Tygacil Drug Information

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 TYGACIL 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.

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 TYGACIL in adult patients. Avoid use of TYGACIL in pediatric patients unless no alternative antibacterial drugs are available. The proposed pediatric doses of TYGACIL were chosen based on exposures observed in pharmacokinetic trials, which included small numbers of pediatric patients.

There are no data to provide dosing recommendations in pediatric patients with hepatic impairment.

Monitoring of Blood Coagulation Parameters

Obtain baseline blood coagulation parameters, including fibrinogen, and continue to monitor regularly during treatment with TYGACIL.

Preparation and Administration

Each vial of TYGACIL 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. Once reconstituted, TYGACIL 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.

TYGACIL may be administered intravenously 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 TYGACIL 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.

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, TYGACIL 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.

Drug Incompatibilities

The following drugs should not be administered simultaneously through the same Y-site as TYGACIL: amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole, and omeprazole.

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, 2514 patients were treated with TYGACIL. TYGACIL 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. 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 between TYGACIL 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 = 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. An analysis of mortality in all trials conducted for approved indications - cSSSI, cIAI, and CABP, including post-market trials (one in cSSSI and two in cIAI) - showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was In comparative clinical studies, infection-related serious adverse reactions were more frequently reported for subjects treated with TYGACIL (7%) versus comparators (6%).

Serious adverse reactions of sepsis/septic shock were more frequently reported for subjects treated with TYGACIL (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established. The most common adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy.

The majority of cases of nausea and vomiting associated with TYGACIL and comparators were either mild or moderate in severity. Discontinuation from TYGACIL was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%).

The following adverse reactions were reported (<2%) in patients receiving TYGACIL in clinical studies: Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis Cardiovascular System: thrombophlebitis Digestive System: anorexia, jaundice, abnormal stools Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia Special Senses: taste perversion Hemic and Lymphatic System: prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia Skin and Appendages: pruritus Urogenital System: vaginal moniliasis, vaginitis, leukorrhea

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of TYGACIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. • anaphylactic reactions • acute pancreatitis • hepatic cholestasis, and jaundice • severe skin reactions, including Stevens-Johnson Syndrome • symptomatic hypoglycemia in patients with and without diabetes mellitus • hypofibrinogenemia

Warfarin

Prothrombin time or other suitable anticoagulation test should be monitored if TYGACIL is administered with warfarin.

Calcineurin Inhibitors

Concomitant use of TYGACIL 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 TYGACIL to avoid drug toxicity.

Oral Contraceptives

Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.

Pregnancy Risk Summary TYGACIL, 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. There are no available data on the risk of major birth defects or miscarriage following the use of TYGACIL 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 TYGACIL 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 respectively. Data Human Data The use of tetracycline-class antibacterial drugs, that includes TYGACIL, 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. 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.

Pediatric Use Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of the increased mortality observed in TYGACIL-treated adult patients in clinical trials, pediatric trials of TYGACIL to evaluate the safety and efficacy of TYGACIL were not conducted.

In situations where there are no other alternative antibacterial drugs, dosing has been proposed for pediatric patients 8 to 17 years of age based on data from pediatric pharmacokinetic studies. Because of effects on tooth development, use in patients under 8 years of age is not recommended.

• TYGACIL is contraindicated for use in patients who have known hypersensitivity to tigecycline or to any of the excipients. Reactions have included anaphylactic reactions.
• Known hypersensitivity to tigecycline.

No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of TYGACIL 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.