Doripenem

In patients with moderate renal impairment (CrCl ≥30 to ≤50 ml/min), the dose of doripenem should be 250 mg every 8 hours. In patients prescribed 1 g every 8 hours as a 4-hour infusion, the dose should be similarly adjusted (moderate renal impairment: 500 mg every 8 hours).

In patients with severe renal impairment (CrCl <30 ml/min), the dose of doripenem should be 250 mg every 12 hours (see section 6.6). In patients prescribed 1 g every 8 hours as a 4-hour infusion, the dose should be similarly adjusted (severe renal impairment: 500 mg every 12 hours).

Due to limited clinical data and an expected increased exposure to doripenem and its metabolite (doripenem-M-1), Doribax should be used with caution in patients with severe renal impairment.

Dose in patients on dialysis

Doribax dosing and administration recommendations for patients on continuous renal replacement therapies are shown in the following table.

CRRT: continuous renal replacement therapy; CVVH: continuous venovenous haemofiltration; CVVHDF: continuous venovenous haemodiafiltration; MIC: minimum inhibitory concentration
^a For patients with acute renal insufficiency on CRRT, an infusion time of 4 hours is required, taking into consideration the possible increases in non-renal clearance of carbapenems in patients with acute renal insufficiency.
^b Patients with chronic renal impairment on CRRT can be treated with either a 1 or 4-hour infusion time. Based mainly on PK/PD considerations, a 4-hour infusion time may be more suitable to maximize the percentage time during the dosing interval that the plasma concentration of doripenem exceeds the minimum inhibitory concentration (%T > MIC).

Dosing recommendations for pathogens with MIC >1 mg/l have not been established for continuous renal replacement therapy due to the potential for accumulation of doripenem and doripenem-M-1 metabolite. Close safety monitoring is advised for patients on continuous renal replacement therapy, due to limited clinical data and an expected increased exposure to doripenem-M-1 metabolite.

There is insufficient information to make dose adjustment recommendationsfor patients on other forms of dialysis.

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 doripenem is not recommended. An interaction with other medicinal products eliminated by renal tubular secretion cannot be excluded.

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.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have occurred in patients receiving beta-lactam antibiotics. Before therapy with doripenem 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. Doripenem 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.

Pseudomembranous colitis due to Clostridium difficile has been reported with doripenem 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 doripenem.

When doripenem was used investigationally via inhalation, pneumonitis occurred. Therefore, doripenem should not be administered by this route.

Seizures have been reported during treatment with carbapenems, including doripenem. 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.

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. The potential risk for humans is unknown. Doripenem 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 doripenem should be made taking into account the benefit of breast-feeding to the child and the benefit of doripenem therapy to the woman.

Fertility

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 doripenem on the ability to drive and use machines have been performed. Based on reported adverse drug reactions, it is not anticipated that doripenem will affect the ability to drive and use machines.

Summary of the safety profile

In 3,142 adult patients (1,817 of which received doripenem) evaluated for safety in phase II and phase III clinical trials, adverse reactions due to doripenem 500 mg every 8 hours occurred at a rate of 32%. Doripenem was discontinued because of adverse drug reactions in 0.1% of patients overall. Adverse drug reactions that led to doripenem 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 doripenem 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.

List of adverse reactions

Adverse drug reactions identified during clinical trials and post-marketing experience with doripenem 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 doripenem:

Infections and infestation

Common: oral candidiasis, vulvomycotic infection

Blood and lymphatic system disorders

Uncommon: thrombocytopenia, neutropenia

Immune system disorders

Uncommon: hypersensitivity reactions

Not known: anaphylaxis

Nervous system disorders

Very common: headache

Uncommon: seizures

Vascular disorders

Common: phlebitis

Gastrointestinal disorders

Common: nausea, diarrhoea

Uncommon: C. difficile colitis

Hepatobiliary disorders

Common: hepatic enzyme increased

Skin and subcutaneous tissue disorders

Common: pruritus, rash

Not known: toxic epidermal necrolysis, Stevens-Johnson syndrome