Famciclovir

Famciclovir 500 mg film-coated tablets

Each tablet contains 500 mg of famciclovir.

For the full list of excipients, see section 6.1.

Film-coated tablet

500 mg: White capsule shaped film-coated tablets, anonymous.

Varicella zoster virus (VZV) infections – herpes zoster

Famciclovir is indicated for

- the treatment of herpes zoster and ophthalmic zoster in immunocompetent adults (see section 4.4).

- the treatment of herpes zoster in immunocompromised adults (see section 4.4).

Herpes simplex virus (HSV) infections – genital herpes

Famciclovir is indicated for

- the treatment of first and recurrent episodes of genital herpes in immunocompetent adults.

- the treatment of recurrent episodes of genital herpes in immunocompromised adults.

- the suppression of recurrent genital herpes in immunocompetent and immunocompromised adults.

Clinical studies have not been conducted in HSV-infected patients immunocompromised for other causes than HIV infection (see section 5.1).

Posology

Herpes zoster and ophthalmic zoster in immunocompetent adults

500 mg three times daily for seven days.

Treatment should be initiated as soon as possible after a diagnosis of herpes zoster or ophthalmic zoster.

Herpes zoster in immunocompromised adults

500 mg three times daily for ten days.

Treatment should be initiated as soon as possible after a diagnosis of herpes zoster.

Genital herpes in immunocompetent adults

First episode of genital herpes: 250 mg three times daily for five days. Initiation of treatment is recommended as soon as possible after a diagnosis of first episode of genital herpes.

Episodic treatment of recurrent genital herpes: 125 mg twice daily for five days. Initiation of treatment is recommended as soon as possible after onset of prodromal symptoms (e.g. tingling, itching, burning, pain) or lesions.

Recurrent genital herpes in immunocompromised adults

Episodic treatment of recurrent genital herpes: 500 mg twice daily for seven days. Initiation of treatment is recommended as soon as possible after onset of prodromal symptoms (e.g. tingling, itching, burning, pain) or lesions.

Suppression of recurrent genital herpes in immunocompetent adults

250 mg twice daily. Suppressive therapy should be discontinued after a maximum of 12 months of continuous antiviral therapy to reassess recurrence frequency and severity. The minimum period of reassessment should include two recurrences. Patients who continue to have significant disease may restart suppressive therapy.

Suppression of recurrent genital herpes in immunocompromised adults

500 mg twice daily.

Patients with renal impairment

Because reduced clearance of penciclovir is related to reduced renal function, as measured by creatinine clearance, special attention should be given to doses in patients with impaired renal function. Dose recommendations for adult patients with renal impairment are provided in Table 1.

Table 1: Dose recommendations for adult patients with renal impairment

Patients with renal impairment on haemodialysis

Since 4-h haemodialysis resulted in up to 75% reduction in plasma penciclovir concentrations, famciclovir should be administered immediately following dialysis. The recommended dose regimens for haemodialysis patients are included in Table 1.

Patients with hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. No data are available for patients with severe hepatic impairment (see sections 4.4 and 5.2).

Elderly (≥65 years)

Dose modification is not required unless renal function is impaired.

Paediatric population

The safety and efficacy of famciclovir in children and adolescents aged less than 18 years have not been established. Currently available data are described in sections 5.1 and 5.2.

Method of administration

Famciclovir can be taken without regard to meals (see section 5.2).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to penciclovir.

Use in patients with renal impairment

In patients with impaired renal function dose adjustment is necessary (see sections 4.2 and 4.9).

Use in patients with hepatic impairment

Famciclovir has not been studied in patients with severe hepatic impairment. Conversion of famciclovir to its active metabolite penciclovir may be impaired in these patients resulting in lower penciclovir plasma concentrations, and thus a decrease of efficacy of famciclovir may occur.

Use for zoster treatment

Clinical response should be closely monitored, particularly in immunocompromised patients.

Consideration should be given to intravenous antiviral therapy when response to oral therapy is considered insufficient.

Patients with complicated herpes zoster, i.e. those with visceral involvement, disseminated zoster, motor neuropathies, encephalitis and cerebrovascular complications should be treated with intravenous antiviral therapy.

Moreover, immunocompromised patients with ophthalmic zoster or those with a high risk for disease dissemination and visceral organ involvement should be treated with intravenous antiviral therapy.

Transmission of genital herpes

Patients should be advised to avoid intercourse when symptoms are present even if treatment with an antiviral has been initiated. During suppressive treatment with antiviral agents, the frequency of viral shedding is significantly reduced. However, transmission is still possible. Therefore, in addition to therapy with famciclovir, it is recommended that patients use safer sex practices.

Excipient

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially “sodium-free”.

Effects of other medicinal products on famciclovir

No clinically significant interactions have been identified.

Concurrent use of probenecid may result in increased plasma concentrations of penciclovir, the active metabolite of famciclovir, by competing for elimination. Therefore patients receiving famciclovir at a dose of 500 mg three times daily co-administered with probenecid, should be monitored for toxicity. If patients experience severe dizziness, somnolence, confusion or other central nervous system disturbances, a dose reduction of famciclovir to 250 mg three times daily may be considered.

Famciclovir needs aldehyde oxidase to be converted into penciclovir, its active metabolite. Raloxifene has been shown to be a potent inhibitor of this enzyme in vitro. Co-administration of raloxifene could affect the formation of penciclovir and thus the efficacy of famciclovir. When raloxifene is co-administered with famciclovir the clinical efficacy of the antiviral therapy should be monitored.

Effects of other medicinal products on famciclovir

No clinically significant interactions have been identified.

Concurrent use of probenecid may result in increased plasma concentrations of penciclovir, the active metabolite of famciclovir, by competing for elimination. Therefore patients receiving famciclovir at a dose of 500 mg three times daily co-administered with probenecid, should be monitored for toxicity. If patients experience severe dizziness, somnolence, confusion or other central nervous system disturbances, a dose reduction of famciclovir to 250 mg three times daily may be considered.

Famciclovir needs aldehyde oxidase to be converted into penciclovir, its active metabolite. Raloxifene has been shown to be a potent inhibitor of this enzyme in vitro. Co-administration of raloxifene could affect the formation of penciclovir and thus the efficacy of famciclovir. When raloxifene is co-administered with famciclovir the clinical efficacy of the antiviral therapy should be monitored.

No studies on the effects on the ability to drive and use machines have been performed. However, patients who experience dizziness, somnolence, confusion or other central nervous system disturbances while taking famciclovir should refrain from driving or operating machinery.

Headache and nausea have been reported in clinical studies. These were generally mild or moderate in nature and occurred at a similar incidence in patients receiving placebo treatment. All other adverse reactions were added during post-marketing.

The pooled global placebo- or active- controlled clinical trials (n=2,326 for famciclovir arm) were retrospectively reviewed to obtain a frequency category for all adverse reactions mentioned below. The following table specifies the estimated frequency of adverse reactions based on all the spontaneous reports and literature cases that have been reported for famciclovir since its introduction to the market.

Adverse reactions (Table 2) are ranked under headings of frequency, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from available data)..

Table 2: Adverse reactions from clinical trials and post-marketing spontaneous reports

*Adverse drug reactions reported from post-marketing experience with famciclovir via spontaneous case reports and literature cases which have not been reported in clinical trials. Because these adverse drug reactions have been reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.

Frequency is therefore listed as “not known”.

Overall, adverse reactions reported from clinical studies with immunocompromised patients were similar to those reported in the immunocompetent population. Nausea, vomiting and abnormal liver function tests were reported more frequently, especially at higher doses.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdose experience with famciclovir is limited. In the event of an overdose supportive and symptomatic therapy should be given as appropriate. Acute renal failure has been reported rarely in patients with underlying renal disease where the famciclovir dose has not been appropriately reduced for the level of renal function. Penciclovir is dialysable; plasma concentrations are reduced by approximately 75% following 4- hours of haemodialysis.

Pharmacotherapeutic group: Nucleosides and nucleotides excluding reverse transcriptase inhibitors

ATC code: J05A B09

Mechanism of action

Famciclovir is the oral prodrug of penciclovir. Famciclovir is rapidly converted in vivo into penciclovir, which has in vitro activity against herpes simplex viruses (HSV types 1 and 2), varicella zoster virus (VZV), Epstein-Barr virus and cytomegalovirus.

The antiviral effect of orally administered famciclovir has been demonstrated in several animal models: this effect is due to in vivo conversion to penciclovir. In virus-infected cells the viral thymidine kinase (TK) phosphorylates penciclovir to a monophosphate form that, in turn, is converted to penciclovir triphosphate by cellular kinases. This triphosphate inhibits viral DNA chain elongation by competitive inhibition with deoxyguanosine triphosphate for incorporation into the growing viral DNA, thus halting virus replication of viral DNA. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2- and 7 hours in VZV-infected cells grown in culture. In uninfected cells treated with penciclovir, concentrations of penciclovir triphosphate are only barely detectable. Hence the probability of toxicity to mammalian host cells is low and uninfected cells are unlikely to be affected by therapeutic concentrations of penciclovir.

Resistance

Like aciclovir, penciclovir resistance is associated with mutations principally in the thymidine kinase (TK) gene resulting in deficiency or altered substrate specificity of this enzyme and to a much lesser extent in the DNA polymerase gene. Most aciclovir-resistant HSV and VZV clinical isolates are also resistant to penciclovir, but cross-resistance is not universal.

Results from 11 worldwide clinical studies involving penciclovir (topical or intravenous formulations) or famciclovir in immunocompetent or immunocompromised patients, including studies of up to 12 months treatment with famciclovir, have shown a small overall frequency of penciclovir resistant isolates: 0.2% (2/913) in immunocompetent patients and 2.1% (6/288) in immunocompromised patients. The resistant isolates were mostly found at the start of treatment or in a placebo group, with resistance occurring on or after treatment with famciclovir or penciclovir only in two immunocompromised patients.

Clinical efficacy

In placebo-controlled and active-controlled studies both in immunocompetent and immunocompromised patients with uncomplicated herpes zoster, famciclovir was effective in the resolution of lesions. In an active-controlled clinical study, famciclovir was shown to be effective in the treatment of ophthalmic zoster in immunocompetent patients.

Efficacy of famciclovir in immunocompetent patients with first episode of genital herpes was shown in three active-controlled studies. Two placebo-controlled studies in immunocompetent patients and one active-controlled study in HIV-infected patients with recurrent genital herpes showed that famciclovir was effective.

Two placebo-controlled 12-month studies in immunocompetent patients with recurrent genital herpes showed that famciclovir-treated patients had a significant reduction of recurrences as compared to placebo-treated patients. Placebo-controlled and uncontrolled studies of up to 16 weeks duration showed that famciclovir was effective in the suppression of recurrent genital herpes in HIV-infected patients; the placebo-controlled study showed that famciclovir significantly decreased the proportion of days of both symptomatic and asymptomatic HSV shedding.

Paediatric population

Famciclovir experimental oral granules were evaluated in 169 paediatric patients 1 month to ≤12 years of age. One hundred of these patients were 1 to ≤12 years of age and were treated with famciclovir oral granules (doses ranged from 150 mg to 500 mg) either twice (47 patients with herpes simplex virus infections) or three times (53 patients with chickenpox) daily for 7 days. The remaining 69 patients (18 patients 1 to ≤12 months, 51 patients 1 to ≤12 years) participated in single-dose pharmacokinetic and safety studies using famciclovir oral granules (doses ranged from 25 mg to 500 mg). Famciclovir weight-based doses were selected to provide penciclovir systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of 500 mg famciclovir. None of these studies comprised a control group; therefore a conclusion on the efficacy of the investigated regimens is not possible. The safety profile was similar to that seen in adults. However, systemic drug exposure in infants <6 months of age was low, thus precluding any assessment of famciclovir's safety in this age group.

Pharmacotherapeutic group: Nucleosides and nucleotides excluding reverse transcriptase inhibitors

ATC code: J05A B09

Mechanism of action

Famciclovir is the oral prodrug of penciclovir. Famciclovir is rapidly converted in vivo into penciclovir, which has in vitro activity against herpes simplex viruses (HSV types 1 and 2), varicella zoster virus (VZV), Epstein-Barr virus and cytomegalovirus.

The antiviral effect of orally administered famciclovir has been demonstrated in several animal models: this effect is due to in vivo conversion to penciclovir. In virus-infected cells the viral thymidine kinase (TK) phosphorylates penciclovir to a monophosphate form that, in turn, is converted to penciclovir triphosphate by cellular kinases. This triphosphate inhibits viral DNA chain elongation by competitive inhibition with deoxyguanosine triphosphate for incorporation into the growing viral DNA, thus halting virus replication of viral DNA. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2- and 7 hours in VZV-infected cells grown in culture. In uninfected cells treated with penciclovir, concentrations of penciclovir triphosphate are only barely detectable. Hence the probability of toxicity to mammalian host cells is low and uninfected cells are unlikely to be affected by therapeutic concentrations of penciclovir.

Resistance

Like aciclovir, penciclovir resistance is associated with mutations principally in the thymidine kinase (TK) gene resulting in deficiency or altered substrate specificity of this enzyme and to a much lesser extent in the DNA polymerase gene. Most aciclovir-resistant HSV and VZV clinical isolates are also resistant to penciclovir, but cross-resistance is not universal.

Results from 11 worldwide clinical studies involving penciclovir (topical or intravenous formulations) or famciclovir in immunocompetent or immunocompromised patients, including studies of up to 12 months treatment with famciclovir, have shown a small overall frequency of penciclovir resistant isolates: 0.2% (2/913) in immunocompetent patients and 2.1% (6/288) in immunocompromised patients. The resistant isolates were mostly found at the start of treatment or in a placebo group, with resistance occurring on or after treatment with famciclovir or penciclovir only in two immunocompromised patients.

Clinical efficacy

In placebo-controlled and active-controlled studies both in immunocompetent and immunocompromised patients with uncomplicated herpes zoster, famciclovir was effective in the resolution of lesions. In an active-controlled clinical study, famciclovir was shown to be effective in the treatment of ophthalmic zoster in immunocompetent patients.

Efficacy of famciclovir in immunocompetent patients with first episode of genital herpes was shown in three active-controlled studies. Two placebo-controlled studies in immunocompetent patients and one active-controlled study in HIV-infected patients with recurrent genital herpes showed that famciclovir was effective.

Two placebo-controlled 12-month studies in immunocompetent patients with recurrent genital herpes showed that famciclovir-treated patients had a significant reduction of recurrences as compared to placebo-treated patients. Placebo-controlled and uncontrolled studies of up to 16 weeks duration showed that famciclovir was effective in the suppression of recurrent genital herpes in HIV-infected patients; the placebo-controlled study showed that famciclovir significantly decreased the proportion of days of both symptomatic and asymptomatic HSV shedding.

Paediatric population

Famciclovir experimental oral granules were evaluated in 169 paediatric patients 1 month to ≤12 years of age. One hundred of these patients were 1 to ≤12 years of age and were treated with famciclovir oral granules (doses ranged from 150 mg to 500 mg) either twice (47 patients with herpes simplex virus infections) or three times (53 patients with chickenpox) daily for 7 days. The remaining 69 patients (18 patients 1 to ≤12 months, 51 patients 1 to ≤12 years) participated in single-dose pharmacokinetic and safety studies using famciclovir oral granules (doses ranged from 25 mg to 500 mg). Famciclovir weight-based doses were selected to provide penciclovir systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of 500 mg famciclovir. None of these studies comprised a control group; therefore a conclusion on the efficacy of the investigated regimens is not possible. The safety profile was similar to that seen in adults. However, systemic drug exposure in infants <6 months of age was low, thus precluding any assessment of famciclovir's safety in this age group.

Pharmacotherapeutic group: Nucleosides and nucleotides excluding reverse transcriptase inhibitors

ATC code: J05A B09

Mechanism of action

Famciclovir is the oral prodrug of penciclovir. Famciclovir is rapidly converted in vivo into penciclovir, which has in vitro activity against herpes simplex viruses (HSV types 1 and 2), varicella zoster virus (VZV), Epstein-Barr virus and cytomegalovirus.

The antiviral effect of orally administered famciclovir has been demonstrated in several animal models: this effect is due to in vivo conversion to penciclovir. In virus-infected cells the viral thymidine kinase (TK) phosphorylates penciclovir to a monophosphate form that, in turn, is converted to penciclovir triphosphate by cellular kinases. This triphosphate inhibits viral DNA chain elongation by competitive inhibition with deoxyguanosine triphosphate for incorporation into the growing viral DNA, thus halting virus replication of viral DNA. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2- and 7 hours in VZV-infected cells grown in culture. In uninfected cells treated with penciclovir, concentrations of penciclovir triphosphate are only barely detectable. Hence the probability of toxicity to mammalian host cells is low and uninfected cells are unlikely to be affected by therapeutic concentrations of penciclovir.

Resistance

Like aciclovir, penciclovir resistance is associated with mutations principally in the thymidine kinase (TK) gene resulting in deficiency or altered substrate specificity of this enzyme and to a much lesser extent in the DNA polymerase gene. Most aciclovir-resistant HSV and VZV clinical isolates are also resistant to penciclovir, but cross-resistance is not universal.

Results from 11 worldwide clinical studies involving penciclovir (topical or intravenous formulations) or famciclovir in immunocompetent or immunocompromised patients, including studies of up to 12 months treatment with famciclovir, have shown a small overall frequency of penciclovir resistant isolates: 0.2% (2/913) in immunocompetent patients and 2.1% (6/288) in immunocompromised patients. The resistant isolates were mostly found at the start of treatment or in a placebo group, with resistance occurring on or after treatment with famciclovir or penciclovir only in two immunocompromised patients.

Clinical efficacy

In placebo-controlled and active-controlled studies both in immunocompetent and immunocompromised patients with uncomplicated herpes zoster, famciclovir was effective in the resolution of lesions. In an active-controlled clinical study, famciclovir was shown to be effective in the treatment of ophthalmic zoster in immunocompetent patients.

Efficacy of famciclovir in immunocompetent patients with first episode of genital herpes was shown in three active-controlled studies. Two placebo-controlled studies in immunocompetent patients and one active-controlled study in HIV-infected patients with recurrent genital herpes showed that famciclovir was effective.

Two placebo-controlled 12-month studies in immunocompetent patients with recurrent genital herpes showed that famciclovir-treated patients had a significant reduction of recurrences as compared to placebo-treated patients. Placebo-controlled and uncontrolled studies of up to 16 weeks duration showed that famciclovir was effective in the suppression of recurrent genital herpes in HIV-infected patients; the placebo-controlled study showed that famciclovir significantly decreased the proportion of days of both symptomatic and asymptomatic HSV shedding.

Paediatric population

Famciclovir experimental oral granules were evaluated in 169 paediatric patients 1 month to ≤12 years of age. One hundred of these patients were 1 to ≤12 years of age and were treated with famciclovir oral granules (doses ranged from 150 mg to 500 mg) either twice (47 patients with herpes simplex virus infections) or three times (53 patients with chickenpox) daily for 7 days. The remaining 69 patients (18 patients 1 to ≤12 months, 51 patients 1 to ≤12 years) participated in single-dose pharmacokinetic and safety studies using famciclovir oral granules (doses ranged from 25 mg to 500 mg). Famciclovir weight-based doses were selected to provide penciclovir systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of 500 mg famciclovir. None of these studies comprised a control group; therefore a conclusion on the efficacy of the investigated regimens is not possible. The safety profile was similar to that seen in adults. However, systemic drug exposure in infants <6 months of age was low, thus precluding any assessment of famciclovir's safety in this age group.

Core:

Microcrystalline cellulose E460

Colloidal anhydrous silica E551

Sodium starch glycolate (Type A)

Low-substituted hydroxypropylcellulose

Croscarmellose sodium

Sodium stearyl fumarate

Film-coat:

Titanium dioxide E 171

Polydextrose E1200

Hypromellose E464

Triacetin E1518

Macrogol 8000

Not applicable

2 years

Keep the blister in the outer carton in order to protect from light.

White opaque PVC/PE/Aclar – Aluminium blisters packs

500 mg tablets: 1, 10, 14, 15, 20, 21, 30, 56 & 60 film-coated tablets. Hospital packs of 50 (50 x 1) film-coated tablets.

Not all pack sizes may be marketed.

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements

Rivopharm UK Ltd

100 Bishopsgate

London

EC2N 4AG

United Kingdom

PL 33155/0116

30/09/2010

31/08/2023