SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Sodium Fusidate 500 mg for Intravenous Infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Sodium Fusidate 500 mg (equivalent to 480 mg fusidic acid) contained in one vial. (The second vial contains buffer solution).

3    PHARMACEUTICAL FORM

Powder for reconstitution and use as an intravenous infusion.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

This product is indicated in the treatment of all staphylococcal infections due to susceptible organisms such as: osteomyelitis, pneumonia, septicaemia, wound infections, endocarditis, superinfected cystic fibrosis, cutaneous infections.

It should be administered intravenously whenever oral therapy is inappropriate, which includes cases where absorption from the gastro-intestinal tract is unpredictable.

4.2    Posology and method of administration

Adults weighing more than 50kg: 500mg sodium fusidate three times daily.

Children and adults weighing less than 50kg: 6-7mg sodium fusidate per kg bodyweight three times daily.

Recommended procedure: To reconstitute, dissolve the contents of one vial containing 500mg sodium fusidate powder (equivalent to 480mg of fusidic acid) in the 10ml buffer provided.

For further instructions on reconstitution of the medicinal product before administration, see section 6.6.

For adults weighing more than 50kg: Add the 10ml fusidate/buffer solution to 500ml of infusion fluid.

For children and adults weighing less than 50kg: Add the 10ml fusidate/buffer solution to 500ml of infusion fluid. Each dose corresponds to 6-7ml of the resulting solution per kg bodyweight.

The diluted fluid should be infused via a central venous line over 2 hours. If a superficial vein is employed a more prolonged period of at least 6 hours is advisable.

This product should be administered intravenously into a wide bore vein with a good blood flow.

Excessive doses may cause venospasm, thrombophlebitis and haemolysis of erythrocytes. Both oral and intravenous presentations have been given concurrently with other antibiotics, e.g. cloxacillin, flucloxacillin, ampicillin, methicillin and erythromycin.

Since it is excreted in the bile, no dosage modifications are needed in renal impairment.

The dosage in patients undergoing haemodialysis needs no adjustment as this product is not significantly dialysed.

Dosage in the elderly: No dosage alterations are necessary in the elderly.

If additional antibacterial therapy is to be employed, it is recommended that for parenteral administration, separate infusion fluids be used.

4.3 Contraindications

Hypersensitivity to fusidic acid and its salts, or any of the excipients.

This product should not be infused with amino acid solutions or in whole blood.

Due to local tissue injury, this product should not be administered intramuscularly or subcutaneously.

4.4 Special warnings and precautions for use

Sodium fusidate must not be co-administered with statins. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination (see section 4.5). In patients where the use of systemic sodium fusidate is considered essential, statin treatment should be discontinued throughout the duration of sodium fusidate treatment. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be reintroduced seven days after the last dose of sodium fusidate. In exceptional circumstances, where prolonged systemic sodium fusidate is needed e.g. for the treatment of severe infections, the need for co-administration of statin and sodium fusidate should only be considered on a case by case basis and under close medical supervision.

Sodium fusidate is metabolised in the liver and excreted in the bile. Caution should be exercised with other antibiotics which have similar biliary excretion pathways e.g. lincomycin and rifampicin. Elevated liver enzymes and jaundice have occurred during systemic therapy but are usually reversible on discontinuation of the drug (see section 4.8).

Periodic liver function tests should be carried out when the product is given:

•    in high oral doses

•    for prolonged periods

•    to patients with liver dysfunction

•    to patients taking potentially hepatotoxic medication

•    to patients with biliary tract obstruction

•    to patients taking concurrent medication with a similar excretion pathway.

Sodium fusidate displaces bilirubin from its albumin binding site in vitro. Caution is necessary if this product is administered to patients with impaired transport and metabolism of bilirubin.

The use of this product in combination with drugs that are CYP-3A4 biotransformed should be avoided. See Section 4.5.

Bacterial resistance has been reported to occur with the use of sodium fusidate. As with all antibiotics, extended or recurrent use may increase the risk of developing antibiotic resistance.

This medicinal product contains 3.2mmol (73mg) sodium per 500mg dose. This should be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic sodium fusidate with statins.

Co-administration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with sodium fusidate is necessary, statin treatment should be discontinued throughout the duration of the sodium fusidate treatment. Also see section 4.4.

In vitro compatibility studies of Sodium Fusidate 500mg for Intravenous Infusion with commonly used infusion solutions have been carried out.

The results showed that sodium fusidate reconstituted at 50mg/ml in buffer solution is physically and chemically compatible for at least 24 hours at room temperature with the following infusion solutions (the figure in parenthesis shows the concentration of sodium fusidate in the final admixture):

Sodium Chloride Intravenous Infusion BP 0.9% (1-2mg/ml).

Dextrose Intravenous Infusion BP 5% (1-2mg/ml).

Compound Sodium Lactate Intravenous Infusion (“Ringer-Lactate Solution”) (1mg/ml).

Sodium Lactate Intravenous Infusion BP (1mg/ml).

Sodium Chloride (0.18%) and Dextrose (4%) Intravenous Infusion BP (1mg/ml). Potassium Chloride (0.3%) and Dextrose (5%) Intravenous Infusion BP (1mg/ml).

Specific pathways of metabolism of this product in the liver are not known, however, an interaction between this product and drugs being CYP-3A4 biotransformed can be suspected. The mechanism of this interaction is presumed to be a mutual inhibition of metabolism. There is insufficient data to characterise the effect of fusidic acid on CYPs in-vitro. The use of this product systemically should be avoided in patients treated with CYP-3A4 biotransformed drugs.

When this product is administered systemically and concomitantly with oral anticoagulants such as coumarin derivatives or anticoagulants with similar actions, the plasma concentration of these agents may increase enhancing the anticoagulant effect. Anticoagulation should be closely monitored and a decrease of the oral anticoagulant dose may be necessary in order to maintain the desired level of anticoagulation. Similarly, discontinuation of this product may require the maintenance dose of anticoagulant to be re-assessed. The mechanism of this suspected interaction remains unknown.

Co-administration of this product and HIV protease inhibitors such as ritonavir and saquinavir causes increased plasma concentrations of both agents which may result in hepatotoxicity.

Co-administration of this product systemically with ciclosporin has been reported to cause increased plasma concentration of ciclosporin.

4.6 Fertility, pregnancy and lactation

There is inadequate evidence of safety in human pregnancy. Animal studies and many years of clinical experience suggest that fusidic acid is devoid of teratogenic effects. There is evidence to suggest that when given systemically, fusidic acid can cross the placental barrier. If the administration of the product to pregnant patients is considered essential, its use requires that the potential benefits be weighed against the possible hazards to the foetus.

Safety in nursing mothers has not been established. When fusidic acid (as the sodium salt) has been given systemically, levels have been detected in the breast milk. Caution is therefore required when the product is used in mothers who wish to breast feed.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

Based on clinical trial data on sodium fusidate administered intravenously, in high doses and concomitantly with other antibiotics in critically ill patients, it is estimated that approximately 30% of the patients may experience an undesirable effect. This number is reduced when the product is administered through a central vein.

Venous intolerance such as venous spasm and thrombophlebitis are very common when the product is administered through a peripheral vein, while common when it is administered through a central line.

Raised bilirubin, liver enzymes and clinical jaundice are considered to be common. These undesirable effects are usually reversible on discontinuation of the drug.

Undesirable effects are listed below, by MedDRA System Organ Class, in decreasing order of frequency within each class. Where frequencies are given, these are based on the clinical trial data, using the stated frequency classification. Where the term ‘Not known’ is given, these effects are derived from spontaneous reports.

Frequency classification:

>1/10

>1/100 and <1/10 >1/1,000 and <1/100 >1/10,000 and <1/1,000

Very rare <1/10,000

Blood and lymphatic system disorders

Not known:    Pancytopenia

Leukopenia*

Thrombocytopenia

Anaemia

*Haematological disorders affecting the white cell line (neutropenia, granulocytopenia, agranulocytosis) and, more rarely, disorders affecting the other two cell lines have been reported, either as isolated events or associated. These abnormalities have been observed especially with treatment of more than 15 days and are reversible upon drug withdrawal.

Immune system disorders

Rare:    Allergic reaction

Not known:    Anaphylactic reaction

Metabolism and nutrition disorders

Uncommon:    Anorexia

Nervous system disorders

Common:    Drowsiness

Dizziness

Uncommon:    Headache

Hepatobiliary disorders

Common:    Hyperbilirubinaemia

Jaundice (see section 4.4)

Hepatic enzymes increased (see section 4.4)

Not known:    Hepatorenal syndrome

Liver function abnormalities like hyperbilirubinaemia with or without jaundice and increase in hepatic enzymes such as alkaline phosphatase and transaminases should lead to withdrawal of treatment. Return of laboratory parameters to normal is usual and generally rapid.

Cholestasis

Skin and subcutaneous tissue disorders

Uncommon:    Rash*

Urticaria

Pruritus

*Rash includes various types of reactions such as erythematous, maculo-papular and pustular.

Musculoskeletal and connective tissue disorders

Not known:    Rhabdomyolysis (see Section 4.4 and 4.5)

Rhabdomyolysis may be fatal. Examples of signs and symptoms are: muscle weakness, muscle swelling and muscle pain, dark urine, myoglobinuria, elevated serum creatine kinase, acute renal failure, cardiac arrhythmia.

Renal and urinary disorders

Not known:    Renal failure

Acute renal failure has been described in patients with jaundice, in particular in the presence of other factors predisposing to renal failure.

General disorders and administration site conditions

Common:    Venous intolerance

Thrombophlebitis Uncommon:    Asthenia

Fatigue Malaise

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

Acute symptoms of overdose include gastrointestinal disturbances and possible effects on liver function. Treatment should be restricted to symptomatic and supportive measures. Dialysis will not increase the clearance of sodium fusidate.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Fusidic acid and its salts are potent anti-staphylococcal agents with unusual ability to penetrate tissue. Bactericidal levels have been assayed in bone and necrotic tissue. Concentrations of 0.03 - 0.12 micrograms/ml inhibit nearly all strains of Staphylococcus aureus. Fusidic acid is active against Staphylococcus epidermidis and methicillin resistant staphylococci.

In severe or deep seated infections and when prolonged therapy may be required, systemic administration of this product should generally be given concurrently with other anti-staphylococcal antibiotic therapy.

5.2 Pharmacokinetic properties

500mg of sodium fusidate given as a single infusion over 2 hours results in a C_max of 52 micrograms/ml. Blood levels are cumulative, reaching concentrations of 60-120 micrograms/ml after repeated infusion of 500mg sodium fusidate every 8 hours for 23 days.

The plasma half-life is approximately 10-15 hours.

This product is excreted mainly in the bile, little or none being excreted in the urine.

5.3    Preclinical safety data

There are no pre-clinical data of relevance to    the prescriber which are additional to

that already included in other sections of the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

The vial of 10ml sterile phosphate-citrate buffer solution (pH 7.4 - 7.6) contains disodium hydrogen phosphate, citric acid, disodium edetate and water for injections. (When reconstituted with powder vial contains 3.1mMol sodium and 1.1mMol phosphate).

6.2    Incompatibilities

Sodium fusidate reconstituted at 50mg/ml in buffer solution is physically incompatible with infusion fluids containing 20% or more of dextrose, lipid infusions and peritoneal dialysis fluids. Precipitation may occur at dilutions which result in a pH of less than 7.4.

6.3    Shelf life

2 years.

After the sodium fusidate dry powder is dissolved in the buffer solution provided and added to 500 ml of infusion fluid, the solution should be used immediately.

6.4    Special precautions for storage

Store in a refrigerator (2°C - 8°C).

When the buffer solution is transferred to the powder vial, this vial should be regarded as a unit dose. The required amount of the sodium fusidate/buffer solution should be used once only and any unused portion discarded.

Nature and contents of container

Pack containing a single pair of vials; one glass vial of sodium fusidate closed with a butyl rubber stopper secured with metal rings and one glass vial of sterile buffer solution 10ml closed with a bromobutyl rubber stopper secured with metal rings.

6.6 Special precautions for disposal

Precipitation can happen when the buffer is stored at low temperatures, which will appear as black spots. If seen, shake the buffer vial until clear before reconstitution with the powder vial. Only clear reconstituted solution free from particles should be used.

7    MARKETING AUTHORISATION HOLDER

Essential Pharma Limited

7 Egham Business Village

Crabtree Road

Egham

Surrey

TW20 8RB

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 41871/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/10/1992 /    18/11/2004

10 DATE OF REVISION OF THE TEXT

25/04/2016