Fucidin I.V. (Sodium Fusidate)

FUCIDIN® Tablets FUCIDIN® I.V. FUCIDIN® Suspension

Leo

Sodium Fusidate

Fusidic Acid

Antibiotic

Action And Clinical Pharmacology: The antibacterial action of fusidic acid results from the inhibition of bacterial protein synthesis. The drug interferes with amino acid transfer from aminoacyl-sRNA to protein on the ribosomes. Fusidic acid may be bacteriostatic or bactericidal depending on inoculum size. Although bacterial cells stop dividing almost within 2 minutes after contact with the antibiotic in vitro, DNA and RNA synthesis continue for 45 minutes and 1 to 2 hours, respectively. Fucidin is active in vitro against gram-positive bacteria and Neisseria species, but has almost no antibacterial activity against gram-negative organisms.

Fucidin is readily absorbed and peak blood concentrations are reached between 2 and 3 hours following oral administration. Average peak concentrations of 25 to 35 µg/mL following single doses of the tablets and suspension are approximately 55 to 80% of those obtained following i.v. infusion of comparable dose. Fusidic acid suspension is less completely absorbed than sodium fusidate tablets, thus a single administration of 737 mg of fusidic acid is required to produce an effective dose comparable to that produced by 500 mg of sodium fusidate. Following a single dose the average peak concentration is reached after approximately 4 hours with the tablets versus 2 hours with the suspension. Although there is a delay in the absorption of the tablets and a lower peak concentration, similar areas under the curve are obtained with all 3 oral formulations.

The plasma half-life of Fucidin has been found to be between 5 and 6 hours (for all dosage forms and routes), which results in significant accumulation with repeated doses. Steady-state levels, usually between 50 to 100 µg/mL, are normally reached within 3 or 4 days with a dose of 500 mg of sodium fusidate or 737 mg of fusidic acid 3 times daily. Cumulative serum levels in humans have been found to be quite variable from patient to patient.

The concentrations observed in various body tissues and fluids, except for urine and possibly sputum are in excess of those required to inhibit most staphylococci in vitro. The minimum inhibitory concentration of Fucidin against S. aureus ranges from 0.03 to 0.50 µg/mL.

Fucidin has been shown to penetrate into avascular foci of infection, such as bone sequestra in patients with osteomyelitis. Fucidin has been found in synovial fluid, in patients with rheumatoid arthritis and osteoarthritis, in burn crusts, in pus and in aqueous humor of uninflamed eyes.

The drug is 97.2% protein bound in human serum thus only 2 to 3% is available in the active free form. The possibility of synergism between sodium fusidate and other antibiotics has been tested. Synergism was demonstrated with penicillin V, penicillin G, erythromycin and picromycin. Synergism between the penicillins and fusidic acid has only been observed with strains of S. aureus that produce small amounts of penicillinase and not with penicillinase stable penicillins.

The MIC’s of combinations of benzylpenicillin or methicillin with fusidic acid were determined by the serial dilution tube titration method. When penicillin was added 2 hours before fusidic acid, the combination was synergistic. However, when penicillin was added at the same time or later than fusidic acid, the two agents acted antagonistically. It has been suggested that these apparently opposing effects occur because fusidic acid rapidly inhibits protein synthesis, but the action of penicillin requires active cell growth. Fucidin and methicillin act antagonistically against staphylococcal strains which are susceptible to methicillin but not in methicillin resistant strains.

Fucidin is excreted almost exclusively in the bile. In individuals with normally functioning gall bladders the Fucidin concentrations were found to be 12 times higher in bile than in serum, but in severely inflamed gall bladders, the concentration fell to only 7% of the serum level. Seven metabolites of Fucidin have been isolated from the bile and only a small amount is excreted unchanged in the feces. The 3 major metabolites have been identified as: 1) a glucuronic acid conjugate, 2) a dicarboxylic ester and 3) a glycol, although the structure of the latter has not been positively confirmed. None of the 3 compounds has significant antibacterial activity as compared to fusidic acid against S. aureus.

Sodium fusidate had no discernible effect on adrenocortical function in investigations of urinary hormone excretion and of eosinophil count.

Fucidin crosses the blood-brain barrier only when the meninges are inflamed.

In one patient given a single dose of 1 g orally, Fucidin crossed the placental barrier.

Fucidin has been given to 40 neonates with spina bifida from the day of birth for up to 1 year. No evidence of liver, renal, blood or ocular toxicity was observed.

Indications And Clinical Uses: The treatment of the following infections when due to susceptible strains of S. aureus, both penicillinase producing and nonpenicillinase producing: skin and soft tissue infections, osteomyelitis.

For patients with staphylococcal infections where other antibiotics have failed (e.g., patients with staphylococcal septicemia, burns, endocarditis, pneumonia, cystic fibrosis).

Appropriate culture and susceptibility studies should be performed. Fucidin is bound to protein, and a small amount of blood in agar medium renders the sensitivity test invalid. While awaiting results of these studies, if antibiotic therapy is considered to be necessary due to a potentially serious infection, Fucidin may be administered to those patients in whom a staphylococcal infection is suspected. This antibiotic treatment may subsequently require modification once these results become available.

No cross resistance has been observed to date between Fucidin and other antibiotics presently in clinical use.

Resistance to Fucidin has readily been induced in vitro. The development of resistance has also been shown to occur in the clinical setting.

Contra-Indications: Known hypersensitivity to fusidic acid and its salts. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Fucidin must not be administered either i.m. or s.c., since it has been demonstrated that local tissue injury occurs. Fucidin should not be infused with amino acid solutions or with whole blood because of the risk of hemolysis of the erythrocytes.

Extreme caution should be exercised in patients with impaired liver function. Liver function tests should be performed regularly during treatment.

Precautions: Fucidin is excreted mainly in the bile and periodic liver function tests should be carried out when high doses are used or when the drug is given for prolonged periods.

Caution should be exercised if Fucidin is administered with other drugs, including antibiotics (e.g., lincomycin and rifampicin), which have a similar biliary excretion pathway.

Cases of jaundice have rarely developed during therapy usually following a rapid infusion or an excessive i.v. dose. The jaundice is usually accompanied by an elevated serum bilirubin level, and occasionally serum transaminases may also be elevated. Alteration of the administration procedure by lengthening the infusion period or changing to oral therapy may help control this adverse effect. Liver function should continue to be closely monitored until the serum bilirubin concentration has returned to a satisfactory level; if an elevated bilirubin level persists, administration of the drug should be discontinued.

Infusions should only be made into a wide bore vein with a good blood flow and completed over a period of not less than 6 hours.

In patients with hypocalcemia, Fucidin i.v. should be administered with caution and serum calcium monitored since the reconstituted i.v. contains a large amount of phosphate/citrate buffer.

Pregnancy and Lactation: Safety during pregnancy has not been established. If administration to pregnant patients is considered to be necessary, its use requires that the potential benefits be weighed against the possible hazards to the fetus. There is evidence to suggest that the drug can penetrate the placental barrier and is detectable in the milk of nursing mothers. Safety in women who are breast-feeding has not been established.

Fusidic acid displaces bilirubin from its albumin binding site in vitro. The clinical significance of this finding is uncertain and kernicterus has not been observed in neonates receiving Fucidin. This observation should be borne in mind when the drug is given to preterm, jaundice, acidotic or seriously ill neonates.

Adverse Reactions: Gastrointestinal Reactions: Nausea, vomiting, epigastric pain, anorexia, diarrhea and dyspepsia. Treatment was discontinued in approximately 1.7% of the patients treated because of gastric intolerance. The incidence of these effects can be lessened by taking the medication with food.

In some patients treated either orally or i.v., jaundice has been reported. The jaundice is usually resolved on cessation of therapy (see Precautions).

Venospasm and thrombophlebitis have been observed with i.v. administration. Inflammation and redness at the infusion site have also been observed.

Skin rashes and pruritus have been observed on rare occasions.

Dizziness, blurred vision, decreased white blood cell count, psychic disturbance, swollen legs and headaches have been generally mild and infrequent.

Symptoms And Treatment Of Overdose: Symptoms: I.V. Infusion: I.V. doses of Fucidin Leo in excess of those recommended may result in hypocalcemia due to the large amount of phosphate/citrate buffer administered (i.e., each 50 mL of phosphate/citrate buffer for i.v. infusion contains 980 mg disodium hydrogen phosphate equivalent to 5.5 mmols phosphate). This may require patient monitoring, serum calcium determinations and treatment as appropriate.

Abnormal liver biochemistry or reversible jaundice have been reported. These symptoms can be alleviated by stopping the drug. If the clinical condition allows, changing to the oral formulation has been associated with a lower incidence of jaundice.

Oral Administration: Early symptoms may include epigastric or gastric discomfort and possibly diarrhea. Prolonged ingestion of high doses may produce jaundice and abnormal liver biochemistry.

Treatment: Since there have not been any reports of accidental massive overdosage with Fucidin, there has been no experience with any specific treatment. Treatment should be restricted to symptomatic and supportive measures. Dialysis is of no benefit, since the drug is not significantly dialyzed.

Dosage And Administration: Fucidin may be administered orally or by i.v. infusion. Do not administer i.m. or s.c.

In fulminating infections, the above recommended oral dosages may be doubled. If additional injectable antibacterial therapy is necessary, use separate infusion fluids.

The total duration of therapy should be dictated by the patient’s clinical condition and the results of bacteriological monitoring. The following guidelines may be used: the minimum duration of treatment should be 1 to 2 weeks for skin and soft tissue infections; for acute osteomyelitis a minimum of 2 to 4 weeks is recommended; the treatment of chronic osteomyelitis may require several months. For more deep seated infections where other antibiotics have failed, a minimum of 2 to 4 weeks is recommended for septicemia, pneumonia and burns; 1 to 2 months for endocarditis.

The dosage in patients undergoing hemodialysis needs no adjustment, as Fucidin is not significantly dialyzed. Fucidin can be given to patients with renal failure since Fucidin is excreted by the biliary route.

Note: Fucidin is not recommended in infections due to streptococci or N. gonorrhea.

If gastrointestinal upset occurs, the symptoms may be lessened by taking the medication with food.

Fucidin i.v. should be administered only into a wide bore vein with a good blood flow over a period not less than 6 hours.

Preparation of Solution for i.v. Infusion: Dissolve one vial of sodium fusidate (500 mg) with the 10 mL of buffer solution provided.

For adults over 50 kg of body weight dilute to 250 to 500 mL with one of the following: sodium chloride i.v. infusion BP 0.9% (1 to 2 mg/mL); dextrose i.v. infusion BP 5% (1 to 2 mg/mL); compound sodium lactate i.v. infusion BP (Ringer’s Lactate solution) (1 mg/mL); potassium chloride 40 mEq (0.3%) and sodium chloride (0.9%) i.v. infusion BP (1 mg/mL); potassium chloride 40 mEq (0.3%) and dextrose (5%), i.v. infusion BP (1 mg/mL).

For children and adults weighing less than 50 kg, the required amount of reconstituted drug should be further diluted at least ten-fold with the appropriate infusion fluid. If opalescence is encountered, the solution should be discarded (e.g., upon use of acidic dextrose solutions).

Infusion solutions containing Fucidin Leo are incompatible with kanamycin, gentamicin, vancomycin, cephaloridine, carbenicillin, whole blood, amino acid solutions and calcium containing solutions. If additional i.v. therapy is to be concurrently employed, it is recommended that separate infusions be used.

Reconstituted solution should be used within 24 hours (refrigerated).

Note: Opalescence may occur with some dextrose diluents which may be slightly acidic. The solution should be discarded.

Note: Fucidin should not be diluted with amino acid solutions or whole blood.

Availability And Storage: I.V.: Each pack of two 10 mL vials for i.v. infusion contains: 1 vial of sodium fusidate 500 mg as a dry powder; and a second vial containing 10 mL sterile phosphate citrate buffer (pH 7.3 to 7.7).

Suspension: Each 5 mL of banana-flavored, aqueous suspension contains: fusidic acid 246 mg . Nonmedicinal ingredients: banana essence, citric acid monohydrate, hydroxyethylcellulose, liquid glucose, methocel A 15, potassium sorbate, sodium phosphate dibasic dihydrate, sodium saccharinate and water purified. Bottles of 50 mL.

Tablets: Each white, ovoid, film-coated tablet contains: sodium fusidate BP 250 mg (equivalent to 240 mg fusidic acid). Nonmedicinal ingredients: cellulose microcrystalline, colloidal anhydrous silica, crospovidone, gelatine, hydroxypropylmethylcellulose, lactose, magnesium stearate, povidone, talc, titanium dioxide. Bottles of 100. Store below 25°C.

Note: Owing to incomplete absorption the effective dose is 70% of the stated drug weight or approximately 172 mg/5 mL.

FUCIDIN® Tablets FUCIDIN® I.V. FUCIDIN® Suspension Leo Sodium FusidateSodium FusidateFusidic Acid Antibiotic

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