Visudin® (Visudine®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceVerteporfinVerteporfin
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  • Visudin®
    lyophilizate in / in 
    Novartis Pharma AG     Switzerland
    • Dosage form: & nbsplyophilizate for the preparation of a solution for intravenous administration
    Composition:

    1 the vial contains:

    active substance: verteporfin 15,000 mg;

    Excipients: butyl hydroxytoluene 0.015 mg, ascorbyl-palmitate 0.150 mg, phosphatidyl glycerol (egg) 48.750 mg, dimyristoyl-phosphatidylcholine 70.500 mg, lactose monohydrate 690,000 mg.

    Description:Dark green mass.
    Pharmacotherapeutic group:Remedies for obstructing neoplasm of vessels
    ATX: & nbsp

    S.01.L.A   Preparations preventing neovascularization

    S.01.L.A.01   Verteporfin

    Pharmacodynamics:

    Verteporfin, benzoporphyrinic derivative of monoacids (BPD-MA), is a mixture of equally active stereoisomers BPD-MAFROM and BPD-MAD at ratio of 1: 1. Verteporfin - a photosensitizer producing cytotoxic agents only in the presence of oxygen when activated by light from a non-thermal red laser (wavelength of 689 ± 3 nm). When energy absorbed by porphyrin is transferred to oxygen, a highly active short-lived singlet oxygen. Singlet oxygen destroys biological structures within the diffusion zone, which leads to local occlusion of vessels, damage and under certain conditions to cell death.Since the light effect is carried out directly on the pathological focus, the preparation is rapidly absorbed and accumulates in rapidly proliferating cells, including endothelial cells of abnormal newly formed vessels of the choroid, and the damage to surrounding tissues is minimized.

    Age-related macular degeneration with predominantly classical subfoveal choroidal neovascularization

    The results of the study of the long-term efficacy and safety of verteporfin for the prevention of visual acuity reduction in two randomized, placebo-controlled, double-blind, multicenter studies have shown that photodynamic therapy (PDT) with verteporfin leads to a statistically significant increase in the proportion of patients with age-related macular degeneration with predominantly classical subfoveal choroidal neovascularization with an OZ decrease of less than 15 letters (3 lines) to ETDRS optotypes (Early Treatment Diabetic Retinopathy Study - study "Treatment of diabetic retinopathy at an early stage") for 12 months (67% compared with 39% in the placebo group, p <0.001) and for 24 months (59% compared with 31% in the placebo group, p <0.001) .Results of the effectiveness of long-term treatment with verteporfin up to 60 months were similar to the results for 24 months. There was no new information on the safety of the drug. Age-related macular degeneration with subfoveal choroidal flush neovaskulyarizaiiey without the classic neovascular membranes

    The results of the study of the efficacy and safety of verteporfin in two randomized, placebo-controlled, double-blind, multicenter studies have shown that PDT with verteporfin in patients with age-related macular degeneration with a hidden subfoveal choroidal neovascularization without the classic neovascular membranes leads to an increase in the proportion of patients with a reduction in OZ for at least 3 24 months line (45.2% compared with 31.5% with placebo, p = 0.032).

    Choroidal neovascularization associated with pathological myopia

    Multicentre, double-blind, placebo-controlled, randomized study showed that PDT with verteporfin in patients from choroidal neovascularization associated with pathological myopia, leads to an increase in the proportion of patients with a decrease in O3 by less than 3 lines in 12 months (86% compared with 67% in the placebo group, p = 0.011) and for 24 months (79% compared with 72% in the placebo group, p = 0.38), an increase in the proportion of patients with an OZ decrease of less than 1.5 lines for 12 months (72% compared with 44% in the placebo group, p = 0.003) and for 24 months (64% compared with 49% in the placebo group, p = 0.106), which led to a conclusion about a possible decrease in clinical efficacy time. However, the results of the efficacy of long-term treatment with verteporfin up to 60 months were similar to the results for 24 months. There was no new information on the safety of the drug.

    Pharmacokinetics:

    Distribution

    After a 10-minute intravenous administration in doses 6 and 12 mg / m body surface, the maximum concentration (CmOh) was 1.5 and 3.5 μg / ml, respectively. After 10- a minute intravenous injection of the drug at a dose of 3-14 mg / m, the volume of distribution was about 0,6 l / kg in steady state, and the ground clearance was 101 ml / kg. Interindividual variability of the difference CmOh immediately after the infusion and CmOh at the moment of photo irradiation was no more than 2multiples of CmOh verteporfina in the blood plasma.

    FROMmOh and the exposure of both stereoisomers increases in proportion to the dose. FROMmOh immediately after the administration of the drug is higher BPD-MAD by compared to BPD-MAFROM. The volume of distribution is about 0.5 l / kg.

    Binding to blood plasma proteins

    In human whole blood, 90% of verteporfin is associated with plasma and 10% is associated with the formed elements of the blood. In human plasma, 90% of verteporfin is associated with lipoprotein fractions and about 6% - with albumin.

    Metabolism

    Hydrolysis of the ethereal group of verteporfin in the blood plasma and with the help of liver enzymes leads to the formation of a two-acid derivative of benzoporphyrin (BPD-DA). BPD-DA is also a photosensitizer, but has a low system exposure: 5-10% of the verteporfin exposure, which indicates that most of the verteporfin is excreted unchanged.

    In vitro no effect of the isoenzymes of the cytochrome P system450 on the metabolism of verteporfin.

    Excretion

    After intravenous infusion, excretion of verteporfin occurs bi-exponentially. The half-life of verteporfin from the blood plasma (T1/2) is approximately 5-6 hours. Derivation of verteporfin and BPD-DA kidneys is less than 1%, which indicates the withdrawal of the drug with bile.

    Pharmacokinetics in some cases

    Impaired liver function

    In a study involving patients with a mild liver function disorder (a change of not more than two indices of the "liver" test), significant differences in the values AUC and CmOh, obtained in these patients, from the values ​​obtained in the control group, was not revealed. However, the elimination half-life increased significantly - by approximately 20%.

    Impaired renal function

    Data on the pharmacokinetics of verteporfin in patients with impaired renal function are absent. Since renal excretion of verteporfin and its metabolite is minimal (less than 1% of the administered dose), significant changes in the exposure of verteporfin in patients with impaired renal function are unlikely.

    Ethnicity and race

    The pharmacokinetics of verteporfin did not differ with the use of the drug at a dose of 6 mg / m2 in the form of a 10-minute infusion both in representatives of the white race, and in Japanese.

    Sex and age

    In the recommended doses, changes in the pharmacokinetic parameters of the drug were not observed depending on the sex of the patient.

    There was a slight increase in CmOh and AUC in patients older than 65 years, compared with those of younger patients, but clinically these differences are not significant.

    Indications:

    - Exudative (moist) form of age-related macular degeneration with predominance of classical subfoveal choroidal neovascularization;

    - Subfoveal choroidal neovascularization in pathological myopia.

    Contraindications:

    - Porphyria;

    - impaired hepatic function;

    - hypersensitivity to verteporfinu or to any of the components of the drug;

    - period of breastfeeding (within 48 hours after drug therapy);

    - age to 18 years.

    Carefully:

    Use with caution in case of poor liver function, biliary obstruction, during general anesthetic treatment (see section "Special instructions").

    Pregnancy and lactation:

    There is no data on the use of the drug Vizudin® in pregnant women. In studies in animals, the teratogenic effect was observed only in rats. Potential risk of use in pregnant women is unknown. Application of the drug Visudin® during pregnancy is not recommended unless absolutely necessary (only if the intended use for the mother exceeds the potential risk to the fetus).

    Verteporfin and its two-acid derivative in a small amount penetrate into breast milk. It is necessary to abandon breastfeeding for at least 48 hours after treatment with Vizudin®.

    Data on the effect of verteporfin on fertility a person is not available. In preclinical studies, the animals showed no impairment of fertility and reproductive toxicity. Patients of reproductive age should be informed of the lack of data on the effect of the drug on fertility.

    Dosing and Administration:

    Therapy with Vizudin® can be initiated and performed only by a doctor who has experience in diagnosing and treating patients with age-related macular degeneration or with pathological myopia.

    Adults

    Photodynamic therapy with the drug Visudin® is carried out in two stages. Intravenous for 10 minutes injected solution of the drug at a dose of 6 mg / m2 body surface in 30 ml of the infusion solution (see below "Instructions for the preparation of a solution of the drug Vizudin®").

    1. 15 minutes after the start of infusion of the solution of the drug Vizudin®, photoactivation is performed (see below "Photoactivation").

    It is necessary to monitor the patient's condition every 3 months, if the disease recurs, treatment with the drug can be repeated up to 4 times a year.

    There is no data on the simultaneous use of the drug for treating both eyes. If simultaneous treatment of both eyes is necessary, the light effect on the second eye should be performed immediately after irradiation of the first eye, but no later than 20 minutes after the initiation of intravenous infusion of the drug.

    Patients with hepatic impairment

    It is necessary to use with caution the drug Vizudin® in patients with impaired liver function of medium degree and with obstruction of the biliary tract, since there is no experience of using the drug in patients of this category. As verteporfin is excreted mainly with bile, in patients with impaired liver function, it is possible to increase its exposure. It is not necessary to correct the dose of the drug in patients with mild liver function disorders, since the exposure of verteporfin in this group of patients increases insignificantly.Contraindicated use of the drug Vizudin® in patients with impaired hepatic function of a serious degree (see section "Contraindications").

    Patients with impaired renal function

    Application of the drug Visudin® in patients with impaired renal function has not been studied. However, according to the pharmacological properties of the drug, dose adjustment in patients of this category is not required.

    Children and teenagers under 18 years of age

    Since the use of the drug Vizudin® in children and adolescents under the age of 18 years has not been studied, the use of the drug in patients of this category is contraindicated (see section "Contraindications").

    Instructions for preparation of solution of the drug Visudin®

    Vizudin® is dissolved in 7 ml of water for injection to give 7.5 ml of a dark green opaque solution at a concentration of 2.0 mg / ml. Before the drug should be visually assessed the quality of dissolution of the drug Vizudin® and the color of the solution. The drug can not be used when the color changes and the appearance of undissolved visible particles. The required volume of solution of the drug Visudin® (in a dose of 6 mg / m2 body surface), calculated from the growth and weight of the patient, must be diluted with 5% dextrose solution until a final volume of 30 ml is obtained.Do not use 0.9% sodium chloride solution or saline solutions for parenteral administration to dilute. For the introduction of the drug is recommended to use a standard drip system with a filter (the filter pore size is not less than 1.2 micrometers).

    After a single administration, an unused solution of the drug Visudin®, remaining in the vial, can not be used.

    It is necessary to conduct a wet cleaning of the floor and all objects contaminated with the product. Avoid getting the solution of the drug Visudin® on the skin and eyes. When working with the drug is recommended to use protective goggles and rubber gloves. Dispose of all materials properly.

    Method of administration

    The drug is intended for intravenous administration.

    Photoactivation

    For photo activation of the drug Vizudin® a beam of non-thermal red light (wavelength 689 ± 3 nm), generated by a diode laser, is conducted to the retina using an optical fiber device mounted in a slit lamp, using special contact lenses. At a recommended light intensity of 600 mW / cm2 to achieve the required dose of irradiation with an energy of 50 J / cm2 it takes 83 seconds. The maximum linear size of the area of ​​choroidal neovascularization is determined by fluorescence angiography and eye-fund photographing (a fundus camera with a 2.4-2.6 fold increase is recommended). The light beam should be directed to newly formed vessels, areas of hemorrhages and / or hypofluorescence zones. For therapeutic treatment of the lesion with indistinct boundaries, the area of ​​light irradiation at 500 μm should be widened from the boundaries of visible lesions. The nasal border of the exposure area should be at least 200 μm from the temporal edge of the optic nerve disc. In clinical studies, the maximum size of the laser spot on the retina for the first treatment was 6400 μm. When treating a lesion whose size exceeds the possible irradiation zone, the light beam should be directed to the lesions with the greatest activity of the pathological process.

    To obtain the optimal therapeutic effect, it is important to follow the above recommendations.

    Side effects:

    The adverse events (AEs) observed with the drug in clinical trials are presented below. AEs are grouped according to the classification of organs and systems of organs MedDRAare listed in order of decreasing frequency of occurrence.

    The following criteria were used to estimate the frequency of occurrence: very often (≥1 / 10), often (≥1 / 100 - <1/10), infrequently (≥ 1/1000 - <1/100), rarely (≥1 / 10000 - <1/1000), very rarely (<1/10000), the frequency is unknown (reports of AE data obtained voluntarily from a population of undetermined size, it is not possible to reliably determine the frequency of development).

    Immune system disorders: often hypersensitivity1.

    Disorders from the metabolism and nutrition: often hypercholesterolemia.

    Disturbances from the nervous system: often - fainting, headache, dizziness; infrequent - decreased sensitivity; frequency is unknown - presyncopal state (vasovagal reactions1).

    Disorders from the side of the organ of vision: often - visual impairment: fuzzy, fogging, blurred vision, light glare, reduced OZ2, visual field defect,such as gray or black haloes, scotoma, black spots; infrequent retinal detachment, retinal hemorrhage, vitreous hemorrhage, retinal edema; rarely - retinal ischemia (impaired perfusion of the vessels of the retina or choroid); frequency unknown - rupture of retinal pigment epithelium, edema of the optic disc.

    Disturbances from the musculoskeletal and connective tissue: often - backache.

    Disturbances from the respiratory system, chest and mediastinal organs: often - shortness of breath.

    Vascular disorders: infrequently - increased blood pressure (BP); frequency is unknown - fluctuation of blood pressure, "hot flashes".

    Violations from the side of the cardio-cardiovascular system: infrequently - hypertension; frequency unknown - myocardial infarction3.

    Disorders from the gastrointestinal tract: infrequently - nausea.

    Disturbances from the skin and subcutaneous tissues: often - reactions photosensitivity4; infrequent rash1, urticaria1, itching1; frequency is unknown - hyperhidrosis.

    General disorders and disorders at the site of administration: often - chest pain, asthenia, edema, inflammation, extravasation at the injection site, pain at the injection site5; infrequently - a fever, a hemorrhage at the injection site, a discoloration of the skin at the injection site, a hypersensitivity reaction at the injection site; rarely - a feeling of indisposition1; frequency unknown - blistering at the injection site.

    Laboratory and instrumental data: frequency unknown irregular heartbeat.

    Violations of the genitals and breast: frequency unknown - pelvic pain.

    References:

    1 Vasovagal reactions (presyncopal states) and hypersensitivity reactions, including general symptoms such as headache, feeling of malaise, syncope, increased sweating, dizziness, rash, hives, itching, dyspnea, hyperemia and changes in blood pressure and heart rate. In rare cases, the occurrence of severe reactions, including the development of seizures.

    2 - A marked decrease in OZ of 4 rows or more within 7 days after treatment was noted in 2.1% of patients in placebo-controlled clinical trials and less than 1% of patients who received the drug in clinical studies without placebo control. In most cases, such a decrease in OC was observed in patients with age-related macular degeneration and latent choroidal neovascularization.Later, partial restoration of OZ was observed in some patients.

    3 - Cases of myocardial infarction were noted mainly in patients with a history of cardiovascular disease, within 48 hours after the administration of the drug.

    4 - Photosensitivity reactions were observed in 2.2% of patients and were expressed in the form of sunburn, which usually occurs on the first day after the injection of the drug Vizudin®. To prevent the development of photosensitivity reactions, follow the instructions for protection against light exposure.

    5 - Pain in the chest and back associated with the administration of the drug, can have different radiation, incl. among other things, the pelvic, humeral or thorax. Back pain with the administration of the drug was not associated with any signs of hemolysis or allergic reactions and, as a rule, was resolved after the end of the infusion.

    If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, inform the doctor about it.

    Overdose:

    An overdose of the drug and / or light irradiation on the eye can lead to indiscriminate disruption of the blood supply to normal retinal vessels with a possible pronounced decrease in O3.

    An overdose of the drug can also lead to an extended period of photosensitization of the patient. In such cases, the patient should extend the time of skin and eye protection from exposure to direct sunlight or bright indoor lighting according to the dose received.

    Interaction:

    Special studies of drug interaction in humans have not been conducted.

    Simultaneous use with other photosensitizing agents (such as tetracycline, sulfanilamide, phenothiazine, sulfonylureas and other oral hypoglycemic agents, thiazide diuretics and griseofulvin) may increase the risk of photosensitivity reactions.

    Damage of the vascular endothelium under the influence of blockers of "slow" calcium channels, polymyxin B or radiotherapy products with their simultaneous application with verteporfinom can lead to increased capture of the drug by the endothelium.

    Antioxidants (for example, beta-carotene), or drugs that inactivate free radicals (for example, dimethylsulfoxide, salts of formic acid, mannitol, ethanol), can inactivate the active forms of oxygen produced by the action of verteporfin, and thus reduce the activity of the drug.

    Because vascular occlusion is the main mechanism of action of verteporfin, there is a possibility that drugs with a vasodilating effect or those that violate thrombus formation and platelet aggregation (eg, thromboxane A2 inhibitors) may reduce the effectiveness of verteporfin.

    Salt solutions precipitate the preparation. To dilute the drug, 0.9% sodium chloride solution or saline solutions for parenteral administration should not be used. Also, do not mix Vizudin® with other medicinal solutions.

    Special instructions:

    During the administration of the drug Visudin® patients should be under medical supervision.

    Light sensitivity and light exposure

    Patients receiving therapy with Visudin®, remain sensitive to light within 48 hours after the administration of the drug. During this period, the patient should avoid exposure to exposed areas of the skin, direct sunlight and bright artificial light (for example, lighting in solariums, halogen lamps or high-power lighting in the operating and dental offices).Within 48 hours after PDT with Visudin®, long-term exposure to light from photometric medical devices, such as an oximeter, should be avoided. If it is necessary to perform a surgical intervention within 48 hours after PDT with the drug Visudin® internal organs should also be protected from exposure to light.

    If you need to stay outdoors during the day, protect your skin with lightproof clothing, and your eyes with dark glasses. UV-protective cream is ineffective in protecting against manifestations of photosensitivity reactions. Natural indoor lighting does not have a dangerous effect, the patient should be advised not to stay in the dark, as natural interior lighting of rooms helps to remove the drug through the skin (the process of "photobleaching").

    Application the patients with impaired liver function of moderate severity or obstruction of bile ducts

    Caution should be exercised when carrying out PDT with the drug Visudin® in patients with impaired liver function of moderate severity or with bile duct obstruction,Since the experience of using the drug in such patients is absent. It is possible to increase the exposure of the drug, since verteporfin is excreted mainly with bile.

    Risk of severe visual acuity reduction

    Patients with a marked decrease in OZ (4 rows or more by ETDRS optotypes) within the first week after treatment with the drug Visudin® a second course of treatment can be carried out after restoration of the OZ to the initial level. The attending physician must carefully evaluate the relationship between the potential benefits of therapy and the possible risk.

    Extravasation in the zone of administration of a solution for infusions

    Extravasation in the zone of administration of the drug Vizudin® can cause severe pain, inflammation, soft tissue swelling, or discoloration of the skin, especially when exposed to light. Pain can be treated with analgesics.

    To prevent the development of extravasation, the drip system for intravenous administration is placed in the largest vein on the front surface of the forearm (preferably in the lateral subcutaneous vein of the arm) and controls the flow of Visudin® into the blood. It should avoid the introduction of the drug into small veins of the dorsum of the brush.If the drug comes into the surrounding tissue from the vein, it should be stopped immediately. To prevent severe local burns, the area of ​​bruising should be protected from exposure to direct light until the edema is resolved and skin color is restored. A cold compress should be applied to the injection site.

    Hypersensitivity reactions

    With the introduction of the drug Vizudin®, there was a development of chest pain, vasovagal reactions and hypersensitivity reactions. Vasovagal reactions and hypersensitivity to the drug manifested common symptoms: fainting, increased sweating, dizziness, rash, dyspnea, hyperemia and changes in blood pressure and heart rate. In rare cases, the occurrence of severe reactions, including the development of seizures. It is necessary to provide medical supervision during the infusion of the drug.

    Anesthesia

    Data on the use of the drug Visudin® in patients under general anesthesia are absent. In studies of sedated or anesthetized animals with bolus administration of the drug at a dose 10 times higher than the therapeutic dose, severe hemodynamic disturbances were observed, in some cases fatal, possibly associated with complement activation.Since the preliminary administration of an antihistamine drug (diphenhydramine) reduced the severity of the condition, it is possible that histamine affects the pathological process. When the drug was administered to animals and a person who was conscious, no hemodynamic disturbances were noted.

    In vitro at a 5-fold increase in Cmax verteporfina in human blood plasma there was a low degree of complement activation reaction. Despite the lack of data on the development of complement activation reactions in clinical studies, it is impossible to exclude the possibility of developing anaphylactic reactions in humans.

    Photoactivation

    Light exposure should be carried out by a laser of a certain wave, which causes optimal photoactivation of verteporfin. The use of a laser that causes partial photoactivation of verteporfin leads to an incomplete clinical effect. With excessive activation of the drug Vizudin®, destruction of surrounding healthy tissues is noted.

    Patients with angina and / or hypertension.

    There is no experience of using the drug in patients with unstable angina (III-IV class) or uncontrolled arterial hypertension.

    Other

    The drug Visudin® contains a small amount of butylhydroxytoluene, which can be irritating to the eyes, skin and mucous membranes. In case of contact with the product, wash eyes, skin and mucous membranes with plenty of water.

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

    In connection with the possibility of developing visual disturbances after drug therapy (such as visual impairment, reduced OZ, visual field defects), vehicles and mechanisms should be discarded before resolving these undesirable phenomena.

    Form release / dosage:Lyophilizate for the preparation of a solution for intravenous administration, 15 mg.
    Packaging:

    For 15 mg in a glass bottle with a rubber stopper and an aluminum cap.

    One bottle with instructions for use in a cardboard box.

    Storage conditions:

    At a temperature of no higher than 25 ° C, in a place protected from light.

    Keep out of the reach of children.

    Shelf life:

    4 years.

    The preparation solution can be stored for 4 hours at the temperature not higher than 25 ° C in the dark place.

    The drug should not be used after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:П N013830 / 01
    Date of registration:08.07.2008 / 26.10.2015
    Expiration Date:Unlimited
    The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland
    Manufacturer: & nbsp
    Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC
    Information update date: & nbsp11.03.2017
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