Rx Drugs Info

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use doribax safely and effectively. See full prescribing information for doribax.
doribax (doripenempowder, for solution for intravenous use
Initial U.S. Approval: 2007

To reduce the development of drug-resistant bacteria and maintain the effectiveness of DORIBAX™ and other antibacterial drugs, DORIBAX™ should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

INDICATIONS AND USAGE

DORIBAX™ is a penem antibacterial indicated in the treatment of the following infections caused by designated susceptible bacteria:

  • Complicated intra-abdominal infections ( 1.1)
  • Complicated urinary tract infections, including pyelonephritis ( 1.2)

DOSAGE AND ADMINISTRATION

  • 500 mg every 8 hours by intravenous infusion administered over one hour for patients ≥18 years of age. ( 2.1)
  • Dosage in patients with impaired renal function ( 2.2):
CrCl (mL/min) Recommended Dose of DORIBAX™
> 50 No dosage adjustment necessary
≥ 30 to ≤ 50 250 mg IV (over 1 hour) every 8 hours
> 10 to < 30 250 mg IV (over 1 hour) every 12 hours

DOSAGE FORMS AND STRENGTHS

500 mg single-use vial ( 3)


CONTRAINDICATIONS

Patients with known serious hypersensitivity to doripenem or to other drugs in the same class or patients who have demonstrated anaphylactic reactions to beta-lactams ( 4)


WARNINGS AND PRECAUTIONS

  • Serious hypersensitivity (anaphylactic) reactions have been reported with carbapenems and other beta-lactams ( 5.1)
  • Loss of seizure control due to lower serum valproic acid levels may result from interaction with sodium valproate ( 5.2)
  • Clostridium difficile-associated diarrhea (ranging from mild diarrhea to fatal colitis): Evaluate if diarrhea occurs ( 5.3)

ADVERSE REACTIONS

Most common adverse reactions (≥ 5%) are headache, nausea, diarrhea, rash and phlebitis.



To report SUSPECTED ADVERSE REACTIONS, contact Ortho-McNeil Pharmaceutical, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch


DRUG INTERACTIONS

Interacting Drug Interaction
Valproic acid Carbapenems may reduce serum valproic acid levels ( 7.1)
Probenecid Reduces renal clearance of doripenem, resulting in increased doripenem concentrations ( 7.2, 12.3)
Drugs metabolized by cytochrome P450 enzymes Doripenem neither inhibits nor induces major cytochrome P450 enzymes ( 12.3)

USE IN SPECIFIC POPULATIONS

  • Dosage adjustment is required in patients with moderately or severely impaired renal function ( 2.2, 12.3)
  • DORIBAX™ has not been studied in pediatric patients. ( 8.4)


See 17 for PATIENT COUNSELING INFORMATION

Revised: 11/2007

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

1 INDICATIONS AND USAGE

1.1 Complicated Intra-Abdominal Infections

1.2 Complicated Urinary Tract Infections, Including Pyelonephritis

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

2.2 Patients with Renal Impairment

2.3 Preparation of Solutions

2.4 Compatibility

2.5 Storage of Constituted Solutions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

5.2 Interaction with Sodium Valproate

5.3 Clostridium difficile-Associated Diarrhea

5.4 Development of Drug-Resistant Bacteria

5.5 Pneumonitis with Inhalational Use

6 ADVERSE REACTIONS

6.1 Adverse Reactions from Clinical Trials

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Valproic Acid

7.2 Probenecid

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

14 CLINICAL STUDIES

14.1 Complicated Intra-Abdominal Infections

14.2 Complicated Urinary Tract Infections, Including Pyelonephritis

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION


FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of DORIBAX™ and other antibacterial drugs, DORIBAX™ should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting and modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

1.1 Complicated Intra-Abdominal Infections

DORIBAX™ (doripenem for injection) is indicated as a single agent for the treatment of complicated intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus and Peptostreptococcus micros.

1.2 Complicated Urinary Tract Infections, Including Pyelonephritis

DORIBAX™ (doripenem for injection) is indicated as a single agent for the treatment of complicated urinary tract infections, including pyelonephritis caused by Escherichia coli including cases with concurrent bacteremia, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa,  and Acinetobacter baumannii.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of DORIBAX™ is 500 mg administered every 8 hours by intravenous infusion over one hour in patients ≥18 years of age. The recommended dosage and administration by infection is described in Table 1:

Table 1: Dosage of DORIBAX™ by Infection
Infection Dosage Frequency Infusion Time (hours) Duration
*
Duration includes a possible switch to an appropriate oral therapy, after at least 3 days of parenteral therapy, once clinical improvement has been demonstrated.
Duration can be extended up to 14 days for patients with concurrent bacteremia.
Complicated intra-abdominal infection 500 mg q8h 1 5–14 days*
Complicated UTI, including pyelonephritis 500 mg q8h 1 10 days*

2.2 Patients with Renal Impairment

Table 2: Dosage of DORIBAX™ in Patients with Renal Impairment
Estimated CrCl (mL/min) Recommended Dosage Regimen of DORIBAX™
> 50 No dosage adjustment necessary
≥ 30 to ≤ 50 250 mg intravenously (over 1 hour) every 8 hours
> 10 to < 30 250 mg intravenously (over 1 hour) every 12 hours

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) × (140 - age in years)
72 × serum creatinine (mg/dL)
Females: Creatinine clearance (mL/min) = 0.85 × value calculated for males

DORIBAX™ is hemodialyzable; however, there is insufficient information to make dose adjustment recommendations in patients on hemodialysis.

2.3 Preparation of Solutions

DORIBAX™ does not contain a bacteriostatic preservative. Aseptic technique must be followed in preparation of the infusion solution.

Preparation of 500 mg dose:

Preparation of 250 mg dose for patients with moderate or severe renal impairment:

To prepare DORIBAX infusions in Baxter Minibag Plus™ infusion bags consult the infusion bag manufacturer's instructions.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit. DORIBAX infusions range from clear, colorless solutions to solutions that are clear and slightly yellow. Variations in color within this range do not affect the potency of the product.

2.4 Compatibility

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.

2.5 Storage of Constituted Solutions

Upon constitution 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.

Following dilution of the suspension with normal saline or 5% dextrose, DORIBAX infusions stored at controlled room temperature or under refrigeration should be completed according to the times in Table 3.

Table 3: Storage and Stability Times of Infusion Solutions Prepared in Normal Saline or 5% Dextrose
Infusion prepared in Stability Time at Room Temp. (includes room temperature storage and infusion time) Stability time at 2–8°C (Refrigeration) (includes refrigerator storage and infusion time)
Normal saline 8 hours 24 hours
5% Dextrose 4 hours 24 hours

Constituted DORIBAX suspension or DORIBAX infusion should not be frozen. This storage information applies also to DORIBAX™ diluted in Baxter Minibag Plus™.

3 DOSAGE FORMS AND STRENGTHS

Single use clear glass vials containing 500 mg (on an anhydrous basis) of sterile doripenem powder.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) and serious skin reactions have been reported in patients receiving beta-lactam antibiotics. 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, IV fluids, IV antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.

5.2 Interaction with Sodium Valproate

Carbapenems may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations cannot be maintained in the therapeutic range or seizures occur. [see Drug Interactions (7.1)]

5.3 Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. [see Adverse Reactions (6.1)]

5.4 Development of Drug-Resistant Bacteria

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

5.5 Pneumonitis with Inhalational Use

When DORIBAX™ has been used investigationally via inhalation, pneumonitis has occurred. DORIBAX™ should not be administered by this route.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of labeling:

6.1 Adverse Reactions from Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be compared directly to rates from clinical trials of another drug and may not reflect rates observed in practice.

During clinical investigations, 853 adult patients were treated with DORIBAX™ IV (500 mg administered over 1 hour q8h) in the three comparative phase 3 clinical studies; in some patients, parenteral therapy was followed by a switch to an oral antimicrobial. [see Clinical Studies (14)] The median age of patients treated with DORIBAX™ was 54 years (range 18–90) in the comparative cUTI study and 46 years (range 18–94) in the pooled comparative cIAI studies. There was a female predominance (62%) in the comparative cUTI study and a male predominance (63%) in the pooled cIAI studies. The patients treated with DORIBAX™ were predominantly Caucasian (77%) in the three pooled phase 3 studies.

The most common adverse reactions (≥ 5%) observed in the DORIBAX™ phase 3 clinical trials were headache, nausea, diarrhea, rash and phlebitis. During clinical trials, adverse drug reactions that led to DORIBAX™ discontinuation were nausea (0.2%), vulvomycotic infection (0.1%) and rash (0.1%).

Adverse reactions due to DORIBAX™ 500 mg q8h that occurred at a rate ≥ 1 % in either indication are listed in Table 4. Hypersensitivity reactions related to intravenous study drug and C. difficile colitis occurred at a rate of less than 1% in the three controlled phase 3 clinical trials.

Table 4: Adverse Reactions* with Incidence Rates (%) of ≥1% and Adverse Events Having Clinically Important Differences in Frequency by Indication in the Three Controlled, Comparative DORIBAX™ Phase 3 Clinical Trials
Complicated Urinary Tract Infections (one trial) Complicated Intra-Abdominal Infections (two trials)
System organ class DORIBAX™
500 mg q8h
(n =376 )
Levofloxacin
250 mg IV q24h
(n = 372)
DORIBAX™
500 mg q8h
(n = 477)
Meropenem
1 g q8h
(n = 469)
*
An adverse drug reaction was defined as an undesirable effect, reasonably associated with the use of DORIBAX™ that may occur as part of its pharmacological action or may be unpredictable in its occurrence.
An adverse event refers to any untoward medical event associated with the use of the drug in humans, whether or not considered drug-related.
includes reactions reported as allergic and bullous dermatitis, erythema, macular/papular eruptions, urticaria and erythema multiforme
§
includes reactions reported as alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, and transaminases increased
  Nervous system disorders
    Headache 16 15 4 5
  Vascular disorders
    Phlebitis 4 4 8 6
  Gastro-intestinal disorders
    Nausea 4 6 12 9
    Diarrhea 6 10 11 11
  Blood and Lymphatic System Disorders
    Anemia 2 1 10 5
  Renal and Urinary Disorders
    Renal impairment/Renal failure <1 0 1 <1
  Skin and subcutaneous disorders
    Pruritus <1 1 3 2
    Rash 1 1 5 2
  Investigations
    Hepatic enzyme elevation§ 2 3 1 3
  Infection and Infestations
    Oral candidiasis 1 0 1 2
    Vulvomycotic infection 2 1 1 <1

6.2 Postmarketing Experience

The following adverse reaction has been identified during post-approval use of doripenem outside of the U.S. Because this reaction was reported voluntarily from a population of uncertain size, it is not possible to reliably estimate its frequency or establish a causal relationship to drug exposure.

 
Anaphylaxis

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

 
Stevens Johnson Syndrome
 
Toxic epidermal necrolysis
 
Interstitial pneumonia
 
Seizure

7 DRUG INTERACTIONS

7.1 Valproic Acid

A clinically significant reduction in serum valproic acid concentrations has been reported in patients receiving carbapenem antibiotics and may result in loss of seizure control. Although the mechanism of this interaction is not fully understood, data from in vitro and animal studies suggest that carbapenem antibiotics may inhibit valproic acid glucuronide hydrolysis. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations cannot be maintained in the therapeutic range or a seizure occurs. [see Warnings and Precautions (5.2)]

7.2 Probenecid

Probenecid interferes with the active tubular secretion of doripenem, resulting in increased plasma concentrations of doripenem. [see Clinical Pharmacology (12.3)] Coadministration of probenecid with DORIBAX™ is not recommended.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Category B: Doripenem was not teratogenic and did not produce effects on ossification, developmental delays or fetal weight following intravenous administration during organogenesis at doses as high as 1 g/kg/day in rats and 50 mg/kg/day in rabbits (based on AUC, at least 2.4 and 0.8 times the exposure to humans dosed at 500 mg q8h, respectively). There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DORIBAX™ is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of subjects in clinical studies of DORIBAX™, 28% were 65 and over, while 12% were 75 and over. 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. These results were similar between doripenem and comparator treatment groups.

No overall differences in safety were observed between older and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Elderly subjects had greater doripenem exposure relative to non-elderly subjects; however, this increase in exposure was mainly attributed to age-related changes in renal function. [see Clinical Pharmacology (12.3)]

This drug 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 or pre-renal azotemia. Because elderly patients are more likely to have decreased renal function or pre-renal azotemia, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Patients with Renal Impairment

Dosage adjustment is required in patients with moderately or severely impaired renal function. [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]  In such patients, renal function should be monitored.

10 OVERDOSAGE

In the event of overdose, DORIBAX™ should be discontinued and general supportive treatment given.

Doripenem can be removed by hemodialysis. In subjects with end-stage renal disease administered DORIBAX™ 500 mg, the mean total recovery of doripenem and doripenem-M1 in the dialysate following a 4-hour hemodialysis session was 259 mg (52% of the dose). However, no information is available on the use of hemodialysis to treat overdosage. [see Clinical Pharmacology (12.3)]

11 DESCRIPTION

DORIBAX™, doripenem monohydrate for injection vials contain 500 mg of doripenem on an anhydrous basis, a white to slightly-yellowish off-white sterile crystalline powder. All references to doripenem activity are expressed in terms of the active doripenem moiety. The powder is constituted for intravenous infusion. The pH of the infusion solution is between 4.5 and 5.5.

DORIBAX™ is not formulated with any inactive ingredients.

DORIBAX™ (doripenem monohydrate) is a synthetic broad-spectrum carbapenem antibiotic structurally related to beta-lactam antibiotics. The chemical name for doripenem monohydrate is (4R,5S,6S)-3-[((3S,5S)-5-[[(aminosulfonyl)amino]methyl]-3-pyrrolidinyl)thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate.

Its molecular weight is 438.52, and its chemical structure is:

Chemical Structure

12 CLINICAL PHARMACOLOGY

Doripenem is a carbapenem with in vitro antibacterial activity against aerobic and anaerobic Gram-positive and Gram-negative bacteria.

12.1 Mechanism of Action

Doripenem is an antibacterial drug. [see Clinical Pharmacology (12.4)]

12.2 Pharmacodynamics

Similar to other beta-lactam antimicrobial agents, the time that unbound plasma concentration of doripenem exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in animal models of infection. However, the pharmacokinetic/pharmacodynamic relationship for doripenem has not been evaluated in patients.

In a randomized, positive- and placebo-controlled crossover QT study, 60 healthy subjects were administered DORIBAX™ 500 mg IV every 8 hours × 4 doses and DORIBAX™ 1g IV every 8 hours × 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.

12.3 Pharmacokinetics

Plasma Concentrations

Mean plasma concentrations of doripenem following a single 1-hour intravenous infusion of a 500 mg dose of DORIBAX™ to 24 healthy subjects are shown below in Figure 1. The mean (SD) plasma Cmax and AUC0–∞ values were 23.0 (6.6) µg/mL and 36.3 (8.8) µg∙hr/mL, respectively.


Figure 1. Average Doripenem Plasma Concentrations Versus Time Following a Single 1-Hour Intravenous Infusion of DORIBAX™ 500 mg in Healthy Subjects (N=24)

Graph

The pharmacokinetics of doripenem (Cmax and AUC) are linear over a dose range of 500 mg to 1g when intravenously infused over 1 hour. There is no accumulation of doripenem following multiple intravenous infusions of either 500 mg or 1g administered every 8 hours for 7 to 10 days in subjects with normal renal function.

Distribution

The average binding of doripenem to plasma proteins is approximately 8.1% and is independent of plasma drug concentrations. The median (range) volume of distribution at steady state in healthy subjects is 16.8 L (8.09–55.5 L), similar to extracellular fluid volume (18.2 L).

Doripenem penetrates into several body fluids and tissues, including those at the site of infection for the approved indications. Doripenem concentrations in peritoneal and retroperitoneal fluid either match or exceed those required to inhibit most susceptible bacteria; however, the clinical relevance of this finding has not been established. Concentrations achieved in selected tissues and fluids following administration of DORIBAX™ are shown in Table 5:

Table 5: Doripenem Concentrations in Selected Tissues and Fluids
Tissue or Fluid Dose
(mg)
Infusion Duration
(h)
Number of Samples or Subjects* Sampling
Period
Concentration Range
(µg/mL or µg/g)
Tissue- or Fluid-To-Plasma Concentration Ratio (%)
Mean (Range)
*
Unless stated otherwise, only one sample was collected per subject;
Time from start of infusion;
Serial samples were collected; maximum concentrations reported;
§
tmax range ;
BQL (Below Quantifiable Limits) in 6 subjects;
#
BQL in 1 subject;
Þ
Median (range)
Retroperitoneal fluid 250 0.5 9 30–90 min§ 3.15–52.4 Range: 4.1(0.5–9.7) at 0.25 h to 990 (173–2609) at 2.5 h
500 0.5 4 90 min§ 9.53–13.9 Range: 3.3 (0.0–8.1) at 0.25 h to 516 (311–842) at 6.5 h
Peritoneal exudate 250 0.5 5 30–150 min§ 2.36–5.17 Range: 19.7 (0.00–47.3) at 0.5 h to 160 (32.2–322) at 4.5 h
Gallbladder 250 0.5 10 20–215 min BQL–1.87 8.02 (0.00–44.4)
Bile 250 0.5 10 20–215 min BQL–15.4# 117 (0.00–611)
Urine 500 1 110 0–4 hr 601 (BQL#–3360)Þ ---
500 1 110 4–8 hr 49.7 (BQL#–635)Þ ---

Metabolism

Metabolism of doripenem to a microbiologically inactive ring-opened metabolite (doripenem-M1) occurs primarily via dehydropeptidase-I. The mean (SD) plasma doripenem-M1-to-doripenem AUC ratio following single 500 mg and 1 g doses in healthy subjects is 18% (7.2%).

In pooled human liver microsomes, no in vitro metabolism of doripenem could be detected, indicating that doripenem is not a substrate for hepatic CYP450 enzymes.

Excretion

Doripenem is primarily eliminated unchanged by the kidneys. The mean plasma terminal elimination half-life of doripenem in healthy non-elderly adults is approximately 1 hour and mean (SD) plasma clearance is 15.9 (5.3) L/hour. Mean (SD) renal clearance is 10.8 (3.5) L/hour. The magnitude of this value, coupled with the significant decrease in the elimination of doripenem with concomitant probenecid administration, suggests that doripenem undergoes both glomerular filtration and active tubular secretion. In healthy adults given a single 500 mg dose of DORIBAX™, a mean of 70% and 15% of the dose was recovered in urine as unchanged drug and the ring-opened metabolite, respectively, within 48 hours. Following the administration of a single 500 mg dose of radiolabeled doripenem to healthy adults, less than 1% of the total radioactivity was recovered in feces after one week.

Special Populations

Patients with Renal Impairment

Following a single 500 mg dose of DORIBAX™, the mean AUC of doripenem in subjects with mild (CrCl 50–79 mL/min), moderate (CrCl 31–50 mL/min), and severe renal impairment (CrCl ≤30 mL/min) was 1.6-, 2.8-, and 5.1-times that of age-matched healthy subjects with normal renal function (CrCl ≥80 mL/min), respectively. Dosage adjustment is necessary in patients with moderate and severe renal impairment. [see Dosage and Administration (2.2)]

A single 500 mg dose of DORIBAX™ was administered to subjects with end stage renal disease (ESRD) either one hour prior to or one hour after hemodialysis (HD). The mean doripenem AUC following the post-HD infusion was 7.8-times that of healthy subjects with normal renal function. The mean total recovery of doripenem and doripenem-M1 in the dialysate following a 4-hour HD session was 231 mg and 28 mg, respectively, or a total of 259 mg (52% of the dose). There is insufficient information to make dose adjustment recommendations in patients on hemodialysis.

Patients with Hepatic Impairment

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 doripenem are not expected to be affected by hepatic impairment.

Geriatric Patients

The impact of age on the pharmacokinetics of doripenem was evaluated in healthy male (n=6) and female (n=6) subjects ≥ 66 years of age. Mean doripenem AUC0-∞ was 49% higher in elderly adults relative to non-elderly adults. This difference in exposure was mainly attributed to age-related changes in creatinine clearance. No dosage adjustment is recommended for elderly patients with normal (for their age) renal function.

Gender

The effect of gender on the pharmacokinetics of doripenem was evaluated in healthy male (n=12) and female (n=12) subjects. Doripenem Cmax and AUC were similar between males and females. No dose adjustment is recommended based on gender.

Race

The effect of race on doripenem pharmacokinetics was examined using a population pharmacokinetic analysis of data from phase 1 and 2 studies. Compared to Caucasians, mean doripenem clearance was 14% greater in Hispanic/Latino subjects whereas no difference in clearance was observed for African Americans. Doripenem clearance in Japanese studies is similar to what has been observed in Western populations. No dosage adjustment is recommended based on race.

Drug Interactions

Probenecid interferes with the active tubular secretion of doripenem, resulting in increased plasma concentrations. Probenecid increased doripenem AUC by 75% and prolonged the plasma elimination half-life by 53%. [see also Drug Interactions (7.2)]

In vitro studies in human liver microsomes and hepatocytes indicate that doripenem does not inhibit the major cytochrome P450 isoenzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A11). Therefore, DORIBAX™ is not expected to inhibit the clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner.

DORIBAX™ is also not expected to have CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4/5, or UGT1A1 enzyme-inducing properties based on in vitro studies in cultured human hepatocytes.

12.4 Microbiology

Mechanism of Action

Doripenem belongs to the carbapenem class of antimicrobials. Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall synthesis with subsequent cell death. In E. coli and P. aeruginosa, doripenem binds to PBP 2, which is involved in the maintenance of cell shape, as well as to PBPs 3 and 4.

Mechanism(s) 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. Although cross-resistance may occur, some isolates resistant to other carbapenems may be susceptible to doripenem.

Interaction with Other Antimicrobials

In vitro synergy tests with doripenem show doripenem has little potential to antagonize or be antagonized by other antibiotics (e.g., levofloxacin, amikacin, trimethoprim-sulfamethoxazole, daptomycin, linezolid, and vancomycin).

Doripenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections. [see Indications and Usage (1)]

 
Facultative Gram-negative microorganisms
 
Acinetobacter baumannii
 
Escherichia coli
 
Klebsiella pneumoniae
 
Proteus mirabilis
 
Pseudomonas aeruginosa
 
Facultative Gram-positive microorganisms
 
Streptococcus constellatus
 
Streptococcus intermedius
 
Anaerobic microorganisms
 
Bacteroides caccae
 
Bacteroides fragilis
 
Bacteroides thetaiotaomicron
 
Bacteroides uniformis
 
Bacteroides vulgatus
 
Peptostreptococcus micros

At least 90 percent of the following microorganisms exhibit an in vitro minimal inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for doripenem of organisms of the same type shown in Table 6. The safety and efficacy of doripenem in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

 
Facultative Gram-positive microorganisms
 
Staphylococcus aureus (methicillin-susceptible isolates only)
 
Streptococcus agalactiae
 
Streptococcus pyogenes
 
Facultative Gram-negative microorganisms
 
Citrobacter freundii
 
Enterobacter cloacae
 
Enterobacter aerogenes
 
Klebsiella oxytoca
 
Morganella morganii
 
Serratia marcescens

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

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 (1,3) (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 6.

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 (2,3) 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 6.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to doripenem as MICs should be determined by standardized test methods (4). The MIC values obtained should be interpreted according to the criteria in Table 6.

Table 6. Susceptibility Test Result Interpretive Criteria for Doripenem
Minimum Inhibitory Concentrations (µg/mL) Disk Diffusion (zone diameters in mm)
*
The current absence of resistant isolates precludes defining any results other than "Susceptible". Isolates yielding MIC or disk diffusion results suggestive of "Nonsusceptible" should be subjected to additional testing.
n/a = not applicable
Pathogen Susceptible* Susceptible
Enterobacteriaceae ≤0.5 ≥23
Pseudomonas aeruginosa ≤2 ≥24
Acinetobacter baumannii ≤1 ≥17
Streptococcus anginosus group (S. constellatus and S. intermedius) ≤0.12 ≥24
Anaerobes ≤1 n/a

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.

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to monitor the performance of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard doripenem powder should provide the MIC values provided in Table 7. For the diffusion techniques using a 10 µg doripenem disk, the criteria noted in Table 7 should be achieved.

Table 7. Acceptable Quality Control Ranges for Susceptibility Testing
QC Organism Minimum Inhibitory Concentrations (µg/mL) Disk Diffusion (zone diameters in mm)
*
This organism may be used for validation of susceptibility test results when testing organisms of the Streptococcus anginosus group
Escherichia coli ATCC 25922 0.015–0.06 28–35
Pseudomonas aeruginosa ATCC 27853 0.12–0.5 29–35
Streptococcus pneumoniae ATCC 49619* 0.03–0.12 30–38
Bacteroides fragilis ATCC 25285 0.12–0.5 n/a
Bacteroides thetaiotaomicron ATCC 29741 0.12–1 n/a

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

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.

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, greater than 1.5 times the exposure to humans at the dose of 500 mg q8h).

14 CLINICAL STUDIES

14.1 Complicated Intra-Abdominal Infections

A total of 946 adults with complicated intra-abdominal infections were randomized and received study medications in two identical multinational, multi-center, double-blind studies comparing DORIBAX™ (500 mg administered over 1 hour q8h) to meropenem (1 g administered over 3–5 minutes q8h). Both regimens allowed the option to switch to oral amoxicillin/clavulanate (875 mg/125 mg twice daily) after a minimum of 3 days of intravenous therapy for a total of 5–14 days of intravenous and oral treatment. Patients with complicated appendicitis, or other complicated intra-abdominal infections, including bowel perforation, cholecystitis, intra-abdominal or solid organ abscess and generalized peritonitis were enrolled.

DORIBAX™ was non-inferior to meropenem with regard to clinical cure rates in microbiologically evaluable (ME) patients, i.e., in patients with susceptible pathogens isolated at baseline and no major protocol deviations at test of cure (TOC) visit, 25–45 days after completing therapy. DORIBAX™ was also non-inferior to meropenem in microbiological modified intent-to-treat (mMITT) patients, i.e., patients with baseline pathogens isolated regardless of susceptibility. Clinical cure rates at TOC are displayed by patient populations in Table 8. Microbiological cure rates at TOC by pathogen in ME patients are presented in Table 9.

Table 8. Clinical Cure Rates in Two Phase 3 Studies of Adults with Complicated Intra-Abdominal Infections
Analysis Populations DORIBAX™ *
n/N (%)
Meropenem
n/N (%)
Treatment Difference
(2-sided 95% CI§)
*
500 mg administered over 1 hour q8h
n = number of patients in the designated population who were cured; N = number of patients in the designated population
1 g administered over 3 – 5 minutes q8h
§
CI = confidence interval
ME = microbiologically evaluable patients
#
mMITT = microbiological modified intent-to-treat patients
Study 1:
ME 130/157 (82.8) 128/149 (85.9) -3.1 (-11.3; 5.2)
mMITT# 143/194 (73.7) 149/191 (78.0) -4.3 (-12.8; 4.3)
Study 2:
ME 128/158 (81.0) 119/145 (82.1) -1.1 (-9.8; 7.8)
mMITT# 143/199 (71.9) 138/186 (74.2) -2.3 (-11.2; 6.6)
Table 9. Microbiological Cure Rates by Infecting Pathogen in Microbiologically Evaluable Adults with Complicated Intra-abdominal Infections
Pathogen DORIBAX™ Meropenem
N* n % N* n %
*
N = number of unique baseline isolates
n = number of pathogens assessed as cured
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
Enterobacteriaceae 315 271 86.0 274 234 85.4
Escherichia coli 216 189 87.5 199 168 84.4
Klebsiella pneumoniae 32 25 78.1 20 19 95.0
Non-fermenters 51 44 86.3 39 28 71.8
Pseudomonas aeruginosa 40 34 85.0 32 24 75.0
Gram-negative, anaerobic
Bacteroides fragilis group 173 152 87.9 181 152 84.0
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
Non-fragilis Bacteroides 14 13 92.9 13 9 69.2
Bacteroides vulgatus 11 11 100.0 8 6 75.0

14.2 Complicated Urinary Tract Infections, Including Pyelonephritis

A total of 1171 adults with complicated urinary tract infections, including pyelonephritis (49 percent of microbiologically evaluable patients) were randomized and received study medications in two multi-center, multinational studies. Complicated pyelonephritis, i.e., pyelonephritis associated with predisposing anatomical or functional abnormality, comprised 17% of patients with pyelonephritis. One study was double-blind and compared DORIBAX™ (500 mg administered over 1 hour q8h) to IV levofloxacin (250 mg q24h). The second study was a non-comparative study but of otherwise similar design. Both studies permitted the option of switching to oral levofloxacin (250 mg every q24h) after a minimum of 3 days of IV therapy for a total of 10 days of treatment. Patients with confirmed concurrent bacteremia were allowed to receive 500 mg of IV levofloxacin (either IV or oral as appropriate) for a total of 10 to 14 days of treatment.

DORIBAX™ was non-inferior to levofloxacin with regard to the microbiological eradication rates in microbiologically evaluable (ME) patients, i.e., patients with baseline uropathogens isolated, no major protocol deviations and urine cultures at test of cure (TOC) visit 5–11 days after completing therapy. DORIBAX™ was also non-inferior to levofloxacin in microbiological modified intent-to-treat (mMITT) patients, i.e., patients with pretreatment urine cultures. Overall microbiological eradication rates at TOC and the 95% CIs for the comparative study are displayed in Table 10. Microbiological eradication rates at TOC by pathogen in ME patients are presented in Table 11.

Table 10. Microbiological Eradication Rates from the Phase 3 Comparative Study of Adults with Complicated Urinary Tract Infections, Including Pyelonephritis
Analysis populations DORIBAX™ *
n/N (%)
Levofloxacin
n/N (%)
Treatment Difference
(2-sided 95% CI§)
*
500 mg administered over 1 hour q8h
n = number of patients in the designated population who were cured; N = number of patients in the designated population
250 mg administered intravenously q24h
§
CI= confidence interval
ME = microbiologically evaluable patients
#
mMITT = microbiological modified intent-to-treat patients
ME 230/280 (82.1) 221/265 (83.4) -1.3 (-8.0, 5.5)
mMITT # 259/327 (79.2) 251/321 (78.2) 1.0 (-5.6, 7.6)
Table 11. Microbiological Eradication Rates By Infecting Pathogen in Microbiologically Evaluable Adults with Complicated Urinary Tract Infections, Including Pyelonephritis
Pathogen DORIBAX™ * Levofloxacin
N n % N n %
*
data from comparative and non-comparative studies
N = number of unique baseline isolates
n = number of pathogens with a favorable outcome (eradication)
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
Non-fermenters 38 27 71.1 8 5 62.5
Acinetobacter baumannii 10 8 80.0 1 0 0.0
Pseudomonas aeruginosa 27 19 70.4 7 5 71.4

15 REFERENCES

  1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – 7th ed. CLSI Document M7-A7. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087, 2006.
  2. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – 9th ed. CLSI Document M2-A9. CLSI, Wayne, PA 19087, 2006.
  3. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 17th Informational Supplement. CLSI document M100-S17. CLSI, Wayne, PA 19087, 2007.
  4. CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – 7th ed. CLSI document M11-A7. CLSI, Wayne, PA 19087, 2007.

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

MINI-BAG Plus is a trademark of Baxter International Inc.

Manufactured by: Shionogi & Co. Ltd.
Osaka 541-0045, Japan

Distributed by: Ortho-McNeil Pharmaceutical, Inc.
Raritan, NJ 08869


DORIBAX (doripenem)
PRODUCT INFO
Product Code 0062-4010 Dosage Form POWDER, FOR SOLUTION
Route Of Administration INTRAVENOUS DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
doripenem (doripenem) Active 500 MILLIGRAM  In 10 MILLILITER
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color Score
Shape Symbol
Imprint Code Coating
Size
PACKAGING
# NDC Package Description Multilevel Packaging
1 0062-4010-02 10 VIAL In 1 CARTON contains a VIAL, SINGLE-DOSE (0062-4010-01)
1 0062-4010-01 10 MILLILITER In 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (0062-4010-02)

Revised: 11/2007Ortho-McNeil Pharmaceutical, Inc.

Data are from FDA and U.S. National Library of Medicine.