Cymevene lyophilisate solution for infusion 500mg vials, 1pc

Composition

1 bottle of lyophilizate for preparation of infusion solution contains:

Active ingredient:  

ganciclovir 500 mg (as ganciclovir sodium salt)

Pharmacological action

Mechanism of action

Ganciclovir is a synthetic analog of 2′ – deoxyguanosine, which inhibits the reproduction of herpes viruses both in vitro and in vivo. Ganciclovir-sensitive viruses 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 virus (Varicella/zoster) and hepatitis B virus. Clinical studies were limited to evaluating the effectiveness of the drug in patients with infected with cytomegalovirus.

In CMV-infected cells, ganciclovir is initially 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, and after the disappearance of ganciclovir from the extracellular fluid, the intracellular half-life of the drug is 18 and 6-24 hours, respectively. Since the phosphorylation of ganciclovir is more dependent on the action of viral kinase, it occurs mainly in infected cells.

The virusostatic effect of ganciclovir is due to the suppression of viral DNA synthesis by: (1) competitive inhibition of the incorporation of deoxyguanosine triphosphate into DNA under the action of DNA polymerase (2) incorporation of ganciclovir triphosphate into viral DNA, resulting in the cessation of viral DNA elongation or very limited elongation. The typical antiviral IC50 for CMV determined in vitro ranges from 0.14 µm (0.04 µg / ml) to 14 µm (3.5 µg/ml).

Viral resistance

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

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

Suction

The total area under the concentration – time curve (AUC 0-24) ranges from 21.4±3.1 to 26.0±6.06 micrograms x hour/ml after infusion of ganciclovir at a dose of 5 mg/kg for 1 hour to HIV – and CMV-infected patients or adult AIDS patients. 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 mcg / ml.

Distribution

The volume of distribution of ganciclovir after intravenous use 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 use of ganciclovir at a dose of 2.5 mg / kg every 8 or 12 hours is 24-67% of plasma concentrations and is equal to 0.50-0.68 mcg / ml. Plasma protein binding is 1-2%.

Metabolism and elimination

After intravenous use 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 detected unchanged in the urine. In patients with normal renal function, the systemic clearance ranges from 2.64±0.38 to 4.52±2.79 ml / min / kg, and the renal clearance ranges from 2.57±0.69 to 3.48±0.68 ml / min / kg, which corresponds to 90-101% of the administered ganciclovir. The elimination half-life in individuals without renal insufficiency ranges from 2.73±1.29 to 3.98±1.78 hours.

Pharmacokinetics in special groups of patients

with renal disease

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

When using an intermittent hemodialysis regimen, the clearance of ganciclovir ranges from 42 to 92 ml / min, and 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 in the period before the next dose of the drug, a larger percentage of the dose taken was removed from the body. In intermittent hemodialysis, the fraction of ganciclovir removed in a single hemodialysis session ranges from 50% to 63%.

Elderly patients

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

Indications

Treatment of life-threatening or vision-threatening manifest CMV infection in immunodeficient individuals, including AIDS.

Prevention of manifest CMV infection in patients after organ transplantation.

Contraindications

• Hypersensitivity to Cimeven, valganciclovir or any other component of the drug.
• Due to the similarity of the chemical structure of Cimeven and acyclovir and valacyclovir, cross-hypersensitivity reactions are possible between these drugs.
• The absolute neutrophil count is less than 500 cells per 1 µl, or the platelet count is less than 25,000 cells per 1 µl, or the hemoglobin level is less than 8 g / dl.
• Children under 12 years of age.

With caution – kidney failure.

Side effects

of HIV-infected patients

Clinical adverse events that occurred in > 2% of patients treated intravenously with ganciclovir, regardless of their causal relationship with the drug and severity :

from the blood system and lymphatic system: neutropenia, anemia, thrombocytopenia, leukopenia, lymphadenopathy;

on the part of the digestive system: diarrhea, abdominal pain, dysphagia, esophageal candidiasis; body as a whole: fever, candidiasis, infection at the injection site, sepsis, secondary sepsis, anorexia, mycobacteriosis mycobacterium avium), pain of various localization, chest pain, bacteremia;

in the Central and peripheral nervous system: hypoesthesia, anxiety, from the side of the skin and its appendages: pruritus;

from the respiratory system: cough, Pneumocystis pneumonia, cough, congestion in the sinuses;laboratory indicators: increased activity of alkaline phosphatase in the blood, increased levels of creatinine in the blood, neutropenia, anemia, thrombocytopenia, increased creatinine;from the side of musculoskeletal system: arthralgia.

Patients after transplantation

Clinical adverse events that occurred in > 5% of patients who received intravenous ganciclovir for the treatment or prevention of manifest CMV infection after bone marrow transplantation, regardless of their causal relationship with the drug and severity:

the bodies of the blood: pancytopenia, leukopenia;body as a whole: the defeat of the mucous membranes, fever, chills, sepsis, anorexia, swelling of the face;

on the part of the digestive system: diarrhea, dyspepsia;

laboratory data: increased creatinine, liver transaminases, hypomagnesemia, hypocalcemia, hypokalemia;

from the nervous system: headache, tremor, confusion; the skin and its appendages: exfoliative dermatitis;

from the respiratory system: rhinitis, shortness of breath;

from the cardiovascular system: tachycardia, hypotension;

from the digestive tract genitourinary: hematuria; senses: bleeding in the eye;

musculoskeletal system: myalgia.

Clinical adverse events that occurred in > 5% of patients who received intravenous ganciclovir after a heart transplant, regardless of the causal relationship with the drug or severity:

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%).

Genitourinary tract: impaired renal function (14%), renal failure (12%).

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

To fully characterize the safety profile of intravenously administered ganciclovir, the relevant adverse events identified with greater frequency with oral use of ganciclovir in HIV-infected or post-organ transplant patients are listed below, regardless of their severity and causal relationship with the drug. Some adverse events with oral use of ganciclovir may be associated with this particular method of taking the drug.

Blood system and lymphatic system: leukocytosis.

Digestive system: constipation, cholangitis, flatulence, vomiting.

The body as a whole: ascites, asthenia, bleeding, bacterial, fungal and viral infections, malaise. Cardiovascular system: vasodilation (decreased blood pressure, redness of the skin of the face).

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 mellitus, 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 system and lymphatic system:aplastic anemia, myelosuppression, eosinophilia.

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

Body as a whole: cachexia, dehydration, weakness, injection site thrombosis, injection site abscess, injection site edema, injection site pain, injection site hemorrhage, malaise, photosensitization reactions.

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

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

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

Genitourinary tract:frequent urination.

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

Experience of post-marketing use of the drug

Adverse events, consistent with spontaneous reports when using ganciclovir in HIV-infected patients and other immunocompromised patients (for example, after transplantation), for which a causal relationship with the drug cannot be excluded: anaphylaxis decreased fertility in men.

Otherwise, the adverse events described during post-marketing use of the drug are similar to those observed in clinical studies.

Interaction

Interactions with intravenous ganciclovir

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

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

This increase cannot be explained by a change in the tubular secretion of the drug, since the percentage of excretion of didanosine 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 carefully monitored for didanosine toxicity.

Imipenem / cilastatin: Seizures were reported in patients receiving ganciclovir and imipenem/cilastatin concomitantly. These drugs should only be given in combination with Cimeven if the potential benefits outweigh the risk.

Mycophenolate mofetil: concomitant use of these drugs, potentially competing for tubular secretion, may lead to an increase in the concentration of ganciclovir and MFKG (mycophenolic acid phenolic glucuronide).

No significant changes in the pharmacokinetics of mycophenolic acid (MFC) are expected, and no dose adjustment of mycophenolate mofetil is required. In patients with impaired renal function who are receiving ganciclovir and MMF concomitantly, the recommended dosage of ganciclovir should be followed and carefully monitored. Other possible drug interactions

Toxicity may increase when ganciclovir is administered concomitantly with other drugs that have a myelosuppressive effect or impair renal function (such as dapsone, pentamidine, flucytosine, vincristine, vinblastiine, adriamycin, amphotericin B, nucleoside analogues and hydroxyurea). Therefore, these drugs should only be administered concomitantly with ganciclovir if the potential benefits outweigh the possible risks.

How to take, course of use and dosage

Adults and children over 12 years of age

Standard dosage for the 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).

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

Standard dosage for prevention in patients after transplantation

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 for 1 hour, daily for 7 days a week, or 6 mg / kg of body weight daily for 5 days a week.

Special dosage instructions for patients with renal insufficiency, the dosage 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 [mmol / L]} for women = 0.85 x indicator for men

Since the dose of ganciclovir should be adjusted in patients with renal insufficiency, it is necessary to carefully monitor serum creatinine concentrations or creatinine clearance.

Patients with leukopenia, severe neutropenia, anemia and thrombocytopenia. Severe leukopenia, neutropenia, anemia, thrombocytopenia, myelosuppression, and aplastic anemia have been reported in patients receiving ganciclovir. Do not start treatment with the drug if the absolute number of neutrophils is less than 500 cells per 1 µl, or platelets – less than 25,000 cells per 1 µl, or if the hemoglobin level is less than 8 g/dl (see “Special instructions” and “Side effects”). Elderly and senile patients: Since senile patients often have reduced renal function, ganciclovir should be prescribed strictly according to their renal function (see above).

Children: The efficacy and safety of ganciclovir in children under 12 years of age, including those with congenital and neonatal CMV infection, have not been established. Because of the possibility of long-term carcinogenicity and toxic effects on the reproductive system, the benefits of treatment should prevail over the possible risks.

Method of preparation of Tsimeven’s solution%^%1. Lyophilized ganciclovir powder is dissolved by injecting 10 ml of sterile water into a vial for injection. Do not use bacteriostatic water for injection containing parabens (parahydroxybenzoates), as they are incompatible with the sterile powder of ganciclovir 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. You can’t put it in the refrigerator.

Instructions for handling the drug Caution should be exercised when coming into 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”). It is necessary to avoid inhalation or direct contact of the powder contained in the vials, or direct contact of the solution with the skin and mucous membranes. Tsimeven’s solution has an alkaline reaction (pH 11). If ganciclovir gets on the skin or mucous membranes, this area should be thoroughly washed with soap and water. In case of contact with the eyes, they are thoroughly washed with just water.

Preparation and use of the infusion solution From a bottle of ganciclovir (concentration of 50 mg/ml), the dose of the drug calculated (taking into account the patient’s body weight) is collected and added to the base infusion solution (saline sodium chloride solution,5% aqueous glucose solution, Ringer’s solution or Ringer-lactate). It is not recommended to administer ganciclovir at concentrations greater than 10 mg/ml.

Ganciclovir should not be mixed with other intravenous medications.

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

The infusion solution should be stored in the refrigerator; it is not recommended to freeze it.

The drug can not be administered intravenously quickly or 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 ganciclovir solution.

Do not exceed the recommended dose, as well as change the mode of use or the rate of infusion.

Overdose

Overdose of intravenously administered ganciclovir

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

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

Nephrotoxicity: increased hematuria in a patient with pre-existing kidney damage, acute renal failure, increased creatinine levels.

Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting.

Neurotoxicity: generalized tremor, convulsions.

In addition, one adult patient was intravitreally administered an excessive volume of ganciclovir solution for intravenous use, after which he developed temporary vision loss and occlusion of the central retinal artery due to increased intraocular pressure caused by the volume of fluid administered.

Hemodialysis and hydration can be used to reduce the level of ganciclovir in plasma with an oral overdose of Cimeven

Special instructions

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

Cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, myelosuppression, and aplastic anemia have been reported in patients taking ganciclovir. Do 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 25,000 cells per 1 µl, or the hemoglobin level is less than 8 g/dl.

During treatment, it is recommended to monitor the detailed blood formula, including the number of platelets. In patients with severe leukopenia, neutropenia, anemia, and/or thrombocytopenia, it is recommended to treat with hematopoietic growth factors and/or temporarily interrupt therapy with the drug.

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

Seizures have been reported in patients taking imipenem / cilastatin and ganciclovir, so ganciclovir should not be administered concomitantly with imipenem/cilastatin unless the potential benefits of therapy outweigh the possible risks.

Both ganciclovir and zidovudine can cause neutropenia and anemia, so some patients may not tolerate the simultaneous use of these drugs in full doses.

Plasma concentrations of didanosine may increase with concomitant use of ganciclovir, so such patients should be carefully monitored for didanosine toxicity.

Concomitant use of ganciclovir and drugs with myelosuppressive or nephrotoxic effects may lead to the development of additive toxicity.

Influence on the ability to drive vehicles and work with machines and mechanisms

Patients taking ganciclovir may experience seizures, drowsiness, dizziness, ataxia, and confusion. Such symptoms can affect the performance of activities that require increased attention, including the ability to drive vehicles and work with machines and mechanisms.

Form of production

Lyophilizate for infusion solution preparation

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

3 years

Active ingredient

Ganciclovir

Conditions of release from pharmacies

By prescription

Dosage form

lyophilizate for solution preparation

Purpose

For adults as directed by your doctor

Indications

Cytomegalovirus infection