Ganciclovir

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Ganciclovir: instructions for use and reviews

1. Release form and composition
2. Pharmacological properties
3. Indications for use
4. Contraindications
5. Method of application and dosage
6. Side effects
7. Overdose
8. Special instructions
9. Application during pregnancy and lactation
10. Use in childhood
11. In case of impaired renal function
12. Use in the elderly
13. Drug interactions
14. Analogs
15. Terms and conditions of storage
16. Terms of dispensing from pharmacies
17. Reviews
18. Price in pharmacies

Latin name: Ganciclovir

ATX code: J05AB06

Active ingredient: ganciclovir (ganciclovir)

Manufacturer: RUE "Belmedpreparaty" (Republic of Belarus)

Description and photo updated: 28.08.

Ganciclovir is an antiviral drug used in the treatment of cytomegalovirus infection.

Release form and composition

Ganciclovir is produced in the form of a lyophilized powder for the preparation of a solution for infusion: a porous mass of white with a yellowish tinge or white, hygroscopic, compacted into a tablet (in bottles of 500 mg, in a cardboard box of 1 or 40 bottles and instructions for the use of Ganciclovir).

The composition of 1 bottle includes:

Active ingredient: ganciclovir (in the form of sodium) - 500 mg;
Auxiliary components: sodium hydroxide - up to pH 10.8-11.4.

Pharmacological properties

Pharmacodynamics

Ganciclovir, the active component of the antiviral drug, is a synthetic analogue of 2'-deoxyguanosine, which inhibits the replication of herpes viruses both in vitro and in vivo.

Ganciclovir-sensitive human viruses:

CMV (cytomegalovirus);
Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2);
Human herpesvirus 6, 7 and 8 types (HHV-6, HHV-7, HHV-8);
EBV (Epstein-Barr virus), or human herpesvirus type 4;
Chickenpox (Virus Varicella Zoster - VZV), or human herpesvirus type 3;
Hepatitis B virus (HBV).

Clinical trials of Ganciclovir are limited to assessing the effectiveness of the drug in the treatment of patients with CMV infection.

Under the influence of the viral protein kinase UL97B, ganciclovir is phosphorylated in cells infected with CMV to ganciclovir monophosphate. Further, under the influence of a number of cellular kinases (phosphotransferases), its phosphorylation occurs with the formation of ganciclovir triphosphate, which begins to be gradually metabolized inside the cell. The process of biotransformation occurs in cells infected with CMV and herpes simplex virus, after removal of ganciclovir from the extracellular fluid, the intracellular half-life is 18 and 6-24 hours, respectively. Since phosphorylation of ganciclovir mainly depends on the action of viral kinase, it occurs to a greater extent in infected cells.

The virostatic effect of ganciclovir is based on suppressing the synthesis of viral deoxyribonucleic acid (DNA) by competitive inhibition of the incorporation of deoxyguanosine triphosphate into it under the influence of DNA polymerase, the inclusion of ganciclovir triphosphate into the viral DNA, as a result of which the elongation of viral DNA stops or its elongation occurs very limited.

In vitro, the antiviral activity of ganciclovir, expressed as the concentration of half-maximal inhibition (IC ₅₀) in relation to CMV, is 0.08-14 μM (0.02-3.5 μg / ml).

The likelihood of developing viral resistance to the drug should be considered in patients showing a repeated weak clinical response or stably shedding the virus during treatment. CMV resistance to ganciclovir can develop after prolonged treatment / prophylaxis with the drug as a result of a selective mutation of the UL97 (viral protein kinase) gene, which is responsible for monophosphorylation of ganciclovir, and, much less often, mutations in the UL54 (viral polymerase) gene. At the same time, a virus with mutations in the UL97 gene shows resistance only to ganciclovir, while a virus with mutations in the UL54 gene is capable of cross-resistance to other antiviral drugs with a similar mechanism of action and vice versa.

The current establishment of CMV resistance to the action of ganciclovir is detected in vitro and is expressed in the following values: IC ₅₀ ≥ 12 μM with an intermediate resistance index of 6 to 12 μM. According to confirmed data, up to 4% of untreated patients contained CMV isolates corresponding to the indicators of resistance or intermediate resistance.

Pharmacokinetics

Absorption: after a single intravenous infusion of ganciclovir for 1 hour at a dose of 5 mg / kg to HIV-positive / CMV-positive patients, the area under the concentration-time pharmacokinetic curve (AUC _0-24) ranged from 21.4 (± 3, 1) up to 26 (± 6.06) μg × h / ml. The maximum plasma concentration (C _max) ranged from 8.27 (± 1.02) to 9.03 (± 1.42) μg / ml;
Distribution by organs and tissues: V _d (volume of distribution) after parenteral administration correlates with the patient's body weight and varies in the state of equilibrium concentration from 0.536 (± 0.078) to 0.87 (± 0.116) l / kg. The level of ganciclovir in the cerebrospinal fluid 0.25-5.67 hours after the administration of the drug intravenously at a dose of 2.5 mg / kg every 8 or 12 hours is 24-67% of that in plasma and is equal to 0.5-0.68 μg / ml. The substance binds to plasma proteins by 1–2% at a plasma concentration of 0.5–51 μg / ml. The concentration of ganciclovir in intraocular fluids and tissues after its intravenous administration can be 40-200% of the plasma concentration. The average level of the substance after an intravenous induction dose is 1.15 μg / ml, after a maintenance dose - 1 μg / ml;
Metabolism and excretion: intravenous administration of the drug in the range of 1.6–5 mg / kg provides linear pharmacokinetics of ganciclovir. The main pathway for its elimination is renal excretion of the unchanged drug by glomerular filtration and active tubular secretion. With normal renal function, 89.6 (± 5)% of the substance administered intravenously is found in the urine unchanged; systemic clearance ranges from 2.64 (± 0.38) to 4.52 (± 2.79) ml / min / kg, and the renal clearance rate is from 2.57 (± 0.69) to 3.48 (± 0.68) ml / min / kg, this corresponds to 90-101% of the received parenteral substance. T _1/2 (half-life) ranges from 2.73 (± 1.29) to 3.98 (± 1.78) hours T _1/2 ganciclovir from the eye is much longer than from plasma, and is 13.3-18.8 hours.

Pharmacokinetic parameters in special groups:

Patients with renal insufficiency: impaired renal function causes a change in the kinetics of ganciclovir. Depending on the level of serum creatinine (Crea), the following changes are observed: Crea ganciclovir less than 124 μmol / ml - total plasma clearance (K) - 3.64 ml / min / kg, T _1/2 - 2.9 h; Crea 125–225 μmol / ml - K - 2 ml / min / kg, T _1/2 - 5.3 h; Crea 226–398 μmol / ml - K - 1.11 ml / min / kg, T _1/2 - 9.7 h; Crea more than 398 μmol / ml - K - 0.33 ml / min / kg, T _1/2 - 28.5 h;
Patients on hemodialysis: hemodialysis leads to a decrease in plasma concentration of ganciclovir after parenteral and oral use by approximately 50%. The use of an intermittent hemodialysis regimen provides ganciclovir clearance rates within 42–92 ml / min, T _1/2 during dialysis - 3.3–4.5 hours. Continuous dialysis helps to reduce ganciclovir clearance to the range of 4–29.6 ml / min., moreover, in the period until the next dose of the drug, a larger percentage of the dose used is removed from the body. Intermittent hemodialysis in one session ensures the removal of the ganciclovir fraction by 50–63%;
Children: the pharmacokinetic characteristics of ganciclovir in children from 9 months to 12 years are the same for both single and multiple (every 12 hours) intravenous administration of the drug at a dose of 5 mg / kg. As a result of a single injection of 5 mg / kg, the average AUC∞ is 19.4 (± 7.1) μg × h / ml, stationary V _d - 0.68 (± 0.2) L / kg, C _max - 7.59 (± 3.21) μg / ml, systemic clearance - 4.66 (± 1.72) ml / min / kg, T _1/2 - 2.49 ± 0.57 h;
Elderly patients: The pharmacokinetics of ganciclovir in patients over 65 years of age has not been studied.

Indications for use

Treatment of life-threatening or vision-threatening cytomegalovirus (CMV) infection in patients with immunodeficiency, including acquired immunodeficiency syndrome (AIDS), iatrogenic immunodeficiency, which is associated with neoplasm chemotherapy or organ transplantation;
Prevention of manifest CMV infection in patients receiving immunosuppressive therapy after organ transplantation.

Contraindications

Pregnancy and lactation (breastfeeding);
Hypersensitivity to the components of the drug, as well as to valganciclovir, acyclovir and valacyclovir.

Ganciclovir, instructions for use: method and dosage

Treatment of CMV infection in adults:

Initial therapy: infusion at a dose of 5 mg / kg for an hour at a constant rate, every 12 hours (daily dose - 10 mg / kg). The duration of the course is 2-3 weeks;
Maintenance therapy: patients with immunodeficiencies at risk of recurrence of CMV retinitis intravenous infusion is administered daily at a dose of 6 mg / kg for 5 days or 5 mg / kg for 7 days;
Therapy for disease progression: patients with AIDS can be prescribed an indefinite treatment, however, even with prolonged use of the drug, there is a possibility of retinitis progression. Patients in whom retinitis progresses during maintenance therapy or due to discontinuation of the drug may be prescribed initial therapy with ganciclovir.

For the prevention of CMV infection:

Initial therapy: infusion of 5 mg / kg every 12 hours (10 mg / kg per day) for 1–2 weeks;
Maintenance therapy: intravenous infusion is administered daily at a dose of 6 mg / kg for 5 days or 5 mg / kg for 7 days.

Patients with renal insufficiency during the use of the drug should carefully monitor the level of serum creatinine.

Elderly patients should be prescribed the drug taking into account the functional state of the kidneys.

The experience of using Ganciclovir in children under 12 years of age is limited. Side effects that develop during therapy are similar to those observed in adults. Due to the likelihood of toxic effects on the reproductive system and long-term carcinogenicity, extreme caution should be exercised during treatment, correlating the benefits of treatment with the possible risk. The drug is contraindicated in neonatal and congenital CMV infection.

To reduce the severity of neutropenia or other cytopenia, it is necessary to reduce the daily dose of ganciclovir. As a rule, the number of cells returns to normal within 3-7 days after dose reduction or discontinuation of therapy. With indisputable signs of bone marrow recovery under close control of the number of white blood cells, a gradual increase in the dose of the drug is possible.

With a significant decrease in the number of blood cells during treatment, it is necessary to suspend the main therapy and / or prescribe treatment with hematopoietic growth factors.

To prepare a solution of Ganciclovir, the lyophilized powder must be dissolved in 10 ml of sterile water for injection. Bacteriostatic water for injection containing parabens (parahydroxybenzoates) must not be used.

The solution prepared in a bottle remains stable at room temperature for 12 hours. Do not store the solution in the refrigerator.

Before administration, a single dose of Ganciclovir should be added to the base infusion solution (5% aqueous dextrose solution, 0.9% sodium chloride solution, Ringer's lactate or Ringer's solution).

It is not recommended to use the drug at a concentration of more than 10 mg / ml.

Ganciclovir should not be mixed with other drugs given intravenously.

Side effects

The most common hematologic side effects during treatment are neutropenia, thrombocytopenia, and anemia.

In patients after transplantation of solid organs and HIV-infected patients, when using Ganciclovir, disorders may occur from some body systems:

The circulatory and lymphatic system: very often - anemia, neutropenia; often - pancytopenia, leukopenia, thrombocytopenia; infrequently - suppression of bone marrow activity;
Invasions and infections: often - sepsis (viremia, bacteremia), hypodermitis, candidiasis, urinary tract infections;
Nutrition and metabolism: often - anorexia, decreased appetite;
Immune system: infrequently - anaphylactic reactions;
Mental disorders: often - pathological thinking, anxiety, depression, confusion; infrequently - psychotic disorders, agitation;
Nervous system: often - insomnia, headache, hypesthesia, dysgeusia, peripheral neuropathy, paresthesia, convulsions, dizziness (except for vertigo); infrequently - tremor;
Cardiovascular system: infrequently - hypotension, arrhythmia;
Respiratory organs: very often - shortness of breath; often - cough;
Sense organs: often - pain in the ear, floating opacity of the vitreous humor, retinal detachment, macular edema, pain in the eyeball; infrequently - conjunctivitis, visual impairment, hearing loss;
Genitourinary system: often - impaired renal function, decreased renal creatinine clearance; infrequently - renal failure, hematuria, male infertility;
Musculoskeletal system: often - arthralgia, myalgia, back pain, muscle cramps;
Digestive system: very often - diarrhea; often - pain in the upper abdomen, vomiting, nausea, abdominal pain, constipation, dysphagia, flatulence, dyspepsia; infrequently - ulcerative stomatitis, bloating, pancreatitis;
Biliary tract and liver: often - an increase in blood alkaline phosphatase, impaired liver function, an increase in aspartate aminotransferase (AST); infrequently - an increase in alanine aminotransferase (ALT);
Subcutaneous fat and skin: often - itching, night sweats, dermatitis; infrequently - urticaria, alopecia, dry skin;
Laboratory indicators: often - weight loss, increase in creatinine in the blood;
Reactions at the injection site and general disorders: often - malaise, fatigue, chills, pyrexia, pain, chest pain, weakness, reaction at the injection site.

Overdose

The symptoms of a Ganciclovir overdose in most episodes are one or more of the following adverse reactions:

Gastrointestinal toxicity: abdominal pain, vomiting, diarrhea;
Neurotoxicity: convulsions, generalized tremor;
Hematotoxicity: myelosuppression, pancytopenia, bone marrow aplasia, neutropenia, leukopenia, granulocytopenia;
Hepatotoxicity: abnormal liver function, hepatitis;
Nephrotoxicity: with existing kidney damage - an increase in hematuria, an increase in creatinine concentration, acute renal failure.

A single case of intravitreal (directly into the vitreous) administration of an excessive amount of Ganciclovir solution for intravenous administration to an adult patient was recorded. This caused the development of temporary loss of vision and occlusion of the central retinal artery due to an increase in intraocular pressure due to the introduction of a significant volume of fluid.

In some cases, a significant excess of the dosage regimen did not cause any adverse events.

Hydration and hemodialysis can be used to reduce plasma levels of ganciclovir due to overdose.

For patients with severe neutropenia, leukopenia, anemia, thrombocytopenia, it is recommended to conduct therapy with hematopoietic growth factors in parallel.

special instructions

Ganciclovir can only be administered intravenously, preferably through a plastic cannula, into a vein with adequate blood flow.

The drug cannot be administered intravenously quickly or in a stream. Subcutaneous or intramuscular administration of the solution can lead to severe tissue irritation due to the high pH of the solution.

Do not exceed the recommended dosage, rate or frequency of infusion.

Before starting treatment, pregnant women should be informed about the likely risk to the fetus, since the drug has a potential carcinogenic and teratogenic effect and can cause malignant neoplasms and congenital malformations.

Ganciclovir can permanently or temporarily inhibit spermatogenesis. During therapy, women of childbearing age are advised to use reliable methods of contraception, men - to use a barrier method of contraception during the use of the drug and at least 90 days after the end of treatment.

Due to the likely long-term carcinogenicity and toxic effect on the reproductive system, extreme caution should be exercised when prescribing Ganciclovir to children and adolescents. Before prescribing a drug, the benefits of treatment must be weighed against the possible risk.

In patients receiving Ganciclovir, cases of severe leukopenia, neutropenia, pancytopenia, anemia, thrombocytopenia, myelosuppression and aplastic anemia were observed. Treatment should not be started with an absolute number of:

Neutrophils - less than 500 cells per 0.00001 dl.;
Platelets - less than 25,000 cells per 0.00001 dl.;
Hemoglobin - less than 8 g / dl.

Ganciclovir should be used with caution in patients who have previously had cytopenia or a history of drug-related cytopenia, as well as in patients who have received radiotherapy.

A complete blood count, including platelet count, is recommended during treatment. More often, hematological monitoring should be done in patients with impaired renal function.

In patients with severe neutropenia, leukopenia, thrombocytopenia, and / or anemia, treatment with hematopoietic growth factors or temporary interruption of therapy is recommended.

Influence on the ability to drive vehicles and complex mechanisms

The effect of Ganciclovir on the ability to drive potentially dangerous machinery or vehicles has not been studied, however, care should be taken if convulsive seizures, drowsiness, dizziness, ataxia and confusion develop during treatment.

Application during pregnancy and lactation

Clinical studies to study the safety of the use of Ganciclovir during pregnancy have not been conducted. The substance easily penetrates the placental barrier. Given the pharmacological mechanism of action, as well as the manifestation of reproductive toxicity in animal tests, there is theoretically a risk of teratogenicity of ganciclovir in humans. In this regard, it should not be prescribed to women during gestation.

During therapy with Ganciclovir, women of reproductive age need to use reliable methods of contraception, and men must use barrier methods of contraception during the course and at least 90 days after its completion.

There are no data on the penetration of ganciclovir into breast milk. However, this possibility cannot be ruled out, as well as the likelihood that the drug can cause serious adverse reactions when ingested with mother's milk. In this regard, during treatment, it is necessary to stop breastfeeding.

Pediatric use

In pediatric practice, the experience of using Ganciclovir for the treatment of children under 12 years of age is limited.

Possible adverse reactions associated with the use of Ganciclovir are similar to those in adults. Due to the likelihood of a long-term toxic effect on the human reproductive system and the carcinogenicity of the substance, special care should be taken during the treatment of children.

The drug is prescribed only if the benefits of therapy exceed the possible risk.

Ganciclovir is not used to treat congenital and neonatal cytomegalovirus in children.

With impaired renal function

The use of Ganciclovir requires careful monitoring of serum creatinine levels and / or its clearance.

The initial dose of Ganciclovir, depending on the CC value:

Above 70 ml / min: 5 mg / kg 1 time in 12 hours;
50–69 ml / min: 2.5 mg / kg once every 12 hours;
25–49 ml / min: 2.5 mg / kg once every 24 hours;
10-24 ml / min: 1.25 mg / kg once every 24 hours;
Below 10 ml / min: 1.25 mg / kg once every 24 hours after hemodialysis.

Use in the elderly

The efficacy and safety of Ganciclovir in the treatment of elderly patients have not been studied. Since this group of people often has reduced renal function, the drug should be prescribed with caution.

Drug interactions

With the simultaneous use of Ganciclovir with other drugs, it is possible:

Imipenem-cilastatin - the occurrence of seizures;
Probenecid - decreased renal clearance of ganciclovir;
Zidovudine - increases the AUC of zidovudine and decreases the concentration of ganciclovir;
Didanosine - an increase in its concentration in blood plasma;
Mycophenolate mofetil (MMF) - increased concentration of mycophenolic acid phenolic glucuronide (HMPA) and Ganciclovir;
Trimethoprim - increased risk of toxicity;
Zalcitabine - the occurrence of peripheral neuropathy.

An increase in toxicity is possible with the simultaneous use of Ganciclovir with drugs that suppress the replication of rapidly dividing cell populations: amphotericin B, pentamidine, dapsone, vincristine, flucytosine, adriamycin, vinblastine, trimethoprim / sulfa combinations, hydroxycarbamide and nucleoside analogs.

Concomitant use of Ganciclovir with drugs that have nephrotoxic or myelosuppressive effects may lead to the development of additive toxicity.

Analogs

Analogues of Ganciclovir are: Zirgan, Tsimeven.

Terms and conditions of storage

Store in a dark place, out of reach of children, at temperatures up to 25 ° C.

Shelf life is 2 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Ganciclovir

Experts say that Ganciclovir is the only drug that for a long time remains the most effective drug for the treatment and prevention of cytomegalovirus and diseases that can provoke it. The chemical structure of the antiviral agent ganciclovir is close to acyclovir, but it is much more toxic. In this case, the drug inhibits the activity of not only cytomegalovirus, but also other viruses (for example, hepatitis B, herpesvirus).

Patients in the few reviews of Ganciclovir indicate that the drug is effective, but due to very strong adverse reactions, it should be used only under strict indications, if other therapy is ineffective.

The price of Ganciclovir in pharmacies

At the moment, the price of Ganciclovir is unknown, since it is not available for sale. The cost of its analogue, Cymeven, whose active ingredient is ganciclovir, for a bottle of lyophilisate for preparing a solution for infusion of 500 mg, is about 1,700 rubles.

Anna Kozlova Medical journalist About the author

Education: Rostov State Medical University, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!