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 50 kg: 500 mg sodium fusidate three times daily.

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

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

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

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

For children and adults weighing less than 50 kg: Add the 10 ml fusidate/buffer solution to 500 ml of infusion fluid. Each dose corresponds to 6-7 ml 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 the active substance or to any of the excipients listed in section 6.1.

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 coadministration of statin and sodium fusidate should only be considered on a case by case basis and under close medical supervision.

In a few cases, serious cutaneous reactions putting life at risk such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome have been reported with systemic fusidic acid/fusidate. Patients should be advised to monitor cutaneous reactions as well as signs and symptoms suggestive of these reactions which usually appear in the first weeks of therapy. If such reactions are suspected to be due to systemic fusidic acid/fusidate, treatment with systemic fusidic acid/fusidate should be stopped and it is recommended not to reintroduce the therapy.

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.

Sodium

This medicinal product contains 72.6 mg sodium per vial, equivalent to 3.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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 500 mg for intravenous infusion with commonly used infusion solutions have been carried out.

The results showed that sodium fusidate reconstituted at 50 mg/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% (1-2 mg/ml).

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

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

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

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

Potassium Chloride (0.3%) and Dextrose (5%) Intravenous Infusion BP (1 mg/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/fusidate 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

Pregnancy

There is inadequate evidence of safety in human pregnancy. Animal studies and many years of clinical experience suggest that fusidic acid/fusidate is devoid of teratogenic effects. There is evidence to suggest that when given systemically, fusidic acid/fusidate 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.

Breast-feeding

Safety in nursing mothers has not been established. When fusidic acid/fusidate (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.

Fertility

There are no adequate clinical data from the use of fusidic acid/fusidate (as the sodium salt) with regard to fertility. Preclinical studies with sodium fusidate in rats showed no effect on fertility.

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:

Very common

(>1/10)

Common

(>1/100 and <1/10)

Uncommon

(>1/1,000 and <1/100)

Rare

(>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:

Acute generalized exanthematous pustulosis

Rash*

Urticaria

Pruritus

Not known:

Toxic epidermal necrolysis (Lyell’s syndrome)**, Stevens-Johnson syndrome (SJS)** and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)** syndrome

*Rash includes various types of reactions such as erythematous, maculopapular and pustular.

** These adverse reactions were identified through post-marketing surveillance. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (see section 4.4)

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 or search for MHRA Yellow Card in the Google Play or Apple App Store

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.