Eligard

General characteristics. Structure:

Active agent: no

excipients: the solvent consisting of copolymer of poly-D, L-laktid-co - glycolide and N-methyl-2-pirrolidona.

1 syringe B contains:
active agent: leyprorelina acetate *
dosage of 7,5 mg:   10,2 mg
dosage of 22,5 mg:   28,2 mg
dosage of 45 mg:  58,2 mg   

excipients: no

* Surplus of a leyprorelin of acetate offsets losses in the syringe and a needle. The recovered solution (the entered dose) contains 7,5 mg, 22,5 mg or 45 mg of a leyprorelin of acetate.

Description
Syringe A (solvent)
Dosage of 7,5 mg: From light yellow to light yellow with a brownish shade transparent, viscous liquid, without visible foreign particles. Existence of vials of air is allowed.
Dosages of 22,5 mg and 45 mg: From colourless to light yellow, transparent, viscous liquid, without visible foreign particles. Existence of vials of air is allowed.

Syringe B (lyophilisate of a leyprorelin of acetate)
Lyophilisate from white till almost white color, without visible foreign particles.

The recovered solution
Dosage of 7,5 mg: from light yellow to light yellow with a brownish shade viscous liquid without visible foreign particles. Existence of vials of air is allowed.
Dosages of 22,5 mg and 45 mg: from colourless till light yellow color viscous liquid without visible foreign particles. Existence of vials of air is allowed.

Pharmacological properties:

Pharmacodynamics. Leyprorelin is a synthetic not peptide analog of natural gonadotrophin-rileasing-hormone (GNRG) which at prolonged use inhibits secretion of a pituitary gonadotrophin and suppresses a testicular steroidogenesis at men. The analog has bigger efficiency, than natural hormone and its influence is reversible at the treatment termination.
Purpose of a leyprorelin at first leads to increase in level of the circulating luteinizing hormone (LH) and follicle-stimulating hormone (FSG) therefore the level of gonadal steroids, testosterone and dihydrotestosterone at men temporarily increases. At long use of a leyprorelin the LG and FSG level decreases. At men the level of testosterone decreases to kastratsionny level (≤ 50 ¡ú/dl) within 3 – 5 weeks after an initiation of treatment. The average level of testosterone in 6 months of treatment makes 6,1 (± 0,4) ¡ú/dl for a dosage of 7,5 mg; 10,1 (± 0,7) ¡ú/dl for a dosage of 22,5 mg and 10,4 (± 0,53) ¡ú/dl for a dosage of 45 mg. These values are comparable to testosterone level after performance of a bilateral orkhiektomiya.

Pharmacokinetics. After the first injection in 4-8 hours the average level of the concentration of a leyprorelin (Cmax) defined in blood serum increases to 25,3 ¡ú/dl, 127 ¡ú/dl and 82 ¡ú/dl at use of a leyprorelin in a dose of 7,5 mg, 22,5 mg and 45 mg respectively.
After initial increase (the phase of the plateau makes from 2 to 28 days for a dosage of 7,5 mg; from 3 to 84 days for a dosage of 22,5 mg, from 3 to 168 days for a dosage of 45 mg) the level of a leyprorelin in serum remained rather stable (0,2 – 2 ng/ml). Data on accumulation of substance at repeated injections are absent.
Communication with proteins of plasma - 43% - 49%.
At introduction of 1 mg of a leyprorelin of acetate to men it became clear to intravenously healthy volunteers that at use of two-chamber model the average clearance made 8,34 l/h with a final elimination half-life about 3 hours.
Researches on drug removal Eligard were not conducted.

Indications to use:

Hormonedependent prostate cancer.

Route of administration and doses:

Eligard appoint in the form of a subcutaneous injection once a month at a dosage 7,5 mg, once in three months at a dosage of 22,5 mg and once in six months at a dosage of 45 mg. The entered solution forms the depot of drug providing continuous release of a leyprorelin during the specified period. Prolonged treatment. At increase in level of prostatspetsifichesky antigen (DOG) against the background of the kastratsionny level of testosterone treatment by Eligard should be stopped.  
The place of an injection should be changed periodically. To avoid hit of drug in an artery or a vein.

Correction of doses for special populations of patients
 There are no clinical data on Eligard's use for patients with a liver or renal failure.

Recommendations about preparation of solution for introduction
Contents of two in advance filled sterile syringes have to be mixed just before introduction. Preparation of mix is made as follows:
1. Before use packaging is got from the refrigerator and maintained at the room temperature until temperature of packaging does not reach room.
2. Take the syringe A and the syringe B from packagings. Take out from the syringe B the short piston with the second limiter, get the long piston from packaging with the syringe A and insert it into the syringe B. 
3. Uncover the syringe A (solvent for solution preparation) and the syringe B ( the acetate lyophilized a leyprorelina) and carefully connect syringes. Mix solution, alternately pressing the piston of the syringe A and the syringe B of 60 times for receiving homogeneous solution. Mix, ready to use, has to be colourless or light yellow.
4. Enter the received mix into the syringe B. Remove the syringe A, continuing to press up to the end on its piston. Note: There can be small bubbles. This normal phenomenon and it does not influence formation of depot after introduction in any way. Insert a sterile needle into the syringe B.
5. Mix is ready for hypodermic introduction.
6. Solution has to be immediately entered after mixing.
Only for disposable. Unused solution has to be destroyed.

Features of use:

Eligard has to be applied under observation of the doctor having experience of use of antineoplastic therapy.
Eligard, as well as other drugs agonists GNRG, within the first week of treatment causes short-term increase in concentration of testosterone, dihydrotestosterone and acid phosphatase in blood serum in this connection, at patients symptoms can amplify or arise new, such as ostealgia, neurologic frustration, hamaturia, obstruction of an ureter or infravezikalny obstruction. These symptoms usually pass at therapy continuation. At use of agonists of GNRG it was reported also about cases of a compression of a spinal cord. If necessary it is necessary to carry out standard treatment of these complications.
For patients with metastasises in a backbone and/or a brain, and also for patients with obstruction of uric ways careful observation within the first several weeks of treatment has to be conducted.
Additional purpose of the corresponding anti-androgen three days before the beginning of therapy by Eligard and continuation of its reception within the first two or three weeks of treatment warns effects of initial increase in level of testosterone.
Anti-androgenic therapy increases risk of fractures of bones as a result of developing of osteoporosis. In addition to long deficit of testosterone the old age, smoking, alcohol consumption, excess weight and insufficient exercise stresses can influence development of osteoporosis.
Due to the possible decrease in tolerance to glucose, the patients suffering from a diabetes mellitus need more careful observation at treatment by drug Eligard.
After castration performance by a surgical way Eligard's use does not lead to further decrease in testosterone in blood serum.

Influence on ability to drive the car and to manage mechanisms
Some side effects of drug, such as the increased fatigue, dizziness, vision disorders, can negatively influence ability to driving and performance of potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

The side effects observed at Eligard's use  are generally caused by pharmacological effect of drug.
From cardiovascular system: heat inflows, increase or lowering of arterial pressure, faint. Peripheral hypostases, an embolism of branches of a pulmonary artery, heartbeat, an asthma were in some cases noted.

From a nervous system: hypesthesia, dizziness, headache, sleeplessness, flavoring disorders, disorders of sense of smell, involuntary movements. Sleep disorders, a depression, peripheral dizziness, amnesia, a visual disturbance and hypersensitivity of skin were in some cases noted.

From the alimentary system: nausea/vomiting, diarrhea, dyspepsia, a lock, dryness in a mouth, an eructation, a meteorism.

From respiratory system: a rhinorrhea, the complicated breath.

From urinogenital system: a dysuria, a nocturia, an oliguria, an infection of uric ways, the complicated urination, bladder spasms, a hamaturia, an acute ischuria, an atrophy of testicles, pain in testicles, infertility, impotence, decrease in a libido.

From endocrine system: pain in chest glands, a gynecomastia.

From a musculoskeletal system: arthralgia, dorsodynia, extremity pain, mialgiya, muscular spasms, muscular weakness.
At patients with surgical or medicamentous castration decrease in density of a bone tissue is noted. It must be kept in mind that long reception of Eligard can also lead to decrease in density of a bone tissue and progressing of osteoporosis.

Disturbances from laboratory indicators: decrease in quantity of erythrocytes, level of hemoglobin and a hematocrit, increase in maintenance of a kreatinfosfokinaza in blood, increase in a blood clotting time, the increased content of alaninaminotranspherase, the increased content of triglycerides in blood, the increased prothrombin time, were also noted exceptional cases of thrombocytopenia and a leukopenia.

Local reactions: a burning/pricking, pain, reddening, bruises and an itch in the place of an injection; seldom – consolidation and an ulceration in a drug injection site. 

Others: feeling of an indisposition, the increased fatigue, weakness, skin rash, an alopecia, the increased perspiration, a fever, change of tolerance to glucose, increase in body weight. In the first weeks after the beginning of therapy by Eligard the aggravation of symptoms of a disease can be observed.

Interaction with other medicines:

Researches on studying of pharmacokinetic interaction of drug Eligard with other drugs were not conducted. About Eligard's interaction with other medicines it was not reported.

Contraindications:

Hypersensitivity to a leyprorelin, other agonists of GNRG or to any excipient which is a part of a dosage form.
Surgical castration.
It is contraindicated to women and children.

Overdose:

Data on overdose are not available for people. In case of overdose the patient should appoint a symptomatic treatment.

Storage conditions:

List B. At  a temperature from 2 °C to 8 °C in original packaging. To store in the place, unavailable to children. Period of validity 2 years. Not to use drug after the period of validity specified on packaging.
Ready solution is stable chemically and physically within 30 minutes at  a temperature of 25 °C.

Issue conditions:

According to the recipe

Packaging:

Two sterile in advance filled polypropylene the syringe, in one (syringe B) lyophilisate of a leyprorelin of acetate for preparation of solution for hypodermic introduction contains (10,2 mg for a dosage of 7,5 mg; 28,2 mg for a dosage of 22,5 mg, 58,2 mg for a dosage of 45 mg), in another (syringe A) – solvent (330 mg for a dosage of 7,5 mg; 440 mg for a dosage of 22,5 mg; 426 mg for a dosage of 45 mg). Contents of two syringes represent the combined system.
The syringe A together with the piston for the syringe B and a bag of a moisture absorber (silica gel) is placed in one polyester strip packaging covered with the aluminum laminated foil.
The syringe B together with a syringe needle 0,9 x 12,3 mm of "monoject" (No. 20 for dosages of 7,5 mg and 22,5 mg; No. 18 for a dosage of 45 mg) in a case from transparent plastic and a bag of a moisture absorber (silica gel) is placed in the strip packaging covered with the aluminum laminated foil.
On one strip packaging with the syringe A complete with the piston and a bag of a moisture absorber and on one strip packaging with the syringe B complete with a syringe needle and a bag of a moisture absorber together with the instruction in a cardboard pack.