’s anterior abdominal wall below the navel line (see figure). With the needle pointed upwards, insert it all the way into the subcutaneous tissue. Do this at a slight angle, almost parallel to the skin.
6. Carefully pull the syringe back approximately 1 cm. This will create a puncture channel for the implant.
7. Insert the implant into the puncture channel by pushing the plunger forward until it locks into place and the patient hears a clicking sound.
8. Withdraw the needle. To ensure proper implant insertion, check that the white tip of the plunger is visible from the end of the needle.
It is usually possible to determine whether a prostate carcinoma is androgen-sensitive within 3 months. The main diagnostic parameter is the analysis of the concentration of prostate-specific antigen (PSA), which is usually more than 10 ng/ml in an active state of tumor development. However, PSA indicators, as well as testosterone indicators in general, should be determined before the start of the drug and after 3 months of use. Test results are considered positive if the testosterone concentration is at the sterility level after 3 months (
Test results are considered negative if the PSA value remains unchanged or increases with the patient's testosterone levels decreasing. In such cases, continuation of hormone-suppressive therapy is not appropriate.
However, if a patient demonstrates a clinical response (e.g., pain relief, no complaints of pain on urination, and return of the prostate to normal size), false negative results should be considered. In such rare cases, leuprorelin should be continued for a further 3 months and PSA levels should be monitored. In addition, the patient's clinical symptoms should be closely monitored.
Treatment of patients with prostate cancer with gonadotropin-releasing hormone analogues can be continued even after the development of castration resistance, ensuring that appropriate instructions are followed.
Treatment for advanced hormone-dependent prostate cancer is usually long-term.
Clinical data have shown that 3 years of androgen deprivation therapy administered concurrently with and after radiotherapy is superior to a 6-month course of androgen deprivation therapy for locally advanced, hormone-dependent prostate cancer. 2-3 years of androgen deprivation therapy is recommended for patients (T3-T4) receiving radiotherapy.
Typically, the treatment of chronic hormone-dependent prostate carcinomas with the use of a drug requires a long period of treatment.
It is necessary to regularly check the therapeutic effect of treatment by means of clinical examinations (rectal palpation of the prostate, ultrasound, bone scan, computed tomography) and examination of phosphatase or PSA levels and serum testosterone (especially if signs of tumor progression occur despite adequate therapy).
Children.
Do not use for the treatment of children.
Overdose
Symptoms: No symptoms of intoxication have been identified so far.
Treatment: In case of overdose, the patient should be given symptomatic treatment and, if necessary, supportive therapy.
Adverse reactions
At the beginning of treatment, a short-term increase in serum testosterone concentration is usually observed, mainly due to the specific pharmacological action of leuprorelin, which may temporarily worsen certain symptoms of the disease (development or worsening of bone pain, urinary tract obstruction and its consequences, spinal cord compression, muscle weakness of the leg, lymphatic edema). This increase in symptoms usually regresses spontaneously, without the need to discontinue leuprorelin. Undesirable side effects may develop due to the suppression of certain sex hormones.
The adverse reactions of leuprorelin listed below are based on clinical trial experience and post-marketing experience. Adverse reactions are grouped by MedDRA system organ class, with the following frequency classification: very common (≥ 1/10), common (≥ 1/100 to < 1/1000), uncommon
On the part of the immune system
Uncommon: systemic allergic reactions (fever, itching, eosinophilia, skin rashes). Very rare: anaphylaxis.
From the side of metabolism, metabolism
Common: increased appetite, decreased appetite.
Rare: changes in metabolic status in patients with diabetes mellitus (decrease or increase in blood glucose levels).
From the psyche
Common: depression, sleep disturbances, mood swings.
From the nervous system
Common: headache, paresthesia.
Rare: dizziness, transient dysgeusia.
Rare: As with other drugs of this class, pituitary apoplexy has been reported very rarely following initial administration of leuprorelin acetate in patients with pituitary adenoma.
Frequency unknown: convulsions.
Cardiovascular system
Frequency unknown: QT prolongation (see sections “Interaction with other medicinal products and other types of interactions” and “Special warnings and precautions for use”).
Very common: hot flushes.
Rare: changes in blood pressure (hypertension or hypotension).
From the digestive system
Common: nausea/vomiting.
Uncommon: diarrhoea.
Skin and subcutaneous tissue disorders
Uncommon: dry skin and/or mucous membranes, night sweats.
Rare: alopecia.
Musculoskeletal and connective tissue disorders
Very common: arthralgia.
Common: joint and/or back pain, muscle weakness.
Frequency not known: bone demineralization (see section "Special warnings and precautions for use").
From the genitourinary and reproductive system
Very common: decreased libido and sexual potency, decreased testicular size.
Common: nocturia, dysuria, pollakiuria, gynecomastia.
Uncommon: dysuria, testicular pain.
Respiratory system
Frequency unknown: interstitial lung disease.
General disorders and administration site conditions
Very common: increased sweating, injection site reactions such as erythema, pain, swelling, itching, which usually resolve with continued treatment.
Common: fatigue, peripheral edema.
Laboratory studies
Very common: weight gain.
Common: weight loss, increased lactate dehydrogenase (LDH), transaminases, γ-GT and alkaline phosphatase, which may be manifestations of the underlying disease.
Special notes:
The response to treatment with Leuprorelin-Vista should be monitored by measuring serum testosterone concentrations 28 days after each injection and before each re-injection of Leuprorelin-Vista, as well as by other laboratory tests such as acid phosphatase and PSA. For example, testosterone levels show an initial surge at the beginning of therapy, which then declines within 2 weeks. After 2-4 weeks, testosterone concentrations reach levels similar to those observed after bilateral orchiectomy and remain at this level throughout the treatment period. Elevations in acid phosphatase may occur early in treatment and are transient. Acid phosphatase usually returns to normal or near normal levels after a few weeks. Injection site abscesses are rare. In one report of an injection site abscess, absorption of leuprorelin from the depot was reduced. Therefore, in such cases, it is recommended to determine the level of testosterone.
Reporting of suspected adverse reactions
Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua
Expiration date
4 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 30 ° C. Keep out of the reach of children.
Packaging
1 implant in a syringe-applicator (the syringe-applicator consists of a polymer body with an implant holder, needle and piston).
1 syringe in a package together with a desiccant capsule. 1 package in a cardboard box.
Vacation category
According to the recipe.
Producer
Location of the manufacturer and address of its place of business
Birkerfeld 11, Lochham, Warngau, Bayern, 83627, Germany.
