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Vancomycin Capsules 250mg

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Vancomycin Capsules 250mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Vancomycin 250 mg (250,000 IU) per capsule as vancomycin hydrochloride.

3    PHARMACEUTICAL FORM

Capsules

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Staphylococcal enterocolitis and pseudomembranous colitis due to Clostridium difficile.

Vancomycin is not significantly absorbed from the normal gastrointestinal tract and is therefore not effective by the oral route for other types of infection.

4.2    Posology and method of administration

Posology

Adults and the elderly: The usual daily dose is 500 mg in divided doses for 7 to 10 days. In severe cases up to 2 g daily in 3 or 4 divided doses. The total daily dosage should not exceed 2 g.

Children: The required dose will depend on their weight. The usual dose is 40 mg/kg daily in 3 or 4 divided doses for 7 to 10 days. The total daily dosage should not exceed 2 g.

Method of administration

For oral administration.

The capsules must be swallowed whole.

4.3    Contraindications

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

4.4 Special warnings and precautions for use

Although in general very little vancomycin is absorbed from the gastrointestinal tract following oral administration, absorption may be enhanced in patients with inflammatory disorders of the intestinal mucosa. These patients may be at risk for the development of adverse reactions. The risk is greater in patients with renal impairment. The greater the renal impairment, the greater the risk of developing the adverse reactions associated with the parenteral administration of vancomycin.

Monitoring of serum concentrations of these patients should therefore be performed. It should be noted that the total systemic and renal clearances of vancomycin are reduced in the elderly

Nephrotoxicity: Nephrotoxicity has occurred in patients receiving vancomycin. It has been reported mostly in patients who have been given excessive intravenous doses, have a pre-existing kidney dysfunction, or are receiving concomitant treatment with an aminoglycoside. In order to minimise the risk of nephrotoxicity when treating patients with underlying renal dysfunction or patients receiving concomitant therapy with an aminoglycoside, serial monitoring of renal function should be performed.

Ototoxicity: Ototoxicity has occurred in patients receiving vancomycin. It may be transient or permanent. It has been reported mostly in patients who have been given excessive intravenous doses, have a pre-existing hearing loss, or are receiving concomitant treatment with an ototoxic drug. Serial tests of auditory function may be helpful in order to minimise the risk of ototoxicity.

Prolonged use of vancomycin may result in the overgrowth of non-susceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

4.5 Interaction with other medicinal products and other forms of interaction

Since there is a risk for systemic absorption (see section 4.4), concomitant and/or subsequent systemic or topical use of other potentially ototoxic and/or nephrotoxic medicinal products should be monitored with great care.

Parenteral administration of vancomycin and anesthetics may cause erythema and anaphylactic reactions.

Some antibiotics were rarely reported to reduce the effect of oral contraceptives by interfering with the bacterial hydrolysis of conjugated steroids in the intestine and thus reabsorption of unconjugated steroid. This would lower the plasma levels of active steroid. This unusual interaction would occur in women with high excretion of conjugated steroids in bile.

4.6 Fertility, pregnancy and lactation

Pregnancy: There is insufficient experience on the use of Vancomycin during pregnancy. The safe use of vancomycin during pregnancy has not been established.

Reproductive studies in animals at doses equivalent to the clinical dose based on body surface area (mg/m3), do not indicate any direct or indirect effects on embryonic development, foetus or gestation.

Vancomycin should only be administered to pregnant women after a careful benefit-risk assessment.

Breastfeeding: Vancomycin is secreted in breast milk and should therefore only be used during lactation if other antibiotics have failed. It is recommended to stop breastfeeding during vancomycin treatment.

Fertility: No definitive fertility studies have been conducted.

4.7 Effects on ability to drive and use machines

Vertigo and dizziness have been reported rarely, and may affect the ability to drive and use machines.

4.8 Undesirable effects

Since vancomycin is not usually significantly absorbed from the gastrointestinal tract, the adverse reactions encountered with parenteral therapy are unlikely to occur after oral administration. However, due to damaged intestinal mucous membranes, some absorption may take place and adverse effects typical of vancomycin administered parenterally may occur. Therefore, the below mentioned undesirable effects related to parenteral use have been included.

The following adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined 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).

Blood and the lymphatic system disorder:

Rare (> 1/10,000 to <1/1,000): Reversible neutropenia, usually starting one week or more after onset of intravenous therapy or after a total dose of more than 25 g, agranulocytoses (granulocyte count less than 500/mm3), eosinophilia, thrombocytopenia, pancytopenia.

Ear and labyrinth disorders:

Rare (> 1/10,000 to <1/1,000): Vertigo, Tinnitus, dizziness.

Very rare (<1/10,000): Transient or permanent loss of hearing

Tinnitus, possibly preceding onset of deafness, should be regarded as an indication to discontinue treatment.

Cardiac disorders:

Very rare (<1/10,000): Cardiac arrest.

Vascular disorders:

Common (>1/100 to <1/10): Decrease in blood pressure.

Respiratory, thoracic and mediastinal disorders:

Common (>1/100 to <1/10): Dyspnoea.

Rare (> 1/10,000 to <1/1,000): Stridor, Shortness of breath.

Not known (cannot be estimated from the available data): Wheezing.

Gastrointestinal disorders:

Rare (> 1/10,000 to <1/1,000): Nausea.

Very rare (<1/10,000): Pseudomembranous enterocolitis.

Skin and subcutaneous tissue disorders:

Common (>1/100 to <1/10): Flushing of the upper body (“red man syndrome”), Exanthema and mucosal inflammation, pruritus, urticaria.

Very rare (<1/10,000): Exfoliative dermatitis, Stevens-Johnson syndrome, Toxic epidermal necrolysis, vasculitis.

Not known (cannot be estimated from the available data): Linear IgA bullous dermatosis. If a bullous disorder is suspected, the drug should be discontinued and specialist dermatological assessment should be carried out.

Renal and urinary disorders:

Common (>1/100 to <1/10): Renal insufficiency manifested primarily by increased serum creatinine or blood urea concentrations.

Rare (> 1/10,000 to < 1/1,000): Interstitial nephritis, acute renal failure.

Intertistial nephritis occurred mostly in patients who were given aminoglycosides concomitantly or who had pre-existing kidney dysfunction. When vancomycin was discontinued, azotaemia resolved in most patients.

General disorders and administration site conditions:

Common (>1/100 to <1/10): Redness of the upper body and the face.

Rare (> 1/10,000 to < 1/1,000): Drug fever, shivering. Pain in the chest and back muscles.

Immune system disorder:

Not known (cannot be estimated from the available data): Anaphylaxis. Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) has been reported during postmarketing experience.

Otoxicity has primarily been reported in patients given high doses, or in patients with concomitant treatment with other ototoxic medicinal product, or in patients with a pre-existing reduction in kidney function or hearing.

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

Toxicity: Limited experience in overdose, however, 500mg IV given to a 2-year-old lead to lethal intoxication. 56g spread over 10 days to an adult caused renal insufficiency.

Symptoms: Overdose may cause nausea, vomiting, epigastric discomfort and diarrhea. Possible symptoms that have been reported as side effects (see section 4.8) are exacerbated at overdose.

Effects on renal function may occur.

Treatment: Gastric lavage, charcoal in repeated doses (reducing half-life). Ensure adequate diuresis.

Vancomycin is poorly removed from plasma by means of dialysis. An increased clearance of vancomycin by high-flux hemodialysis, hemofiltration or hemoperfusion with polysulfon resin has been reported.

Symptomatic treatment.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: intestinal antiinfective, antibiotics, ATC code: A 07 AA 09

Mechanism of action: Vancomycin is a tricyclic glycopeptide antibiotic with a molecular weight of 1449. Vancomycin base 1 g corresponds to 0.67 mmol. Among other actions, vancomycin exerts its effect by blocking the synthesis of the bacterial cell wall at an earlier stage than do beta-lactam antibiotics. In addition, vancomycin may alter bacterial cell membrane permeability and RNA synthesis.

Mechanism(s) of resistance: Acquired resistance to glycopeptides is most common in enterococci and is based on acquisition of various van gene complexes which modifies the D-alanyl-D-alanine target to D-alanyl-D-lactate or D-alanyl-D-serine which bind vancomycin poorly. In some countries, increasing cases of resistance are observed in enterococci; multiresistant strains of Enterococcus faecium are especially alarming.

Van genes have rarely been found in Staphylococcus aureus, where changes in cell wall structure result in “intermediate” susceptibility, which is most commonly heterogeneous.

There is no cross-resistance between vancomycin and other classes of antibiotics. Cross-resistance with other glycopeptide antibiotics, such as teicoplanin, does occur. Secondary development of resistance during therapy is rare.

Vancomycin is active mainly against gram-positive aerobic and anaerobic bacteria. Clostridium difficile is sensitive to orally administered vancomycin. Vancomycin is not active in vitro against Gram-negative bacilli, mycobacteria or fungi.

The emergence of resistance towards vancomycin differs from one hospital to another and a local microbiological laboratory should therefore be contacted for relevant local information.

5.2    Pharmacokinetic properties

Vancomycin is not normally absorbed from the gastro-intestinal tract, but in patients with inflammatory disorders of the intestinal mucosa some systemic absorption may occur. The orally administered drug is active only locally within the gut lumen, making it useful in enterocolitis. An oral dose is excreted exclusively in the faeces.

During multiple dosing of 250mg every 8 hours for 7 doses, faecal concentrations of vancomycin, in volunteers, exceeded 100mg/kg in the majority of samples. No blood concentrations were detected and urinary recovery did not exceed 0.76%.

5.3    Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.

Administration of vancomycin oral solution, 2 g daily for 16 days to anephric patients with no inflammatory bowel disease, gave measurable serum levels of >0.66 pg/ml in 2 out of 5 patients. With doses of 2 g daily, concentrations of >3,100 mg/kg were found in the faeces and levels of <1 pg/ml were found in the serum of patients with normal renal function who had pseudomembranous colitis.

Following parenteral administration vancomycin is excreted renally, nearly completely as the microbiologically active substance. The serum half-life in adult patients with normal renal function has been reported to be about 4-6 hours, in children 2.2-3 hours. Impaired renal function can prolong the elimination (up to 7.5 days).

Mutagenic and tumorigenic potential: Vancomycin was only limitedly tested with regard to mutagenic effect. Tests performed so far yielded negative results. Fertility studies and long-term investigations in animals with regard to evaluate carcinogenic potential are not available.

Teratogenic potential: In teratogenic studies, where rats and rabbits received doses approximately corresponding to the human dose based on body surface (mg/m3), no direct or indirect teratogenic effects were observed.

Animal studies of the use during the perinatal/postnatal period and regarding effects on fertility are not available.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Polyethylene glycol 6000.

Capsule: Black iron oxide E-172, titanium dioxide E-171, yellow iron oxide E-172, Indigo carmine E-132, gelatin.

Printing ink on the capsules: Shellac, propylene glycol, sodium hydroxide, povidone, titanium dioxide E-171.

6.2    Incompatibilities

Not applicable

6.3    Shelf life

2 years

6.4    Special precautions for storage

Room temperature (15-25°C). Protect from moisture.

6.5    Nature and contents of container

Unit dose blister packs of PVC/PE/PCTFE on aluminium foil.

Pack size: 28 capsules.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Xellia Pharmaceuticals ApS Dalslandsgade 11,

2300 Copenhagen S Denmark

8    MARKETING AUTHORISATION NUMBER(S)

PL 17815/0042

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/08/1996

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DATE OF REVISION OF THE TEXT

10/11/2015