Вантас®

General characteristics. Structure:

Active ingredient: 50,0 mg of a gistrelin of acetate.

Excipients: stearic acid, acrylic polymer: 2 hydroxyethylmethacrylate, 2-gidroksipropilmetakrilat, триметилпропантриметакрилат.

The sterile, not biodegraded, controlled by diffusion system of delivery of medicinal substance with a hydrogel tank containing 50 mg of a gisterelin of acetate which is an agonist of the luteinizing hormone (LH) the hormone rileasing (HR). Vantas is shown for palliative treatment of late stages of a prostate cancer and intended for continuous hypodermic delivery of a gisterelin of acetate (50 mkg/days) within 12 months.

Pharmacological properties:

Pharmacodynamics. Gistrelin is a synthetic analog of natural LGRG. After Vantas's implantation, гистрелин it is released in fabric that leads to secretion oppression by a hypophysis of luteinizing hormone which in turn leads to decrease in concentration of testosterone in blood serum at men. This effect is reversible at the therapy termination. At the beginning Vantas, as well as other agonists of LGRG, can temporarily increase concentration of testosterone in blood serum.

In one month after implantation of concentration of testosterone decrease to limits which are observed after castration, and remain reduced until Vantas remains in an organism. Such oppression leads to regression of a tumor of a prostate and symptomatic improvement of a state at most of patients.

The implant is entered subcutaneously and remains in an injection site within 12 months. Active ingredient is released through a hydrogel tank by a dose about 50 mkg of a gistrelin a day.

The hydrogel tank of an implant determines diffusion speed to the environment with a water basis. Hydrogel is insoluble, however on the structure is similar to living tissue that promotes its biocompatibility as reduces mechanical irritation of surrounding cells and fabrics. Besides, it shows weak surface intention of in vivo that reduces ability of proteins to absorption and accumulation on a surface. It is important for the prevention of thrombosis and other processes of biological rejection.

Pharmacokinetics. Absorption. After hypodermic introduction of one implant Vantas on 50 mg at patients with the progressing prostate cancer (n=17) peak concentration in serum 1,10 ± 0,375 ng/ml (average value ± SD) were observed on average in 12 hours. Long hypodermic release was demonstrated by levels in serum which were supported during all 52 weeks period drug actions.

Average concentration of a gistrelin in serum for the end of the 52 weeks period of effect of drug made 0,13 ± 0,065 ng/ml. At measurement of concentration of a gistrelin in serum after introduction of the second implant in 52 weeks of concentration in serum which were observed in 8 weeks after introduction of the second implant were comparable with the level which was observed during the same period after introduction of the first implant. Average speed of hypodermic release of active ingredient from 41 implants which was counted on residual contents of active ingredient equaled 56,7 ± 7,71 mkg/days during the 52 weeks period of effect of drug. Relative bioavailability of an implant Vantas at patients who have a prostate cancer with normal function of kidneys and a liver made 92% in comparison with a hypodermic bolyusny dose at healthy male volunteers. Concentration of a gistrelin in serum were proportional to a dose after introduction of one, two or four implants Vantas on 50 mg (50, 100 or 200 mg in the form of a gistrelin of acetate) to 42 patients who have a prostate cancer.

Distribution. The expressed volume of distribution of a gistrelin after introduction of a hypodermic bolyusny dose (500 mkg) at healthy adult volunteers made 58,4 ± 7,86 l. The share of untied drug in plasma which was measured by in vitro made 29,5% ± 8,9% (average value ± SD).

Biotransformation. The research of metabolism of the drug in vitro using hepatocytes of the person found the only metabolite of a gistrelin which is result of S-terminal dealkylation. Peptide fragments which are result of hydrolysis are also probable metabolites. After introduction of a hypodermic bolyusny dose to healthy volunteers the expressed clearance of a gistrelin made 179 ± 37,8 ml/min. (average value ± SD), and the terminal elimination half-life made 3,92 ± 1,01 hour (average value ± SD). The expressed clearance after introduction of an implant Vantas on 50 mg (in the form of a gistrelin of acetate) at 17 patients who have a prostate cancer made 174 ± 56,5 ml/min. (average value ± SD).

Removal. Researches of removal of active ingredient at use of implants Vantas on 50 mg were not conducted.

The Luteinizing Hormone (LH) was returned to normal level within 1–6 weeks after removal of an implant. Testosterone level was also returned to normal limits within 2 weeks after increase in the LG level that indicated reversible inhibition.

Renal failure. When comparing average concentration of a gistrelin in blood serum at 42 patients who have a prostate cancer and a renal failure from easy to moderate degree (clearance of creatinine of 15-60 ml/min.) and at 92 patients without renal or liver failure, levels were approximately for 50% higher at patients with a renal failure (0,392 ng/ml against 0,264 ng/ml). Big concentration were observed at patients with higher degree of a renal failure. There are no data on patients with a heavy renal failure. These changes, as a result of a renal failure, are not considered as clinically significant. Therefore this subpopulation of patients does not need dose adjustment.

Liver failure. Influence of a liver failure on pharmacokinetics of a gistrelin is studied insufficiently.

Indications to use:

Palliative treatment of the progressing prostate cancer.

Route of administration and doses:

The recommended Vantas's dose makes one implant for 12 months. The implant is established subcutaneously on the internal surface of a shoulder. Every day in an organism 50 mkg of a gistrelin of acetate are released on average. In 12 months of treatment the implant should be removed. Along with removal of an implant it is necessary to establish a new implant for treatment continuation.

For the procedure of introduction and the subsequent removal of an implant it is necessary to use sterile gloves and to adhere to asepsis techniques to minimize risk of an infection.

Definition of the site of introduction. The patient has to lie on spin, the hand which it uses less often (that is the left hand at the patient right-handed person) has to be bent so that the doctor had easy access to the internal surface of a shoulder. The hand should be propped up pillows so that the patient could hold it in such position easily. The optimum site for introduction is located approximately on the middle of distance from a shoulder joint to an elbow joint in a fold between a biceps and a triceps.

Preparation of the device for implantation. The device for implantation is prepared before preparation of the site of introduction and before the introduction. The device for implantation is got from a sterile package. The device is equipped with the cannula extended at all length. It is checked, controlling a position of the green button of reverse motion. This button has to be completely exposed forward, towards a cannula, from the handle aside.

Delete a metal cover from a glass bottle, delete a rubber bung and use a clip like "Mosquito" to grasp one of implant tips. It is necessary to avoid compression or a latching of a middle part of an implant not to allow disturbance of its form.

Insert an implant into the device for implantation. The implant will be located in a cannula in such a way that at the bottom of a cut only its tip will be visible.

Introduction of an implant. Clear the site of introduction by means of a tampon about povidone-iodine and lay over the place of surgical intervention sterile napkins (for illustration clearness it is not shown in the photo which accompanies this section).

Anesthesia. Check whether the patient on allergic reactions to lidocaine/adrenaline suffers. Enter the corresponding amount of anesthetic, since the planned site of a section further инфильтруя at all length of an implant - 32 mm.

Section. By means of a scalpel do a superficial section of skin 2-3 mm long on the internal surface of a shoulder perpendicularly to biceps length.

Introduction. Hold the device for implantation for the handle, as shown in an illustration. Enter a device tip into a section so that the cut was directed up, push the device subcutaneously to the line noted on a cannula. To make sure that the device is located subcutaneously it is necessary to watch that during introduction the device for implantation visually raised skin. It is necessary to make sure that the device for implantation did not enter muscular tissue.

Holding the device on site, at the same time transfer a thumb to the green button of reverse motion. Press the button to remove blocking, then delay the button back against the stop, holding the device on site. The cannula leaves a section, leaving an implant in a derma. Take out the device for implantation from a section. Correctness of installation of an implant can be checked by a palpation.

Note: do not try to advance the device more deeply after introduction, in order to avoid disturbance of integrity of an implant. If you wish to begin the procedure again, take out the device, grasp an implant by a tip to take out it, install the button of reverse motion in most antelocation, recharge an implant and begin the procedure again.

Closing of a section. Close a section by means of one-two seams (at choice) with the nodes directed in a section. Impose a thin layer of ointment with an antibiotic directly on a section.

Close a section two surgical plasters. Impose gauze laying of 10х10 cm in size on a section and fix by bandage.

Procedure of removal and introduction of a new implant. The implant Vantas should be deleted in 12 months of treatment.

Placement of an implant. The location of an implant can be defined by a site palpation about the section made last year. Usually the implant can be propalpirovat easily. Press a distal tip of an implant to define the provision of a proximal tip of rather old section.

If it is difficult to define the location of an implant, it is possible to use ultrasound. If the location of an implant cannot be defined by means of ultrasound, it is necessary to use other techniques of receiving display, such as computer tomography or MRT.

Preparation of the site for introduction of an implant. Position of the patient and preparation of the site for implantation same, as well as for the first implantation. Clear the site of introduction by means of a tampon about povidone-iodine and lay over the place of surgical intervention sterile napkins.

Anesthesia. At first define whether is not present at the patient of an allergy to lidocaine/adrenaline, then press down a tip of an implant which is located far away from the first section. Enter the corresponding amount of lidocaine/adrenaline about a section, then advance a needle below an implant on all its length, constantly entering a small amount of anesthetic into skin. Anesthetic will lift an implant in a mesoderm. If it is necessary to enter a new implant, there are two options: or to place an implant in same "pocket", as previous, or, using the same section, to enter an implant in an opposite direction. If you place an implant in an opposite direction, before explantation it is necessary to enter anesthetic along length of a new implant.

Section/explantation. By means of a scalpel do a section 2-3 mm long about a tip of an implant and about 1-2 mm in depth. Usually a tip of an implant it is visible via the thin pseudo-capsule of fabric. If the implant is not visible, press a distal tip of an implant and its promassazhiruyta towards a section. Carefully make "notch" on the pseudo-capsule to open a polymer tip.

Take a tip by means of a clip like "Mosquito" and take out an implant. At introduction of a new implant continue as directed rather initial introduction. The new implant can be entered through the same section. It is alternatively possible to use other hand for introduction of an implant.

Abnormal liver function and kidneys. Vantas's use for patients with an abnormal liver function is investigated insufficiently. From easy to moderate degree (clearance of creatinine of 15-60 ml / хв) dose adjustment is not required to patients with a renal failure.

Vantas did not investigate on patients with a heavy renal failure who have a prostate cancer.

Features of use:

Vantas is not intended for use for women. Researches at pregnancy and in the period of a lactation at women were not conducted.

Gistrelin causes temporary increase in concentration of testosterone in blood serum within the first week of treatment. At patients deterioration in symptoms or development of new symptoms, including a joint pain, an ostealgia, a neuropathy, a hamaturia, obstruction of an opening of an ureter or a bladder can be observed. It was reported about cases of obstruction of an ureter and a compression of a spinal cord which can lead to paralysis which is followed or is not followed by deadly complications, in connection with use of agonists of LH-RH. Patients with metastatic damages of a backbone and/or obstruction of urinary tract have to be under careful observation within the first weeks of therapy. It is necessary to consider need of use for such patients of preventive treatment by anti-androgens. At emergence of a compression of a spinal cord or a renal failure it is necessary to begin standard therapy of such complications.

Installation of an implant is the surgical procedure. It is necessary to adhere accurately to recommendations concerning installation and removal of an implant to reduce risk of complications and rejection of an implant.

If it is difficult to determine location of an implant by a palpation, it is possible to use ultrasound or a computer tomography. Reactions to treatment by Vantas should be monitored by means of regular measurement of concentration in serum of testosterone and a specific antigen of a prostate, especially in cases when the expected clinical or biochemical reaction to treatment was not reached.

Results of definition of testosterone depend on an analysis method. For adoption of the correct clinical and therapeutic decision it is recommended to consider type and accuracy of methodology of quantitative definition.

The container of this medicine contains latex rubber that can entail heavy allergic reactions.

Ability to influence speed of response at control of motor transport and work with other mechanisms.

Researches of influence on ability to drive the car and to use mechanisms were not conducted.

Side effects:

Undesirable effects are presented in the table on systems of bodies and frequency of emergence: very often (≥1/10); often (≥1/100 to <1/10); infrequently (≥1/1000 to <1/100); seldom (≥1/10000 to <1/1000).

Infections and invasions. Seldom: skin infections.

System of blood and lymphatic system. Infrequently: anemia.

Endocrine system, metabolism and disturbances of food. Often: increase in body weight, the increased glucose level in blood. Infrequently: the increased testosterone level in blood, decrease in body weight, a liquid delay, a hypercalcemia, a hypercholesterolemia, strong thirst for food, the increased appetite.

Mental disorders. Often: depression, decrease in a libido, sleeplessness.

Nervous system. Often: dizziness, headache. Infrequently: tremor, lethargy.

Cardiovascular system. Very often: inflows крови*. Often: reddening. Infrequently: the accelerated heartbeat, ventricular extrasystoles, hematomas.

Respiratory organs. Often: an asthma after an exercise stress.

System of digestion. Often: lock, hepatic frustration. Infrequently: nausea, discomfort in a stomach, increase in level of aspartate aminotransferase, increase in level of a lactate dehydrogenase in blood.

Skin. Often: hypertrichosis. Infrequently: the strengthened sweating at night, an itch, a hyperhidrosis.

Skeletal and muscular system. Often: arthralgia, extremity pain. Infrequently: a dorsodynia, spasms of muscles, infiltration in muscles, neck pain.

Urinary system. Often: polakizuriya, renal failure, ischuria. Infrequently: renal failure, nephrolithiasis, dysuria, hamaturia, reduced clearance of creatinine.

Reproductive system. Often: erectile dysfunction *, atrophy of testicles *, гинекомастия*. Infrequently: sexual dysfunction, a stethalgia, hypersensitivity of mammary glands, an itch of generative organs (at men), the increased level of acid phosphatase in a prostate.

The general frustration and irritation in an injection site. Often: reaction on the site of introduction, an erythema on the site of introduction, an adynamy, weakness, pain, hypersensitivity. Infrequently: peripheral hypostasis, the pain (strengthened), hypostasis, pain (nonspecific), an indisposition, a cryesthesia, irritability, stent occlusion, developing of bruises.

Seldom: inflammation. * The expected pharmacological reaction to testosterone oppression. Also there can be a decrease in density of bones at men who gave in to an orkhiektomiya or were treated by LH-RH agonist/analogue.

Interaction with other medicines:

Researches of pharmacokinetic interaction of Vantas with other medicines were not conducted. Treatment gistreliny leads to oppression of pituitary and gonadal system. It can affect results of the diagnostic check of pituitary/gonadotropic and gonadal functions which is carried out to time or after treatment gistreliny.

Contraindications:

Hypersensitivity to a gistrelin or to any of implant excipients, the hormone gonadotrophin-rileasing (HGR), agonists/analogues of GRG or stearic acid. Also it was reported about anaphylactic reactions to releasing-hormones (LGRG) or their agonists / analogs synthetic lyuteiniziruyushche. Vantas is not shown to women and children in a type of lack of data on safety and clinical performance.

Overdose:

Information on overdose by drug is absent.

Storage conditions:

Implant: to store in the place, unavailable to children, in the refrigerator at a temperature of 2-8 °C. Not to freeze! To store in original packaging, in the place protected from light.

The device for implantation: to store in the place, unavailable to children, at the room temperature (20–25 °C) in the place protected from light. Not to store in the refrigerator and not to freeze!

Issue conditions:

According to the recipe

Packaging:

Implant – on 1 implant in a glass bottle; on 1 bottle in cardboard packaging. The device for implantation – on 1 device in a package; on 1 package in cardboard packaging.