Cymeven lyophilisate 500mg, No. 1

• treatment of life-threatening or vision-threatening overt CMV infection in immunocompromised individuals, including AIDS;

• prevention of manifest CMV infection in patients after organ transplantation.

Adults and children over 12 years old

Standard dosage for the treatment of CMV retinitis

Initial therapy: intravenous infusion at a dose of 5 mg / kg of body weight for 1 hour, every 12 hours (10 mg / kg / day) for 14-21 days (for patients with normal renal function).

Maintenance therapy: 5 mg / kg by intravenous infusion over 1 hour, daily for 7 days a week or 6 mg / kg daily for 5 days a week.

Standard Dosage for Prophylaxis in Post-Transplant Patients

Initial therapy: intravenous infusion at a dose of 5 mg / kg for 1 hour, every 12 hours for 7-14 days (for patients with normal renal function).

Maintenance therapy: 5 mg / kg by intravenous infusion over 1 hour, daily for 7 days a week or 6 mg / kg daily for 5 days a week.

Method for preparing a solution of the drug Tsimeven

1. Lyophilized powder of ganciclovir is dissolved by introducing 10 ml of sterile water for injection into a vial. Do not use bacteriostatic water for injection containing parabens (parahydroxybenzoates), as they are incompatible with sterile ganciclovir powder and may cause precipitation.

2. Shake the bottle to dissolve the drug.

Inspect the prepared solution for mechanical impurities.

The prepared solution in the vial is stable at room temperature for 12 hours. You cannot put it in the refrigerator.

Instructions for handling the drug

Since ganciclovir is considered a potential carcinogen and mutagen for humans, care must be taken when handling it (see section 'Special instructions'). Avoid inhalation or direct contact of the powder contained in the vials, or direct contact of the solution with the skin and mucous membranes. The solution of the drug Cymeven has an alkaline reaction (pH 11). If ganciclovir comes in contact with the skin or mucous membranes, wash the area thoroughly with soap and water. In case of contact with eyes, they are thoroughly rinsed with plain water.

Preparation and administration of the infusion solution

From a bottle of ganciclovir (concentration 50 mg / ml), a calculated (taking into account the patient's body weight) dose of the drug is taken and added to the basic infusion solution (0.9% sodium chloride solution, 5% aqueous dextrose solution, Ringer's solution or Ringer's lactate). It is not recommended to administer ganciclovir at a concentration of more than 10 mg / ml.

Ganciclovir should not be mixed with other intravenous drugs.

Since ganciclovir is diluted with non-bacteriostatic sterile water, the infusion solution should be used within 24 hours of preparation to reduce the risk of bacterial contamination.

Keep the infusion solution refrigerated; it is not recommended to freeze it.

The drug should not be administered intravenously quickly or in a jet!

Excessive plasma concentrations of ganciclovir may increase its toxicity. Intramuscular or subcutaneous injection can cause severe tissue irritation due to the high pH (about 11) of the ganciclovir solution.

Do not exceed the recommended dose, or change the administration mode or infusion rate.

Lyophilisate for preparation of solution for infusion of white or almost white color.

1 fl. ganciclovir sodium 546 mg,?

which corresponds to the content of ganciclovir 500 mg

• the absolute number of neutrophils is less than 500 cells in 1 ?l or the number of platelets is less than 25,000 cells in 1 ?l or the hemoglobin level is less than 8 g / dl;

• children under 12 years of age;

• hypersensitivity to ganciclovir, valganciclovir or any other component of the drug.

• due to the similarity of the chemical structure of ganciclovir, acyclovir and valacyclovir, cross-hypersensitivity reactions are possible between these drugs.

Renal failure with caution

pharmachologic effect

Mechanism of action

Ganciclovir is a synthetic analogue of 2'-deoxyguanosine that inhibits the multiplication of herpes viruses both in vitro and in vivo. Active against human cytomegalovirus (CMV), herpes simplex viruses type 1 and 2 (Herpes simplex 1 and 2), human herpes virus type 6, 7 and 8, Epstein-Barr virus, chickenpox virus (Varicella zoster) and hepatitis B virus. Clinical studies were limited to assessing the effectiveness of the drug in patients infected with cytomegalovirus.

In CMV-infected cells, ganciclovir is first phosphorylated by viral protein kinase to form ganciclovir monophosphate. Further phosphorylation occurs under the action of several cellular kinases, resulting in the formation of ganciclovir triphosphate, which then undergoes slow intracellular metabolism. It has been shown that this metabolism occurs in cells infected with human CMV and herpes simplex virus, while after the disappearance of ganciclovir from the extracellular fluid, the intracellular half-life of the drug is 18 and 6-24 hours, respectively. Since phosphorylation of ganciclovir is more dependent on the action of viral kinase, it occurs predominantly in infected cells.

The virostatic effect of ganciclovir is due to the suppression of viral DNA synthesis by: (1) competitive inhibition of the incorporation of deoxyguanosine triphosphate into DNA by DNA polymerase; (2) the incorporation of ganciclovir triphosphate into viral DNA, resulting in the cessation of viral DNA elongation or very limited elongation. The typical minimum concentration of the drug in the blood causing an inhibitory antiviral effect against CMV, equal to 50% of the maximum (IC50), determined in vitro, is in the range from 0.14 ?M (0.04 ?g / ml) to 14 ?M (3.5 ?g / ml).

Viral resistance

The current definition of CMV resistance to ganciclovir is based on in vitro determination: the median IC50 exceeds 1.5 ?g / ml (6.0 ?M). CMV resistance to ganciclovir is rare (about 1%). Resistance was observed in patients with AIDS and CMV retinitis who had never received ganciclovir. In the first 6 months of treatment with CMV retinitis with Cymeven (in infusion or in capsules), viral resistance is determined in 3-8% of patients. Virus resistance was also observed in patients receiving long-term therapy with Cymeven in infusions for CMV retinitis. The main mechanism of CMV resistance to ganciclovir is a decrease in the ability to form active triphosphate. Resistant viruses have been described containing mutations in the UL97 CMV gene, which is responsible for phosphorylation of ganciclovir. Mutations in the viral DNA polymerase gene have also been described,determining viral resistance to ganciclovir, and viruses with this mutation can be resistant to other drugs acting on CMV.

Pharmacokinetics

Suction

After infusion of ganciclovir at a dose of 5 mg / kg for 1 hour for HIV- and CMV-infected patients or adults with AIDS, the total area under the concentration-time curve (AUC0-24) ranges from 21.4 ± 3.1 to 26.0 ± 6.06 ?g x hour / ml. The maximum concentration of the drug in plasma (Cmax) ranged from 7.59 ± 3.21 and 8.27 ± 1.02 to 9.03 ± 1.42 ?g / ml.

Distribution

The volume of distribution of ganciclovir after intravenous administration correlates with body weight and, when the equilibrium concentration is reached, is 0.5-0.8 L / kg. The concentration of the drug in the cerebrospinal fluid 0.25-5.67 hours after intravenous administration of ganciclovir at a dose of 2.5 mg / kg every 8 or 12 hours is 24-67% of the plasma concentration and is equal to 0.50-0.68 ?g / ml. The connection with plasma proteins is 1-2%.

Metabolism and excretion

After intravenous administration at doses from 1.6 to 5.0 mg / kg, the kinetics of ganciclovir is linear. The main route of elimination is renal excretion of the unchanged drug by glomerular filtration and tubular secretion. In patients with normal renal function, 89.6 ± 5.0% of the intravenous dose of ganciclovir is found unchanged in the urine. In individuals with normal renal function, systemic clearance is in the range from 2.64 ± 0.38 to 4.52 ± 2.79 ml / min / kg, and renal clearance is from 2.57 ± 0.69 to 3.48 ± 0.68 ml / min / kg, which corresponds to 90-101% of the administered ganciclovir. The half-life in individuals without renal failure ranges from 2.73 ± 1.29 to 3.98 ± 1.78 hours.

Pharmacokinetics in special patient groups

Kidney disease

Hemodialysis reduces plasma concentrations of ganciclovir after intravenous and oral administration at doses of 1.25-5.0 mg / kg by about 50%.

When using an intermittent hemodialysis scheme, the clearance rates of ganciclovir are from 42 to 92 ml / min, the half-life of the drug during dialysis is 3.3-4.5 hours. With continuous dialysis, the clearance of ganciclovir was lower (4.0-29.6 ml / min), but a greater percentage of the dose taken was removed from the body until the next dose. In intermittent hemodialysis, the fraction of ganciclovir removed in one hemodialysis session ranges from 50% to 63%.

Elderly patients

No studies have been conducted in persons over 65 years of age.

Side effect

HIV-infected patients

Clinical side effects, which were observed in? 2% of patients receiving intravenous ganciclovir, regardless of their causal relationship with the use of the drug and the severity:

From the side of the central nervous system and peripheral nervous system: hypesthesia, anxiety.

From the digestive system: diarrhea, abdominal pain, dysphagia, esophageal candidiasis.

From the hematopoietic and lymphatic system: neutropenia, anemia, thrombocytopenia, leukopenia, lymphadenopathy.

From the respiratory system: cough, pneumocystis pneumonia, cough with phlegm, congestion in the paranasal sinuses.

From the musculoskeletal system: arthralgia.

On the part of laboratory parameters: increased activity of alkaline phosphatase in the blood, hypercreatininemia;

Dermatological reactions: itching.

Others: fever, candidiasis, infections at the injection site, sepsis, incl. secondary sepsis, anorexia, infection caused by the Mycobacterium avium complex, pain of various localization, incl. chest pain, bacteremia, inflammation at the injection site.

Patients after transplantation

Clinical adverse events that were observed in ?5% of patients receiving intravenous ganciclovir for the treatment or prevention of manifest CMV infection after bone marrow transplantation, regardless of their causal relationship with the use of the drug and the severity:

From the side of the central nervous system and peripheral nervous system: headache, tremor, confusion.

From the side of the cardiovascular system: tachycardia, decreased blood pressure.

From the digestive system: diarrhea, nausea, dyspepsia, bloating.

From the urinary system: hematuria.

From the hematopoietic system: pancytopenia, leukopenia.

From the respiratory system: rhinitis, shortness of breath.

Dermatological reactions: exfoliative dermatitis.

From the senses: hemorrhage in the eye.

From the musculoskeletal system: myalgia.

Laboratory indicators: increased concentration of creatinine, activity of 'hepatic' transaminases, hypomagnesemia, hypocalcemia, hypokalemia.

Others: damage to the mucous membranes, fever, tremors, sepsis, anorexia, facial edema.

Clinical adverse events reported in ?5% of patients receiving intravenous ganciclovir after heart transplant, regardless of drug causation or severity:

From the side of the central and peripheral nervous system: headache (18%), confusion (5%), peripheral neuropathy (7%).

From the side of the cardiovascular system: increased blood pressure (20%).

From the genitourinary system: deterioration of renal function (14%), renal failure (12%).

From the side of metabolism and nutrition: edema (9%).

Respiratory system: pleural effusion (5%).

Others: infections (18%).

Due to the high bioavailability of intravenously administered ganciclovir, it cannot be excluded that intravenous administration of the drug may result in the same adverse events as in studies with oral administration of ganciclovir.

For a complete description of the safety profile of intravenous ganciclovir, the following are the corresponding adverse events identified with a higher frequency with oral ganciclovir in HIV-infected patients or patients after organ transplantation, regardless of their severity and causal relationship with the use of the drug. Some adverse events with oral ganciclovir may be associated with this particular way of taking the drug:

From the side of the central and peripheral nervous system: depression, dizziness, insomnia.

From the side of the cardiovascular system: vasodilation (lowering blood pressure, redness of the skin of the face).

From the digestive system: constipation, cholangitis, flatulence, vomiting.

From the hematopoietic and lymphatic system: leukocytosis.

From the side of metabolism and nutrition: diabetes mellitus, hyponatremia, hypoproteinemia, weight loss.

From the liver and biliary tract: cholestatic jaundice.

Dermatological reactions: increased sweating.

From the senses: amblyopia, taste disturbances.

Others: ascites, asthenia, bleeding, bacterial, fungal and viral infections, malaise.

Other adverse events

The following are significant adverse events that were not listed above, as did not meet the inclusion criteria (less than 2%):

From the side of the central and peripheral nervous system: agitation, convulsions, hallucinations, psychosis, thought disorder, 'nightmares', ataxia, coma, dry mouth, euphoria, nervousness, drowsiness.

From the side of the cardiovascular system: arrhythmia (including ventricular), deep vein thrombophlebitis, migraine, phlebitis.

From the digestive system: gastrointestinal bleeding, belching, fecal incontinence, ulcerative stomatitis, pancreatitis, glossitis.

On the part of the blood and lymphatic system: aplastic anemia, myelosuppression, eosinophilia; potentially life-threatening bleeding against the background of thrombocytopenia; episodes of infections due to suppression of the bone marrow and the immune system (local and systemic infections and sepsis).

From the genitourinary system: frequent urination.

From the musculoskeletal system: myasthenic syndrome.

Dermatological reactions: dermatitis, acne, alopecia, herpes simplex, urticaria.

From the senses: retinal detachment, visual impairment, blindness, hearing loss, pain in the eyeball, glaucoma, destruction of the vitreous body.

On the part of laboratory parameters: increased activity of creatine phosphokinase and lactate dehydrogenase in the blood, hypoglycemia.

Others: cachexia, dehydration, weakness, thrombosis at the injection site, abscess at the injection site, edema at the injection site, pain at the injection site, hemorrhages at the injection site, malaise, photosensitivity reactions.

Experience of post-registration use of the drug

Side effects, in accordance with spontaneous reports when using ganciclovir in HIV-infected patients and other patients with weakened immunity (for example, after transplantation), for which a causal relationship with the use of the drug cannot be excluded: anaphylaxis, decreased fertility in men.

Otherwise, the side effects described during the post-registration use of the drug are similar to those noted in clinical studies.

Application during pregnancy and lactation

Category C drug (according to the FDA classification - US Food and Drug Administration).

During treatment with ganciclovir, women of childbearing age should be advised to use reliable methods of contraception. Men are advised to use a barrier method of contraception during treatment and for at least 90 days after it ends.

In animal studies, the teratogenicity of the drug was revealed. The safety of ganciclovir in human pregnancy has not been established. Prescribing the drug to pregnant women should be avoided unless the potential benefit to the mother outweighs the potential risk to the fetus.

ѕери- и постнатальное развитие после воздействи¤ ганцикловира не изучалось, однако нельз¤ исключить, что ганцикловир может выводитьс¤ с молоком и вызывать серьезные нежелательные реакции у грудного ребенка.  орм¤щие матери должны быть проинструктированы о необходимости прекратить кормление грудью при приеме препарата ?имевен.

ѕрименение при нарушени¤х функции почек

— осторожностью примен¤ть при почечной недостаточности. ?озы следует корригировать в соответствии с   .

ѕрименение у детей

ѕротивопоказание: детский возраст до 12 лет.

Ёффективность и безопасность ганцикловира у детей, в том числе при врожденной и неонатальной ?ћ¬ инфекции, не установлены. »з-за веро¤тности отдаленной канцерогенности и токсического действи¤ на репродуктивную систему, следует про¤вл¤ть чрезвычайную осторожность. ѕреимущества лечени¤ должны превосходить возможный риск.

ѕрименение у пожилых пациентов

»сследований у лиц старше 65 лет не проводилось. ѕоскольку у лиц старческого возраста функци¤ почек нередко снижена, ганцикловир следует назначать строго с учетом функции почек

ќсобые указани¤

vанцикловир обладает потенциальным тератогенным и канцерогенным действием, может вызывать врожденные пороки развити¤ и злокачественные новообразовани¤. vанцикловир может временно или стойко угнетать сперматогенез (см. разделы ЂЅеременность и период кормлени¤ грудьюї и Ђѕобочное действиеї).

” больных, принимавших ганцикловир, наблюдались случаи т¤желой лейкопении, нейтропении, анемии, тромбоцитопении, панцитопении, миелосупрессии и апластической анемии. Ќе следует начинать лечение ганцикловиром, если абсолютное число нейтрофилов меньше 500 клеток/мкл или число тромбоцитов меньше 25000 клеток/мкл или гемоглобин меньше 8 г/дл (см. разделы Ђќсобые указани¤ по дозированиюї и Ђѕобочное действиеї).

¬ ходе лечени¤ рекомендуетс¤ мониторировать число форменных элементов крови, включа¤ число тромбоцитов. ” больных с т¤желой лейкопенией, нейтропенией, анемией и/или тромбоцитопенией рекомендуетс¤ проводить лечение гемопоэтическими ростовыми факторами и/или временно прервать терапию препаратом (см. разделы Ђќсобые указани¤ по дозированиюї и Ђ‘армакокинетика у особых групп пациентовї).

ѕри нарушении функции почек рекомендуетс¤ проводить коррекцию дозы препарата в зависимости от    (см. разделы Ђќсобые указани¤ по дозированиюї и Ђ‘армакокинетика у особых групп пациентовї).

” больных, принимающих ганцикловир, могут возникать судорожные припадки, сонливость, головокружение, атакси¤, спутанность сознани¤ и/или кома.

” больных, принимающих имипенем/циластатин и ганцикловир, описано развитие судорог, поэтому ганцикловир не следует назначать одновременно с имипенемом/циластатином, если только потенциальные преимущества терапии не превышают возможного риска (см. раздел Ђ¬заимодействие с другими лекарственными средствамиї).

 ак ганцикловир, так и зидовудин могут вызывать нейтропению и анемию, поэтому некоторые пациенты могут не переносить одновременный прием этих препаратов в стандартных рекомендованных дозах (см. раздел Ђ¬заимодействие с другими лекарственными средствамиї).

ѕри одновременном приеме ганцикловира могут увеличиватьс¤ плазменные концентрации диданозина, поэтому таких пациентов следует тщательно наблюдать на предмет ¤влений токсичности диданозина (см. раздел Ђ¬заимодействие с другими лекарственными средствамиї).

ќдновременный прием ганцикловира и препаратов, обладающих миелосупрессивным или нефротоксичным эффектами, может привести к развитию аддитивной токсичности (см. раздел Ђ¬заимодействие с другими лекарственными средствамиї).

¬ли¤ние на способность к вождению транспортных средств и работу с машинами и механизмами

” больных, принимающих ганцикловир, могут возникать судорожные припадки, сонливость, головокружение, атакси¤, спутанность сознани¤. ѕодобные симптомы могут повли¤ть на выполнение видов де¤тельности, требующих повышенного внимани¤, в том числе способность к вождению транспортных средств и работу с машинами и механизмами. ѕри развитии этих симптомов пациентам следует отказатьс¤ от вождени¤ транспортных средств и работы с машинами и механизмами.

ѕередозировка

ѕри передозировке в некоторых случа¤х никаких нежелательных ¤влений не возникало. ” большинства пациентов отмечалось одно или несколько из следующих нежелательных ¤влений.

vематологическа¤ токсичность: панцитопени¤, миелосупресси¤, аплази¤ костного мозга, лейкопени¤, нейтропени¤, гранулоцитопени¤.

vепатотоксичность: гепатит, нарушение функции печени.

Ќефротоксичность: нарастание гематурии у пациента с уже имеющимс¤ поражением почек, остра¤ почечна¤ недостаточность, повышение концентрации креатинина.

vастроинтестинальна¤ токсичность: боли в животе, диаре¤, рвота.

Ќейротоксичность: генерализованный тремор, судороги.

 роме того, одному взрослому пациенту интравитреально был введен избыточный объем раствора ганцикловира дл¤ внутривенного введени¤, после чего у него развилась временна¤ потер¤ зрени¤ и окклюзи¤ центральной артерии сетчатки вследствие повышени¤ внутриглазного давлени¤, вызванного введенным объемом жидкости.

?л¤ снижени¤ концентрации ганцикловира в плазме при передозировке препарата ?имевен можно примен¤ть гемодиализ и гидратацию (см. раздел Ђ‘армакокинетика у особых групп пациентовї). ” больных с т¤желой лейкопенией, нейтропенией, анемией и/или тромбоцитопенией рекомендуетс¤ проводить лечение гемопоэтическими ростовыми факторами (см. раздел Ђќсобые указани¤ї).

Ћекарственное взаимодействие

¬заимодействие при внутривенном введении ганцикловира

—тепень св¤зывани¤ ганцикловира с белками плазмы составл¤ет всего лишь 1-2%, поэтому взаимодействий, обусловленных вытеснением препаратов из мест св¤зи с белками плазмы, ожидать не следует.

?иданозин: установлено, что при одновременном применении диданозина и внутривенном или пероральном введении ганцикловира концентрации диданозина в плазме стойко повышаютс¤. ѕри внутривенном введении ганцикловира в дозах 5-10 мг/кг массы тела/сут AUC диданозина увеличивалась на 38-67%. Ёто возрастание нельз¤ объ¤снить изменением канальцевой секреции препарата, поскольку процент выведени¤ диданозина повышалс¤. ?анное увеличение AUC может быть вызвано либо повышенной биодоступностью, либо уменьшением скорости метаболизма.  линически значимых изменений концентраций ганцикловира при этом не было. ќднако, с учетом повышени¤ плазменных концентраций диданозина в присутствии ганцикловира, больных следует тщательно наблюдать во избежание токсичности диданозина.

»мипенем/циластатин: у больных, одновременно получавших ганцикловир и имипенем/циластатин, наблюдались судороги. Ётот препарат следует назначать в комбинации с препаратом ?имевен только в том случае, предполагаема¤ польза от лечени¤ препаратом превышает потенциальный риск развити¤ побочных эффектов.

ћикофенолата мофетил (ћћ‘): одновременное назначение этих препаратов, потенциально конкурирующих при канальцевой секреции, может приводить к повышению концентрации ганцикловира и фенольного глюкуронида микофенольной кислоты. —ущественного изменени¤ фармакокинетики микофеноловой кислоты не ожидаетс¤, корректировать дозу микофенолата мофетила не требуетс¤. ” больных с нарушением функции почек, которые одновременно получают ганцикловир и ћћ‘, необходимо соблюдать рекомендации по дозированию ганцикловира и проводить тщательное наблюдение.

Other possible drug interactions

It is possible to increase toxicity when prescribing ganciclovir simultaneously with other drugs that have myelosuppressive effects or impair renal function (such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, nucleoside analogs and hydroxycarbamide). Therefore, these drugs should be administered concurrently with ganciclovir only when the expected benefit of drug treatment outweighs the potential risk of side effects (see section 'Special instructions').