tigecycline 50 MG Injection [Tygacil]

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.

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 mg dose, reconstitute two vials; for a 50 mg dose, reconstitute one vial). The maximum concentration in the intravenous bag should be 1 mg/mL. The reconstituted solution should be yellow to orange in color; if not, the solution should be discarded . Parenteral drug products should be inspected visually for particulate matter and discoloration (e.g., green or black) prior to administration. Storage of Reconstituted Solution Once reconstituted, tigecycline for injection 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). If the storage conditions exceed 25°C (77°F) after reconstitution, tigecycline should be used immediately. Alternatively, tigecycline for injection mixed with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into the intravenous bag. Administration of the Diluted Solution Tigecycline for injection may be administered by intravenous infusion through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of tigecycline for injection with 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP or Lactated Ringer’s Injection, USP. Injection should be made with an infusion solution compatible with tigecycline and with any other drug(s) administered via this common line. 2.6 Drug Compatibilities Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer’s Injection, USP. When administered through a Y-site, tigecycline for injection is compatible with the following drugs or diluents when used with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP: amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol, Lactated Ringer’s, lidocaine HCl, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HCl, theophylline, and tobramycin. 2.7 Drug Incompatibilities The following drugs should not be administered simultaneously through the same Y-site as tigecycline for injection: amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole and omeprazole.

WARNINGS AND PRECAUTIONS All-Cause Mortality: A meta-analysis of Phase 3 and 4 clinical trials demonstrated an increase in all-cause mortality in tigecycline-treated patients compared to controls with a risk difference of 0.6% (95% CI 0.1, 1.2). The cause of this increase has not been established. An increase was also seen in a meta-analysis limited to the approved indications [0.6% (95% CI 0, 1.2)]. The greatest difference in mortality was seen in tigecycline-treated patients with ventilator-associated pneumonia. ( 5.1 , 5.2 ) Anaphylactic Reactions: have been reported with tigecycline for injection, and may be life-threatening. Avoid use in patients with known hypersensitivity to tetracyclines. ( 5.3 ) Hepatic Adverse Effects: have been reported with tigecycline for injection. Patients who develop abnormal liver function tests during tigecycline for injection therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. ( 5.4 ) Pancreatitis: including fatalities, has been reported with tigecycline for injection. If pancreatitis is suspected, then consider stopping tigecycline for injection. ( 5.5 ) Monitoring Blood Coagulation Parameters: Hypofibrinogenemia has been reported with tigecycline for injection. Monitor blood coagulation parameters, including fibrinogen, at baseline and regularly during treatment with tigecycline for injection. ( 5.6 ) Tooth Discoloration and Enamel Hypoplasia: The use of tigecycline for injection during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown) and enamel hypoplasia. ( 5.7 ) Inhibition of Bone Growth: The use of tigecycline for injection during the second and third trimester of pregnancy, infancy, and childhood up to the age of 8 years may cause reversible inhibition of bone growth. ( 5.8 ) Clostridioides difficile associated Diarrhea (CDAD): evaluate if diarrhea occurs. (5.9 ) 5.1 All-Cause Mortality An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4 clinical trials in tigecycline-treated patients versus comparator-treated patients. In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4% (150/3,788) of patients receiving tigecycline for injection and 3% (110/3,646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, the adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between tigecycline for injection and comparator-treated patients. An analysis of mortality in all trials conducted for approved indications (cSSSI, cIAI, and CABP), including post-market trials showed an adjusted mortality rate of 2.5% (66/2,640) for tigecycline and 1.8% (48/2,628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0, 1.2). The cause of this mortality difference has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. Tigecycline for injection should be reserved for use in situations when alternative treatments are not suitable [see Boxed Warning, Indications and Usage ( 1.4 ), Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] . 5.2 Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia A trial of patients with hospital acquired, including ventilator-associated, pneumonia failed to demonstrate the efficacy of tigecycline for injection. In this trial, patients were randomized to receive tigecycline for injection (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received tigecycline for injection had lower cure rates (47.9% versus 70.1% for the clinically evaluable population). In this trial, greater mortality was seen in patients with ventilator-associated pneumonia who received tigecycline for injection (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients) [see Adverse Reactions ( 6.1 )] . Particularly high mortality was seen among tigecycline-treated patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 [50%] versus 1/13 [7.7%] in comparator-treated patients). 5.3 Anaphylactic Reactions Anaphylactic reactions have been reported with nearly all antibacterial agents, including tigecycline for injection, and may be life-threatening. Tigecycline for injection is structurally similar to tetracycline-class antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline-class antibacterial drugs. 5.4 Hepatic Adverse Effects Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Hepatic dysfunction may occur after the drug has been discontinued. 5.5 Pancreatitis Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment. The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis [see Adverse Reactions ( 6.2 )] . 5.6 Monitoring of Blood Coagulation Parameters Hypofibrinogenemia has been reported in patients treated with tigecycline for injection [see Adverse Reactions ( 6.2 )] . Obtain baseline blood coagulation parameters, including fibrinogen, and continue to monitor regularly during treatment with tigecycline for injection. 5.7 Tooth Discoloration and Enamel Hypoplasia The use of tigecycline for injection during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of tetracyclines, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Advise the patient of the potential risk to the fetus if tigecycline for injection is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4 )]. 5.8 Inhibition of Bone Growth The use of tigecycline for injection during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the tetracycline was discontinued. Advise the patient of the potential risk to the fetus if tigecycline for injection is used during the second or third trimester of pregnancy [see Use in Specific Populations ( 8.1 , 8.4)]. 5.9 Clostridioides difficile Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including tigecycline for injection, and may range in severity from mild diarrhea to fatal colitis. Treatmen

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 )

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