tygacil

Important safety information

All-Cause Mortality : A meta-analysis of Phase 3 and 4 clinical trials demonstrated an increase in all-cause mortality in TYGACIL-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 0.0, 1.2)]. The greatest difference in mortality was seen in TYGACIL-treated patients with ventilator-associated pneumonia. ( 5.1 , 5.2 ) • Anaphylactic Reactions : have been reported with TYGACIL, and may be life-threatening. Avoid use in patients with known hypersensitivity to tetracyclines. ( 5.3 ) • Hepatic Adverse Effects : have been reported with TYGACIL. Patients who develop abnormal liver function tests during TYGACIL 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 TYGACIL. If pancreatitis is suspected, then consider stopping TYGACIL. ( 5.5 ) • Monitoring Blood Coagulation Parameters: Hypofibrinogenemia has been reported with TYGACIL. Monitor blood coagulation parameters, including fibrinogen, at baseline and regularly during treatment with TYGACIL. ( 5.6 ) • Tooth Discoloration and Enamel Hypoplasia : The use of TYGACIL 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 TYGACIL 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 TYGACIL-treated patients versus comparator-treated patients. In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving TYGACIL 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, the adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between TYGACIL 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% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 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. TYGACIL 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 TYGACIL. In this trial, patients were randomized to receive TYGACIL (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 TYGACIL 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 TYGACIL (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients) [see Adverse Reactions (6.1) ] . Particularly high mortality was seen among TYGACIL-treated patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 [50.0%] versus 1/13 [7.7%] in comparator-treated patients). 5.3 Anaphylactic Reactions Anaphylactic reactions have been reported with nearly all antibacterial agents, including TYGACIL, and may be life-threatening. TYGACIL 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 TYGACIL [see Adverse Reactions (6.2) ] . Obtain baseline blood coagulation parameters, including fibrinogen, and continue to monitor regularly during treatment with TYGACIL. 5.7 Tooth Discoloration and Enamel Hypoplasia The use of TYGACIL 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 TYGACIL 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 TYGACIL 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 TYGACIL 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 TYGACIL, 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 strains 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.…