1. Name Of The Medicinal Product
VELOSEF FOR INJECTION 500MG
VELOSEF FOR INJECTION 1G
2. Qualitative And Quantitative Composition
Velosef for Injection is a sterile powder blend of cefradine and L-arginine. After reconstitution, Velosef for Injection 500mg provides 500mg of cefradine activity and Velosef for Injection 1g provides 1g of cefradine activity.
3. Pharmaceutical Form
Powder for solution for injection; intramuscular or intravenous injection and intravenous infusion.
4. Clinical Particulars
4.1 Therapeutic Indications
The treatment of infections of the urinary and respiratory tracts, and of the skin and soft tissues, bones and joints; also septicaemia and endocarditis. These include:
Upper respiratory infections - pharyngitis, sinusitis, otitis media, tonsillitis, laryngo-tracheo-bronchitis.
Lower respiratory infections - acute and chronic bronchitis, lobar and bronchopneumonia.
Urinary tract infections - cystitis, urethritis, pyelonephritis.
Skin and soft tissue infections - abscess, cellulitis, furunculosis, impetigo.
Cefradine has been shown to be effective in reducing the incidence of postoperative infections in patients undergoing surgical procedures associated with a high risk of infection. It is also of value where post-operative infection would be disastrous and where patients have a reduced host resistance to bacterial infection. Protection is best ensured by achieving adequate local tissue concentrations at the time contamination is likely to occur. Thus, cefradine should be administered immediately prior to surgery and continued during the postoperative period.
Bacteriological studies to determine the causative organisms and their sensitivity to cefradine should be performed. Therapy may be instituted prior to receiving the results of the sensitivity test.
4.2 Posology And Method Of Administration
Sterile cefradine for injection is indicated primarily as an intramuscular injection for those patients unable to tolerate oral medication. It is also indicated for intravenous use either by direct injection or by intravenous infusion for the treatment of serious and life-threatening infections.
Instructions for reconstitution for intramuscular or intravenous injection and intravenous infusion are given in section 6.6.
Adults:
Treatment:
The usual dose range of cefradine for injection is 2-4g daily in four equally divided doses. This may be increased up to 8g a day for severe infections, e.g. septicaemia and endocarditis. For the majority of infections, the usual dose is 500mg q.i.d. in equally spaced doses; severe or chronic infections may require larger doses. Prolonged intensive therapy is needed for complications such as prostatitis and epididymitis. Patients who are severely ill and who require high serum levels of cefradine for treating their infections should be started on intravenous therapy.
Limited experience indicates that intraperitoneal administration of cefradine may be effective after surgery in cases of peritonitis where a surgical drainage system has been established.
Prophylaxis:
The recommended dose for surgical prophylaxis is a single, pre-operative 1-2g IM or IV dose. Subsequent parenteral or oral doses can be administered as appropriate.
Children:
The usual dose is 50-100mg/kg/day total given in four equally divided doses. More serious illnesses may require 200-300mg/kg/day.
Elderly:
There are no specific dosage recommendations or precautions for use in the elderly except, as with other drugs, to monitor those patients with impaired renal or hepatic function.
All patients, regardless of age and weight:
Therapy should be continued for a minimum of 48-72 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. In infections caused by haemolytic strains of streptococci, a minimum of 10 days of treatment is recommended to guard against the risk of rheumatic fever or glomerulonephritis. In the treatment of chronic urinary tract infections, frequent bacteriological and clinical appraisal is necessary during therapy and may be necessary for several months afterwards. Persistent infections may require treatment for several weeks. Smaller doses than those indicated above should not be used. Doses for children should not exceed doses recommended for adults. As cefradine is available in both injectable and oral form, patients may be changed from the cefradine injectable to cefradine oral at the same dosage level.
Renal Impairment Dosage:
Patients not on dialysis:
The following dosage schedule is suggested as a guideline based on a dosage of 500mg Q6H and on creatinine clearance. Further modification in the dosage schedule may be required because of the dosage selected and individual variation.
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Patients on chronic, intermittent haemodialysis:
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Further modification of the dosage schedule may be necessary in children.
4.3 Contraindications
Patients with known hypersensitivity to the cephalosporin antibiotics or to any component of the formulation.
4.4 Special Warnings And Precautions For Use
There is evidence of partial cross-allergenicity between the penicillins and the cephalosporins. Therefore cefradine should be used with caution in those patients with known hypersensitivity to penicillins. There have been instances of patients who have had reactions to both drug classes (including anaphylaxis).
Dosage should be reduced in renal failure (see Section 4.2)
After treatment with cefradine a false positive reaction for glucose in the urine may occur with Benedict's solution or Fehling's solution or with reagent tablets such as Clinitest*, but not with enzyme-based tests such as Clinistix* or Diastix*.
As with all antibiotics, prolonged use may result in overgrowth of non-susceptible organisms.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Loop diuretics may increase nephrotoxicity of cephalosporins.
Probenecid has been seen to raise serum concentrations of cefradine, by reducing renal clearance of the cephalosporins.
4.6 Pregnancy And Lactation
Although animal studies have not demonstrated any teratogenicity, safety in pregnancy has not been established. Cefradine is excreted in breast milk and should be used with caution in lactating mothers.
4.7 Effects On Ability To Drive And Use Machines
Since this medicine may cause dizziness, patients should be cautioned about operating hazardous machinery, including automobiles.
4.8 Undesirable Effects
Limited essentially to gastro-intestinal disturbances and on occasion to hypersensitivity phenomena. The latter are more likely to occur in individuals who have previously demonstrated hypersensitivity and those with a history of allergy, asthma, hay fever or urticaria. The majority of reported side-effects have been mild and are rare, and include glossitis, heartburn, headache, dizziness, dyspnoea, paraesthesia, nausea, vomiting, diarrhoea, abdominal pain, candidal overgrowth, vaginitis. Skin and hypersensitivity reactions include urticaria, pruritus, skin rashes, fever, arthralgia and oedema.
As with other cephalosporins, there have been rare reports of erythema multiforme, Stevens Johnson Syndrome, anaphylaxis and toxic epidermal necrolysis. Also, mild transient eosinophilia, leucopenia and neutropenia, rarely positive direct Coombs tests and pseudomembranous colitis have been reported.
Elevations of BUN, serum creatinine and reversible interstitial nephritis have been reported. Transient hepatitis and cholestatic jaundice have been reported very rarely. Elevations of ALT, AST, total bilirubin and alkaline phosphatase have been observed.
Injection:
As with other parenterally administered antibiotics, transient pain may be experienced at the injection site, but is seldom the cause for discontinuing treatment. Thrombophlebitis has been reported following intravenous injection.
Since sterile abscesses have been reported following accidental subcutaneous injection, the preparation should be administered by deep intramuscular injection.
4.9 Overdose
None known
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Actions:
Cefradine is a broad-spectrum bactericidal antibiotic active against both Gram-positive and Gram-negative bacteria. It is also highly active against most strains of penicillinase-producing Staphylococci.
Microbiology:
The following organisms have shown in vitro sensitivity to cefradine:
Gram-positive - Staphylococci (both penicillin sensitive and resistant strains), Streptococci, Streptococcus pyogenes (beta haemolytic) and Streptococcus pneumoniae.
Gram-negative - E. coli, Klebsiella, spp, P. mirabilis, Haemophilus influenzae, Salmonella spp. (including Salmonella typhi) and Neisseria spp.
Because cefradine is unaffected by penicillinase, many strains of E. coli and Staphylococcus aureus which produce this enzyme are susceptible to cefradine but resistant to ampicillin.
Cefradine has a high degree of stability to beta-lactamases. It has a low degree of protein binding and a large volume of distribution. Therefore, tissue levels are generally found to be high.
5.2 Pharmacokinetic Properties
Following intramuscular administration of a single 0.5g dose of cefradine to normal volunteers, the average peak serum concentration was 8.41 microgram/ml with the time to peak concentration being 0.93 hours. The serum half-life averaged 1.25 hours. A single 1g intravenous dose resulted in serum concentrations of 86 micrograms/ml at 5 minutes and 12 micrograms/ml at 1 hour; these concentrations declined to 1 microgram/ml at 4 hours. Continuous infusion of 500mg per hour into a 70kg man maintained a concentration of about 21.4 microgram/ml cefradine activity; this study showed that a serum concentration of approximately 3 microgram/ml can be obtained for each milligram of cefradine administered per kg of body weight per hour of infusion.
Cefradine is excreted unchanged in the urine. The kidneys excrete 57% to 80% of an intramuscular dose in the first six hours; this results in a high urine concentration, e.g. 880 micrograms/ml of urine after a 500mg intramuscular dose. Probenecid slows tubular secretion and almost doubles peak serum concentration.
Assays of bone obtained at surgery have shown that cefradine penetrates bone tissue.
5.3 Preclinical Safety Data
No further information is available for this established product.
6. Pharmaceutical Particulars
6.1 List Of Excipients
L-Arginine sterile.
6.2 Incompatibilities
None known.
6.3 Shelf Life
36 months.
6.4 Special Precautions For Storage
Storage before reconstitution: Do not store above 25°C.
Storage after reconstitution: Solutions for IM or IV Injection should be used immediately (see also section 6.6 below).
6.5 Nature And Contents Of Container
500mg or 1g Type III Ph Eur clear glass vial with siliconed, butyl rubber stopper and aluminium seal.
500mg : packs of 5 vials
1g : single vial pack.
6.6 Special Precautions For Disposal And Other Handling
Reconstitution:
For intramuscular use: Aseptically add sterile water for injections or 0.9% sodium chloride injection according to following table:
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* The preparation contains no bactericide and is intended for single use only and not multiple dose.
Shake to effect solution and withdraw the entire contents
For intravenous use: Cefradine for injection may be administered by direct intravenous injection or by infusion. A 3 microgram/ml serum concentration can be maintained for each milligram of cefradine per kg body weight per hour of infusion.
For direct intravenous administration: Suitable reconstitution solutions for intravenous injection solutions are:
Sterile Water for Injections;
5% Dextrose Injection;
0.9% Sodium Chloride Injection.
Aseptically add 5ml of the reconstitution solution to the 500mg vial or 10ml of the reconstituted solution to the 1g vial. Shake to effect solution and withdraw the entire contents. The solution may be slowly injected directly into a vein over a 3 to 5 minute period.
For continuous or intermittent intravenous infusion:
Suitable reconstitution solutions for intravenous infusion solutions are:
Sterile Water for Injections (50mg/ml cefradine solutions are approximately isotonic);
5% or 10% Dextrose Injection;
0.9% Sodium Chloride Injection;
Sodium Lactate Injection (M/6 sodium lactate);
Dextrose and Sodium Chloride Injection;
Lactated Ringer's Injection; Ringer's Injection;
5% Dextrose in Lactated Ringer's Injection;
5% Dextrose in Ringer's Injection.
Aseptically add 5ml of the reconstitution solution to the 500mg vial or 10ml of the reconstituted solution to the 1g vial and shake to effect solution. Aseptically transfer the entire contents to the IV infusion diluent.
Reconstituted solutions may vary in colour from light to straw yellow; however, this does not affect the potency.
Protect solutions of cefradine from concentrated light or direct sunlight.
Stability
From a microbial point of view, all strengths of reconstituted product should be used immediately, unless reconstitution has taken place in controlled and validated aseptic conditions.
If the reconstituted product is not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
For solutions for intramuscular and direct intravenous injection, chemical and physical in-use stability has been demonstrated for 2 hours at room temperature (25°C) and 12 hours when stored in a refrigerator at 2°-8°C.
For solutions for intravenous infusion, using Water for Injection, Glucose 5% or Sodium Chloride 0.9%, for concentrations up to 10mg/ml (1%), chemical and physical in-use stability has been demonstrated for 12 hours at room temperature (25°C) and 1 week when stored in a refrigerator at 2°-8°C and, for concentrations up to 50mg/ml (5%), chemical and physical in-use stability has been demonstrated for 10 hours at room temperature (25°C) or 48 hours at 2°-8°C.
In the case of prolonged infusion, replace 5% infusions every 10 hours and 1% infusions every 12 hours with freshly-prepared solutions.
7. Marketing Authorisation Holder
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Uxbridge Business Park
Sanderson Road
Uxbridge
Middlesex
UB8 1DH
8. Marketing Authorisation Number(S)
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9. Date Of First Authorisation/Renewal Of The Authorisation
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10. Date Of Revision Of The Text
June 2005
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