FAMCICLOVIR - GENERIC DRUG - PACKAGE LEAFLET - LEAFLETS

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Famciclovir - Generic Drug - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Famciclovir

Famciclovir Sandoz 125 mg film-coated tablets
Famciclovir Sandoz 250 mg film-coated tablets
Famciclovir Sandoz 500 mg film-coated tablets

Why is Famciclovir used - Generic drug? What is it for?

Famciclovir Sandoz is an antiviral medicine. It prevents the infecting virus from reproducing. Since the virus reproduces quickly when the infection begins, you will get better treatment results if you take Famciclovir Sandoz as soon as the first symptoms appear.

Famciclovir Sandoz is used to treat two types of viral infections in adults:

Herpes zoster, which is a "viral infection caused by a virus called varicella zoster (the same virus that causes chickenpox). Famciclovir Sandoz prevents the virus from spreading in the body so healing can occur faster.
Famciclovir Sandoz is also used to treat infections in the area around the eye or even in the eye itself (ophthalmic zoster).
Genital herpes. Genital herpes is a viral infection caused by the herpes simplex virus type 1 or 2. It is normally transmitted sexually. It causes blisters and burning or itching of the genitals, which can be painful. Famciclovir Sandoz is used to treat infections with genital herpes in adults People who have frequent episodes of genital herpes can also take Famciclovir Sandoz to try to prevent new episodes.

Contraindications When Famciclovir should not be used - Generic drug

Do not take Famciclovir Sandoz

If you are allergic to famciclovir, any of the other ingredients of this medicine (listed in section 6), or penciclovir (active metabolite of famciclovir and a component of some other medicines).

Ask your doctor for advice if you think you are allergic.

Precautions for use What you need to know before taking Famciclovir - Generic drug

Warnings and precautions Talk to your doctor before taking Famciclovir Sandoz.

If you have kidney problems (or have had them in the past). Your doctor may decide to prescribe a lower dose of Famciclovir Sandoz.
If you have any immune system disorders.
If you have liver problems. If any of these apply to you, talk to your doctor before taking Famciclovir Sandoz.

Children and adolescents (under 18 years of age)

The use of Famciclovir Sandoz in children and adolescents is not recommended.

Prevention of the transmission of genital herpes to other individuals

If you are taking Famciclovir Sandoz for the treatment or suppression of genital herpes, or if you have suffered from genital herpes in the past, you should continue to have safe sex using condoms. This is important to prevent transmission of the infection to others. individuals. You shouldn't have sex if you have genital blisters.

Interactions Which drugs or foods can modify the effect of Famciclovir - Generic drug

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.

It is especially important that you tell your doctor or pharmacist if you are taking any of the following medicines:

Raloxifene (used to prevent and treat osteoporosis).
Probenecid (used to treat the high blood levels of uric acid associated with gout, and to raise the blood levels of penicillin-like antibiotics), or any other medicine that can damage the kidneys.

Famciclovir Sandoz with food and drink

Famciclovir Sandoz can be taken with or without food.

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Famciclovir Sandoz should not be used during pregnancy unless clearly necessary. Your doctor will discuss with you the potential risks of taking Famciclovir Sandoz during pregnancy. Famciclovir Sandoz should not be used during breastfeeding unless absolutely necessary. Your doctor will discuss with you the possible risks of taking Famciclovir Sandoz while breastfeeding.

Driving and using machines

Famciclovir Sandoz can cause dizziness, sleepiness or confusion. Do not drive or use machines if you experience any of these symptoms while taking Famciclovir Sandoz.

Famciclovir Sandoz 125 mg film-coated tablets contain lactose

If you have been told by your doctor that you have an intolerance to some sugars, such as lactose, contact your doctor before taking this medicine.

Famciclovir Sandoz 250 mg film-coated tablets contain lactose

If you have been told by your doctor that you have an intolerance to some sugars, such as lactose, contact your doctor before taking this medicine.

Dose, Method and Time of Administration How to use Famciclovir - Generic drug: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

The daily dose and duration of treatment will depend on the type of viral infection you have - see below. Your doctor will prescribe the correct dose for you.
For best results, start taking the medicine as soon as possible after the first signs and symptoms appear.
Avoid having sexual contact if you experience symptoms of genital herpes - even if you have already started treatment with Famciclovir Sandoz. This is because it could transmit the infection to your partner.
If you have or have had kidney problems, your doctor may decide to give you a lower dose of Famciclovir Sandoz.

Dose for Herpes zoster

If you have a normal immune system, the recommended dose is

500 mg three times a day, for seven days

If your immune defenses are reduced, the recommended dose is

500 mg three times a day, for ten days

Dose for genital herpes

The dose depends on the condition of your immune system, and the stage of the infection.

If you have a normal immune system, the doses are as follows:

For the first rash, the recommended dose is:

250 mg three times a day, for five days.

For the treatment of further rashes, the recommended dose is:

125 mg twice a day, for five days.

For the prevention of future rashes, the recommended dose is:

250 mg twice a day.

Your doctor will tell you how long to continue taking the tablets.

If your immune defenses are low, the doses are as follows:

For the treatment of the ongoing rash, the recommended dose is:

500 mg twice a day, for seven days.

For the prevention of future rashes, the dose is:

500 mg twice a day.

Your doctor will tell you how long to continue taking the tablets.

If you forget to take Famciclovir Sandoz

If you forget to take a dose of Famciclovir Sandoz, you should take it as soon as you remember.

Then take the next dose as planned. However, do not take two doses in less than 1 hour: in this case you should skip the missed dose. Also do not take a double dose to make up for a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken an overdose of Famciclovir - Generic drug

If you have taken more tablets than you have been told to take, or if someone else has accidentally taken your medicine, contact your doctor or hospital immediately. Show them your box of tablets.

Taking too much Famciclovir Sandoz can affect the kidneys. In patients who already have kidney problems, if doses are not adequately decreased, this can rarely lead to kidney failure.

Side Effects What are the side effects of Famciclovir - Generic drug

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects of Famciclovir Sandoz are:

Most of these side effects are rare or uncommon (affects 1 to 100 out of 10,000 patients).

Severe rash of blisters on the skin or mucous membranes of the lips, eyes, mouth, nasal passages or genitals (these could be signs of a severe allergic skin reaction).
Bruising with no explainable cause, reddish or purple spots on the skin or nosebleeds (these could be signs of a decrease in the number of platelets).
Swelling under the skin surface (eg swelling of the face, swelling around the eye, swelling of the eyelid, swelling of the throat).
Yellow discoloration of the skin and / or eyes (signs of jaundice).
Purple patches of skin, itching, burning (signs of inflammation of the blood vessels).

Contact a doctor or go to the nearest hospital emergency department if you experience any of these side effects.

Very common side effects (these side effects affect more than 1 in 10 people)

Headache

Common side effects (these side effects affect up to 1 in 10 people)

Feeling sick (nausea)
He retched
Abdominal pain
Diarrhea
Dizziness
Rash
Itching
Abnormal values in liver function tests

Uncommon side effects (these side effects affect up to 1 in 100 people)

Confusion
Somnolence (usually in older people)
Itchy rash (hives)

Rare side effects (these side effects affect up to 1 in 1000 people)

Hallucinations (seeing or hearing things that aren't really there)
Palpitations (signs of abnormal heartbeat)

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date refers to the last day of that month.
Do not store above 25 ° C.
Store in the original package to protect from moisture.
Do not use this medicine if you notice that the pack is damaged or shows signs of tampering.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Other information

What Famciclovir Sandoz contains

Famciclovir Sandoz 125 mg film-coated tablets

The active ingredient is famciclovir.
The other ingredients are: anhydrous lactose, sodium starch glycolate (type A), hydroxypropylcellulose and magnesium stearate. The tablet coating consists of: hypromellose, titanium dioxide (E 171), Macrogol 4000 and Macrogol 6000.

Famciclovir Sandoz 250 mg film-coated tablets

The active ingredient is famciclovir.
The other ingredients are anhydrous lactose, sodium starch glycolate (type A), hydroxypropylcellulose and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide (E171), Macrogol 4000 and Macrogol 6000.

Famciclovir Sandoz 500 mg film-coated tablets

The active ingredient is famciclovir.
The other ingredients are sodium starch glycolate (type A), hydroxypropylcellulose and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide (E171), Macrogol 4000 and Macrogol 6000.

What Famciclovir Sandoz looks like and contents of the pack

Famciclovir Sandoz is available as film-coated tablets.

Famciclovir Sandoz 125 mg film-coated tablets:

White, round, biconvex film-coated tablet with beveled edges, debossed with "FV" on one side and "125" on the other.

Famciclovir Sandoz 250 mg film-coated tablets:

White, round, biconvex film-coated tablet with beveled edges, debossed with "FV" on one side and "250" on the other.

Famciclovir Sandoz 500 mg film-coated tablets:

White, oval, biconvex film-coated tablet with bevelled edges, engraved with "FV 500" on one side only.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information on Famciclovir - Generic drug can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

FAMCICLOVIR SANDOZ TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 125 mg, 250 mg or 500 mg of famciclovir.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Varicella-zoster virus (VZV) infections - herpes zoster

Famciclovir Sandoz 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 Sandoz 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

No clinical studies have been conducted in immunocompromised patients with HSV from causes other than HIV infections (see section 5.1).

04.2 Posology and method of administration

Herpes zoster in immunocompetent adults

500 mg three times a day for seven days for the acute treatment of ophthalmic zoster.

Treatment should begin as soon as possible after the diagnosis of shingles.

Herpes zoster in immunocompromised adults

500 mg three times a day for ten days.

Treatment should begin as soon as possible after the diagnosis of shingles.

Genital herpes in immunocompetent adults

First episode of genital herpes: 250 mg three times a day for five days. It is recommended to start treatment as soon as possible after the diagnosis of the first episode of genital herpes.

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

Suppression of recurrent genital herpes in immunocompetent adults

250 mg twice a day. Suppressive therapy should be discontinued after a maximum of 12 months of continuous antiviral treatment to reassess the frequency and severity of recurrences. The minimum revaluation period must include two recurrences. Patients who continue to have significant disease can start suppressive treatment again.

Suppression of recurrent genital herpes in immunocompromised adults

500 mg twice a day.

Patients with impaired renal function

Since reduced penciclovir clearance is related to decreased renal function, as measured by creatinine clearance, particular attention should be paid to dosage in patients with impaired renal function. The recommended doses in adult patients with renal impairment are shown in Table 1.

Table 1 Recommended doses in adult patients with impaired renal function

Indication and nominal dose Creatinine clearance [ml / min] Adjusted dose Herpes zoster in immunocompetent adults 500 mg three times a day for 7 days ≥ 60 500 mg three times a day for 7 days 40-59 500 mg twice a day for 7 days 20-39 500 mg once daily for 7 days 250 mg once daily for 7 days Patients on hemodialysis 250 mg after each dialysis for 7 days Herpes zoster in immunocompromised adults 500 mg three times a day for 10 days ≥ 60 500 mg three times a day for 10 days 40-59 500 mg twice a day for 10 days 20-39 500 mg once daily for 10 days 250 mg once daily for 10 days Patients on hemodialysis 250 mg after each dialysis for 10 days Genital herpes in immunocompetent adults - first episode of genital herpes 250 mg three times a day for 5 days ≥ 40 250 mg three times a day for 5 days 20-39 250 mg twice a day for 5 days 250 mg once daily for 5 days Patients on hemodialysis 250 mg after each dialysis for 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 125 mg once daily for 5 days Patients on hemodialysis 125 mg after each dialysis for 5 days Genital herpes in immunocompromised adults - episodic treatment of recurrent genital herpes 500 mg twice a day for 7 days ≥ 40 500 mg twice daily for 7 days 20-39 500 mg once daily for 7 days 250 mg once daily for 7 days Patients on hemodialysis 250 mg after each dialysis for 7 days Suppression of recurrent genital herpes in immunocompetent adults 250 mg twice a day ≥ 40 250 mg twice a day 20-39 125 mg twice a day 125 mg once daily Patients on hemodialysis 125 mg after each dialysis Suppression of recurrent genital herpes in immunocompromised adults 500 mg twice a day ≥ 40 500 mg twice a day 20-39 500 mg once a day 250 mg once a day Patients on hemodialysis 250 mg after each dialysis

Patients with renal impairment on hemodialysis

Since a 4-hour hemodialysis resulted in an up to 75% reduction in penciclovir plasma concentrations, famciclovir should be administered immediately following dialysis. Recommended doses for hemodialysis patients are shown in Table 1.

Patients with impaired hepatic function

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

Elderly patients (≥ 65 years old)

No dosage adjustments are required, except in cases of impaired renal function.

Pediatric population

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

Method of administration

Famciclovir Sandoz can be taken either with or without meals (see section 5.2).

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Hypersensitivity to penciclovir.

04.4 Special warnings and appropriate precautions for use

Use in patients with renal impairment

Dosage adjustments should be made in patients with impaired renal function (see sections 4.2 and 4.9).

Use in patients with hepatic impairment

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

Use for the treatment of herpes zoster

The clinical response must be carefully monitored, particularly in immunocompromised patients. When response to oral therapy is considered insufficient, intravenous antiviral therapy should be considered.

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.

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

Transmission of genital herpes

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

Other

Famciclovir Sandoz 125 mg and 250 mg tablets contain lactose. Patients with rare hereditary forms of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption syndrome should not take this medicine..

04.5 Interactions with other medicinal products and other forms of interaction

Effects of other medicinal products on famciclovir

No clinically significant interactions have been identified.

Concomitant use of probenecid may result in increased plasma concentrations of penciclovir, the active metabolite of famciclovir, due to competition in elimination.

Therefore patients receiving famciclovir at a dose of 500 mg three times daily administered concomitantly with probenecid should be monitored for toxicity. If patients experience severe dizziness, somnolence, confusion or other central nervous system disturbances, dose reduction of famciclovir to 250 mg three times a day may be considered.

Famciclovir requires the enzyme aldehyde oxidase to be converted to its active metabolite penciclovir. 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 administered with famciclovir, the clinical efficacy of antiviral therapy should be monitored.

04.6 Pregnancy and breastfeeding

Pregnancy

There are limited data (less than 300 episodes of pregnancy) on the use of famciclovir in pregnant women.Based on these limited data, the cumulative analysis of both potential and retrospective pregnancies did not provide evidence that the medicinal product causes specific fetal changes or congenital abnormalities. Animal studies have not shown any embryotoxic or teratogenic effects with famciclovir or penciclovir (the active metabolite of famciclovir) Famciclovir should only be used in pregnancy if the potential benefits outweigh the potential risks.

Feeding time

It is not known whether famciclovir is excreted in human milk. Animal studies have shown excretion of penciclovir in breast milk. If the condition of the woman requires treatment with famciclovir, interruption of breastfeeding may be considered.

Fertility

Clinical data show no influence of famciclovir on male fertility after long-term treatment at the oral dose of 250 mg twice daily (see section 5.3).

04.7 Effects on ability to drive and use machines

No studies have been conducted to investigate the effects on the ability to drive and use machines. However, patients taking Famciclovir Sandoz who experience dizziness, somnolence, confusion or other central nervous system disorders should refrain from driving vehicles. and from using machinery.

04.8 Undesirable effects

Headache and nausea have been reported in clinical trials. These effects were generally mild or moderate in intensity and also occurred with a similar frequency in patients taking placebo. All other adverse reactions were observed from marketing.

The overall pool of placebo- or active-controlled clinical trials (n = 2326 in the Famvir arm) were retrospectively analyzed to obtain a classification of the frequency with which the adverse reactions listed below were observed. In the table below, the estimated frequency of adverse reactions is based on all spontaneous reports and cases described in the literature that have been reported for Famvir since its inception.

Adverse reactions (Table 2) are listed by frequency, using the following convention: very common (≥ 1/10); common (≥ 1/100,

Table 2 Adverse reactions

Disorders of the blood and lymphatic system Rare: Thrombocytopenia. Psychiatric disorders Uncommon: Confusion (predominantly in the elderly). Rare: Hallucinations. Nervous system disorders Very common: Headache. Common: Dizziness Not common: Somnolence (predominantly in the elderly) Gastrointestinal disorders Common: Nausea, vomiting. Hepatobiliary disorders Common: Abnormal liver function tests. Rare: Cholestatic jaundice. Skin and subcutaneous tissue disorders Common: Rash, itching. Uncommon: Angioedema (e.g. face edema, eyelid edema, periorbital area edema, pharyngeal edema), urticaria Not known: Severe skin reactions (e.g. erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)

Overall, the adverse reactions observed in clinical studies in immunocompromised patients were comparable to those reported in the immunocompetent population. Nause, vomiting and abnormal liver function tests have been reported more frequently, especially at high doses.

04.9 Overdose

Cases of famciclovir overdose are limited. In the event of an overdose, appropriate symptomatic and supportive therapy should be instituted. Acute renal failure has been reported rarely in patients with latent renal disease in whom the dose of famciclovir was not adequately reduced, depending on the level of renal function. Penciclovir is dialyzable; plasma concentrations are reduced by approximately 75% after 4 hours of hemodialysis.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Nucleosides and nucleotides, excluding reverse transcriptase inhibitors.

ATC code: JO5A B09.

Mechanism of action

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

The antiviral effect of orally administered famciclovir has been demonstrated in several animal models: this effect is due to the conversion in vivo to penciclovir. In virus-infected cells, viral thymidine kinase (TK) phosphorylates penciclovir to a monophosphate form which, in turn, is converted to penciclovir triphosphate by cellular kinases. This triphosphate remains in infected cells for more than 12 hours and inhibits viral DNA chain elongation by competitive inhibition with deoxyguanosine triphosphate for incorporation into growing viral DNA, thereby blocking viral DNA replication. In cells not infected with the virus, the concentration of penciclovir triphosphate is at the limit of the threshold of determination. Therefore, the likelihood of toxicity to mammalian host cells is low and therapeutic concentrations of penciclovir are unlikely to lead to pharmacological effects on uninfected cells.

Resistence

As with aciclovir, the most common form of resistance observed in Herpes simplex virus (HSV) strains has been a deficiency in the production of the enzyme thymidine kinase (TK). to penciclovir.

Results from 11 international clinical studies conducted in immunocompetent or immunocompromised patients treated with penciclovir (topical and intravenous formulations) or famciclovir, including those studies in which patients were treated with famciclovir for up to 12 months, showed a overall low frequency of viral isolates resistant to penciclovir: 0.2% (2/913) in immunocompetent patients and 2.1% (6/288) in immunocompromised patients. Resistant isolates were mainly detected at initiation of therapy or in a placebo group, and resistance occurred during or after treatment with famciclovir or penciclovir in only two immunocompromised patients.

Clinical efficacy

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

The efficacy of famciclovir in immunocompetent patients with a first episode of genital herpes was demonstrated in three active-controlled studies. Two placebo-controlled studies in immunocompetent patients and one active-controlled study in HIV-infected patients with genital herpes recurrent have shown that famciclovir is effective.

Two 12-month placebo-controlled studies conducted in immunocompetent patients with recurrent genital herpes demonstrated that patients treated with famciclovir had a significant reduction in recurrences compared to patients treated with placebo. Placebo-controlled and uncontrolled studies of up to 16 weeks duration have shown that famciclovir is effective in the suppression of recurrent genital herpes in HIV-infected patients; the placebo-controlled study demonstrated that famciclovir significantly reduced the proportion of days of symptomatic and asymptomatic spread of the herpes simplex virus.

Pediatric population

The investigational formulation of famciclovir granules for oral use was studied in 169 pediatric patients aged 1 month to 12 years. One hundred of these patients, aged 1 to 12 years, were treated with famciclovir oral granules (at doses between 150 and 500 mg) twice daily (47 patients with herpes simplex infections) or three times daily (53 patients with chickenpox) for 7 days. The remaining 69 patients (18 patients aged 1 to 12 months, 51 patients aged 1 to 12 years) participated in pharmacokinetic and safety using single doses of famciclovir oral granules (at doses between 25 and 500 mg). Doses of famciclovir, based on body weight, were selected to obtain a similar "systemic exposure of penciclovir to" the systemic exposure of penciclovir observed in adults following administration of 500 mg of famciclovir. None of these studies included a control group; therefore no conclusion can be drawn on the efficacy of the dosing regimens studied. The safety profile was similar to that observed in adults. However, systemic exposure to the drug was low in children less than 6 months of age, thus preventing any safety assessment of famciclovir in this population.

05.2 Pharmacokinetic properties

General features

Absorption

Famciclovir is the oral prodrug of penciclovir, an active metabolite against viruses. After oral administration, famciclovir is rapidly and extensively absorbed and converted to penciclovir. The bioavailability of penciclovir after oral administration of famciclovir was found to be 77%. The peak plasma concentration of penciclovir after oral doses of 125 mg, 250 mg, 500 mg and 750 mg of famciclovir was 0.8 mcg / ml, 1.6 mcg / ml, 3.3 mcg / ml, respectively. and 5.1 mcg / ml, and was obtained at a median time of 45 minutes after administration.

The curves of penciclovir plasma concentrations versus time are similar after both single and repeated administration (three times and twice daily), indicating that there is no accumulation of penciclovir after repeated administration of famciclovir.

The systemic availability (AUC) of orally administered famciclovir-derived penciclovir is not affected by food.

Distribution

Penciclovir and its 6-deoxy precursor are poorly bound to plasma proteins (less than 20%).

Metabolism and elimination

Famciclovir is eliminated primarily as penciclovir and as a 6-deoxy precursor, both of which are excreted in the urine. There are no concentrations of unchanged famciclovir in the urine. Tubular secretion contributes to the renal elimination of penciclovir.

The terminal plasma elimination half-life of penciclovir after both single and repeated administration of famciclovir was approximately 2 hours.

Results from preclinical studies did not demonstrate any potential for inducing cytochrome P450 enzymes and inhibiting CYP3A4.

Characteristics in special populations

Patients with herpes zoster infections

Uncomplicated herpes zoster infection does not significantly alter the pharmacokinetics of penciclovir following oral administration of famciclovir. Following single and repeated dose administration of famciclovir in patients with herpes zoster, the terminal plasma half-life of penciclovir was 2, respectively. 8 and 2.7 hours.

Subjects with renal impairment

After administration of single and repeated doses, the apparent plasma clearance, renal clearance and the constant rate of plasma elimination of penciclovir decreased proportionally with the decrease in renal function. Dose adjustment is required in patients with renal impairment (see section 4.2).

Subjects with hepatic impairment

Mild and moderate hepatic impairment demonstrated no effect on the systemic availability of penciclovir following oral administration of famciclovir. No dose adjustment is required for patients with mild to moderate hepatic impairment (see sections 4.2 and 4.4). The pharmacokinetics of penciclovir have not been studied in patients with severe hepatic impairment. In these patients, the conversion of famciclovir to the active metabolite penciclovir may be impaired, resulting in lower plasma concentrations of penciclovir and thus a possible reduction in the efficacy of famciclovir.

Elderly (≥ 65 years old)

Based on comparative studies, after oral administration of famciclovir the mean AUC value was approximately 30% higher and the renal clearance of penciclovir approximately 20% lower in elderly volunteers (65-79 years) compared to younger volunteers. . In part these differences may be due to differences in renal function in the two groups. No dose adjustment is required based on age as long as renal function is not impaired (see section 4.2).

Sex

Small differences in renal clearance of penciclovir between females and males have been reported which have been attributed to gender differences in renal function. No dose adjustment is required based on gender.

Pediatric patients

Repeated oral doses of famciclovir (250 or 500 mg three times daily) administered to pediatric patients (6-11 years) with hepatitis B infection had no significant effect on penciclovir pharmacokinetics compared to single dose administration. . There was no accumulation of penciclovir.

In children (1-12 years) with herpes simplex infection or with chickenpox given single doses of famciclovir (see section 5.1), the apparent clearance of penciclovir increased with increasing body weight in a non-linear fashion. L "Plasma elimination half-life of penciclovir tended to decrease with decreasing age, from a mean of 1.6 hours in patients aged 6 to 12 years, to a mean of 1.2 hours in patients aged 6 to 12 years. 1 to 2 years not completed.

05.3 Preclinical safety data

General toxicity

Studies of pharmacological safety and repeated dose toxicity reveal no particular risks for humans.

Genotoxicity

Famciclovir was not genotoxic in a comprehensive series of in vitro and in vivo tests capable of detecting gene mutation, chromosomal damage and repairable DNA damage. Penciclovir, similarly to other substances of the same class, caused chromosomal damage, but did not induce either gene mutation in bacterial or mammalian cell systems, or increase in DNA repair. in vitro.

Carcinogenesis

An increased incidence of mammary adenocarcinoma, a tumor commonly observed in this species of rats used in carcinogenicity studies, was reported at high doses in female rats. There was no effect on the incidence of neoplasm in male rats or mice. of both sexes.

Reproductive toxicity

Impaired fertility (including pathophysiological changes of the testes, altered sperm morphology, decreased sperm concentration and motility, and decreased fertility) was found in male rats given 500 mg / kg / day. In addition, degenerative changes of the testicular epithelium were observed in general toxicity studies. This effect was reversible and was also observed with other substances of this class. Animal studies did not indicate any adverse effects on female fertility.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Famciclovir Sandoz 125 and 250 mg film-coated tablets:

hydroxypropylcellulose, anhydrous lactose, sodium carboxymethyl starch, magnesium stearate, hypromellose, titanium dioxide (E 171), macrogol 4000, macrogol 6000.

Famciclovir Sandoz 500 mg film-coated tablets:

hydroxypropyl cellulose, sodium carboxymethyl starch, magnesium stearate, hypromellose, titanium dioxide (E 171), macrogol 4000, macrogol 6000.