Doribax 500mg powder for solution for infusion Ref.[2763] Active ingredients: Doripenem

Posology

The recommended dose and administration by infection is shown in the following table:

* 1 g every 8 hours as a 4-hour infusion may be considered in patients with augmented renal clearance (particularly those with creatinine clearance (CrCl) ≥ 150 ml/min) and/or in infections due to non-fermenting gram-negative pathogens (such as Pseudomonas spp. and Acinetobacter spp.). This dose regimen is based on PK/PD data (see sections 4.4, 4.8 and 5.1).
** Based mainly on PK/PD considerations, a 4-hour infusion time may be more suitable for infection with less susceptible pathogens (see section 5.1). This dosing regimen should also be considered in particularly severe infections.

For infusion solution shelf life see section 6.3.

The usual treatment duration of doripenem therapy ranges from 5-14 days and should be guided by the severity, site of the infection, infecting pathogen and the patient’s clinical response. The usual treatment duration for patients with nosocomial pneumonia, including ventilator-associated pneumonia is 10 to 14 days and is often in the upper range for patients infected with non-fermenting gram-negative pathogens (such as Pseudomonas spp. and Acinetobacter spp.) (see section 5.1).

Doripenem was given for up to 14 days in clinical studies and the safety of longer durations of therapy has not been established. After commencing treatment with intravenous doripenem, a switch to appropriate oral therapy to complete the treatment course is possible once clinical improvement has been established.

Dose in paediatric patients

Doribax is not recommended for use in children below 18 years of age due to a lack of safety and efficacy data.

Dose in patients with impaired renal function

In patients with mild renal impairment (i.e. creatinine clearance (CrCl) is > 50 to ≤ 80 ml/min), no dose adjustment is necessary.

In patients with moderate renal impairment (CrCl ≥ 30 to ≤ 50 ml/min), the dose of Doribax should be 250 mg every 8 hours (see section 6.6). In patients with severe renal impairment (CrCl < 30 ml/min), the dose of Doribax should be 250 mg every 12 hours (see section 6.6). In patients receiving 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).

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), (see section 5.1).
c For infusion solution shelf life see section 6.3.

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 (see sections 4.4 and 5.2). 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 (see section 4.4).

There is insufficient information to make dose adjustment recommendations for patients on other forms of dialysis (see section 5.2).

Dose in elderly patients (≥ 65 years of age)

No dose adjustment is necessary in elderly patients, except in cases of moderate to severe renal impairment (see Dose in patients with impaired renal function above and section 5.2).

Dose in patients with impaired hepatic function

No dose adjustment is necessary.

Method of administration

Doribax is to be reconstituted and then further diluted (see section 6.6) prior to administration by intravenous infusion over a period of 1 or 4 hours.

In a phase I study in healthy subjects receiving doripenem 2 g infused over 1 hour every 8 hours for 10 to 14 days, the incidence of rash was very common (5 of 8 subjects). The rash resolved within 10 days after doripenem administration was discontinued.

In the event of overdose, Doribax should be discontinued and general supportive treatment given until renal elimination takes place. Doribax can be removed by continuous renal replacement therapy or haemodialysis (see section 5.2). However, no information is available on the use of either of these therapies to treat overdose.

3 years.

Storage of reconstituted solutions: Upon reconstitution with sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for injection, Doribax suspension in the vial may be held for up to 1 hour below 30°C prior to transfer and dilution in the infusion bag.

Following dilution in the infusion bag with sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml (5%) solution for injection, Doribax infusions stored at room temperature or under refrigeration should be completed according to the times in the following table:

Time by which reconstitution, dilution and infusion must be completed for Doribax infusion solutions

* Once removed from the refrigerator, infusions should be completed within the room temperature stability time, provided the total refrigeration time, time to reach room temperature and infusion time does not exceed refrigeration stability time.
+ Dextrose 50 mg/ml (5%) solution for injection should not be used for infusion durations greater than 1 hour.

Chemical and physical in-use stability has been demonstrated for the times and solutions shown in the above table.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

This medicinal product does not require any special storage conditions.

For storage conditions after reconstitution of the medicinal product, and infusion solutions, see section 6.3.

Clear 20 ml Type I glass vial.

The medicinal product is supplied in cartons containing 10 vials.

Each vial is for single use only.

Doribax is reconstituted and then further diluted prior to infusion.

Preparation of 500 mg dose of solution for infusion using the 500 mg vial

1. Add 10 ml of sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for injection to the 500 mg vial and shake it to form a suspension.
2. Inspect the suspension visually for foreign matter. Note: the suspension is not for direct infusion.
3. Withdraw the suspension using a syringe and needle and add it to an infusion bag containing 100 ml of either sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml (5%) solution for injection and mix to complete dissolution. Infuse all of this solution to administer a 500 mg dose of doripenem.

Preparation of 250 mg dose of solution for infusion using the 500 mg vial

1. Add 10 ml of sterile water for injections or sodium chloride 9 mg/ml (0.9%) solution for injection to the 500 mg vial and shake it to form a suspension.
2. Inspect the suspension visually for foreign matter. Note: the suspension is not for direct infusion.
3. Withdraw the suspension using a syringe and needle and add it to an infusion bag containing 100 ml of either sodium chloride 9 mg/ml (0.9%) solution for injection or dextrose 50 mg/ml (5%) solution for injection and mix to complete dissolution.
4. Remove 55 ml of this solution from the infusion bag and discard. Infuse all of the remaining solution to administer a 250 mg dose of doripenem.

Doribax solutions for infusion 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.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.