Tigecycline

RECENT MAJOR CHANGES SECTION Contraindications ( 4 ) 1/2025 Warnings and Precautions, Tetracycline-Class Adverse Effects ( 5.11 ) 3/2025

1 INDICATIONS AND USAGE Tigecycline for Injection is a tetracycline class antibacterial indicated in patients 18 years of age and older for: Complicated skin and skin structure infections ( 1.1 ) Complicated intra-abdominal infections ( 1.2 ) Community-acquired bacterial pneumonia ( 1.3 ) Limitations of Use : Tigecycline for Injection is not indicated for treatment of diabetic foot infection or hospital-acquired pneumonia, including ventilator-associated pneumonia. ( 1.4 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tigecycline for Injection and other antibacterial drugs, Tigecycline for Injection should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. ( 1.5 ) 1.1 Complicated Skin and Skin Structure Infections Tigecycline for Injection is indicated in patients 18 years of age and older for the treatment of complicated skin and skin structure infections caused by susceptible isolates of Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus ), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis. 1.2 Complicated Intra-abdominal Infections Tigecycline for Injection is indicated in patients 18 years of age and older for the treatment of complicated intra-abdominal infections caused by susceptible isolates of Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus ), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros. 1.3 Community-Acquired Bacterial Pneumonia Tigecycline for Injection is indicated in patients 18 years of age and older for the treatment of community-acquired bacterial pneumonia caused by susceptible isolates of Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae , and Legionella pneumophila . 1.4 Limitations of Use Tigecycline for Injection is not indicated for the treatment of diabetic foot infections. A clinical trial failed to demonstrate non-inferiority of Tigecycline for Injection for treatment of diabetic foot infections. Tigecycline for Injection is not indicated for the treatment of hospital-acquired or ventilator-associated pneumonia. In a comparative clinical trial, greater mortality and decreased efficacy were reported in Tigecycline for Injection-treated patients [see Warnings and Precautions ( 5.2 )]. 1.5 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tigecycline for Injection and other antibacterial drugs, Tigecycline for Injection 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 or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to tigecycline. Tigecycline for Injection may be initiated as empiric monotherapy before results of these tests are known.

2 DOSAGE AND ADMINISTRATION Initial dose of 100 mg, followed by 50 mg every 12 hours administered by intravenous infusion over approximately 30 minutes to 60 minutes. (2.1) Severe hepatic impairment (Child Pugh C): Initial dose of 100 mg followed by 25 mg every 12 hours. (2.2) Obtain baseline blood coagulation parameters, including fibrinogen, and continue to monitor regularly during treatment with tigecycline for injection. (2.4 , 5.6) See Full Prescribing Information for instructions on reconstitution of the lyophilized powder, and preparation and administration of the intravenous infusion. (2.4) 2.1 Recommended Adult Dosage The recommended dosage regimen for tigecycline for injection is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous infusions of tigecycline for injection should be administered over approximately 30 minutes to 60 minutes every 12 hours. The recommended duration of treatment with tigecycline for injection for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 days to 14 days. The recommended duration of treatment with tigecycline for injection for community-acquired bacterial pneumonia is 7 days to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient’s clinical and bacteriological progress. 2.2 Dosage in Patients With Hepatic Impairment No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline for injection should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6) ] . 2.3 Dosage in Pediatric Patients The safety and efficacy of the proposed pediatric dosing regimens have not been evaluated due to the observed increase in mortality associated with tigecycline for injection in adult patients. Avoid use of tigecycline for injection in pediatric patients unless no alternative antibacterial drugs are available. Under these circumstances, the following doses are suggested: Pediatric patients aged 8 years to 11 years should receive 1.2 mg/kg of tigecycline for injection every 12 hours by intravenous infusion over approximately 30 minutes to 60 minutes to a maximum dose of 50 mg of tigecycline for injection every 12 hours. Pediatric patients aged 12 years to 17 years should receive 50 mg of tigecycline for injection every 12 hours by intravenous infusion over approximately 30 minutes to 60 minutes. The proposed pediatric doses of tigecycline for injection were chosen based on exposures observed in pharmacokinetic trials, which included small numbers of pediatric patients [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3) ] . There are no data to provide dosing recommendations in pediatric patients with hepatic impairment. 2.4 Monitoring of Blood Coagulation Parameters Obtain baseline blood coagulation parameters, including fibrinogen, and continue to monitor regularly during treatment with tigecycline [see Warnings and Precautions (5.6) ] . 2.5 Preparation and Administration Reconstitution and Dilution: Each vial of tigecycline for injection should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringer’s Injection, USP to achieve a concentration of 10 mg/mL of tigecycline. (Note: Each vial contains a 6% overage. Thus, 5 mL of reconstituted solution is equivalent to 50 mg of the drug.) The vial should be gently swirled until the drug dissolves. Reconstituted solution must be transferred and further diluted for intravenous infusion. Withdraw 5 mL of the reconstituted solution from the vial and add to a 100 mL intravenous bag for infusion (for a 100 m …

3 DOSAGE FORMS AND STRENGTHS For Injection: Each single-dose 5 mL glass vial and 10 mL glass vial contain 50 mg of tigecycline as an orange lyophilized powder for reconstitution. For Injection: 50 mg, lyophilized powder for reconstitution in a single-dose 5 mL vial or 10 mL vial. ( 3 )

4 CONTRAINDICATIONS Tigecycline for injection is contraindicated for use in patients who have known hypersensitivity to tigecycline or to any of the excipients. Reactions have included anaphylactic reactions [ see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.2 ) ] . Known hypersensitivity to tigecycline. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: All-Cause Mortality [see Boxed Warning and Warnings and Precautions (5.1) ] Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia [see Warnings and Precautions (5.2) ] Anaphylaxis [see Warning and Precautions (5.3) ] Hepatic Adverse Effects [see Warnings and Precautions (5.4) ] Pancreatitis [see Warnings and Precautions (5.5) ] The most common adverse reactions (incidence >5%) are nausea, vomiting, diarrhea, abdominal pain, headache, and increased serum glutamic pyruvic transaminase (SGPT). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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. In clinical trials, 2,514 patients were treated with tigecycline for injection. Tigecycline for injection was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of adverse reactions through test of cure reported in ≥2% of patients in these trials. Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of Patients Treated in Clinical Studies Body System Adverse Reactions Tigecycline for Injection (N=2514) Comparators a (N=2307) Body as a Whole Abdominal pain 6 4 Abscess 2 2 Asthenia 3 2 Headache 6 7 Infection 7 5 Cardiovascular System Phlebitis 3 4 Digestive System Diarrhea 12 11 Dyspepsia 2 2 Nausea 26 13 Vomiting 18 9 Hemic and Lymphatic System Anemia 5 6 Metabolic and Nutritional Alkaline Phosphatase Increased 3 3 Amylase Increased 3 2 Bilirubinemia 2 1 BUN Increased 3 1 Healing Abnormal 3 2 Hyponatremia 2 1 Hypoproteinemia 5 3 SGOT Increased b 4 5 SGPT Increased b 5 5 Respiratory System Pneumonia 2 2 Nervous System Dizziness 3 3 Skin and Appendages Rash 3 4 a Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid. b LFT abnormalities in tigecycline-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy. In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving tigecycline for injection and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between tigecycline for injection and comparator-treated patients (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. Table 2. Patients with Outcome of Death by Infection Type Tigecycline for Injection Comparator Risk Difference * Infection Type n/N % n/N % % (95% CI) cSSSI 12/834 1.4 6/813 0.7 0.7 (-0.3, 1.7) cIAI 42/1382 3.0 31/1393 2.2 0.8 (-0.4, 2.0) CAP 12/424 2.8 11/422 2.6 0.2 (-2.0, 2.4) HAP 66/467 14.1 57/467 12.2 1.9 (-2.4, 6.3) Non-VAP a 41/336 12.2 42/345 12.2 0.0 (-4.9, 4.9) VAP a 25/131 19.1 15/122 12.3 6.8 (-2.1, 15.7) RP 11/128 8.6 2/43 4.7 3.9 (-4.0, 11.9) DFI 7/553 1.3 3/508 0.6 0.7 (-0.5, 1.8) Overall Adjusted 150/3788 4.0 110/3646 3.0 0.6 (0.1, 1.2) ** CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; RP = Resistant pathogens; DFI = Diabetic foot infections. * The difference between the percentage of patients who died in tigecycline and comparator treatment groups. The 95% CI for each infection type was calculated using t …

7 DRUG INTERACTIONS Warfarin : Suitable anticoagulation test should be monitored if tigecycline for injection is administered to patients receiving warfarin. (7.1) Calcineurin Inhibitors : Serum concentrations of calcineurin inhibitors (e.g., tacrolimus, cyclosporine) should be monitored during treatment with tigecycline for injection due to risk of toxicity. (7.2) 7.1 Warfarin Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline for injection is administered with warfarin [see Clinical Pharmacology (12.3) ] . 7.2 Calcineurin Inhibitors Concomitant use of tigecycline for injection and calcineurin inhibitors such as tacrolimus or cyclosporine may lead to an increase in serum trough concentrations of the calcineurin inhibitors. Therefore, serum concentrations of the calcineurin inhibitor should be monitored during treatment with tigecycline for injection to avoid drug toxicity. 7.3 Oral Contraceptives Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.

8 USE IN SPECIFIC POPULATIONS Lactation: Avoid breastfeeding for longer than 3 weeks while taking tigecycline for injection. A lactating woman may also pump and discard breast milk during treatment and for 9 days after the last dose of tigecycline for injection ( 8.2 ) Pediatrics: Use in patients under 18 years of age is not recommended. Pediatric trials were not conducted because of the higher risk of mortality seen in adult trials ( 8.4 ) 8.1 Pregnancy Risk Summary Tigecycline for injection, like other tetracycline class antibacterial drugs, may cause permanent discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy [see Warnings and Precautions ( 5.7 , 5.8), Data, and Use in Specific Populations ( 8.4 )] . There are no available data on the risk of major birth defects or miscarriage following the use of tigecycline for injection during pregnancy. Administration of intravenous tigecycline in pregnant rats and rabbits during the period of organogenesis was associated with reduction in fetal weights and an increased incidence of skeletal anomalies (delays in bone ossification) at exposures of 5 and 1 times the human exposure at the recommended clinical dose in rats and rabbits, respectively. Advise the patient of the potential risk to the fetus if tigecycline for injection is used during the second or third trimester. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U. S. general population, the estimated background risk in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data The use of tetracycline-class antibacterial drugs, that includes tigecycline for injection, during tooth development (second and third trimester of pregnancy) may cause permanent discoloration of deciduous teeth. This adverse reaction is more common during long-term use of tetracyclines but has been observed following repeated short-term courses. Tigecycline for injection may cause reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. Animal Data In embryo-fetal development studies, tigecycline was administered during the period of organogenesis at doses up to 12 mg/kg/day in rats and 4 mg/kg in rabbits or 5 and 1 times the systemic exposure at the recommended clinical dose, respectively. In the rat study, decreased fetal weight and fetal skeletal variations (reduced ossification of the pubic, ischial, and supraoccipital bones and increased incidences of rudimentary 14 th rib) were observed in the presence of maternal toxicity at 12 mg/kg/day (5 times the recommended clinical dose based on systemic exposure). In rabbits, decreased fetal weights were observed in the presence of maternal toxicity at 4 mg/kg (equivalent to the human exposure at the recommended clinical dose). In preclinical safety studies, 14 C-labeled tigecycline crossed the placenta and was found in fetal tissues. 8.2 Lactation Risk Summary There are no data on the presence of tigecycline in human milk; however, tetracycline-class antibacterial drugs are present in breast milk. It is not known whether tigecycline has an effect on the breastfed infant or on milk production. Tigecycline has low oral bioavailability; therefore, infant exposure is expected to be low. Tigecycline is present in rat milk with little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tigecycline fo …

12.1 Mechanism of Action Tigecycline is a tetracycline class antibacterial drug [see Microbiology (12.4) ].

11 DESCRIPTION Tigecycline for injection, USP is a tetracycline class antibacterial for intravenous infusion. The chemical name of tigecycline is (4 S ,4a S ,5a R ,12a S )-9-[2-( tert -butylamino)acetamido]-4,7­-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide. The molecular formula is C 29 H 39 N 5 O 8 and the molecular weight is 585.65. Tigecycline USP is an orange powder. The following represents the chemical structure of tigecycline: Figure 1: Structure of Tigecycline Tigecycline for injection, USP is an orange colored lyophilized cake or powder. Each single-dose 10 mL vial contains 50 mg tigecycline lyophilized powder for reconstitution for intravenous infusion and 100 mg of lactose monohydrate. The pH is adjusted with hydrochloric acid, and if necessary sodium hydroxide. The product does not contain preservatives. FDA approved acceptance criteria for assay differs from USP test. Tigecycline Chemical Structure

10 OVERDOSAGE No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of tigecycline for injection at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. Tigecycline is not removed in significant quantities by hemodialysis.

16 HOW SUPPLIED/STORAGE AND HANDLING Tigecycline for Injection, USP is an orange lyophilized cake or powder, and is supplied as follows: NDC Tigecycline for Injection, USP Package Factor 71288- 019 -92 50 mg tigecycline lyophilized powder for reconstitution in a 10 mL glass Single-Dose Vial 10 vials per carton Prior to reconstitution, Tigecycline for Injection, USP should be stored at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] The reconstituted solution of Tigecycline for Injection, USP may be stored at room temperature (not to exceed 25°C/77°F) for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag) [see Dosage and Administration ( 2.5 )] . The container closure is not made with natural rubber latex.