Brivirac - Package Leaflet

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

Active ingredients: Brivudine

Brivirac 125 mg tablets

Why is Brivirac used? What is it for?

Brivirac contains the active substance brivudine. Brivirac has an antiviral effect and prevents the virus that causes St. Anthony's Fire (the varicella-zoster virus) from multiplying.

Brivirac is used in adults who do not have abnormalities of the immune system (the body's defenses) for the early treatment of St. Anthony's Fire (herpes zoster).

Contraindications When Brivirac should not be used

Do not take Brivirac

  • if you are allergic (hypersensitive) to the active substance brivudine
  • if you are allergic (hypersensitive) to any of the other ingredients of Brivirac (see section 6)
  • if you are pregnant or breastfeeding
  • if you are under 18.

In particular, DO NOT take Brivirac:

  • if you are taking anticancer medicines (chemotherapy), in particular if you are being treated with:
    • 5-fluorouracil (also called 5-FU, an active substance belonging to the group called 5-fluoropyrimidines)
    • creams, ointments, eye drops or any other form of medicine for external use containing 5-fluorouracil
    • active ingredients converted by the body into 5-fluorouracil such as:
      • capecitabine
      • floxuridine
      • tegafur
    • any other active ingredient of the 5-fluoropyrimidine group
    • associations of the aforementioned active ingredients
  • if your immune system (i.e. your body's defenses against infections) is severely compromised; eg. if you are being treated with:
    • anticancer medicines (chemotherapy) or
    • immunosuppressive medicines (i.e. medicines that suppress or decrease the function of your immune system)
  • if you are taking a medicine containing flucytosine to treat a fungal infection.
  • if you are taking a warts medicine containing an active substance from the 5-fluoropyrimidine group.

Precautions for use What you need to know before taking Brivirac

Talk to your doctor or pharmacist before taking Brivirac.

Do not take Brivirac together with medicines containing 5-FU or other 5-fluoropyrimidines (see sections "Do not take Brivirac" and "Other medicines and Brivirac").

Do not take Brivirac if the rash has already fully developed (the onset of scabs). If in doubt, ask your doctor.

Ask your doctor for advice before taking Brivirac if you have chronic liver disease (eg chronic hepatitis).

You should not take Brivirac for more than 7 days, as extending the duration of treatment beyond the recommended time of 7 days increases the risk of developing hepatitis (see also section 4).

Children and adolescents

Do not give Brivirac to children and adolescents between 0 and 18 years, as safety and efficacy have not been studied in this age group.

Interactions Which drugs or foods may change the effect of Brivirac

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

PLEASE NOTE:

Special warning for patients treated with products containing 5-fluorouracil or other 5-fluoropyrimidines (see also red box above):

Brivirac should not be used concomitantly with any chemotherapy medicine containing any of the following active substances, as the harmful effects of these medicines can greatly increase and be fatal:

  • 5-fluorouracil, including forms to be used topically
  • capecitabine
  • floxuridine
  • tegafur
  • other 5-fluoropyrimidines
  • combinations of any of the above substances with other active ingredients.

Do not take Brivirac with medicines containing the active substance flucytosine used to treat fungal infections. Do not take Brivirac and contact your doctor immediately if:

  • is undergoing therapy based on any of the above medicines
  • you will be treated with any of the above medicines within 4 weeks after the end of treatment with Brivirac.

If you have accidentally taken Brivirac concomitantly with any of the medicines listed above:

  • stop taking both medicines
  • consult a doctor immediately. It may be necessary to go to the hospital for treatment.

Symptoms and signs of 5-fluorouracil toxicity due to the above interactions include:

  • malaise; diarrhea; inflammation of the mouth and / or the inner mucosa of the mouth; decreased number of white blood cells and bone marrow depression; rash and redness all over the body, with skin painful to the touch, followed by large blisters leading to large areas of skin exfoliation (toxic epidermal necrolysis) (see also section 4).
  • Post-marketing experience indicates a possible interaction of brivudine with dopaminergic drugs against Parkinson's disease, which may favor the onset of a chorea attack (abnormal, involuntary, dance-like movements, in particular of the arms, legs and face). Brivirac with food and drink You can take Brivirac with or without food.

Warnings It is important to know that:

Pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before using any medicine.

Do not use Brivirac during pregnancy.

Do not use Brivirac if you are breastfeeding. The active substance in Brivirac can pass to your baby through breast milk.

Driving and using machines

Dizziness and somnolence have been observed in some patients taking Brivirac, although uncommon. If you notice these side effects, do not drive vehicles, do not use machines or do any work without secure support. Ask your doctor for advice.

Brivirac contains lactose

This medicinal product contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Brivirac: Posology

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

The recommended dose is:

1 Brivirac 125 mg tablet once a day for 7 days.

Take the Brivirac tablet at about the same time each day.

Brivirac can be taken with or without food.

Swallow the tablet whole with a sufficient amount of liquid, e.g. a glass of water.

You should start treatment as soon as possible, which means that if possible you should start taking Brivirac:

  • within 3 days of the appearance of the first skin signs of St. Anthony's Fire (rash) or
  • within 2 days of the appearance of the first blisters.

Complete the 7 day treatment even if you feel better sooner.

If symptoms persist or worsen during the week of treatment, please contact your doctor.

Taking the usual dose of Brivirac reduces the risk of developing postherpetic neuralgia in patients over the age of 50. Postpetic neuralgia is persistent pain that develops in the area previously affected by shingles after the rash has improved.

Duration of treatment

This medicine is intended for short-term use. It should only be taken for 7 days. Do not take this medicine for a second course of treatment.

Use in children and adolescents

Do not take Brivirac if you are under 18 years old.

If you forget to take Brivirac

If you forget to take your tablet at your usual time, take it as soon as you remember. Take the next tablet the following day at about the same time as the previous day. Continue with the new dose until the end of the 7-course treatment cycle. days.

Do not take a double dose to make up for a forgotten tablet.

If you repeatedly forget to take your daily dose, please tell your doctor.

If you stop taking Brivirac

Do not stop taking Brivirac without consulting your doctor first. For the treatment to be fully effective, the medicine must be taken for 7 days. 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 too much Brivirac

If you take more tablets than you should, contact your doctor. He will decide if further measures are needed.

Side Effects What are the side effects of Brivirac

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

Stop taking Brivirac and tell your doctor immediately if you have an allergic reaction with signs and symptoms including itchy or red skin (rash), increased sweating, swelling (of the hands, feet, face, tongue, lips, eyelids or larynx ), difficulty in breathing (see also section 4) These symptoms can be severe and require urgent medical attention.

The following side effect has been observed commonly (may affect up to 1 in 10 patients):

  • nausea (malaise).

The following side effects have been observed uncommonly (may affect up to 1 in 100 patients):

  • a decrease in the number of a type of white blood cell (granulocytes)
  • an increase in the number of certain types of white blood cells (eosinophils, lymphocytes, monocytes)
  • a decrease in the number of red blood cells (anemia)
  • allergic reactions including:
    • itchy skin (itching)
    • redness of the skin (erythematous rash)
    • increased sweating
    • swelling of: hands, feet, face, tongue, lips, eyelids, larynx (larynx edema)
    • cough, difficulty in breathing and / or shortness of breath
  • lack of appetite
  • anxiety
  • insomnia, sleepiness
  • headache
  • dizziness
  • dizziness
  • abnormal sensations such as burning, numbness, tingling sensation, most frequently in the arms and legs (paraesthesia)
  • increased blood pressure
  • indigestion (dyspepsia), vomiting, stomach pain
  • diarrhea
  • excess gas in the stomach or intestines (flatulence)
  • constipation
  • chronic liver disease with accumulation of fat (fatty liver)
  • increase in blood levels of certain substances produced by the liver (increase in liver enzymes)
  • weakness, tiredness (fatigue)
  • flu-like symptoms (malaise, fever, aches and chills)

The following side effects have been rarely seen (may affect up to 1 in 1000 patients):

  • low blood pressure
  • decrease in the number of platelets in the blood
  • hallucinations, delirium
  • confusional state
  • tremor
  • altered sense of taste
  • ear pain
  • inflammation of the liver (hepatitis), increased bilirubin in the blood
  • bone pain

The following side effects have also been reported, although their frequency is not known (frequency cannot be estimated from the available data):

  • loss of balance
  • inflammation of blood vessels (vasculitis)
  • rapid onset liver failure
  • localized skin inflammation that occurs in the same place for a certain period of time (fixed rash), skin inflammation with exfoliation (exfoliative dermatitis), severe rash over the entire surface of the body and inside the mouth due to allergic reaction (erythema multiforme), ulceration of the skin, mouth, eyes and genital areas (Stevens Johnson syndrome).

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: http://www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can also help provide more information on safety. of this medicine.

Expiry and Retention

Keep out of the reach and sight of children.

Do not use this medicine after the expiry date which is stated on the carton and blister. The expiry date refers to the last day of that month.

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

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.

Deadline "> Other information

What Brivirac contains

The active ingredient is brivudine.

1 Brivirac tablet contains 125 mg of brivudine.

The other ingredients are:

  • microcrystalline cellulose
  • lactose monohydrate
  • povidone K 24-27
  • magnesium stearate

What Brivirac looks like and contents of the pack

Brivirac 125 mg tablets are round, flat, white or almost white with beveled edges.

The tablets are contained in a blister inside a box.

Brivirac is available in packs containing 1 and 7 tablets and in multipacks including 5 cartons, each containing 7 tablets.

Not all pack sizes may be marketed.

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.

Further information on Brivirac 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 interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 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 RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

BRIVIRAC 125 MG TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

1 tablet contains 125 mg of brivudine.

Excipient with known effect: lactose monohydrate. Each tablet contains 37 mg of lactose monohydrate.

For the full list of excipients, see section 6.1

03.0 PHARMACEUTICAL FORM -

Tablet

White or almost white flat tablets with beveled edges.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Early treatment of acute herpes zoster infections in immunocompetent adults.

04.2 Posology and method of administration -

Dosage

Adults: one Brivirac tablet once a day for seven days.

Treatment should begin as soon as possible, preferably within 72 hours of the appearance of the first skin manifestations (usually a "rash of onset") or 48 hours of the appearance of the first blister. The tablets should be taken at approximately the same time each day. If symptoms persist or worsen during the 7 days of treatment, the patient should be advised to seek medical attention. The product is intended for short-term use.

This treatment also reduces the risk of developing postherpetic neuralgia in patients over the age of 50 at the normal dosage indicated above (1 tablet of Brivirac once a day for 7 days).

After a first course of therapy (7 days) a second course should not be performed.

Special populations

Elderly patients

No dosage adjustment is necessary in patients over 65 years of age.

Patients with renal or hepatic impairment

As a consequence of renal or hepatic impairment, no significant changes are observed in systemic exposure to brivudine; therefore no dose adjustment is necessary in patients with moderate to severe renal impairment and in patients with moderate to severe hepatic impairment (see also paragraph 5.2).

Pediatric population

Brivirac is contraindicated in children aged 0-18 years as safety and efficacy in this age group have not been established (see section 4.3).

Method of administration

Oral use.

Food intake does not significantly affect the absorption of brivudine (see section 5.2).

04.3 Contraindications -

Brivirac must not be administered in case of hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients undergoing antineoplastic chemotherapy

The use of Brivirac is contraindicated in patients undergoing cancer chemotherapy, especially if treated with 5-fluorouracil (5 FU), including its topical preparations, its pro-drugs (eg capecitabine, floxuridine, tegafur) , and combinations containing these active substances, or other 5-fluoropyrimidines (see also sections 4.4 and 4.5).

Patients undergoing antifungal therapy with flucytosine

The use of Brivirac is contraindicated in patients undergoing antifungal therapy with flucytosine, as it is a pro-drug of 5-fluorouracil (5 FU).

Immunocompromised patients

The use of Brivirac is contraindicated in immunocompromised patients, such as patients undergoing antineoplastic chemotherapy, immunosuppressive therapy.

Children

The safety and efficacy of Brivirac in children have not been established, therefore its use is not indicated.

Pregnancy and breastfeeding

Brivirac is contraindicated during pregnancy or lactation (see also section 4.6).

04.4 Special warnings and appropriate precautions for use -

Brivirac and 5-fluorouracil, including its topical preparations or its pro-drugs (e.g. capecitabine, floxuridine, tegafur) or combinations containing these active substances, and other 5-fluoropyrimidines (e.g. flucytosine) not should be administered simultaneously and a minimum interval of 4 weeks should be observed before starting treatment with 5-fluoropyrimidine drugs. As an additional precaution, the activity of the DPD enzyme should be monitored before starting any treatment with 5-fluoropyrimidine drugs in patients who have recently been given Brivirac (see also sections 4.5 and 4.8).

Brivirac should not be used if the skin manifestations have already fully developed.

Brivirac should be used with caution in patients with chronic liver disease such as hepatitis. Post-marketing data indicate that prolonging treatment beyond the recommended duration of 7 days increases the risk of developing hepatitis (see also section 4.8).

Since lactose is present among the excipients, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take the drug.

04.5 Interactions with other medicinal products and other forms of interaction -

Contraindications for concomitant use of 5-fluorouracil (including its topical preparations and pro-drugs, eg capecitabine, floxuridine, tegafur) or other 5-fluoropyrimidines such as flucytosine (see also section 4.3).

This interaction, resulting in increased fluoropyrimidine toxicity, is potentially fatal.

Brivudine, through its main metabolite bromovinyluracil (BVU), exerts an "irreversible inhibition of dihydroxypyrimidine dehydrogenase (DPD), an enzyme that regulates the metabolism of both natural nucleosides (eg: thymidine) and pyrimidine-based drugs such as 5-fluorouracil (5-FU): As a consequence of inhibiting the enzyme, there is an overexposure and increased toxicity of 5-FU.

Clinical studies have shown that in healthy adults undergoing a course of Brivirac-based therapy (125 mg once a day for 7 days), complete functional recovery of the DPD enzyme activity occurs 18 days after the last administration.

Brivirac and 5-fluorouracil or other 5-fluoropyrimidines such as capecitabine, floxuridine, and tegafur (or combinations containing these active substances) or flucytosine should not be administered concurrently and a minimum interval of 4 weeks should be observed before starting drug treatment. based on 5-fluoropyrimidine. As an additional precaution, the activity of the DPD enzyme should be monitored before starting any treatment with 5-fluoropyrimidine drugs in patients who have recently been given Brivirac.

In the event of accidental administration of 5-FU or related drugs to patients treated with Brivirac, both drugs should be discontinued and drastic measures to reduce the toxicity of 5-FU should be implemented. Immediate hospitalization is recommended and all measures must be taken to prevent systemic infections and dehydration. Signs of 5-FU toxicity include nausea, vomiting, diarrhea and in severe cases stomatitis, mucositis, toxic epidermal necrolysis, neutropenia and bone marrow depression.

Dopaminergic drugs and / or Parkinson's disease

Post-marketing experience indicates a possible interaction of brivudine with dopaminergic drugs against Parkinson's disease such as to precipitate chorea.

Other information

No induction or inhibition potential of the hepatic P450 enzyme system has been demonstrated.

Food intake does not significantly alter the absorption of brivudine.

04.6 Pregnancy and breastfeeding -

Brivirac is contraindicated during pregnancy or in women who are breastfeeding.

Studies in animals have not shown embryotoxic or teratogenic effects. Toxic effects on the fetus were observed only at high doses. However, the safety of Brivirac in pregnant women has not been established.

Animal studies have shown that brivudine and its major metabolite bromovinyluracil (BVU) are excreted in milk.

04.7 Effects on ability to drive and use machines -

There are no studies on the effect of Brivirac on the ability to drive or use machines. When driving vehicles, operating machines or working without a secure foothold, it should be taken into account that dizziness and somnolence have been reported in some cases (see section 4.8).

04.8 Undesirable effects -

Summary of the safety profile

Brivudine has been administered to more than 3900 patients in clinical trials. The most serious, but rare, reaction was hepatitis. This reaction has also been observed during post-marketing surveillance.

The only common adverse reaction was nausea (2.1%). The other most frequent (uncommon and rare) adverse reactions were those related to the nervous system and psychiatric disorders SOC. An effect of brivudine on the CNS was also evidenced by post-marketing surveillance data.

Skin and subcutaneous tissue disorders have been observed during clinical use of the product, also highlighted by post-marketing surveillance data.

The incidence and type of undesirable reactions were comparable to those known to occur with other nucleoside antiviral agents belonging to the same class.

Summary table of adverse reactions

The table below lists the adverse reactions to brivudine grouped by system in order of decreasing severity.

System / organ classification Common (≥1 / 100, Uncommon (≥ 1 / 1,000 to Rare (≥ 1 / 10,000, Not known (frequency cannot be estimated from the available data) Disorders of the blood and lymphatic system granulocytopenia, eosinophilia, anemia, lymphocytosis, monocytosis thrombocytopenia Disorders of the immune system allergic / hypersensitivity reactions (peripheral edema and edema of the tongue, lips, eyelids, larynx and face, itching, rash, increased sweating, cough, dyspnoea, bronchoconstriction) Metabolism and nutrition disorders anorexia Psychiatric disorders insomnia, anxiety hallucinations, confusional state Nervous system disorders headache, dizziness, vertigo, somnolence, paraesthesia dysgeusia, tremor balance disorders Ear and labyrinth disorders ear pain Vascular pathologies hypertension hypotension vasculitis Gastrointestinal disorders nausea vomiting, diarrhea, dyspepsia, abdominal pain, constipation, flatulence Hepato-biliary disorders fatty liver, increased liver enzymes hepatitis, increased bilirubin in the blood acute liver failure Skin and subcutaneous tissue disorders fixed rash, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome Disorders of the musculoskeletal system bone pain General disorders and administration site conditions asthenia, fatigue, flu-like illness (malaise, fever, aches, chills)

Description of selected adverse reactions

Brivudine may interact with chemotherapeutic agents of the 5-fluoropyrimidine class. This interaction, which induces increased fluoropyrimidine toxicity, is potentially fatal (see also 4.4 and 4.5).

Signs of 5-FU toxicity include nausea, vomiting, diarrhea and, in severe cases, stomatitis, mucositis, toxic epidermal necrolysis, neutropenia and bone marrow depression (see also section 4.5).

Hepatotoxic effects have occurred both in clinical trials and during post-marketing experience. These effects consist of cholestatic or cytolytic hepatitis, cholestatic jaundice or elevated liver enzymes. Most cases of hepatitis started from 3 to 28 days after the 7-day end of treatment. Post-marketing data indicate that prolonging treatment beyond the recommended 7-day period increases the risk of hepatitis.

Pediatric population

Brivudine has not been studied in the pediatric population and its use in children is not indicated. Therefore the safety profile in the pediatric population is unknown.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose -

Acute overdose with Brivirac has not been reported so far. Following intentional or accidental overdose, appropriate symptomatic and supportive therapy should be instituted.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Antiviral

ATC code J05AB15

Brivudine, the active substance in Brivirac, is one of the strongest nucleoside analogues that inhibits the replication of the Varicella Zoster virus (VZV). Particularly sensitive are the clinical strains of the VZV. In virus-infected cells, brivudine undergoes a series of successive phosphorylations that produce brivudine triphosphate, which is responsible for inhibiting viral replication. The intracellular conversion of brivudine into its phosphorylated derivatives is catalyzed by virus-encoded enzymes, mainly thymidine kinase. phosphorylation occurs only in infected cells, which explains the high selectivity of brivudine for viral targets. Brivudine triphosphate, once formed in virus infected cells, remains inside the cells for more than 10 hours and interacts with viral DNA polymerase. This interaction results in potent inhibition of viral replication. The resistance mechanism is based. on viral thymidine kinase (TK) deficiency. However, in clinical practice, the requirements for resistance are chronic antiviral treatment and patient immunodeficiency, both of which are unlikely to occur with the indicated indications and posology.

The concentration of brivudine capable of inhibiting viral replication in vitro (IC50) corresponds to 0.001 mcg / ml (range 0.0003 - 0.003 mcg / ml). Thus, brivudine is approximately 200 to 1000 times more potent than aciclovir and penciclovir in inhibiting VZV replication in vitro. The maximum plasma concentration (Cssmax) of brivudine of individuals who received the proposed dose (125 mg once per day) is 1.7 mcg / ml (ie 1000 times the IC50 "in vitro") and the minimum concentration (Cssmin) is 0.06 mcg / ml (ie at least 60 times the IC50). Brivudine had an onset of action very rapid under conditions of high viral growth, reaching 50% inhibition of viral replication within 1 h of drug exposure. Brivudine also exhibits antiviral activity in experimental animals infected with Simian virus (monkeys) or herpes simplex virus type I (mice and guinea pigs). Brivudine is active against herpes simplex virus type I, while it does not significant antiviral activity against herpes simplex type II.

Inhibition of virus replication underlines the efficacy of Brivirac, in patients with the initial stage of herpes zoster, in accelerating the resolution of skin manifestations. The high in vitro antiviral potency of brivudine is reflected in the superior clinical efficacy observed in comparative clinical studies with aciclovir, regarding the time period from the start of treatment to the last vesicular eruption: the mean time was reduced by 25% with brivudine (13.5 hours) compared to aciclovir (18 hours).

In addition, the relative risk of developing postherpetic neuralgia (PHN) in immunocompetent patients over the age of 50 who were treated for herpes zoster with brivudine was 25% lower (33% of patients reported PHN ) compared to aciclovir (43% of patients reported PHN).

05.2 "Pharmacokinetic properties -

Absorption

Brivudine is rapidly absorbed following oral administration of Brivirac. The bioavailability of brivudine is approximately 30% of the oral dose of Brivirac, due to an elevated first pass metabolism. The mean peak steady state plasma concentrations of brivudine following administration of an oral dose of 125 mg of Brivirac is 1.7 μg / ml and is reached 1 h post dose. Food intake slightly delays the absorption of brivudine but does not affect the total amount of drug absorbed.

Distribution

Brivudine distributes extensively into tissues as indicated by the high volume of distribution (75 L). Brivudine is highly bound to plasma proteins (> 95%).

Biotransformation

Brivudine is extensively and rapidly metabolised by the enzyme pyrimidine phosphorylase which cleaves the carbohydrate to give bromovinyl uracil (BVU), a metabolite with no virustatic activity. BVU is the only metabolite detected in human plasma and its peak concentration. plasma is a factor of two higher than that of the parent compound.

BVU is further metabolised to uracylacetic acid, the major polar metabolite detected in human urine but not detectable in plasma.

Elimination

Brivudine is effectively eliminated with a total body clearance of 240 mL / min. The terminal plasma half-life of brivudine is approximately 16 h. Brivudine is excreted in the urine (65% of the administered dose) primarily as uracylacetic acid and multiple polar urea-like compounds. Unchanged brivudine accounts for less than 1% of the dose. of Brivirac excreted in the urine. The kinetic parameters of BVU, in terms of terminal half-life and clearance are of the same order of magnitude as the parent compound.

Linearity / non-linearity

Linear kinetics were observed over the dose range of 31.25 to 125 mg.

Steady state conditions for brivudine are reached after 5 days of daily administration of Brivirac, with no indication of further subsequent accumulation.

Elderly patients and patients with renal or hepatic impairment

The main kinetic parameters (AUC, Cmax and terminal plasma half-life) of brivudine measured in elderly patients and in patients with moderate to severe renal impairment (creatinine clearance between 26 and 50ml / min / 1.73m² of body surface area and creatinine clearance

05.3 Preclinical safety data -

Non-clinical data reveal no special hazard for humans for short-term use based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential, reproductive toxicity.

Preclinical effects of acute and chronic toxicity were observed in short-term studies at exposures considered sufficiently in excess of the maximum human exposure. Data collected from long-term animal studies, with daily drug exposure close to the clinical range, were not considered significant for short-term treatment in humans. The target organ of toxicity in all species used for preclinical studies was the liver.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Microcrystalline cellulose, lactose monohydrate, povidone K 24-27, magnesium stearate.

06.2 Incompatibility "-

Not relevant.

06.3 Period of validity "-

3 years.

06.4 Special precautions for storage -

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

06.5 Nature of the immediate packaging and contents of the package -

a) Nature of the container

Rigid opaque PVC film blister and aluminum foil.

b) Contents of the container

Original pack with 7 tablets.

Hospital pack with 35 (5 x 7) tablets.

Sample pack with 1 tablet.

Not all pack sizes may be marketed.

06.6 Instructions for use and handling -

Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

Laboratori Guidotti S.p.A. - Via Livornese 897, Pisa - La Vettola

Dealer for sale: A. Menarini Industrie Farmaceutiche Riunite s.r.l. - Via Sette Santi 3, Florence

08.0 MARKETING AUTHORIZATION NUMBER -

AIC n. 035720010 - "125 mg tablets" 7 tablets in PVC / AL blister

AIC n. 035720022 - "125 mg tablets" 35 (5x7) tablets in PVC / AL blister

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

Date of first authorization: 06/07/2000

Date of the most recent renewal: 06/07/2015

10.0 DATE OF REVISION OF THE TEXT -

February 2016

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -

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