Valcyte

A means for highly active antiviral therapy, prescribed for patients with severe viral lesions, the application of which requires compliance with certain rules.

Indications Valcyte

• cytomegalovirus lesion of photosensitive cells of the retina in patients over 16 years of age with acquired immunodeficiency syndrome;
• prevention of infection with cytomegalovirus in recipients of solid organs older than 16 years.

[1]

Release form

Available in tablet form with film coating. The unit of release contains 450 mg of L-valyl ester of ganciclovir.

Pharmacodynamics

The 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 is active against viruses: herpes (type 1, 2, 6, 7 and 8), Epstein-Barr, chickenpox, hepatitis B and cytomegalovirus.

Catalysts of the process of hydrolysis of the ester compound of ganciclovir are enzymes of esterase, which splice the Valcite at a good rate and enter the human body at a good rate.

When ganciclovir penetrates into the cells infected by viruses, a phosphorylation reaction catalyzed by the protein kinase of the virus begins, with the formation of monophosphate, then the triphosphate of this substance. Since it activates the beginning of this protein kinase process, the virus proceeds mainly in infected cells.

The mechanism of inhibition of the biosynthesis of viral deoxyribonuclease is due to the replacement of deoxyguanosine triphosphate in the deoxyribonuclease of the virus with ganciclovir triphosphate, which is inserted into the place of the natural element and leads to an interruption in the construction of a chain of viral DNA, or substantially 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) - from 0.02 μg / ml to 3.5 μg / ml.

Inside the affected cells, ganciclovir triphosphate is gradually metabolized. From the moment when this substance ceases to be detected in the extracellular fluid, the time interval of its half-elimination from cells infected with cytomegatovirus is ¾ day; herpes simplex virus - from six hours to a day.

Virostatic action of the drug is confirmed by a decrease in the excretion of cytomegalovirus from 46% to 7% from the body of people with AIDS and the newly diagnosed cytomegalovirus-associated retinitis after four weeks of treatment with Valcitol.

Pharmacokinetics

The processes occurring in the body after the administration of this drug have been studied using the example of people on treatment, cytomegalovirus and HIV-seropositive, with acquired immunodeficiency syndrome and CMV-associated retinitis, and solid body receptors.

Values that characterize the effect of ganciclovir on the body after taking Valcitum - its ability to assimilate (bioavailability) and preservation of renal function. Its bioavailability was similar for all groups of patients taking the drug. Systemic exposure of the active component after organ transplantation corresponded to the order of dosing of the renal function, respectively.

Suction

The active ingredient of the drug is well absorbed in the gastroduodenal zone, rapidly cleavable, forming ganciclovir, part of which in the total blood flow after oral administration of Valcitol is approximately 60%. The systemic effect of the medication is insignificant and transient. The total serum concentration during the first day of the study and the largest plasma density are approximately 1% and 3% of the dose of the active component, respectively. These indicators increase with the use of Valtsite tablets together with food.

Distribution

Since the cleavage of valganciclovir hydrochloride occurs very rapidly, it was not considered appropriate to determine its binding to serum albumins. The compound of ganciclovir with serum albumins at a drug density of 0.5-51 μg / ml is defined as 1-2%. The volume of its spread in a state of equilibrium after a one-time 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 with good speed to form ganciclovir, no other cleavage products have been determined.

Excretion

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

Disorders of renal function caused a slowing of the rate of blood purification from ganciclovir, which contributed to an increase in half-life in the terminal phase. This category of patients requires an adjusted dosage.

Pharmacokinetic indices in patients operated on for liver transplantation, with a single dose of standard dose of Valcit (900 mg per day) were comparable to those in patients with a stably functioning transplanted liver.

With a single dose of a standard dose of Valcit (900 mg / day), the presence of cystic fibrosis did not affect the ganciclovir digestion clinic in lung transplant recipients. The complex of clinical manifestations was comparable with exposure in the treatment of other recipients of transplanted solid organs with cytomegalovirus-associated lesions. 

[2], [3]

Dosing and administration

This tool assumes a faithful adherence to the manual for dosing, since ganciclovir is absorbed from it ten times better than from the capsules of the same name.

Basic dosages of the drug

Induction therapy: persons 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 in the evening at intervals of 12 hours) for three weeks. It should be noted that prolonged induction treatment increases the likelihood of myelotoxicity.

Supportive therapy requires a single dose of 0.9 g per day. Similar assignments are made for patients with cytomegalovirus-associated inflammation of the retina in remission. In cases of clinical deterioration, the doctor may prescribe a second induction treatment.

To prevent infection with cytomegalovirus in the recipients of donor organs, 0.9 g of Valcitol is administered once-only from the tenth to the hundredth postoperative day.

Use Valcyte during pregnancy

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

During the course of Valtsita, patients of fertile age should use reliable contraceptives, male patients - barrier methods throughout the treatment time and at the end of it - at least three months.

Contraindicated for women bearing a baby, and nursing mothers. 

Contraindications

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

Exercise caution when choosing a treatment regimen for elderly people and with kidney dysfunction.  

[4]

Side effects Valcyte

The negative consequences of taking Valcit, revealed experimentally, are similar to those registered with the therapeutic use of ganciclovir.

The most common negative effects observed in patients with cytomegalovirus retinitis and acquired immunodeficiency syndrome: diarrhea, a decrease in the number of neutrophils, a febrile state, infection of the mouth with Candida fungi, migraine and fatigue.

Recipients of donor organs most often recorded indigestion, trembling limbs and the whole body, rejection of the transplant, nausea, migraine, swelling of the legs, constipation, insomnia, pain in the back, high blood pressure, vomiting. Most of the adverse events were mild or moderate. In the case of solid body organs, the most common cases of side effects, according to the researchers, can be called leukopenia, diarrhea and nausea, neutropenia of varying severity.

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

The negative consequences of taking Valcit, observed more often than in 5% of cases of preventive reception in the recipients of donor organs, and also in the treatment of cytomegalovirus-associated inflammation of the retina:

Organs of digestion: diarrhea, nausea and vomiting, abdominal and epigastric pain, constipation, digestive disorders, flatulence, accumulation of fluid in the abdominal cavity, hepatic dysfunction.

Systemic complaints: febrile condition, fatigue, swelling of the legs, peripheral edema, weight loss, anorexia, fluid loss, rejection of the transplanted organ.

Hemopoiesis: a decrease in neutrophils, hemoglobin, platelets, white blood cells.

Infection of the mouth with fungi of the genus Candida.

The organs of the central and peripheral nervous system: diffuse pain syndrome in the head, insomnia, peripheral nerve lesions, numbness and tremor of parts of the body, dizziness, depressive states.

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

Respiratory organs: dyspnea, respiratory events and infection of the upper respiratory tract, accumulation of fluid in the pleural cavity, pneumonia, including pneumocystis.

Vision: vagueness of visual objects, separation of the retina from the vascular membrane.

Skeleton and musculature: back pain, limbs, joints, muscular spasms.

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

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

Parameters of tests: increase in the level of creatinine and potassium, decrease in potassium, magnesium, glucose, phosphorus, calcium.

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

Adverse events complicating the condition of patients and associated with taking the drug, the frequency of occurrence of which does not exceed 5%:

Hemopoiesis: suppression of bone marrow activity, and, as a consequence, inadequate production of blood cells (pancytopenia, aplastic anemia). Reduction of neutrophils to less than 500 cells in one microliter of blood was observed with a higher frequency in patients with cytomegalovirus-associated inflammation of the retina (16%) than in the recipients of donor organs (5%).

Excretion: a decrease in creatinine clearance and, as a consequence, its hyperconcentration, which was observed with a greater frequency in the recipients of donor organs than in persons with CMV-associated inflammation of the retina. Renal dysfunction is a specific consequence of transplantation.

Hemostasis: bleeding with a life threat, probably due to a sharp decrease in the number of platelets.

Central and peripheral nervous system: muscle spasms, hallucinations, confused consciousness, excessive excitation and other mental disorders.

Other: sensitization to the Valcite.

[5],

Overdose

There is evidence of the development of a medullary aplasia with a fatal outcome in an adult who took a ten-fold higher dose of drugs over several days (including renal dysfunction).

There is a possibility that when taking doses exceeding the recommended dose, the nephrotoxic properties of the drug increase.

Lower the serum content of the active ingredient is possible by applying hemodialysis and hydration.

The consequences of exceeding the amounts of ganciclovir introduced into the vein should be taken into account when considering the dosing of Valtsita, since the active substance of this agent is transformed into ganciclovir. There are descriptions of episodes of ganciclovir overdose during its clinical trials and application when injected directly into a vein. In some observed individuals, an overdose did not cause negative consequences. 

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

• on the composition of the blood: 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 kidney: increased renal impairment, if they exist before treatment, acute renal failure, serum hypercreatininaemia;
• on the gastroduodenal tract: abdominal pain, digestive disorders:
• on the nervous system: generalized tremor, muscular spasms.

[6], [7]

Interactions with other drugs

Animal studies did not show significant mutual adverse effects with the following drugs, which are most likely to be administered concomitantly with valtice-valacyclovir and didanosine, nelfinavir and cyclosporin, mycophenolate mofetil and omeprazole.

It is possible to expect mutual reactions with other drugs specific for ganciclovir, since the cleavage of valganciclovir hydrochloride occurs with its release fairly quickly.

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

It is not desirable to combine with the ß-lactam antibiotic Imipenem + Cilastatin, since in such cases convulsive reactions in patients were observed.

Combination with probenecid can reduce renal excretion and increase digestibility of ganciclovir, hence its toxicity.

Combination with Zidovudine increases the risk of neutropenia and anemia, it is necessary to adjust the dosage of these drugs to some patients.

When combined with didanosine, plasma concentrations of the latter significantly increase. It is necessary to consider the possibility of toxic effect of didanosine, and to 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, taking into account the effect of renal failure on the pharmacokinetics of these drugs, can hypothetically increase their concentration. It is assumed that correction of the dose of Mycophenolate Mofetil is not required, and the dose of Valtsita will have to be adjusted for patients with renal insufficiency, and carefully monitor them.

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

The combination with Stavudine, Trimethoprim, Cyclosporin did not reveal a significant drug interaction and dosage adjustment will not be required.  

It is undesirable to combine ganciclovir with other drugs that have myelosuppressive action or cause kidney failure, since they can mutually enhance the undesirable effects on the body. When these drugs are prescribed in combination with ganciclovir, the potential benefit should be commensurate with the likely risk.

[8], [9]

Storage conditions

Store in accordance with temperature conditions up to 30 ° C. Keep away from children

Shelf life

Shelf life 3 years.