4.1. Therapeutic indications

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).

4.2. Posology and method of administration

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

Indication and nominal dose regimen

Creatinine clearance

[ml/min]

Adjusted dose regimen

Herpes zoster in immunocompetent adults

500 mg three times daily for 7 days

≥60

500 mg three times daily for 7 days

40 to 59

500 mg twice daily for 7 days

20 to 39

500 mg once daily for 7 days

< 20

250 mg once daily for 7 days

Haemodialysis patients

250 mg following each dialysis during 7 days

Herpes zoster in immunocompromised adults

500 mg three times daily for 10 days

≥60

500 mg three times daily for 10 days

40 to 59

500 mg twice daily for 10 days

20 to 39

500 mg once daily for 10 days

< 20

250 mg once daily for 10 days

Haemodialysis patients

250 mg following each dialysis during 10 days

Genital herpes in immunocompetent adults – first episode of genital herpes

250 mg three times daily for 5 days

≥40

250 mg three times daily for 5 days

20 to 39

250 mg twice daily for 5 days

< 20

250 mg once daily for 5 days

Haemodialysis patients

250 mg following each dialysis during 5 days

Genital herpes in immunocompetent adults – episodic treatment of recurrent genital herpes

125 mg twice daily for 5 days

≥ 20

125 mg twice daily for 5 days

< 20

125 mg once daily for 5 days

Haemodialysis patients

125 mg following each dialysis during 5 days

Genital herpes in immunocompromised adults – episodic treatment of recurrent genital herpes

500 mg twice daily for 7 days

≥40

500 mg twice daily for 7 days

20 to 39

500 mg once daily for 7 days

< 20

250 mg once daily for 7 days

Haemodialysis patients

250 mg following each dialysis during 7 days

Suppression of recurrent genital herpes in immunocompetent adults

250 mg twice daily

≥40

250 mg twice daily

20 to 39

125 mg twice daily

< 20

125 mg once daily

Haemodialysis patients

125 mg following each dialysis

Suppression of recurrent genital herpes in immunocompromised adults

500 mg twice daily

≥ 40

500 mg twice daily

20 to 39

500 mg once daily

< 20

250 mg once daily

Haemodialysis patients

250 mg following each dialysis

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 patients (>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.

Black patients

A placebo-controlled study in immunocompetent black patients with recurrent genital herpes showed no difference in efficacy between patients receiving famciclovir 1000 mg twice daily for one day and placebo. There were no unexpected or new safety findings in this trial in Black patients.

This lack of efficacy in the one-day treatment regimen cannot be extrapolated to the five-day treatment regimen for recurrent genital herpes (125 mg twice daily for five days) or other indications in Black patients.

Method of administration

For oral use.

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

4.3. Contraindications

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

Hypersensitivity to penciclovir.

4.4. Special warnings and precautions for use

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.

Sodium

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

4.5. Interaction with other medicinal products and other forms of interaction

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. Raloxifen 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 raloxifen is coadministered with famciclovir the clinical efficacy of the antiviral therapy should be monitored.

4.6. Fertility pregnancy and lactation

Women of childbearing potential

There are no data supporting any special recommendations in women of child-bearing potential.

Patients with genital herpes should be advised to avoid intercourse when symptoms are present even if treatment has been initiated. It is recommended that patients use safer sex practice (see section 4.4).

Pregnancy

There is a limited amount of data (less than 300 pregnancy outcomes) from the use of famciclovir in pregnant women. Based on these limited amounts of information, the cumulative analysis of both prospective and retrospective pregnancy cases did not provide evidence indicating that the product causes any specific foetal defect or congenital anomaly. Animal studies have not shown any embryotoxic or teratogenic effects with famciclovir or penciclovir (the active metabolite of famciclovir). Famciclovir should only be used during pregnancy when the potential benefits of treatment outweigh the potential risks.

Breast-feeding

It is unknown whether famciclovir is excreted in human breast milk. Animal studies have shown excretion of penciclovir in breast milk. If the woman's condition mandates treatment with famciclovir, discontinuation of breast-feeding may be considered.

Fertility

Clinical data do not indicate an impact of famciclovir on male fertility following long-term treatment at an oral dose of 250 mg twice daily (see section 5.3).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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=2326 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 the available data).

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

System Organ Class

Very Common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Rare

(≥ 1/10,00 to < 1/1,000)

Very Rare

(<10,000)

Not known

(cannot be estimated from the available data)

Blood and lymphatic system disorders

Thrombocytopenia

Immune system disorders

Anaphylactic shock*, Anaphylactic reaction*

Psychiatric disorders

Confusional state (predominantly in elderly)

Hallucinations

Nervous system disorders

Headache

Dizziness

Somnolence (predominantly in elderly)

Seizure*

Cardiac disorders

Palpitations

Gastro-intestinal disorders

Nausea, vomiting, abdominal pain, diarrhoea

Hepatobiliary disorders

Abnormal liver function tests

Cholestatic jaundice

Skin and subcutaneous tissue disorders

Rash, pruritus

Angioedema, (e.g. face oedema, eyelid oedema, periorbital oedema, pharyngeal oedema), urticaria

Serious skin reactions* (e.g. erythema multiforme, Stevens- Johnson Syndrome, Toxic Epidermal Necrolysis), Hypersensitivity vasculitis*.

*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.

4.9. Overdose

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.