Lyukrin Depot - instructions for use, doses, side effects, contraindications

Active substanceLeiprorelinLeiprorelin

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Lucrin Depot®

lyophilizate w / m PC

Abbott Laboratories SA Spain

Lucrin Depot®

lyophilizate PC

Abbott Laboratories SA Spain

Lucrin Depot®

lyophilizate w / m PC

Abbott Laboratories SA Spain

Eligarde

lyophilizate PC

Astellas Farma Europe BV Netherlands

Dosage form: & nbsplyophilizate for the preparation of a suspension for intramuscular and subcutaneous administration of prolonged action

Composition:

For the preparation in the vial:

1 bottle with lyophilizate contains:

Active substance: leuprorelin acetate - 3.75 mg. Excipients: gelatin - 0,65 mg, lactic and glycolic acids, copolymer - 33,10 mg, mannitol - 6,60 mg.

1 ampoule with a solvent contains: carmellose sodium - 10,0 mg, mannitol - 100.00 mg, polysorbate 80 - 2.0 mg, water for injection - up to 2.0 ml.

For the preparation in a two-chamber syringe:

The camera with lyophilizate contains:

Active substance: leuprorelin acetate - 3.75 mg. Excipients: gelatin - 0,65 mg, lactic and glycolic acids, copolymer - 33,10 mg, mannitol - 6,60 mg.

The chamber with the solvent contains: carmellose sodium - 5.0 mg, mannitol - 50.0 mg, polysorbate 80-1.0 mg, water for injection - up to 1,0 ml.

Description:

Lyophilizate: White powder.

Solvent: colorless clear solution.

Finished suspension: a suspension of white color.Upon settling, a white precipitate forms, which is easily resuspended by shaking.

Pharmacotherapeutic group:An antineoplastic agent, a gonadotropin-releasing hormone analog

ATX: & nbsp

L.02.A.E Analogues of gonadotropin-releasing hormone

L.02.A.E.02 Leiprorelin

Pharmacodynamics:

Leuprorelin, a gonadotropin-releasing hormone agonist (GnRH), is an effective inhibitor of gonadotropin secretion with long-term admission in therapeutic doses. In humans, the appointment of leuprorelin leads to an initial increase in the concentrations of luteinizing (LH) and follicle-stimulating (FSH) hormones, which leads to a tragatory increase in the concentrations of sex hormones (testosterone and dihydrotestosterone in men, estrone and estradiol in women).

However, the long-term administration of leuprorelin leads to a decrease in the concentrations of LH, FSH and sex hormones. In men, the concentration of testosterone is reduced to the castration or prepubertal level. In women who are in a state before menopause, the concentration of estrogen falls to the postmenopausal level. These hormonal changes occur within a month from the beginning of therapy with the drug in the recommended doses.

Suppression of steroidogenesis in the ovaries and testes is reversible and stops after the end of therapy.

Pharmacokinetics:

Bioavailability of the drug with subcutaneous and intramuscular injection is comparable. The approximate value of absolute bioavailability when the drug is administered at a dose of 7.5 mg is 90%.

After a single intramuscular and subcutaneous injection of leuprorelin in patients with prostate cancer at doses of 3.75 mg and 7.5 mg, the mean concentrations of the drug in plasma by the end of the first month were 0.7 ng / ml and 1.0 ng / ml, respectively.

Serum leuprorelin concentration of 3.75 mg is determined for 12 months in 11 patients with premenopausal breast cancer. The average concentration of leuprorelin exceeded 0.1 ng / ml after 4 weeks and remained stable after repeated administration (at 8 and 12 weeks).

No cumulation of the drug was noted.

The average equilibrium volume of distribution is 27 liters. The connection with plasma proteins is 43-49%. The system clearance is 7.6 l / h. The elimination half-life is about 3 hours. Leiprorelin, being a peptide, undergoes metabolic degradation mainly by peptidase to shorter inactive peptides - pentapeptide (metabolite I), tripeptides (metabolites II and III) and dipeptide (metabolite IV).The time to reach the maximum concentration of the main metabolite M-1 is 2-6 hours and corresponds to 6% of the maximum concentration of leuprorelin. 1 week after the injection, the average plasma concentration of M-1 is 20% of the average concentration of leuprorelin.

After the administration of 3.75 mg leuprorelin, the leuprorelin and M-1 levels in the urine were less than 5% of the administered dose 27 days after the drug was administered.

Special Groups

Pharmacokinetics of the drug in patients with impaired liver or kidney function has not been investigated.

Indications:

- Progressive prostate cancer (palliative treatment), incl. when orchiectomy or treatment with estrogens are not shown or are not applicable in this patient.

- Endometriosis (for up to 6 months as the main therapy or addition to surgical treatment). Therapy of endometriosis and its relapses in combination with hormone replacement therapy.

- Fibromyoma of the uterus (for up to 6 months as a pre-operative preparation for the removal of fibroids or hysterectomy, as well as for symptomatic treatment and improvement in women during menopause that refuse surgery).

- Breast cancer in the perimenopausal period in combination with hormone therapy.

- Children with premature puberty (PPP) of the central genesis.

Contraindications:

- Hypersensitivity to leuprorelin, similar to preparations of protein origin or to any other auxiliary substance included in the composition of the dosage form.

- Surgical castration.

- Pregnancy and the period of breastfeeding.

- Vaginal bleeding of unknown etiology.

- Prostate cancer (hormone-independent).

- Children under the age of 18, except for children with premature puberty (PPP) of the central genesis.

- Women over 65 years.

Carefully:In patients with metastases in the spine, with obstruction of the urinary tract or with hematuria.

Pregnancy and lactation:

The drug is contraindicated in pregnancy and lactation, therefore before starting the use of the drug it is recommended to exclude the presence of pregnancy.

Dosing and Administration:

Administer intramuscularly or subcutaneously once a month. The injection site should be periodically changed. The injection suspension is prepared immediately prior to administration using the supplied solvent at a concentration of 3.75 mg / ml.

When prostate cancer or breast cancer a single dose of 3.75 mg. The duration of treatment is determined by the doctor.

When endometriosis, uterine fibroids - 3.75 mg.

Women of reproductive age are given the first injection on the third day of menstruation. Duration of treatment is no more than 6 months.

With premature puberty (PPS) - 1 initial dose - 0.3 mg / kg (minimum 7.5 mg) - once every four weeks.

The initial dose can be determined based on the weight of the child's body:

Weight of child's body	Dosage	Number of syringes or flasks for injection	Total dose
<25 kg	3.75 mg	2	7.5 mg
> 25 to 37.5 kg	3.75 mg	3	11.25 mg
> 37.5 kg	3.75 mg	4	15 mg

Note: If two or more injections are needed to obtain the desired total dose, they must be administered simultaneously.

The maintenance dose for PPP

If complete suppression of disease progression is not achieved, the dose should be increased every 4 weeks by 3.75 mg.

Cancellation of Lucrin Depot® should be considered before the age of 11 in girls and 12 years of age in boys.

Instructions for the preparation of a suspension and injection of the drug Lyukrin Depot® in the bottles:

- Collect 1 ml of solvent from the ampoule into the syringe with the needle in the kit, and insert it into the vial with lyophilizate (the solvent residues should bedispose of).

- Shake the bottle well until a uniform suspension is obtained. The suspension becomes milky.
- Immediately after the dilution, dial the entire contents of the vial (or 2 bottles) into the syringe (maximum 2 ml per syringe) and make a subcutaneous or intramuscular injection.

Although the prepared suspension of Lucrin Depot® remains stable for 24 hours after reconstitution, it should be used immediately after preparation. The rest of the drug must be disposed of.

Instructions for injection of the drug Lyukrin Depot® in two-chamber syringes:

- Screw the white piston into the end plug until the plug starts to rotate.

- Hold the syringe in the VERTICAL POSITION. Enter the solvent, SLOWLY (for 6-8 seconds) by pressing ON the piston, until the first plug is on the blue line in the middle of the syringe.
- Continue to hold the syringe VERTICALLY. With gentle rocking, mix the lyophilizate thoroughly with the solvent until a uniform suspension (suspension) is formed. The suspension becomes milky.
- Hold the syringe VERTICALLY. With the other hand, remove the needle cap from the top, without unscrewing it.
- Hold the syringe VERTICALLY. Push the piston forward to remove air from the syringe. - Immediately after the formation of the suspension, immediately enter the entire contents of the syringe intramuscularly or subcutaneously, since the suspension settles very quickly.

Side effects:

From the cardiovascular system: swelling, stenocardia, palpitations, bradycardia, tachycardia, arrhythmia, chronic heart failure, changes in the electrocardiogram (ECG), vasodilation, increased blood pressure (BP), decreased blood pressure, orthostatic hypotension, myocardial infarction, phlebitis, venous and arterial thromboembolism .h. thromboembolism of the pulmonary artery, stroke, thrombosis, transient ischemic attacks, violation of peripheral circulation, sudden cardiac death.

From the digestive system: increase, decrease or lack of appetite, impaired taste, dry mouth or hypo-salivation, thirst, dysphagia, nausea, vomiting, diarrhea or constipation, flatulence, gastrointestinal bleeding, gastritis, increased activity of "liver" transaminases, severe liver damage.

From the endocrine system: pain in the mammary glands, soreness of the mammary glands, gynecomastia, galactorrhea, an increase in the thyroid gland, apoplexy of the pituitary gland, impaired glucose tolerance, diabetes mellitus, androgen-like effects - virilization, acne, seborrhea, hair growth, voice change.

From the hematopoiesis: anemia, thrombocytopenia, an increase in the number of leukocytes, leukopenia, neutropenia, an increase in prothrombin and activated partial thromboplastin time.

From the musculoskeletal system: pain in the bones, arthralgia, myalgia, increased muscle tone; a change in bone density with bone densitometry in women as a result of a decrease in estrogen levels, and osteoporosis.

From the central and peripheral nervous system: headache, dizziness, confusion, fainting, sleep disturbances (insomnia, increased drowsiness), increased irritability, depression, paresthesia, memory impairment, hallucinations, hyperesthesia, inhibition, emotional lability, personality changes, neuromuscular disorders, peripheral neuropathy, convulsions, muscle weakness, cases the emergence of suicidal thoughts in patients and suicidal attempts.

On the part of the respiratory system: cough, shortness of breath, epistaxis, pharyngitis, pleural effusion, fibrous formations in the lungs, pulmonary infiltrates, respiratory distress, interstitial lung disease.

From the skin and its appendages: dermatitis, dry skin, pruritus, rash (including maculopapular), urticaria, ecchymosis (skin hemorrhages), alopecia, hyperpigmentation, skin discoloration, eczema, nail changes, photosensitivity reactions; in women - acne, hypertrichosis, hirsutism.

From the sense organs: conjunctivitis, impaired vision and hearing, tinnitus.

From the genitourinary system: dysuria, hematuria, polyuria, irregular periodicity of the menstrual cycle, dysmenorrhea, vaginal bleeding, dryness of the vaginal mucosa, vaginitis, vaginal discharge (bleeding), prostatic pain, swelling of the penis, testicular atrophy, testicular pain, decreased libido, erectile dysfunction .

Violations from laboratory indicators: increased blood urea nitrogen concentrations, increased uric acid concentrations, hypercalcemia and hypercreatininaemia, hypoProteinemia, hyperlipidemia (increase in total cholesterol, low-density lipoprotein cholesterol, triglycerides), hyperphosphatemia, hypoglycemia, hyperglycemia, hypokalemia, hyperuricemia; increased activity of alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase (ACT), an increase in the concentration of bilirubin in the blood, the appearance of protein in the urine, an increase in the number of reticulocytes, an increase in the concentration of PSA (prostate-specific antigen).

Local reactions: tissue tightening, hyperemia, edema, irritation and pain at the injection site, abscess.

Other: allergic reactions (including anaphylactic shock), asthenia, fatigue, peripheral edema, increase or decrease in body weight, change in body odor, flu-like syndrome, blood "flushes" to the skin of the face and upper chest, increased sweating, adherence (in the first week of treatment), acute urinary retention and / or spinal cord compression (in men in the first 2 weeks of treatment), growth retardation (in children), development of secondary tumor diseases (skin cancer, new infections cervical and breast mammary glands).

Overdose:

There are no data on the overdose of leuprorelin in humans.In patients with prostate cancer, the appointment of leuprorelin at a dose of up to 20 mg / day for 2 years did not cause adverse events other than those observed with the drug at a dose of 1 mg / day. In case of an overdose, the patient should be given symptomatic treatment.

Interaction:

Pharmacokinetic studies on the drug interaction Lyukrin Depo ® with other drugs have not been conducted. However, since leuprorelin is a substance of a peptide nature and undergoes primary decomposition under the influence of peptidase, rather than cytochrome P450 enzymes, and about 46% of the drug binds to blood plasma proteins, drug interaction is unlikely.

Special instructions:

Lucrin Depot® should only be used under medical supervision.

Convulsions

Post-marketing messages about convulsions were received on the background of the use of leuprorelin. Seizures were observed in patients of the following categories: women; children; patients with seizures, epilepsy, cerebrovascular disorders, developmental anomalies or tumors of the central nervous system, as well as patients taking drugs simultaneously,which can cause convulsions, for example, bupropion or selective serotonin reuptake inhibitors (SSRIs). Cases of seizures in patients without any of the described conditions are also described.

Prostate Cancer

In most patients, the testosterone concentration rises from baseline during the first week, and then decreases to or below the baseline concentration at the end of the second week of treatment. Postastratsionnaya concentration is achieved within 2-4 weeks and maintained throughout the period of regular use of the drug.

During the first few weeks of treatment with Lucrin Depot®, transient symptoms of impairment may develop or additional signs and symptoms of the underlying disease may appear. In a small number of patients, pains in the bones that can stop with symptomatic treatment may increase. Increased symptoms of worsening during the first several weeks of treatment with Lucrin Depot® in patients with spinal metastases, with obstruction of the urinary tract or with hematuria, may lead to neurological problems such as temporary weakness of the lower limbs, paresthesia and weighting of the urological symptoms.As with other analogues of GnRH, when using the drug Lyukrin Depot, there were isolated cases of obstruction of the urinary tract and compression of the spinal cord, which can be complicated by paralysis with / without fatal outcome. Therefore, during the first few weeks of treatment, patients with metastases in the spine and severe obstruction of the urinary tract require careful observation.

Men taking GnRH analogues had hyperglycemia and a high risk of developing diabetes mellitus. Hyperglycemia can be a signal for both the development of diabetes mellitus and the worsening of glycemic control in patients with diabetes. It is necessary to monitor the concentration of glucose in the blood and / or glycosylated hemoglobin (HbAlc) and treat hyperglycemia or diabetes mellitus.

An increased risk of myocardial infarction, sudden death and stroke in men receiving analogues of GnRH has been reported. According to the available data, the risk is low and when prescribing therapy for patients with prostate cancer it should be evaluated, taking into account risk factors for the development of cardiovascular diseases.It is necessary to follow the symptoms and indicators that indicate the development of cardiovascular diseases in patients taking analogues of GnRH.

Influence on the interval QT/QTc

During prolonged therapy for deprivation of androgens, an interval elongation was observed QT. The physician should correlate the benefits of therapy for androgen deprivation with potential risks in patients with congenital syndrome of an elongated QT, with deviations from the norm of the content of electrolytes, with chronic heart failure, as well as in patients taking antiarrhythmic drugs of class IA (eg: quinidine, procainamide) or class III (amiodarone, sotalol).

Endometriosis / Fibromyoma of the uterus

At the very beginning of the course of treatment, a transient increase in the concentration of sex hormones is usually noted, which determines the physiological manifestations of the action of the drug. Some aggravation of symptoms at the beginning of therapy with the drug Lucrin Depot® passes quickly enough with the continuation of treatment with adequately selected doses of the drug. Reported cases of severe vaginal bleeding, requiring conservative or surgical treatment.

During treatment and before the restoration of menstruation, non-hormonal methods of contraception should be used.

Ability to fertilize or fertility, suppressed as a result of therapy, is restored in the period up to 24 weeks after the end of treatment.

Reduction of bone density with bone densitometry in women as a result of a decrease in the concentration of estrogens is reversible, and after the cessation of leuprorelin treatment, bone tissue density is restored.

The use of the drug Lucrin Depot in women causes oppression of the pituitary-gonadotropic system. After the end of treatment, the function is restored after 3 months. However, diagnostic tests that testify to the function of the pituitary gland or gonads, carried out during treatment and up to 3 months after its termination, may be distorted.

The drug is prescribed for treatment premature puberty, based on the following criteria:

- Clinical diagnosis of PPP (idiopathic or neurogenic) with the appearance of secondary sexual characteristics of up to 8 years in girls and up to 9 years in boys.

- The diagnosis should be confirmed by the GnRH stimulation test,and also it is necessary to take into account that the bone age is one year ahead of the biological one.

Initial examination includes:

a) measurement of height and weight;

b) determination of the concentration of sex hormones;

at) determination of the concentration of adrenal steroids to exclude congenital hyperplasia of the adrenal glands;

d) determination of the concentration of human chorionic gonadotropin to exclude the presence of a tumor secreting chorionic gonadotropin;

e) ultrasound examination of the pelvic and adrenal glands to exclude steroid-producing tumors;

(e) computed tomography of the head to exclude intracranial tumors.

The dose of Lucrin Depo ® preparation for the preparation of depot suspensions should be individualized for each child. The dose is based on the ratio of the amount of the drug to the body weight (mg / kg). Young children require higher doses in terms of mg / kg.

When using any form of dosing, one or two months after the start of therapy or a dose change, a child's follow-up examination should be performed with a GnRH stimulation test,sex hormones and staging by Tammer to confirm suppression. Measure the advance of bone age should be carried out every 6-12 months. The dose should be titrated until the absence of disease progression, according to clinical and / or laboratory data.

The first dose, which was sufficient to maintain adequate suppression, can be maintained throughout the therapy in most children. However, there is no sufficient amount of data to establish a corrected dose for patients moving to higher weight categories after initiating therapy at a very young age and using low dosages.

It is recommended to confirm adequate suppression in patients whose weight significantly increased during treatment.

Cancellation of Lucrin Depot® should be considered before the age of 11 in girls and 12 years of age in boys.

Violations of the regimen of the drug or an incorrectly chosen dose can lead to inadequate control of the pubertal process. Among the consequences of inadequate control are the resumption of puberty symptoms, such as menstruation, development of the mammary glands and growth of testicles.The long-term consequences of inadequate control of the secretion of gonadal steroids are unknown, but, perhaps, they include the subsequent disruption of growth in adulthood.

Laboratory research

Monitoring response to therapy with Lucrin Depot® should to spend one or two months after the start of therapy with the help of a test for stimulating GnRH and determining the concentrations of sex hormones.

The concentration of sex hormones can increase above the limits of the prepubertal level in case of an inadequate dose. Once the therapeutic dose has been established, the concentration of gonadotropins and sex hormones will decrease to prepubertal levels.

Information for parents

Before starting therapy with Lucrin Depot®, parents or guardians should be warned about the importance of continuous therapy.

During the first two months of therapy, girls may have menstruation or spotting. If the bleeding lasts more than two months, you should inform the doctor about it. The doctor should immediately report the occurrence of irritation at the injection site and any unusual symptoms or symptoms.

Effect on the ability to drive transp. cf. and fur:

Data on the effect of the drug on the ability to drive and work with mechanisms there. However, since it is possible the occurrence of such side effects as drowsiness, dizziness, etc., it is recommended that during therapy with Lucrin Depot®, refrain from driving and practicing other activities requiring high concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Liofilizate for the preparation of a suspension for intramuscular and subcutaneous administration of prolonged action 3.75 mg.

Packaging:

The drug in the vial:

According to 44.1 mg of lyophilizate in a 9 ml glass vial, sealed with a rubber stopper, fixed on a vial with an aluminum cap, onto which a polypropylene lid is placed. 2 ml of solvent in an ampoule of transparent glass.

A kit for single-dose administration contains the components necessary for one intramuscular or subcutaneous injection:

- one vial containing lyophilizate;

- one ampoule of transparent glass containing a solvent for the preparation;

- two blister packs, each containing one sterile needle;

- one disposable empty sterile propylene syringe;

- a napkin, impregnated with 70% isopropyl alcohol, in laminated polyethylene paper.

One set in a blister pack together with instructions for use in a cardboard bundle.

The drug in a two-chamber syringe:

44.1 mg of lyophilizate and 1 ml of solvent for suspension in different chambers of a two-chamber syringe consisting of an anterior complex with a sealed plastic cap, a glass cartridge with rubber stoppers and a finger rest.

A kit for single-dose administration contains the components necessary for one intramuscular or subcutaneous injection:

- one two-chamber syringe containing lyophilizate in the chamber nearest to the needle, and in the chamber nearest to the piston, a solvent;

- one plastic piston;

- one or two napkins impregnated with 70% isopropyl alcohol, in laminated polyethylene paper.

One set together with instructions for use in a plastic case with a first-opening control system.

Storage conditions:

At a temperature of 15 to 25 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the drug after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N 015554/01

Date of registration:10.03.2009

The owner of the registration certificate:Abbott Laboratories SAAbbott Laboratories SA Spain

Manufacturer: & nbsp

TAKEDA PHARMACEUTICAL COMPANY, Limited Japan

Representation: & nbspABBOTT LABORATORIES LLC ABBOTT LABORATORIES LLC Russia

Information update date: & nbsp06.11.2015

Illustrated instructions

Instructions

Lucrin Depot® (Lucrin depot®)