MEDOCEF Powder for solution for injection / infusion Ref.[50940] Active ingredients:

Hypersensitivity

Patients receiving beta-lactam or cephalosporin antibiotics including cefoperazone reported serious and sometimes fatal anaphylactic reactions. These reactions were more prone in individuals which have previously manifested hypersensitivity reactions to various allergens.

Before starting the treatment, it should be carefully determined whether the patient did not show allergic reactions to cephalosporins, penicillins, or other medicinal products in the past (see section 4.3).

Antibiotics should be administered with caution to all patients who have experienced any type of allergic reaction, especially allergies to medicinal products.

If an allergic reaction occurs, the drug should be discontinued and appropriate medical therapy should be initiated.

Serious anaphylactic reactions require immediate treatment with epinephrine. If indicated, oxygen and intravenous corticosteroids should be administered. Secure the airway, including intubation.

Serious and rarely fatal skin reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome and exfoliative dermatitis have been reported in patients receiving cefoperazone.

If a severe skin reaction occurs, cefoperazone should be discontinued and appropriate therapy instituted (see section 4.8).

Use in patients with hepatic impairment

Cefoperazone is extensively excreted in bile. In patients with liver disease or biliary obstruction, half plasma concentration of cefoperazone and renal excretion are increased.

Therapeutic levels of cefoperazone are achieved even with severe impairment of liver function in bile and its half-life is extended only 2- to 4 fold (see section 4.2).

General

Serious haemorrhage cases, including fatalities, have been reported with cefoperazone. Those at risk include patients with poor diet, malabsorption states and patients on prolonged intravenous alimentation regimens. These patients should be monitored for signs of bleeding, thrombocytopenia, and hypoprothrombinemia. Cefoperazone should be discontinued if there is persistent bleeding and no alternative explanations are identified.

As with other antibiotics, an excessive development of non-susceptible organism may occur during long-term therapy with cefoperazone.

The patient should be carefully monitored during treatment.

During prolonged use of cefoperazone, regular monitoring for possible/potential dysfunctions including renal, hepatic and hematopoietic system is advisable, as with any preparation for systemic administration.

This is especially important for newborns, especially premature and for the children.

For almost all antibiotics, including cefoperazone, cases of diarrhea caused by Clostridium difficile (CDAD - Clostridium difficile associated diarrhea) have been reported. Severity of diarrhea may range from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile causes increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history check is necessary since they have been reported cases where diarrhea appeared to/for more than two months after the administration of antibacterial agents.

Paediatric population

Cefoperazone has been successfully used in childhood. It has not been extensively tested in premature neonates and infants. Prior to initiating therapy in infants and neonates it is necessary to consider the potential benefit against the potential risks (see section 5.3).

In newborns with jaundice cefoperazone do not displace bilirubin from its binding sites on plasma proteins.

Medocef contains 34.4 mg of sodium in one 1g vial and 68.8 mg sodium in one 2g vial. To be taken into consideration by patients on a controlled sodium diet.

Alcohol

Disulfiram-like reactions characterized by tachycardia, flushing, sweating and headaches were reported on alcohol and cefoperazone concomitant consumption or within five days after. The same reaction has been reported with other cephalosporins. The patient should be instructed about the dangers of drinking alcohol during treatment with cefoperazone.

For patients requiring oral or parenteral artificial nutrition, solutions containing ethanol during treatment should be discontinued.

Laboratory tests

A false positive result may occur with Benedict’s or Fehling agents, when used to determine urine glucose.

Aminoglycosides

Cephalosporins may increase the nephrotoxic effect of aminoglycosides. Increased monitoring is required in patients receiving concomitant aminoglycosides and cephalosporins due to nephrotoxicity.

Anticoagulants (vitamin K antagonists)

Cefoperazone may increase the anticoagulant effect of vitamin K antagonists, including warfarin. Elevated INR and bleeding parameters should be monitored when a vitamin K antagonist is used in combination with cefoperazone.

Live vaccines

Antibiotics may prevent the strain in the vaccine from multiplying to elicit an immune response and thus reduce the therapeutic effect of the vaccine. Avoid concomitant use of live attenuated vaccines and antibiotics.

Diarrhea

Clostridium difficile has been reported with almost all antibacterial agents, including cefoperazone. The therapeutic efficacy of oral and rectal drugs may be reduced due to the development of cefoperazone-induced diarrhea.

Pregnancy

Reproduction studies performed in mice, rats and monkeys have shown no effects on fertility or teratogenicity when using tenfold higher dose than doses for humans. There are no adequate and well-controlled studies in pregnant women.

Cefoperazone may be used during pregnancy only when strictly necessary because the results of animal reproduction studies may not be identical to those in humans.

Breast-feeding

Cefoperazone is excreted in small amounts in breast milk, however caution should be exercised when cefoperazone is administered to a nursing mother.

Fertility

No effect on fertility was observed in preclinical studies in sexual adult rats. However, side effects were seen on the testes in prepubertal rat studies. Clinical data on fertility in men and women are not available. Because effects on animals do not always predict a response in humans, caution should be exercised when a man or woman is planning a child.

Clinical experience suggests that cefoperazone is unlikely to affect a patient’s ability to drive or operate machinery.

Table with an overview of adverse reactions and their frequency:

^* Adverse reactions reported during post-marketing experience

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Tel: +357 22608607, Fax: +357 22608669, Website: www.moh.gov.cy/phs.

Aminoglycosides

Do not combine cefoperazone solutions with aminoglycoside antibiotics, because they share a physical incompatibility. If the combination therapy with aminoglycosides is necessary (see section 4.1), additional intravenous infusion using the second intravenous cannulation and adequate flushing intravenous cannula should be used in the time between single doses.

It is also recommended to administer the first dose of cefoperazone before the administration of aminoglycosides.