Doribax 500mg Injection

DORIBAX u00c6 is indicated for the treatment of the following infections caused by susceptible bacteria:

• Nosocomial pneumonia, excluding ventilator-associated pneumonia, due to:
• Staphylococcus aureus (methicillin-susceptible strains only)
• Streptococcus pneumonia
• Acinetobacter baumannii
• Enterobacter cloacae
• Escherichia coli
• Klebsiella pneumoniae
• Haemophilus influenza
• Pseudomonas aeruginosa
• Complicated intra-abdominal infections, due to
• Escherichia coli
• Klebsiella pneumonia
• Pseudomonas aeruginosa
• Bacteroides caccae
• Bacteroides fragilis
• Bacteroides thetaiotaomicron
• Bacteroides uniformis
• Bacteroides vulgatis
• Enterococcus faecalis
• Streptococcus intermedius
• Streptococcus constellatus
• Peptostreptococcus micros
• Complicated urinary tract infections, including pyelonephritis, due to
• Escherichia coli (including levofloxin-resistant strains) with or without co-current bacteraemia
• Klebsiella pneumonia
• Proteus mirabilis
• Pseudomonas aeruginosa
• Acinetobacter baumannii
• Enterococcus faecalis

Posology

The recommended dose of DORIBAX u00c6 is 500 mg administered every 8 hours by intravenous infusion. The recommended dosage and administration by infection is described in Table 1.

Table 1: Dosage of DORIBAX u00c6 by infection

* One-hour infusions are recommended for treatment of patients with nosocomial pneumonia. For patients who are at risk for infection with less susceptible pathogens, four-hour infusions are recommended.

Treatment duration should be guided by the severity of illness, infecting pathogen, and the patientu2019s clinical response. The usual treatment duration is 7 to 14 days for patients with nosocomial pneumonia.

Special populations

Paediatric population

The safety and efficacy of doripenem in children and adolescents aged < 18 years have not yet been established. No data are available.

Patients with impaired renal function

In patients whose creatinine clearance (CrCl) is > 50 mL/min, no dosage adjustment is necessary. In patients with moderate renal impairment (CrCl u2265 30 to u2264 50 mL/min), the dosage of DORIBAX u00c6 should be 250 mg every 8 hours. In patients with severe renal impairment (CrCl > 10 to < 30 mL/min), the dosage of DORIBAX u00c6 should be 250 mg every 12 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; 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 (see section 5.2).

The following formula may be used to estimate CrCl. The serum creatinine used in the formula should represent a steady state of renal function.

Males: Creatinine clearance (mL/min) = weight (kg) x (140 u2013 age in years) / (0.82 x plasma creatinine (u03bcmol/L))

Females: Creatinine clearance (mL/min) = weight (kg) x (140 u2013 age in years) / (0.85 x plasma creatinine (u03bcmol/L))

In patients with augmented renal clearance, it is recommended that the dose of DORIBAXu00c6 be doubled to 1 g every 8 hours by intravenous infusion over 30 minutes for 10 u2013 14 days. This is also recommended when non-fermenting Gram-negative bacteria are suspected or confirmed as the cause of infection, and concomitant treatment with an aminoglycoside antibacterial medicine should be considered in these cases.

Patients on dialysis

DORIBAX u00c6 dosing and administration recommendations for patients on continuous renal replacement therapies are shown in Table 2.

Table 2: Dosage of DORIBAX u00c6 in patients on continuous renal replacement therapies

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. These recommendations are based on limited clinical data and simulation data.

Dosing recommendations for pathogens with MIC >1 u03bcg/mL have not been established for continuous renal replacement therapy due to the potential for accumulation of doripenem and doripenem-M-1 metabolite (see section 4.4 and 5.2). Close safety monitoring is advised for these patients due to limited clinical data and an expected increased exposure to doripenem-M-1 metabolite.

As many patients receiving DORIBAXu00c6 are not candidates for traditional short-term intermittent haemodialysis due to haemodynamic instability or other risks, there is insufficient data to provide dosing recommendations for subjects on intermittent haemodialysis.

Patients with hepatic impairment

No dosage adjustment is necessary.

Method of administration

DORIBAXu00c6 500 mg is a powder for solution for infusion. For instructions on preparation of DORIBAX u00c6 solution for infusion see section 6.6. DORIBAX u00c6 infusions range from clear, colourless solutions to solutions that are clear and slightly yellow. Variations in colour within this range do not affect the potency of the product.

Known hypersensitivity to doripenem, to other medicines in the same class, or to betalactams.

Ventilator-associated pneumonia

A study in the use of DORIBAX u00c6 in a fixed 7-day regimen in ventilator-associated pneumonia has shown an increase in mortality.

Hypersensitivity reactions

Serious and fatal hypersensitivity (anaphylactic) reactions have occurred in patients receiving beta-lactam antibiotics, including DORIBAX u00c6 (see section 4.3). These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Before therapy with DORIBAX u00c6 is instituted, careful inquiry should be made to determine whether the patient has had a previous hypersensitivity reaction to other carbapenems, cephalosporins, penicillin or other allergens. If DORIBAX u00c6 is to be given to a penicillin- or other beta-lactam-allergic patient, caution should be exercised because cross-hyperreactivity among beta-lactam antibiotics has been clearly documented. If an allergic reaction to DORIBAX u00c6 occurs, discontinue DORIBAX u00c6. Serious acute hypersensitivity (anaphylactic) reactions require immediate emergency treatment.

Pseudomembranous colitis

Pseudomembranous colitis due to C. difficile has been reported with DORIBAX u00c6 and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who have received DORIBAX u00c6 and who present with diarrhoea.

Overgrowth of non-susceptible bacteria

Prescribing DORIBAX u00c6 in the absence of a proven or strongly suspected bacterial infection or for prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of medicine-resistant bacteria.

Interaction with valproic acid

DORIBAX u00c6 reduced serum valproic acid concentration to sub-therapeutic levels in healthy subjects. Therapeutic monitoring of valproic acid and use of alternative therapies should be considered in patients (see section 4.5 and 5.2).

End stage renal disease (ESRD)

The exposure to metabolite doripenem-M-1 in patients with ESRD may be increased to levels for which no in vivo safety data are presently available. The metabolite lacks microbiological activity, but other possible pharmacological effects are unknown. Therefore, close safety monitoring is advised (see section 4.2 and 5.2).

Pneumonitis with inhalational use

When used investigational via inhalation, pneumonitis has occurred. DORIBAX u00c6 should not be administered by this route.

Probenecid

Probenecid competes with DORIBAX u00c6 for active tubular secretion and reduces the renal clearance of DORIBAX u00c6. Coadministration of probenecid with DORIBAX u00c6 is not recommended.

Valproic acid

DORIBAX u00c6 reduced serum valproic acid concentration to sub-therapeutic levels in healthy subjects (see section 5.2), Therefore, valproic acid concentrations in the blood should be monitored if DORIBAX u00c6 is administered concomitantly with valproic acid or sodium valproate and alternative therapies should be considered (see section 4.4).

Cytochrome P450 isoenzymes

DORIBAX u00c6 is not expected to inhibit clearance of medicines that are metabolised by CYP 450 isoenzymes in a clinically relevant manner.

Pregnancy

Safety in pregnancy has not been demonstrated.

Breastfeeding

Safety in lactation has not been demonstrated. DORIBAX u00c6 was found to be present in the breast milk of rats at a concentration of u2159 (one sixth) of the plasma concentration.

No studies on the effects of DORIBAX u00c6 on the ability to drive and use machines have been performed. It is not anticipated that DORIBAX u00c6 will affect the ability to drive and use machines.

a. Summary of the safety profile

Adverse reactions that led to DORIBAXu00c6 discontinuation were nausea (0,1 %), diarrhoea (0,1 %), pruritis (0,1 %), vulvomycotic infection (0,1 %), hepatic enzyme increased (0,2 %) and rash (0,2 %).

b. Tabulated summary of adverse reactions

Adverse events from clinical trials

In 1 817 adult patients, who received DORIBAX u00c6 in phase 2 and 3 clinical trials (500 mg administered every 8 hours), adverse reactions that were observed are listed in Table 3:

Table 3 : Adverse drug events observed in clinical trials occurring at a rate u2265 1 %

Table 4: Adverse drug events observed in < 1 % of DORIBAX u00c6 -treated Patients in Clinical Trials

System organ class

Adverse drug reaction

Gastrointestinal disorders

C. difficile colitis

Immune system disorders

Hypersensitivity

Adverse reaction information from spontaneous reports

The following adverse reactions have been identified during post-approval use of DORIBAX u00c6.

Table 5: Adverse drug events identified during post-marketing experience with DORIBAX u00c6

System organ class

Adverse drug reaction

Blood and the lymphatic system disorders

Thrombocytopenia, neutropenia

Immune system disorders

Anaphylaxis

Skin and subcutaneous tissue disorders

Toxic epidermal necrolysis, Stevens-Johnson syndrome

Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety App (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. You can also report side effects to Acino Pharma via email on [email protected]

In the event of overdose, DORIBAX u00c6 should be discontinued and general supportive treatment given until renal elimination takes place. DORIBAX u00c6 can be removed by continuous renal replacement therapy or haemodialysis. However, insufficient information is available on the use of either of these therapies to treat overdosage.