Doribax Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

DORIBAX^® (doripenem for injection) is a carbapenem antibiotic indicated for the treatment of adults (18 years and older) with the following infections when caused by susceptible strains of the designated microorganisms:

Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia caused by Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus pneumoniae, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa.

Note: Adjunctive use of an aminoglycoside was permitted in the nosocomial pneumonia clinical studies (see Product Monograph Part II: CLINICAL TRIALS).

Complicated Intra-Abdominal Infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides caccae, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus and Peptostreptococcus micros.

Complicated Urinary Tract Infections, Including Pyelonephritis caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Acinetobacter baumannii.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify causative organisms and to determine their susceptibility to doripenem. Once these results are available, antimicrobial therapy should be adjusted accordingly. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Empiric therapy with DORIBAX^® may be initiated before the results of these tests are known.

Geriatrics (≥ 65 years of age): Evidence from clinical studies suggests that use in the geriatric population is not associated with significant differences in safety or effectiveness (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics). Population pharmacokinetic data showed there is no independent effect of age on the pharmacokinetics of doripenem. Dosage adjustment is not required in elderly patients with normal renal function (see DOSAGE AND ADMINISTRATION, Patients with Renal Impairment).

Pediatrics (<18 years of age): No data available (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics).

CONTRAINDICATIONS

DORIBAX^® is contraindicated in patients with known hypersensitivity to doripenem monohydrate or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING BETA-LACTAMS. ANAPHYLACTIC AND ANAPHYLACTOID REACTIONS HAVE BEEN OBSERVED WITH DORIBAX^® (see WARNINGS AND PRECAUTIONS, Immune, Hypersensitivity Reactions)

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 (see WARNINGS AND PRECAUTIONS, Nervous System Disorders, Seizures and ADVERSE REACTIONS).

Case reports in the literature have shown that co-administration of carbapenems to patients receiving valproic acid or sodium valproate results in a reduction in serum valproic acid concentrations which may drop below the therapeutic range, therefore increasing the risk of breakthrough seizures. Alternative antibacterial and anticonvulsant therapies or supplemental anticonvulsant therapy should be considered. Therefore frequent monitoring of serum valproic acid concentration is considered after initiating therapy if DORIBAX^® is administrated concomitantly with valproic acid or sodium valproate (see DRUG INTERACTIONS).

General

For ventilator-associated pneumonia, the treatment duration should be guided by the severity of illness, infecting pathogen and the patient’s clinical response. Consideration should be given to treat patients with ventilator-associated pneumonia for more than 7 days (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Prescribing DORIBAX^® in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and may increase the risk of the development of drug-resistant bacteria.

Experience in patients who are severely immunocompromised, receiving immunosuppressive therapy, and patients with severe neutropenia is limited since this population was excluded from clinical trials.

Seizures have been infrequently reported during treatment with carbapenems (see WARNINGS AND PRECAUTIONS, Nervous System Disorders, Seizures).

DORIBAX^® should not be used to treat infections caused by methicillin-resistant staphylococci.

Doripenem reduced serum valproic acid concentrations to sub-therapeutic levels in healthy subjects. Therapeutic monitoring of valproic acid and use of alternative therapies should be considered in patients (see DRUG INTERACTIONS).

Gastrointestinal

Clostridium difficile-associated disease

Clostridium difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including DORIBAX^®. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases (see ADVERSE REACTIONS).

Hepatic/Biliary/Pancreatic

The safety, efficacy and pharmacokinetics of DORIBAX^® in patients with known hepatic impairment have not been established.

Immune

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) and serious skin reactions have been reported in patients receiving beta-lactam antibiotics (see CONTRAINDICATIONS). Anaphylactic and anaphylactoid reactions have been observed with DORIBAX^®. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Before therapy with DORIBAX^® is instituted, careful inquiry should be made to determine whether the patient has had a previous hypersensitivity reaction to other carbapenems, cephalosporins, penicillins or other allergens. If this product 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^® occurs, discontinue the drug. Serious acute hypersensitivity (anaphylactic) reactions require emergency treatment with epinephrine and other emergency measures, including oxygen, i.v. fluids, i.v. antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.

Nervous System Disorders

Seizures

During clinical trials of adult patients with nosocomial pneumonia treated with DORIBAX^® (500 mg), seizures, irrespective of drug relationship, occurred in 0.2% of patients during study therapy. In clinical trials in adults with nosocomial pneumonia treated with DORIBAX^® greater than 500 mg, seizures occurred at 1.2%. These experiences have occurred most commonly in patients with CNS disorders (e.g. stroke or history of seizures and/or compromised renal function) and at doses greater than 500 mg.

Close adherence to the recommended dosage regimen is urged, especially in patients with known factors that predispose to convulsive activity. Anticonvulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of DORIBAX^® re-examined to determine whether it should be adjusted or the antibiotic discontinued.

Renal

In patients with moderately or severely impaired renal function (CrCl > 10 to ≤ 50 mL/min), dosage adjustment is required (see DOSAGE AND ADMINISTRATION, Patients with Renal Impairment). In such patients, renal function should be monitored.

Evidence from clinical studies suggests more adverse events occurred in patients with moderately or severely impaired renal function than patients with CrCl > 50 mL/min. Most adverse events that occurred at a higher rate in patients with moderately or severely impaired renal function also occurred at a higher rate in patients > 65 years of age, as would be expected since renal function declines with age. Clinical response rates were also lower for these patients as compared to patients with normal renal function. There is limited clinical experience with this population, and in addition there are no clinical data for patients with severe renal impairment using the four-hour DORIBAX^® infusion. PK/PD modeling indicates a potential for reduced efficacy of DORIBAX^® against pathogens with MICs ≥ 4µg/mL in certain situations, even when using the extended duration of infusion of four hours (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics).

No data on the safety and efficacy in patients with end-stage renal disease (CrCl ≤ 10 mL/min) or those on dialysis methods other than continuous renal replacement therapy compared to non-renally impaired patients are available.

Due to limited clinical data and an expected increased exposure of doripenem and its metabolite, DORIBAX^® should be used with caution in patients with severe renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).

DORIBAX^® can be removed by hemodialysis. In subjects with end-stage renal disease requiring dialysis administered DORIBAX^® 500 mg, the mean total recovery of doripenem and doripenem M-1 in the dialysate following a 4-hour dialysis session was 259 mg (52% of the dose). However, there is insufficient information to make dose adjustment recommendations in patients with end-stage renal disease (CrCl ≤ 10 mL/min) or in patients on dialysis methods other than continuous renal replacement therapy. Therefore, DORIBAX^® is not recommended for patients with CrCl ≤ 10 mL/min or for patients on any type of dialysis other than continuous renal replacement therapy.

Continuous Renal Replacement Therapy

The exposure to the metabolite doripenem-M-1 in patients on continuous renal replacement therapy 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 DOSAGE AND ADMINISTRATION, Patients on Continuous Renal Replacement Therapy and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Patients on Continuous Renal Replacement Therapy)

Respiratory

Pneumonitis with Inhalation Use

When used investigationally in clinical trials via inhalation, pneumonitis has occurred. DORIBAX^® should not be administered by this route.

Skin

The incidence of rash (as judged by clinical investigators as being possibly or probably related to DORIBAX^® ) in 1761 patients receiving doripenem 1.5 g daily (500 mg every 8 hours) in 6 Phase III studies was 1.0%. In a Phase 1 study in healthy subjects receiving doripenem 6 g daily (2 g every 8 hours), rash occurred in 5 of 8 subjects.

Cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported from post-market sources (see ADVERSE REACTIONS).

Special Populations

Pregnant Women: There are no adequate and well-controlled studies in pregnant women. DORIBAX^® should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Doripenem was not teratogenic and did not produce effects on ossification, developmental delays or fetal weight in preclinical studies. Because animal reproduction studies are not always predictive of a human response, this drug should be used during pregnancy only if clearly needed.

Nursing Women: It is not known whether DORIBAX^® is excreted in human milk. A study in rats has shown that doripenem and its metabolite are transferred to milk. Because many drugs are excreted in human milk, DORIBAX^® should be administered to nursing mothers only when the potential benefit justifies the potential risk to the baby.

Pediatrics (< 18 years of age): Safety and effectiveness in pediatric patients below the age of 18 have not been established. Therefore, use in patients under 18 years of age is not recommended.

Geriatrics (> 65 years of age): Of the total number of subjects in clinical studies treated with DORIBAX^®, 31% were 65 years and over, while 14% were 75 years and over. No differences were seen in clinical cure rates in elderly patients versus younger patients with nosocomial pneumonia. Clinical cure rates in complicated intra-abdominal and complicated urinary tract infections were slightly lower in patients ≥ 65 years of age and also in the subgroup of patients ≥ 75 years of age versus patients < 65. Cure rates were similar between DORIBAX^® and comparator treatment groups.

Population pharmacokinetic data showed there is no independent effect of age (18 years or older) on the pharmacokinetics of doripenem. Dose adjustment is not required in elderly patients with normal renal function.

DORIBAX^® is known to be excreted substantially by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Renal above).

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The overall rate of adverse drug reactions assigned by clinical investigators as being possibly or probably related to DORIBAX^® in Phase III clinical trials was 24%. The most common adverse drug reactions (≥1%) assigned by clinical investigators as being possibly or probably related to DORIBAX^® in clinical trials were diarrhea (3.4%), headache (3.2%), phlebitis (3.2%), nausea (2.7%), vomiting (1.6%), hepatic enzymes increased (1.2%), gamma-glutamyltransferase increased (1.1%), and rash (1.0%). The majority (97%) of related adverse drug reactions were reported as mild or moderate in severity. Serious adverse drug reactions were atrial fibrillation, atrial flutter, renal failure, renal impairment, cholestasis, liver function test abnormal, convulsion, and hypotension; each was reported once (<0.1%). During clinical trials, the most common related adverse drug reaction (≥0.2%) that led to DORIBAX^® discontinuation was hepatic enzyme increased (0.2%). DORIBAX^® was discontinued due to a related adverse drug reaction in 1.2% of patients.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The safety of DORIBAX^® in patients with nosocomial pneumonia (NP), complicated intra-abdominal infection (cIAI), and complicated urinary tract infection (cUTI) was evaluated in five Phase III double-blind, controlled trials and one Phase III non-comparative study (cUTI) involving 3086 adult patients (1761 of whom received DORIBAX^®). Adverse drug reactions due to DORIBAX^® that occurred at a rate ≥1% (as judged by the investigator to be possibly or probably related to DORIBAX^®) are listed in Table 1.1. Adverse drug reactions with an incidence of <1.0% and ≥0.1% (as judged by the investigator to be possibly or probably related to DORIBAX^®) are listed in Table 1.2.

Table 1.1: Adverse Drug Reactions (%) Observed in Six Phase III Clinical Trials Occurring at a Rate ≥1%

DORIBAX^® COMPARATOR¹ Body System or Organ Class (N=1761) (N=1325) Dictionary-derived Term % % Gastrointestinal disorders 8.3 7.8 Diarrhea 3.4 4.3 Nausea 2.7 1.7 Vomiting 1.6 1.1

Investigations 4.2 4.9 Hepatic enzyme increased 1.2 1.4 Gamma-glutamyltransferase

increased

1.1 1.4

Nervous system disorders 4.1 2.0 Headache 3.2 1.1

Vascular disorders 3.6 2.0 Phlebitis 3.2 1.7

Skin and subcutaneous tissue

disorders

2.4 1.8

Rash 1.0 0.2 ¹ Refer to PRODUCT MONOGRAPH, Part II: CLINICAL TRIALS

Table 1.2: Less Common Clinical Trial Adverse Drug Reactions Observed in Six Phase III Clinical Trials Occurring at a Rate of <1.0% and ≥ 0.1%

The following significant but non-serious adverse drug reactions (as judged by the investigator as probably/possibly related to DORIBAX^®) occurred at a rate of <0.1% arrhythmia, delirium, rhabdomyolysis, vasculitis, coagulopathy, encephalopathy, bronchospasm, generalized edema, urticaria localized and swelling face.

Abnormal Hematologic and Clinical Chemistry Findings

Table 1.3 shows the most frequently observed drug-related laboratory abnormalities reported as an adverse experience during treatment with DORIBAX^®.

Table 1.3: Incidence (%) of Specific Drug-Related Chemical and Hematologic Laboratory Adverse Experiences Reported in Six Phase III Clinical Trials Occurring at a Rate ≥0.1%

Ventilator-Associated Pneumonia

The use of DORIBAX^® 1g q8h in a fixed 7-day course in patients with ventilator-associated pneumonia (VAP) has been associated with a higher mortality rate and a lower clinical cure rate compared to a fixed 10-day course of a comparator.

Consideration should be given to treat patients with ventilator-associated pneumonia for more than 7 days. Treatment duration should be guided by the severity of illness, infecting pathogen and the patient’s clinical response (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Post-Market Adverse Drug Reactions

The following adverse reactions have been identified during post-approval use of DORIBAX^®. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency:

Blood and the lymphatic system disorders

Thrombocytopenia, Neutropenia

Immune system disorders

Anaphylaxis

Skin and subcutaneous tissue disorders

Toxic epidermal necrolysis, Stevens-Johnson syndrome

The following treatment-emergent adverse events (known to occur with beta-lactams including carbapenems) have been reported voluntarily during post-approval use of DORIBAX^® They are included due to their seriousness, although it is not possible to estimate their frequency and causality has not been established:

Interstitial pneumonia

Agranulocytosis

Leukopenia

Hemolytic anemia and pancytopenia have been reported during treatment with carbapenems.

DRUG INTERACTIONS

Overview

In vitro studies in human liver microsomes and hepatocytes indicate that doripenem does not inhibit the major cytochrome P450 isoenzymes. Therefore, DORIBAX^® is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner.

DORIBAX^® also is not expected to have enzyme-inducing properties based on in vitro studies in cultured human hepatocytes.

Drug-Drug Interactions

Probenecid

Probenecid competes with doripenem for active tubular secretion and thus reduces the renal clearance of doripenem. Probenecid increased doripenem AUC by 75% and plasma half-life by 53%. Coadministration of probenecid with DORIBAX^® is not recommended.

Valproic Acid

Reduction in serum valproic acid concentrations to below the therapeutic concentration range (50 to 100 µg/mL) was observed by 12 hours after initiation of doripenem in healthy subjects co-administered both drugs. Patients with seizure disorders controlled with valproic acid or sodium valproate may be at an increased risk for breakthrough seizures when treated with DORIBAX^® concomitantly. Alternative antibacterial and anticonvulsant therapies or supplemental anti-convulsant therapy should be considered. A similar drug interaction involving other carbapenem antibacterials and valproic acid or sodium valproate has been described in published case reports. Therefore, valproic acid concentrations in the blood should be monitored if DORIBAX^® is administered concomitantly with valproic acid or sodium valproate. The pharmacokinetics of doripenem were unaffected by the co-administration of valproic acid.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

On the basis of pharmacokinetic data in patients with moderate to severe renal impairment, the dose of DORIBAX^® should be adjusted (see Recommended Dose and Dosage Adjustment, Patients with Renal Impairment).

Recommended Dose and Dosage Adjustment

The recommended dose of DORIBAX^® for patients aged 18 years and older is 500 mg administered every 8 hours by intravenous infusion. The recommended dosage and infusion time by indication are described in Table 1.4:

Table 1.4: Dosage of DORIBAX^® by Indication

Indication Dosage Frequency Infusion Time

(hours)

Duration^b

Nosocomial pneumonia

including ventilator–

associated pneumonia

500 mg Every 8

hours

1 or 4^a 7-14 days^c

Complicated intra-

abdominal infection

500 mg Every 8

hours

1 5-14 days

Complicated UTI, including

pyelonephritis

500 mg Every 8

hours

1 10 days^{d a} One-hour infusions are recommended for treatment of patients with nosocomial pneumonia. For patients with late onset VAP (> 5 days ventilation) who are at risk for infection with less susceptible pathogens, four-hour infusions are recommended (based primarily on pharmacokinetic/pharmacodynamic modeling) [See ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics and Product Monograph Part II: CLINICAL TRIALS. See also Reconstitution and Dilution].

^b Duration includes a possible switch to an appropriate oral therapy, after at least 3 days of parenteral therapy, once clinical improvement has been demonstrated.

^c See below for duration recommendations for patients with ventilator-associated pneumonia. ^d Duration can be extended up to 14 days for patients with concurrent bacteremia; data for this regimen is limited to E. coli infections only (see Product Monograph, Part II: CLINICAL TRIALS).

The usual treatment duration for patients with nosocomial pneumonia, including ventilator-associated pneumonia, is 7 to 14 days and should be guided by the severity of illness, infecting pathogen and the patient’s clinical response.

In a Phase III study in patients with ventilator-associated pneumonia, a fixed 7-day course of DORIBAX^® (1 gram every 8 hours as a 4-hour infusion) failed to demonstrate non-inferiority to a 10-day course of imipenem/cilastatin therapy. Consideration should be given to treat patients with ventilator–associated pneumonia for more than 7 days (see ADVERSE REACTIONS).

DORIBAX^® was given for up to 14 days in clinical studies and the safety of longer durations of therapy has not been established.

Patients with Renal Impairment

Following a single 500 mg dose of DORIBAX^®, the mean AUC of doripenem in subjects with mild (CrCl > 50 mL/min), moderate (CrCl 31 – 50 mL/min), and severe (CrCl < 30 mL/min) renal impairment was 1.6-, 2.8-, and 5.1-times that of age-matched healthy subjects with normal renal function (CrCl >80 mL/min), respectively.

In patients whose creatinine clearance (CrCl) is > 50 mL/min, no dosage adjustment is necessary. In patients with moderate renal impairment (CrCl ≥ 30 to ≤ 50 mL/min), the dosage of DORIBAX^® should be 250 mg administered every 8 hours as a one-hour i.v. infusion. In patients with severe renal impairment (CrCl > 10 to < 30 mL/min), the dosage of DORIBAX^® should be 250 mg administered every 12 hours as a one-hour i.v. infusion. For patients with late onset VAP (> 5 days ventilation) who are at risk for infection with less susceptible pathogens, four-hour infusions are recommended, with dose adjustments made for CrCl as described above; this recommendation is based on PK/PD modeling and target attainment is not always reached for less susceptible pathogens (see WARNINGS AND PRECAUTIONS, Renal and ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, PK/PD Index).

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 - age in years) 72 x serum creatinine (mg/dl)

Females: Creatinine clearance (mL/min) = 0.85 x value calculated for males.

Patients on Continuous Renal Replacement Therapy

DORIBAX^® dosing and administration recommendations for patients on continuous renal replacement therapies are shown in Table 1.5.

Table 1.5: Dosage of DORIBAX^® in Patients on Continuous Renal Replacement Therapies

CRRT

procedure

Estimated CrCl

(mL/min) ^a

Dose

Frequency

Infusion timeb,c,d

Target attainment (MIC)

CVVH ≤ 30 mL/min 250 mg every 12 hours 4 hours ≤ 1 μg/mL CVVHDF < 5 mL/min 250 mg every 12 hours 4 hours ≤ 1 μg/mL CVVHDF 5-30 mL/min 500 mg every 12 hours 4 hours ≤ 1 μg/mL CRRT: continuous renal replacement therapy; CVVH: continuous venovenous hemofiltration; CVVHDF: continuous venovenous hemodiafiltration; MIC: minimum inhibitory concentration

^a For estimation of CrCl, see DOSAGE AND ADMINISTRATION, Patients with Renal Impairment ^b 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.

^c 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)

^d For infusion solution shelf life, see STORAGE AND STABILITY.

Dosing recommendations for pathogens with MIC >1 μg/mL have not been established for continuous renal replacement therapy due to the potential for accumulation of doripenem and doripenem-M-1 metabolite (see WARNINGS AND PRECAUTIONS, Renal , Continuous Renal Replacement Therapy and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Patients on Continuous Renal Replacement Therapy). 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 WARNINGS AND PRECAUTIONS, Renal , Continuous Renal Replacement Therapy).

There is insufficient information to make dose adjustment recommendations in patients with CrCl ≤ 10 mL/min or on other forms of dialysis. Therefore, DORIBAX^® is not recommended for patients with CrCl ≤ 10 mL/min or on other forms of dialysis other than continuous renal replacement therapy (see WARNINGS AND PRECAUTIONS, Renal and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).

Patients with Hepatic Impairment

The safety, efficacy and pharmacokinetics of DORIBAX^® in patients with known hepatic impairment have not been established. As doripenem does not appear to undergo hepatic metabolism, the pharmacokinetics of DORIBAX^® are not expected to be affected by hepatic impairment.

Other

No dosage adjustment is recommended based on age (18 years of age and older), gender or race (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pediatrics, Gender and Race).

Administration

DORIBAX^® is to be reconstituted and then further diluted prior to administration by intravenous infusion. Each vial contains 500 mg doripenem and is for single use only.

Reconstitution and Dilution:

Aseptic technique must be followed in preparation of the infusion solution. 5% Dextrose should not be used for infusion durations lasting longer than one hour.

Preparation of 500 mg dose:

1. 1. Add 10 mL of sterile water for injection or 0.9% sodium chloride injection (normal saline) and gently shake to form a suspension.
2. 2. Inspect the suspension visually for foreign material. Note: the suspension is not for direct infusion.
3. 3. Withdraw the suspension using a syringe and needle and add it to an infusion bag containing 100 mL of normal saline or 5% dextrose.
4. 4. To ensure complete transfer of the vial contents, repeat steps 1 to 2, and withdraw the second 10 mL suspension using a syringe and needle and add it to the same infusion bag. Infuse all of this solution to administer a 500 mg dose of doripenem.

Preparation of a 250 mg dose for patients with moderate or severe renal impairment (see Recommended Dose and Dosage Adjustment, Patients with Renal Impairment):

1. 1. Add 10 mL of sterile water for injection or 0.9% sodium chloride injection (normal saline) and gently shake to form a suspension.
2. 2. Inspect the suspension visually for foreign material. Note: the suspension is not for direct infusion.
3. 3. Withdraw the suspension using a syringe and needle and add it to an infusion bag containing 100 mL of normal saline or 5% dextrose.
4. 4. To ensure complete transfer of the contents of the vial to the infusion solution, repeat steps 1 to 2, and withdraw the second 10 mL suspension using a syringe and needle and add it to the same infusion bag.
5. 5. Remove 60 mL of this solution from the bag and discard. Infuse all of the remaining solution to administer a 250 mg dose of doripenem.

DORIBAX^® 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.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to use, whenever solution and container permit.

Compatibility and Stability

The compatibility of DORIBAX^® with other drugs has not been established. DORIBAX^® should not be mixed with or physically added to solutions containing other drugs.

Storage of Reconstituted Suspension

Upon reconstitution with sterile water for injection or 0.9% sodium chloride (normal saline) injection, DORIBAX^® suspension in the vial may be held for 1 hour prior to transfer and dilution in the infusion bag.

Storage of the Infusion Solution

Following dilution with normal saline or 5% dextrose, DORIBAX^® infusions stored at room temperature or under refrigeration should be completed according to the times in Table 1.6.

Table 1.6: Storage of Infusion Solutions Prepared in Normal Saline or

5% Dextrose

Diluent Stability time (hours)

Room Temp. 2-8°C (Refrigeration) Normal saline 12 72*

5% Dextrose⁺ 4 24*

* 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.

⁺ 5% Dextrose should not be used for infusion durations longer than 1 hour.

Constituted DORIBAX^® suspension or DORIBAX^® infusion should not be frozen.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

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 hemodialysis. In subjects with end-stage renal disease administered DORIBAX^® 500 mg, the mean total recovery of doripenem and doripenem M-1 in the dialysate following a 4-hour hemodialysis session was 259 mg (52% of the dose). However, insufficient information is available on the use of either of these therapies to treat overdosage.

The highest total daily dose administered in Phase I clinical trials was 6 g (2 g every 8 hours) (N=8).

With administration of a 6 g daily dose of doripenem (2 g every 8 hours), a higher rate of rash was seen.

ACTION AND CLINICAL PHARMACOLOGY

Doripenem is a synthetic broad spectrum beta-lactam carbapenem antibacterial agent with in vitro antibacterial activity against aerobic and anaerobic gram-positive and gram-negative bacteria.

Mechanism of Action

Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis (see PRODUCT MONOGRAPH Part II: MICROBIOLOGY).

Interaction with Other Antimicrobials

In vitro, doripenem showed little potential to antagonize or be antagonized by other antibiotics (see PRODUCT MONOGRAPH Part II: MICROBIOLOGY).

Mechanisms of Resistance

Bacterial resistance mechanisms that affect doripenem include drug inactivation by carbapenem-hydrolyzing enzymes, mutant or acquired PBPs, 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 carbapenem hydrolyzing beta-lactamases.

Pharmacodynamics

PK/PD Index

Similar to other beta-lactam antimicrobial agents, the time (% of the dosing interval) that the plasma concentration of free doripenem exceeds the MIC (%ƒT>MIC) of the infecting organism has been shown to best correlate with efficacy in nonclinical pharmacokinetic/pharmacodynamic studies. %ƒT>MIC (±SD) required to achieve a bacteriostatic effect, 1 log₁₀ reduction and 2 log₁₀ reduction in a neutropenic murine thigh infection model were 29% (±5.3), 36% (±7.4), and 43% (±7.1) respectively. Based on human pharmacokinetic modeling and simulations, extending the infusion time to 4 hours generally increases the %ƒT>MIC for the recommended dose Estimates of PK/PD target attainment rates are summarized in Table 1.7.

Table 1.7: Estimated Target Attainment Rates (%) for DORIBAX^® PK/PD Target of 35% fT>MIC

PK/PD target of 35% fT>MIC corresponds to exposure required to achieve approximately 1 log ₁₀ reduction in a neutropenic murine thigh infection model.

PK data were obtained from 303 subjects, including 176 healthy volunteers, 109 patients with cUTI and pyelonephritis, and 18 patients with nosocomial pneumonia. A two-compartment model with zero-order input and first-order elimination best described the PK of doripenem following i.v. administration. 5000 subjects were simulated per Monte Carlo simulation scenario.

QT Study

In a randomized, positive- and placebo-controlled crossover QT study, 60 healthy subjects were administered DORIBAX^® 500 mg i.v. every 8 hours infused over 1 hour × 4 doses and DORIBAX^® 1g i.v. every 8 hours infused over 1 hour × 4 doses, placebo, and a single oral dose of positive control. At both the 500 mg and 1g doripenem doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.

Pharmacokinetics

Plasma Concentrations: Average plasma concentrations (µg/mL) of doripenem following single one-hour and four-hour intravenous infusions of a 500 mg dose administered to healthy adult subjects with normal renal function (CrCL ≥ 80mL/min) are presented in Table 1.8

Table 1.8: Plasma Concentrations of Doripenem After Single-Dose Administration

Dose and Infusion

Duration

Time Relative to Start of Infusion (hour) Average Plasma Concentration (µg/mL)

500 mg over 1 hour

0.5 1 2 3 4 6 7 8 9 20.2 20.9 6.13 2.69 1.41 0.45 -- 0.13 -- 500 mg over 4

hours

4.01 5.70 7.26 8.12 8.53 1.43 0.78 -- 0.28

The pharmacokinetics of doripenem (C_max and AUC) are linear over a dose range of 500 mg to 2 g when intravenously infused over 1 hour and 500 mg to 1 g when intravenously infused over 4 hours. There is no accumulation of doripenem following multiple intravenous infusions of 500 mg, 1 g or 2 g administered every 8 hours for 7 days up to 14 days in subjects with normal renal function.

Plasma Pharmacokinetic Parameters: Mean (SD) plasma pharmacokinetic parameters of doripenem following multiple intravenous infusions of 500 mg administered every 8 hours over 30 minutes to healthy adult subjects with normal renal function (CrCL ≥ 80 mL/min) are presented in Table 1.9.

Table 1.9: Plasma Pharmacokinetic Parameters of Doripenem

After Multiple-Dose Administration

Parameter

500 mg over 30 minutes

q8h N 5

T_max^a (h) 0.50 (0.50-0.50)

C_max (µg/mL) 31.4 (3.61)

AUC_τ (µg•h/mL) 35.5 (4.42)

t_1/2 (h) 0.872 (0.0723)

Accumulation Ratio^b 0.926 (0.0808)

^a Expressed as median (minimum - maximum)

^b Calculated as AUC_τ (multiple-dose) divided by AUC_τ (single-dose)

Absorption: DORIBAX^® is administered intravenously and therefore has 100% bioavailability.

Distribution: The average binding of doripenem to plasma proteins is approximately 8.1% and is independent of plasma drug concentrations. The volume of distribution at steady state of doripenem is approximately 16.8 L, similar to extracellular fluid volume (18.2 L) in man. Doripenem penetrates well into several body fluids and tissues, achieving concentrations either matching or exceeding those required to inhibit most susceptible bacteria. Concentrations achieved in selected tissues and fluids following administration of DORIBAX^® are shown in Table 1.10.

Table 1.10 : Doripenem Concentrations in Selected Tissues and Fluids

Tissue or Fluid Dose

(mg)

Infusion Duration (h)

Number of Samples or Subjects^a

Sampling Period

Concentration Range (µg/mL or µg/g)

Tissue- or Fluid-

To-Plasma Concentration Ratio (%) Mean (Range)

Prostate 250 0.5 or 1 8 60-160 min 0.760-10.3 81.3 (15.0-426)

500 0.5 or 1 5 90-130 min 1.04-4.51 33.5 (18.7-49.9) Peritoneal

exudates

250 0.5 5^f 30-150 min^g 2.36-5.17 25.1 (14.4-47.3)

Gallbladder 250 0.5 10 20-215 min BQL-1.87^h 8.02 (0.00-44.4) Bile 250 0.5 10 20-215 min BQL-15.4^d 117 (0.00-611)

Urine

500 0.5, 1 or 4 118 0-4 hr 623 (BQL^e-3360)ⁱ ---

500 0.5, 1 or

4 118 4-8 hr 47.1 (BQL^e-635)ⁱ --- ^a Unless stated otherwise, only one sample was collected per subject; ^b Below quantitation limit (BQL) in 3 subjects; ^c BQL in 2 subjects; ^d BQL in 4 subjects; ^e BQL in 1 subject; ^f Serial samples were collected and maximal concentration is reported for each subject; ^g t_max range; ^h BQL in 6 subjects; ⁱ Median (range) of average concentrations over the collection interval

In addition, although clinical relevance is uncertain, concentrations approximating 3 µg/mL or µg/g or higher have been achieved in joint fluid, synovial membrane, bony tissue and skin tissue following a 250 mg dose of DORIBAX^®.

Metabolism: Metabolism of doripenem to a microbiologically inactive ring-opened metabolite (doripenem-M-1) occurs primarily via dehydropeptidase-I. No CYP450-mediated in vitro metabolism of doripenem could be detected in the presence or absence of NADPH.

Doripenem degraded less than 20% after a 90-minute incubation with recombinant human renal DHP-I similar to the rate for meropenem, whereas imipenem underwent extensive hydrolysis.

Excretion: Doripenem is primarily eliminated unchanged by the kidneys. Mean plasma terminal elimination half-life of doripenem in healthy young adults is approximately 1 hour and plasma clearance is approximately 15.9 L/hour. Mean renal clearance is 10.3 L/hour. The magnitude of this value, coupled with the significant decrease in the elimination of doripenem seen with concomitant probenecid administration, suggests that doripenem undergoes both glomerular filtration and tubular secretion. In healthy young adults given a single 500 mg dose of DORIBAX^®, 71% and 15% of the dose was recovered in urine as unchanged drug and ring-opened metabolite, respectively. Following the administration of a single 500 mg dose of radiolabeled doripenem to healthy young adults, less than 1% of the total radioactivity was recovered in feces.

Special Populations and Conditions

Pediatrics: The pharmacokinetics of doripenem have not been established in patients under 18 years of age.

Geriatrics: The impact of age on the pharmacokinetics of doripenem was evaluated in healthy male and female subjects ≥ 66 years of age. Doripenem AUC increased 49% in elderly adults relative to young adults. These changes were mainly attributed to age-related changes in creatinine clearance. No dosage adjustment is recommended for elderly patients with normal renal function (see DOSAGE AND ADMINISTRATION, Other).

Gender: The effect of gender on the pharmacokinetics of doripenem was evaluated in healthy male and female subjects. Doripenem AUC was 15% higher in females compared to males. No dose adjustment is recommended based on gender (see DOSAGE AND ADMINISTRATION, Other).

Race: The effect of race on doripenem pharmacokinetics was examined through a population pharmacokinetic analysis. No significant difference in mean doripenem clearance was observed across race groups and therefore no dosage adjustment is recommended based on race (see DOSAGE AND ADMINISTRATION, Other).

Hepatic Insufficiency: The pharmacokinetics of doripenem in patients with hepatic impairment have not been established. As doripenem does not appear to undergo hepatic metabolism, the pharmacokinetics of DORIBAX^® are not expected to be affected by hepatic metabolism (see DOSAGE AND ADMINISTRATION, Patients with Hepatic Impairment).

Renal Insufficiency: Following a single 500 mg dose of DORIBAX^®, AUC increased 1.6 fold, 2.8-fold, and 5.1-fold in subjects with mild (CrCl 51-79 mL/min), moderate (CrCl 31-50 mL/min), and severe renal impairment (CrCl <30 mL/min), respectively, compared to age-matched healthy subjects with normal renal function (CrCl >80 mL/min). Dosage adjustment is recommended in patients with moderate to severe renal impairment (see DOSAGE AND ADMINISTRATION, Patients with Renal Impairment).

Plasma Pharmacokinetic Parameters in Subjects with Renal Impairment: Mean (SD) plasma pharmacokinetic parameters of doripenem following a single infusion of 500 mg doripenem administered over one-hour in healthy volunteers with and without renal impairment are presented in Table 1.11.

Table 1.11: Plasma Pharmacokinetic Parameters of Doripenem After Single-Dose (500 mg over 1 hour)

Administration in Healthy Volunteers with and without Renal Impairment

Normal Renal

Function

Mild

Renal Impairment

Moderate Renal Impairment

Severe

Renal Impairment

PK Parameter (CrCl ≥80 mL/min) (CrCl 51-79 mL/min) (CrCl 31-50 mL/min) (CrCl 10-30 mL/min) Number of

subjects 8 6 6 6

C_max (µg/mL) 31.7 (9.20) 41.3 (9.42) 38.5 (5.95) 36.4 (6.28) t_max (hr)^a 0.5 (0.50-0.50) 0.5 (0.50-0.50) 0.5 (0.25-0.50) 0.5 (0.25-0.75) AUC_∞ (µg·hr/mL) 37.3 (5.35) 61.4 (18.0) 106 (18.6) 190 (26.4) t_1/2 (hr) 1.11 (0.192) 1.31 (0.377) 2.67 (0.638) 4.62 (0.496) CL (L/hr) 13.7 (1.98) 8.64 (2.05) 4.84 (0.750) 2.68 (0.389) V_ss (L) 16.5 (3.57) 13.3 (5.07) 15.7 (3.33) 16.8 (2.77) ^a Expressed as median (minimum - maximum)

Patients on Continuous Renal Replacement Therapy: DORIBAX^® dosage adjustment is necessary in patients receiving continuous renal replacement therapy (see DOSAGE AND ADMINISTRATION, Patients on Continuous Renal Replacement Therapy). In a study where 12 subjects with end stage renal disease received a single 500 mg dose of doripenem as a 1-hour i.v. infusion, the systemic exposure to doripenem and doripenem-M-1 were increased compared with healthy subjects. The amount of doripenem and doripenem-M-1 removed during a 12-hour CVVH session was approximately 28% and 10% of the dose, respectively; and during a 12-hour CVVHDF session was approximately 21% and 8% of the dose, respectively. Dosing recommendations for patients on continuous renal replacement therapy were developed to achieve doripenem systemic exposures similar to subjects with normal renal function who receive doripenem 500 mg as a 1-hour infusion, to maintain doripenem concentrations above a minimum inhibitory concentration of 1 µg/mL for at least 35% of the dosing interval, and to maintain doripenem and doripenem-M-1 exposures below those observed with a 1-hour infusion of 1 g doripenem every 8 hours in healthy subjects. These dosing recommendations were derived by modeling data from subjects with end stage renal disease receiving continuous renal replacement therapy, and take into consideration the potential increases in non-renal clearance of carbapenems in patients with acute renal insufficiency compared to patients with chronic renal impairment. Doripenem-M-1 had a slow elimination in subjects on continuous renal replacement therapy, and the half-life (and AUC) has not been satisfactorily determined. Therefore, it may not be excluded that the exposure obtained in patients receiving continuous renal replacement therapy will be higher than estimated and thus higher than metabolite exposures observed with a 1-hour infusion of 1 g doripenem every 8 hours in healthy subjects. The in vivo consequences of the increased exposures to the metabolite are unknown as data on pharmacological activity, except for antimicrobiological activity, are lacking (see WARNINGS AND PRECAUTIONS, Renal , Continuous Renal Replacement Therapy). If the doripenem dose is increased beyond the recommended dose for continuous renal replacement therapy, the systemic exposure of the doripenem-M-1 metabolite is further increased. The clinical consequences of such an increase in exposure are unknown.

The systemic exposures to doripenem and doripenem-M-1 were increased in subjects with end stage renal disease receiving hemodialysis compared with healthy subjects. In a study where six subjects with end stage renal disease received a single dose of 500 mg doripenem by i.v. infusion, the amount of doripenem and doripenem-M-1 removed during a 4-hour hemodialysis session was approximately 46% and 6% of the dose, respectively.

There is insufficient information to make dose adjustment recommendations in patients on dialysis methods other than continuous renal replacement therapy (see DOSAGE AND ADMINISTRATION, Patients on Continuous Renal Replacement Therapy).

STORAGE AND STABILITY

DORIBAX^® vials should be stored at 15°C-30°C.

For infusion solution storage conditions, see DOSAGE AND ADMINISTRATION, Storage of the Infusion Solution.

DORIBAX^® must be reconstituted and then further diluted prior to infusion (see DOSAGE AND ADMINISTRATION, Administration).

DOSAGE FORMS, COMPOSITION AND PACKAGING

DORIBAX^® is supplied as sterile single-use clear 20 mL glass vials containing 500 mg (on an anhydrous basis) of sterile doripenem powder.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common name: Doripenem monohydrate

Chemical name: (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate

Molecular formula and molecular mass: C₁₅H₂₄N₄O₆S₂.H₂O; 438.52 (420.51 on anhydrous basis)

Structural formula:

. H₂O

N S

O

H₃C

HO H

CO₂H

H CH₃

H H NH

H N

H

S NH₂ O O

H

Physicochemical properties: Doripenem monohydrate is a white to slightly yellowish, off-white crystalline powder. It is sparingly soluble in water, slightly soluble in methanol, and practically insoluble in ethanol. The pK_a1 is 2.8 and the pK_a2 is 7.9.

CLINICAL TRIALS

Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia

Table 2.1: Summary of Phase III Clinical Trials and Patient Demographics in Two Phase III Trials of Adults with Nosocomial Pneumonia

Study No. Trial design Dosage, route of administration

and duration

No. of subjects^a

Demography:

Gender Mean age (age range)

DORI-09

(Trial 1)

Multicentre, randomized, open-label

(with in-house blinding) study of

doripenem versus

piperacillin/tazobactam in the treatment

of nosocomial pneumonia^c

Treatment: i.v. infusion of doripenem^d 500 mg administered over 1 hour every 8 hours or

piperacillin/tazobactam 4.5 g administered over 30 minutes every 6 hours for 7 to 14 days^b.

444 309 M, 135 F

58.7 yrs (18-97 yrs)

DORI-10

(Trial 2)

Multicentre, randomized open-label

(with in-house blinding) study of

doripenem versus imipenem in the

treatment of ventilator-associated

pneumonia ^c

Treatment: i.v. infusion of doripenem^e 500 mg administered over 4 hours every 8 hours or imipenem/cilastatin 500 mg administered over 30 minutes every 6 hours or 1,000 mg

administered over 1 hour every 8 hours for 7 to 14 days

525 409 M, 116 F

51.5 yrs (18-93 yrs)

^a Intent-to-Treat analysis group

^b Both regimens allowed for switch to oral levofloxacin therapy (750 mg once daily) after 9 or more doses of doripenem or 12 or more doses of piperacillin/tazobactam if protocol-specified criteria indicating sufficient clinical improvement were met ^c Both studies allowed for the adjunctive use of amikacin

^d In the Clinically Evaluable analysis group, 78 % of patients treated with doripenem and 85 % treated with comparator received an adjunctive aminoglycoside (57 % and 61% for more than 3 days, respectively) ^e In the Clinically Evaluable analysis group, 21 % of patients treated with doripenem and 25 % treated with comparator received an adjunctive aminoglycoside (12 % and 11% for more than 3 days, respectively)

Table 2.2: Clinical Cure Rates at Test of Cure Visit^a in Two Phase III Trials of Adults with Nosocomial Pneumonia

Population DORIBAX^®

Comparator Difference

N Cured % N Cured % (95% CI^e)

Trial 1 CE^b 134 109 81.3 119 95 79.8 1.5 (-9.1; 12.1) cMITT^c 213 148 69.5 209 134 64.1 5.4 (-4.1; 14.8) ME^d 84 69 82.1 83 65 78.3 3.8 (-9.4; 17.1) Trial 2 CE^b 126 86 68.3 122 79 64.8 3.5 (-9.1; 16.1) cMITT^c 244 144 59.0 249 144 57.8 1.2 (-7.9; 10.3) ME^d 116 80 69.0 110 71 64.5 4.4 (-8.7; 17.6) a

b

c

d

e

Test of cure visit 6 - 20 days after completing therapy

Clinically Evaluable

Clinical Modified Intent-to-Treat

Microbiologically Evaluable

The 2-sided 95% CI was based on the normal approximation to the difference of two binomial proportions with continuity correction

Table 2.3: Microbiological Cure Rates By Infecting Pathogen in Microbiologically

Evaluable Adults with Nosocomial Pneumonia^a Pathogen DORIBAX^® Comparator

Trial 1 N^b n ^c % N^b n ^c %

Gram-positive, aerobic Staphylococcus aureus

Methicillin susceptible

14 13 92.9 15 15 100.0

Streptococcus pneumoniae 7 6 85.7 6 5 83.3 Gram-negative, aerobic Enterobacter cloacae 11 11 100.0 6 5 83.3 Escherichia coli 9 7 77.8 8 7 87.5 Klebsiella pneumoniae 14 11 78.6 11 7 63.6 Haemophilus influenzae 8 8 100.0 10 8 80.0 Pseudomonas aeruginosa 18 15 83.3 17 12 70.6

Trial 2 N^b n^b % N^b n^b % Gram-positive, aerobic Staphylococcus aureus

Methicillin susceptible

17 12 70.6 21 15 71.4

Streptococcus pneumoniae 9 8 88.9 7 7 100.0 Gram-negative, aerobic Enterobacter cloacae 16 12 75.0 10 7 70.0 Escherichia coli 12 9 75.0 17 10 58.8 Klebsiella pneumoniae 15 12 80.0 10 6 60.0 Haemophilus influenzae 32 25 78.1 37 30 81.1 Pseudomonas aeruginosa 20 13 65.0 14 5 35.7 ^a At test of cure visit (6 – 20 days after completing therapy)

^b N = number of unique baseline isolates

^c n = number of pathogens assessed as eradicated

Complicated Intra-Abdominal Infections

Table 2.4: Summary of Phase III Clinical Trials and Patient Demographics in Two Phase III Trials in Adults with Complicated Intra-Abdominal Infections

Study No. Trial design Dosage, route of administration

and duration

No. of

subjects^a

Demography:

Gender Mean age (age range)

DORI-07

(Trial 1)

Multicentre, randomized, double-blind

study of doripenem versus meropenem in

the treatment of complicated intra-

abdominal infections

Treatment: i.v. infusion of doripenem

500 mg administered over 1 hour

every 8 hours or meropenem 1 g

administered over 3-5 minutes every 8

hours for 5 to 14 days ^b

471 290 M, 181 F

47.4 yrs (18-93 yrs)

DORI-08

(Trial 2)

Multicentre,randomized, double-blind

study of doripenem versus meropenem in

the treatment of complicated intra-

abdominal infections

Treatment: i.v. infusion of doripenem

500 mg administered over 1 hour

every 8 hours or meropenem1 g

administered over 3-5 minutes every 8

hours for 5 to 14 days ^b

475 297 M, 178 F

46.2 yrs (18-96 yrs)

^a Intent-to-Treat analysis group

^b Both regimens allowed for switch to oral amoxicillin/clavulanate therapy (875/125 mg twice daily) after 9 or more doses of IV study drug therapy if protocol-specified criteria indicating sufficient clinical improvement were met

Table 2.5: Clinical Cure Rates at Test of Cure Visit^a in Two Phase III Trials in Adults with Complicated Intra-Abdominal Infections

Population DORIBAX^®

Comparator Difference

N Cured % N Cured % (95% CI^e)

ME ^b 325 275 84.6 309 260 84.1 0.5 (-5.5; 6.4) mMITT ^c 395 301 76.2 375 290 77.3 -1.1 (-7.4; 5.1) CE ^d 380 324 85.3 378 326 86.2 -1.0 (-6.2; 4.3) a

b

c

d

e

Test of cure visit 21 – 60 days after completing therapy

Microbiologically Evaluable

Microbiological Modified Intent-to-Treat

Clinically Evaluable

The 2-sided 95% CI was based on the normal approximation to the difference of two binomial proportions with continuity correction

Table 2.6: Microbiological Cure Rates By Infecting Pathogen in Microbiologically

Evaluable Adults with Complicated Intra-abdominal Infections^a Pathogen DORIBAX^® Comparator

N^b n^c % N^b n^c % Gram positive, aerobic Streptococcus constellatus 10 9 90.0 7 5 71.4 Streptococcus intermedius 36 30 83.3 29 21 72.4 Gram positive, anaerobic Peptostreptococcus micros 13 11 84.6 14 11 78.6 Gram negative, aerobic Escherichia coli 216 189 87.5 199 168 84.4 Klebsiella pneumoniae 32 25 78.1 20 19 95.0 Pseudomonas aeruginosa 40 34 85.0 32 24 75.0 Gram negative, anaerobic Bacteroides caccae 25 23 92.0 19 18 94.7 Bacteroides fragilis 67 56 83.6 68 54 79.4 Bacteroides

thetaiotaomicron

34 30 88.2 36 32 88.9

Bacteroides uniformis 22 19 86.4 18 15 83.3 Bacteroides vulgatus 11 11 100.0 8 6 75.0 ^a At test of cure visit (21 – 60 days after completing therapy)

^b N = number of unique baseline isolates

^c n = number of pathogens assessed as eradicated

Complicated Urinary Tract Infections, Including Pyelonephritis

Table 2.7: Summary of Phase III Clinical Trials and Patient Demographics in Two Phase III Trials in Adults with Complicated Urinary Tract Infections, including Pyelonephritis

Study No. Trial design Dosage, route of administration

and duration

No. of

subjects^a

Demography:

Gender Mean age (age range)

DORI-05

(Trial 1)

Multicentre, randomized, double-blind

study of doripenem versus levofloxacin

in the treatment of complicated urinary

tract infections or pyelonephritis

Treatment: i.v. infusion of doripenem 500 mg administered over 1 hour every 8 hours or levofloxacin 250 mg administered over 1 hour every 24 hours for 10 days (up to 14 days for patients who were bacteremic at baseline) ^b

748 288 M and 460

F. 51.2 yrs (18-93 yrs)

DORI-06

(Trial 2)

Multicentre, open-label, single arm study

of doripenem in the treatment of

complicated lower urinary tract

infections or pyelonephritis

Treatment: i.v. infusion of doripenem 500 mg administered over 1 hour every 8 hours for 10 days (up to 14 days for patients who were bacteremic at baseline) ^b

423 176 M, 247 F

52.0 yrs (18-97 yrs)

^a Intent-to-Treat analysis group

^b Both regimens allowed for switch to oral levofloxacin therapy (250 mg every 24 hours) after 9 or more doses of IV study drug therapy if protocol-specified criteria indicating sufficient microbiological and clinical improvement were met.

Table 2.8: Microbiological Eradication and Clinical Cure Rates at Test of Cure Visit^a in Two Phase III Trials of Adults with Complicated Urinary Tract Infections, Including Pyelonephritis

Population DORIBAX^®

Comparator Difference

N Cured % N Cured %

(95% CI^e)

ME ^b 530 439 82.8 265 221 83.4 -0.6 (-6.4; 5.2) mMITT ^c 664 537 80.9 321 251 78.2 2.7 (-3.0; 8.3) CE ^d 543 511 94.1 266 240 90.2 3.9 (-0.5; 8.2) a

b

c

d

e

Test of cure visit 5 – 11 days after completing therapy

Microbiologically Evaluable (Microbiological Eradication)

Microbiological Modified Intent-to-Treat (Microbiological Eradication)

Clinically Evaluable (Clinical Cure)

The two-sided 95% CI was based on the normal approximation to the difference of two binomial proportions with continuity correction

Table 2.9: Microbiological Eradication Rates By Infecting Pathogen in

Microbiologically Evaluable Adults with Complicated Urinary Tract Infections, Including Pyelonephritis^a

Pathogen DORIBAX^®

Comparator

N^b n^c % N^b n^c % Gram negative, aerobic

Escherichia coli 357 313 87.7 211 184 87.2 Klebsiella pneumoniae 33 26 78.8 8 5 62.5 Proteus mirabilis 30 22 73.3 15 13 86.7 Acinetobacter baumannii 10 8 80.0 1 0 0.0 Pseudomonas aeruginosa 27 19 70.4 7 5 71.4 ^a At test of cure visit (5 – 11 days after completing therapy)

^b N = number of unique baseline isolates

^c n = number of pathogens assessed as eradicated

DETAILED PHARMACOLOGY

Animal Pharmacology

Pharmacodynamics

Safety Pharmacology

In vitro and in vivo studies were conducted to characterize non-microbiological pharmacological actions of doripenem. The doses used for in vivo safety pharmacology studies resulted in doripenem plasma exposure either equaling or exceeding that obtained in human clinical studies.

In safety pharmacology studies, (rat CNS; cardiovascular: human ether-a-go-go related gene (HERG) assay, dog Purkinje fibres, anesthetized rat, conscious dog) doripenem had no effects in vitro at concentrations up to 300 μM , or in vivo at the tested doses.

No effects of doripenem were observed in respiratory, kidney function of gastrointestinal motility studies.

Seizures

A series of studies were conducted to characterize doripenem for pharmacologic activities indicative of seizure potential.

Doripenem was compared to other $-lactam antibiotics for its binding affinity to the GABA receptor. Doripenem, when tested at concentrations between 0.3 and 10mM, was unable to substantially displace a GABA_A agonist from the GABA_A receptor site in mouse brain synaptic membranes. At 10mM, three other antibiotics (imipenem, panipenem, cefazolin) caused over 90% displacement of ³H-muscimol from its binding site, while meropenem caused approximately 50% displacement.

Doripenem was assessed for its ability to induced seizure or seizure-related neurological activity in mice, rats and dogs. Following direct administration into the lateral ventricle of mice, doripenem did not produce convulsions at doses at least 10-fold greater than convulsion-producing doses of imipenem, panipenem and cefazolin. Likewise, data suggest that doripenem has weaker convulsion-inducing effects than imipenem or meropenem when administered by intraventricular or intravenous injection to dogs and rats implanted with EEG electrodes.

The interaction of doripenem with the antiepileptic agent sodium valproate was investigated in rats. In a pentylenetetrazol-induced seizure model, doripenem at 100 to 1,000 mg/kg i.v. had no influence on the anticonvulsive effects of sodium valproate. In a bicuculline-induced seizure model, doripenem given at 300 mg/kg or 1,000 mg/kg i.v. did not affect the anticonvulsive effects of sodium valproate. Comparator compounds panipenem/betamipron and meropenem were found to interfere with anticonvulsive effects of sodium valproate in these models.

Pharmacokinetics

Doripenem has an elimination half-life (t_1/2) of <1 hour in mice, rats, rabbits, dogs, and monkeys. Renal excretion is the predominant route of elimination, with no evidence of tissue accumulation after repeat-dose administration. Excretion of doripenem into bile is minimal. While some doripenem is excreted into milk, the majority is eliminated within 24 hours. In adult and juvenile animals, doripenem mainly distributes to the kidney. In pregnant rats, distribution of doripenem to the fetus is limited.

Significant in vivo metabolism is found in rats but is more limited in dogs and monkeys. Doripenem undergoes rapid ß-lactam ring cleavage in plasma and kidney, forming the biologically inactive metabolite, doripenem dicarboxylic acid (doripenem-M-1). Doripenem is minimally metabolized by hepatic P450, and is less susceptible to hydrolysis by animal and human renal dehydropeptidase-I (DHP-I) compared to other carbapenems. Cilastatin (DHP-I inhibitor) administered to monkeys does not increase doripenem plasma levels. Neither doripenem nor doripenem-M-1 are inducers or inhibitors of P450 isoforms.

Doripenem decreases the plasma concentration of valproic acid when the drugs were co-administered in monkeys and rats. Probenecid, a tubular secretion inhibitor, elevates plasma levels of doripenem in monkeys. However, doripenem does not act as a substrate for P-glycoprotein nor for the probenecid-sensitive drug transporter proteins OAT1 and OAT3.

Human Pharmacology

Pharmacodynamics

In a randomized, positive- and placebo-controlled crossover QT study, 60 healthy subjects were administered DORIBAX^® 500 mg i.v. every 8 hours as a 1-hour infusion × 4 doses and DORIBAX^® 1g i.v. every 8 hours as a 1-hour infusion × 4 doses, placebo, and a single oral dose of positive control. At both the 500 mg and 1g DORIBAX^® doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time (see Table 2.10).

Pharmacokinetics

In Vitro

Plasma Protein Binding

The mean in vitro plasma protein binding of doripenem at a high plasma concentration of 100 µg/mL was 8.1% in pooled human plasma. It has not been established to which proteins doripenem binds.

In Vitro Metabolism

A study using human liver microsomes was conducted to determine if doripenem was a substrate of cytochrome P450 enzymes. The study results indicated that doripenem is not a major substrate for human hepatic CYP isoenzymes, and that CYP-dependent hepatic metabolic pathways have little or no role in the elimination of doripenem.

Enzyme Induction and Inhibition

Doripenem and its main metabolite (inactive) are inactive as inhibitors of several human microsomal CYP isozymes, and they did not induce CYP isoenzymes or UDP glucuronosyltransferase expression in cultured human hepatocytes.

In Vivo

Clinical pharmacology studies were conducted to assess the impact of renal function and age on the pharmacokinetics and pharmacodynamics of doripenem. The effect of therapeutic and supratherapeutic doses of doripenem on electrocardiogram intervals was also assessed. Refer to Table 2.10.

Table 2.10: Clinical pharmacology studies – renal impairment, gender and electrocardiogram interval

Study Study Design

/No. of Subjects

Dose Regimen Results and Conclusions

DORI-02

A Phase 1 open-label

controlled study to

evaluate the safety,

tolerability and

pharmacokinetics of

doripenem

administered

intravenously to

subjects with renal

impairment

Non-randomized,

open-label, controlled single dose study.

N = 32 (M = 27

F = 5)

Doripenem for injection,

i.v.:

• 500 mg x 30 min, single

dose

The extent of systemic exposure (AUC_∞) to doripenem in the mild, moderate, severe and end-stage (post-dialysis infusion) renal impairment groups was, on average, 1.61, 2.83, 5.10, and 7.30-fold greater than in the pooled normal controls. The mean apparent terminal half-life appeared to increase with reduced renal function, ranging from approximately 1 hour (normal controls) to 5 hours (severe renal impairment); in subjects with ESRD the mean values were approximately 6 hours (post-dialysis infusion) and 9 hours (pre-dialysis infusion). Estimates for clearance tended to decrease with decreased renal function, ranging from a mean of 8.64 L/h (mild impairment) to 1.99 L/h (ESRD, post-dialysis infusion). The mean apparent V_ss of doripenem at steady state (approximately 13 to 17 L) did note change appreciably with renal impairment, hence the longer apparent terminal half-life in subjects with renal impairment was a result of reduced clearance of doripenem. The mean renal clearance of doripenem in control subjects was 11.3 L/h, which is nominally similar to glomerular filtration rate in man, and decreased with increasing degree of renal impairment. Study Study Design

/No. of Subjects

Dose Regimen Results and Conclusions

DORI-NOS-1005

An open-label

pharmacokinetic

study of doripenem in

healthy subjects and

subjects with end-

stage renal disease

receiving

hemodialysis

Non-randomized, open-label, 2-period,

controlled,

single-dose study

N = 12 (M = 10 F = 2)

Doripenem for injection, i.v.:

• 500 mg x 60 min, single dose

  The extent of systemic exposure to doripenem in pre-dialysis and post-dialysis infusion periods for the ESRD subjects were, on average, 3.3 and 7.7 times that in the healthy subjects with normal renal function. The extent of systemic exposure, up to the last quantifiable concentration to doripenem-M-1 in pre-dialysis and post-dialysis periods for the ESTD subjects were, on average, 15 and 39 times that in healthy subjects with normal renal function. The mean estimated amount of doripenem-M-1 in the dialysate was 259 mg (52% of the dose) suggesting that doripenem and doripenem-M-1 are readily removed during a hemodialysis session in ESRD subjects. Doripenem 500 mg, infused over 1 hour to healthy subjects (single dose) and subjects with ESRD (two single doses at an 8-day interval), was safe and well tolerated.

DORI-NOS-1006

An open-label, single-

centre,

pharmacokinetic

study of doripenem in

healthy elderly and

non-elderly adults

Non-randomized, open-label,

single-dose study

N = 24 (M = 12, F = 12)

Doripenem for injection, i.v.:

• 500 mg x 60 min, single dose

  Doripenem AUC and C_max values for the 500 x 60 –minute infusion in the elderly subjects were 49% and 23% higher than the respective values in young subjects. The same trends were seen for doripenem-M-1. Similarly, doripenem AUC and C_max values in female subjects was 15% and 13% higher than the respective values in male subjects. Thus the extent of doripenem exposure was higher for elderly and female subjects than for young and male subjects. As seen with doripenem, doripenem-M-1 AUC and C_max values in elderly subjects were approximately 50% higher than the respective values in young subjects.

DORI-NOS-1001

A randomized,

double-blind,

placebo- and positive-

controlled crossover

study evaluating

electrocardiogram

intervals in healthy

adults receiving

multiple intravenous

infusions of

doripenem at

therapeutic and

supratherapeutic

doses

Randomized, double-blind, placebo- and

positive-

controlled,

N = 60 (M = 32 F = 28)

Doripenem for injection, i.v.:

• 500 mg x 60 min q8h (4 doses)
• 1000 mg x 60 min q8h (4 doses)

Moxifloxacin tablets, oral:

• 400 mg, single dose

Placebo (for doripenem and moxifloxacin)

Doripenem and doripenem-M-1 pharmacokinetic parameters were consistent between the 500 mg to 1000 mg treatments. The increases in exposure were in the same ration as the increase in dose. Administration of multiple doses of doripenem at therapeutic and supratherapeutic doses was not associated with QT/QT_c interval prolongation or changes in heart rate and other ECG parameters (PR, QRS, T-wave and U-wave morphology) in these healthy adults.

M= male; F=female

MICROBIOLOGY

Mechanism of Action

Doripenem is a synthetic broad-spectrum beta-lactam carbapenem antibacterial agent with in vitro antibacterial activity against aerobic and anaerobic gram-positive and gram-negative bacteria. Doripenem shares the bactericidal mode of action of other $-lactams by targeting penicillin-binding proteins (PBPs) to inhibit the biosynthesis of the bacterial wall, and has a high affinity for multiple major PBPs of susceptible species. In S. aureus doripenem binds to PBPs 1, 2, and 4. In E. coli and in P. aeruginosa doripenem binds to PBP2, which is involved in the maintenance of cell shape, as well as to PBPs 3 and 4.

Interaction with Other Antimicrobials

Additivity or weak synergy with amikacin and levofloxacin has been seen for P. aeruginosa and for gram-positives with daptomycin, linezolid, levofloxacin, and vancomycin.

Mechanisms of Resistance

Bacterial resistance mechanisms that affect doripenem include drug inactivation by carbapenem-hydrolyzing enzymes, mutant or acquired PBPs, 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 carbapenem hydrolyzing beta-lactamases.

Cross-resistance

Although cross-resistance may occur, some strains resistant to other carbapenems may be susceptible to doripenem.

Resistance Selection In Vitro

In vitro selection for doripenem-resistant strains of Pseudomonas aeruginosa at a concentration four times the MIC (Minimum Inhibitory Concentration) occurred at a frequency of <2X10^-9 for seven of eight strains exposed to doripenem.

Spectrum of Activity

Doripenem has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND CLINICAL USE section.

Table 2.11 contains information on the in vitro activity of clinical isolates from surveillance studies, individual in vitro studies and Phase 3 clinical trials.

Table 2.11: In vitro activities of doripenem against pathogenic organisms (clinical isolates) for which the clinical efficacy of doripenem has been demonstrated

Organism

# of isolates

MIC (μg/mL)

Range 50% 90% Gram-Positive Aerobes

Streptococcus pneumoniae 475 ≤ 0.06-1 ≤ 0.06 0.5

Streptococcus intermedius

86 ≤ 0.015 – 0.12 0.03 0.03

Streptococcus constellatus 15 ≤ 0.015 – 0.12 0.03 0.012 Staphylococcus aureus (MSSA)

759 ≤ 0.06 – 2 ≤ 0.06 ≤ 0.06

Gram-Negative Aerobes

Acinetobacter baumannii 3331 ≤ 0.5- ≥8 2 ≥8 Enterobacter cloacae 41 ≤ 0.03-1 0.12 0.5 Escherichia coli

1008 ≤ 0.06-0.25 ≤ 0.06 ≤ 0.06

Klebsiella pneumoniae 191 ≤ 0.015-1 ≤ 0.10 ≤ 0.20 Haemophilus influenzae 81 ≤ 0.06-0.5 0.12 0.5 Proteus mirabilis 125 ≤ 0.06-1 0.12 0.25 Pseudomonas aeruginosa 522 ≤ 0.06-8 0.5 4 Anaerobes

Bacteroides fragilis 116 0.25 – 16 0.5 1 Bacteriodes thetaiotaomicron 44 0.12 – 2 0.5 1 Bacteroides caccae 46 0.12 – 8 0.25 0.5 Bacteroides uniformis 38 0.12 – 8 0.25 0.5 Bacteroides vulgatus 21 0.12 – 8 0.12 0.25

Peptostreptococcus micros 30 ≤0.03 – 0.25 0.06 0.25

The following in vitro data are available but their clinical significance are unknown. The efficacy of doripenem in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Table 2.12 contains information on the in vitro activity of clinical isolates from surveillance studies, individual in vitro studies, and Phase 3 clinical trials.

Table 2.12: In vitro activities of doripenem against pathogenic organisms (clinical isolates) for which the clinical efficacy has not been demonstrated

Organism

# of isolates

MIC (μg/mL)

Range 50% 90% Gram-Positive Aerobes

Enterococcus faecalis 413 ≤ 0.06 – 8 4 8 Staphylococcus epidermidis ^a 1038 ≤ 0.06- ≥16 1 8 Staphylococcus haemolyticus ^a 154 ≤ 0.06 - ≥16 8 ≥ 16 Streptococcus agalactiae 205 ≤0.013 – 0.25 ≤ 0.025 ≤ 0.06 Streptococcus pyogenes 152 ≤0.004 – 0.06 ≤ 0.016 ≤ 0.016 Viridans group streptococcus

100 0.016->32 0.03 0.25

Gram-Negative Aerobes Acinetobacter calcoaceticus 42 0.2 – 100 0.8 3.1 Aeromonas spp. 31 0.06 – 8 0.5 2 Citrobacter diversus 25 0.016 – 0.06 0.03 0.03 Citrobacter freundii 101 ≤0.025 – 0.8 ≤ 0.10 ≤ 0.40 Enterobacteriaceae 1830 ≤0.03 – 32 ≤ 0.03 0.06 Enterobacter aerogenes 54 0.025 – 6.2 0.2 0.4 Klebsiella oxytoca 115 ≤0.015 – 0.8 ≤ 0.1 ≤ 0.1 Morganella morganii 116 0.06 – 1.6 0.8 ≤0.8 Proteus vulgaris 79 0.06 – 2 ≤0.5 ≤0.8 Providencia rettgeri 85 0.06 – 100 ≤0.4 ≤1.6 Providencia stuartii 96 ≤0.12 - 1 0.12 0.25 Serratia marcescens 303 ≤ 0.03-8 ≤ 0.25 ≤ 0.5

Anaerobes

Bacteroides ovatus 27 0.12 – 2 0.5 1 Other Bacteroides fragilis group species 39 0.12 – 6 0.05 2 Bilophila wadsworthia 21 0.03 – 0.12 0.12 0.12 Clostridium spp. 25 0.03 – 4 1 2 Peptostreptococcus magnus 21 0.0156 – 0.5 0.06 0.12 Porphyromonas spp. 20 0.03 – 4 0.031 0.5 Prevotella spp. 20 0.03 – 1 0.12 0.25 Suterella wadsworthensis 12 0.06 – 32 4 8 ^a Includes methicillin-susceptible and methicillin-resistant strains.

Susceptibility Test Methods

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of doripenem powder. The MIC values should be interpreted according to the criteria provided in Table 2.13.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10 μg of doripenem to test the susceptibility of microorganisms to doripenem. Results should be interpreted according to the criteria in Table 2.13.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to doripenem as MICs should be determined by standardized test methods. The MIC values obtained should be interpreted according to the criteria in Table 2.13.

Table 2.13: Susceptibility Interpretive Criteria for Doripenem

Minimum Inhibitory Concentrations

(μg/mL)

Disk Diffusion (Zone diameters in mm)

Pathogen S I R S I R Enterobacteriaceae ≤1 2-4 ≥8 ≥18 15-17 ≤14 Acinetobacter spp. ≤1 2-4 ≥8 ≥19 16 – 18 ≤15 Pseudomonas

aeruginosa

≤1 2-4 ≥8 ≥19 17-18 ≤16

Haemophilus spp. ≤1 2-4 ≥8 ≥18 16-17 ≤15 Staphylococcus spp. ≤1 2-4 ≥8 ≥15 13 - 14 ≤12 Streptococcus

pneumoniae

≤1 --- ≥2^a ≥25

--- ≤24

Streptococcus spp.

other than S.

pneumoniae

≤1 --- ≥2 ^a ≥25

--- ≤24

Anaerobes ^b ≤1 2-4 ≥8 n/a n/a n/a ^a This interpretive standard is applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood inoculated with direct colony suspension and incubated in ambient air at 35° C for 20-24 hrs.

^b Agar dilution

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used or where a prolonged infusion of drug can be used. This category also provides a buffer zone that prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected (see PRODUCT MONOGRAPH Part I: ACTION AND CLINICAL PHARMACOLOGY, Table 1.6).

Quality Control

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard doripenem powder should provide the MIC values noted in Table 2.14. For diffusion techniques using a 10 μg doripenem disk, the criteria noted in Table 2.14 should be achieved.

Table 2.14: Acceptable Quality Control Ranges for Susceptibility Testing

QC Organism Minimum Inhibitory

Concentrations^a (μg/mL)

Disk Diffusion ^b (zone diameters in mm) Staphylococcus aureus ATCC ^® 25923^ab n/a 33-42 Staphylococcus aureus ATCC 29213^b 0.015 – 0.06 n/a Escherichia coli ATCC 25922 ^b 0.015-0.06 28-35 Enterococcus faecalis ATCC 29212 ^b 1-4 n/a Haemophilus influenzae ATCC 49766 ^b 0.06-0.25 n/a Haemophilus influenzae ATCC 49247 ^b n/a 21-31 Pseudomonas aeruginosa ATCC 27853 ^b 0.12-0.5 29-35 Streptococcus pneumoniae ATCC 49619 0.03-0.12 30-38 Bacteriodes fragilis ATCC 25285 0.12-0.5 ^c n/a Bacteriodes thetaiotaomicron ATCC

29741

0.12-1 ^c n/a

ATCC^® is a registered trademark of the American Type Culture Collection; n/a = not applicable

^a Reference CLSI M100—S18 , M7-A7, Table 3 and 3A;

^b Reference CLSIM100-S18, M2-A9, Table 3 and 3A;

^c Anaerobic broth microdilution (Reference CLSI M11-A7 Table 6)

TOXICOLOGY

The toxicity of doripenem was characterized in single- and repeated-dose intravenous (i.v.) toxicity studies (up to 3 months duration), genotoxicity, reproductive and developmental toxicity studies, and in studies assessing phototoxicity, local tolerability, potential antigenic and hematolytic effects and hepatotoxicity.

The single-dose i.v. toxicity of doripenem was evaluated in rats, rabbits, and dogs. A single bolus i.v. dose of 2000 mg/kg was non-toxic to rats. In rabbits, single i.v. infusions of # 200 mg/kg were not nephrotoxic, while doses of $400 mg/kg caused nephrotoxicity. Doripenem was toxic to dogs following a single i.v. dose of 1000 mg or 2000 mg/kg. The principal target organs of toxicity were the kidney and the gastrointestinal tract. The approximate lethal dose was >2000 mg/kg.

Repeat dose i.v. toxicity studies were conducted in rats, rabbits and dogs. Doripenem was nontoxic when administered for 3 months i.v. at doses of 300 mg/kg in rats and 100 mg/kg in dogs. At daily doses of 1000 mg/kg in rats, a decrement in body weight gain was observed. At daily i.v. doses of 250 mg/kg and higher in dogs, the gastrointestinal tract was the primary target organ. Doripenem was not nephrotoxic in rabbits at doses as high as 200 mg/kg when administered daily for 5 days.

The significant toxicity studies are presented in Table 2.15 below.

Table 2.15: Summary of Significant Toxicity Studies

Type of

Study

Species/Strain Sex/No. Per Group

Duration/ Route

Dosage (mg/kg)^a

Principal Effects Observed

Single dose

intravenous

toxicity study

in rats

Rat (Sprague-Dawley)

6/sex/group

Single

dose, i.v. – slow bolus

2000

Mild hypopnea, loose feces, and dark yellow urine color observed.

Single dose

intravenous

renal toxicity

study in

rabbits

Rabbit (Japanese White)

4 males/group

Single

dose, i.v. infusion

200

400

600

200 mg/kg: ↓ Food consumption

400 and 600 mg/kg: Transient ↓ body weight, ↓ Food consumption, glucose and protein in the urine, CREAT ↑ 48% (400 mg/kg) ↑ 138% (600 mg/kg), BUN ↑ 40% (400 mg/kg) ↑ 160% (600 mg/kg), fine granulation of the kidney surface and white striation in the cortex were observed bilaterally at necropsy, kidney enlargement, kidney pale coloration (400 mg/kg).

Tubular necrosis in the renal cortex and tubular dilation with flattened epithelium were observed in all animals. Microscopic findings did not indicate a dose response between 400 and 600 mg/kg.

Single dose

intravenous

renal toxicity

study in

rabbits

Rabbit (Japanese White)

4 males/group

Single

dose, i.v. infusion

250

400

250 mg/kg: transient ↓ food consumption, microscopically, fine granular surface of kidney and tubular necrosis.

400 mg/kg: transient ↓ food consumption, diarrhea on Day 2 followed by death in one animal on Day 3. In urine, positive tests for protein, glucose or occult blood. Slight ↑ creatinine, BUN, microscopically, fine granular surface of kidney and tubular necrosis of cortex.

Type of

Study

Species/Strain Sex/No. Per Group

Duration/ Route

Dosage (mg/kg)^a

Principal Effects Observed

Single dose intravenous toxicity study in dogs

Dog (Beagle)

1/sex/group

Single

dose, i.v. infusion

1000

2000

1000 and 2000 mg/kg (male and female): vomiting and slight hypoactivity; loose, mucoid and or bloody feces, hematuria, ↓ body weight, ↓ Food consumption. Urinalysis: positive occult blood, protein urea, RBC and epithelial cells in sediment. Hematology: ↑ WBC, ↑ NEUT, ↓ EOSIN, ↓ LYMPH, ↓ APTT. Clinical Chemistry: ↑ BUN and CREAT. Necropsies not performed.

2000 mg/kg: Necropsy: pale kidneys. necrosis or regeneration of the tubular epithelium in the renal cortex; ↓ in chief cells of gastric mucosa and regeneration and dilation of gastric glands in the male; cyst-like dilated crypts filled with cellular debris in duodenum, colon and rectum.

Two-week intravenous toxicity study in dogs with direct

Coombs' test

Dog (Beagle)

3 Males

3 Females

i.v.

infusion

14 days

10

30

100

No noteworthy findings. Negative ex-vivo Coomb’s test.

Intravenous one-month toxicity study in rats

Rat (Sprague-

Dawley)

10 Males

10 Females

i.v. slow bolus

28 days

100

300

1000

Loose feces at all doses resolved within 2 weeks.

At ≥100 mg/kg ↑ number of animals with ketone bodies and positive urobilinogen tests (considered false positive reactions to doripenem-derived material).

Enlarged cecum and spleen, histologically splenic white pulp germinal center hypertrophy at ≥300 mg/kg.

1-Month

repeated dose intravenous toxicity study in dogs

Dog

(Beagle)

3/sex/group at 125 and 250

5/sex/group at 500

i.v.

infusion

30-31 days

125^b 250

500

250 mg/kg: ↓ body weight, ↓ RBC, HGB, HCT, platelet count, ↑ kidney weight

500 mg/kg: mortality, abnormal feces, refusal to feed, ↓ body weight, ↓ food consumption (females), ↓ RBC, HGB, HCT (females), ↓ platelet count, ↑ kidney weight. Erosion or ulcer of GI mucosa and ballooning of gastric parietal cells observed in 1 animal that died.

Intravenous one-month toxicity study in dogs

Dog (Beagle)

3 Males

3 Females

i.v.

infusion

30 days (twice

daily

dosing)

40

100

200

No noteworthy findings.

Type of

Study

Species/Strain Sex/No. Per Group

Duration/ Route

Dosage (mg/kg)^a

Principal Effects Observed

3-Month

repeated dose intravenous toxicity study in rats

Rat (Sprague-Dawley)

10 Males

10 Females

i.v. slow bolus

91 days

92 days

100

300

1000

Loose stool, ↓ body weight gain (1000 mg/kg), brownish urine, ↓ total excretion of Na⁺ and Cl^- in urine, ↑ kidney weight (1000 mg/kg males), enlargement of cecum and kidney, no histopathological abnormalities in kidney.

All changes noted at end of dosing period except body weight tended toward recovery by the end of the 4-week treatment-free period

3-Month

repeated dose intravenous toxicity study in dogs

Dog (Beagle)

3 Males

3 Females

i.v.

infusion

Males: 91 days

Females: 92 days

40

100

250

250 mg/kg: ↑ mucous feces, 2 females with transient recumbancy (Day 1), bilirubin positive, slight anemia, slight vacuolization of renal proximal tubule epithelium, ↑ hemosidirin deposits in spleen, slight inflammatory cell infiltration of large intestinal mucosa. Hypertrophy of germinal centre of spleen white pulp, in females at 40 mg/kg, and in males and females at 100 and 250 mg/kg.

Intravenous repeated dose nephrotoxicity study in

rabbits

Rabbit (Japanese White)

4 Males/group

Intravenou s

Infusion

5 days

0

50

100

200

50 mg/kg: No treatment related findings.

100 mg/kg: One death on Day 3, diarrhea observed prior to death. ↓ food consumption and body weight, slight ↑ creatinine. Early death animal exhibited swelling, cloudy cortex, dark red medulla and tubular necrosis in the renal cortex.

200 mg/kg: One death on Day 4, diarrhea observed prior to death. ↓ food consumption and body weight, slight ↑ creatinine, significant ↓ potassium. Early death animal exhibited swelling, cloudy cortex, dark red medulla and tubular necrosis in the renal cortex.

Nephrotoxicity was estimated to be greater than Tienam^TM and similar to that of cefotiam

5-Day

repeated dose intravenous renal toxicity study in

rabbits

Rabbit (Japanese White)

4 Males/group

Intravenou s

Infusion

5 days

0

50

100 200

50 and 100 mg/kg: No treatment related findings.

200 mg/kg: ↓ food consumption,

Severity of nephrotoxicity was considered as follows:

cefmenoxime > cefazolin = biapenem > imipenem/cilastatin = meropenem trihydrate = doripenem

Type of

Study

Species/Strain Sex/No. Per Group

Duration/ Route

Dosage (mg/kg)^a

Principal Effects Observed

1-Month

repeated dose

intravenous

toxicity study

in juvenile

dogs

Dog (Beagle)

3 Males

3 Females

1 month

i.v.

infusion

0

40

100

250

No deaths in any group. Spontaneous activity ↓ in females at 250 mg/kg; bloody, mucous stool at 100 mg/kg and 250 mg/kg. Hematocrit values ↓ in females at 250 mg/kg group on Day 27. All changes were reversible.

1-Month

repeated dose

intravenous

toxicity study

in juvenile

dogs

Dog (Beagle)

3 Males

3 Females

1 month

i.v.

infusion (twice

daily

dosing)

0

120

160

200

No treatment-related effects observed.

Hepatotoxi-

city study

Rat (Sprague-

Dawley)

6 Males

Dog (Beagle, mixed breed)

4 Males

14 days, then 27- or 28-day

drug

withdrawal period,

followed by a single challenge dose.

i.v.

infusion

0

10

100 (rat)

Rat: no noteworthy findings

Dog: ↑ in AST and ALT in 1 dog, and localized inflammatory cell infiltration with eosinophils and a few mononuclear lymphocytes, hemosiderin deposition and a slight ↑ in microgranulomas in the perivascular space in another dog were not clearly related to the administration of the challenge dose.

Hepatotoxi-

city study

Dog (Beagle, mixed breed)

4-5 Males

5 days

week for 3 weeks,

then 4-

week drug withdrawal period,

followed by a single challenge dose.

i.v.

infusion

10

100

No treatment related effects on ALT, AST, ALP, bilirubin or free endotoxin during or after the treatment period, or following challenge administration.

^a For repeat dose studies the highest No Observed Adverse Effect Level (NOAEL) is underlined. ^bNOAEL < 125 mg/kg

↓ = decrease, ↑ = increase, ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, RBC = red blood cells, WBC = white blood cells, NEUT = neutrophils, EOSIN = eosinophils, LYMPH = lymphocytes, BUN = blood urea nitrogen, CREAT = creatinine, APTT = activated partial thromboplastin time.

Carcinogenicity

Because of the short duration of treatment and intermittent clinical use, long-term carcinogenicity studies have not been conducted with doripenem.

Mutagenicity

Doripenem did not show evidence of mutagenic activity in standard tests that included bacterial reverse mutation assay, chromosomal aberration assay with Chinese hamster lung fibroblast cells, and mouse bone marrow micronucleus assay.

Teratogenicity/ Impairment of 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 1g/kg/day (based on AUC, at least equal to the exposure to humans at the dose of 500 mg administered every 8 hours).

The significant reproductive toxicity studies are presented in Table 2.16 below.

Table 2.16: Summary Of Significant Reproductive Toxicity Studies

Type of Study Species/Strain

Sex/No. Per Group

Duration/Route Dosage

(mg/kg)

Principal Effects Observed

Study on

fertility and

early

embryonic

development

to

Implantation

Rat (Sprague-

Dawley)

24 Males

24 Females

Intravenous

Infusion

Males: 9 weeks premating -

termination;

Females: 2 weeks premating - GD 7

100

300

1000

No major toxicity findings

NOAEL values (mg/kg/day):

General toxicity in female and male parents: 1000

Reproductive toxicity in female and male parents: 1000

Developmental toxicity in embryos and fetuses: 1000

Study of

embryo-fetal

development:

A teratology

study in the rat

Rat (Sprague-

Dawley)

35 females /group

Intravenous

Infusion

GD 7 – 17

100

300

1000

1000 mg/kg/day: ↓ food consumption, suppressed body weight gain

1000 mg/kg/day: Abnormal delivery in 1 animal (all pups stillborn)

NOAEL values (mg/kg/day):

General maternal toxicity: 300

Reproductive maternal toxicity: 300

Developmental toxicity in fetuses and pups: 1000

Study on

intravenous

administration

during the

period of

organogenesis

in rabbits.

Rabbit (Japanese white)

14-16 females /group

Intravenous

Infusion

GD 6 – 18

12.5

25

50

25 and 50 mg/kg: transient loose feces, ↓ maternal weight gain and/or food consumption, and cecal enlargement. Reddish-brown urine (false positive to doripenem-related materials) observed at 50 mg/kg from Day 7 on.

NOAEL values (mg/kg/day):

General maternal toxicity: 12.5

Reproductive maternal toxicity: 50

Developmental toxicity in fetuses and pups: 50 Type of Study Species/Strain

Sex/No. Per Group

Duration/Route Dosage

(mg/kg)

Principal Effects Observed

Study of

embryo-fetal

development

Effects on

nursing

performance in

rats

Rat ( Sprague-

Dawley)

11-12 females/group

i.v.

GD 7-17

(F₀ females only)

30

100

300

1000

1000 mg/kg/day: Death during delivery

NOAEL values (mg/kg/day): Reproductive maternal toxicity: 300 Developmental toxicity in pups: 1000

Study on pre-

and postnatal

development

and maternal

function

Rat (Sprague-

Dawley)

18-20 females /group

i.v.

GD 7-LD 21

(F₀ females only)

100

300

600

1000

No major toxicity findings

NOAEL values (mg/kg/day): General maternal toxicity: 1000 Reproductive maternal toxicity: 1000 Developmental toxicity in pups: 1000

No Observed Adverse Effect Level (NOAEL), ↓ = decrease, ↑ = increase

Other Studies

Antigenicity

Sensitizing antigenicity of i.v. doripenem was observed in combination with adjuvant and/or protein-conjugate in mice and guinea pigs, and is comparable to that of imipenem. There was weak immunological cross-reactivity between imipenem and doripenem, but cross-reactivity of doripenem with other ß-lactam antibiotics (penicillin G, cephalothin, flomoxef) was not observed.

Hemolytic Effects

The direct Coombs’ reaction with doripenem, using human red blood cells or dog blood ex-vivo, was negative, indicating that the likelihood of a hemolytic adverse reaction occurring is very low.

Hepatotoxicity

The hepatic toxicity of doripenem was evaluated in rats and dogs. No meaningful signs of toxicity or liver pathology were observed.

Local Tolerance

The vascular and muscular irritation of doripenem was investigated in rabbits. Vascular and muscular damage was comparable to that seen with physiologic saline, and local irritancy of the drug was weak. It is unlikely that the i.v. administration of doripenem would have serious effects even in the event of a dosing error during clinical use (insertion into muscle).

Phototoxicity

Doripenem was not phototoxic when administered intravenously to mice for 5 days at dose levels up to 100 mg/kg.

REFERENCES

1. 1.

   Réa-Neto A, Niederman M, Lobo S, Schroeder E, Lee M, Kaniga K, Ketter N,

   Prokocimer P, Friedland I. Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open-label, multicenter study. Curr Med Res Opin. 11 Jun 2008.

2. 2. Chastre J, Wunderlink R, Prokocimer P, Lee M, Kaniga K, Friedland I. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia; a multicentre randomized study. Crit Care Med 2008;36(4):1089-1096.
3. 3.

   Merchant S, Gast C, Nathwani D, Lee M, Quintana A, Ketter N, Friedland I, Ingham M.

   Hospital resource utilization with doripenem versus imipenem in the treatment of ventilator-associated pneumonia. Clin Ther.2008 Apr;30(4):717-33.

4. 4. Lucasti C, Jasovich A, Umeh O, Jiang J, Kaniga K, Friedland I. Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicentre, randomized, double-blind, non-inferiority study. Clin Ther 2008;30(5):868-883.
5. 5. Naber KG, Llorens L, Kaniga K, Kotey P, Hedrich D, Redman R. Intravenous doripenem 500 mg versus levofloxacin 250 mg with an option to switch to oral therapy for the treatment of complicated lower urinary tract infection and pyelonephritis. Antimicrob. Agents Chemother. 2009; e-pub ahead of print 6 July 2009
6. 6. Clinical Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 7^th ed. Approved Standard CLSI Document M7-A7 Wayne, PA; Jan 2006:26 (No. 2).
7. 7. National Committee for Clinical Laboratory Standards. Method for antimicrobial susceptibility testing of anaerobic bacteria. 3^rd ed. Approved Standard NCCLS Document M11-A6. Wayne, PA; Jan 2004:24(No. 2).
8. 8. Clinical Laboratory Standards Institute. Performance standards for antimicrobial disk susceptibility tests. 9^th ed. Approved Standard NCCLS Document M2-A9 Wayne, PA; Jan 2006:23 (No. 1).