BUSERELIN-DEPO lyophilisate for the preparation of a suspension for intramuscular administration of prolonged action 3.75 mg bottle No. 1

The effect of "Buserelin" on the female body

The effect of “Buserelin” for uterine fibroids depends on the type of myomatous nodes and the individual characteristics of the patient’s body. It is worth noting that reviews of taking this drug are not always positive, since it causes a number of side effects. At the same time, it is worth noting that when using Buserelin in the form of a nasal spray. Negative manifestations were practically not noticed. Numerous studies show that after therapy with Buserelin, many women develop early menopause. The drug has found wide use in the postoperative period to eliminate the risk of fibroid recurrence.

Compound

Active substance: buserelin acetate 3.93 mg
Excipients:

• DL-lactic and glycolic acid copolymer - 200 mg;
• mannitol - 85 mg;
• carmellose sodium - 30 mg;
• polysorbate 80 - 2 mg.

Description of the dosage form

Active substance: lyophilized powder (fragile lyophilisate) white or white with a slight yellowish tint.

Solvent: transparent colorless solution.

Reconstituted suspension: shake the contents of the bottle until a homogeneous suspension of white or white with a slight yellowish tint is obtained; the suspension should not separate for at least 5 minutes. When standing, the suspension settles, but easily resuspends when shaken. The suspension should pass freely through the needle No. 0804.

pharmachologic effect

Pharmacological action - antiestrogenic, antigonadotropic, antitumor, antiandrogenic.

Pharmacodynamics

A synthetic analogue of natural GnRH. Buserelin competitively binds to the receptors of the cells of the anterior pituitary gland, causing a short-term increase in the level of sex hormones in the blood plasma. Further use of therapeutic doses leads (on average after 12–14 days) to a complete blockade of the gonadotropic function of the pituitary gland, thus inhibiting the release of LH and FSH. As a result, there is a suppression of the synthesis of sex hormones in the gonads, which is manifested by a decrease in the concentration of estradiol in the blood plasma to post-menopausal values ​​in women and a decrease in testosterone content to a post-castration level in men.

The testosterone concentration during continuous treatment for 2–3 weeks decreases to the level characteristic of the orchiectomy state, i.e. pharmacological castration is caused.

Pharmacokinetics

Bioavailability is high. After intravenous administration, Cmax in plasma is achieved after approximately 2–3 hours and remains at a level sufficient to inhibit the synthesis of gonadotropins by the pituitary gland for at least 4 weeks.

Indications for the drug Buserelin-depot

• hormone-dependent prostate cancer;
• mammary cancer;
• endometriosis (pre- and postoperative periods);
• uterine fibroids;
• hyperplastic processes of the endometrium;
• infertility treatment (during an in vitro fertilization program).

• Contraindications

• hypersensitivity to the components of the drug;
• pregnancy;
• breastfeeding period.

Use during pregnancy and breastfeeding

The drug is contraindicated in pregnant and lactating women.

Side effects

Allergic reactions: urticaria, skin hyperemia, rarely - angioedema.

From the side of the central nervous system: frequent mood swings, sleep disturbances, depression, headache.

From the musculoskeletal system: with long-term use - bone demineralization, which is a risk of developing osteoporosis.

In women - headache, depression, sweating and changes in libido, dryness of the vaginal mucosa, pain in the lower abdomen, rarely - menstrual bleeding (during the first weeks of treatment).

In men, when treating prostate cancer during the first 2-3 weeks after the first injection, buserelin can cause exacerbation and progression of the underlying disease (associated with stimulation of the synthesis of gonadotropins and, accordingly, testosterone), gynecomastia, possible hot flashes, increased sweating and decreased potency (rarely requires a change therapy), transient increase in the concentration of androgens in the blood, urinary retention, renal edema - swelling of the face, eyelids, legs; muscle weakness in the lower extremities. At the beginning of treatment, patients with prostate cancer may experience a temporary increase in bone pain; in this case, symptomatic therapy should be carried out. Isolated cases of ureteral obstruction and spinal cord compression have been noted.

Other: in isolated cases (the cause-and-effect relationship has not been clearly established) - pulmonary embolism, dyspeptic symptoms.

Interaction

The simultaneous use of Buserelin-depot with drugs containing sex hormones (for example, in the mode of ovulation induction) may contribute to the occurrence of ovarian hyperstimulation syndrome. With simultaneous use, buserelin may reduce the effectiveness of hypoglycemic agents.

Directions for use and doses

For hormone-dependent prostate cancer - 3.75 mgV/m every 4 weeks.

In the treatment of endometriosis, hyperplastic processes of the endometrium - 3.75 mgv/m once every 4 weeks. Treatment should begin in the first five days of the menstrual cycle. Duration of treatment is 4–6 months.

For the treatment of uterine fibroids - 3.75 mg once every 4 weeks. Treatment should begin in the first five days of the menstrual cycle. The duration of treatment before surgery is 3 months, in other cases - 6 months.

When treating infertility using in vitro fertilization (IVF) - 3.75 mgv/m once at the beginning of the follicular phase (on the 2nd day of the menstrual cycle) or in the middle of the luteal phase (21–24 days) of the menstrual cycle preceding stimulation. After blockade of pituitary function, confirmed by a decrease in the concentration of estrogen in the blood serum by at least 50% of the initial level (usually determined 12–15 days after the injection of Buserelin-depot), in the absence of ovarian cysts (according to ultrasound), the thickness of the endometrium is not more than 5 mm stimulation of superovulation with gonadotropic hormones begins under ultrasound monitoring and control of the level of estradiol in the blood serum.

Rules for preparing the suspension and administering the drug

The drug is administered only intramuscularly.

A suspension for intramuscular injection is prepared using the supplied solvent immediately before administration.

The drug should be prepared and administered only by specially trained medical personnel.

The bottle with Buserelin-depot must be kept strictly vertical. By lightly tapping the bottle, it is necessary to ensure that all the lyophilisate is at the bottom of the bottle.

Open the syringe, attach a needle with a pink pavilion (1.2×50 mm) to it to withdraw the solvent.

Open the ampoule and draw the entire contents of the ampoule with solvent into the syringe, set the syringe to a dose of 2 ml.

Remove the plastic cap from the bottle containing the lyophilisate. Disinfect the rubber stopper of the bottle with an alcohol swab. Insert the needle into the bottle with the lyophilisate through the center of the rubber stopper and carefully introduce the solvent along the inner wall of the bottle, without touching the contents of the bottle with the needle. Remove the syringe from the bottle.

The bottle should remain motionless until the lyophilisate is completely saturated with the solvent and a suspension is formed (approximately 3–5 minutes). After which, without turning the bottle over, you should check the presence of dry lyophilisate at the walls and bottom of the bottle. If dry residues of the lyophilisate are detected, leave the bottle until they are completely saturated.

After the healthcare worker has ensured that there are no residues of dry lyophilisate, the contents of the bottle should be carefully mixed in a circular motion for 30–60 s until a homogeneous suspension is formed. Do not invert or shake the bottle, as this may cause flakes to fall out and the suspension to become unusable.

Quickly insert the needle through the rubber stopper into the bottle. Then lower the cut of the needle down and, tilting the bottle at an angle of 45°, slowly draw the entire suspension into the syringe. Do not invert the bottle when taking it. A small amount of the drug may remain on the walls and bottom of the bottle. Consumption for the residue on the walls and bottom of the bottle is taken into account.

Immediately replace the needle with a pink pavilion with a needle with a green pavilion (0.8x40 mm), carefully turn the syringe over and remove air from it.

Buserelin-depot suspension should be administered immediately after preparation.

Use an alcohol swab to disinfect the injection site. Insert the needle deep into the gluteal muscle, then pull the syringe plunger back slightly to ensure that there is no damage to the vessel. Inject the suspension slowly with constant pressure on the syringe plunger. If the needle becomes clogged, replace it with another needle of the same diameter.

Overdose

Currently, no cases of overdose of Buserelin-depot have been reported.

Precautionary measures

Among women

Patients with any form of depression during treatment with Buserelin-depot should be under close medical supervision.

Ovulation induction should be performed under strict medical supervision.

In the initial stage of treatment with the drug, the development of ovarian cysts is possible.

Before starting treatment with the drug, it is recommended to exclude pregnancy and stop taking hormonal contraceptives, however, during the first two months of using the drug, it is necessary to use other (non-hormonal) methods of contraception.

In men

In order to effectively prevent possible side effects in the first phase of the drug's action, it is necessary to use antiandrogens two weeks before the first injection of Buserelin-depot and for two weeks after the first injection.

special instructions

Influence on the ability to drive a car and other mechanisms. Caution should be exercised when prescribing the drug to patients engaged in potentially hazardous activities that require increased attention and speed of mental and motor reactions.

Release form

Lyophilisate for the preparation of a suspension for intramuscular administration of prolonged action. 320.93 mg of lyophilisate containing 3.75 mg of buserelin, in dark glass bottles with a capacity of 10 ml. The bottles are hermetically sealed with rubber stoppers and aluminum-plastic caps. 2 ml of solvent in neutral glass ampoules.

1 vial is placed in a blister pack. with the drug; 1 amp. with solvent; 1 disposable syringe, capacity 5 ml; 1 sterile injection needle, size 0.8 mm × 40 mm, with a green pavilion, complete with a syringe; 1 sterile solvent needle, size 1.2 mm × 50 mm, with a pink pavilion; 1 knife for opening ampoules or 1 scarifier; 2 alcohol swabs.

When packing solvents into imported ampoules that have rings for opening, an ampoule scarifier or a knife for opening ampoules is not inserted.

1 blister pack of the kit is placed in a cardboard pack.

Manufacturer

Lyophilisate manufacturer:

1. JSC "Pharm-Sintez"

Address: 115419, Russia, Moscow, 2nd Roshchinsky proezd, 8.

Tel.; Fax.

Legal address: 111024, Russia, Moscow, st. 2-ya Kabelnaya, 2, p. 9.

email or

2. LLC "

Legal address: 129344, Russia, Moscow, st. Yeniseiskaya, 3, bldg. 4.

Production address: 171130, Tver region, Vyshnevolotsky district, Zelenogorsky village, st. Sovetskaya, 6A or

3. LLC "Diamed"

Legal address: 123182, Russia, Moscow, st. Zhivopisnaya, 46, p. 8.

Production address: 123182, Russia, Moscow, st. Zhivopisnaya, 46, building 8

Manufacturer of solvent (Mannitol solution for injection 0.8%)

1. JSC "Pharm-Sintez".

Address: 115419, Russia, Moscow, 2nd Roshchinsky proezd, 8.

Tel.; Fax.

Legal address: 111024, Russia, Moscow, st. 2-ya Kabelnaya, 2, p. 9.

email or

2. LLC "

Legal address: 129344, Russia, Moscow, st. Yeniseiskaya, 3, bldg. 4.

Production address: 171130, Russia, Tver region, Vyshnevolotsky district, Zelenogorsky village, st. Sovetskaya, 6A or

3. Altair LLC

Legal address: 142100, Russia, Moscow region, Podolsk, st. Komsomolskaya, 1.

Production address: 142279, Russia, Moscow region, Serpukhov district, pos. Obolensk, building 31.

Organization receiving complaints.

JSC "Pharm-Sintez"

Legal address: 111024, Russia, Moscow, st. 2-ya Kabelnaya, 2, p. 9.

Postal address: 115419, Russia, Moscow, 2nd Roshchinsky proezd, 8.

Tel.; Fax.

e-mail, www.pharm-sintez.ru.

Conditions for dispensing from pharmacies

• On prescription.

Storage conditions for the drug Buserelin-depot

• In a dry place, protected from light, at a temperature of 8 to 25 °C.
• Keep out of the reach of children.

Shelf life of the drug Buserelin-depot

• Lyophilisate - 3 years; solvent - 5 years.
• Do not use after the expiration date stated on the package.

The role of buserelin in the treatment of common forms of prostate cancer (PCa).

The role of buserelin in the treatment of common forms of prostate cancer (PCa).

S.V. Mishugin, A.A. Drobyazko, A.A. Mordovin, A.A. Gritskevich, I.G. Rusakov.

Since 1941, following a study published by Huggins and Hodges demonstrating the dependence of prostatic cells on androgens, hormone therapy (HT) has been the mainstay of treatment for locally advanced and metastatic PCa [1]. The basis of any HT strategy is the principle of androgen blockade, which can be achieved by turning off the production of endogenous testosterone [2], as well as stopping the androgenic effect due to the competitive action of medicinal agents [3].

Currently, the main method of androgen deprivation is medical castration using LHRH agonists [4]. Today, preference is given to drug androgen deprivation rather than surgical castration. This is due to the psycho-emotional state of patients after surgery and many side effects, with an equal clinical effect, which is reflected in a number of studies. It is also possible to use intermittent hormone therapy regimens, which leads to regression of adverse reactions during temporary drug withdrawal [5,6].

One of the drugs of this group widely used in clinical practice is buserelin.

The drug buserelin is enclosed in microspheres with different resorption periods, the basis of which is a biosoluble copolymer of DL lactic and glycolic acids. Microspheres in the form of an aqueous suspension are injected deeply intramuscularly. After injection of the drug, a gradual release of the LHRH analogue from the surface of the microspheres begins, which during the first few days leads to stimulation of the synthesis of gonadotropins, and then to desensitization of the pituitary gland and blockade of the pituitary-gonadal axis. Subsequently, the microspheres, undergoing biodegradation in tissues, slowly release the LHRH analogue they contain, long-term maintaining the concentration of the drug in the blood necessary for desensitization of the pituitary gland [7,8,9].

From the beginning of December 2011 to December 2014, we observed 142 patients with prostate cancer aged 56 to 70 years who were treated with LHRH analogues. The average age of patients was 64.6 years.

Before the start of treatment, all patients underwent an examination, which included a survey, examination, and determination of PSA levels in the blood serum (at least 7-10 days after transrectal/transurethral manipulations). To assess the local extent of the tumor process, a digital rectal examination was performed in all cases. To determine the location, size and extent of the primary tumor, all patients underwent TRUS of the prostate. After receiving the measurement data, the prostate volume was calculated using software. In order to identify regional and distant metastases, transabdominal ultrasound of the abdominal organs, retroperitoneum and pelvis, chest radiography, and bone scanning were performed in all cases. To clarify the extent of the primary tumor and the condition of the pelvic lymph nodes, patients underwent CT or MRI of the pelvis. Also, all patients underwent clinical and laboratory tests (analyses of the general, biochemical composition of the blood, its coagulation system, general urine analysis and bacteriological examination of urine (as indicated), electrocardiography). To verify the diagnosis, all patients underwent transrectal biopsy of the prostate gland under ultrasound guidance.

75 had locally advanced PCa, 67 had generalized PCa (Table 1). The patients are divided into two groups.

In the first group (n=55), patients received therapy with the drug Buserelin-depot, in the second (n=87) - one of the other LHRH analogues (goserelin, leuprorelin, triptorelin). The period of drug treatment was at least 6 months.

Table 1. Distribution of patients by disease stage

At the time of inclusion in the study, 137 (96.5%) of 142 men had complaints. The main symptoms of the disease were urinary disorders (77.6% of cases in the group of patients receiving Buserelin and 66.7% in the group receiving other LHRH analogues), pain of various locations caused by the primary tumor (5.5% of cases in the first group and 13.8% in second), bone metastases (30.9% of patients from the first group and 35.6% from the second), as well as impaired outflow of urine from the collecting system (23.6% of patients from the first group and 17.2% from the second) (Table 2 ).

Table 2. Complaints of 142 patients with advanced prostate cancer.

The purpose of the study was to evaluate the effectiveness of the drug Buserelin-depot at a dose of 3.75 mg, with a dosage frequency of 1 time in 28 days, by studying the dynamics of testosterone, PSA levels, and prostate volume; to determine the effect of the drug on the activity status of patients and the level of pain and compare it with a group of patients treated with other LHRH analogues, and monitor side effects.

Patients of group 2 received one of the LHRH analogues also once every 28 days. In addition to hormone therapy, patients with bone metastases were treated with other specialized treatment methods: palliative distant therapy for bone metastases, treatment with zoledronic acid.

During histological verification of the diagnosis, moderately and poorly differentiated forms of prostate cancer predominated (Table 3).

Table 3. Histological types of tumors

For patients in both groups, before the start of treatment, PSA and testosterone levels were determined, activity status was assessed according to the Karnofsky scale, pain status according to the WHO scale, and prostate volume was measured using TRUS.

Subsequently, all patients underwent PSA and testosterone monitoring every 4 weeks; after 3 months, a control determination of prostate volume was performed; upon completion of treatment, the activity status and pain status of the patients were re-determined.

All patients had PSA above normal before treatment. The average PSA value in the first group was 107.3 ng/ml, in the second - 97.5 ng/ml. After the start of treatment, most patients had positive PSA dynamics, characterized by a sharp decrease in the first 2 months of treatment, after which gradual regression and stabilization of indicators occurred.

During therapy with Buserelin-depot in patients with prostate cancer, a consistent decrease in average PSA values ​​was revealed from 107.3 ng/ml to 37.8 ng/ml after 2 months, to 27.9 ng/ml after 4 months, to 3.3 ng /ml after 6 months. In the group of patients treated with other LHRH analogues, there was also a regression of the average PSA value: from 97.5 ng/ml to 24.05 ng/ml after 2 months, to 12.35 ng/ml after 4 months, to 3. 1 ng/ml after 6 months.

The dynamics of prostate volume correlated with a decrease in PSA levels. During therapy with Buserelin-depot in patients with prostate cancer, a decrease in the volume of the prostate gland was noted from 55.9 to 39.8 cm3 by 6 months of treatment (-28.8%). The average volume of the prostate gland in patients of group 2 was 63.9 cm3. After 6 months of treatment, the volume of the gland decreased by 33.2% (42.7 cm3). The registered change in the volume of the prostate gland during treatment became a prerequisite for reducing the symptoms of urinary disorders in the vast majority of patients in the study groups.

The average testosterone level in patients of the first group before treatment was 17.7 ng/ml, in the second group the average value was 14.21 ng/ml.

During the therapy, a decrease in testosterone levels to post-castration values ​​was achieved in patients of both groups within a month after the start of hormone therapy. In the first group: from initial 17.7 to 2.12 ng/ml after 2 months and 0.41 ng/ml after 4 months of treatment. In the second group, after 2 months there was a decrease in the average testosterone level from 14.21 to 1.53 ng/ml and to 0.39 ng/ml after 4 months of treatment. After 4 months of treatment, no further significant changes in testosterone levels were observed.

The treatment provided was intermittent. Considering the positive results of 6 months of therapy in the buserelin group and the other LHRH agonists group, further use of the drugs was discontinued with subsequent dynamic monitoring of PSA and testosterone levels.

The dynamics of testosterone levels were monitored in the first and second groups of patients after discontinuation of treatment with LHRH analogues. When analyzing the data obtained, it turned out that an increase in testosterone levels above castration values ​​when using buserelin occurs 1 month after completion of treatment, and in the second group of patients, where other LHRH analogues were used, this was noted after 1.8 months. Further observation showed that the time to restore initial testosterone levels occurred in the buserelin group after 2.4 months, and when using other LHRH analogues after 3.2 months.

In 822 patients before treatment, the activity status on the Karnofsky scale was 80-100%, in 35 – 60-70% and in 25 patients – 50-60% when assessing both groups. It should be noted that patients with generalized forms of prostate cancer had a lower status index. Upon completion of HT, a change in activity status in a positive direction occurred in 5 (9%) patients of group 1 and in 8 (9.2%) in the group of patients receiving therapy with LHRH agonists (Table 4).

Table 4. Activity status of patients in groups before and after treatment

Before the prescription of hormonal therapy, 66 patients (46.5%) had pain syndrome. 76 patients did not require pain relief. 22 (15.5%) patients took non-narcotic analgesics irregularly, 16 (11.3%) patients required inconsistent use of narcotic analgesics to reduce pain, and 28 (19.7%) patients constantly took non-narcotic analgesics. After 6 months of drug use, the number of patients who did not require analgesics in both groups increased by 5.8%. At the same time, none of the patients was able to completely abandon the use of analgesic drugs (Table 5).

Table 5. Dynamics of pain status of patients in groups according to the WHO scale.

When using Buserelin-depot, the vast majority of patients complained of hot flashes and sweating, which was also noted by patients treated with other LHRH agonists. There were no cases of urinary retention, muscle weakness in the lower extremities, edema or lymphostasis. It should be noted that most side effects are completely reversible after discontinuation of the drugs.

Experience with the use of Beserelin Depot has shown that it is highly effective for the treatment of hormone-dependent prostate cancer. The use of Buserelin-depot leads to a decrease in PSA levels, ensures a stable decrease in serum testosterone levels to the post-castration level, a decrease in the volume of the prostate gland and a decrease in symptoms of urinary disorders in the absence of serious side problems. A number of patients showed an increase in activity status, as well as a decrease in the need and dose of analgesics.

An earlier restoration of the initial testosterone level was noted after completion of the course of Buserelin-depot compared to other LHRH analogues, which reduces the severity of side effects of HT and improves the quality of life of patients.

Buserelin depot can be recommended for use as independent therapy or in combination with other hormonal drugs in patients with prostate cancer.

Bibliography

1. Huggins C., Hodges CV Studies on prostatic cancer. II The effect of castration, estrogen and androgen injections on serum. Cancer Res 1944;1:293–297.
2. Oefelein MG, Feng A, Scolieri MJ, et al. Reassessment of the definition of castrate levels of testosterone: implications for clinical decision making. Urology 2000;56:1021-4.
3. Evans CP, Fleshner N, Fitzpatrick JM, et al. An evidence-base approach to understanding the pharmacological class effect in the management of prostatic diseases. BJU Int 2005;95:742-9.
4. Seidenfeld J., Samson DJ, Hasselblad V. et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Annals of Internal Medicine, 2000, v. 132, issue 7, p. 566-577.
5. Anderson J, Abrahamsson PA, Crawford D, et al. Management of advanced prostate cancer: can we improve on androgen deprivation therapy. BJU Int 2008;101:1497-1501.
6. Heidenreich A, Pfister D, Ohlamann CH, et al. Androgen deprivation for advanced prostate cancer. Urologe 2008;47:270-83.
7. Klioze SS, Miller MF, Spiro TP. A randomized, comparative study of buserelin with DES/ orchiectomy in the treatment of stage D2 prostatic cancer patients. Am J Clin Oncol 1988;11(Suppl 2):S17-S182
8. Huben RP, Murphy GP. A comparison of diethylstilbestrol or orchiectomy with buserelin and with methotrexate plus diethylbestrol or orchiectomy in newly diagnosed patients with clinical stage D2 cancer of the prostate. Cancer 1988; 62:1881-7.
9. Bruun E, Frimodt-Moller C. The effect of buserelin versus conventional antiandrogenic treatment in patients with T2-4NXM1 prostatic cancer. A prospective, randomized multicentre phase III trial. The “Danish Buserelin Study Group”. Scand J Urol Nephrol 1996;30:291-7.

Side effects of Buserelin

It is worth noting that “Buserelin” for fibroids and other diseases has a number of side effects:

• From the gastrointestinal tract: thirst, nausea and vomiting, weight gain or loss;
• From the central nervous system: headaches and dizziness, insomnia, constant feeling of weakness and fatigue, depression, anxiety;
• From the cardiovascular system: strong heartbeats, increased blood pressure;
• From the senses: visual impairment, hearing impairment, tinnitus;
• From the endocrine system: hot flashes, severe sweating, decreased libido, pain in the lower abdomen;
• Allergic reactions of varying intensity.

Mode of application

Side effects can be minimized and positive results can be achieved from taking Buserelin by strictly following the dosage and dosage regimen recommended by your doctor. They directly depend on the form of release of the drug. Thus, a nasal spray is usually used three times a day at equal intervals at a rate of 0.9 mg per day. During treatment, oral contraceptives cannot be used, so it is recommended to replace them with other methods of contraception. Intramuscular injections of Buserelin are given every 28 days, starting 5 days before the start of the cycle. If the product is used as preoperative preparation, then injections are given within three months. As for conservative therapy, its course lasts six months.

Contraindications:

• Allergic reaction to buserelin acetate or additional substances;
• Pregnancy and lactation;
• Kidney failure;
• Depression;
• Diabetes mellitus along with two or more complications.