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GANCYCLOVIR-PHARMEX lyophilisate for infusion solution 500 mg

Instruction manual

For medical use of the drug

Ganciclovir Pharmex

(ganciclovir-pharmex)

Structure:

Active substance: ganciclovir;

1 vial contains 500 mg ganciclovir (as ganciclovir sodium salt).

Dosage form.

Lyophilisate for solution for infusion.

Basic physicochemical properties: lyophilized porous mass or powder of white or almost white color.

Pharmacotherapeutic group.

Antiviral agents for systemic use. nucleosides and nucleotides, with the exception of reverse transcriptase inhibitors. ganciclovir.

ATX Code J05A B06.

Pharmacological properties.

Pharmacodynamics

Ganciclovir is a synthetic nucleoside analogue of guanine that inhibits the replication of herpes viruses in vitro and in vivo. Such viruses as cytomegalovirus (CMV), herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2), human herpes viruses type 6, 7 and 8 (HHV-6, HHV-7, HHV-8 are sensitive to ganciclovir ), Epstein-Barr virus, chickenpox virus (Varicella zoster), hepatitis B. Clinical studies were limited to evaluating the effectiveness of the drug for patients with cytomegalovirus infection.

In the cell, ganciclovir is phosphorylated by cellular deoxyguanosine kinase to ganciclovir monophosphate. Further phosphorylation is carried out using several cellular kinases with the formation of ganciclovir triphosphate, which is then subject to slow intracellular metabolism. This metabolism has been shown to occur in cells infected with human cytomegalovirus and herpes simplex virus, and after the disappearance of ganciclovir from the extracellular fluid, the intracellular elimination half-life is 18 and 6-24 hours, respectively. Since the phosphorylation of ganciclovir is more dependent on the action of the viral kinase, it occurs predominantly in infected cells.

The virologostatic effect of ganciclovir is due to suppression of viral DNA synthesis by: competitive inhibition of the incorporation of deoxyguanosine triphosphate into DNA under the action of DNA polymerase; the inclusion of ganciclovir triphosphate in viral DNA, which leads to the cessation of the extension of viral DNA or its very limited extension. Typical Antiviral IC50 in relation to cytomegalovirus, determined in vitro, is in the range from 0.08 μm (0.02 μg / ml) to 14 μm (3.5 μg / ml).

Viral resistance

The possibility of developing viral resistance should be considered in patients who repeatedly exhibit a poor clinical response or who have sustained virus isolation during therapy.

Ganciclovir resistance to cytomegalovirus may develop after prolonged treatment or prophylaxis with ganciclovir with selective mutation of the viral kinase gene (UL97), which is responsible for monophosphorylation of ganciclovir and / or, less often, the viral polymerase gene (UL54). Viruses containing mutations in the UL97 gene are resistant to ganciclovir only, while viruses with a mutation in UL54 may show cross-resistance to other antiviral agents that target viral polymerase and vice versa.

The current definition of CMV resistance to ganciclovir is based on the definition of in vitro antiviral activity: median inhibitory concentration (IC50) ≥ 12.0 μM, a value of 6.0 μM and 50 corresponding to resistance or transient resistance.

In a prospective study of 76 previously untreated AIDS patients with severe immunosuppression and CMV retinitis who started ganciclovir therapy (iv induction / iv supportive treatment or iv induction / oral supportive treatment), the number of patients carrying resistant viruses (IC50 6.0 μM) - increased during treatment, namely, 3.7%, 5.4%, 11.4% and 27.5% at the beginning of treatment, after 3, 6 and 12 months, respectively.Similarly, in another study of AIDS patients with CMV retinitis who were treated with intravenous ganciclovir for ≥3 months, 7.8% of patients were carriers of viruses with IC50 12.0 μM. Combined data from 4 clinical trials for CMV retinitis treatment showed resistance (IC50 6.0 μM) in 3.2% (median exposure of 75 days) with intravenous ganciclovir and 6.5% (median exposure of 165 days) with oral ganciclovir.

Pharmacokinetics

Suction

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 total area under the concentration-time curve (AUC0–24) ranges from 21.4 ± 3.1 to 26 ± 6.06 μg × h / ml. The maximum concentration in blood plasma (Cmax) was in the range from 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, when equilibrium concentration is reached, is from 0.536 ± 0.078 (n = 15) to 0.870 ± 0.116 (n = 16) 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 the plasma concentration and is 0.5–0.68 μg / ml Communication with blood plasma proteins at ganciclovir concentrations of 0.5 and 51 μg / ml - 1-2%.

After intravenous administration of ganciclovir, intraocular concentrations of ganciclovir are from 40 to 200% of those that are simultaneously measured in blood plasma. The average intraocular concentrations after induction and maintenance dosing of ganciclovir intravenously were 1.15 and 1.0 μg / ml, respectively. The half-life of ganciclovir from the eye is significantly longer than from blood plasma and is estimated to range from 13.3 to 18.8 hours.

Metabolism and excretion

Following intravenous administration in doses of 1.6 to 5 mg / kg, the kinetics of ganciclovir is linear. The main route of excretion is renal excretion of the unchanged drug by glomerular filtration and tubular secretion. In patients with normal renal function, 89.6 ± 5% of the intravenously administered dose of ganciclovir is found in the urine unchanged. In persons with normal renal function, systemic clearance is in the range from 2.64 ± 0.38 to 4.52 ± 2.79 ml / min / kg, and renal clearance is 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 failure ranges from 2.73 ± 1.29 to 3.98 ± 1.78 hours.

Pharmacokinetics in special groups of patients

Kidney disease

Impaired renal function leads to changes in the kinetics of ganciclovir, as shown in the table below.

Ganciclovir
Serum Creatinine (μM / L) Systemic clearance from plasma (ml / min / kg) Plasma half-life (hours)

125–225 (n = 9)

226–398 (n = 3)

398 (n = 5)

3,64

2,00

1,11

0,33

2,9

5,3

9,7

28,5

Hemodialysis patients

Hemodialysis reduces the concentration of ganciclovir in blood plasma after intravenous and oral administration by about 50%.

When using an intermittent hemodialysis regimen, ganciclovir clearance indicators range from 42 to 92 ml / min, the half-life of the drug during dialysis is 3.3–4.5 hours. With continuous dialysis, ganciclovir clearance was less (4–29.6 ml / min), but a larger percentage of the dose was removed from the body before the next dose. With intermittent hemodialysis, the fraction of ganciclovir removed in one hemodialysis session is from 50 to 63%.

Children

The pharmacokinetics of ganciclovir has also been studied in 10 children aged 9 months to 12 years. The pharmacokinetic characteristics of ganciclovir after a single and multiple (with an interval of 12 hours) intravenous administration of the drug at a dose of 5 mg / kg were the same. After a single dose of 5 mg / kg, the exposure measured as AUC∞ was 19.4 ± 7.1 6 μg x h / ml, the volume of distribution in equilibrium was 0.68 ± 0.20 l / kg, Cmax - 7.59 ± 3.21 μg / ml, systemic clearance - 4.66 ± 1.72 ml / min / kg, and t1/2 - 2.49 ± 0.57 hours.This range of pharmacokinetic parameters in children with intravenous administration of ganciclovir is comparable to that characteristic for adults.

Elderly patients

A study involving persons over 65 years of age was not conducted.

Clinical characteristics.

Indications.

Treatment of cytomegalovirus (CMV) infection that threatens life or vision in people with immunodeficiency (acquired immunodeficiency syndrome (AIDS), iatrogenic immunosuppression associated with organ transplantation or chemotherapy of tumors).

Prevention of cytomegalovirus infection in patients receiving immunosuppressive therapy after organ transplantation.

Contraindications

Hypersensitivity to ganciclovir, valganciclovir or to another component of the drug.

Due to the similarity of the chemical structure of ganciclovir, acyclovir and valaciclovir between these drugs, possible cross-sensitivity reactions. Therefore, ganciclovir is contraindicated for use with hypersensitivity to acyclovir or valaciclovir.

The absolute number of neutrophils is less than 500 cells in 1 μl or the number of platelets is less than 25,000 cells in 1 μl.

The period of pregnancy and lactation, as well as men who plan paternity.

Special security measures.

Caution when preparing ganciclovir solution

Since ganciclovir is considered potentially teratogenic and carcinogenic to humans, the drug should be handled with caution.

Inhalation or direct contact with the powder contained in the vials or direct contact of the reconstituted solution with the skin or mucous membranes should be avoided. Ganciclovir alkaline solution (pH about 11). This operation is recommended to be carried out in polyethylene gloves and goggles.

Due to the high pH level (9–11) and potential carcinogenic effect, ganciclovir solution should be prepared with caution. When preparing a solution of ganciclovir, it is recommended to use rubber or protective gloves.

If ganciclovir gets on the skin or mucous membranes, this place must be thoroughly washed with soap and water; eyes should be washed with sterile or running water, if not sterile.

Interaction with other drugs and other types of interactions.

Didanosine. it was found that with the simultaneous use of didanosine and intravenous or oral administration of ganciclovir, the concentration of didanosine in blood plasma is steadily increasing. with intravenous administration of ganciclovir in doses of 5–10 mg / kg per day, the auc of didanosine increases by 38–67%, and with oral administration of doses of 3–6 g / day, by 84–124%. 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 carefully monitored

Tags: Ganciclovir