INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo RANFRADIN 250 Capsules
RANFRADIN 500 Capsules

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

RANFRADIN 250 Capsules
RANFRADIN 500 Capsules

COMPOSITION:
Ranfradin 250 Capsules
Each capsule contains
Cefradine        250 mg

Ranfradin 500 Capsules
Each capsule contains
Cefradine        500 mg

PHARMACOLOGICAL CLASSIFICATION:
A 20.1.1 Broad and medium spectrum antibiotics.

PHARMACOLOGICAL ACTION
Cefradine is a broad spectrum, bactericidal antibiotic active against Gram-positive and Gram-negative bacteria. This antibiotic demonstrates high activity against most strains of penicillinase producing staphylococci.
Microbiology
The following organisms have shown in vitro sensitivity to cefradine: (In vitro sensitivity does not necessarily imply in vivo efficacy)
Gram-positive: Staphylococci (both penicillin sensitive and resistant strains), Group A Beta-haemolytic streptococci, and Streptococcus pneumoniae.
Gram-negative: Escherichia coli, Klebsiella species, Proteus mirabilis, Haemophilus influenzae and Neisseria species.
Pseudomonas are uniformly resistant.
Because cefradine is unaffected by penicillinase, many strains of E.coli and Staphylococcus aureus that produce this enzyme are susceptible to cefradine.
When tested by in vitro methods staphylococci exhibit cross resistance between cefradine and methicillin type antibiotics.
Pharmacokinetics
Cefradine is absorbed following oral administration in the fasting state following doses of 250 mg and 500 mg, average peak serum levels of approximately 9 and 16,5 mcg/mL, respectively, were obtained at one hour. The presence of food in the gastro-intestinal tract delays the absorption but does not affect the total amount of cefradine absorbed. Measurable serum levels are present six hours after administration. Over 90% of the medicine is excreted unchanged in the urine within 6 hours. Peak urine concentrations are approximately 1 600 mcg/mL following a 250 mg dose and 3 200 mcg/mL following a 500 mg dose. After 48 hours administration of 100 mg/kg/day of cefradine for the treatment of otitis media, cefradine has been measured in the middle ear exudate at an average level of 3,6 mcg/mL.

INDICATIONS
Cefradine is indicated for use primarily in the treatment of infections of the genitourinary, gastro-intestinal and respiratory tracts and in the skin and soft tissues caused by susceptible organisms as listed below:
Staphylococcal infections (including infections caused by both penicillinase producing and non-penicillinase producing strains): Abscess, furunculosis, bronchitis and impetigo.
Streptococcal infections (beta-haemolytic): Cellulitis, pneumonia, follicular tonsillitis, otitis media, pharyngitis, sinusitis, scarlet fever, septic sore throat and urinary tract infections.
Pneumococcal infections: Lobar pneumonia, bronchitis, cellulitis and otitis media.
Haemophilus influenzaeinfections: Otitis media and laryngotracheo-bronchitis.
E.coliinfections: Abscess and urinary tract infections.
Klebsiella infections: Lobar pneumonia and urinary tract infections.
Bacteriology 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.

CONTRA-INDICATIONS
Cefradine is contra-indicated in patients with known hypersensitivity to the cephalosporin family of antibiotics. Safety in pregnancy and lactation have not been established. Cefradine is secreted in breast milk during lactation.

WARNINGS
Cefradine should be administered cautiously to any patient who has demonstrated some form of allergy.
The diagnosis of pseudomembranous colitis must be considered in patietns who develop diarrhoea in association with its use. Such colitis may be life-threatening and appropriate measures should be taken including discontinuation of cefradine.
Before cefradine therapy is instituted, careful enquiry should be made concerning previous hypersensitivity reactions to cephalosporins and penicillin. Serious acute hypersensitivity reactions may require adrenaline and other emergency measures. There is evidence of partial cross-allergenicity between the penicillins and the cephalosporins. Patients have been reported to have had severe reactions, including anaphylaxis to both medicines.

DOSAGE AND DIRECTIONS FOR USE
Cefradine capsules may be administered on a four times a day regimen. Studies with the capsules have demonstrated that they may be administered according to a twice a day regimen. Those situations in which a twice a day regimen may be used are noted below:
Cefradine may be given without regard to meals.
Adults
For respiratory tract infections (other than lobar pneumonia) the usual dose is 250 mg four times a day in equally spaced doses. Mild or moderately severe upper respiratory tract infections and skin and/or soft tissue infections can be treated with capsules, 500 mg twice a day. For genitourinary tract infections and lobar pneumonia the usual dose is 500 mg four time a day in equally spaced doses; severe or chronic infections may require larger doses. Mild or moderately severe urinary tract infections can be treated with capsules, 1000 mg twice a day. Prolonged intensive therapy is recommended for prostatitis and epididymitis.
Children (older than 6 years)
The usual dose is from 25 to 50 mg/kg/day, given four times a day in equally divided and spaced doses. For otitis media due to H.influenzae, doses from 75 to 100 mg/kg day in equally divided and spaced doses is recommended. The maximum dose should not exceed 4 grams per day.
All patients, irrespective of age and mass
Larger doses (up to 1 gram four times a day) may be given for severe chronic infections. Therapy should be continued for a minimum of 48 to 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 treatment is recommended to guard against the risk of rheumatic fever or glomerulonephritis. In the treatment of chronic urinary infections, frequent bacteriologic and clinical appraisal is necessary for several months afterwards. Stubborn 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.
Renal impairment dosage
The following dosage schedule based on a dosage of 500 mg every six hours and on creatinine clearance is suggested as a guideline. Further modification in the dosage schedule may be required because of the dosage selected and individual variation.
Creatinine clearance         Dose Time interval
>20 mL/min         500 mg         6 hours
5-20 mL/min         250 mg         6 hours
<5 mL/min         250 mg         12 hours
On chronic, intermittent hemodialysis:
250 mg start
250 mg at 12 hours
250 mg 36-48 hours (after start)
Children may require dosage modification proportional to their weight and severity of infection.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects
Untoward reactions are essentially gastro-intestinal disturbances and on occasion, to hypersensitivity phenomena. The latter are more likely to occur in individuals who previously have demonstrated hypersensitivity phenomena and those with a history of allergy, asthma, hay fever, or urticaria.
Gastro-intestinal: Glossitis, nausea, vomiting, diarrhoea or loose stools, abdominal pain and heartburn and colitis were reported by some patients. Sore mouth or tongue or a black hairy tongue have less frequently been reported.
Skin and hypersensitivity reactions: Fever, reactions resembling serum sickness, anaphylaxis have been reported. A mild urticaria or skin rash , pruritus, and joint pains were reported.
Blood: Mild, transient eosinophilia, leukopenia and neutropenia, thrombocytopenia, less frequently agranulocytosis, haemolytic anaemia.
Liver: Cases of elevated SGOT, SGPT, total bilirubin and alkaline phosphatase have been observed; in most patients the values were only mildly elevated and tended to return to normal at the end of therapy. No consistent pattern was observed that would suggest hepatocellular damage.
Nephrotoxicity, hepatitis and cholestatic jaundice have occurred less frequently.
Renal: Mild elevations of blood urea have been reported. In most cases, however, the values tended to return to normal. In adults for whom serum creatinine determinations were performed the rise in blood urea was not accompanied by a rise in serum creatinine, which would suggest an extrarenal mechanism for the elevation of blood urea.
Other side effects reported were dizziness and tightness in the chest, and candidal vaginitis.
Precautions
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. (see warnings)
There have been instances of patients who have had reactions to both drug classes (including anaphylaxis).
Pseudomembranous colitis has been reported with the use of cephalosporins (and other broad spectrum antibiotics); therefore, it is important to consider this diagnosis in patients who develop diarrhoea in association with antibiotic use. (see warnings).
Some patients with syphilis and other spirochaete infections may experience a Jarisch-Hexheimer reaction shortly after starting treatment with cefradine. Symptoms include fever, chills, headache and reactions at the site of the lesions. The reaction can be dangerous in cardiovascular syphilis or where there is a serious risk of increased local damage such as with optic atrophy.
Patients with known or suspected renal impairment should receive careful clinical observation and appropriate laboratory studies since cefradine may accumulate in the serum and tissues unless the dosage is suitably reduced (see “Dosage and directions for use”).
Prolonged use may result in overgrowth of non susceptible organisms.
After treatment with cefradine, a false positive reaction for glucose in the urine may occur with Benedict’s or Fehling’s solution or with Clinitest tablets but not with enzyme based tests such as Clinistix and Tes-Tape.
A false positive Coombs’test has been reported.
Interactions:
The concomitant use of a nephrotoxic agent such as the aminoglycoside gentamycin may increase the risk of kidney damage. There is also some evidence of enhanced nephrotoxicity with a loop diuretic like frusemide. Renal excretion is inhibited by probenecid. Probenecid prolongs the half life of cefradine by competing with it for renal tubular secretion and may be used therapeutically for this purpose. There may be antagonism between cefradine and bacteriostatic antibacterials.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
See side effects and special precautions. Treatment is symptomative and supportive.

IDENTIFICATION:
Ranfradin 250 Capsules:
Opaque, hard gelatin, self locked capsules of size `2' with blue cap and orange body imprinted with 250 on both cap and body in black edible ink containing white or slightly yellow granular powder.
Ranfradin 500 Capsules:
Opaque, hard gelatin, self locked capsules of size `0' with blue cap and blue body impritnted with 500 on both cap and body in black edible ink containing white or slightly yellow granular powder.

PRESENTATION:
Ranfradin 250 Capsules: Carton containing blister strip of 20 or 100 capsules.
Ranfradin 500 Capsules: Carton containing blister strip of 20 or 100 capsules.

STORAGE INSTRUCTIONS:
Store below 25°C protected from moisture
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:
Ranfradin 250 Capsules:        34/20.1.1/0163
Ranfradin 500 Capsules:        34/20.1.1/0164

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
RANBAXY (SA) (PTY) LTD
Third Floor
Outspan House
1006 Lenchen Avenue North
Centurion

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
December 2001

Amended: 12-04-2001

New addition to this site: March 2002

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