4.3 Contraindications
Hypersensitivity to fusidic acid and its salts, or any of the excipients.
Contra-indicated in patients with known hypersensitivity to fusidic acid and its salts.
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
Fucidin® 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 Fucidin® is considered essential, statin treatment should be discontinued throughout the duration of Fucidin® 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 re-introduced seven days after the last dose of Fucidin®. In exceptional circumstances, where prolonged systemic Fucidin® is needed e.g for the treatment of severe infections, the need for co-administration of statin and Fucidin® 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 high oral doses are used, when the drug is given for prolonged periods and in patients with liver dysfunction.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 fusidateThis product 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 clinical significance of this finding is uncertain and kernicterus has not been observed in neonates receiving Sodium Fusidate 500mg for Intravenous Infusion*. However, this observation should be borne in mind when the drug is given to pre-term, jaundiced, acidotic or seriously ill neonates.
The use of this product in combination with drugs that are CYP-3A4 biotransformed should be avoided. See Section 4.5
Patients given this product systemically in combination with HMG-CoA reductase inhibitors should be closely clinically monitored. 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 3.2 mmol (73 mg) sodium per 500 mg 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
See 4.4.
The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic Fucidin® 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 Fucidin® is necessary, statin treatment should be discontinued throughout the duration of the Fucidin® 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 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 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.
Systemic co-administration of this product with HMG-CoA reductase inhibitors such as statins may cause increased plasma concentrations of both agents and rare cases of rhabdomyolysis have been reported for this combination. Patients on this combination should be closely clinically monitored.
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.
4.8 Undesirable effects
In some patients, particularly in the young and elderly, a reversible jaundice has been reported. Jaundice has been seen most frequently in patients receiving this product in high dosage, or where the drug has been infused too rapidly or at too high a concentration in the infusion fluid. In some instances instituting oral therapy may be beneficial. If the jaundice persists this product should be withdrawn, following which the serum bilirubin will invariably return to normal. Reported reactions are thrombophlebitis and,rarely, skin rashes and other allergic reactions including anaphylaxis. Isolated cases of haematological abnormalities which can affect the 3 blood cell lines but mainly white blood cells e.g. bone marrow depression, neutropenia, granulocytopenia, agranulocytosis and pancytopenia have been reported. Reported less often is a depressive effect on the platelets and red blood cells with reports of thrombocytopenia and various anaemias. These abnormalities have been observed especially with treatment of more than 15 days. Acute renal failure has been described in patients with jaundice, particularly in the presence of other factors predisposing to renal failure.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.
· 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
4.9 Overdose
Acute symptoms of overdose include gastrointestinal disturbances and possible effects on liver function.There has been no experience of overdosage. Treatment should be restricted to symptomatic and supportive measures. Dialysis is of no benefit, since the drug is not significantly dialysed.Dialysis will not increase the clearance of sodium fusidate.
10 DATE OF REVISION OF THE TEXT
February 2006. February 2010
April 2011
23 December 2011
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