Composition, form of production and packaging
Liofilizate for the preparation of a solution for infusions in the form of white or almost white powder, hygroscopic or sintered mass (porous cake).
1 f.
Acyclovir 250 mg
Excipients: sodium hydroxide.
Glass bottles (5) - plastic trays (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
The description of the drug was approved by the manufacturer for the 2006 print edition.
PHARMACHOLOGIC EFFECT
An antiviral drug, a synthetic analogue of the purine nucleoside, which has the ability to inhibit the in vitro and in vivo replication of Herpes simplex type 1 and 2 viruses, the Varicella zoster virus, the Epstein-Barr virus (EBV) and cytomegalovirus (CMV). In cell culture, acyclovir has the most pronounced antiviral activity against Herpes simplex type 1, followed in order of decreasing activity: Herpes simplex type 2, Varicella zoster, EBV and CMV.
The effect of acyclovir on viruses is highly selective. Acyclovir is not a substrate for the enzyme thymidine kinase of uninfected cells, so it is low-toxic for mammalian cells. Thymidine kinase cells infected with Herpes simplex type 1 and 2 viruses, Varicella zoster, EBV and CMV, converts acyclovir to acyclovir monophosphate, an analogue of the nucleoside, which is then sequentially converted to a diphosphate and triphosphate by cell enzymes. Inclusion of acyclovir triphosphate in a chain of viral DNA and subsequent chain termination block further replication of the viral DNA.
In patients with severe immunodeficiency, prolonged or repeated courses of therapy with acyclovir can lead to the formation of resistant strains, and therefore further treatment with acyclovir may not be effective. Most of the isolated strains with reduced sensitivity to acyclovir showed a relatively low content of viral thymidine kinase, a breakdown in the structure of viral thymidine kinase or DNA polymerase. The effect of acyclovir on strains of the Herpes simplex virus in vitro can also lead to the formation of less sensitive strains. There is no correlation between the sensitivity of strains of the Herpes simplex virus to acyclovir in vitro and the clinical efficacy of the drug.
It was shown that IV injection of Zovirax in high doses reduces the frequency of occurrence and retards the development of cytomegalovirus infection. If, after such an infusion therapy, acyclovir is administered for oral administration at high doses for 6 months, the mortality and frequency of viremia develop.
PHARMACOKINETICS
Distribution
In adults, the mean C max of acyclovir 1 hour after the infusion at a dose of 2.5 mg / kg, 5 mg / kg, 10 mg / kg and 15 mg / kg was 22.7 Ојmol (5.1 Ојg / ml), 43.6 Ојmol (9.8 Ојg / ml) , 92 Ојmol (20.7 Ојg / ml) and 105 Ојmol (23.6 Ојg / ml), respectively. C min of the drug in the plasma 7 hours after the infusion was 2.2 Ојmol (0.5 Ојg / ml), 3.1 Ојmol (0.7 Ојg / ml), 10.2 Ојmol (2.3 Ојg / ml) and 8.8 Ојmol (2.0 Ојg / ml), respectively.
The concentration of acyclovir in the cerebrospinal fluid is approximately 50% of its plasma concentration.
Acyclovir is bound to an insignificant degree with blood plasma proteins (9-33%).
Excretion
In adults, after intravenous administration of acyclovir, T 1/2 from plasma is about 2.9 hours. Most of the drug is excreted by the kidneys unchanged. Renal clearance of acyclovir significantly exceeds the creatinine clearance, which indicates the excretion of acyclovir by not only glomerular filtration, but also tubular secretion. The main metabolite of acyclovir is 9-carboxymethoxy-methylguanine, which accounts for about 10-15% of the dose administered in urine.
In the administration of acyclovir 1 h after administration of 1 g of probenecid T 1/2, acyclovir and AUC increased by 18 and 40%, respectively.
Pharmacokinetics in special clinical cases
In children older than 1 year, C max and C min , corresponding to that in adults, were observed when Zovirax was administered at a dose of 250 mg / m 2 instead of 5 mg / kg (adult dose) and at a dose of 500 mg / m 2 instead of 10 mg / kg (dose for adults).
In newborns (0 to 3 months) with acyclovir administered as an infusion lasting more than 1 hour every 8 hours, C max was 61.2 Ојmol (13.8 Ојg / ml) and C min was 10.1 Ојmol (2.3 Ојg / ml), and T 1/2 - 3.8 hours.
In elderly patients, the clearance of acyclovir decreases with age, in parallel with the decrease in creatinine clearance, however, T 1/2 acyclovir varies insignificantly.
In patients with chronic renal insufficiency, T 1/2 acyclovir averaged 19.5 hours, and during hemodialysis T 1/2 averaged 5.7 hours, the concentration of acyclovir in plasma decreased by approximately 60%.
INDICATIONS
- treatment of infections caused by the Herpes simplex virus type 1 and 2;
- prevention of infections caused by the Herpes simplex virus type 1 and 2, in patients with immunodeficiency;
- treatment of infections caused by the virus Varicella zoster;
- treatment of infections caused by the Herpes simplex virus type 1 and 2 in newborns;
- Prevention of cytomegalovirus infection in recipients of bone marrow transplants.
DOSING MODE
The drug is intended for intravenous infusion.
Adults for treatment of infections caused by Herpes simplex viruses (excluding herpetic encephalitis) and Varicella zoster , the drug is prescribed at a dose of 5 mg / kg body weight every 8 hours.
To treat infections caused by the virus Varicella zoster, and herpetic encephalitis in patients with immunodeficiency , infusion is performed at a dose of 10 mg / kg body weight every 8 hours (with normal kidney function).
For prevention of cytomegalovirus infection in bone marrow transplantation, the drug is used at a dose of 500 mg / m 2 of the body surface 3 times / day at intervals of 8 hours. Duration of treatment is from 5 days to transplantation and up to 30 days after transplantation.
In patients with obesity, the same doses are recommended, as in patients with normal body weight.
When prescribing intravenous infusions of Zovirax, patients with renal insufficiency should adjust the dosage regimen in accordance with a decrease in creatinine clearance.
Clearance of creatinine Recommended doses
25-50 ml / min 5-10 mg / kg or 500 mg / m 2 every 12 hours
10-25 ml / min 5-10 mg / kg or 500 mg / m 2 every 24 hours
0 (anuria) - 10 ml / min With continuous ambulatory peritoneal dialysis: 2.5-5 mg / kg or 250 mg / m 2 every 24 hours
When hemodialysis: 2.5-5 mg / kg or 250 mg / m 2 every 24 hours and after dialysis.
Children aged 3 months to 12 years of dose of Zovirax for IV infusion are established depending on the body surface area.
In newborns the dosing regimen is set depending on the body weight; for infections caused by the Herpes simplex virus type 1 and 2, the recommended dose is 10 mg / kg every 8 hours. The duration of treatment for herpes encephalitis and infections caused by the Herpes simplex virus in newborns is usually 10 days.
For infections caused by Herpes simplex viruses (other than herpetic encephalitis) and Varicella zoster, the drug is administered at a dose of 250 mg / m 2 every 8 hours.
For the treatment of herpetic encephalitis and infections caused by the virus Varicella zoster, the drug is prescribed in children with immunodeficiency at a dose of 500 mg / m 2 every 8 hours (with normal kidney function).
Limited data suggest that for the prevention of cytomegalovirus infection in children older than 2 years who underwent bone marrow transplantation , Zovirax can be administered at the doses recommended for adults.
Children with reduced renal function require a dose adjustment in accordance with the degree of renal failure.
In elderly patients with reduced clearance of creatinine, a dose reduction should be considered.
The course of treatment with Zovirax in the form of IV infusions is usually 5 days, but may vary depending on the patient's condition and response to therapy.
The duration of preventive use of Zovirax in the form of intravenous infusions is determined by the duration of the infection risk period.
Rules for the preparation and administration of a solution
The recommended dose of Zovirax should be administered as a slow intravenous infusion for 1 hour.
The following volumes of water for injection or a solution of sodium chloride for injection (0.9%) are used to prepare a solution of Zovirax with a content of 1 ml of a solution of 25 mg of acyclovir.
Dose of Zovirax in 1 ampoule (mg) Volume of dilution solution (ml)
125 5
250 10
500 20
The recommended volume of dilution solution should be added to the ampoule with Zoviraks powder and gently shaken until the contents of the ampoule completely dissolve.
The solution of Zoviraks obtained after dilution can be administered by means of a special infusion pump that regulates the rate of administration of the drug. A different route of administration is possible, while the prepared Zoviraks solution is diluted to give an acyclovir concentration not exceeding 5 mg / ml (0.5%). To do this, add the prepared solution to the selected infusion solution, which is recommended below, and shake well for complete mixing of solutions.
For children and newborns who need to enter minimal volumes of solutions, it is recommended to add 4 ml of the prepared Zoviraks solution (100 mg of acyclovir) to 20 ml of the solvent.
For adults, it is recommended to use infusion solutions in packs of 100 ml, even if it gives the concentration of acyclovir significantly below 0.5%. Thus, a 100 ml infusion solution can be used to administer any dose of acyclovir between 250 mg and 500 mg (10 and 20 ml diluted solution). For doses between 500 mg and 1000 mg of acyclovir, a second infusion solution of this volume should be used.
Zovirax for IV infusion is compatible with the following infusion solutions and remains diluted with them for 12 hours at room temperature (15 В° to 25 В° C): 0.45% and 0.9% sodium chloride solutions for IV infusions; 0.18% sodium chloride solution and 4% glucose solution for intravenous infusions; 0.45% sodium chloride solution and 2.5% glucose solution for intravenous infusions; Hartman solution.
Since no antibacterial preservative is included in the solution, dissolution and dilution should be carried out completely under aseptic conditions immediately prior to administration of the preparation.
The unused solution is destroyed.
If the solution becomes cloudy or the crystals fall out, it should be destroyed.
SIDE EFFECT
On the part of the digestive system: nausea, vomiting, reversible increase in the level of bilirubin and activity of liver enzymes; very rarely - hepatitis, jaundice.
On the part of the hematopoiesis system: anemia, leukopenia and thrombocytopenia.
From the urinary system: rarely - increased levels of urea and creatinine in the blood, which is due to the magnitude of C max and the state of the patient's water balance. To avoid these phenomena, it is necessary to administer the drug as a slow infusion for 1 hour and maintain the patient's water balance. The symptoms of renal insufficiency arising on the background of Zoviraks therapy usually quickly stop when the patients are rehydrated and / or the dose is reduced or canceled. Progression to acute renal failure occurs in exceptional cases.
From the side of the central nervous system: reversible neurological disorders, such as confusion, hallucinations, agitation, tremors, drowsiness, psychosis, convulsions and coma (usually in predisposed patients).
Allergic reactions: rash, photosensitivity, urticaria, pruritus, fever; rarely - shortness of breath, angioedema, anaphylaxis.
Local reactions: severe inflammatory reactions leading to necrosis were observed when a solution of Zovirax fell under the skin.
CONTRAINDICATIONS
- Hypersensitivity to acyclovir or valaciclovir.
It should be used with caution in case of dehydration, renal insufficiency, neurological disorders, as well as during the development of reactions to cytotoxic drugs with their intravenous administration (and when indicating such reactions in the anamnesis).
PREGNANCY AND LACTATION
The appointment of Zovirax during pregnancy and lactation (breastfeeding) requires caution and is possible only after evaluating the intended benefit to the mother and the potential risk to the fetus and the baby.
There was no increase in the number of birth defects in children whose mothers received Zovirax during pregnancy, compared with the general population.
When using Zoviraks in the form of lyophilizate during lactation (breastfeeding), it should be borne in mind that after taking Zovirax inside at a dose of 200 mg 5 times / day, acyclovir was detected in breast milk in concentrations of 0.6-4.1% of plasma concentrations. At such concentrations in breast milk, infants breastfed can receive acyclovir in a dose of 0.3 mg / kg / day.
APPLICATION FOR FUNCTIONS OF THE LIVER
When prescribing intravenous infusions of Zovirax, patients with renal insufficiency should adjust the dosage regimen in accordance with a decrease in creatinine clearance.
Clearance of creatinine Recommended doses
25-50 ml / min 5-10 mg / kg or 500 mg / m 2 every 12 hours
10-25 ml / min 5-10 mg / kg or 500 mg / m 2 every 24 hours
0 (anuria) - 10 ml / min With continuous ambulatory peritoneal dialysis: 2.5-5 mg / kg or 250 mg / m 2 every 24 hours
When hemodialysis: 2.5-5 mg / kg or 250 mg / m 2 every 24 hours and after dialysis.
APPLICATION FOR CHILDREN
Children aged 3 months to 12 years of dose of Zovirax for IV infusion are established depending on the body surface area.
In newborns the dosing regimen is set depending on the body weight; for infections caused by the Herpes simplex virus type 1 and 2, the recommended dose is 10 mg / kg every 8 hours. The duration of treatment for herpes encephalitis and infections caused by the Herpes simplex virus in newborns is usually 10 days.
APPLICATION IN ELDERLY PATIENTS
In elderly patients with reduced clearance of creatinine, a dose reduction should be considered.
SPECIAL INSTRUCTIONS
In patients with herpetic encephalitis receiving Zovirax in high doses, it is necessary to monitor renal function (especially with dehydration or with an initial impairment of kidney function).
With caution and under the control of kidney function, Zovirax should be used concurrently with drugs that disrupt kidney function (eg, cyclosporin, tacrolimus).
The prepared Zoviraks solution has pH = 11, so it can not be used inside.
OVERDOSE
Symptoms: increased serum creatinine, blood urea nitrogen, renal failure. Neurological symptoms include confusion, hallucinations, agitation, convulsions and coma.
Treatment: conduct symptomatic therapy. Hemodialysis is indicated.
DRUG INTERACTION
Clinically significant interactions of Zovirax with other medications have not been reported.
Calcium channel blockers and cimetidine increase the AUC of acyclovir and reduce its renal clearance (correction of the dosage regimen of Zovirax is not required).
With the simultaneous use of Zovirax with drugs that are excreted by active tubular secretion, an increase in the concentration of active substances or their metabolites in plasma is possible (caution is needed when assigning such combinations).
The combined use of aciclovir and mycophenolate mofenil, an immunosuppressant used in organ transplantation, leads to an increase in the AUC of acyclovir and the inactive metabolite of mycophenolate mofenil.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
List B. The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. The shelf life is 5 years.
