SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 125 mg brivudine.
Excipient with known effect: Each tablet contains 33 mg lactose-monohydrate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
4.2 Posology and method of administration
Posology
Adults take one tablet
The treatment should be initiated as soon as possible, preferably within 72 hours after onset of the skin symptoms (generally zoster rash) or 48 hours after onset of skin blisters. Tablets should be taken at approximately the same time each day.
If the symptoms persist or worsen during the 7-day treatment, the patient should be advised to consult a doctor.
This treatment additionally reduces the risk of developing post-zoster neuralgia in patients over 50 years of age at the usual above-mentioned dosage (once a day 1 tablet
After a first treatment cycle of 7 days, a second cycle should not be performed.
1 Special populations
Elderly Dose adjustment is not required in patients over 65 years.
Hepatic or renal impairment No significant changes in systemic exposure to brivudine were observed as consequence of hepatic or renal impairment; Therefore, no dose adjustment is required in patients with moderate to severe hepatic or renal impairment (see also section 5.2).
Paediatric population
Method of administration
Oral use Food intake does not significantly affect the absorption of brivudine (see section 5.2).
4.3 Contraindications
Cancer chemotherapy with fluoropyrimidines Brivudine is contraindicated in patients who recently received or are currently receiving or are planned to receive (within 4 weeks) cancer chemotherapy with medicines containing 5-fluorouracil (5-FU) including also its topical preparations , its prodrugs (e.g. capecitabine, tegafur) and combination products containing these active substances or other fluoropyrimidines (see also sections 4.3 Immunocompromised patients, 4.4, 4.5 and 4.8).
Anti-fungal therapy with flucytosine Brivudine is contraindicated in patients who recently received or are currently receiving antifungal therapy with flucytosine because it is a prodrug of 5-fluorouracil (5-FU) (see also sections 4.4, 4.5 and 4.8).
The interaction between brivudine and fluoropyrimidines (e.g. capecitabine, 5-FU, etc.) is potentially fatal (see sections 4.4, 4.5 and 4.8).
Immunocompromised patients Brivudine is contraindicated in immunocompromised patients such as those who recently received or are currently receiving cancer chemotherapy or patients under immunosuppressive therapy.
Children Safety and efficacy of brivudine in children have not been established and therefore its use is not indicated.
Hypersensitivity Brivudine must not be administered in case of hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Pregnancy and lactation Brivudine is contraindicated during pregnancy or in nursing mothers (see section 4.6).
2 4.4 Special warnings and precautions for use
Brivudine must not be administered in patients who recently received or are currently
receiving or are planned to receive (within 4 weeks) cancer chemotherapy with medicines
containing 5-fluorouracil (5-FU), including also its topical preparations, its prodrugs (e.g.
capecitabine, tegafur) and combination products containing these active substances or other
fluoropyrimidines (see also sections 4.3, 4.5 and 4.8).
Brivudine must not be administered in patients who recently received or are currently
receiving antifungal therapy with flucytosine (a prodrug of 5-fluorouracil).
The interaction between brivudine and fluoropyrimidines (e.g. capecitabine, 5-FU, tegafur, flucytosine, etc.) is potentially fatal. Fatal cases have been reported following this drug interaction. There must be at least a 4-week waiting period between end of treatment with brivudine and start of fluoropyrimidines (e.g. capecitabine, 5-FU, tegafur, flucytosine, etc.) therapy (see sections 4.3, 4.5 and 4.8).
In the event of accidental administration of brivudine in patients who recently received or are currently receiving fluoropyrimidines, all drugs must be discontinued, and effective measures must be taken to reduce the toxicity of the fluoropyrimidine drugs: Immediate admission to hospital and all measures to prevent systemic infections and dehydration. Special centres for poisoning (if available) have to be contacted as soon as possible to find appropriate action against fluoropyrimidine toxicity (see sections 4.3, 4.5 and 4.8).
Brivudine is not to be used if cutaneous manifestations are already fully developed. Brivudine should be used with caution in patients with chronic liver diseases such as hepatitis. Post- marketing data indicate that extending treatment over the recommended duration of 7 days increases the risk for development of hepatitis (see also section 4.8).
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
A clinically significant interaction (potentially fatal) between brivudine and fluoropyrimidines (e.g. capecitabine, 5-FU, tegafur, flucytosine, etc.) has been described (see also sections 4.3, 4.4 and4.8). This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal.
Brivudine, through its main metabolite bromovinyl uracil (BVU), exerts an irreversible inhibition of dihydropyrimidine dehydrogenase (DPD), an enzyme which regulates the metabolism of both natural nucleosides (e.g. thymidine) and pyrimidine-based drugs (fluoropyrimidines) such as capecitabine or 5-fluorouracil (5-FU). As a consequence of the enzyme inhibition, overexposure and enhanced toxicity to fluoropyrimidines occur.
Clinical evidence has shown that, in healthy adults receiving therapeutic course of brivudine (125 mg brivudine once a day for 7 days), complete functional recovery of DPD enzyme activity occurs after 18 days from last dosing.
Anyway, brivudine must not be administered in patients who recently received or are currently receiving or are planned to receive (within 4 weeks) cancer chemotherapy with medicines containing 5-fluorouracil (5-FU) including also its topical preparations, its prodrugs (e.g. capecitabine, tegafur)
3 and combination products containing these active substances or other fluoropyrimidines (see also sections 4.3, 4.4 and 4.8).
Brivudine must not be administered in patients who recently received or are currently receiving anti- fungal therapy with flucytosine (a prodrug of 5-fluorouracil).
A minimum 4 weeks interval must be observed between end of treatment with brivudine and starting treatment with capecitabine or other fluoropyrimidine drugs including flucytosine.
In the event of accidental administration of brivudine in patients that recently received or are currently receiving fluoropyrimidines, all drugs must be discontinued and effective measures must be taken to reduce the toxicity of the fluoropyrimidine drugs: Immediate admission to hospital and all measures to prevent systemic infections and dehydration. Special centres for poisoning haveto be contacted (if available) as soon as possible to find appropriate action against fluoropyrimidine toxicity (see sections 4.3, 4.4 and 4.8). Signs of fluoropyrimidine drugs toxicity include nausea, vomiting, diarrhoea, and in severe cases stomatitis, mucositis, toxic epidermal necrolysis, neutropenia and bone marrow depression.
Dopaminergic drugs and / or Parkinson's disease Post marketing experiences indicates a possible interaction of brivudine with anti-Parkinson dopaminergic drugs to precipitate chorea.
Other interactions No potential or induction or inhibition of the liver P450 enzyme system has been demonstrated.
Food intake does not significantly affect the absorption of brivudine.
4.6 Fertility, pregnancy and lactation
Pregnancy and breast-feeding
Animal studies have not shown any embryotoxic or teratogenic effects. Foetotoxic effects were only seen at high doses. However, the safety of
Animal studies have shown that brivudine and its main metabolite bromvinyluracil (BVU) pass into breast milk.
4.7 Effects on ability to drive and use machines
There are no studies on the effects of
4.8 Undesirable effects
Summary of the safety profile
Brivudine has been administered in clinical trials to over 3900 patients. The most serious, but rarely occurring was hepatitis. This side effect has been also recorded during post-marketing surveillance.
4 The only common adverse reaction was nausea (2.1%). The next most frequent adverse reactions (uncommon and rare) were those pertaining to the nervous system and psychiatric disorders SOC. An effect of brivudine on the CNS is also apparent from the post marketing surveillance data.
Skin and subcutaneous tissue disorders have been relevant during clinical use of the product, as is also apparent from the post marketing surveillance data.
Tabulated list of adverse reactions
The table below lists the adverse drug reactions to brivudine by system organ classes of decreasing seriousness.
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System organ class Common Uncommon Rare Not known (≥ 1/100 (≥ 1/1000 to < 1/100) (≥ 1/10000 to (cannot be estimated to <1/10) <1/1000) from the available data) Blood and lymphatic Granulocytopenia, Thrombocytopenia system disorders Eosinophilia, Anaemia, Lymphocytosis, Monocytosis
Immune system Allergic / hypersensitivity disorders reactions (peripheral edema and edema of tongue, lips, eyelid, larynx and face, pruritus, skin rash, increased perspiration, cough, dyspnea, bronchoconstriction)
Metabolism and anorexia nutrition disorders Psychiatric disorders Insomnia, Anxiety Hallucinations, disorder Confusional state
Nervous system Headache, Dizziness, Dysgeusia, Balance disorder disorders Vertigo, Somnolence, Tremor Paraesthesia Ear and labyrinth Ear pain disorders Vascular disorders Hypertension Hypotension Vasculitis Gastrointestinal Nausea Vomiting, Diarrhoea, disorders Dyspepsia, Abdominal pain, Constipation, Flatulence Hepatobiliary Fatty liver, hepatic Hepatitis, blood Acute liver failure disorders enzymes increased Bilirubin increased Skin and Fixed Exanthem, subcutaneous tissue exfoliative Dermatitis, disorders Erythema multiforme, Stevens-Johnson- Syndrome Musculoskeletal and Bone pain connective tissue disorders General disorders and Asthenia, Fatigue, administration site Flu-like illness (Malaise, conditions Fever, Pain, Chills)
Description of selected adverse reactions
Brivudine can interact with chemotherapeutic agents of the fluoropyrimidine class. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal (see also sections 4.3, 4.4 and 4.5).
Signs of fluoropyrimidine drugs toxicity include nausea, vomiting, diarrhoea, and in severe cases, stomatitis, mucositis, toxic epidermal necrolysis, neutropenia and bone marrow depression (see also sections 4.3, 4.4 and 4.5).
6 Hepatotoxic effects have occurred both in clinical trials and during post-marketing surveillance. These effects consist in either cholestatic or cytolytic hepatitis, cholestatic icterus, or elevation of liver enzymes. Most cases of hepatitis had onset in between 3 and 28 days after the end of the 7-day treatment. Post marketing data indicate that extending the treatment over the recommended 7 days increases the risk of hepatitis.
Paediatric population Brivudine has not been studied and it is not indicated in children. Therefore, the safety profile in the pediatric population is unknown.
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 national reporting system listed in Appendix V.
4.9 Overdose
To date, no acute over dose with
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiviral for systemic use Nucleosides and nucleotides excluding reverse transcriptase inhibitors ATC code: J05AB15
Brivudine, the active substance of
In virus-infected cells, brivudine undergoes a series of sequential phosphorylations yielding brivudine triphosphate which is responsible for the inhibition viral replication. Intracellular transformation of brivudine into phosphorylated derivatives is catalyzed by viral encoded enzymes, mainly thymidine kinase. Phosphorylation occurs only in infected cells, explaining the high selectivity of brivudine toward viral targets. Brivudine triphosphate, once formed in virus infected cells, persists intracellularly for more than 10 hours and interacts with the viral DNA polymerase. This interaction results in the potent inhibition of viral replication.
The mechanism of resistance is based on the deficiency of the viral thymidine kinase (TK). However, in the clinical setting requisites for resistance are the, chronic antiviral therapy and patient immunodeficiency of the patients, both conditions which are unlikely to occur under the claimed indications.
The Brivudine concentration capable of inhibiting in-vitro viral replication(IC50) corresponds to 0.001 μg/ ml (0.0003 - 0.003 μg/ ml). Thus, brivudine is approximately 200 to 1000-fold more potent than aciclovir and penciclovir in inhibiting in vitro VZV replication. Brivudine plasma concentrations in humans receiving the recommended dosage of 125 mg once a day, are at peak (CSSmax) of 1.7 μg/ ml (i.e. 1000-fold in vitro IC50) and reach the minimum concentrations (CSSmin) of 0,06 μg/ ml (i.e. the 60-fold IC50 value). Brivudine has a very fast onset of action in conditions of florid viral growth, reaching 50% inhibition of viral replication within 1 h of exposure to the drug.
7 Brivudine shows antiviral activity also in experimental animals infected either by Simian virus (monkey) or herpes simplex virus type 1 (mice and guinea pigs). Brivudine is active against herpes simplex virus type 1, while it has no significant antiviral activity against herpes simplex virus type 2.
The inhibition of viral replication underlies the efficacy of
5.2 Pharmacokinetic properties
Absorption Brivudine is rapidly absorbed after oral
Distribution Brivudine is extensivelydistributed in tissues as indicated by the large volume of distribution (75 l). Brivudine is markedly bound (> 95%) to plasma proteins.
Biotransformation Brivudine is rapidly metabolised through the enzyme pyrimidine phosphorylase, which cleaves the sugar moiety giving rise to bromovinyl uracil (BVU), a metabolite devoid of virustatic activity. BVU is the only metabolite detected in plasma of man and its peak plasma concentration exceeds by a factor of two that of the parent compound. BVU is further metabolised to uracil acetic acid, the principal polar metabolite found in urine of man but undetectable in plasma.
Elimination Brivudine is efficiently excreted with a total body clearance of 240 ml/ min. The terminal half-life in plasma of brivudine is approximately 16 hours. Brivudine is eliminated with the urine (65% of the administered dose), mainly as uracil acetic acid and more polar urea-like compounds.
Unchanged brivudine represents less than 1% of the
Linearity/non-linearity A linear kinetics was observed within the dosage range 31.25 - 125 mg. The steady state conditions of brivudine are reached after 5 days of daily
Elderly and patients with renal and hepatic impairment The main kinetic parameters (AUC, Cmax, and terminal half-life) of brivudine measured in the elderly as well as in patients with moderate or severe renal impairment (creatinine clearance ranged 26 to 50 ml/min /1.73 m2 body surface area and < 25 ml/min/1.73 m2 of body surface area, respectively) and in
8 patients with moderate to severe liver impairment (Child-Pugh Class B-C) are comparable to those control subjects. Therefore, in these cases no dose adjustment is required.
5.3 Preclinical safety data
Pre-clinical data reveal no special hazard for short-term use in humans based on conventional studies of safety pharmacology, genotoxicity, toxicity to reproduction and carcinogenic potential.
Preclinical effects for acute and chronic toxicity were observed in short term studies at exposure considered sufficiently in exceed of the maximum human exposure. The data collected from long-term studies in animals at daily drug exposure close to the clinical range are not considered to have significance for short-term treatment in humans. The target organ for toxicity in all species used in preclinical studies was the liver.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose Lactose monohydrate Crospovidone (type B) Povidone K 30 Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months
6.4 Special precautions for storage
This medical product does not require any special temperature storage conditions. Keep the blister in the outer carton in order to protect from light.
6.5 Nature and contents of container
White PVC aluminium blister containing 7 tablets per blister.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: {DD month YYYY}
[To be completed nationally]
10. DATE OF REVISION OF THE TEXT
[To be completed nationally] {MM/YYYY}
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