cefotax vial

Composition

Each vial contains

Cefotaxime sodium 262.5 mg, 525 mg, 1048 mg, 2096.6 mg
Equivalent to Cefotaxime. . 250 mg, 500, 1 g, 2 g

Each ampoule solvent contains

Water for injection. 2 ml , 5 ml, 10 ml

Therapeutic indications

Cefotax is indicated in the treatment of serious infections, either before the infecting, organism has been identified or when caused by bacteria of established sensitivity, including:

Osteomyelitis,
Septicaemia,
Bacterial endocarditis,
Meningitis,
And other serious bacterial infections suitable for parenteral antibiotic therapy.

Cefotax may be used for pre-operative prophylaxis in patients undergoing surgical "procedures. That may be classified as contaminated or potentially so.

Posology and Method of Administration:

Cefotax may be administered intravenously by bolus injection or by infusion, or by intramuscular injection.

The dosage, route and frequency of administration should be determined by the severity of infection, the sensitivity of causative organisms and condition of the patient.

Therapy may be initiated before the results of sensitivity tests are known.

Adults dosage

The recommended dosage for mild to moderate infections is 1 g 12 hourly.

However, dosage may be varied according to the severity of the infection, sensitivity of causative- organisms and condition of the patient.

Therapy may be initiated before the results of sensitivity tests are known.

In severe Infections dosage may be increased up to 12 g daily given in three or four divided doses.

For infections caused by sensitive Pseudomonas species, daily doses of greater than 6 g will usually be required

Children dosage

The usual dosage range is 100-150 mg/kg/day in two to four divided doses.

However in very severe infections, doses of up to 200 mg/kg/day may be required.

Neonates dosage

The recommended dosage is 50 mg/kg/day in two to four divided doses. In severe infections 150-200 mg/kg/day, in divided doses, have been given.

Dosage in renal impairment

Because of extra-renal elimination, it is only necessary to reduce the dosage of Cefotax In severe renal failure IGFR <5 ml/min = serum creatinine approximately 751 micromollitre).

After an initial loading dose of 1g, daily dose should be halved without change in the frequency of dosing, i.e. 1 g twelve hourly becomes 0.5 g twelve hourly. 1 g eight hourly becomes 0.5 g eight hourly, 2 g eight hourly becomes 1 g eight hourly etc. As in all other patients, dosage may require further adjustment according, to the course of the infection and the general condition of the patient.

Dosage in hepatic impairment

No dosage adjustment is required.

Intravenous and Intramuscular Administration

Reconstitute Cefotax with Water for injection as directed in instructions for use/Handling). Shake well until dissolved and then withdraw the entire contents of the vial into the syringe.
Intravenous administration (Injection or Infusion]: Cefotax may be administered by intravenous Infusion using the fluids in (instructions for use/Handling). The prepared infusion may be administered over 20-60 minutes.
For intermittent I.V. The solution must be injected over a period of 3 to 5 minutes. During post-marketing surveillance.
Potentially life-threatening arrhythmia has been reported in a very few patients who received rapid intravenous administration of Cefotaxime through a central venous catheter.
Cefotax and amino glycosides should not be mixed in the same syringe or perfusion fluid.

cefotax vial - patient information

Contraindications

Hypersensitivity to Cefotaxime, to other cephalosporin or to any of the excipients. Previous immediate and/or severe hypersensitivity reaction to penicillin or to any other beta-lactarn medicinal products.

Special Warnings and Precautions for use

Special caution is required to determine any other type of previous hypersensitivity reactions to penicillin or to other beta-lactarn medicinal products because patients hypersensitive to these medicines may be hypersensitive to Cefotaxime as well cross- allergy).

As with other antibiotics, the use of Cefotaxime, especially if prolonged, may result in overgrowth of non susceptible organisms, such as Enterococcus spp., Candida, and Pseudomonas aeruginosa. Repeated evaluation of the condition of the patient is essential. If super infection occurs during treatment with Cefotaxime, appropriate measures should be taken and specific anti-microbial therapy should be instituted if considered clinically necessary.

Anaphylactic reaction

Preliminary enquiry about hypersensitivity to penicillin and other -Lactam antibiotics is necessary before prescribing cephalosporin, since cross allergy occurs in 5-10% of cases. The use of Cefotaxime is strictly contra-indicated in subjects with previous history of immediate-type hypersensitivity to cephalosporin. Since cross allergy exists between penicillin and cephalosporin, use of the latter should be undertaken with extreme caution in penicillin-sensitive subjects. Serious, including fatal hypersensitivity reactions have been reported in patients receiving Cefotaxime. If a hypersensitivity reaction occurs, treatment must be stopped.

Serious bullous reactions

Cases of serious bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with Cefotaxime (see Undesirable effects]. Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.

Patients with renal insufficiency

The dosage should be modified according to the creatinine clearance calculated. Patients with severe renal dysfunction should be placed on the dosage schedule recommended under "Posology and Method of Administration". Caution should be exercised if Cefotaxime is administered together with amino glycosides or other nephrotoxic drugs. Renal function must be monitored in these patients, the elderly, and those with pre-existing renal impairment.

Haematological reactions

Leucopoenia, neutropenia, and more rarely, agranulocytosis may develop during treatment with Cefotaxime, particularly if given over long periods. For treatment courses lasting longer than 7-10 days, the blood white cell count should be monitored; and treatment stopped in the event of neutropenia.

Some cases of eosinophilia and thrombocytopenia, rapidly reversible on stopping the treatment, have been reported. Cases of haemolytic anaemia have also been reported.

Sodium intake

The sodium content of Cefotax should be taken into account when prescribing to patients requiring sodium restriction.

Clostridium difficile associated disease (e.g. Pseudo membranous colitis)

Cefotaxime may predispose patients to pseudo membranous colitis. Although any antibiotic may predispose to pseudo membranous colitis, the risk is higher with broad spectrum drugs, such as cephalosporin. This side effect, which may occur more frequently in patients, receiving higher doses for prolonged periods, should be considered as potentially serious. " Diarrhoea, particularly If severe and/or persistent, occurring during treatment or in the initial weeks following treatment, may be symptomatic of Clostridium difficile associated ,disease (CDAD: CDAD may range in severity from mild to life-threatening, the most severe form of which is Pseudo membranous colitis. .

The diagnosis of this rare but possibly fatal condition can be confirmed by endoscopy • and/or histology. , It is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of Cefotaxime. 'If a diagnosis of pseudo membranous colitis is suspected, Cefotaxime should be stopped, immediately and appropriate Specific anti-microbial therapy should be started without delay.

Interaction with other medicinal products

Amino glycosde antibiotics and diuretics: As with other cephalosporin, Cefotaxime may potentiate nephrotoxic effects of nephrotoxic drugs such as amino glycosides or potent diuretics '(e.g. furosemide). Renal function must be monitored.

Uricosurics: Probenecid interferes with renal tubular transfer of cephalosporin, thereby, delaying their excretion and increasing their plasma concentrations.

Interference with Laboratory Tests

A false positive Coombs' test may be seen during treatment with cephalosporin. This phenomenon may occur during treatment with Cefotaxime and can interfere with blood cross-matching. , A false positive reaction to urinary glucose may occur with copper reduction methods. Benedict's. Fehhng's or Clinitest) but not with the use of specific glucose oxidase methods. .

There is potential for mezlocillin and azlocillin to reduce the clearance of Cefotaxime.

Pregnancy and lactation

Pregnancy

The safety of Cefotaxime has not been established in human pregnancy.

Animal studies do not indicate direct or indirect harmful effects With respect to reproductive toxicity.

There are, however, no adequate and well-controlled studies in pregnant women.

Cefotaxime crosses the placental barrier. Therefore, Cefotax should not be used during pregnancy unless the anticipated benefit outweighs any potential risks.

Lactation

Cefotaxime passes into human breast milk in small amounts and is usually compatible with breast feeding, but careful monitoring of the infant is recommended.

Effects on the physiological intestinal flora of the breast-fed infant leading to diarrhoea, colonisation by yeast-like fungi and sensitisation of the infant cannot be excluded.

Therefore. A decision must be made whether to discontinue breast-feeding or to discontinue therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Effects on ability to drive and to use machines

Cefotaxime has been associated with dizziness, which may affect the ability to drive or operate machinery.

There is no evidence that Cefotaxime directly impairs the ability to drive or to operate machines. High doses of Cefotaxime, particularly in patients with renal insufficiency, may cause encephalopathy (e.g. impairment of consciousness, abnormal movements and convulsions). Patients should be advised not to drive or operate machinery if any such symptoms occur.

Undesirable effects

The side effects are classified according to organ class to very common, common, uncommon, rare, very rare, not known (cannot be estimated from available data)*.

Infections and infestations side effects

Not known: Super infection.

Blood and the Lymphatic system disorders

Uncommon: Leucopoenia, eosinophilia, thrombocytopenia.

Not known: Neutropenia, granulocytopenia, agranulocytosis, haemolytic anaemia. Immune system disorders:

Uncommon: Jarisch-Herxheimer reaction.

Not known: Anaphylactic reactions, angioedema, bronchospasm, anaphylactic shock. Nervous system disorders:

Uncommon: Convulsions.

Not known: Headache, dizziness, encephalopathy (e.g. impairment of consciousness, abnormal movements).

Cardiac disorders

Not known: Arrhythmia following rapid bolus infusion through central venous catheter.

Gastrointestinal disorders

Not known: Nausea, vomiting, abdominal pain, pseudo membranous colitis. Hepato-biliary disorders:

Uncommon Increase in liver enzymes and bilirubin.

Not known: Hepatitis * (sometimes with jaundice).

Skin and subcutaneous disorders

Uncommon Rash, pruritus, urticaria, drug fever. ,.

Not known Erythema multiforme, Stevens-Johnson syndrome,

Toxic epidermal necrolysis.

Renal and Urinary disorders

Uncommon Decrease in renal function/increase of creatinine [particularly when co-prescibed with amino glycosides).

Not known: nephritis, candidiasis.

General disorders and administration site conditions

Very common: For I.M formulation: Pain at the injection site.

Uncommon; Fever, inflammatory reactions at the injection Site, including phlebitis / thrombophlebitis.

Post – marketing experience:

Jarisch-Herxheimer reaction:

For the treatment of borreliosis, a Jarisch-Herxheimer reaction may develop during the first days of treatment.

The occurrence of one or more of the following symptoms has been reported after several weeks' treatment of borreliosis: skin rash, itching, fever, leucopoenia, and increase in liver, enzymes. Difficulty of breathing, joint discomfort.

Hepatic – biliary disorders

Increase in liver enzymes and/or' bilirubin have been observed. These laboratory abnormalities may rarely exceed twice the upper limit of the normal range and elicit a pattern of liver injury, usually cholestatic and most often asymptomatic.

Over dosage

Symptoms of overdose may largely correspond to the profile of side effects.
There is a risk k of reversible encephalopathy in cases of administration of high doses of beta – Lactam antibiotics including Cefotaxime.
In case of overdose, Cefotax must be discontinued, and supportive treatment initiated, which includes measures to accelerate elimination, and symptomatic treatment of adverse reactions (i.e. convulsion).
No specific antidote exists. Serum levels of Cefotaxime may be reduced by peritoneal dialysis or haemodialysis.

Pharmacological properties

Pharmaco- therapeutic group

Beta-Lactam antibiotics, cephalosporin.

Mode of action

Cefotaxime is a third generation broad spectrum bactericidal cephalosporin.
The bactericidal properties are due to the inhibitory effect of Cefotaxime on bacterial cell wall synthesis.

Mechanism of resistance

Resistance to Cefotaxime may be due to production of extended – spectrum beta lactamases that can efficiently hydrolyse the drug, to the induction and l or constitutive expression of AmpC enzymes, to Impermeability or to efflux pump mechanisms.
More than one of these possible mechanisms may co-exist in a single bacterium.

Pharmacokinetic properties

After a 1000 mg intravenous bolus, mean peak plasma concentrations of Cefotaxime usually range between 81 and 102 microgram/ml.
Doses of 500 mg and 2000 mg produce concentrations of 38 and 200 microgram/ml, respectively, There is no accumulation following administration of 1000 mg intravenously or 500 mg intramuscularly for 10 or 14 days.
The apparent volume of distribution at steady-state of Cefotaxime is 21.6 litres/1.73 m2 after1 g intravenous 30 minute infusions.
Concentrations of Cefotaxime (usually determined by non-selective assay) have been studied in a wide range of human body tissues and fluids. Cerebrospinal fluid concentrations are low when the meninges are not inflamed, but are between 3 and 30 microgram/ml in children with meningitis. Cefotaxime usually passes the blood-brain barrier in levels above the minimum inhibitory concentration of common sensitive pathogens when the meninges are inflamed. Concentrations 10.2-5.4 microgram/ml), inhibitory for most Gram-negative bacteria, are attained in purulent sputum, bronchial secretions and pleural fluid after doses of 1 or 2 g. Concentrations likely to be effective against most sensitive organisms are similarly attained in female reproductive organs, otitis media effusions, prostatic tissue, interstitial fluid, renal tissue, peritoneal fluid and gall bladder wall, after usual therapeutic doses. High concentrations of Cefotaxime and desacetyl-cefotaxime are attained in bile.
Cefotaxime is partially metabolised prior to excretion. The principal metabolite is the microbiologically active product, desacetyl-cefotaxime. Most of a dose of Cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime. Plasma clearance is reported to be between 260 and 390 ml/minute and renal clearance 145 to 217 ml/minute.
After intravenous administration of Cefotaxime to healthy adults, the elimination half-life of the parent compound is 0.9 to 1.14 hours and that of the desacetyl metabolite, about 1.3 hours
In neonates the pharmacokinetics are influenced by gestational and chronological age, the half-life being prolonged in premature and low birth weight neonates of the same age.
In severe renal dysfunction the elimination half-life of Cefotaxime itself is increased minimally to about 2.5 hours, whereas that of desacetyl-cefotaxime is increased to about 10 hours. Total urinary recovery of Cefotaxime and its principal metabolite decreases with reduction in renal function.

Storage

Before reconstitution, store at a temperature not exceeding 30'C.
After reconstitution, store at room temperature for 24 hours or store at 12-8' C for 10 days
Cefotax 250 mg should be used immediately after reconstitution. .

Packaging

· Cefotax 250 mg. 500 mg vials

Carton box containing 1 vial + 1 ampoule solvent (2 ml) of sterile water for injection and Insert leaflet.

· Cefotax 1 g vials

Carton box containing 1 vial + 1 ampoule solvent (5 ml) of sterile water for injection and insert leaflet.

· Cefotax 2 g vials

Carton box containing 1 vial + 1 ampoule solvent (10 ml) of sterile water for injection and Insert leaflet.

Special Precautions for Disposal and Other Handling

When dissolved in Water for Injections PhEur, Cefotax forms a straw-coloured solution suitable for intravenous and intramuscular injection.

Variations in the intensity of colour of the freshly prepared solutions do not indicate a change in potency or safety.

Dilution table (Intramuscular and Intravenous Administration)

Approx. Displacement volume	Approx. Available volume	Diluents to be added	Vial size
0.2 ml	2.2 ml	2 ml	250 , 500 mg
0.5 ml	4,5 ml	4 ml	1 g
1.2 ml	11.2 ml	10 ml	2 g

Reconstituted solution

Whilst it is preferable to use only freshly prepared solutions for both intravenous and intramuscular injection, Cefotax is compatible with several commonly used intravenous infusion fluids and will retain satisfactory potency for up to 24 hours at room temperature in the following: Water for Injection, sodium chloride intravenous infusion, 5% glucose intravenous infusion, sodium chloride and glucose intravenous infusion, compound sodium lactate intravenous infusion (Ringer-lactate solution for injection).

Intravenous Infusion

1-2 g Cefotax are dissolved in 40-100 ml of infusion fluid.

Cefotax is also compatible with metronidazole infusion (500 mg/100ml) and both will maintain potency at room temperature for up to 24 hours. Some increase in colour of prepared solutions may occur on storage. However, provided the recommended storage conditions are observed, this does not indicate change in potency or safety.

Date of revision

June 2015

Manufacturing company

EGYPTIAN INT. PHARMACEUTICAL INDUSTRIES CO.

EIPICO

10^TH OF RAMADAN CITY, INDUSTRIAL AREA B1, P.O, BOX: 149 TENTH, EGYPT .

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