INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
OFRAMAX 250 (Injection)
OFRAMAX 1 g (Injection)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

OFRAMAX 250 (Injection)
OFRAMAX 1 g (Injection)

COMPOSITION:
Oframax 250
Each vial contains:
Ceftriaxone sodium (Sterile)
equivalent to ceftriaxone 250 mg

Oframax 1 g
Each vial contains:
Ceftriaxone sodium (Sterile)
equivalent to ceftriaxone 1 g

PHARMACOLOGICAL CLASSIFICATION:
A 20.1.1. Broad and medium spectrum antibiotics

PHARMACOLOGICAL ACTION
Ceftriaxone is a broad-spectrum cephalosporin with a long plasma elimination half-life of approximately 8 hours in normal adults.
Antimicrobial Profile
(In vitro sensitivity does not necessarily imply in vivo efficacy).
The in vitro spectrum of activity of ceftriaxone encompasses:
(a) Gram-positive organisms:
Streptococcus pneumoniae, Streptococcus Group A (including Streptococcus pyogenes), Streptococcus Group B (including Streptococcus agalactiae), Streptococcus viridans, Streptococcus bovis (Group D), Staphylococcus aureus (methicillin sensitive). Peptostreptococcus sp., and Clostridium sp.
Note: Methicillin-resistant Staphylococcus spp. are resistant to ceftriaxone. Enterococcus faecalis, Enterococcus faecium and Listeria monocytogenes are resistant.
(b) Gram-negative organisms:
Haemophilus influenzae (including ampicillin-resistant strains), Haemophilus parainfluenzae, Neisseria meningitidis, Neisseria gonorrhoeae (including penicillin-resistant strains),Escherichia coli, Klebsiella sp**, Enterobacter sp*, Serratia marcescens, Citrobacter sp., Proteus mirabilis, Indole-positive Proteus (including Morganella morganii), Salmonella sp., Shigella sp., Yersinia pestis and Treponema pallidum (in animal experiments).
*Some isolates of these species are resistant to ceftriaxone, due to the production of the chromosomally encoded beta-lactamases.
**Some isolates of these species are resistant due to production of extended spectrum plasmid mediated beta-lactamase.
(c) Organisms which are only partially sensitive to ceftriaxone in vitro. Staphylococcus epidermidis, Pseudomonas aeruginosa, Acinetobacter sp. and Bacteroides sp. Ceftriaxone is stable in relation to the majority of beta-lactamases.
The following organisms are resistant:
Ureaplasma urealyticum, Mycoplasma sp., Mycobacterium sp., Fungi.
It is essential to note that recommended media (free from inhibitory substances especially thymidine and thymine) and methods must be used for satisfactory sensitivity testing.

Pharmacokinetics
The maximum plasma concentration after a single IM dose of 1.0 g is about 81 mg/L and is reached in 2-3 hours after the dose. The area under the plasma concentration-time curve after IM administration is equivalent to that after IV administration of an equivalent dose, indicating 100% bioavailability of intramuscularly administered ceftriaxone.
On intravenous administration, ceftriaxone diffuses into the tissue fluid, where-if it is given in the recommended dosage range-bactericidal concentrations lasting 24 hours may be maintained. Ceftriaxone is reversibly bound to albumin, and the binding decreases with the increase in concentration e.g. from 95% binding at plasma concentrations of <100 mg/L to 85% binding at 300 mg/L. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma.
The volume of distribution of ceftriaxone is 7-12 L. After a dose of 1-2 g, concentrations above the minimal inhibitory concentrations of most pathogens responsible for infection are detected for more than 24 hours in the following tissues or body fluids: lung, heart, biliary tract/liver, tonsil, middle ear and nasal mucosa, bone; and cerebral, pleural, prostatic and synovial fluids.
In healthy, young adult volunteers the total plasma clearance is 10-22 mL/min. The renal clearance is 5-12 mL/min. 50-60% of ceftriaxone is excreted unchanged in the urine, while 40-50% is excreted unchanged in the bile. The elimination half life in adults is about eight hours.
The substance is largely inactivated in the faeces due to metabolism by intestinal flora.
The mean plasma elimination half life is 8 hours in healthy, young adult volunteers. In neonates, urinary recovery accounts for about 70% of the dose. In infants aged less than eight days and in elderly persons aged over 75 years, the average elimination half life is usually 2-3 times that in the young adult group.
In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered and the elimination half life is only slightly increased. If kidney function alone is impaired, biliary elimination of ceftriaxone is increased; if liver function alone is impaired, renal elimination is increased.
In meningitis patients, administration of 50 mg per kg bodymass leads within 2-24 hours to cerebro spinal fluid concentrations several times as high as the minimum in vitro inhibitory concentrations required for the most common causative organisms of meningitis.

INDICATIONS:
Infections caused by pathogens sensitive to ceftriaxone such as

-	sepsis
-	meningitis in neonates and infants
-	perioperative prophylaxis of infections
-	renal and urinary tract infections
-	respiratory tract infections, particularly pneumonia, and ear, nose and throat infections.
-	infections of the bones, joints, soft tissue, skin and of wounds.
-	abdominal infections (peritonitis, infections of the biliary tract).
-	uncomplicated gonorrhoea

CONTRAINDICATIONS
Allergy to cephalosporins. In patients hypersensitive to penicillin, the possibility of allergic cross reactions should be borne in mind. (see warnings)
Pregnancy and Lactation
Safety in human pregnancy has not been established. As ceftriaxone is excreted in the breast milk at low concentrations, caution is advised in nursing mothers.

WARNINGS:
Before therapy with Oframax is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins or other medicines. About 10% of penicillin-sensitive patients may also be allergic to cephalosporins although the true incidence is uncertain. Great care should be taken if Oframax is to be given to such patients.

DOSAGE AND DIRECTIONS FOR USE:
Standard dosage
Adults and children over twelve: 1-2g ceftriaxone once daily (every 24 hours).
In severe infections and in cases in which the pathogens are only moderately sensitive to ceftriaxone, the daily dosage may be increased to 4 g administered daily.
Infants and young children may receive from 20-80 mg per kg body-mass daily; depending on the severity of the infection, usually 12-24 hourly.
In cases of premature babies, the daily dosage should not exceed 50 mg per kg body mass on account of the immaturity of the infant’s enzyme systems.
Elderly patients: The dosages recommended for adults require no modification in the case of geriatric patients.
Duration of therapy: The duration of therapy varies according to the course of the disease. Administration of ceftriaxone should be continued for a minimum of 48 to 72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained.
Special dosage instructions: Meningitis: In bacterial meningitis in neonates and children, treatment begins with doses of 100 mg per kg (not to exceed 4 g) once daily. As soon as the causative organism has been identified and its sensitivity determined, the dosage can be reduced accordingly.
Gonorrhoea: For the treatment of gonorrhoea (penicillinase-producing and non-penicillinase- producing strains), a single IM dose of 250 mg ceftriaxone is recommended.
Perioperative prophylaxis: A single dose of 1-2 g ceftriaxoneadministered 30-90 minutes prior to surgery. In colorectal surgery, concurrent (but separate) administration of ceftriaxone with a 5-nitroimidazole, eg. ornidazole, has proven effective.
Impaired renal and hepatic function: In patients with impaired renal function, there is no need to reduce the dosage ofceftriaxoneprovided that the hepatic function is intact.
In case of severe renal failure (creatinine clearance <10 mL/min) the ceftriaxone dosage should not exceed 2 g daily. In patients with liver damage, there is no need for the dosage to be reduced provided renal function is intact.
In cases of concomitant severe renal and hepatic dysfunction, the plasma concentrations of ceftriaxone should be determined at regular intervals. In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. Serum concentrations should be monitored, however, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be reduced.
Intramuscular Injection
For IM injection, Oframax 250 should be dissolved in 2 mL and Oframax1 g in 3.5 mL of water for injection. Oframaxdissolved in a 1% lidocaine solution can reduce pain at the site of injection. Oframax must be injected well within the body of a relatively large muscle. It is recommended that not more than 1 g be injected on either side. Reconstitution with 1% lidocaine (without adrenaline) has no effect on the absorption or the elimination of Ceftriaxone. The lidocaine solution must never be administered intravenously.
Intravenous Injection
For IV injection, Oframax 250 is dissolved in 5 mL water for injection and Oframax 1 g dissolved in 10 mL water for injection. The intravenous administration should be given over two to four minutes.
Intravenous infusion
The infusion should be given over a period of at least 30 minutes. For IV infusion, 2 g of Oframax is dissolved in approximately 40 mL of sterile water for injection.
Ceftriaxone solutions should not be mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, owing to possible incompatibility.
Incompatibilities: Ceftriaxone should not be added to solutions containing calcium such as Hartmann’s solution and Ringers solution. Ceftriaxone is incompatible with amsacrine, vancomycin and fluconazole and aminoglycosides.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side effects
Systemic:
Gastro-intestinal complaints: Loose stools/diarrhoea, nausea, vomiting, stomatitis, glossitis.
Haematological changes: Eosinophilia, haematoma or bleeding, thrombocytopenia, neutropenia, leukopenia, granulocytopenia and haemolytic anaemia.
Isolated cases of agranulocytosis (<500/mm³) have been reported, most of them following total doses of 20 g or more.
Exanthema, allergic dermatitis, pruritus, urticaria, oedema, erythema multiforme may occur.
Other side effects include headaches and dizziness, increase in liver enzymes, oliguria, increase in serum creatinine, mycosis of the genital tract, fever, shivering and anaphylactic or anaphylactoid reactions.
Nephrotoxicity has been reported. Acute interstitial nephritis is also a possibility as a manifestation of hypersensitivity.
Anaphylactic shock may occur: Anaphylactic shock requires immediate counter measures.
Acute renal tubular necrosis has followed excessive dosage and has also been associated with the use of Oframax in older patients or those with pre-existing renal impairment, or with the concomitant administration of nephrotoxic agents such as aminoglycosides.
Hepatitis and cholestatic jaundice have occurred less frequently.
Prolonged use may result in overgrowth of non-susceptible organisms.
Pseudomembranous colitis has been reported with Oframax. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of Oframax. Superinfections with non-susceptible micro-organisms may occur.
Local
Inflammatory reactions in the vein wall may occur after IV administration. These may be minimised by slow (2-4 minutes) injection of Oframax.
Intramuscular injection without lidocaine solution is painful.
Shadows which have been mistaken for gall stones have been detected by sonograms of the gallbladder, usually following higher than the standard recommended dose.
These shadows are, however, precipitates of calcium ceftriaxone which disappear on completion or discontinuation of ceftriaxone therapy.
In less frequent cases, these findings have been associated with symptoms. In symptomatic cases, conservative non-surgical management is recommended. Discontinuation of Oframax treatment in symptomatic cases should be at the discretion of the clinician.
Studies have shown that Oframax, can displace bilirubin from serum albumin. Caution should be exercised when considering Oframax treatment in hyperbilirubinemic neonates. Oframax should not be used in neonates (especially prematures) at risk of developing bilirubin encephalopathy.
During prolonged treatment the blood profile should be checked at regular intervals
Renal and haemotological status should be monitored especially during prolonged and high dose therapy.
Interactions:
No impairment of renal function has been observed after concurrent administration of large doses of Oframax and potent diuretics (eg. furosemide). There is no evidence that Oframax increases renal toxicity of aminoglycosides. No effects similar to that of disulfiram has been demonstrated after administration of alcohol with Oframax.
Oframax does not contain an N-methyl-thiotetrazole moiety associated with possible ethanol intolerance and bleeding problems. The elimination of Oframax is not altered by probenecid.
In an in vitro study antagonistic effects have been observed with the combination of chloramphenicol and Oframax.
There may be antagonism between Oframax and bacteriostatic antibacterial agents. Oframax may interfere with the Jaffe method of measuring creatinine concentrations and may produce falsely high values; this should be borne in mind when measuring renal function.
In patients treated with ceftriaxone the Coombs’test may become false positive. Oframax may result in false positive tests for galactosemia.
Likewise, nonenzymatic methods for the glucose determination in urine may give false positive results. For this reason urine glucose determination during therapy with Oframax should be done enzymatically.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
In the case of overdosage, plasma concentration would not be reduced by haemodialysis or peritoneal dialysis. Treatment is supportive and symptomatic.

IDENTIFICATION:
Oframax 250:
White to yellowish orange, crystalline powder in 5 ml clear glass USP type I, moulded vials with blue flip-off seals.
Oframax 1 g:
White to yellowish orange, crystalline powder in 15 ml clear glass USP type I, moulded vials with blue flip-off seals.
On constitution a pale yellow to reddish orange clear solution is obtained.

PRESENTATION
Oframax 250: Cartons containing 1 clear glass USP Type I vial.
Oframax 1g: Cartons containing 1 clear glass USP Type I vial.

STORAGE INSTRUCTIONS
Store below 25°C, protected from light and moisture. Do not freeze.
Reconstituted solution to be stored in original vials.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
Oframax 250: 34/20.1.1/0318
Oframax 1 g: 34/20.1.1/0319
Botswana
Oframax 250: R9800314
Oframax 1 g: R9800315

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
RANBAXY (SA) (PTY) LTD
3rd Floor
Outspan House
1006 Lenchen Avenue North
Centurion

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
October 2001

Updated on this site: June 2005
Source: Pharmaceutical Industry

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