Cymevent, lyophilizate 500 mg

Hanciclovir is a synthetic analogue of 2′-deoxyguanosine which inhibits the reproduction of herpes viruses both in vitro and in vivo. Viruses sensitive to ganciclovir include human cytomegalovirus (h-CMV), herpes simplex viruses -1 and -2 (Herpes simplex 1 and 2), human herpes virus types 6, 7 and 8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus (EBV), varicella/zoster and hepatitis B virus. Clinical studies have been limited to evaluating the efficacy 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.

This metabolism has been shown to occur in cells infected with human CMV and herpes simplex virus, with an intracellular half-life of 18 and 6-24 hours, respectively, after ganciclovir disappears from the extracellular fluid. Since phosphorylation of ganciclovir depends to a greater extent on the action of viral kinase, it occurs predominantly in infected cells.

The viral-static action of ganciclovir is due to inhibition of viral DNA synthesis by: (1) competitive inhibition of deoxyguanosine triphosphate incorporation into DNA by DNA polymerase action (2) incorporation of ganciclovir triphosphate into viral DNA, leading to cessation of viral DNA elongation or very limited elongation of it. Typical antiviral IC50 against CMV determined in vitro,
ranges from 0.14 µM (0.04 µg/ml) to 14 µM (3.5 µg/ml).

Viral resistance

The current definition of CMV resistance to ganciclovir is based on an in vitro determination: the median suppressive concentration (IC50) exceeds 1.5 µg/ml (6.0 µM). Resistance of CMV to ganciclovir is rare (about 1%). Resistance has been observed in patients with AIDS and CMV retinitis who have never received ganciclovir.

In the first 6 months of treatment of CMV retinitis with Cymevent (in infusions or capsules), viral resistance was detected in 3-8% of patients. Viral resistance was also noted in patients receiving long-term therapy with Cymevent 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 containing mutations in the gene UL97 of CMV responsible for phosphorylation of ganciclovir have been described. Mutations in the viral DNA polymerase gene that determine viral resistance to ganciclovir have also been described, and viruses with this mutation may also be resistant to other drugs acting on CMV.

Pharmacokinetics

Absorption

. After infusion of ganciclovir at a dose of 5 mg/kg for 1 hour in HIV- and CMV-infected patients or adult AIDS patients, the total area under the concentration-time curve (AUC_0-24) ranged from 21.4±3.1 to 26.0±6.06 µg x hour/ml. The maximum plasma concentration of the drug (C_max) ranged from 7.59±3.21 and 8.27±1.02 to 9.03±1.42 μg/mL.

Distribution

The volume of distribution of ganciclovir after intravenous administration correlates with body weight and is 0.5-0.8 L/kg when reaching equilibrium concentration. The concentration of the drug in 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 plasma concentration and is equal to 0.50-0.68 µg/ml. The binding to plasma proteins is 1-2%.

Metabolism and excretion

After intravenous administration with doses from 1.6 to 5.0 mg/kg ganciclovir kinetics is linear. The main route of excretion is renal excretion of unchanged drug by glomerular filtration and tubular secretion.

In patients with normal renal function, 89.6±5.0% of the intravenously administered dose of ganciclovir was found unchanged in the urine. In subjects with normal renal function, systemic clearance ranged from 2.64±0.38 to 4.52±2.79 ml/min/kg, and renal clearance ranged from 2.57±0.69 to 3.48±0.68 ml/min/kg, corresponding to 90-101% of ganciclovir administered. The half-life in persons without renal insufficiency ranges from 2.73±1.29 to 3.98±1.78 hours.

Pharmacokinetics in special patient groups

Renal disease

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

In an intermittent hemodialysis regimen, ganciclovir clearance rates are 42 to 92 mL/min and the half-life of the drug during dialysis is 3.3-4.5 hours. On continuous dialysis, ganciclovir clearance was lower (4.0-29.6 ml/min), but a higher percentage of the administered dose was removed from the body before the next dose. In intermittent hemodialysis, the fraction of ganciclovir removed in a single hemodialysis session ranged from 50% to 63%.

Elderly patients

There have been no studies in persons over 65 years of age.

Indications

Treatment of life- or vision-threatening manifest CMV infection in persons with immunodeficiencies, including AIDS.

Prevention of manifest CMV infection in patients after organ transplantation.

Active ingredient

Composition

1 bottle of lyophilisate for preparation of solution for infusion contains:

the active substance:

ganciclovir 500 mg (in the form of ganciclovir sodium salt)

How to take, the dosage

Adults and children over 12 years of age

Standard dosing for treatment of CMV retinitis

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

Supportive therapy: 5 mg/kg by intravenous infusion for 1 hour, daily for 7 days per week or 6 mg/kg body weight daily for 5 days per week.

Standard dosing 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).

Supportive therapy: 5 mg/kg by intravenous infusion for 1 hour, daily for 7 days per week or 6 mg/kg body weight daily for 5 days per week.

Special Dosing Instructions
For patients with renal impairment, doses should be adjusted as shown in the table below.
Creatinine clearance can be calculated from serum creatinine using the following formula:
for men = {(140 – age [years]) x body weight [kg]} / {72 x 0.011 x serum creatinine [μmol/L]}
for women = 0.85 x index for men

Because the dose of ganciclovir must be adjusted in patients with renal impairment, serum creatinine concentrations or creatinine clearance must be monitored closely.

Patients with leukopenia, marked neutropenia, anemia and thrombocytopenia. In patients receiving ganciclovir there have been cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, myelosuppression and aplastic anemia.
The drug should not be started when absolute number of neutrophils is less than 500 cells per 1 mcl, or platelets – less than 25000 cells per 1 mcl, or when hemoglobin level is less than 8 g/dl (see “Special indications” and “Administration guidelines”). “
Elderly and senile patients: Since senile patients often have reduced renal function, ganciclovir should be prescribed with strict regard to renal function (see above).

Children: The efficacy and safety of ganciclovir in children under 12 years of age, including in congenital and neonatal CMV infection, have not been established. Because of the potential for long-term carcinogenicity and reproductive toxicity, the benefits of treatment should outweigh the possible risks.

The method of preparing Zymeven solution
1. Lyophilized ganciclovir powder is dissolved by infusing the vial with 10 ml of sterile water for injection. Do not use bacteriostatic water for injection containing parabens (parahydroxybenzoates), because they are incompatible with sterile ganciclovir powder and can cause precipitation.
2. Shake the bottle to dissolve the drug.
3. Inspect the prepared solution for mechanical impurities.
The prepared solution in the bottle is stable at room temperature for 12 hours.
Do not put it in the fridge.

Instructions for handling the drug
Caution should be exercised when in contact with the drug.
Since ganciclovir is considered a potential carcinogen and mutagen for humans, care should be taken when handling it (see “Special Instructions”). Inhalation or direct contact of the powder contained in the vials or direct contact of the solution with the skin and mucous membranes should be avoided. Cymeven’s solution has an alkaline reaction (pH 11). In case of contact of ganciclovir with skin or mucous membranes, the place should be thoroughly washed with soap and water.
In case of contact with eyes, they are thoroughly washed with just water.

Preparing and administering the infusion solution
From the vial with ganciclovir (concentration 50 mg/ml) a calculated (taking into account the body weight of the patient) dose of the drug is taken and added to the basic infusion solution (physiological sodium chloride solution, 5% aqueous glucose solution, Ringer or Ringer-lactate solution). It is not recommended to administer ganciclovir at a concentration of more than 10 mg/ml.

Hanciclovir should not be mixed with other intravenous medications.

Because 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.

The infusion solution should be stored in the refrigerator; freezing is not recommended.

The drug should not be administered intravenously rapidly or by jetting! Excessive concentrations of ganciclovir in the plasma may increase its toxicity. Intramuscular or subcutaneous injection can cause severe tissue irritation due to the high pH (about 11) of ganciclovir solution.

The recommended dose should not be exceeded, and the mode of administration or infusion rate should not be changed.

Interaction

Interactions with intravenous ganciclovir

The degree of binding of ganciclovir to plasma proteins is only 1-2%, so interactions due to displacement of the drug from protein binding sites should not be expected.

Didanosine: concomitant administration of didanosine and intravenous or oral administration of ganciclovir has been found to persistently increase plasma concentrations of didanosine. When ganciclovir was administered intravenously in doses of 5 – 10 mg/kg per day, the AUC of didanosine increased by 38 – 67%.

This increase cannot be explained by changes in the tubular secretion of the drug, because the excretion rate of didanosine was increased. This increase in AUC may be due to either increased bioavailability or decreased metabolic rate. There were no clinically significant changes in ganciclovir concentrations. However, given the increased plasma concentrations of didanosine in the presence of ganciclovir, patients should be closely monitored for didanosine toxicity.

Imipenem/cilastatin: Seizures have been observed in patients who received ganciclovir and imipenem/cilastatin simultaneously. These drugs should be used in combination with Cymevent only if the possible benefits outweigh the risks.

Mycophenolate mofetil: concomitant administration of these drugs potentially competing in tubular secretion may lead to increased concentrations of ganciclovir and MFCG (mycophenolic acid phenolic glucuronide).

No significant changes in the pharmacokinetics of mycophenolic acid (MPA) are expected and no dose adjustment of mofetil mycophenolate is required. In patients with impaired renal function who receive ganciclovir and MMF concomitantly, recommendations on ganciclovir dosing and close monitoring should be followed.Other possible drug interactions

An increased toxicity is possible when ganciclovir is prescribed simultaneously with other drugs that have myelosuppressive effects or impair renal function (such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, nucleoside analogues and hydroxyurea). Consequently, these drugs should be administered concomitantly with ganciclovir only if the potential benefits outweigh the possible risks.

Special Instructions

Hanciclovir has potential teratogenic and carcinogenic effects and may cause congenital malformations and malignancies. Ganciclovir can temporarily or persistently inhibit spermatogenesis.

There have been cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, myelosuppression, and aplastic anemia in patients who have taken ganciclovir. You should not start treatment with Ganciclovir if the absolute neutrophil count is less than 500 cells per 1 µl, or the platelet count is less than 25000 cells per 1 µl, or the hemoglobin level is less than 8 g/dL.

In the course of treatment, it is recommended that a detailed blood count, including platelet count, be monitored. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, treatment with hematopoietic growth factors and/or temporary interruption of therapy with the drug is recommended.

In case of impaired renal function it is recommended to adjust the dose of the drug depending on creatinine clearance.

In patients taking imipenem/cilastatin and ganciclovir seizures have been described, so ganciclovir should not be administered simultaneously with imipenem/cilastatin unless the potential benefits of therapy exceed the possible risks.

Both ganciclovir and zidovudine can cause neutropenia and anemia, so some patients may not tolerate concomitant administration of these drugs at full doses.

The concomitant administration of ganciclovir may increase plasma concentrations of didanosine, so these patients should be closely monitored for signs of didanosine toxicity

The simultaneous administration of ganciclovir and drugs with myelosuppressive or nephrotoxic effects may lead to additive toxicity.

Impact on the ability to drive vehicles and operate machines

Patients taking ganciclovir may experience seizures, drowsiness, dizziness, ataxia, confusion. These symptoms may affect performance of activities requiring increased attention, including the ability to drive vehicles and operate machines.

Contraindications

With caution – renal failure.

Side effects

HIV-infected patients

The clinical adverse events reported in > 2% of patients receiving ganciclovir intravenously, regardless of their causal relationship to the drug and severity:

Blood and lymphatic system: neutropenia, anemia, thrombocytopenia, leukopenia, lymphadenopathy;

Digestive system: diarrhea, abdominal pain, dysphagia, esophageal candidiasis; body in general: fever, candidiasis, infections at the injection site, sepsis, secondary sepsis, anorexia, mycobacteriosis mycobacterium avium), pain of various localization, chest pain, bacteremia;

From the central and peripheral nervous system: hypoesthesia, anxiety; from the skin and its appendages: itching;

respiratory system: cough, pneumocystis pneumonia, cough with sputum, congestion in the sinuses;
laboratory parameters: increased activity of alkaline phosphatase in blood, increased blood creatinine level, neutropenia, anemia, thrombocytopenia, increased creatinine level;
musculoskeletal system: arthralgia.

Patients after transplantation

The clinical adverse events noted in > 5% of patients who received ganciclovir intravenously to treat or prevent manifest CMV infection after bone marrow transplantation, regardless
of their causal relationship to the drug and severity:

Hematopoietic organs: pancytopenia, leukopenia;body in general: mucous membrane lesions, fever, shivering, sepsis, anorexia, facial edema;

Digestive organs: diarrhea, dyspepsia;

laboratory: increased creatinine levels, hepatic transaminase activity, hypomagnesemia, hypocalcemia, hypokalemia;

Nervous system disorders: headache, tremor, confusion; skin and its appendages: exfoliative dermatitis;

respiratory system: rhinitis, shortness of breath;

cardiovascular system: tachycardia , arterial hypotension;

urinary tract: hematuria; sensory organs: hemorrhage in the eye;

musculoskeletal system: myalgia.

The clinical adverse events reported in > 5% of patients receiving intravenous ganciclovir after heart transplantation, regardless of causality to the drug or severity:

The body as a whole: infections (18%).
Metabolic and nutritional disorders: edema (9%).
Central and peripheral nervous system: headache (18%), confusion (5%), peripheral neuropathy (7%).
Respiratory organs: pleural effusion (5%).

Cardiovascular system:arterial hypertension (20%).

Urinary tract: deterioration of renal function (14%), renal failure (12%).

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

In order to fully characterize the safety profile of intravenously administered ganciclovir, the relevant adverse events that have been found to be more frequent with oral administration of ganciclovir in HIV-infected or organ transplant patients, regardless of their severity or causal relationship to the drug, are listed below. Some adverse events with oral administration of ganciclovir may be associated with this route of administration.

Blood and lymphatic system: leukocytosis.

Digestive organs: constipation, cholangitis, flatulence, vomiting.

The body in general: ascites, asthenia, bleeding, bacterial, fungal and viral infections, malaise. Cardiovascular system: vasodilation (decreased BP, reddening of the facial skin).

The central and peripheral nervous system: depression, dizziness, insomnia.
Liver and biliary tract: cholestatic jaundice.

Skin:increased sweating.
Sensory organs:amblyopia, taste disorders.
Metabolic and nutritional disorders: diabetes, hyponatremia, hypoproteinemia, weight loss.

Other adverse events

The following are significant adverse events that were not listed above because they did not meet the inclusion criteria (less than 2%).
Blood and lymphatic system:aplastic anemia, myelosuppression, eosinophilia.

Digestive organs:gastrointestinal bleeding, belching, fecal incontinence, ulcerative stomatitis, pancreatitis, glossitis.
Infections:episodes of infections due to bone marrow and immune system suppression (local and systemic infections and sepsis).
Bleeding: potentially life-threatening bleeding with thrombocytopenia.

The body in general: cachexia, dehydration, weakness, thrombosis at the injection site, abscess at the injection site, swelling at the injection site, pain at the injection site, hemorrhage at the injection site, malaise, photosensitization reactions.

Central and peripheral nervous system: agitation, seizures, hallucinations, psychosis, thought disorder, “nightmare” dreams, ataxia, coma, dry mouth, euphoria, nervousness, drowsiness.

The skin and its appendages: dermatitis, acne, alopecia, herpes simplex, urticaria.

Sensory organs: retinal detachment, visual disturbances, blindness, decreased hearing, pain in the eyeball, glaucoma, destruction of the vitreous body.
Laboratory findings: increased activity of creatine phosphokinase and
lactate dehydrogenase in the blood, hypoglycemia.

The genitourinary tract:rapid urination.

Cardiovascular system: arrhythmias (including ventricular), deep vein thrombophlebitis, migraine, phlebitis.
Musculoskeletal system: myasthenic syndrome.

Post-registration experience with the drug

An adverse event according to spontaneous reports when using ganciclovir in HIV-infected patients and other immunocompromised patients (for example, after transplantation) for which a causal relationship to the drug cannot be excluded: anaphylaxis decreased fertility in men.

Otherwise the adverse events described with post-registration use of the drug are similar to those seen in clinical studies.

Overdose

Intravenous ganciclovir overdose

In some cases, no adverse events have occurred in overdose. Most patients experienced one or more of the following adverse events:

Hematological toxicity: pancytopenia, myelosuppression, bone marrow aplasia, leukopenia, neutropenia, granulocytopenia.
Hepatotoxicity: hepatitis, liver function impairment.

Nephrotoxicity: increase of hematuria in patients with pre-existing renal damage, acute renal failure, increased creatinine levels.

Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting.

Neurotoxicity: generalized tremors, seizures.

In addition, one adult patient received an excessive volume of ganciclovir intravitreal solution, after which he developed temporary vision loss and central retinal artery occlusion due to increased intraocular pressure caused by the volume of fluid injected.

Hemodialysis and hydration can be used to reduce plasma levels of ganciclovir in oral Zimewen overdose.