DESCRIPTION:

CEFRINEX (Cephradine) is a first-generation cephalosporin antibacterial given orally and by parenteral route in the treatment of susceptible infections and in the prophylaxis of infections during surgical procedures. Chemically, cephradine is (6R,7R)-7-[(R)-2-Amino-2-(1,4-cyclohexadien-1-yl)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The molecular formula is C₁₆H₁₉N₃O₄S.

COMPOSITION:

CEFRINEX 250mg Capsules:
Each Capsule Contains:
Cephradine U.S.P. ……250mg
(Product Specs.: U.S.P.)
“Product contains Lactose”

CEFRINEX 500mg Capsule:
Each Capsule Contains:
Cephradine U.S.P. ……500mg
(Product Specs.: U.S.P.)

CEFRINEX 125mg/5ml Suspension:
Each 5ml Contains:
Cephradine U.S.P. … 125mg
(Product Specs.: U.S.P.)

CEFRINEX 250mg/5ml Suspension:
Each 5ml Contains:
Cephradine U.S.P. … 250mg
(Product Specs.: U.S.P.)

CLINICAL PHARMACOLOGY:
Pharmacodynamic Properties:
Pharmacotherapeutic group: first generation cephalosporin,
ATC code: J01DB09

Mechanism of Action:
Cephradine inhibits the final transpeptidation step of the peptidoglycan synthesis in bacterial cell wall by binding to one or more of the penicillin-binding proteins (PBPs), thus arresting cell wall synthesis leading to bacterial cell death.

Microbiology:

Gram-Positive Bacteria:
Staphylococci (both penicillin sensitive and resistant strains), Streptococci, Streptococcus pyogenes (beta haemolytic) and Streptococcus pneumonia.

Gram-Negative Bacteria:
Escherichia coli, Klebsiella spp., Proteus mirabilis, Haemophilus influenza, Shigella spp., Salmonella spp., (including Salmonella typhi) and Neisseria spp.

Pharmacokinetic Properties

Absorption:
CEFRINEX has a high degree of stability to many 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.

Oral CEFRINEX can be given twice or four times daily and is well absorbed. Cefradine is acid stable and is rapidly absorbed following oral administration in the fasting state.

Distribution:
Following doses of 250mg, 500mg and 1000mg average peak serum levels of approximately 9, 16.5, and 24.2 mcg/mL, respectively, were obtained at one hour. The presence of food in the gastrointestinal tract delays the absorption but does not affect the total amount of cefradine absorbed. Measurable serum levels are present six hours after administration.

Elimination:
Over 90% of the drug is excreted unchanged in the urine within 6 hours. Peak urine concentrations are approximately 1600 mcg/ml following a 250mg dose, 3200 mcg/mL following a 500mg dose, and 4000 mcg/mL following a 1000mg dose. After 48 hours administration of 100mg/kg/day of CEFRINEX for the treatment of otitis media, cephradine has been measured in the middle ear exudate at an average level of 3.6 mcg/mL.

SPECIFIC POPULATIONS

Renal impairment
Plasma concentration of cephradine is prolonged in patients with renal impairment.

THERAPEUTIC INDICATIONS:
CEFRINEX (Cephradine) is indicated in the treatment of following infections:

Upper respiratory tract infections:
Sinusitis, pharyngitis, tonsillitis, laryngo-tracheo bronchitis and otitis media.

Lower respiratory tract infections:
Acute and chronic bronchitis, lobar and bronchopneumonia.

Urinary tract infections:
Cystitis, urethritis and pyelonephritis.

Skin and soft tissue infections:
Impetigo, abscess, cellulitis and furunculosis.

Gastrointestinal tract infections:
Bacillary dysentery, enteritis and peritonitis

DOSAGE AND ADMINISTRATION:
CEFRINEX (Cephradine) may be given with regards to meal.

Adults
Respiratory tract infections, skin and soft tissue infections:
The usual dose is 250mg or 500mg four times daily or 500mg or 1g twice daily depending upon the severity of infection.

Urinary tract infection:
The usual dose is 500mg four times daily or 1g twice daily. This may need to be increased for severe or chronic infections. Prolonged intensive therapy is needed for complications such as prostatitis and epididymitis.

Gastrointestinal tract infections:
500mg three or four times daily.

Pediatrics
The usual dose is 25 to 50mg/kg/day total, given in two or four equally divided doses. For otitis media daily doses from 75 to 100mg/kg in divided doses every 6 to 12 hours are recommended. The dose should not exceed 4g per day.

Duration of treatment
For severe or chronic infection larger dose of up to 1g four times daily may be given. Administration should be continued for a minimum of 48- 72 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. For infections caused by hemolytic strains of streptococci, a minimum of 10 days treatment is recommended to guard against the risk of rheumatic fever or glomerulo-nephritis. For 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 should not be used. Doses for children should not exceed those recommended for adults.

SPECIAL POPULATION

Renal Impairment

Patients not on dialysis:
The following dosage schedule guideline is based on a dosage of 500mg 6 hourly and on creatinine clearance. Further modification in the dosage schedule may be required because of the dosage selected and individual variation.

Patients on chronic, intermittent hemodialysis:

Children may require dosage modification proportional to their weight and severity of infection.

Direction for Preparation Oral Suspension
Add small quantity of pre-boiled cool water in the bottle and shake, add more water upto the mark given on the label and shake vigorously to make suspension. Once reconstituted the suspension must be used within 14 days when stored in refrigerator or within 7 days at room temperature. Close the bottle properly after use.

CONTRAINDICATIONS:
Cephradine is contraindicated in patients with known hypersensitivity to cephradine or to any excipient of the product.

WARNINGS AND PRECAUTIONS:

• Cephradine should be used with caution in patients with known hypersensitivity to penicillins because of partial allergenicity between penicillins and the cephalosporins.
• Caution should be exercised in patients with renal failure and dosage should be reduced.
• False positive reaction for glucose in the urine may occur with Benedict’s or Fehling’s solution or with reagent tablets such as Clinitest following administration of cephradine.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine.
• Prolonged use with antibiotics may result in overgrowth of non-susceptible microorganisms.

DRUG INTERACTIONS:

• Concomitant administration with loop diuretics may increase nephrotoxicity of cephalosporins.
• Concomitant administration of probenecid raises serum concentrations of cephradine, by reducing renal clearance.

ADVERSE EFFECTS:

General:

Gastrointestinal:
Glossitis, nausea, vomiting, diarrhea or loose stools, tenesmus, abdominal paincolitis and pseudomembranous colitis.

Hypersensitivity:
Mild urticaria or skin rash, edema, erythema, pruritis, joint pain and drug fever.

Hematologic:
Mild, transient eosinophilia, leukpenia and neutropenia.

Other: Headache, dizziness, dyspnea, paresthesia, candida overgrowth and vaginitis.

Rare: Antibiotic-associated colitis, Headache, Vomiting, abdominal discomfort.

Not Known: Vaginitis, candidal overgrowth, candidiasis, Eosinophilia, blood disorders (including thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia and haemolytic anaemia), Fever, athralgia, serum sickness-like reactions, anaphylaxis, Confusion, sleep disturbances, Hypersensitivity, hyperactivity, hypertonia, dizziness, nervousness, Diarrhoea, nausea, glossitis, heartburn, Liver, enzyme disturbances, transient hepatitis, cholestatic jaundice, Rashes, toxic epidermal necrolysis, pruritis, urticaria, erythema multiforme, Stevens-Johnson syndrome, oedema, Reversible interstitial nephritis, Reversible interstitial nephritis, joint pain.

USE IN PREGNANCY AND LACTATION:

Pregnancy:
There are no adequate and well-controlled studies in pregnant women. As with all medicines, use should be avoided in pregnancy especially in the first trimester, unless considered essential by the physician.

Lactation:
Cephradine is excreted in breast milk and therefore should be used with caution in nursing mothers.

OVERDOSE:
There is no relevant data available on overdosage. In the event of overdose, the patient be treated symptomatically, and supportive measures should be instituted as required.

Shelf Life: 3 Years

INSTRUCTIONS:

• Protect from heat, sunlight & moisture.
• Store at room temperature (15°C-30°C).
• Keep out of the reach of children.
• Patients and healthcare professionals can also report suspected adverse drug reaction at ade@bosch-pharma.com.
• To be sold on prescription of a registered medical practitioner only.

PRESENTATION:

CEFRINEX 250mg capsules in blister pack of 1×12’s

CEFRINEX 500mg capsules in blister pack of 2×6’s.

CEFRINEX 125mg / 5ml Suspension: Pack contain dry powder for 90ml suspension (after reconstitution) in Glass bottle.

CEFRINEX 250mg / 5ml Suspension: Pack contain dry powder for 90ml suspension (after reconstitution) in Glass bottle.

DESCRIPTION:

CEFRINEX (Cephradine) is a first-generation cephalosporin antibacterial given orally and by parenteral route in the treatment of susceptible infections and in the prophylaxis of infections during surgical procedures.

Chemically, cephradine is (6R,7R)-7-[(R)-2-Amino-2-(1,4-cyclohexadien-1-yl)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The molecular formula is C₁₆H₁₉N₃O₄S.

COMPOSITION:

Cefrinex 250mg vial:
Each vial contains: Cephradine U.S.P. …. 250mg with
Sterile Arginine U.S.P.
(Product Specs.: U.S.P.)

Cefrinex 500mg vial:
Each vial contains:
Cephradine U.S.P. …. 500mg
with Sterile Arginine U.S.P.
(Product Specs.: U.S.P.)

Cefrinex 1000mg vial:
Each vial contains:
Cephradine U.S.P. …. 1000mg
with Sterile Arginine U.S.P.
(Product Specs.: U.S.P.)

CLINICAL PHARMACOLOGY:

Pharmacodynamic Properties:
Pharmacotherapeutic group: first generation cephalosporin,
ATC code: J01DB09

Mechanism of Action:
Cephradine inhibits the final transpeptidation step of the peptidoglycan synthesis in bacterial cell wall by binding to one or more of the penicillin-binding proteins (PBPs), thus arresting cell wall synthesis leading to bacterial cell death.

Microbiology:

Gram-Positive Bacteria:
Staphylococci (both penicillin sensitive and resistant strains), Streptococci, Streptococcus pyogenes (beta haemolytic) and Streptococcus pneumonia.

Gram-Negative Bacteria:
Escherichia coli, Klebsiella spp., Proteus mirabilis, Haemophilus influenza, Shigella spp., Salmonella spp., (including Salmonella typhi) and Neisseria spp.

Pharmacokinetic Properties
Following intramuscular injection of cephradine, peak plasma concentrations of about 6 μg/mL and 14 μg/mL have been obtained within 1 to 2 hours of doses of 500mg and 1g respectively. Cephradine is widely distributed to body tissues and fluids, but does not enter the CSF in significant quantities. It crosses the placenta into fetal circulation and is distributed in small amounts into breast milk.  Therapeutic concentrations may be found in bile.  Only 8% to 12% is bound to plasma proteins. A plasma halflife of about 1 hour has been reported. Cephradine is excreted unchanged in the urine by glomerular filtration and tubular secretion. Over 60% to 80% of an intramuscular dose is being recovered within 6 hours.

SPECIFIC POPULATIONS

Renal Impairment
Plasma concentration of cephradine is prolonged in patients with renal impairment.

THERAPEUTIC INDICATIONS:
CEFRINEX (Cephradine) is indicated in the treatment of following infections due to susceptible organisms:

• Respiratory tract infections
• Urinary tract infections
• Skin and skin structure infections
• Bone infections
• Septicemia

CEFRINEX (Cephradine) is effective in the prevention of postsurgical infections in patients about to undergo surgical procedures which are classified as contaminated or potentially contaminated, or in which infection at the operative site would present a serious risk, e.g. vaginal hysterectomy, cesarean section and prosthetic arthroplasty.

DOSAGE AND ADMINISTRATION:

Adults:
The usual daily dosage of CEFRINEX (Cephradine) Injection is 2 to 4g daily in four equally divided doses intramuscularly or intravenously (e.g., 500mg to 1g qid). A dosage of 500mg qid is adequate in uncomplicated pneumonia, skin and skin structure infections and most urinary tract infections. In bone infections the usual dosage is 1g qid administered intravenously. In severe infections such as endocarditis, 2g qid given intravenously is recommended. Alternatively, in severe infections, the dose may be increased by giving injections every four hours. The maximum dose should not exceed 8g per day.

Prophylaxis:
To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended doses are as follows:

• 1g IV or IM administered 30 to 90 minutes prior to start of surgery.
• 1g every 4 to 6 hours after the first dose for one to two doses, or for up to 24 hours postoperatively.

Prophylaxis in cesarean section:
The first dose of 1g is administered intravenously as soon as the umbilical cord is clamped. The second and third doses should be given as 1g intravenously or intramuscularly at 6 and 12 hours after the first dose.

Pediatrics
The usual dose range is 50 to 100mg/kg/day in equally divided doses four times a day and should be regulated by age, weight of the patient and severity of the infection being treated. The maximum pediatric daily dose should not exceed the dose recommended for adults.

Patients with Renal Impairment:

Patients not on dialysis:
The following dosage schedule guidelines are based on a dosage of 500mg 6 hourly and on creatinine clearance. Further modification in the dosage schedule may be required because of the dosage selected and individual variation.

Patients on chronic, intermittent hemodialysis:

Children may require dosage modification proportional to their weight and severity of infection.

Method of Administration:

Parentral:
CEFRINEX (Cephradine) may be given intravenously and by deep intramuscular injection. To minimize pain and induration, intramuscular injection should be made into a large muscle mass, such as gluteus or lateral aspect of the thigh. Intravenously, CEFRINEX (Cephradine) may be administered by either direct intravenous injection or by intravenous infusion. For direct intravenous injection, the solution may be slowly injected directly in to the vein over a 3 to 5 minutes period or may be given as a supplementary injection through the injection site on an administration set when the infusion solution is compatible with cephradine.

For intramuscular use:
Aseptically add Sterile Water for Injection according to the following table:

Shake well to dissolve and withdraw the required amount. CEFRINEX (Cephradine) contains no bacteriostat and is not multiple-dose use. Solutions should be used within 2 hours if held at room temperature. Reconstituted solution may vary in color from light to straw yellow, however, this does not affect the potency. If a local anesthetic is considered desirable for intramuscular use only, 0.5% lidocaine hydrochloride injection is recommended as diluent in place of above mentioned volumes of Sterile Water for Injection. Other diluents suitable for intramuscular use are lidocaine hydrochloride injection 1% or procaine hydrochloride injection 1% or 2%.

For direct intravenous injection:
Suitable intravenous injection diluents are Sterile Water for Injection, 5% dextrose injection or sodium chloride injection. Aseptically add 5mL of diluent to 250mg or 500mg vials and 10mL to the 1g vial. Shake well to dissolve and withdraw the entire content. These solutions should be used within 2 hours when held at room temperature.

For continuous or intermittent IV infusion:
Suitable intravenous infusion solutions are 5% or 10% dextrose injection, sodium chloride injection, sodium lactate injection (M/6 sodium lactate), dextrose and sodium chloride injection (5%; 0.9%) or (5%; 0.45%), 10% invert sugar in water for injection. Sterile Water for Injection may be used as IV infusion solution for CEFRINEX (Cephradine) at a cephradine concentration of 30 to 50mg/mL (30mg/mL is approximately isotonic). To prepare CEFRINEX (Cephradine) for transfer into an IV infusion container, aseptically add 10ml of Sterile Water for Injection or a suitable infusion solution to 1g vial and shake well to dissolve. Aseptically transfer the entire content to the IV infusion container. For prolonged infusions, replace the infusion every 10 hours with a freshly prepared solution. Infusion solutions of CEFRINEX (Cephradine) in Sterile Water for Injection that are frozen immediately after reconstitution in the original container are stable for as long as six weeks when stored at -20°C. Extemporaneous mixtures of CEFRINEX (Cephradine) with other antibiotics are not recommended. Protect solutions of CEFRINEX (Cephradine) from concentrated light or direct sunlight.

CONTRAINDICATIONS:
Cephradine is contraindicated in patients with known hypersensitivity to cephradine or to any excipient of the product.

WARNINGS AND PRECAUTIONS:

• Cephradine should be used with caution in patients with known hypersensitivity to penicillins because of partial allergenicity between penicillins and the cephalosporins.
• Caution should be exercised in patients with renal failure and dosage should be reduced.
• False positive reaction for glucose in the urine may occur with Benedict’s or Fehling’s solution or with reagent tablets such as Clinitest following administration of cephradine.
• Prolonged use with antibiotics may result in overgrowth of non-susceptible microorganisms.

DRUG INTERACTIONS:

• Concomitant administration with loop diuretics may increase nephrotoxicity of cephalosporins.
• Concomitant administration of probenecid raises serum concentrations of cephradine, by reducing renal clearance.

ADVERSE EFFECTS:

The following adverse reactions have been reported following the use of cephradine:

Gastrointestinal: Glossitis, nausea, vomiting, diarrhea or loose stools, tenesmus, abdominal pain, colitis and pseudomembranous colitis.

Hypersensitivity: Mild urticaria or skin rash, edema, erythema, pruritis, joint pain and drug fever.

Hematologic: Mild, transient eosinophilia, leukopenia and neutropenia.

Other: Headache, dizziness, dyspnea, paresthesia, candidal overgrowth and vaginitis.

USE IN PREGNANCY AND LACTATION:

Pregnancy:
There are no adequate and well-controlled studies in pregnant women. As with all medicines, use should be avoided in pregnancy especially in the first trimester, unless considered essential by the physician.

Lactation:
Cephradine is excreted in breast milk and therefore should be used with caution in nursing mothers.

OVERDOSE:
There is no relevant data available on overdosage. In the event of overdose, the patient be treated symptomatically, and supportive measures should be instituted as required.

SHELF LIFE: 3 Years

INSTRUCTIONS:

• Protect from heat, sunlight and moisture, store at 25°C.
• Keep out of reach of children.
• The expiration date refers to the product correctly stored at the required conditions.
• Patients and healthcare professionals can also report suspected adverse drug reaction at ade@bosch-pharma.com.
• To be sold on prescription of a registered medical practitioner only.

PRESENTATION:

CEFRINEX 250mg Injection
Pack of 1 vial + 5 ml sterile water for injection as a solvent.

CEFRINEX 500mg Injection
Pack of 1 vial + 5 ml sterile water for injection as a solvent.

CEFRINEX 1000mg Injection
Pack of 1 vial + 5 ml sterile water for injection as a solvent.