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warnings and cautions
5 WARNINGS AND PRECAUTIONS QT Prolongation : Avoid use in patients with known QT prolongation, ventricular arrhythmias including torsades de pointes, and patients receiving drugs that prolong the QT interval such as antiarrhythmic agents. ( 5.1 ) Embryo-Fetal Toxicity : May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.2 , 8.1 , 8.3 ) Clostridioides difficile -associated Diarrhea (CDAD) : Evaluate patients who develop diarrhea. ( 5.3 ) 5.1 QT Prolongation XENLETA has the potential to prolong the QT interval of the electrocardiogram (ECG) in some patients. Avoid XENLETA use in the following patients: Patients with known prolongation of the QT interval Patients with ventricular arrhythmias including torsades de pointes Patients receiving Class IA (for example, quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic agents Patients receiving other drugs that prolong the QT interval, such as antipsychotics, erythromycin, pimozide, moxifloxacin, and tricyclic antidepressants In patients with renal failure who require dialysis, metabolic disturbances associated with renal failure may lead to QT prolongation. In patients with mild, moderate, or severe hepatic impairment, metabolic disturbances associated with hepatic impairment may lead to QT prolongation. If use with XENLETA cannot be avoided in specific populations predisposed to QT prolongation or those receiving another drug that prolongs the QT interval, ECG monitoring is recommended during treatment. The magnitude of QT prolongation may increase with increasing concentrations of XENLETA or increasing the rate of infusion of the intravenous formulation. Therefore, the recommended dose and infusion rate should not be exceeded. 5.2 Embryo-Fetal Toxicity Based on findings from animal studies, lefamulin may cause fetal harm when administered to pregnant women. Animal studies indicate that administration of lefamulin resulted in an increased incidence of post-implantation fetal loss and stillbirths in rats and rabbits treated during the period of organogenesis or in rats treated from the beginning of organogenesis through the time of weaning. Additional rat pup deaths were observed during early lactation that were likely related to maternal treatment with lefamulin. Decreased fetal body weights and ossification in rats and rabbits, and apparent delay in sexual maturation in rats may indicate treatment-related developmental delay, while other findings such as malformations in rats at systemic exposures lower than the systemic exposure in CABP patients may indicate a risk for embryo-fetal toxicity. Verify pregnancy status in females of reproductive potential prior to initiating XENLETA. Advise females of reproductive potential to use effective contraception during treatment with XENLETA and for 2 days after the final dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus [see Use in Specific Populations ( 8.1 , 8.3 )] . 5.3 Clostridioides difficile -associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XENLETA, 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 Development of Drug-Resistant Bacteria Prescribing XENLETA 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.
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: QT Prolongation [see Warnings and Precautions ( 5.1 )] . Clostridioides difficile -associated Diarrhea [see Warnings and Precautions ( 5.3 )] . Most common adverse reactions (incidence ≥2%) are: XENLETA Injection : administration site reactions, hepatic enzyme elevation, nausea, hypokalemia, insomnia, headache. ( 6.1 ) XENLETA Tablets : diarrhea, nausea, vomiting, hepatic enzyme elevation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Nabriva Therapeutics US, Inc. at 1-855-5NABRIVA 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. XENLETA was evaluated in two clinical trials in CABP patients (Trial 1 and Trial 2). Across the two trials, a total of 641 patients were treated with XENLETA. Trial 1 (intravenous [IV] to oral dosing switch trial) enrolled 551 adult patients, 276 randomized to XENLETA (273 received at least one dose of XENLETA) and 275 randomized to moxifloxacin (273 received at least one dose of moxifloxacin). Trial 2 (oral dosing only trial) enrolled 738 adult patients, 370 randomized to XENLETA (368 received at least one dose of XENLETA) and 368 randomized to moxifloxacin (all 368 received at least one dose of moxifloxacin). Trial 1 enrolled patients with Pneumonia Outcomes Research Team (PORT) Risk Class III-V. The mean duration of intravenous treatment was 6 days; the mean total duration of treatment was 7 days. Trial 2 enrolled patients with PORT Risk Class II-IV. The mean duration of treatment was 5 days for XENLETA and 7 days for moxifloxacin. In Trial 1 and Trial 2 (pooled), the median age of patients treated with XENLETA was 61 (range 19-97) years; 42% of patients were 65 years or older and 18% were 75 years or older. Patients were predominantly male (58%) and white (79%) and had a median body mass index (BMI) of 26.0 (range 13.0-56.8) kg/m 2 . Approximately 52% of XENLETA-treated patients had creatinine clearance (CrCl) <90 mL/min. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 1 and Trial 2 (pooled), serious adverse reactions occurred in 36/641 (5.6%) patients treated with XENLETA and 31/641 (4.8%) patients treated with moxifloxacin. Treatment was discontinued due to an adverse reaction in 21/641 (3.3%) patients treated with XENLETA and 21/641 (3.3%) patients treated with moxifloxacin. Death within 28 days occurred in 8/641 (1.2%) patients treated with XENLETA and 7/641 (1.1%) patients treated with moxifloxacin. Most Common Adverse Reactions Table 2 and Table 3 include adverse reactions occurring in ≥2% of patients receiving XENLETA in Trials 1 and 2. Table 2: Adverse Reactions Occurring in ≥2% of Patients Receiving XENLETA in Trial 1 *Administration site reactions include infusion site pain, infusion site phlebitis, and injection site reaction. **Hepatic enzyme elevation includes alanine aminotransferase increased, aspartate aminotransferase increased, and liver function test increased. Adverse Reaction Trial 1 IV ± Oral Dosing XENLETA N=273 Moxifloxacin N=273 Administration site reactions* 7% 3% Hepatic enzyme elevation** 3% 3% Nausea 3% 2% Hypokalemia 3% 2% Insomnia 3% 2% Headache 2% 2% Table 3: Adverse Reactions Occurring in ≥2% of Patients Receiving XENLETA in Trial 2 **Hepatic enzyme elevation includes alanine aminotransferase increased, aspartate aminotransferase increased, and liver function test increased. Adverse Reaction Trial 2 Oral Dosing XENLETA N=368 Moxifloxacin N=368 Diarrhea 12% 1% Nausea 5% 2% Vomiting 3% 1% Hepatic enzyme elevation** 2% 2% Selected Adverse Reactions Occurring in Less Than 2% of Patients Receiving XENLETA in Trials 1 and 2 Blood and Lymphatic System Disorders: anemia, thrombocytopenia Cardiac Disorders: atrial fibrillation, palpitations Gastrointestinal Disorders: abdominal pain, constipation, dyspepsia, epigastric discomfort, erosive gastritis Infections and Infestations: Clostridioides difficile colitis, oropharyngeal candidiasis, vulvovaginal candidiasis Investigations: alkaline phosphatase increased, creatine phosphokinase increased, electrocardiogram QT prolonged, gamma-glutamyl transferase increased Nervous System Disorders: somnolence Psychiatric Disorders: anxiety Renal and Urinary Disorders: urinary retention
adverse reactions table
<table ID="table2" width="675" styleCode="Noautorules"><caption>Table 2: Adverse Reactions Occurring in ≥2% of Patients Receiving XENLETA in Trial 1</caption><col width="40%" align="left"/><col width="30%" align="center"/><col width="30%" align="center"/><tfoot><tr valign="top"><td colspan="4" align="left"><paragraph styleCode="footnote">*Administration site reactions include infusion site pain, infusion site phlebitis, and injection site reaction.</paragraph><paragraph styleCode="footnote">**Hepatic enzyme elevation includes alanine aminotransferase increased, aspartate aminotransferase increased, and liver function test increased.</paragraph></td></tr></tfoot><tbody><tr valign="top"><td rowspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Reaction</content></td><td colspan="2" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Trial 1 IV ± Oral Dosing</content></td></tr><tr valign="top"><td styleCode="Botrule Rrule" align="center"><content styleCode="bold">XENLETA N=273</content></td><td styleCode="Botrule Rrule"><content styleCode="bold">Moxifloxacin N=273</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Administration site reactions*</td><td styleCode="Botrule Rrule">7%</td><td styleCode="Botrule Rrule">3%</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Hepatic enzyme elevation**</td><td styleCode="Botrule Rrule">3%</td><td styleCode="Botrule Rrule">3%</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Nausea</td><td styleCode="Botrule Rrule">3%</td><td styleCode="Botrule Rrule">2%</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Hypokalemia</td><td styleCode="Botrule Rrule">3%</td><td styleCode="Botrule Rrule">2%</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Insomnia</td><td styleCode="Botrule Rrule">3%</td><td styleCode="Botrule Rrule">2%</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Headache</td><td styleCode="Botrule Rrule">2%</td><td styleCode="Botrule Rrule">2%</td></tr></tbody></table>