Tironem

Tironem

doripenem

Manufacturer:

Sanbe

Marketer:

Sanbe
Full Prescribing Info
Contents
Doripenem.
Description
Each vial contains: Doripenem Monohydrate equivalent to Doripenem 500 mg.
Action
Pharmacology: Mechanism of Action: Doripenem is synthetic carbapenems antibacterial agent.
Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem inactivates multiple essential penicillin-binding proteins (PBPs), resulting in inhibition of cell wall synthesis with subsequent cell death.
In vitro doripenem showed little potential to antagonize or be antagonized by other antibacterial agents.
Additive activity or weak synergy with Amikacin and Levofloxacin has been seen for Pseudomonas aeruginosa and for gram-positive bacteria with Daptomycin, Linezolid, Levofloxacin and Vancomycin.
Mechanism of Resistance: Bacterial resistance mechanisms that effect Doripenem include active substance inactivation by carbapenem-hydrolyzing enzymes, mutants or acquired PBP's, decreased outer membrane permeability and active efflux. Doripenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by gram positive and gram negative bacteria, with the exception of relatively rare carbapenem hydrolyzing beta-lactamases. Species resistant to other carbapenems do generally express coresistance to Doripenem. Methicillin-resistant staphylococci should always be considered as resistant to Doripenem. As with other antimicrobial agents, including carbapenems, Doripenem has been shown to select for resistant bacterial strains.
Breakpoints: Minimum Inhibitory Concentration (MIC) breakpoints established by the European Committee of Antimicrobial Susceptibility Testing (EUCAST) are as follows: Non species related: Staphylococci: S ≤ 1 mg/L and R > 4 mg/L inferred from the Methicillin breakpoint
Enterobactericeae: S ≤ 1 mg/L and R > 4 mg/L
Acinetobacter spp.: S ≤ 1 mg/L and R > 4 mg/L
Pseudomonas spp.: S ≤ 1 mg/L and R > 4 mg/L
Streptococcus spp. other than S. Pneumonia: S ≤ 1 mg/L and R > 1 mg/L
S. Pneumonia: S ≤ 1 mg/L and R > 1 mg/L
Enterococci: "inappropriate target"
Haemophilus spp.: S ≤ 1 mg/L and R > 1 mg/L
N. Gonorrhoeae: IE (Insufficient Evidence)
Anaerobes: S ≤ 1 mg/L and R > 1 mg/L
Susceptibility: The prevalence of acquired resistance vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Localised clusters of infection due to carbapenem-resistant have been reported in the European Union. The information below gives only approximate guidance on the probability as to whether the micro organism will be susceptible to Doripenem or not.
Commonly Susceptible Species: Gram-positive aerobes: Enterococcus faecalis*s
Staphylococcus aureus (methicillin susceptible strains only)*^
Staphylococcus spp. (methicillin susceptible strains only)*
Streptococcus pneumoniae*
Streptococcus spp.
Gram-negative aerobes: Citrobacter diversus
Citrobacter freundii
Enterobacter aerogenes
Haemophilus influenzae
*
Escherichia coli
Klebsiella pneumoniae
*
Klebsiella oxytoca
Morganella morganii
Proteus mirabilis
*
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Salmonella
species
Serratia marcescens
Shigella
species
Anaerobes: Bacteroides fragilis*
Bacteroides caccae
*
Bacteroides ovatus
Bacteroides uniformis
*
Bacteroides thetaiotaomicron
*
Bacteroides vulgatus
*
Bilophila wadsworthia
Peptostreptococcus magnus
Peptostreptococcus micros
*
Porphyromonas
spp.
Prevotella
spp.
Sutterella wadsworthenis

Species for which acquired resistance may be a problem: Acinetobacter baumanii*
Acinetobacter
spp.
Burkholderia cepacias
+
Pseudomonas aeruginosa
+
Inherently resistant organisms: Gram-positive aerobes: Enterococcus faecium
Gram-negative aerobes: Stenotrophomonas malthopilia
Legionella spp.
* species against which activity has been demonstrated in clinical studies
S species that show natural intermediate susceptibility
+ species with > 50% acquired resistance in one or more Member State
^ all Methicillin-resistant Staphylococci should be regarded as resistant to Doripenem.
Indications/Uses
TIRONEM is indicated for the treatment of the following infections in adults: Nosocomial pneumonia (including ventilator-associated pneumonia);
Complicated intra-abdominal infections.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Dosage/Direction for Use
The recommended dosage and administration by infection is shown in the table as follows: (see Table 1)


Click on icon to see table/diagram/image


The usual treatment duration of TIRONEM therapy is 5-14 days and should be guided by the severity, site of the infection, and the patient's clinical response. TIRONEM 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 TIRONEM, a switch to appropriate oral therapy to complete the treatment course is possible once clinical improvement has been established.
Dosage in pediatric patients: TIRONEM is not recommended for use in children below 18 years of age due to a lack of safety and efficacy data.
Dosage in patients with impaired renal function: In patients with mild renal impairment (i.e. creatinine clearance (CrCl) is 51-79 mL/min), no dosage adjustment is necessary. In patient with moderate renal impairment (CrCl 30-50 mL/min), the dosage of TIRONEM should be 250 mg every 8 hours. In patients with severe renal impairment (CrCl < 30 mL/min), the dosage of TIRONEM should be 250 mg every 12 hours. Due to limited clinical data and an expected increased exposure of TIRONEM and its metabolite, TIRONEM should be used with caution in patients with severe renal impairment.
Dosage in patients on dialysis: TIRONEM is hemodialyzable, however, there is insufficient information to make dose adjustment recommendation in patients on dialysis. Therefore, TIRONEM is not recommended for patients on any type of dialysis.
Dosage in elderly patients (> 65 years of age): No dosage adjustment is necessary in elderly patients, except in cases of moderate to severe renal insufficiency (see Dosage in patients with impaired renal function mentioned previously).
Dosage in patients with impaired hepatic function: No dosage adjustment is necessary.
METHOD FOR ADMINISTRATION: TIRONEM is to be reconstituted and then further diluted prior to administration by intravenous infusion over a period of one or four hours.
Reconstitution: Reconstitution with NaCl 9 mg/mL (0.9%) as solvent: Make suspension by dissolve 10 mL purified water or NaCl 0.9% solution.
Suspension inspections by visual to see whether there is foreign object. Notes: suspension is not directly use for infusion.
Take a suspension with syringe and needle, and add to 100 mL NaCl 0.9% solution infusion bag. Infusion all solution with 500 mg TIRONEM dose.
Reconstitution with dextrose 50 mg/mL (5%) as solvent: Add 10 mL water for injections to 500 mg TIRONEM vial and shake until suspension is formed.
After reconstituted with water for injections, colour of suspension is white to slightly yellowish.
Check suspension by visual to see whether there is foreign object. Notes: suspension is not directly use for infusion.
Take a suspension with syringe and needle, and add to 100 mL dextrose 5% infusion bag. Infusion all solution with 500 mg TIRONEM dose.
After reconstituted with water for injection or NaCl 0.9% solution for injection, TIRONEM in vial may be held up for up to 1 hour below 25˚C prior to transfer and dilution in the infusion bag.
Following dilution in the infusion bag with NaCl 0.9% solution for injection or Dextrose 5% solution for injection, TIRONEM infusions stored at controlled room temperature or under refrigeration should be completed according to the stability times.
Reconstitution stability used: (see Table 2)


Click on icon to see table/diagram/image


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 5% solution for injection should not be used for infusion durations greater than 1 hour.
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°-8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
TIRONEM solution for infus usually clear color and no color to clear and slightly yellowish. Intensity of color solution will increase as storage time increases. This color variation does not affect product potential.
All unused residual product must be thrown away in accordance with applicable regulations.
Overdosage
No case of overdose has been reported. In the event of overdose, TIRONEM should be discontinued and general supportive treatment given until renal elimination takes place. TIRONEM can be removed by haemodyalisis; however, no information is available on the use of haemodialysis to treat overdose by TIRONEM.
Contraindications
Hypersensitivity to the active substance.
Hypersensitivity to any other carbapenem antibacterial agent.
Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of betalactam antibacterial agent (e.g. Penicillins or Cephalosporins).
Special Precautions
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity reactions (anaphylactic) have occurred in patient receiving beta-lactam antibiotics. Before therapy with TIRONEM 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. TIRONEM should be used with caution in patients with such a history. If a hypersensitivity reaction to TIRONEM occur, it should be discontinued immediately and appropriate measures taken. Serious acute hypersensitivity (anaphylactic) reactions require immediate emergency treatment.
Seizures: Although infrequently, seizure have been reported during treatment with other Carbapenems.
Pseudomembranous colitis: Just like the use of any antibacterial drugs, Pseudomembranous colitis due to Clostridium difficile has been reported with TIRONEM as with nearly all antibacterial agents and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patient who present with diarrhea during or subsequent to the administration of Doripenem (see Adverse Reactions).
Super-infection: Administration of TIRONEM, like other antibiotics, has been associated with emergence and selection of strains with reduced susceptibility. Patients should be carefully monitored during therapy. If super-infection occurs, appropriate measures should be taken. Prolonged use of TIRONEM should be avoided.
Pneumonitis: Pneumonitis can occur if TIRONEM used via inhalation. Therefore, TIRONEM should not be administered by this route.
Use in Pregnancy: Clinical data of TIRONEM on pregnancy are very limited. Animal studies are insufficient to draw conclusion for pregnancy, embryonal/foetal development, parturition or postnatal development. The potential risk for human is unknown. TIRONEM should not be used during pregnancy unless clearly necessary.
Use in Lactation: It is not known whether TIRONEM is excreted in human breast milk. A study in rats has shown that TIRONEM and its metabolite are transferred to milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with TIRONEM should be made taking into account the benefit of breastfeeding to the child and the benefit of TIRONEM therapy to the woman.
Effects on Ability to Drive and Use Machines: No studies on the effects of TIRONEM on the ability to drive and use machines have been performed. Based on reported adverse drug reaction, it is not anticipated that TIRONEM will affect the ability to drive and use machines.
Use In Pregnancy & Lactation
Use in Pregnancy: Clinical data of TIRONEM on pregnancy are very limited. Animal studies are insufficient to draw conclusion for pregnancy, embryonal/foetal development, parturition or postnatal development. The potential risk for human is unknown. TIRONEM should not be used during pregnancy unless clearly necessary.
Use in Lactation: It is not known whether TIRONEM is excreted in human breast milk. A study in rats has shown that TIRONEM and its metabolite are transferred to milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with TIRONEM should be made taking into account the benefit of breastfeeding to the child and the benefit of TIRONEM therapy to the woman.
Adverse Reactions
Adverse drug reactions that led to TIRONEM discontinuation were nausea, diarrhea, pruritus, vulvomycotic infection, hepatic enzyme increased and rash. The most common adverse reactions were headache, diarrhea and nausea (see Table 3).


Click on icon to see table/diagram/image

Drug Interactions
TIRONEM undergoes little to no Cytochrome P450 (CYP450) mediated metabolism. Based on in vitro studies it is not expected that TIRONEM will inhibit or induce the activities of CYP450. Therefore, no CYP450-related drug interactions are to be expected.
Carbapenem antibacterial agents may reduce serum valproic acid concentrations. Serum concentrations of valproic acid should be monitored if TIRONEM is administered concomitantly with valproic acid.
Probenecid competes with TIRONEM for renal tubular secretion and reduces the renal clearance of TIRONEM. In an interaction study, the mean TIRONEM AUC increased by 75% following co-administration with probenecid. Therefore, co-administration of probenecid with TIRONEM is not recommended. An interaction with other drugs eliminated by renal tubular secretion can not be excluded.
Storage
Store below 30°C.
MIMS Class
ATC Classification
J01DH04 - doripenem ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.
Presentation/Packing
Powd for infusion (vial) 500 mg x 1's.
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