Cymevene^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Cheplapharm Arzneimittel, GmbH (Germany)

Manufactured By

BSP Pharmaceuticals S.p.A. (Italy)

Labeled By

PRESTIGE PROMOTION VERKAUFSFORDERUNG & WERBESERVICE, GmbH (Germany)

Quality Control Release

PRESTIGE PROMOTION VERKAUFSFORDERUNG & WERBESERVICE, GmbH (Germany)

Or

CHEPLAPHARM ARZNEIMITTEL, GmbH (Germany)

ATC Code

J05AB06 (Ganciclovir)

Active Substance

Ganciclovir (Rec.INN registered by WHO)

Dosage Form

Cymevene®

Lyophilizate for preparation of solution for infusion 500 mg: fl. 1 pc.

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of solution for infusion in the form of a porous mass, compacted into a tablet, sometimes in the form of separate parts of a tablet, white or almost white in color; reconstituted solution is a clear or slightly opalescent, colorless or slightly yellowish liquid.

Colorless glass vials with a capacity of 10 ml (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug

Pharmacotherapeutic Group

Antiviral agent

Pharmacological Action

Mechanism of action

Ganciclovir is a synthetic analogue of 2′-deoxyguanosine that inhibits the replication of herpes viruses both in vitro and in vivo. It is active against human cytomegalovirus (CMV), herpes simplex viruses types 1 and 2 (Herpes simplex 1 and 2), human herpesviruses 6, 7, and 8, Epstein-Barr virus, varicella-zoster virus, and hepatitis B virus. Clinical studies have been limited to evaluating the drug’s efficacy in patients infected with cytomegalovirus.

In CMV-infected cells, Ganciclovir is first phosphorylated by the viral protein kinase to form ganciclovir monophosphate. Further phosphorylation is carried out by 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. Because the phosphorylation of ganciclovir is more dependent on the action of the viral kinase, it occurs predominantly in infected cells.

The virustatic effect of ganciclovir is due to the inhibition of viral DNA synthesis by: (1) competitive inhibition of the incorporation of deoxyguanosine triphosphate into DNA by DNA polymerase; (2) incorporation of ganciclovir triphosphate into viral DNA, leading to cessation or very limited elongation of viral DNA. The typical minimum blood concentration of the drug causing a 50% inhibitory antiviral effect against CMV (IC₅₀), 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 in vitro determination: the median IC₅₀ exceeds 1.5 µg/ml (6.0 µM). Resistance of CMV to ganciclovir develops rarely (about 1%). Resistance has been observed in patients with AIDS and CMV retinitis who have never received Ganciclovir. Within the first 6 months of treatment of CMV retinitis with Cymevene^® (infusions or capsules), viral resistance is detected in 3-8% of patients. Virus resistance has also been observed in patients receiving long-term therapy with Cymevene^® infusions for CMV retinitis. The main mechanism of CMV resistance to ganciclovir is a reduced ability to form the active triphosphate. Resistant viruses containing mutations in the CMV UL97 gene responsible for ganciclovir phosphorylation 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 active against CMV.

Pharmacokinetics

Absorption

After a 1-hour infusion of ganciclovir at a dose of 5 mg/kg to HIV- and CMV-infected patients or adult AIDS patients, the total area under the concentration-time curve (AUC_0-24) ranges 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 at steady-state concentration 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 plasma concentrations and is 0.50-0.68 µg/ml. Plasma protein binding is 1-2%.

Metabolism and excretion

After intravenous administration in doses from 1.6 to 5.0 mg/kg, the kinetics of ganciclovir are 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 intravenously administered dose of Ganciclovir is found unchanged in the urine. In individuals with normal renal function, systemic clearance ranges from 2.64±0.38 to 4.52±2.79 ml/min/kg, and 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 half-life in individuals without renal failure ranges from 2.73±1.29 to 3.98±1.78 hours.

Pharmacokinetics in special patient groups

Renal impairment

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

When using intermittent hemodialysis, ganciclovir clearance values range from 42 to 92 ml/min, and the half-life of the drug during dialysis is 3.3-4.5 hours. With continuous dialysis, ganciclovir clearance was lower (4.0-29.6 ml/min), but a larger percentage of the administered dose was removed from the body before the next dose. With intermittent hemodialysis, the fraction of ganciclovir removed in one hemodialysis session ranges from 50% to 63%.

Elderly patients

Studies in persons over 65 years of age have not been conducted.

Indications

• Treatment of life-threatening or sight-threatening manifest CMV infection in persons with immunodeficiencies, including AIDS;
• Prevention of manifest CMV infection in patients after organ transplantation.

ICD codes

Dosage Regimen

Adults and children over 12 years

Standard dosing for the treatment of CMV retinitis

Initial therapy: IV infusion at a dose of 5 mg/kg body weight over 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 dosing for prophylaxis in patients after transplantation

Initial therapy: IV infusion at a dose of 5 mg/kg over 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.

Special dosing instructions

Patients with renal failure

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 concentration [µmol/l]

For women = 0.85 x value for men

Since the dose of ganciclovir should be adjusted in patients with renal failure, serum creatinine concentrations or creatinine clearance should be carefully monitored.

Patients with leukopenia, severe neutropenia, anemia and thrombocytopenia

Cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, myelosuppression and aplastic anemia have been observed in patients receiving Ganciclovir.

Treatment with the drug should not be started if the absolute neutrophil count is less than 500 cells/µl, platelets are less than 25,000 cells/µl, or hemoglobin is less than 8 g/dl (see sections “Special Instructions” and “Adverse Reactions”).

Elderly and senile patients

Since renal function is often reduced in elderly individuals, Ganciclovir should be prescribed strictly taking into account renal function (see above).

Children

The drug is contraindicated in children under 12 years of age (see section “Contraindications”).

The efficacy and safety of ganciclovir in children, including for congenital and neonatal CMV infection, have not been established. Due to the potential for long-term carcinogenicity and toxicity to the reproductive system, extreme caution should be exercised. The benefits of treatment must outweigh the possible risk.

Method for preparing the Cymevene^® solution

1. The lyophilized ganciclovir powder is dissolved by adding 10 ml of sterile water for injections to the vial. Bacteriostatic water for injections containing parabens (parahydroxybenzoates) must not be used as they are incompatible with sterile ganciclovir powder and may cause precipitation.
2. Shake the vial to dissolve the drug.

Inspect the prepared solution for the presence of mechanical impurities.

The prepared solution in the vial is stable at room temperature for 12 hours. It must not be refrigerated.

Instructions for handling the drug

Since Ganciclovir is considered a potential human carcinogen and mutagen, caution should be exercised when handling it (see section “Special Instructions”). Avoid inhaling or having direct contact with the powder contained in the vials or direct contact of the solution with the skin and mucous membranes. The Cymevene^® solution has an alkaline reaction (pH 11). If ganciclovir comes into contact with the skin or mucous membranes, the area should be washed thoroughly with soap and water. If it gets into the eyes, they should be rinsed thoroughly with plain water.

Preparation and administration of the infusion solution

The calculated dose of the drug (based on the patient’s body weight) is drawn from the vial of ganciclovir (concentration 50 mg/ml) and added to the base infusion solution (0.9% sodium chloride solution, 5% aqueous dextrose solution, Ringer’s solution or Ringer’s lactate solution). It is not recommended to administer Ganciclovir at a concentration greater than 10 mg/ml.

Ganciclovir should not be mixed with other intravenously administered drugs.

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 of preparation.

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

The drug must not be administered by rapid intravenous or bolus injection!

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

The recommended dose should not be exceeded, nor should the administration regimen or infusion rate be changed.

Adverse Reactions

HIV-infected patients

Clinical side effects reported in ≥2% of patients receiving Ganciclovir intravenously, regardless of causality and severity

Central and peripheral nervous system: hypesthesia, anxiety.

Digestive system: diarrhea, abdominal pain, dysphagia, esophageal candidiasis.

Hematopoietic and lymphatic system: neutropenia, anemia, thrombocytopenia, leukopenia, lymphadenopathy.

Respiratory system: cough, pneumocystis pneumonia, productive cough, sinus congestion.

Musculoskeletal system: arthralgia.

Laboratory parameters: increased blood alkaline phosphatase activity, hypercreatininemia;

Dermatological reactions: itching.

Other: fever, candidiasis, injection site infections, sepsis, including secondary sepsis, anorexia, Mycobacterium avium complex infection, pain of various locations, including chest pain, bacteremia, injection site inflammation.

Post-transplant patients

Clinical adverse events reported in ≥5% of patients receiving Ganciclovir intravenously for the treatment or prevention of manifest CMV infection after bone marrow transplantation, regardless of causality and severity:

Central and peripheral nervous system: headache, tremor, confusion.

Cardiovascular system: tachycardia, decreased blood pressure.

Digestive system: diarrhea, nausea, dyspepsia, abdominal distension.

Urinary system: hematuria.

Hematopoietic system: pancytopenia, leukopenia.

Respiratory system: rhinitis, dyspnea.

Dermatological reactions: exfoliative dermatitis.

Sense organs: eye hemorrhage.

Musculoskeletal system: myalgia.

Laboratory parameters: increased creatinine concentration, “liver” transaminase activity, hypomagnesemia, hypocalcemia, hypokalemia.

Other: mucosal lesions, fever, chills, sepsis, anorexia, facial edema.

Clinical adverse events reported in ≥5% of patients receiving Ganciclovir intravenously after heart transplantation, regardless of causality or severity

Central and peripheral nervous system: headache (18%), confusion (5%), peripheral neuropathy (7%).

Cardiovascular system: increased blood pressure (20%).

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

Metabolism and nutrition: edema (9%).

Respiratory system: pleural effusion (5%).

Other: infections (18%).

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

To fully characterize the safety profile of intravenously administered ganciclovir, the corresponding adverse events identified with a higher frequency during oral administration of ganciclovir in HIV-infected or post-transplant patients are listed below, regardless of their severity and causality. Some adverse events with oral ganciclovir may be specifically related to this route of administration.

Central and peripheral nervous system: depression, dizziness, insomnia.

Cardiovascular system: vasodilation (decreased BP, facial flushing).

Digestive system: constipation, cholangitis, flatulence, vomiting.

Hematopoietic and lymphatic system: leukocytosis.

Metabolism and nutrition: diabetes mellitus, hyponatremia, hypoproteinemia, weight loss.

Liver and biliary tract: cholestatic jaundice.

Dermatological reactions: increased sweating.

Sense organs: amblyopia, taste perversion.

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

Other adverse events

Significant adverse events not listed above because they did not meet the inclusion criteria (less than 2%) are listed below:

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

Cardiovascular system: arrhythmia (including ventricular), deep vein thrombophlebitis, migraine, phlebitis.

Digestive system: gastrointestinal bleeding, belching, fecal incontinence, ulcerative stomatitis, pancreatitis, glossitis.

Blood and lymphatic system: aplastic anemia, myelosuppression, eosinophilia; potentially life-threatening bleeding due to thrombocytopenia; episodes of infections due to bone marrow and immune system suppression (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 sensory organs: retinal detachment, vision disorders, blindness, hearing loss, eye pain, glaucoma, vitreous destruction.

From laboratory parameters: increased activity of creatine phosphokinase and LDH in the blood, hypoglycemia.

Other: 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, photosensitivity reactions.

Post-marketing experience with the drug

Adverse effects, according to spontaneous reports from the use of ganciclovir in HIV-infected patients and other immunocompromised patients (e.g., post-transplantation), for which a causal relationship with drug use cannot be excluded: anaphylaxis, decreased fertility in men.

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

Contraindications

• Absolute neutrophil count less than 500 cells per 1 µl or platelet count less than 25,000 cells per 1 µl or hemoglobin level 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 between these drugs are possible.

With caution renal failure.

Use in Pregnancy and Lactation

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

Women of childbearing potential should be advised to use reliable contraception during treatment with ganciclovir. Men are advised to use barrier contraception during treatment and for at least 90 days after its completion.

Animal studies have revealed the teratogenicity of the drug. The safety of ganciclovir in human pregnancy has not been established. The use of the drug in pregnant women should be avoided unless the potential benefit to the mother outweighs the possible risk to the fetus.

Peri- and postnatal development following exposure to ganciclovir has not been studied, however, it cannot be ruled out that Ganciclovir may be excreted in milk and cause serious adverse reactions in the breastfed infant. Nursing mothers should be instructed to discontinue breastfeeding while taking Cymevene^®.

Use in Renal Impairment

Use with caution in renal failure. Doses should be adjusted according to CrCl.

Pediatric Use

Contraindication: children under 12 years of age.

The efficacy and safety of ganciclovir in children, including for congenital and neonatal CMV infection, have not been established. Due to the potential for long-term carcinogenicity and reproductive toxicity, extreme caution should be exercised. The benefits of treatment should outweigh the possible risk.

Geriatric Use

No studies have been conducted in persons over 65 years of age. Since renal function is often reduced in elderly persons, Ganciclovir should be prescribed strictly taking renal function into account.

Special Precautions

Ganciclovir has potential teratogenic and carcinogenic effects, may cause congenital malformations and malignant neoplasms. Ganciclovir may temporarily or permanently suppress spermatogenesis (see sections “Pregnancy and Lactation” and “Adverse Reactions”).

Cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, myelosuppression and aplastic anemia have been observed in patients taking Ganciclovir. Treatment with ganciclovir should not be initiated if the absolute neutrophil count is less than 500 cells/µl, or the platelet count is less than 25,000 cells/µl, or hemoglobin is less than 8 g/dl (see sections “Special Dosage Instructions” and “Adverse Reactions”).

Monitoring of blood cell counts, including platelet count, is recommended during treatment. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, treatment with hematopoietic growth factors and/or temporary interruption of therapy is recommended (see sections “Special Dosage Instructions” and “Pharmacokinetics in Special Patient Groups”).

In case of impaired renal function, dose adjustment of the drug depending on CrCl is recommended (see sections “Special Dosage Instructions” and “Pharmacokinetics in Special Patient Groups”).

Patients taking Ganciclovir may experience seizures, drowsiness, dizziness, ataxia, confusion and/or coma.

Seizures have been reported in patients taking imipenem/cilastatin and Ganciclovir, therefore Ganciclovir should not be administered concurrently with imipenem/cilastatin unless the potential benefits of therapy outweigh the possible risk (see section “Drug Interactions”).

Both Ganciclovir and zidovudine can cause neutropenia and anemia, so some patients may not tolerate concurrent administration of these drugs at standard recommended doses (see section “Drug Interactions”).

Plasma concentrations of didanosine may increase with concurrent administration of ganciclovir, so such patients should be closely monitored for signs of didanosine toxicity (see section “Drug Interactions”).

Concomitant use of ganciclovir and drugs with myelosuppressive or nephrotoxic effects may lead to the development of additive toxicity (see section “Drug Interactions”).

Effect on ability to drive and operate machinery

Patients taking Ganciclovir may experience seizures, drowsiness, dizziness, ataxia, confusion. Such symptoms may affect the performance of activities requiring increased attention, including the ability to drive vehicles and operate machinery. If these symptoms develop, patients should refrain from driving vehicles and operating machinery.

Overdose

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 concentration.

Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting.

Neurotoxicity: generalized tremor, convulsions.

In addition, one adult patient received an excessive volume of intravenous ganciclovir solution intravitreally, resulting in 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 concentrations of ganciclovir in case of Cymevene^® overdose (see section “Pharmacokinetics in Special Patient Groups”). In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, treatment with hematopoietic growth factors is recommended (see section “Special Precautions”).

Drug Interactions

Interactions with intravenous administration of ganciclovir

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

Didanosine: It has been established that with simultaneous use of didanosine and intravenous or oral ganciclovir, plasma concentrations of didanosine are persistently increased. With intravenous ganciclovir at doses of 5-10 mg/kg body weight/day, the AUC of didanosine increased by 38-67%. This increase cannot be explained by a change in tubular secretion of the drug, as the percentage of didanosine excretion increased. This increase in AUC may be due to either increased bioavailability or a decreased metabolic rate. There were no clinically significant changes in ganciclovir concentrations. However, given the increase in plasma concentrations of didanosine in the presence of ganciclovir, patients should be closely monitored to avoid didanosine toxicity.

Imipenem/cilastatin: Seizures have been observed in patients receiving Ganciclovir and imipenem/cilastatin concurrently. This drug should be prescribed in combination with Cymevene^® only if the anticipated benefit of treatment with the drug outweighs the potential risk of adverse effects.

Mycophenolate mofetil (MMF): Concomitant administration of these drugs, which potentially compete for tubular secretion, may lead to increased concentrations of ganciclovir and the phenolic glucuronide of mycophenolic acid. No significant change in the pharmacokinetics of mycophenolic acid is expected; no adjustment of the mycophenolate mofetil dose is required. In patients with impaired renal function who are concurrently receiving Ganciclovir and MMF, ganciclovir dosing recommendations must be followed and close monitoring is necessary.

Other possible drug interactions

Toxicity may be enhanced when ganciclovir is administered concomitantly with other drugs that have myelosuppressive effects or impair renal function (such as: dapsone, pentamidine, flucytosine, vincristine, vinblastine, doxorubicin, amphotericin B, nucleoside analogues and hydroxycarbamide). Therefore, these drugs should be administered concomitantly with ganciclovir only when the anticipated benefit of treatment with the drug outweighs the potential risk of adverse effects (see section “Special Precautions”).

Storage Conditions

Storage conditions

At a temperature not exceeding 30°C (86°F).

Keep out of reach of children.

Shelf Life

Shelf life

3 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.