Doribax: Package Insert and Label Information

DORIBAX- doripenem powder, for solution
Janssen Pharmaceuticals, Inc.

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 every 8 hours 1 5–14 days *
Complicated UTI, including pyelonephritis 500 mg every 8 hours 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®
*
[see Preparation of 250 mg DORIBAX® dose using the 250 mg vial (2.3.2) and Preparation of 250 mg DORIBAX® dose using the 500 mg vial (2.3.3)]
> 50 No dosage adjustment necessary
≥ 30 to ≤ 50 250 mg * administered intravenously (over 1 hour) every 8 hours
> 10 to < 30 250 mg * administered 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.

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.

Preparation of 500 mg DORIBAX® dose using the 500 mg vial

  • Constitute the 500 mg vial with 10 mL of sterile water for injection or 0.9% sodium chloride injection (normal saline) and gently shake to form a suspension. The resultant concentration is approximately 50 mg/mL. CAUTION: THE CONSTITUTED SUSPENSION IS NOT FOR DIRECT INJECTION.
  • Withdraw the suspension using a syringe with a 21 gauge needle and add it to an infusion bag containing 100 mL of normal saline or 5% dextrose; gently shake until clear. The final infusion solution concentration is approximately 4.5 mg/mL.

Preparation of 250 mg DORIBAX® dose using the 250 mg vial

  • Constitute the 250 mg vial with 10 mL of sterile water for injection or 0.9% sodium chloride injection (normal saline) and gently shake to form a suspension. The resultant concentration is approximately 25 mg/mL. CAUTION: THE CONSTITUTED SUSPENSION IS NOT FOR DIRECT INJECTION.
  • Withdraw the suspension using a syringe with a 21 gauge needle and add it to an infusion bag containing either 50 or 100 mL of normal saline or 5% dextrose; gently shake until clear. The final infusion solution concentration is approximately 4.2 mg/mL (50 mL infusion bag) or approximately 2.3 mg/mL (100 mL infusion bag).

Preparation of 250 mg DORIBAX® dose using the 500 mg vial

  • Constitute the 500 mg vial with 10 mL of sterile water for injection or 0.9% sodium chloride injection (normal saline) and gently shake to form a suspension. The resultant concentration is approximately 50 mg/mL. CAUTION: THE CONSTITUTED SUSPENSION IS NOT FOR DIRECT INJECTION.
  • Withdraw the suspension using a syringe with a 21 gauge needle and add it to an infusion bag containing 100 mL of normal saline or 5% dextrose; gently shake until clear.
  • Remove 55 mL of this solution from the bag and discard.
  • Infuse the remaining solution, which contains 250 mg (approximately 4.5 mg/mL).

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 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 12 hours 72 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 250 mg or 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-reactivity 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, as clinically indicated.

5.2 Seizures

Seizures have been reported during treatment with doripenem (see section 6.2). In clinical trials, doripenem-treated patients with pre-existing central nervous system (CNS) disorders (e.g. stroke or history of seizures), patients with compromised renal function and patients given doses greater than 500 mg every 8 hours appear to be at greater risk for developing seizures.

5.3 Interaction with Valproic Acid

Due to a drug interaction, patients with seizure disorders controlled with valproic acid or sodium valproate will be at an increased risk for breakthrough seizures when treated with DORIBAX® concomitantly. Reduction in serum valproic acid concentrations to below the therapeutic concentration range (50 to 100 mcg/mL) was observed by 12 hours after the initiation of doripenem in healthy subjects co-administered both drugs. A similar drug interaction involving other carbapenem antibacterials and valproic acid has been described in published case reports. In some of these reports, increasing the dose of valproic acid or sodium valproate did not result in increased valproic acid serum concentrations. Alternative antibacterial therapies should be considered for patients receiving valproic acid or sodium valproate. If administration of DORIBAX® is necessary, supplemental anti-convulsant therapy should be considered. [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]

5.4 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)]

5.5 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.

5.6 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, 1338 adult patients were treated with DORIBAX® (1076 patients received doripenem 500 mg administered over 1 hour every 8 hours and 262 patients received doripenem 500 mg administered over 4 hours every 8 hours); 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 complicated urinary tract infections (cUTI) study, 46 years (range 18–94) in the pooled comparative complicated intra-abdominal infections (cIAI) studies, and 56 years (range 18–94) in the other Phase 3 trials. There was a female predominance (62%) in the comparative cUTI study and a male predominance (63% and 75%) in the comparative cIAI and other Phase 3 trials, respectively. The patients treated with DORIBAX® were predominantly Caucasian (79%) in the five comparator-controlled Phase 3 studies.

The most common adverse drug reactions (≥ 5%) observed in the five DORIBAX® comparator-controlled Phase 3 clinical trials were anemia, headache, nausea, diarrhea, rash, phlebitis, and elevated hepatic enzymes. During clinical trials, adverse events led to discontinuation of DORIBAX® in 4.1% (55 of 1338) of patients compared to 4.3% (58 of 1325) of comparator-treated patients.

Adverse reactions due to DORIBAX® 500 mg every 8 hours that occurred at a rate ≥ 1 % are listed in Table 4. Hypersensitivity reactions related to intravenous study drug occurred at a rate of less than 1%.

Table 4: Adverse Reactions with Incidence Rates (%) of ≥1% in the Controlled Phase 3 Clinical Trials
Complicated Urinary TractInfections (one trial) Complicated Intra-AbdominalInfections (two trials) Other Phase 3 Trials(two trials)
System organ class DORIBAX® 500 mg administered every 8 hours(n =376 ) Levofloxacin250 mg administered IV every 24 hours(n = 372) DORIBAX® 500 mg administered every 8 hours(n = 477) Meropenem1 g administered every 8 hours(n = 469) DORIBAX® 500 mg administered every 8 hours(n =485 ) Comparator *(n=484)
*
Comparators include piperacillin/tazobactam (4.5 g every 8 hours) and imipenem (500 mg every 6 hours or 1 g every 8 hours)
including preferred terms (alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, and transaminases increased) and laboratory test values (ALT or AST ≤ ULN at baseline and >5 × ULN at End of Treatment (EOT))
Nervous system disorders
Headache 16 15 4 5 3 3
Vascular disorders
Phlebitis 4 4 8 6 2 1
Gastro-intestinal disorders
Nausea 4 6 12 9 7 7
Diarrhea 6 10 11 11 12 14
C. difficile colitis <1 0 <1 0 1 2
Blood and Lymphatic System Disorders
Anemia 2 1 10 5 5 6
Skin and subcutaneous disorders
Pruritus 1 1 3 2 1 1
Rash 1 1 4 2 6 5
Investigations
Hepatic Enzyme elevation 2 4 2 4 7 6
Infections and Infestations
Oral candidiasis 1 0 1 2 3 1
Vulvomycotic infection 2 1 1 <1 0 <1

In a Phase 1 study of healthy subjects receiving doripenem doses greater than the approved dose of 500 mg every 8 hours for 10 to 14 days, the incidence of rash was higher than that observed in subjects who received 500 mg every 8 hours. The rash resolved within 10 days after doripenem administration was discontinued.

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