Drug: Doribax

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:

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The following adverse reactions are discussed in greater detail in other sections of labeling:
  • Anaphylaxis and serious hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
  • Seizures [see WARNINGS AND PRECAUTIONS]
  • Interaction with sodium valproate [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]
  • Clostridium difficile-associated diarrhea [see WARNINGS AND PRECAUTIONS]
  • Development of drug-resistant bacteria [see WARNINGS AND PRECAUTIONS]
  • Pneumonitis with inhalational use [see WARNINGS AND PRECAUTIONS]
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]. 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
System organ class Complicated Urinary Tract Infections (one trial) Complicated IntraAbdominal Infections (two trials) Other Phase 3 Trials (two trials) DORIBAX® 500 mg administered every 8 hours
(n =376 ) Levofloxacin 250 mg administered IV every 24 hours
(n = 372) DORIBAX® 500 mg administered every 8 hours
(n = 477) Meropenem 1 g administered every 8 hours
(n = 469) DORIBAX® 500 mg administered every 8 hours
(n =485 ) Comparator*
(n=484) 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 2 1 1 < 1 0 < 1 * 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 x ULN at End of Treatment (EOT)) 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. Postmarketing Experience The following adverse reactions have been identified during post-approval use of doripenem. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Anaphylaxis
Leukopenia
Neutropenia
Seizure
Thrombocytopenia
Toxic epidermal necrolysis, Stevens-Johnson Syndrome
Interstitial pneumonia Read the Doribax (doripenem for injection) Side Effects Center for a complete guide to possible side effectsLearn More »

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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 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*† * 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. 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* administered intravenously (over 1 hour) every 8 hours > 10 to < 30 250 mg* administered intravenously (over 1 hour) every 12 hours * [see Preparation of 250 mg DORIBAX® dose using the 250 mg vial and Preparation of 250 mg DORIBAX® dose using the 500 mg vial] 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: (weight in kg) x (140 – age) (72) x serum creatinine (mg/100 mL) Females: (0.85) x (above value) DORIBAX® is hemodialyzable; however, there is insufficient information to make dose adjustment recommendations in patients on hemodialysis. 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).
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. 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™.

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Valproic Acid Co-administration of DORIBAX® with valproic acid causes the serum concentrations of valproic acid to fall below the therapeutic range, increasing the risk for breakthrough seizures. Although the mechanism of this interaction is not fully understood, data from in vitro and animal studies suggest that doripenem may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the plasma concentrations of valproic acid. This is consistent with case reports for other carbapenems, where serum concentrations of valproic acid were reduced upon co-administration with a carbapenem. If administration of DORIBAX® is necessary, supplemental anti-convulsant therapy should be considered. The pharmacokinetics of doripenem were unaffected by the co-administration of valproic acid. [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY] Probenecid Probenecid interferes with the active tubular secretion of doripenem, resulting in increased plasma concentrations of doripenem. [see CLINICAL PHARMACOLOGY] Coadministration of probenecid with DORIBAX® is not recommended. Read the Doribax Drug Interactions Center for a complete guide to possible interactions Learn More »

Source: http://www.rxlist.com

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. 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. 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.

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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. Last reviewed on RxList: 1/30/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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 doripenemM1 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]

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Dosage Forms And Strengths Single use clear glass vials containing 250 mg or 500 mg (on an anhydrous basis) of sterile doripenem powder. Storage And Handling DORIBAX® is supplied as single use type 1 clear glass vials containing 250 mg or 500 mg (on an anhydrous basis) of sterile doripenem powder. Vials are packaged individually and in cartons containing 10 vials. NDC: 59630-320-01 – 500 mg/vial, single vial
NDC: 59630-320-10 – 500 mg/vial, 10 vials/carton
NDC: 59630-309-01 – 250 mg/vial, single vial
NDC: 59630-309-10 – 250 mg/vial, 10 vials/carton Storage of DORIBAX® vials DORIBAX® should be stored at 25°C (77°F); excursions permitted to 15°–30°C (59° to 86°F) [refer to USP controlled room temperature]. Manufactured by: Shionogi & Co. Ltd. Osaka 541-0045, Japan. Manufactured for: Shionogi Inc. Florham Park, NJ 07932. Revised: Jan 2014 Last reviewed on RxList: 1/30/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Increased Mortality In Ventilator-Associated Bacterial Pneumonia In a clinical trial of patients with ventilator-associated bacterial pneumonia comparing doripenem to imipenem, more subjects receiving doripenem died 23% (31/135) compared to those receiving imipenem 16.7% (22/132) based on 28-day all-cause mortality in the intent-to-treat (ITT) population. Clinical response rates were also lower in the doripenem arm. Doripenem is not approved for the treatment of ventilator-associated bacterial pneumonia. 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. 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. 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 and CLINICAL PHARMACOLOGY] 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] 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. Pneumonitis With Inhalational Use When DORIBAX® has been used investigationally via inhalation, pneumonitis has occurred. DORIBAX® should not be administered by this route. Nonclinical Toxicology 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 1 g/kg/day (based on AUC, greater than 1.5 times the exposure to humans at the dose of 500 mg administered every 8 hours). Use In Specific Populations 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 administered every 8 hours, 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. 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. Pediatric Use Safety and effectiveness in pediatric patients have not been established. 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. 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. Elderly subjects had greater doripenem plasma concentrations relative to non-elderly subjects; however, this increase in exposure was mainly attributed to age-related changes in renal function. [see CLINICAL PHARMACOLOGY] No overall differences in safety were observed between older and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Patients With Renal Impairment Dosage adjustment is required in patients with moderately or severely impaired renal function. [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY] In such patients, renal function should be monitored. Last reviewed on RxList: 1/30/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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