Source: European Medicines Agency (EU) Revision Year: 2014 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340, Beerse, Belgium
The selection of doripenem to treat an individual patient should take into account the appropriateness of using a carbapenem antibacterial agent based on factors such as severity of the infection, the prevalence of resistance to other suitable antibacterial agents and the risk of selecting for carbapenem-resistant bacteria.
Caution on the choice of antibiotic agent and dose should be taken when treating patients with late-onset ventilator-associated pneumonia (>5 days hospitalisation) and in other nosocomial pneumonia cases where pathogens with decreased susceptibility are suspected or confirmed, such as Pseudomonas spp. and Acinetobacter spp. (see sections 4.2 and 5.1).
Concomitant use of an aminoglycoside may be indicated when Pseudomonas aeruginosa infections are suspected or proven to be involved in the approved indications (see section 4.1).
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have occurred in patients receiving beta-lactam antibiotics. Before therapy with Doribax is started, careful inquiry should be made concerning a previous history of hypersensitivity reactions to other active substances in this class or to beta-lactam antibiotics. Doribax should be used with caution in patients with such a history. Should a hypersensitivity reaction to doripenem occur, it should be discontinued immediately and appropriate measures taken. Serious acute hypersensitivity (anaphylactic) reactions require immediate emergency treatment.
Seizures have been reported during treatment with carbapenems, including doripenem (see section 4.8). Seizures in clinical trials with doripenem occurred most commonly in those with pre-existing central nervous system (CNS) disorders (e.g. stroke or history of seizures), compromised renal function and at doses greater than 500 mg.
Pseudomembranous colitis due to Clostridium difficile has been reported with Doribax and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of Doribax (see section 4.8).
Administration of doripenem, like other antibiotics, has been associated with emergence and selection of strains with reduced susceptibility. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken. Prolonged use of Doribax should be avoided.
The concomitant use of doripenem and valproic acid/sodium valproate is not recommended (see section 4.5).
When Doribax was used investigationally via inhalation, pneumonitis occurred. Therefore, doripenem should not be administered by this route.
The exposure to the metabolite doripenem-M-1 in patients on continuous renal replacement therapy may be increased to levels where no in vivo safety data are presently available. The metabolite lacks target pharmacological activity but other possible pharmacological effects are unknown. Therefore, close safety monitoring is advised. (see sections 4.2 and 5.2).
In two clinical trials of patients with nosocomial pneumonia (N=979), 60% of the clinically-evaluable Doribax-treated patients had ventilator-associated pneumonia (VAP). Of these, 50% had late-onset VAP (defined as that occurring after five days of mechanical ventilation), 54% had an APACHE (Acute Physiology And Chronic Health Evaluation) II score >15 and 32% received concomitant aminoglycosides (76% for more than 3 days).
In two clinical trials of patients with complicated intra-abdominal infections (N=962) the most common anatomical site of infection in microbiologically-evaluable Doribax-treated patients was the appendix (62%). Of these, 51% had generalised peritonitis at baseline. Other sources of infection included colon perforation (20%), complicated cholecystitis (5%) and infections at other sites (14%). Eleven percent had an APACHE II score of >10, 9.5% had post-operative infections, 27% had single or multiple intra-abdominal abscesses and 4% had concurrent bacteraemia at baseline.
In two clinical trials of patients with complicated urinary tract infections (N=1,179), 52% of microbiologically-evaluable Doribax-treated patients had complicated lower urinary tract infections and 48% had pyelonephritis, of which 16% were complicated. Overall, 54% of patients had a persistent complication, 9% had concurrent bacteraemia and 23% were infected with a levofloxacin resistant uropathogen at baseline.
The experience in patients who are severely immunocompromised, receiving immunosuppressive therapy, and patients with severe neutropenia is limited since this population was excluded from phase III trials.
Doripenem undergoes little to no Cytochrome P450 (CYP450) mediated metabolism. Based on in vitro studies it is not expected that doripenem will inhibit or induce the activities of CYP450. Therefore, no CYP450-related drug interactions are to be expected (see section 5.2).
It has been shown that co-administration of doripenem and valproic acid significantly reduces serum valproic acid levels below the therapeutic range. The lowered valproic acid levels can lead to inadequate seizure control. In an interaction study, the serum concentrations of valproic acid were markedly reduced (AUC was reduced by 63%) following co-administration of doripenem and valproic acid. The interaction had a fast onset. Since patients were administered only four doses of doripenem, a further decrease of valproic acid levels with longer concomitant administration cannot be excluded. Decreases in valproic acid levels have also been reported when co-administered with other carbapenem agents, achieving a 60-100% decrease in valproic acid levels in about two days. Therefore, alternative antibacterial or supplemental anticonvulsant therapies should be considered.
Probenecid competes with doripenem for renal tubular secretion and reduces the renal clearance of doripenem. In an interaction study, the mean doripenem AUC increased by 75% following co-administration with probenecid. Therefore, co-administration of probenecid with Doribax is not recommended. An interaction with other medicinal products eliminated by renal tubular secretion cannot be excluded.
For doripenem, limited clinical data on exposed pregnancies are available. Animal studies are insufficient with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential risk for humans is unknown. Doribax should not be used during pregnancy unless clearly necessary.
It is unknown whether doripenem is excreted in human breast milk. A study in rats has shown that doripenem and its metabolite are transferred to milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Doribax should be made taking into account the benefit of breast-feeding to the child and the benefit of Doribax therapy to the woman.
There are no clinical data available regarding potential effects of doripenem treatment on male or female fertility. Intravenous injection of doripenem had no adverse effects on general fertility of treated male and female rats or on postnatal development and reproductive performance of the offspring at doses as high as 1 g/kg/day (based on AUC, at least equal to the exposure to humans at the dose of 500 mg administered every 8 hours).
No studies on the effects of Doribax on the ability to drive and use machines have been performed. Based on reported adverse drug reactions, it is not anticipated that Doribax will affect the ability to drive and use machines.
In 3,142 adult patients (1,817 of which received Doribax) evaluated for safety in phase II and phase III clinical trials, adverse reactions due to Doribax 500 mg every 8 hours occurred at a rate of 32%. Doribax was discontinued because of adverse drug reactions in 0.1% of patients overall. Adverse drug reactions that led to Doribax discontinuation were nausea (0.1%), diarrhoea (0.1%), pruritus (0.1%), vulvomycotic infection (0.1%), hepatic enzyme increased (0.2%) and rash (0.2%). The most common adverse reactions were headache (10%), diarrhoea (9%) and nausea (8%).
The safety profile in approximately 500 patients who received Doribax 1 g every 8 hours as a 4-hour infusion in phase I, II and III clinical trials, was consistent with the safety profile for patients receiving 500 mg every 8 hours.
Adverse drug reactions identified during clinical trials and post-marketing experience with Doribax are listed below by frequency category. Frequency categories are defined as follows: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse drug reactions identified during clinical trials and post-marketing experience with Doribax:
Common: oral candidiasis, vulvomycotic infection
Uncommon: thrombocytopenia, neutropenia
Uncommon: hypersensitivity reactions (see section 4.4)
Not known: anaphylaxis (see section 4.4)
Very common: headache
Uncommon: seizures (see section 4.4)
Common: phlebitis
Common: nausea, diarrhoea
Uncommon: C. difficile colitis (see section 4.4)
Common: hepatic enzyme increased
Common: pruritus, rash
Not known: toxic epidermal necrolysis, Stevens-Johnson syndrome
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.3.
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