Famvir - instructions for use, doses, side effects, contraindications, price, where to buy

Famvir®

Suction

The increase in the concentration of penciclovir in the blood plasma occurs in proportion to the increase in a single dose of famciclovir in the range of 125-1000 mg.

In another study, the Cmax of penciclovir after oral administration of 250 mg, 500 mg, or 1000 mg famciclovir was 1.5 μg/ml, 3.2 μg/ml, and 5.8 μg/ml, respectively.

Systemic bioavailability (area under the pharmacokinetic concentration-time curve - AUC) of penciclovir does not change when administered concomitantly with food.

The AUC of penciclovir with a single dose of famciclovir and when dividing the daily dose of the drug into two or three doses are the same, which indicates the absence of accumulation of penciclovir with repeated use of famciclovir.

Distribution

The binding of penciclovir and its 6-deoxy precursor to plasma proteins is less than 20%.

Metabolism and excretion

After oral administration, famciclovir is quickly and completely converted into a pharmacologically active metabolite, penciclovir, and is then excreted mainly in the form of penciclovir and its 6-deoxy precursor, which are excreted by the kidneys; unchanged famciclovir is not detected in the urine. The half-life (T1/2) of penciclovir from blood 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 are detected (T1/2 in the final phase after taking 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 elimination of penciclovir from blood plasma and the degree of renal dysfunction.

Patients with liver dysfunction

In patients with mild to moderate hepatic impairment, there is no increase in the AUC of penciclovir.

The pharmacokinetics of penciclovir in patients with severe hepatic impairment has not been studied. The conversion of famciclovir to the active metabolite penciclovir may be impaired in this group of patients, leading to a decrease in penciclovir plasma concentrations and, as a consequence, a decrease in the effectiveness of famciclovir.

Patients aged ≥ 65 years

Patients aged 65 to 79 years have an approximately 40% increase in mean penciclovir AUC and an approximately 20% decrease in penciclovir renal clearance compared with persons younger than 65 years. These pharmacokinetic characteristics of penciclovir may be partly 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 renal dysfunction.

Floor

The gender of the patient does not have a significant effect on the pharmacokinetic parameters of the drug (slight differences in the clearance of penciclovir in men and women). No dose adjustment 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 black volunteers and black patients with impaired renal or liver function did not differ from those in Caucasians.

Famciclovir

Suction

Famciclovir is a prodrug. After oral administration, famciclovir is rapidly and almost completely absorbed and quickly converted into a pharmacologically active metabolite, penciclovir. The bioavailability of penciclovir after oral administration of famciclovir is 77%. The increase in the concentration of penciclovir in the blood plasma occurs in proportion 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 after oral administration of 125 mg, 250 mg, 500 mg or 750 mg of famciclovir is achieved on average after 45 minutes and averages 0.8 mcg/ml, 1.6 mcg/ml and 3. 3 μg/ml and 5.1 μg/ml, respectively. In another study, the Cmax of penciclovir after oral administration of 250 mg, 500 mg, or 1000 mg famciclovir was 1.5 μg/ml, 3.2 μg/ml, and 5.8 μg/ml, respectively.

Systemic bioavailability (area under the pharmacokinetic concentration-time curve - AUC) of penciclovir does not change when administered concomitantly with food.

Distribution

Plasma protein binding of penciclovir and its 6-deoxy precursor is less than 20%

Metabolism and excretion

The half-life (T1/2) of penciclovir from blood plasma in the final phase after taking a single and repeated doses is about 2 hours.

Pharmacokinetics in special cases

Patients with VZV infection

Patients with impaired renal function

Patients with liver dysfunction

In patients with mild to moderate hepatic impairment, there is no increase in the AUC of penciclovir. The pharmacokinetics of penciclovir in patients with severe hepatic impairment has not been studied. The conversion of famciclovir to the active metabolite penciclovir may be impaired in this group of patients, leading to a decrease in penciclovir plasma concentrations and, as a consequence, a decrease in the effectiveness of famciclovir.

Patients aged ≥65 years

Floor

Race

Pharmacological properties of the drug Famciclovir

Antiviral agent. After oral administration, famciclovir is rapidly converted to penciclovir, which has in vitro and in vivo activity against human herpes viruses, including Varicella zoster and Herpes simplex types I and II, as well as Epstein-Barr viruses and cytomegalovirus. Penciclovir enters virus-infected cells, where, under the action of viral thymidine kinase, it is quickly converted into monophosphate, which in turn, with the participation of cellular enzymes, turns into triphosphate. Penciclovir triphosphate resides in virus-infected cells for more than 12 hours, suppressing the synthesis of viral DNA in them, disrupting viral replication. The half-life of penciclovir triphosphate in cells affected by Varicella zoster , Herpes simplex I and II is 9, 10 and 20 hours, respectively. The concentration of penciclovir triphosphate in uninfected cells does not exceed the minimum detectable value, therefore, in therapeutic concentrations, penciclovir has no effect on uninfected cells. Penciclovir is active against recently discovered acyclovir-resistant strains of the Herpes simplex with altered DNA polymerase. It has been established that the incidence of resistance to famciclovir (penciclovir) does not exceed 0.3%, and 0.19% in patients with a reduced immune status. The use of famciclovir significantly reduces the severity and duration of postherpetic neuralgia in patients with herpes zoster.

Recommendations for the treatment of genital herpes

Genital herpes is a sexually transmitted disease manifested by recurrent lesions of the genital organs. The causative agents are herpes simplex viruses, predominantly type II, although over the past two decades the etiological role of type I virus has increased significantly.

Table. Doses of medications for the treatment of genital herpes

Despite the severe clinical manifestations of primary infection and potentially dangerous complications leading to hospitalization and death, genital herpes has received insufficient attention in the non-specialized medical literature. Meanwhile, the spread of the disease has become epidemic, which is associated with a large number of undiagnosed and untreated cases and a high frequency of asymptomatic and subclinical course (2). Symptomatic genital herpes affects 86 million people worldwide. The total number of people affected by the virus cannot be determined, but it is assumed that, for example, in the United States, every fourth to sixth person is a carrier of the virus (3-4).

The main drugs for the treatment of genital herpes are antiviral drugs from the group of nucleoside analogues. The most widely used drug continues to be acyclovir, which appeared on the global pharmaceutical market about 20 years ago. Being an analogue of nucleosides, the drug undergoes phosphorylation under the influence of viral thymidine kinase, and then, with the help of host cell enzymes, is converted into di- and triphosphate. The latter acts as a substrate for viral DNA polymerase, thus leading to disruption of DNA virus replication.

The effectiveness of acyclovir for the treatment of genital herpes has been shown in numerous clinical studies. When taken orally, the drug is well tolerated by patients and has an excellent benefit/risk ratio. Side effects occur in less than 10% of patients and are usually limited to nausea, vomiting and headache (5).

The main disadvantages of acyclovir include low bioavailability (15-20%) and short half-life from tissues (0.7 hours) and blood plasma (2.7 hours) (5). To maintain therapeutic concentrations in the body, the drug must be taken up to 5 times a day, which negatively affects patients’ accuracy in following the treatment regimen and can lead to a decrease in the effectiveness of therapy.

The pharmacokinetic disadvantages of acyclovir were largely overcome with the development of valacyclovir, a prodrug that is metabolized in the intestinal wall and liver to form acyclovir. Valacyclovir has significantly greater oral bioavailability (54%) and provides higher and longer-lasting serum acyclovir concentrations (6-8), allowing twice-daily dosing. With repeated oral administration of valacyclovir in high doses (4-8 g/day), the concentrations of the active substance in the blood are comparable to the concentrations created by intravenous administration of acyclovir (5-10 mg/kg 3 times/day) (8, 9).

The kinetics of acyclovir released from valacyclovir is similar to the kinetics of acyclovir preparations in healthy volunteers, patients with kidney disease, HIV infection (10), elderly patients and senile volunteers, both receiving and not receiving concomitant diuretic therapy (11).

The safety profile of valacyclovir is not significantly different from the safety profile of acyclovir. Better absorption results in a lower incidence of gastrointestinal adverse reactions (5). In patients with AIDS and other immune disorders, thrombotic microangiopathy has been described when using valacyclovir in high doses (8 g/day), but the cause-and-effect relationship between the drug and this complication has not been definitively confirmed (12). Thrombotic microangiopathy was not observed in patients receiving high doses of valacyclovir after renal transplantation (13). In addition, for the treatment of genital herpes, the drug is used in significantly lower doses.

The third nucleoside analogue, famciclovir, like valacyclovir, is a prodrug that is converted into penciclovir in the intestinal wall and in the liver. Penciclovir has a mechanism and spectrum of antiviral action similar to acyclovir, but due to low bioavailability it can only be used topically (5). When administered orally, penciclovir has a bioavailability of 77% (14). Compared to acyclovir, penciclovir has a significantly longer tissue half-life (10–20 h) (15). Intracellular concentrations of penciclovir triphosphate are approximately 30-fold higher than those of acyclovir triphosphate (16). However, herpes simplex virus DNA polymerase has a greater affinity for acyclovir triphosphate than for penciclovir triphosphate. Thus, the differences in the mechanism of action between penciclovir and acyclovir are predominantly quantitative and tend to balance each other out (16).

Acyclovir and penciclovir do not differ in activity against herpes simplex virus in cell culture, but after discontinuation of acyclovir, viral replication resumes much faster than after discontinuation of penciclovir (13). Famciclovir is superior to valacyclovir in its ability to reverse “competent latency,” a state in which the virus is able to reactivate and cause disease relapse (18, 19). In an observational study, patients treated with famciclovir (250 mg 3 times a day for 5 days) had fewer relapses within 1-6 months after the first episode than patients treated with acyclovir (200 mg 5 times a day). within 5 days) (20).

Famciclovir has an excellent safety profile. A tolerability analysis based on the results of 13 clinical trials showed that the adverse reaction profile of famciclovir in patients with genital herpes (791 patients) was no different from placebo (21). Studies in healthy male volunteers did not reveal clinically significant pharmacokinetic interactions of famciclovir with allopurinol, digoxin, cimetidine, zidovudine, or theophylline (22). The bioavailability of penciclovir from the metabolism of famciclovir is independent of food intake (23). Its pharmacokinetics do not differ between young and elderly individuals (24). When taken for 4-12 months by healthy male volunteers, the drug had no negative effect on sperm (25).

Acyclovir, valacyclovir, and famciclovir exhibit comparable clinical efficacy, resulting in decreased duration and severity of genital herpes episodes and decreased viral shedding (26–28). However, they have no effect on viruses in the dormant stage.

Treatment of
the first episode of genital herpes
The first episode of primary genital herpes is considered to be the clinical manifestation of the disease in patients without antibodies to herpes simplex viruses type I or II. The first episode is characterized by the most severe course. Typically, in addition to local lesions that persist for 2-3 weeks, systemic symptoms and regional adenopathy are observed. A small number of patients, often those who are immunocompromised, develop viral meningitis.

Symptomatic treatment of the first episode consists of prescribing analgesics. Opioid medications should be avoided as they cause constipation. For etiotropic treatment, nucleoside analogues are used.

The effectiveness of oral acyclovir at a dose of 200 mg 5 times a day. for 5-10 days is indicated in double-blind, placebo-controlled clinical studies (29, 30). In patients receiving acyclovir, the period of virus shedding, crust formation time, and healing time were significantly shortened. Increasing the oral daily dose of the drug to 4 g did not lead to an increase in the effectiveness of therapy (31). In addition, gastrointestinal side effects were significantly more common with the high dose (8%) than with the standard dose (0%).

In order to improve patient adherence to treatment, the US Centers for Disease Control and Prevention (CDC) recommends the use of acyclovir 400 mg 3 times a day, but this regimen is not approved by the FDA. Topical acyclovir cream is not effective (6). Addition of the cream to oral therapy also did not improve clinical outcomes (32). In severe cases with neurological complications, acyclovir is recommended to be administered intravenously at 5-10 mg/kg 3 times a day (5).

Valacyclovir at a dose of 1 g 2 times a day. shows equal effectiveness with acyclovir at a dose of 200 mg 5 times a day. during the first episode of genital herpes in immunocompetent patients (33). The tolerability of valacyclovir is similar to that of acyclovir (33). In different countries, valacyclovir is approved at a dose of 500 mg or 1 g 2 times a day for the treatment of the first episode of genital herpes. within 10 days (25).

Famciclovir was studied in comparative clinical studies with acyclovir (200 mg 5 times a day) in doses of 125, 250 and 500 mg 3 times a day (27, 28). No study showed significant differences between comparison groups. For the treatment of genital herpes, famciclovir is recommended to be prescribed at a dose of 250 mg 3 times a day. for 5 days, for severe infection - 10 days (25).

Episodic
treatment of recurrent genital herpes
In clinical studies, when using acyclovir in a standard daily dose (200 mg 5 times / day) for episodic treatment of recurrent genital herpes, a shortening of the period of virus shedding, crusting time and healing time was noted. The duration of symptoms and the timing of new relapses were not affected by the drug (28, 34). Recommendations for the management of genital herpes issued in 1998 by the US Centers for Disease Control and Prevention (CDC) suggested the use of acyclovir in doses of 400 mg 3 times a day. or 800 mg 2 times/day. within 5 days. However, these treatment regimens have not been studied in adequate clinical studies.

When applied topically in the form of a 5% polyethylene glycol ointment, acyclovir led to a decrease in the period of virus shedding, but did not cause clinical improvement (6).

Valaciclovir at a dose of 500 or 1000 mg 2 times a day. for 5 days, prescribed on the first day after the onset of symptoms, significantly reduced the period of virus shedding and accelerated the healing of lesions compared to placebo (35). Tolerability of the drug did not differ from tolerability of placebo. One study showed that fewer patients (10%) developed vesicululcerative lesions with valacyclovir than with placebo (25). Another study suggests, based on the natural shedding period of the virus, that a 3-day course of valacyclovir treatment is as effective as a 5-day course (36). In July 2001, the FDA approved a 3-day course of treatment for recurrent genital herpes with valacyclovir (500 mg twice daily). Comparative studies with acyclovir showed equal clinical efficacy of both drugs (37). An important advantage of valacyclovir is its more convenient mode of administration.

Famciclovir at doses of 125, 250, and 500 mg twice daily given within 6 hours of symptom onset resulted in decreased healing time, viral shedding time, and duration of lesion swelling compared with placebo (38). With its use, pain, burning, tingling, and tenderness to the touch significantly decreased. Side effects of famciclovir were no different from placebo. Famciclovir is recommended for episodic treatment of recurrent genital herpes at a dose of 125 mg 2 times a day. within 5 days. The advantages of famciclovir, like valacyclovir, are that the treatment regimen is more convenient compared to acyclovir.

The effectiveness of episodic treatment of recurrent genital herpes depends on the time of initiation of medication. A Canadian study showed that when famciclovir was started within 6 hours of the onset of prodromal symptoms or first genital lesions, there was a significant reduction in viral shedding and faster healing of lesions. Moreover, taking the drug before the onset of viral shedding increased the likelihood of preventing viral shedding during relapse (39). Treatment of relapse should begin as quickly as possible, so patients must always have a supply of the drug.

Continued
suppressive therapy
For patients with frequent (more than 6-8 per year) and severe relapses, psychological trauma or disruption of normal lifestyle caused by the disease, ongoing suppressive therapy is indicated. For this purpose, acyclovir 400 mg 2 times a day is used for a long time (for 6-12 months); valacyclovir 500 mg 1 time/day. (if the number of relapses is 10 or less per year) or 1000 mg 1 time / day. (with more than 10 relapses per year) or famciclovir 250 mg 2 times a day. Daily acyclovir has been shown to reduce relapse rates by 80%, with 25-30% of patients remaining relapse-free (40). Similar results were obtained in studies with valacyclovir and famciclovir. When using famciclovir in a daily dose of 500 mg, divided into 2 doses, for 16 weeks, relapses did not develop during the treatment period in 78% of patients (41), when using valacyclovir in the same dose - in 69% of patients (33). All three drugs have proven to be effective for long-term suppressive therapy of recurrent genital herpes. Apparently, the decisive factors when choosing a specific drug should be the cost of the annual dose and the convenience of the regimen for the patient.

Suppressive therapy is well tolerated. Its safety has been demonstrated with daily use for 5 years (42). However, before prescribing suppressive therapy, it is recommended to conduct hematological and biochemical studies and determine the state of renal function. During treatment, patients should be under medical supervision; women are advised to avoid pregnancy.

Daily suppressive therapy leads to a significant reduction in asymptomatic viral shedding, but does not completely eliminate it. The patient should be warned when deciding on its appointment. As an alternative, the patient should be offered selective prophylaxis (eg during periods of stress). To date, a reduction in the risk of infection transmission under the influence of suppressive therapy has not been proven.

Regardless of whether suppressive treatment is given or not, relapse rates decrease on average 7 years after the first episode, so lifelong treatment is usually not necessary.

Treatment of
genital herpes in pregnant women
Women suffering from genital herpes during pregnancy have an increased risk of spontaneous abortions and the birth of low-weight children. In rare cases, a congenital infection in the fetus may develop. The risk of infection is highest during the passage of the child through the birth canal. The risk of transmission is estimated to be 50% for primary maternal herpes during childbirth and 0–3% for recurrent herpes (43). Most often, infection occurs from asymptomatic mothers (44).

In newborns, the disease occurs in three main forms: localized, with damage to the central nervous system, and disseminated. Mortality is 15% for infection involving the central nervous system and 57% for disseminated infection (45).

In order to reduce the risk of subclinical viral shedding and relapse episodes during labor, many clinicians recommend suppressive antiviral therapy for pregnant women. Nucleoside analogues are not officially approved for use during pregnancy, but many studies have shown the safety of acyclovir (46, 47). Valacyclovir and famciclovir, according to the FDA classification, are classified as group B, i.e., drugs for which no teratogenic effect was detected in animal experiments, and adequate clinical trials in humans have not been conducted. Studies are currently underway to determine the effectiveness and safety of valacyclovir during pregnancy.

Data on the effectiveness of suppressive therapy in preventing infection in the fetus are extremely limited. A randomized trial of 46 women with a first episode of genital herpes was unable to determine the effectiveness of treatment with acyclovir started at 36 weeks' gestation because no newborns developed infection. However, in the group of patients receiving suppressive therapy, a significant reduction in the rate of cesarean section was noted (48). Another placebo-controlled study of 150 women with a history of genital herpes (49) showed that acyclovir (200 mg three times daily) given from 38 weeks of pregnancy was able to prevent relapses. In patients receiving acyclovir, relapse did not occur in any case, while in the control group there were 33 relapses, of which 21 occurred during childbirth.

Treatment
of genital herpes caused by acyclovir - resistant strains
Long-term treatment with nucleoside analogues, as a rule, is not associated with the risk of developing viral resistance. In immunocompetent patients receiving suppressive therapy, acyclovir-resistant strains of the herpes simplex virus were isolated, but correlations between in vitro

and therapeutic efficacy of the drug was not observed (25). The most common mechanism of resistance is a gene mutation that disrupts thymidine kinase production (50), and acyclovir-resistant strains typically exhibit cross-resistance to penciclovir. Much less common are mutations that lead to dysfunction of thymidine kinase and DNA polymerase (50, 51). In these cases, selective resistance to one of the drugs is possible. Mathematical analysis suggests that changes in the current viral resistance pattern may take decades (52).

In immunocompromised patients with long-term use of antiviral drugs, resistance develops in approximately 5% of cases and can lead to treatment failure (53, 54). Clinically significant resistance has also been described in patients who have undergone bone marrow transplantation (55).

Foscarnet is currently considered as the drug of choice for the treatment of acyclovir-resistant herpes simplex virus infections (56). It is a non-competitive inhibitor of viral DNA polymerase. The drug blocks receptors for binding to viral DNA pyrophosphate and disrupts the elongation of its chain. Unlike acyclovir and penciclovir, it does not require phosphorylation by thymidine kinase and is active against acyclovir-resistant thymidine kinase-deficient strains (56).

Foscarnet has low bioavailability when taken orally, so it is administered intravenously and locally. The effectiveness of intravenous foscarnet for genital herpes caused by acyclovir-resistant strains has been shown in several clinical studies. In an uncontrolled study, the drug was effective in 81% of patients with acyclovir-resistant genital herpes that developed against the background of HIV infection (57). In another study in patients with HIV infection, foscarnet was superior to vidarabine in terms of time to healing of herpes mucocutaneous lesions caused by acyclovir-resistant strains and the time to cessation of viral shedding (58). When applied topically, the drug did not show sufficient effectiveness (25).

Foscarnet is a potentially toxic drug. Side effects include renal dysfunction, gastrointestinal disorders, disturbances in magnesium and calcium metabolism, anemia, genital ulceration, and seizures (59). To prevent serious side effects, treatment should be carried out under close medical supervision, an adequate level of hydration should be maintained, and concomitant administration of pentamidine should be avoided.

The use of foscarnet limits the intravenous route of administration. Resistance to it can develop due to mutations in DNA polymerase (60). Clinical strains of herpes simplex virus that are resistant to both acyclovir and foscarnet have been described (61).

Pronounced activity against herpes simplex virus in vitro

and
in vivo
exhibited by cidofovir (62, 63). It is an acyclic analogue of phosphanate and has a broad spectrum of antiviral activity. The drug is phosphorylated by cellular enzymes into active diphosphate, bypassing the first step of phosphorylation with viral enzymes required for acyclovir and penciclovir (64). Cidofovir has low bioavailability when taken orally (less than 5%), which allows it to be used only topically. The advantage is the long half-life from the cell. Intracellular concentrations of cidofovir mono- and diphosphate are maintained for 24 and 65 hours, respectively (65).

The effectiveness of a single dose of the drug compared with placebo was shown in immunocompetent patients with recurrent genital herpes (66). In this study, 12 hours after the onset of the first lesions, patients received cidofovir gel at a concentration of 1.3 or 5% or placebo. Local toxic reactions of the drug slowed down the healing of injuries in a number of patients. They were dose-dependent in nature and were observed in three of 23 patients treated with 5% gel and in 1 of 21 patients treated with 3% gel. Further studies are needed to determine the maximum gel concentration that is well tolerated by patients.

In a placebo-controlled clinical trial, cidofovir gel applied once daily for 5 days showed significant virological and clinical effects in patients with acyclovir-resistant genital herpes associated with HIV infection (67). Complete resolution of clinical symptoms was observed in 27% of patients receiving cidofovir 0.3%, 33% receiving cidofovir 1%, and 0% of patients receiving placebo. The median reduction in lesion area was 58% in patients treated with cidofovir, compared with 0% in the control group. Unfortunately, the small number of patients participating in this study does not allow us to assess the statistical significance of the results obtained.

In a clinical study in bone marrow transplant patients, cidofovir was effective against genital herpes caused by viral strains resistant to acyclovir and foscarnet (61).

There is experience with the use of tifluridine ophthalmic solution for the treatment of genital herpes caused by acyclovir-resistant strains (). Tifluridine is a pyrimidine nucleoside analog that, like cidophyr, acts independently of viral thymidine kinase. High toxicity does not allow taking the drug orally. Small clinical trials have shown a beneficial effect of tifluridine in acyclovir-resistant genital herpes in patients with HIV infection (68). In infections caused by acyclovir- or acyclovir/foscarnet-resistant herpes simplex viruses, tifluridine exhibited a synergistic effect with interferon-a (69). However, further study in large controlled studies is necessary to determine the therapeutic value of tifluridine for genital herpes.

Several studies examining the effectiveness of topical interferon formulations for the treatment of genital herpes have reported conflicting results. Local application of interferon α-2a 6 times a day. in the form of an aqueous solution was found to be ineffective for the treatment of herpes genital lesions (70). In contrast, a placebo-controlled study that included 387 patients showed the effectiveness of interferon α-2a gel when used 4 times a day. within 4 days if genital herpes recurs (71). In patients of both sexes, the period of virus shedding decreased; in addition, in men there was a significant decrease in pain, itching and crust formation time. A study of 25 patients showed a beneficial effect of interferon-β (72).

In Germany and Canada, edoxudin, an analogue of deoxythymidine that exhibits pronounced antiherpes activity in vitro,

and
in vivo
(73, 74). The mechanism of action of the drug is similar to acyclovir. When applied topically, it is better absorbed than polyethylene glycol-based acyclovir ointment. In a multicenter, placebo-controlled study, edoxudine 3% cream applied for 5 days significantly reduced viral shedding in patients of both sexes (75). Women also experienced a decrease in pain and adenopathy in the groin area.

A dosage form of acyclovir with controlled release of the active substance has been developed (76). Its advantage is the extension of the half-life of acyclovir. Clinical trials conducted in Europe indicate that long-acting acyclovir is equally effective as short-acting acyclovir. It has been suggested that the use of a drug with an extended half-life may lead to a reduction in relapse rates during suppressive therapy, but this requires further study.

Experiments on guinea pigs and a clinical study showed the beneficial effect of resiquimod, an immune response modifier from the group of imidazoquinolines (77, 78). In patients with genital herpes, when local treatment was started within 24 hours after the onset of symptoms, an increase in the time until relapse occurred. In 52 immunocompetent patients with a history of at least 6 relapses per year, the median time to first relapse was 169 days with resiquimod and 57 days with placebo (79). The drug is currently undergoing phase III clinical trials.

Despite advances in the treatment of genital herpes over the past few years, the epidemic of the disease continues to spread throughout the world. The main drugs used to treat infection are nucleoside analogues. The emergence of generic acyclovir drugs has significantly reduced the cost of treatment. New drugs in this group - the prodrugs valacyclovir and famciclovir - have better pharmacokinetic properties compared to acyclovir, which can improve patient compliance with the treatment regimen. When treating the first episode of genital herpes, the drugs show comparable clinical efficacy.

There have been no head-to-head comparative studies between the three nucleoside analogues in the episodic treatment of recurrent genital herpes. Apparently, the selection of an antiviral agent should be individual. To determine the patient's preferences, all three drugs should be tried (not simultaneously).

Episodic treatment is not suitable for all patients. Due to good efficacy and safety, suppressive therapy is now becoming increasingly widespread. It has been suggested that suppressive therapy, by reducing asymptomatic viral shedding, can stop the spread of infection, but this has not been proven to date. Acyclovir has been successfully used for suppressive therapy. It is not inferior in effectiveness to valacyclovir. Once daily dosing of valaciclovir is convenient for patients with a low relapse rate. Comparative studies of acyclovir and famciclovir have not been conducted.

Relapses of the disease can also develop during suppressive therapy, which is associated with the short half-life of antiviral drugs. If suppressive therapy is discontinued, the risk of infection transmission may increase. This issue needs to be studied in dedicated clinical studies. Until the results of these studies are available, suppressive therapy should be discontinued carefully, with the patient counseled about the safety of sexual behavior.

Famciclovir drug overdose, symptoms and treatment

The described cases of overdose (10.5 g) of famciclovir were not accompanied by clinical manifestations. Maintenance therapy is prescribed according to indications. If recommendations for reducing the dose of famciclovir are not followed, taking into account renal function, cases of acute renal failure have been reported in patients with kidney disease. Penciclovir is eliminated during hemodialysis (after 4 hours of hemodialysis, the plasma concentration decreases by approximately 75%).

List of pharmacies where you can buy Famciclovir:

Moscow
Saint Petersburg

Famvir tablets 500 mg No. 3

Compound

Active substance: famciclovir - 500 mg. Excipients: sodium starch glycolate - 27.35 mg, hydroxypropylcellulose - 15.48 mg, magnesium stearate - 4.1 mg.

Pharmacokinetics

After oral administration, famciclovir is rapidly and almost completely absorbed and is rapidly converted to active penciclovir. The bioavailability of penciclovir after oral administration of famciclovir is 77%. At doses of famciclovir 125 mg, 250 mg or 500 mg, Cmax of penciclovir is achieved on average after 45 minutes.

No accumulation was observed with repeated doses of the drug. Plasma protein binding of penciclovir and its 6-deoxy precursor is less than 20%.

T1/2 of penciclovir from plasma in the final phase after taking single and repeated doses is about 2 hours.

Famciclovir is excreted primarily in the form of penciclovir and its 6-deoxy precursor, which are excreted unchanged in the urine; famciclovir is not detected in urine.

Indications for use

Herpes zoster (VZV infection):

for the treatment of herpes zoster, including ophthalmoherpes in immunocompetent patients;
for the treatment of herpes zoster in immunocompromised patients.

Genital herpes (infection caused by HSV):

treatment of the first episode and relapses of genital herpes in immunocompetent patients;
treatment of relapses of genital herpes in immunocompromised patients;
for the prevention of exacerbations of genital herpes (suppressive therapy) in immunocompetent and immunocompromised patients;

Herpes labialis (infection caused by HSV):

treatment of relapses of labial herpes in immunocompetent patients;
treatment of relapses of orolabial herpes in immunocompromised patients.

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 the effectiveness and safety of use in patients in this category;
lactase deficiency, lactose intolerance, glucose-galactose malabsorption, since the drug (film-coated tablets, 125 mg and 250 mg) contains lactose.

Directions for use and doses

Treatment should begin immediately after diagnosis.

When taken orally, a single dose is 250-500 mg. The frequency and duration of use depend on the indications, the state of the immune system, kidney function, and the effectiveness of treatment.

Storage conditions

The drug should be stored out of the reach of children in its original packaging at a temperature not exceeding 25 °C.

Best before date

3 years. The drug should not be used after the expiration date.

special instructions

Use with caution in patients with impaired renal function.

In the presence of clinical manifestations of genital herpes, even if antiviral treatment is started, patients should avoid sexual contact.

Description

Antiviral drug.

Dosage form

White, oval, biconvex, film-coated tablets with beveled edges, engraved “FV500” on one side.

Use in children

Contraindicated for people under 18 years of age.

Action

Antiviral agent. After oral administration, famciclovir is rapidly converted in vivo to penciclovir, which has in vivo and in vitro activity against human herpes viruses, including Varicella zoster virus and Herpes simplex types 1 and 2, as well as Epstein-Barr virus and cytomegalovirus.

Penciclovir enters virus-infected cells, where, under the action of viral thymidine kinase, it is quickly converted into monophosphate, which in turn, with the participation of cellular enzymes, turns into triphosphate. Penciclovir triphosphate resides in virus-infected cells for more than 12 hours, inhibiting viral DNA synthesis and viral replication in them. The half-life of penciclovir triphosphate in cells affected by Varicella zoster and Herpes simplex is 9, 10 and 20 hours, respectively. The concentration of penciclovir triphosphate in uninfected cells does not exceed the minimum detectable level, therefore, at therapeutic concentrations, penciclovir has no effect on uninfected cells.

Penciclovir is active against recently discovered acyclovir-resistant strains of the Herpes simplex virus with altered DNA polymerase.

Famciclovir significantly reduces the intensity and duration of postherpetic neuralgia in patients with herpes zoster.

In a placebo-controlled study in patients with immunodeficiency due to HIV infection, it was shown that famciclovir at a dose of 500 mg 2 times a day reduced the number of days of Herpes simplex virus shedding (both with and without clinical manifestations).

Side effects

Possible: mild to moderate headaches, nausea.

Rarely: vomiting, dizziness, skin rash; mainly in elderly patients - confusion, hallucinations.

In patients with reduced immunity: possible abdominal pain, fever; rarely – granulocytopenia and thrombocytopenia.

Use during pregnancy and breastfeeding

Since the safety of famciclovir during pregnancy and lactation has not been studied, use is not recommended unless the expected benefit of therapy for the mother outweighs the potential risk to the fetus or infant.

It is not known whether penciclovir is excreted into breast milk in humans.

Famciclovir does not have a significant effect on sperm count, morphology or motility of human sperm.

Experimental studies did not reveal the embryotoxic and teratogenic effects of famciclovir and penciclovir.

Studies in rats treated with famciclovir orally have shown that penciclovir is excreted in breast milk.

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.

Interaction

Concomitant use with probenecid may lead to increased penciclovir plasma concentrations. To prevent the development of toxic reactions, patients receiving Famvir® at a dose of 500 mg simultaneously with probenecid should be monitored, taking into account the possibility of reducing the dose of famciclovir.
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 or aluminum hydroxide) or in patients who had previously received treatment (multiple doses) with allopurinol, cimetidine, theophylline, zidovudine, promethazine .
With a single dose of famciclovir (at a dose of 500 mg) together with emtricitabine or zidovudine, no changes in the pharmacokinetic parameters of penciclovir, zidovudine, zidovudine metabolite (zidovudine glucuronide) and emtricitabine were detected.
With single or repeated use of famciclovir (at a dose of 500 mg 3 times a day) together with digoxin, no changes in the pharmacokinetic parameters of penciclovir and digoxin were observed.
Considering that the conversion of the inactive metabolite 6-deoxypenciclovir (formed during deacetylation of famciclovir) into penciclovir is catalyzed by the enzyme aldehyde oxidase, drug interactions may develop when using Famvir® 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 aldehyde oxidase inhibitors in vitro, there was no impairment in the formation of penciclovir from famciclovir. However, when taking famciclovir together with a powerful in vitro aldehyde oxidase inhibitor, raloxifene, the formation of penciclovir from famciclovir may be impaired, and as a result, the effectiveness of famciclovir may be reduced. It is necessary to evaluate the clinical effectiveness of antiviral therapy when used concomitantly with raloxifene.
Considering that famciclovir is a weak inhibitor of aldehyde oxidase in vitro, it may influence the pharmacokinetic parameters of drugs metabolized with the participation of this enzyme.
In experimental studies, famciclovir did not have an inducing effect on the cytochrome P450 system and did not inhibit the CYP3A4 isoenzyme.

Overdose

There are limited data on overdose with famciclovir.

Treatment: symptomatic and supportive. Cases of acute renal failure have rarely been reported in patients with renal disease when recommendations for dose reduction of famciclovir are not followed based on renal function. Penciclovir, which is an active metabolite of famciclovir, is eliminated by hemodialysis. Penciclovir plasma concentrations are reduced by 75% after hemodialysis for four hours.

Impact on the ability to drive vehicles and operate machinery

The drug Famvir® is not expected to affect the ability to drive vehicles and/or operate machines, however, patients who experience dizziness, drowsiness, confusion or other disorders of the central nervous system while using the drug Famvir® should refrain from following these instructions types of activities during the period of drug use.

Special instructions for the use of Famciclovir

Since the safety of famciclovir during pregnancy and lactation has not been studied, its use during this period is not recommended unless the possible benefits of treatment outweigh the potential risks. It is not known whether penciclovir is excreted in breast milk. Famciclovir does not have a pronounced effect on the spermogram, morphology or motility of human sperm. Experimental studies have not revealed the embryotoxic and teratogenic effects of famciclovir and penciclovir. Caution should be exercised when treating patients with impaired renal function, for whom adjustment of the dosage regimen may be required. Special precautions in patients old age is not required.

Famciclovir in the treatment of herpetic infections

In human infectious pathology, herpes viruses play an important role due to their wide distribution in the population, tendency to persist for life in the body and ability to cause acute, chronic and latent forms of the disease. Numerous studies have shown that 65–90% of the adult and child population of the planet are infected with herpes simplex viruses. Compared to the 1980s, by the end of the millennium the number of registered herpes patients had increased in the United States by 13–40% and in European countries by 7–16%. Thus, in 1999, 86 million patients with genital herpes were registered in the world - the most common disease among sexually transmitted infections (STIs). In Russia, visits to doctors of various specialties (dermatologists, gynecologists, urologists) regarding genital herpes is no more than 15% of the actual frequency. The incidence over the past 5 years has more than doubled, and the total number of patients is about 8 million people (Kkhakhalin L.N., 1999).

Considering that 20–30% of patients with herpes develop a relapse of the disease during the first two to three years, the total number of such patients is constantly increasing. The cause of genital herpes is the so-called herpes simplex virus (HSV). There are two main antigenic types of the virus - HSV-1 and HSV-2, which differ in immunogenicity, virulence, and resistance to various factors, which ultimately determines the characteristics of the clinical manifestations of the disease. Previously, it was believed that HSV-1 only causes damage to the skin of the face, upper limbs and trunk, as well as the mucous membranes of the oral cavity. In recent years, its etiological role in genital herpes has been established, which may reflect the prevalence of orogenital sex. According to seroepidemiological studies, HSV-1 infection is detected in 20–40%, and HSV-2 infection in 50–70% of patients with genital herpes. The increase in incidence is also largely associated with the spread of asymptomatic and undiagnosed forms of the disease: only 20% of those infected with HSV have diagnosed symptomatic genital herpes, 60% have unrecognized symptomatic herpes (atypical form) and 20% have asymptomatic herpes. Currently, only 27% of patients diagnosed with genital herpes receive antiviral treatment. In addition to the risk of transmitting the virus to a sexual partner, asymptomatic shedding of the virus in women is the cause of neonatal infection and 50% of all infections in newborns. Herpetic infection can also cause reproductive dysfunction, miscarriage, premature birth and fetal pathology. It is possible that HSV may be involved in the development of genital cancer and immunodeficiency states, which makes it possible to consider herpesvirus infections as an important medical and social problem in practical health care.

In Russia, there are 8 million patients with genital herpes.

The second most important member of the herpesvirus family is varicella-zoster virus (VZV).
It causes 2 different clinical diseases - chickenpox and herpes zoster. The development of shingles is the result of reactivation of a latent virus in the body after chickenpox in childhood. According to foreign literature [3], every second person who has reached the age of 85 years old gets sick with Herpes zoster once, and in 4% of cases the disease occurs more than once. An important problem with herpes zoster is pain; approximately half of patients over 60 years of age develop postherpetic neuralgia. Moreover, the frequency of its development increases with age. 67% of doctors in the UK consider this the most difficult aspect of treating herpes. Even after the rash resolves, pain may remain for several months to a year. In addition, Herpes zoster in immunocompromised patients can be complicated by hematogenous dissemination, the occurrence of damage to the central nervous system, as well as visceropathy. In recent years, significant progress has been made in the treatment of herpes thanks to the introduction into clinical practice of synthetic nucleosides, among which famciclovir (Famvir) is promising.

Famciclovir

is a precursor to penciclovir and has a number of significant advantages compared to acyclovir:

Famciclovir is the only antiviral drug that reduces the duration of postherpetic neuralgia in herpes zoster.

• high affinity for viral thymidine kinase (100 times higher) and more pronounced blocking of viral replication between doses of the drug;
• famciclovir has the highest bioavailability (77% versus 10–20% for acyclovir) and the longest period of residence in a virus-infected cell (up to 20 hours);

• constant concentration of the drug in infected cells provides a long-term antiviral effect and makes it possible to take the drug less often;

• famciclovir has the property of penetrating Schwann cells surrounding nerve fibers. In VZV-infected cells, half-lives are 9 hours for phosphorylated penciclovir and 0.8 hours for phosphorylated acyclovir [6,7,8]. Therefore, famciclovir is the only antiviral drug that reduces the duration of postherpetic neuralgia in herpes zoster (by 100 days compared to placebo) (Fig. 1).

Rice. 1. Duration of postherpetic neuralgia in herpes zoster.

For clinicians,
the high clinical effectiveness of Famvir for genital herpes
:

• famvir reduces the number of relapses by 80% (Fig. 2) [11];

• causes the absence of relapses in almost one third of patients;

• prevents the spread of the virus (73% of patients receiving Famvir had a negative culture test for the virus compared to 46% of patients receiving placebo) (Fig. 3) [12];

• reduces the time it takes for the virus to spread to 1.8 days compared to 3.4 days in the placebo group (P<0.001);

• 30% of virus strains resistant to acyclovir are sensitive to famvir therapy.

Rice. 2. Famvir reduces the number of relapses by 80%.

Rice.
3. Famvir is able to stop the spread of the virus. The treatment strategy for patients with genital herpes
is determined by a number of factors: the frequency of relapses and the severity of clinical manifestations of the disease, as well as the presence of psychosocial problems and the risk of transmitting the infection to a sexual partner or newborn.

Currently, there are two approaches to treatment: episodic or preventive (suppressive) therapy. The goals of treatment are to relieve acute symptoms of the disease, reduce the frequency and severity of relapse, prevent reactivation of the virus, and improve the patient's quality of life. Episodic therapy is carried out only during the period of exacerbation of the disease and significantly reduces pain and discomfort in the affected area, shortens the healing time of herpetic eruptions, and also shortens the period of viral shedding to 1.8 days compared to 3.4 days in the placebo group.

In the United States, the Centers for Disease Control and Prevention (CDC) has approved Famciclovir for the episodic treatment of recurrent genital herpes at a dose of 125 mg twice daily for 5 days; for the first episode of genital herpes, Famciclovir is recommended at 250 mg 3 times daily for 5 days. –10 days [5,9,10].

According to the results of a multicenter study conducted by Merz et al. (1997), which included 375 women with a history of at least 6 relapses of genital herpes, taking famciclovir at a dose of 250 mg twice a day for 4 months was the most effective: prevention of relapses was observed in 90% of patients in this group compared with other regimens dosing and administration of the drug, as well as with the placebo group [9,10].

In another study conducted by Diaz-Mitoma et al. (1998), suppressive therapy with famciclovir was carried out for 1 year by administering 125 mg of the drug 3 times a day, 250 mg 2 times a day, 250 mg 3 times a day or placebo. All three doses of famciclovir significantly delayed the onset of clinically confirmed relapse. In the group receiving 250 mg twice daily, the median time to first relapse was 336 days, compared with 47 days in the placebo group. In 72% of patients receiving famciclovir therapy, relapses of genital herpes were not observed within 1 year after the start of treatment. In the group without treatment (placebo), there were only 22% of such patients. Thus, famciclovir has been shown to be effective as a preventive treatment for recurrent genital herpes at a dose of 250 mg 2 times a day [9,10].

Clinical trial to study the effectiveness of famciclovir for herpes zoster

showed that famciclovir 250 mg 3 times a day for 7 days has the same effectiveness in healing skin rashes as acyclovir 800 mg 5 times a day for the same period of time, however. in patients with the highest risk of long-term persistence of pain - these are patients over 50 years of age - pain in the acute phase disappeared 1.5 times faster than with the use of acyclovir.

Prescribing famciclovir makes it possible to reduce the daily and course doses of the drug by 5 times, compared with acyclovir: the course dose for famciclovir is 5.25 g, for acyclovir - 28.0 g. This circumstance is especially important when treating elderly patients. It should be noted that treatment is most effective when famvir is prescribed in the first 48 hours from the onset of the rash [3,8].

A clinical and laboratory study of the effectiveness of famciclovir for genital herpes was also conducted at the Central Scientific Research Institute of Medical Sciences of the Ministry of Health of the Russian Federation.

[2]. Monotherapy for relapses was carried out in 110 patients (62 men and 48 women) aged 18 to 50 years. The duration of the disease varied from several months to 10 years, the duration of relapses ranged from 5 to 21 days. 79 patients (71.8%) had a severe course of genital herpes (relapses 1–2 times a month and remissions less than 6 weeks), 28 patients (25.5%) had a moderate disease (exacerbations 1 time every 2–3 months and remission 2–3 months), a mild course of the disease (1–3 relapses per year, remission for at least 4 months) was observed in only 3 patients (2.7%).

The results of the study confirmed the high effectiveness of famvir in the treatment of genital herpes. Monotherapy of herpes relapses with famciclovir at a course dose of 2.5 g reduced the duration of herpes relapses by more than 2 times - from 8.7 to 3.8 days (P<0.05), when taking famciclovir at a course dose of 1.25 g duration relapse also decreased, but to a lesser extent - from 8.6 to 5.0 days.

Famciclovir was well tolerated; adverse reactions in the form of headache were noted by 5 of 110 patients (4.5%), diarrhea developed in 2 patients (1.8%). No other reactions, including allergic ones, were noted. These phenomena were not a reason to stop taking the drug or adjust the dose.

A comparative assessment of the clinical effectiveness of famciclovir showed a significant (P<0.05) reduction in the duration of exacerbation at a course dose of 2.5 g compared to 1.25 g.

conclusions

1. Famciclovir is a highly effective drug for the treatment and prevention of relapses of genital herpes and herpes zoster.

2. Famciclovir has an analgesic effect, especially pronounced in herpes zoster.

3. Famciclovir is the only antiviral drug that reduces the duration of postherpetic neuralgia in herpes zoster.

4. Suppressive therapy with famvir for 1 year reduces the number of relapses of genital herpes by 80% and the absence of relapses in almost a third of patients.

5. For genital herpes, famvir prevents the spread of the virus and reduces the time it takes for the virus to spread.

6. 30% of virus strains resistant to acyclovir are sensitive to famvir therapy.
Literature:
1. Yatsukha M.V., Gubanova E.I., Masyukova S.A. Dynamics of the incidence of genital herpes and the activities of health care facilities in Moscow and the Moscow region. Current problems of dermatology and venereology. Collection of scientific works. Moscow, 2000, pp. 94–95

2. Vladimirova E.V. The effectiveness of famciclovir in the treatment of recurrent genital herpes (clinical and laboratory study). Dissertation. Candidate of Medical Sciences, Moscow, 1998, 110 p.

3. Gross G. Herpes – simplex – Virus und Varicella – Zoster – Virus – Infektionen // “Dermatologie, heutiger Stand”, Stuttgart – New – York, Georg Thieme Verlag, – 1995, pp. 43 – 50.

4. Elion GB Acyclovir discovery, mechanism of action and selectivity // J. Med.Virol. – 1993 – , – Suppl.1, – p.2 – 6.

5. Centers for Disease Control and Prevention. 1998. CDC 1998. Guidelines for treatment of Sexually Transmitted Diseases. Morb.Mortal.Wkly.Rep.47,1–118.

6. Earnshaw DL, Bacon TH, Darlison SJ et al. Penciclovir mode of action studies in HSV – I. HSV – 2 and VZV infected MRC – 5 cells, providing a rationale for its persistent antiviral activity.// Antimicrob Agents Chemother, 1992, 36: p.2747 – 57.

7. Pue MA, Benet L2.Pharmacokinetics of famciclovir in man // Antiviral Chem Chemother, – 1993, – (Suppl. 1) – p.47 – 55.

8. Degreef H, Famciclovir Herpes Zoster Clinical Study Group. Famciclovir, a new oral antiherpes drug: results of the first controlled clinical study demonstrating its efficacy and safety in the treatment of uncomplicated herpes zoster in immunocompetent patients // Int.J. Antimicrob Agents, – 1994, – 4: p.241 – 6.

9. Stanberry L. et al. Antiviral Research 42(1999), 1–14

10. Leung DT, Sacks SL Current Recommendations for the treatment of genital herpes//Drags, 2000, Dec;60 (6): 1329–1352

11. Diaz–Mitoma F et al. Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. JAMA. 1998; 280:887–892

12. Saks SL et al. Patient–initiated, twice–daily oral famciclovir for early recurrent genital herpes: a randomized double–blind multicenter trial. JAMA. 1996; 276:44–49.

Famciclovir–

Famvir (trade name)

(Novartis Pharma)