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warnings and cautions
5 WARNINGS AND PRECAUTIONS Serious hypersensitivity (anaphylactic) reactions have been reported with carbapenems and other beta-lactams ( 5.1 ) It has been shown that co-administration of DORIBAX ® with valproic acid reduces the serum concentration of valproic acid. Patients with seizure disorders controlled with valproic acid or sodium valproate will therefore be at an increased risk for breakthrough seizures. ( 5.2 ) Clostridium difficile -associated diarrhea (ranging from mild diarrhea to fatal colitis): Evaluate if diarrhea occurs ( 5.3 ) 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 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) ] 5.3 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: Anaphylaxis and serious hypersensitivity reactions [see Warnings and Precautions (5.1) ] Interaction with sodium valproate [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] Clostridium difficile -associated diarrhea [see Warnings and Precautions (5.3) ] Development of drug-resistant bacteria [see Warnings and Precautions (5.4) ] Pneumonitis with inhalational use [see Warnings and Precautions (5.5) ] 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. 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 every 8 hours) 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 administered every 8 hours 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 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. with Incidence Rates (%) of ≥1% and Adverse Events An adverse event refers to any untoward medical event associated with the use of the drug in humans, whether or not considered drug-related. 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 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) 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 includes reactions reported as alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, and transaminases increased 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 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 Neutropenia Leukopenia Thrombocytopenia 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 Seizure
adverse reactions table
<table width="100%"> <caption>Table 4: Adverse Reactions<footnote>An adverse drug reaction was defined as an undesirable effect, reasonably associated with the use of DORIBAX<sup>®</sup> that may occur as part of its pharmacological action or may be unpredictable in its occurrence.</footnote> with Incidence Rates (%) of ≥1% and Adverse Events<footnote ID="t4f2">An adverse event refers to any untoward medical event associated with the use of the drug in humans, whether or not considered drug-related.</footnote> Having Clinically Important Differences in Frequency by Indication in the Three Controlled, Comparative DORIBAX<sup>®</sup> Phase 3 Clinical Trials</caption> <col align="left" width="28%" valign="middle"/> <col align="center" width="18%" valign="middle"/> <col align="center" width="18%" valign="middle"/> <col align="center" width="18%" valign="middle"/> <col align="center" width="18%" valign="middle"/> <thead> <tr styleCode="Botrule"> <th/> <th colspan="2">Complicated Urinary Tract Infections (one trial)</th> <th colspan="2">Complicated Intra-Abdominal Infections (two trials)</th> </tr> <tr> <th styleCode="Toprule">System organ class</th> <th styleCode="Toprule">DORIBAX<sup>®</sup> 500 mg administered every 8 hours (n =376 )</th> <th styleCode="Toprule">Levofloxacin 250 mg administered IV every 24 hours (n = 372)</th> <th styleCode="Toprule">DORIBAX<sup>®</sup> 500 mg administered every 8 hours (n = 477)</th> <th styleCode="Toprule">Meropenem 1 g administered every 8 hours (n = 469)</th> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">Nervous system disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td>Headache</td> <td>16</td> <td>15</td> <td>4</td> <td>5</td> </tr> <tr> <td> <content styleCode="bold">Vascular disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td>Phlebitis</td> <td>4</td> <td>4</td> <td>8</td> <td>6</td> </tr> <tr> <td> <content styleCode="bold">Gastro-intestinal disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td>Nausea</td> <td>4</td> <td>6</td> <td>12</td> <td>9</td> </tr> <tr> <td>Diarrhea</td> <td>6</td> <td>10</td> <td>11</td> <td>11</td> </tr> <tr> <td> <content styleCode="bold">Blood and Lymphatic System Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td>Anemia<footnoteRef IDREF="t4f2"/> </td> <td>2</td> <td>1</td> <td>10</td> <td>5</td> </tr> <tr> <td> <content styleCode="bold">Renal and Urinary Disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td>Renal impairment/Renal failure<footnoteRef IDREF="t4f2"/> </td> <td><1</td> <td>0</td> <td>1</td> <td><1</td> </tr> <tr> <td> <content styleCode="bold">Skin and subcutaneous disorders</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td>Pruritus</td> <td><1</td> <td>1</td> <td>3</td> <td>2</td> </tr> <tr> <td>Rash</td> <td>1</td> <td>1</td> <td>5</td> <td>2</td> </tr> <tr> <td> <content styleCode="bold">Investigations</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td>Hepatic enzyme elevation<footnote>includes reactions reported as alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, and transaminases increased</footnote> </td> <td>2</td> <td>3</td> <td>1</td> <td>3</td> </tr> <tr> <td> <content styleCode="bold">Infection and Infestations</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td>Oral candidiasis</td> <td>1</td> <td>0</td> <td>1</td> <td>2</td> </tr> <tr> <td>Vulvomycotic infection</td> <td>2</td> <td>1</td> <td>1</td> <td><1</td> </tr> </tbody> </table>