Valcite

A highly active antiviral therapy agent prescribed to patients with severe viral infections, the use of which requires compliance with certain rules.

Indications Valcite

• cytomegalovirus damage to photosensitive cells of the retina in patients over 16 years of age with acquired immunodeficiency syndrome;
• prevention of cytomegalovirus infection in solid organ recipients over 16 years of age.

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Release form

Available in film-coated tablet form. Each unit contains 450 mg of ganciclovir L-valyl ester.

Pharmacodynamics

A derivative of the active ingredient (L-valyl ester of ganciclovir or valganciclovir hydrochloride) is ganciclovir, a synthetic substance with properties similar to 2-deoxyguanosine. This substance exhibits activity against viruses: herpes (types 1, 2, 6, 7 and 8), Epstein-Barr, chickenpox, hepatitis B and cytomegalovirus.

The catalysts for the hydrolysis process of the ether compound ganciclovir are esterase enzymes, which quickly break down Valcyte that has entered the human body.

When ganciclovir penetrates into virus-infected cells, a phosphorylation reaction begins, catalyzed by viral protein kinase, with the formation of monophosphate, and then triphosphate of this substance. Since the beginning of this process is activated by viral protein kinase, it occurs mainly in infected cells.

The mechanism of inhibition of the biosynthesis of viral deoxyribonuclease is due to the replacement of deoxyguanosine triphosphate in the viral deoxyribonuclease with ganciclovir triphosphate, which is built in place of the natural element and leads to the interruption of the construction of the viral DNA chain or significantly limits its elongation. According to laboratory studies, the optimal density of the active component of the drug, suppressing the activity of cytomegalovirus kinases by 50% (IC50) is from 0.02 μg/ml to 3.5 μg/ml.

Inside the affected cells, ganciclovir triphosphate is gradually metabolized. From the moment this substance ceases to be detected in the extracellular fluid, the period of its half-life from cells affected by cytomegaly virus is ¾ of a day; by the herpes simplex virus - from six hours to a day.

The virostatic effect of the drug is confirmed by a decrease in the excretion of cytomegalovirus from 46 to 7% from the body of individuals with AIDS and newly diagnosed cytomegalovirus-associated retinitis after four weeks of treatment with Valcyte.

Pharmacokinetics

The processes occurring in the body after the administration of this drug were studied using the example of individuals undergoing treatment, cytomegalovirus- and HIV-seropositive, with acquired immunodeficiency syndrome and CMV-associated retinitis, and recipients of solid organs.

The values characterizing the effect of ganciclovir on the body after taking Valcyte are its ability to be absorbed (bioavailability) and the preservation of renal function. Its bioavailability was similar for all groups of patients taking the drug. The systemic effect of the active component after organ transplantation corresponded to the dosage order according to renal function.

Suction

The active ingredient of the drug is well absorbed in the gastroduodenal zone, quickly breaks down, forming ganciclovir, the part of which in the general bloodstream after oral administration of Valcyte is approximately 60%. The systemic effect of the drug is insignificant and short-term. The total serum concentration during the first day of the study and the highest plasma density are approximately 1% and 3% of the dose of the active component, respectively. These indicators increase when Valcyte tablets are taken with food.

Distribution

Since valganciclovir hydrochloride is rapidly metabolized, it was not considered practical to determine its binding to serum albumin. Ganciclovir binding to serum albumin at a drug density of 0.5-51 μg/ml is determined to be 1-2%. Its distribution volume at steady state after a single intravenous injection is 0.680±0.161 l per kilogram of body weight.

Metabolism

When entering the human body, the active ingredient of the drug is hydrolyzed at a good rate to form ganciclovir; no other breakdown products have been identified.

Withdrawal

The active component of the drug and the metabolite are eliminated through the glomerular filter and renal tubules. More than 80% of the total clearance of ganciclovir is due to the purification of the blood through the kidneys.

Renal impairment resulted in a slower rate of ganciclovir clearance from the blood, which contributed to an increase in the terminal half-life. This category of patients requires an adjusted dosage.

Pharmacokinetic indices in subjects undergoing liver transplantation, with a single administration of a standard dose of Valcyte (900 mg per day), were comparable with similar parameters in subjects with a stable functioning transplanted liver.

In a single standard dose of Valcyte (900 mg daily), the presence of cystic fibrosis did not affect the clinical absorption of ganciclovir in lung transplant recipients. The complex of clinical manifestations was comparable to the exposure in the treatment of other solid organ transplant recipients with cytomegalovirus-associated lesions.

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Dosing and administration

This drug requires careful adherence to the dosage instructions, as ganciclovir is absorbed from it ten times better than from capsules of the same name.

Basic dosages of the drug

Induction therapy: individuals with cytomegalovirus-associated inflammation of the retina in the acute period are prescribed a single dose of 0.9 g (two tablets in the morning and evening at an interval of 12 hours) for three weeks. It should be taken into account that prolonged induction treatment increases the likelihood of myelotoxicity.

Maintenance therapy involves a single dose of 0.9 g per day. The same prescriptions are given to patients with cytomegalovirus-associated inflammation of the retina in remission. In cases of clinical deterioration, the doctor may prescribe repeated induction treatment.

To prevent cytomegalovirus infection in recipients of donor organs, 0.9 g of Valcyte is prescribed once from the tenth to the hundredth postoperative day.

Use Valcite during pregnancy

The permissible carcinogenicity of this drug has been proven experimentally on laboratory animals (mice). Ganciclovir, which is formed as a result of the breakdown of the active substance of the drug, negatively affects the ability to reproduce and has teratogenic properties.

During the course of Valcyte, female patients of fertile age must use reliable contraceptives, and male patients must use barrier methods throughout the entire treatment period and after its completion – for at least three months.

Contraindicated for pregnant and nursing women.

Contraindications

• allergic reactions to the components of the drug, as well as acyclovir, valacyclovir;
• pregnant and lactating women;
• children 0-12 years old;
• neutropenia (absolute neutrophil count in 1 µl of blood <500);
• anemia (hemoglobin level <80g/l);
• thrombocytopenia (absolute number of platelets in 1 µl of blood <25 thousand);
• creatinine clearance <10 ml/min.

Exercise caution when choosing a treatment regimen for elderly patients and those with renal dysfunction.

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Side effects Valcite

The adverse effects of taking Valcyte, identified experimentally, are similar to those registered with the therapeutic use of ganciclovir.

The most common adverse effects reported in patients with cytomegalovirus retinitis and acquired immunodeficiency syndrome are diarrhea, decreased neutrophil count, fever, oral Candida infection, migraine, and fatigue.

The most common side effects reported by donor organ recipients were upset stomach, tremors of the limbs and the whole body, transplant rejection, nausea, migraine, swelling of the legs, constipation, insomnia, back pain, high blood pressure, and vomiting. Most of the adverse effects were mild or moderate. According to the researchers, the most common side effects reported by solid organ recipients were leukopenia, diarrhea, nausea, and neutropenia of varying severity.

Side effects after organ transplantation observed in at least 2% of cases and not recorded in the group of people with CMV-associated retinitis: high blood pressure, increased blood creatinine and/or potassium levels, liver dysfunction.

Adverse effects of taking Valcyte, observed more often than in 5% of cases of prophylactic administration in recipients of donor organs, as well as in the treatment of cytomegalovirus-associated inflammation of the retina:

Digestive system: diarrhea, nausea and vomiting, abdominal and epigastric pain, constipation, digestive disorders, flatulence, fluid accumulation in the abdominal cavity, liver dysfunction.

Systemic complaints: fever, fatigue, leg swelling, peripheral edema, weight loss, anorexia, fluid loss, organ transplant rejection.

Hematopoiesis: decreased levels of neutrophils, hemoglobin, platelets, and leukocytes.

Infection of the oral cavity with Candida fungi.

Organs of the central and peripheral nervous system: diffuse pain syndrome in the head, insomnia, damage to peripheral nerves, numbness and tremor of body parts, dizziness, depressive states.

Skin: itchy irritations, excessive sweating at night, acne.

Respiratory system: shortness of breath, respiratory symptoms and infection of the upper respiratory tract, accumulation of fluid in the pleural cavity, pneumonia, including pneumocystis pneumonia.

Vision: blurred vision, separation of the retina from the choroid.

Skeleton and muscles: pain in the back, limbs, joints, muscle spasms.

Isolation: renal dysfunction, urinary disorders, urinary tract infections.

Heart and blood vessels: increase or decrease in blood pressure.

Analysis parameters: increased levels of creatinine and potassium, decreased levels of potassium, magnesium, glucose, phosphorus, calcium.

Various postoperative complications: pain syndrome, infection of the postoperative wound, increased drainage and slow healing.

Side effects that complicate the condition of patients and are associated with taking the drug, the frequency of occurrence of which does not exceed 5%:

Hematopoiesis: suppression of bone marrow activity and, as a consequence, insufficient production of blood cells (pancytopenia, aplastic anemia). A decrease in neutrophils to less than 500 cells per microliter of blood was observed with greater frequency in patients with cytomegalovirus-associated retinal inflammation (16%) than in recipients of donor organs (5%).

Isolation: decreased creatinine clearance and, as a result, its hyperconcentration, which was observed with greater frequency in recipients of donor organs than in individuals with CMV-associated retinal inflammation. Renal dysfunction is a specific consequence of transplantation.

Hemostasis: life-threatening bleeding, probably due to a sharp decrease in the platelet count.

Central and peripheral nervous system: muscle spasms, hallucinations, confusion, hyperarousal and other mental abnormalities.

Others: sensitization to Valcyte.

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Overdose

There is evidence of the development of medullary aplasia with a fatal outcome in an adult who took a tenfold excess of the drug dose (taking into account renal dysfunction) over several days.

There is a possibility that taking doses higher than recommended may increase the nephrotoxic properties of the drug.

It is possible to reduce the serum content of the active ingredient by using hemodialysis and hydration.

The consequences of exceeding the doses of ganciclovir administered intravenously should be taken into account when considering the dosage of Valcyte, since the active substance of this drug is transformed into ganciclovir. There are descriptions of episodes of overdose of ganciclovir during its clinical trials and use by injection directly into the vein. In some observed individuals, overdose did not cause negative consequences.

In most cases, one or a combination of several of the following toxic effects was observed:

• on the blood composition: bone marrow dysfunction, a decrease in the number of all blood cells or any type - leukopenia, neutropenia, granulocytopenia;
• on the liver: hepatitis, dysfunction;
• on the kidneys: worsening of renal impairment if present before treatment, acute renal failure, serum hypercreatininemia;
• on the gastrointestinal tract: abdominal pain, digestive disorders:
• on the nervous system: generalized tremor, muscle spasms.

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Interactions with other drugs

Animal studies have not shown significant interactions with the following drugs that are most likely to be co-administered with Valcyte: valacyclovir and didanosine, nelfinavir and cyclosporine, mycophenolate mofetil and omeprazole.

Interactions with other drugs specific to ganciclovir can be expected, since the breakdown of valganciclovir hydrochloride occurs with its excretion quite quickly.

Ganciclovir binds to plasma albumin by no more than 2%, so substitution reactions with the resulting compounds are not expected.

Combination with the ß-lactam antibiotic Imipenem+Cilastatin is undesirable, since in such cases convulsive reactions were observed in patients.

Combined administration with Probenecid can reduce renal excretion and increase absorption of ganciclovir, and therefore its toxicity.

Concomitant use with Zidovudine increases the risk of neutropenia and anemia; dosages of these drugs should be adjusted in some patients.

When combined with Didanosine, plasma concentrations of the latter increase significantly. It is necessary to take into account the possibility of the toxic effect of Didanosine and monitor the condition of patients receiving these drugs simultaneously.

The combination of a single intravenous injection of a standard dose of ganciclovir with the administration of mycophenolate mofetil powder, given the effect of renal insufficiency on the pharmacokinetics of these drugs, could hypothetically lead to an increase in their concentrations. It is assumed that no dose adjustment of mycophenolate mofetil will be required, but the dose of Valcyte will have to be adjusted for patients with renal insufficiency, and they should be closely monitored.

When combined with Zalcitabine, the absorption of oral ganciclovir is increased by 13%.

Combination with Stavudine, Trimethoprim, Cyclosporine did not reveal significant drug interactions and dosage adjustments will not be required.

Combination of ganciclovir with other drugs that have myelosuppressive action or cause renal failure is undesirable, since they can mutually enhance the undesirable effects on the body. When prescribing these drugs in combination with ganciclovir, it is necessary to weigh the potential benefit against the probable risk.

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Storage conditions

Store at temperatures up to 30°C. Keep out of reach of children.

Shelf life

Shelf life is 3 years.