Product Overview
Composition
Each 500 mg film-coated tablet contains:
active substance:
famciclovir - 500.00 mg;
Excipients:
pregelatinized starch - 74.80 mg,
microcrystalline cellulose - 44.00 mg,
croscarmellose sodium - 40.80 mg,
sodium lauryl sulfate - 6.80 mg,
colloidal anhydrous silicon dioxide - 6.80 mg,
stearic acid - 6.80 mg;
film coating :
Opadry white OY-S-28924 (hypromellose-5cP - 7.48 mg, titanium dioxide - 4.08 mg, hypromellose-15cP - 2.48 mg, macrogol-4000 - 1.48 mg, macrogol-6000 - 1.48 mg) - 17.00 mg.
pharmachologic effect
ATC:
J.05.AB09 Famciclovir
Pharmacodynamics:
After oral administration, famciclovir is rapidly converted to penciclovir, which is active against human herpes viruses, including Varicella Zoster virus (VZV) and Herpes Simplex (HSV) types 1 and 2, as well as viruses Epstein-Barr and cytomegalovirus.
Penciclovir enters the cells infected with the virus, where, under the action of viral temidine kinase, it quickly turns into monophosphate, which in turn turns into triphosphate. Penciclovir triphosphate inhibits the replication of viral DNA (deoxyribonucleic acid).
The intracellular half-life of penciclovir triphosphate for cell culture infected with HSV 1 is 10 hours, HSV 2 - 20 hours; VZV - 7 hours.
The concentration of penciclovir triphosphate in uninfected cells does not exceed the minimum detectable, therefore, in therapeutic concentrations, penciclovir does not affect uninfected cells.
As with acyclovir, resistance to penciclovir is most often associated with mutations in the viral thymidine kinase gene, leading to a deficiency or impairment of the enzyme's substrate specificity. Changes in the DNA polymerase gene are much less common.
The use of famciclovir for the treatment of herpes zoster (caused by VZV) in immunocompetent and immunocompromised patients has been shown to accelerate the healing of the skin and mucous membranes.
Famciclovir is effective in treating various manifestations of ophthalmic herpes caused by VZV.
Famciclovir significantly reduces the severity and duration of postherpetic neuralgia in patients with herpes zoster.
One-day treatment of immunocompetent patients with famciclovir at a dose of 1500 mg 1 time per day or 750 mg 2 times a day contributes to the rapid resolution of the manifestations of recurrent labial herpes (caused by HSV).
The use of the drug in immunocompetent patients at a dose of 1000 mg 2 times a day for 1 day, 125 mg 2 times a day for 5 days or 500 mg 2 times a day for 3 days accelerates the healing of the skin and mucous membranes in case of recurrent genital herpes (caused by HSV).
Famciclovir at a dose of 500 mg 2 times a day for 7 days is effective in the treatment of various manifestations of herpes zoster in patients with reduced immunity due to infection with the human immunodeficiency virus (HIV).
In HIV-infected patients, the drug in a dose of 500 mg 2 times a day for 7 days accelerates the healing of the skin and mucous membranes in case of recurrence of genital herpes, and also reduces the number of days of HSV shedding (both with clinical manifestations and without them).
Famciclovir has not been studied in immunocompromised patients for other reasons.
The efficacy of a one-day administration of famciclovir at a dose of 1000 mg 2 times a day for the treatment of recurrent genital herpes in immunocompetent patients of the Negroid race did not exceed that for placebo.
The safety profile of a one-day administration of the drug at a dose of 1000 mg 2 times a day in this category of patients was similar to that established previously.
Pharmacokinetics: Absorption Famciclovir is a prodrug. After oral administration, famciclovir is rapidly and almost completely absorbed and rapidly converted into the pharmacologically active metabolite - penciclovir. The bioavailability of penciclovir after oral administration of famciclovir is 77%. The increase in plasma concentration of penciclovir is proportional to the increase in a single dose of famciclovir in the range of 125-1000 mg.
According to the study, the maximum concentration (Cmax) of penciclovir in blood plasma after oral administration of 125 mg, 250 mg or 500 mg of famciclovir is achieved on average after 45 minutes and averages 0.8 μg / ml, 1.6 μg / ml and 3, 3 μg / ml, respectively. Another study demonstrates the maximum concentration (Cmax) of penciclovir after oral administration of 250 mg, 500 mg or 1000 mg of famciclovir at values ​​of 1.5 μg / ml, 3.2 μg / ml and 5.8 μg / ml, respectively.
The systemic bioavailability (area under the concentration-time curve (AUC)) of penciclovir is independent of meal time.
AUC of penciclovir with a single dose of famciclovir and when dividing the daily dose of the drug into two or three doses coincide, which indicates the absence of accumulation of penciclovir with repeated use of famciclovir.
Metabolism
After oral administration, famciclovir is rapidly and completely converted into a pharmacologically active metabolite - penciclovir.
Distribution
Plasma protein binding of penciclovir and its 6-deoxy precursor is less than 20%.
Excretion
Famciclovir is excreted mainly in the form of penciclovir and its 6-deoxy precursor, which are excreted unchanged through the kidneys; famciclovir is not detected in urine. The half-life (T1 / 2) of penciclovir from plasma in the final phase after taking a single and repeated doses is about 2 hours.
Pharmacokinetics in special cases
Patients with VZV infection
In patients with uncomplicated VZV infection, no significant changes in the pharmacokinetic parameters of penciclovir were detected (T1 / 2 of penciclovir from plasma in the final phase after taking a single and repeated doses of famciclovir is 2.8 and 2.7 hours, respectively).
Patients with impaired renal function
After taking single and repeated doses of famciclovir, there is a linear relationship between a decrease in plasma clearance, renal clearance, the rate of release of penciclovir from blood plasma and the degree of impaired renal function.
Pharmacokinetic features of the drug use in patients with severe (uncompensated) renal impairment have not been studied.
Patients with impaired liver function
In patients with mild to moderate hepatic impairment, there is no increase in the AUC value of penciclovir. The pharmacokinetics of penciclovir in patients with severe liver dysfunction have not been studied.
The conversion of famciclovir to the active metabolite penciclovir in this group of patients may be impaired, which leads to a decrease in the plasma concentration of penciclovir and, as a consequence, a decrease in the effectiveness of famciclovir.
Patients> 65 years of age
In patients aged 65 to 79 years, there is an increase in the average AUC of penciclovir by approximately 40% and a decrease in its renal clearance by approximately 20% compared with those under 65 years of age. These pharmacokinetic features of penciclovir may be partially due to age-related changes in renal function in patients over 65 years of age.
No dose adjustment is required in patients of this age group in the absence of impaired renal function.
Gender The
gender of the patient has no significant effect on the pharmacokinetic parameters of the drug (minor differences in the clearance of penciclovir in men and women). No dose adjustment of the drug is required depending on gender.
Race
When using famciclovir (single or multiple doses of 500 mg 1, 2 or 3 times a day), the pharmacokinetic parameters of the drug in healthy Negroid volunteers and Negroid patients with impaired renal or liver function did not differ from those in Caucasians.
Indications
Herpes zoster (VZV infection):
- for the treatment of herpes zoster, including ophthalmic herpes in immunocompetent patients;
- for the treatment of herpes zoster in immunocompromised patients.
Genital herpes (HSV infection):
- treatment of the first episode and recurrence of genital herpes in immunocompetent patients;
- treatment of recurrent genital herpes in immunocompromised patients;
- for the prevention of exacerbations of genital herpes (suppressive therapy) in immunocompetent and immunocompromised patients.
Labial herpes (HSV infection):
- treatment of relapses of labial herpes in immunocompetent patients;
- treatment of recurrent orolabial herpes in immunocompromised patients.
Application during pregnancy and lactation
However, since there is insufficient data on the safety of famciclovir use in pregnant and lactating women, its use during pregnancy and during breastfeeding is possible only if the benefits of therapy to the mother outweigh the potential risk to the fetus and child.
There are no data requiring special recommendations for patients with preserved reproductive potential.
Famciclovir does not have a pronounced effect on spermogram, morphology or motility of human sperm. A decrease in fertility was noted in an experimental model in male rats receiving famciclovir at a dose of 500 mg / kg body weight; in female rats, no pronounced decrease in fertility was noted.
Contraindications
-
Hypersensitivity to famciclovir or any of the components of the drug. Hypersensitivity to penciclovir.
-
Children under 18 years of age due to the lack of data on efficacy and safety in patients of this age category.
-
Severe liver dysfunction due to the lack of data on efficacy and safety in patients of this category.
Caution should be exercised when treating patients with impaired renal function, for whom a dosage adjustment may be required.
Special precautions are not required in elderly patients and patients with mild to moderate hepatic impairment.
Side effects
Cases of headache and nausea were reported, but these events were mild to moderate and were noted with the same frequency in patients receiving placebo. Other adverse events (AEs) were identified in clinical practice when using the drug in the post-registration period.
AEs reported in clinical trials in immunocompromised patients were similar to those reported in immunosuppressed patients.
To assess the incidence of adverse reactions, the criteria of the World Health Organization (WHO) were used: very often (> 1/10); often (from> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rare (<1/10000), frequency unknown.
Disturbances from the blood and lymphatic system: rarely - thrombocytopenia;
Mental disorders: infrequently - confusion (mainly in elderly patients); rarely - hallucinations;
Disturbances from the nervous system: very often - headache, often - dizziness, infrequently - drowsiness (mainly in elderly patients), the frequency is unknown - convulsions *;
Heart disorders: rarely - a feeling of "palpitations";
Disturbances from the gastrointestinal tract: often - nausea, vomiting, abdominal pain, diarrhea;
Disturbances from the liver and biliary tract: rarely - cholestatic jaundice;
Immune system disorders: frequency unknown - anaphylactic shock *, anaphylactic reaction *;
Disorders from the skin and subcutaneous tissues: often - rash, itching; infrequently - angioedema (edema of the face, eyelids, periorbital region, pharynx), urticaria; frequency unknown - severe skin reactions * (including erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), allergic vasculitis).
Laboratory and instrumental data: often - violation of liver function indicators
* - AEs that were not observed during clinical trials, identified in post-marketing observations, and also described in the literature. Since information about these AEs was obtained by spontaneous reporting and the exact number of patients who took the drug has not been determined, it is not possible to estimate the frequency of occurrence of these reactions, and therefore, the frequency of these reactions is indicated as "frequency unknown"
If any of the side effects indicated in the instructions are aggravated , or you notice any other side effects not listed in the instructions, please inform your doctor.
Interaction
There were no clinically significant changes in the pharmacokinetic parameters of penciclovir with its single use (at a dose of 500 mg) immediately after taking antacids (magnesium and aluminum hydroxide) or in patients who had previously received treatment with allopurinol, cimetidine, theophylline, zidovudine, promethazine (multiple doses) ...
With a single dose of famciclovir (at a dose of 500 mg) together with emtricitabine or zidovudine, there were no changes in the pharmacokinetic parameters of penciclovir, zidovudine, zidovudine metabolite (zidovudine glucuronide) and emtricitabine.
With single and repeated use of famciclovir (at a dose of 500 mg 3 times a day) together with digoxia, no changes in the pharmacokinetic parameters of penciclovir and digoxin were observed.
Considering that the conversion of the inactive metabolite of 6-deoxypenciclovir (formed during the deacetylation of famciclovir) into penciclovir is catalyzed by the enzyme aldehyde oxidase, it is possible for drug interactions to develop when Favirox is used together with drugs that are metabolized with the participation of this enzyme or inhibit its activity.
When famciclovir was used together with cimetidine and promethazine, which are inhibitors of aldehyde oxidase in vitro, no disturbance in the formation of penciclovir from famciclovir was found. However, when taking famciclovir together with a potent in vitro aldehyde oxidase inhibitor, raloxifene, the formation of penciclovir from famciclovir may be impaired, and as a result, the effectiveness of famciclovir may decrease. It is necessary to evaluate the clinical efficacy of antiviral therapy when administered concomitantly with raloxifene.
Considering that famciclovir is a weak inhibitor of aldehydroxidase in vitro, its effect on the pharmacokinetic parameters of drugs metabolized with the participation of this enzyme is possible.
In experimental studies, famciclovir did not have an inducing effect on the cytochrome P450 system and did not inhibit the CYP3A4 enzyme.
How to take, course of administration and dosage
The drug should be taken orally, regardless of food intake, without chewing, drinking water. Treatment with the drug should be started as early as possible, immediately after the first symptoms of the disease appear (tingling, itching and burning).
VZV (herpes zoster) infection, including ophthalmic herpes, in immunocompetent patients:
The recommended dose is 500 mg 3 times a day for 7 days.
VZV (herpes zoster) infection in immunocompromised patients:
The recommended dose is 500 mg 3 times a day for 10 days.
HSV (labial or genital herpes) infection in immunocompetent patients:
- For the first episode of genital herpes, the recommended dose is 250 mg 3 times a day for 5 days;
- In case of recurrence of genital herpes, 1000 mg 2 times a day for 1 day or 125 mg 2 times a day for 5 days or 500 mg once is prescribed, followed by 3 doses of 250 mg every 12 hours.
- With relapses of labial herpes - 1500 mg once a day for 1 day or 750 mg 2 times a day for 1 day.
HSV (orolabial or genital herpes) infection in immunocompromised patients:
The recommended dose is 500 mg 2 times a day for 7 days.
For the prevention of exacerbations of genital herpes (suppressive therapy), 250 mg is used 2 times a day. The duration of therapy depends on the severity of the disease. A periodic assessment of possible changes in the course of the disease after 12 months is recommended.
In HIV-infected patients, the effective dose is 500 mg 2 times a day.
Patients ≥ 65 years of age
In elderly patients with normal renal function, dosage adjustment of famciclovir is not required.
Patients with impaired renal function
In patients with impaired renal function, there is a decrease in the clearance of penciclovir.
Recommendations for adjusting the dosage regimen in immunocompetent patients with impaired renal function, depending on creatinine clearance, are presented in Table 1.
Recommendations for adjusting the dosage regimen in immunocompromised patients with impaired renal function, depending on creatinine clearance, are presented in Table 2.
Table 1. Correction of the dosage regimen in immunocompetent patients with impaired renal function
| VZV (herpes zoster) infection | ||
| Dosage regimen | Creatinine clearance | Corrected dosing regimen |
| 500 mg 3 times a day for 7 days
| ≥ 60 | 500 mg 3 times a day for 7 days |
| 40-59 | 500 mg 2 times a day for 7 days | |
| 20-39 | 500 mg once a day for 7 days | |
| <20 | 250 mg once a day for 7 days | |
| Patients on hemodialysis or receiving a hemodialysis procedure | 250 mg after each dialysis session for 7 days | |
| HSV infection | ||
| Genital herpes, first episode | ||
| 250 mg 3 times a day for 5 days | ≥ 40 | 250 mg 3 times a day for 5 days |
| 20-39 | 250 mg 2 times a day for 5 days | |
| <20 | 250 mg once a day for 5 days | |
| Patients on hemodialysis or receiving a hemodialysis procedure | 250 mg after each dialysis session for 5 days | |
| With relapses of genital herpes | ||
| 1000 mg 2 times a day for 1 day | ≥ 60 | 1000 mg 2 times a day for 1 day |
| 40-59 | 500 mg 2 times a day for 1 day | |
| 20-39 | 500 mg once | |
| <20 | 250 mg once | |
| Patients on hemodialysis or receiving a hemodialysis procedure | 250 mg once after dialysis session | |
| 125 mg 2 times a day for 5 days | ≥ 20 | 125 mg 2 times a day for 5 days |
| <20 | 125 mg once a day for 5 days | |
| Patients on hemodialysis or receiving a hemodialysis procedure | 125 mg after each dialysis session for 5 days | |
| 500 mg once, followed by 3 doses of 250 mg every 12 hours
| ≥ 40 | 500 mg once, followed by 3 doses of 250 mg every 12 hours |
| 20-39 | 250 mg once, followed by 3 doses of 250 mg every 12 hours | |
| <20 | 250 mg once, followed by 250 mg the next day | |
| Patients on hemodialysis or receiving a hemodialysis procedure | 250 mg once after dialysis session | |
| For the prevention of exacerbations of genital herpes (suppressive therapy) | ||
| 250 mg 2 times a day | ≥ 40 | 250 mg 2 times a day |
| 20-39 | 125 mg 2 times a day | |
| <20 | 125 mg once a day | |
| Patients on hemodialysis or receiving a hemodialysis procedure | 125 mg after each dialysis session | |
| Labial herpes | ||
| 1500 mg once | ≥ 60 | 1500 mg once |
| 40-59 | 750 mg once | |
| 20-39 | 500 mg once | |
| <20 | 250 mg once | |
| Patients on hemodialysis or receiving a hemodialysis procedure | 250 mg once after dialysis session | |
| 750 mg 2 times a day | ≥ 60 | 750 mg 2 times a day for 1 day |
| 40-59 | 750 mg once | |
| 20-39 | 500 mg once | |
| <20 | 250 mg once | |
| Patients on hemodialysis or receiving a hemodialysis procedure | 250 mg once after dialysis session | |
Table 2. Correction of the dosage regimen in immunocompromised patients with impaired renal function
| VZV (herpes zoster) infection | ||
| Dosage regimen | Creatinine clearance | Corrected dosing regimen |
| 500 mg 3 times a day for 10 days | ≥ 60 | 500 mg 3 times a day for 10 days |
| 40-59 | 500 mg 2 times a day for 10 days | |
| 20-39 | 500 mg once a day for 10 days | |
| <20 | 250 mg once a day for 10 days | |
| Patients on hemodialysis or receiving a hemodialysis procedure | 250 mg after each dialysis session for 10 days | |
| HSV infection (orolabial or genital herpes) | ||
| 500 mg 2 times a day for 7 days | ≥ 40 | 500 mg 2 times a day for 7 days |
| 20-39 | 500 mg once a day for 7 days | |
| <20 | 250 mg once a day for 7 days | |
| Patients on hemodialysis or receiving a hemodialysis procedure | 250 mg after each dialysis session for 7 days | |
Patients with renal impairment who are on hemodialysis or receiving a hemodialysis procedure
Since after a 4-hour hemodialysis, the plasma concentration of penciclovir is reduced by 75%, famciclovir should be taken immediately after the hemodialysis procedure. The recommended dose adjustment regimen is described in Tables 1 and 2.
Patients with impaired liver function
For patients with mild to moderate hepatic impairment, dose adjustment is not required.
There is no experience of using the drug in patients with severe liver dysfunction.
Black patients
The efficacy of a one-day administration of famciclovir at a dose of 1000 mg 2 times a day for the treatment of recurrent genital herpes in immunocompetent black patients did not exceed that for placebo. The clinical significance of dosing regimens for the treatment of both recurrent genital herpes (within 2 or 5 days) and other infections caused by VZV and HSV is unknown.
Overdose
Cases of an overdose of famciclovir (10.5 g) have been described without clinical manifestations.
Treatment: symptomatic and supportive. Failure to comply with recommendations to reduce the dose of famciclovir taking into account renal function in patients with kidney disease rarely reported cases of acute renal failure. Penciclovir, which is the active metabolite of famciclovir, is excreted during hemodialysis. Plasma concentrations of penciclovir are reduced by 75% after hemodialysis for 4 hours.
Special instructions
Genital herpes is a sexually transmitted disease. During relapses, the risk of infection increases. In the presence of clinical manifestations of the disease, even if antiviral treatment is started, patients should avoid sexual intercourse.
During suppressive th
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