Kyivmedpreparat #Preparations_for_the_treatment_of_infections #Antiviral_agents #HEALTH_CARE
Pharmacological properties
Pharmacodynamics. acyclovir is a synthetic analogue of a purine nucleoside with in vivo and in vitro inhibitory activity against human herpesvirus, which includes herpesvirus type i and ii, varicella-zoster virus and herpes zoster virus, epstein-barr virus and cytomegalovirus. in cell culture, acyclovir is most active against herpes simplex virus type i and further, in decreasing activity, against herpes simplex virus type ii, varicella-zoster virus and herpes zoster, epstein-barr virus and cytomegalovirus.
The inhibitory activity of acyclovir against the aforementioned viruses is highly selective. The enzyme thymidine kinase in a normal uninfected cell does not use acyclovir as a substrate, therefore, the toxic effect on the cells of the host organism is minimal. However, thymidine kinase, encoded in the viruses of herpes simplex, chickenpox, herpes zoster and Epstein-Barr virus, converts acyclovir into acyclovir monophosphate, a nucleoside analogue, which is then converted sequentially into diphosphate and triphosphate using cell enzymes. Following integration into viral DNA, acyclovir triphosphate interacts with viral DNA polymerase, resulting in the termination of the synthesis of the viral DNA chain.
With prolonged or repeated courses of treatment of critically ill patients with reduced immunity, it is possible to reduce the sensitivity of certain strains of the virus, which do not always respond to treatment with acyclovir. Most clinical cases of insensitivity are associated with viral thymidine kinase deficiency, but viral thymidine kinase and DNA damage have been reported. In vitro interactions of certain herpes simplex viruses with acyclovir can also lead to the formation of less sensitive strains. The relationship between the sensitivity of individual herpes simplex viruses in vitro and the clinical results of treatment with acyclovir is not fully understood.
Pharmacokinetics. Acyclovir is partially absorbed in the intestine. The average peak stable concentration (Cssmax) in blood plasma after taking a dose of 200 mg with a 4-hour interval is 3.1 μmol (0.7 μg / ml), respectively, the level in blood plasma (Cssmin) will be 1.8 μmol (0 , 4 μg / ml). The corresponding Cssmax levels after 400 mg and 800 mg doses at 4-hour intervals are 5.3 μmol (1.2 μg / ml) and 8 μmol (1.8 μg / ml), and the equivalent Cssmin levels are 2.7 μmol (0.6 μg / ml) and 4 μmol (0.9 μg ml).
In adults, the final T ½ with intravenous administration of acyclovir is about 2.9 hours. Most of the preparation is excreted unchanged by the kidneys. The renal clearance of acyclovir is significantly higher than the clearance of creatinine, which indicates that the excretion of the preparation by the kidneys is carried out by not only glomerular filtration, but also by tubular secretion.
9-carboxymethoxymethylguanine is the only important metabolite of acyclovir that can be detected in urine and accounts for about 10-15% of the dose used. If acyclovir is used one hour after taking 1 g of probenecid, the final T½ and AUC increase by 18 and 40%, respectively.
In patients with chronic renal failure, the mean final T½ is 19.5 hours. The mean T½ of acyclovir during hemodialysis is 5.7 hours. The level of acyclovir in blood plasma during dialysis decreases by about 60%.
The concentration of the preparation in the cerebrospinal fluid is about 50% of the corresponding concentration in the blood plasma. The level of binding to blood plasma proteins is relatively low (9–33%) and does not change when interacting with other preparations.
With the simultaneous use of acyclovir and zidovudine for the treatment of HIV-infected patients, no changes in the pharmacokinetics of these preparations have been revealed.
Indications
Treatment of viral infections of the skin and mucous membranes caused by the herpes simplex virus, including primary and recurrent genital herpes; suppression (prevention of recurrence) of infections caused by the herpes simplex virus in patients with normal immunity; prevention of infections caused by the herpes simplex virus in patients with immunodeficiency; treatment of infections caused by the varicella zoster virus (chickenpox and herpes zoster).
Application
The tablet should be taken whole with water. when using high doses of acyclovir, an adequate level of body hydration should be maintained.
Adults
Treatment of infections caused by the herpes simplex virus. For the treatment of infections caused by the herpes simplex virus, it is necessary to take Herpevir tablets at a dose of 200 mg 5 times a day at approximately 4-hour intervals, with the exception of the night period.
Treatment should be 5 days, but if the primary infection is severe, it can be continued.
For patients with severe immunodeficiency (for example, after bone marrow transplantation) or for patients with reduced absorption in the intestine, the dose can be doubled to 400 mg or the corresponding dose can be used for intravenous administration.
Treatment should be started as early as possible after the onset of infection. In the case of recurrent herpes, it is better to start treatment in the prodromal period or after the first signs of skin lesions appear.
Prevention of recurrence (suppressive therapy) of infections caused by the herpes simplex virus. In patients with normal immunity, to prevent recurrence of infections caused by the herpes simplex virus, Herpevir tablets at a dose of 200 mg are taken 4 times a day with a 6-hour interval.
For convenience, most patients can take 400 mg of Herpevir 2 times a day at 12-hour intervals.
Treatment will be effective even after the cancellation of the tableted Herpevir up to 200 mg, which are taken 3 times a day with an 8-hour interval or even 2 times a day with a 12-hour interval.
In some patients, a radical improvement is noted after taking a daily dose of 800 mg Herpevir.
To monitor possible changes in the natural course of the disease, therapy with Herpevir should be interrupted periodically at intervals of 6-12 months.
Prevention of infections caused by the herpes simplex virus. For the prevention of infections caused by the herpes simplex virus, patients with immunodeficiency should take Herpevir tablets at a dose of 200 mg 4 times a day with a 6-hour interval. For patients with significant immunodeficiency (for example, after bone marrow transplantation) or in patients with reduced absorption in the intestine, the dose can be doubled to 400 mg or the appropriate dose can be used for intravenous administration.
The duration of prophylaxis depends on the length of the risk period.
Treatment for chickenpox and herpes zoster. For the treatment of infections caused by the viruses of chickenpox and herpes zoster, Herpevir tablets should be taken at a dose of 800 mg 5 times a day at 4-hour intervals, with the exception of the night period. Treatment should continue for 7 days.
Patients with severe immunodeficiency (for example, after bone marrow transplantation) or patients with reduced absorption in the intestine are best used in / in the introduction.
Treatment should be started as early as possible after the onset of the disease, the result will be better if treatment is started immediately after the appearance of the rash.
Elderly patients. It should be borne in mind the possibility of impaired renal function in elderly patients, and the dose for them should be changed accordingly (see Renal failure). It is necessary to maintain an adequate level of hydration of the body.
Renal failure Herpevir should be used with caution in patients with renal insufficiency. It is necessary to maintain an adequate level of hydration of the body.
In the prevention and treatment of herpes simplex virus infections in patients with renal insufficiency, the recommended oral doses do not lead to the accumulation of acyclovir, the level of which would exceed the safe level established for intravenous administration. However, for patients with severe renal failure (creatinine clearance 10 ml / min), it is recommended to set a dose of 200 mg 2 times a day with an interval of about 12 hours.
In the treatment of infections caused by the Varicella zoster virus (chickenpox and herpes zoster), for patients with significantly reduced immunity, it is recommended in severe renal failure (creatinine clearance 10 ml / min) to establish a dose of 800 mg 2 times a day with approximately 12-hour intervals. and for patients with moderate renal failure (creatinine clearance within 10-25 ml / min) - 800 mg 3 times a day with an interval of about 8 hours.
Children.
Herpevir tablets are used in children over the age of 2 years.
For the treatment and prevention of infections caused by the herpes simplex virus in children with immunodeficiency at the age of 2 years, doses can be used as for adults.
For the treatment of chickenpox in children aged 6 years and older, 800 mg of Herpevir 4 times a day, children aged 2-6 years can receive 400 mg of Herpevir 4 times a day. The duration of treatment is 5 days.
More precisely, the dose can be calculated by the child's body weight - 20 mg / kg of body weight per day (not to exceed 800 mg) Herpevir, divided into 4 doses.
There are no special data on the use of Herpevir for the prevention (prevention of recurrence) of infections caused by the herpes simplex virus, or for the treatment of infections caused by the herpes zoster virus, in children with normal immunity.
Children under the age of 2 years are not prescribed this dosage form of the preparation.
Contraindications
Individual hypersensitivity to acyclovir, valacyclovir or other components of the preparation.
Side effects
Blood system and lymphatic system: anemia, thrombocytopenia, leukopenia.
Immune System: Anaphylaxis.
Mental and nervous system disorders: headache, dizziness, agitation, confusion, tremors, ataxia, dysarthria, hallucinations, psychotic symptoms, convulsions, drowsiness, encephalopathy, coma. The above neurological reactions are generally reversible and usually occur in patients with renal insufficiency or other risk factors (see SPECIAL INSTRUCTIONS).
Respiratory system and chest organs: shortness of breath.
Digestive system: nausea, vomiting, diarrhea, abdominal pain.
Hepatobiliary system: reversible increase in the level of bilirubin and liver enzymes, jaundice, hepatitis.
Skin and subcutaneous tissues: itching, rash (including photosensitivity), urticaria, increased diffuse hair loss. Since hair loss can be associated with a wide variety of diseases and medications, no clear association has been identified with acyclovir. Angioedema.
Kidneys and urinary system: increased levels of urea and creatinine in the blood, acute renal failure, pain in the kidneys. Kidney pain can be associated with renal failure and crystalluria.
General disorders: fatigue, fever.
Special instructions
Acyclovir is excreted from the body mainly by renal clearance, therefore, the dose should be reduced in patients with renal insufficiency (see application). in elderly patients, the likelihood of impaired renal function is also high, therefore, a dose reduction may be required for this group of patients. patients with renal insufficiency and elderly patients are at risk of neurological side effects and therefore should be closely monitored to identify these side effects. according to the obtained data, such reactions are generally reversible after discontinuation of treatment (see side effects).
Particular attention should be paid to maintaining an adequate level of hydration in patients receiving high doses of acyclovir.
During pregnancy and breastfeeding. There was no increase in the number of congenital malformations in children whose mothers used acyclovir during pregnancy, compared with the general population. However, Herpevir tablets should be used when the potential benefit of the preparation to the mother outweighs the possible risk to the fetus.
When taken orally 200 mg of acyclovir 5 times a day, acyclovir passes into breast milk in concentrations of 0.6–4.1% of the corresponding level of acyclovir in blood plasma. Potentially, a child fed with this milk can assimilate acyclovir at a dose of up to 0.3 mg / kg of body weight per day. Therefore, caution should be exercised when prescribing acyclovir for breastfeeding, taking into account the risk / benefit ratio.
Children. Herpevir tablets are used in children over the age of 2 years.
The ability to influence the reaction rate when driving or working with other mechanisms. When deciding on the possibility of driving a car and other mechanisms, the clinical status of the patient and the profile of side effects of the preparation should be taken into account. Clinical studies of the effect of acyclovir on the reaction rate when driving vehicles or other mechanisms have not been conducted. In addition, the pharmacology of acyclovir does not give reason to expect any negative effects.
Interactions
No clinically important interactions of acyclovir with other preparations have been identified.
Acyclovir is excreted mainly unchanged by the kidneys by tubular secretion, therefore, any preparations that have a similar release mechanism can increase the concentration of acyclovir in the blood plasma. Probenecid and cimetidine increase the T½ of acyclovir and AUC.
With simultaneous use with immunosuppressants in patients after organ transplantation, the level of acyclovir and the inactive metabolite of the immunosuppressive preparation also increases in the blood plasma, but given the broad therapeutic index of acyclovir, dose adjustment is not required.
Overdose
Symptoms acyclovir is only partially absorbed in the gastrointestinal tract. Accidental intake of up to 20 g of acyclovir by patients inside did not cause a toxic effect. in case of accidental repeated overdose of oral acyclovir within several days, gastroenterological (such as nausea and vomiting) and neurological symptoms (headache and confusion) occur. in case of an overdose of intravenous acyclovir, the level of serum creatinine, urea nitrogen in the blood increases and, accordingly, renal failure develops. neurological manifestations of an overdose can be confusion, hallucinations, agitation, convulsions, and coma.
Treatment. The patient must be carefully examined to identify symptoms of intoxication. Since acyclovir is well excreted by hemodialysis, the latter should be used in case of overdose.
Storage conditions
In its original packaging at a temperature not exceeding 25 ° C.
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