"According to the World Health Organization, in 2010, malaria caused an estimated 219 million illnesses and 660,000 deaths, mostly children under 5 years old in Africa. These numbers represent a 25% decrease in malaria deaths globally and a 33% re"...
An increase in all-cause mortality has been observed across Phase 3 and 4 clinical trials in TYGACIL (tigecycline) -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 (tigecycline) 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 TYGACIL (tigecycline) and comparator-treated patients. The cause of this increase has not been established. This increase in all-cause mortality should be considered when selecting among treatment options [see ADVERSE REACTIONS].
Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including TYGACIL (tigecycline) , and may be life-threatening. TYGACIL (tigecycline) is structurally similar to tetracycline-class antibiotics and should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics.
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. Adverse events may occur after the drug has been discontinued.
Mortality Imbalance and Lower Cure Rates in Ventilator-Associated Pneumonia
A trial of patients with hospital acquired pneumonia failed to demonstrate the efficacy of TYGACIL (tigecycline) . In this trial, patients were randomized to receive TYGACIL (tigecycline) (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 (tigecycline) 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 (tigecycline) (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients) [see ADVERSE REACTIONS]. Particularly high mortality was seen among TYGACIL (tigecycline) -treated patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 [50.0%] versus 1/13 [7.7%] in comparator-treated patients).
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].
Use During Pregnancy
TYGACIL (tigecycline) may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline [see Use in Specific Populations].
The use of TYGACIL (tigecycline) 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). Results of studies in rats with TYGACIL (tigecycline) have shown bone discoloration. TYGACIL (tigecycline) should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.
Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL (tigecycline) , 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 CD AD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CD AD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CD AD has been reported to occur over two months after the administration of antibacterial agents.
If CD AD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Patients With Intestinal Perforation
Caution should be exercised when considering TYGACIL (tigecycline) monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with TYGACIL (tigecycline) and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with TYGACIL (tigecycline) had higher APACHE II scores (median =13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.
TYGACIL (tigecycline) is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACIL (tigecycline) .
As with other antibacterial drugs, use of TYGACIL (tigecycline) may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.
Development of Drug-Resistant Bacteria
Prescribing TYGACIL (tigecycline) in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline. No mutagenic or clastogenic potential was found in a battery of tests, including in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, in vitro forward mutation assay in CHO cells (HGRPT locus), in vitro forward mutation assays in mouse lymphoma cells, and in vivo mouse micronucleus assay. Tigecycline did not affect mating or fertility in rats at exposures up to 5 times the human daily dose based on AUC (28 mcg·hr/mL at 12 mg/kg/day). In female rats, there were no compound-related effects on ovaries or estrous cycles at exposures up to 5 times the human daily dose based on AUC.
Use In Specific Populations
Teratogenic Effects - Pregnancy Category D.
Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with slight reductions in fetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively (28 mcg-hr/mL and 6 mcg-hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose.
There are no adequate and well-controlled studies of tigecycline in pregnant women. TYGACIL (tigecycline) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TYGACIL (tigecycline) is administered to a nursing woman.
Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of effects on tooth development, use in patients under 8 years of age is not recommended.
Of the total number of subjects who received TYGACIL (tigecycline) in Phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over. No unexpected overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out.
No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg dose of tigecycline [see CLINICAL PHARMACOLOGY].
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 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 and DOSAGE AND ADMINISTRATION].
Last reviewed on RxList: 8/5/2010
This monograph has been modified to include the generic and brand name in many instances.
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