FDA label 26c28132-7b77-4df1-a2ae-96c50892475e

5. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Hypersensitivity reactions have been reported in patients treated with EXBLIFEP. Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, have been reported with beta-lactam antibacterial drugs. If an allergic reaction to EXBLIFEP occurs, discontinue the drug and institute appropriate therapy. ( 5.1 ) Neurotoxicity : Neurotoxicity has been reported during treatment with cefepime, a component of EXBLIFEP. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment of cefepime. If neurotoxicity occurs, discontinue EXBLIFEP and institute appropriate supportive measures. ( 5.2 ) Clostridioides difficile -Associated Diarrhea (CDAD) : CDAD has been reported with nearly all systemic antibacterial agents, including EXBLIFEP. Evaluate if diarrhea occurs. ( 5.3 ) 5.1. Hypersensitivity Reactions Hypersensitivity reactions have been reported in patients treated with EXBLIFEP [see Adverse Reactions ( 6.1 )] . Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs [see Contraindications ( 4 )] . Before therapy with EXBLIFEP is instituted, carefully inquire about previous hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other beta-lactams because cross-hypersensitivity among beta-lactam antibacterial drugs has been reported. If an allergic reaction to EXBLIFEP occurs, discontinue the drug and institute appropriate supportive measures. 5.2. Neurotoxicity Neurotoxicity has been reported during treatment with cefepime, a component of EXBLIFEP, including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus [see Adverse Reactions ( 6.2 )] . Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. However, some cases of neurotoxicity occurred in patients receiving a dosage adjustment appropriate for their degree of renal impairment. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis. If neurotoxicity associated with EXBLIFEP therapy occurs, discontinue EXBLIFEP and institute appropriate supportive measures. 5.3. Clostridioides difficile -associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including EXBLIFEP, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing isolates 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 antibacterial drug 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 antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.4. Positive Direct Coombs' Tests Positive direct Coombs' tests with or without hemolysis have been reported during treatment with cefepime, a component of EXBLIFEP. In patients who develop hemolytic anemia, discontinue the drug and institute appropriate therapy. Positive Coombs' test may be observed in newborns whose mothers have received cephalosporin antibacterial drugs before parturition. 5.5. Prolonged Prothrombin Time Many cephalosporins, including cefepime, a component of EXBLIFEP, have been associated with a decrease in prothrombin activity. Those at risk of developing a prolonged prothrombin time include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated. 5.6. Development of Drug-Resistant Bacteria Prescribing EXBLIFEP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 5.7. Interactions with Urine Glucose Testing The administration of cefepime, a component of EXBLIFEP, may result in a false-positive reaction for glucose in the urine when using some methods (e.g., Clinitest TM tablets) [see Drug Interactions ( 7.3 )] .

6. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the Warnings and Precautions section: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Neurotoxicity [see Warnings and Precautions ( 5.2 )] Clostridioides difficile -associated Diarrhea [see Warnings and Precautions ( 5.3 )] The most frequently reported adverse reactions occurring in ≥5% of patients treated with EXBLIFEP were transaminases increased, increased bilirubin, headache, and phlebitis/infusion site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Allecra Therapeutics SAS at 1-800-880-1978 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. EXBLIFEP was evaluated in a phase 3 comparator-controlled clinical trial in cUTI, including pyelonephritis (also referred to as Trial 1), which included 516 patients treated with EXBLIFEP 2.5 grams (2 grams cefepime and 0.5 grams enmetazobactam) every 8 hours infused over 2 hours, and 518 patients treated with the comparator piperacillin/tazobactam 4.5 grams (4 grams piperacillin and 0.5 grams tazobactam) every 8 hours infused over 2 hours. No switch to oral therapy was permitted. Patients were to receive treatment for 7 days; those with baseline bacteremia could receive up to 14 days of treatment. The mean duration of therapy was 8 days in both treatment groups. The mean age of patients treated with EXBLIFEP was 55 years and 40% of patients were 65 years of age or older. Patients were predominantly female (54%) and White (94%). Most patients were enrolled in Europe (93%). Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation Treatment was discontinued due to adverse reactions in 3% (13/516) of patients receiving EXBLIFEP and in 2% (10/518) of patients receiving piperacillin/tazobactam. The most common adverse reactions leading to discontinuation of EXBLIFEP were hypersensitivity, nausea, and increased transaminases, each 0.4% (2/516). The other adverse reactions resulting in discontinuation of EXBLIFEP were abdominal pain, bacterial infection, chest pain, eructation, fungal infection, gastroenteritis, headache, insomnia, pneumonia, restlessness, and urinary retention, each 0.2% (1/516). Death was reported in 3 (0.6%) patients who received EXBLIFEP and in 3 (0.6%) patients who received piperacillin/tazobactam. Common Adverse Reactions The most frequently reported adverse reactions (5% or greater) in patients receiving EXBLIFEP were transaminases increased, bilirubin increased, headache, and phlebitis/infusion site reactions. Table 3 lists selected adverse reactions occurring in 1% or greater of patients receiving EXBLIFEP in Trial 1. Table 3: Selected Adverse Reactions Occurring in 1% or Greater of cUTI Patients Receiving EXBLIFEP in Trial 1 a Transaminases increased includes alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hepatic enzyme increased, liver function test increased, transaminases increased, and hypertransaminasemia. b Bilirubin increased includes blood bilirubin increased, bilirubin conjugated increased, and hyperbilirubinemia. c Headache includes headache and tension headache. d Phlebitis/Infusion site reactions includes phlebitis, thrombophlebitis, thrombophlebitis superficial, injection site inflammation, infusion site extravasation, injection site thrombosis, vessel puncture site pain, vessel puncture site hematoma, and rash erythematous e Anemia includes anemia, hypochromic anemia, iron deficiency anemia, and normocytic anemia. f Hypersensitivity includes allergic cough, dermatitis allergic, hypersensitivity, periorbital edema, pruritus, rash, and urticaria. The Trial was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the EXBLIFEP and Piperacillin/Tazobactam treatment groups. Adverse Reactions EXBLIFEP (N=516) N (%) Piperacillin/Tazobactam (N=518) N (%) Transaminases increased a 101 (20) 103 (20) Bilirubin increased b 36 (7) 21 (4) Headache c 26 (5) 12 (2) Phlebitis/Infusion site reactions d 24 (5) 2 (<1) Diarrhea 21 (4) 26 (5) Anemia e 16 (3) 16 (3) Hypersensitivity f 10 (2) 3 (<1) Vomiting 9 (2) 6 (1) Nausea 6 (1) 3 (<1) Other Adverse Reactions Associated With EXBLIFEP The following selected adverse reactions were reported in EXBLIFEP-treated patients at a rate of less than 1% in Trial 1: Blood and lymphatic system disorders : eosinophilia, partial thromboplastin time prolonged, thrombocytopenia Gastrointestinal Disorders : eructation Infections and Infestations: Clostridioides difficile colitis Laboratory Investigations : alkaline phosphatase increased Vascular Disorders : epistaxis Metabolism and nutrition disorders : hypocalcemia, hyperkalemia Nervous System Disorders : dizziness Psychiatric Disorders : restlessness Renal and urinary disorders : blood urea nitrogen increased, blood creatinine increased Other Adverse Reactions Associated with Cefepime in Other Clinical Trials Additionally, adverse reactions reported with cefepime alone in other clinical trials that were not reported in the EXBLIFEP-treated patients in Trial 1 are listed below: Infections and infestations : oral candidiasis, vaginitis Blood and lymphatic system disorders : Coombs' test positive (without hemolysis), prothrombin time prolonged, leukopenia, neutropenia General disorders and administration site conditions : pyrexia, Laboratory Investigations : increased calcium, increased phosphorus, decreased phosphorus Laboratory Changes Associated with EXBLIFEP The incidence of patients with increases in ALT, AST, or total bilirubin laboratory values greater than specified levels is presented in Table 4 . Table 4: Selected Laboratory Abnormalities Exceeding Specified Levels in Trial 1 N, total number of patients in treatment arm; N w , number of patients with baseline lab data available in each baseline toxicity subgroup; n, number of patients meeting criteria; ULN, Upper Limit of Normal. Laboratory Parameter EXBLIFEP (N=516) n/N w (%) Piperacillin/Tazobactam (N=518) n/N w (%) Alanine aminotransferase (U/L) >3x ULN 14/514 (3) 6/515 (1) Aspartate aminotransferase (U/L) >3x ULN 11/514 (2) 6/515 (1) Bilirubin, total (mg/dL) >2x ULN 2/514 (<1) 7/515 (1) 6.2. Postmarketing Experience The following adverse reactions and altered laboratory tests have been identified during post-approval use of cefepime or other cephalosporin-class antibacterial drugs. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Blood and lymphatic system disorders : Agranulocytosis, aplastic anemia, hemolytic anemia, pancytopenia Nervous system disorders : Encephalopathy (including disturbance of consciousness, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus Immune system disorders : Anaphylaxis including anaphylactic shock, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis Hepatobiliary disorders : Hepatic dysfunction including cholestasis Renal and urinary disorders : Renal dysfunction, toxic nephropathy Vascular disorders : Hemorrhage

<table ID="t3" width="100%"><caption>Table 3: Selected Adverse Reactions Occurring in 1% or Greater of cUTI Patients Receiving EXBLIFEP in Trial 1 </caption><col width="37.467%" align="left"/><col width="31.267%" align="left"/><col width="31.267%" align="left"/><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">^a Transaminases increased includes alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hepatic enzyme increased, liver function test increased, transaminases increased, and hypertransaminasemia. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">^b Bilirubin increased includes blood bilirubin increased, bilirubin conjugated increased, and hyperbilirubinemia. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">^c Headache includes headache and tension headache. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">^d Phlebitis/Infusion site reactions includes phlebitis, thrombophlebitis, thrombophlebitis superficial, injection site inflammation, infusion site extravasation, injection site thrombosis, vessel puncture site pain, vessel puncture site hematoma, and rash erythematous </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">^e Anemia includes anemia, hypochromic anemia, iron deficiency anemia, and normocytic anemia. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">^f Hypersensitivity includes allergic cough, dermatitis allergic, hypersensitivity, periorbital edema, pruritus, rash, and urticaria. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">The Trial was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the EXBLIFEP and Piperacillin/Tazobactam treatment groups. </paragraph></td></tr></tfoot><tbody><tr><td align="left" valign="top" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Adverse Reactions</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">EXBLIFEP</content> <content styleCode="bold">(N=516)</content> <content styleCode="bold">N (%)</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Piperacillin/Tazobactam</content> <content styleCode="bold">(N=518)</content> <content styleCode="bold">N (%)</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Transaminases increased^a</td><td align="center" valign="middle" styleCode="Botrule Rrule">101 (20) </td><td align="center" valign="middle" styleCode="Botrule Rrule">103 (20) </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Bilirubin increased^b</td><td align="center" valign="middle" styleCode="Botrule Rrule">36 (7) </td><td align="center" valign="middle" styleCode="Botrule Rrule">21 (4) </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Headache^c</td><td align="center" valign="middle" styleCode="Botrule Rrule">26 (5) </td><td align="center" valign="middle" styleCode="Botrule Rrule">12 (2) </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Phlebitis/Infusion site reactions^d</td><td align="center" valign="middle" styleCode="Botrule Rrule">24 (5) </td><td align="center" valign="middle" styleCode="Botrule Rrule">2 (&lt;1) </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Diarrhea </td><td align="center" valign="middle" styleCode="Botrule Rrule">21 (4) </td><td align="center" valign="middle" styleCode="Botrule Rrule">26 (5) </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Anemia^e</td><td align="center" valign="middle" styleCode="Botrule Rrule">16 (3) </td><td align="center" valign="middle" styleCode="Botrule Rrule">16 (3) </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Hypersensitivity^f</td><td align="center" valign="middle" styleCode="Botrule Rrule">10 (2) </td><td align="center" valign="middle" styleCode="Botrule Rrule">3 (&lt;1) </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Vomiting </td><td align="center" valign="middle" styleCode="Botrule Rrule">9 (2) </td><td align="center" valign="middle" styleCode="Botrule Rrule">6 (1) </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Nausea </td><td align="center" valign="middle" styleCode="Botrule Rrule">6 (1) </td><td align="center" valign="middle" styleCode="Botrule Rrule">3 (&lt;1) </td></tr></tbody></table>

<table ID="t4" width="100%"><caption>Table 4: Selected Laboratory Abnormalities Exceeding Specified Levels in Trial 1 </caption><col width="37.833%" align="left"/><col width="32.067%" align="left"/><col width="30.100%" align="left"/><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">N, total number of patients in treatment arm; N_w, number of patients with baseline lab data available in each baseline toxicity subgroup; n, number of patients meeting criteria; ULN, Upper Limit of Normal. </paragraph></td></tr></tfoot><tbody><tr><td align="left" valign="top" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Laboratory Parameter</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">EXBLIFEP</content> <content styleCode="bold">(N=516)</content> <content styleCode="bold">n/N</content><content styleCode="bold">_w</content><content styleCode="bold">(%)</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Piperacillin/Tazobactam</content> <content styleCode="bold">(N=518)</content> <content styleCode="bold">n/N</content><content styleCode="bold">_w</content><content styleCode="bold">(%)</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule"><content styleCode="bold">Alanine aminotransferase (U/L)</content></td><td align="center" valign="middle" styleCode="Botrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/></tr><tr><td align="center" valign="middle" styleCode="Botrule Lrule Rrule">&gt;3x ULN </td><td align="center" valign="middle" styleCode="Botrule Rrule">14/514 (3) </td><td align="center" valign="middle" styleCode="Botrule Rrule">6/515 (1) </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule"><content styleCode="bold">Aspartate aminotransferase (U/L)</content></td><td align="center" valign="middle" styleCode="Botrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/></tr><tr><td align="center" valign="middle" styleCode="Botrule Lrule Rrule">&gt;3x ULN </td><td align="center" valign="middle" styleCode="Botrule Rrule">11/514 (2) </td><td align="center" valign="middle" styleCode="Botrule Rrule">6/515 (1) </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule"><content styleCode="bold">Bilirubin, total (mg/dL)</content></td><td align="center" valign="middle" styleCode="Botrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/></tr><tr><td align="center" valign="middle" styleCode="Botrule Lrule Rrule">&gt;2x ULN </td><td align="center" valign="middle" styleCode="Botrule Rrule">2/514 (&lt;1) </td><td align="center" valign="middle" styleCode="Botrule Rrule">7/515 (1) </td></tr></tbody></table>