Tigecycline (Tygacil)
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Tigecycline (Tygacil)

TYGACIL®
(tigecycline) for Injection for Intravenous Use

DRUG DESCRIPTION

TYGACIL (tigecycline) is a tetracycline derivative (a glycylcycline) for intravenous infusion. The chemical name of tigecycline is (4S,4aS,5aR,12aS)-9-[2-(tert-butylamino)acetamido]-4,7-bis(dimethylamino)-l,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-l,ll-dioxo-2-naphthacenecarboxamide. The empirical formula is C29H39N5O8 and the molecular weight is 585.65.

The following represents the chemical structure of tigecycline:

TYGACIL (tigecycline)  Structural Formula Illustration"

TYGACIL (tigecycline) is an orange lyophilized powder or cake. Each TYGACIL 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.

What are the possible side effects of tigecycline (Tygacil)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using tigecycline and call your doctor at once if you have a serious side effect such as:

  • diarrhea that is watery or bloody;
  • severe headache, ringing in your ears, dizziness, nausea, vision problems, pain behind your eyes;
  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or
  • severe pain in your upper...

Read All Potential Side Effects and See Pictures of Tygacil »

What are the precautions when taking tigecycline (Tygacil)?

Before using tigecycline, tell your doctor or pharmacist if you are allergic to it; or to tetracyclines (such as doxycycline, minocycline, tetracycline); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: severe liver disease.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths or sunlamps. Use a sunscreen and...

Read All Potential Precautions of Tygacil »

Last reviewed on RxList: 8/5/2010
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

TYGACIL (tigecycline) is a tetracycline-class antibacterial indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the conditions listed below for patients 18 years of age and older:

Complicated Skin and Skin Structure Infections

Complicated skin and skin structure infections caused by 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, Klebsiellapneumoniae, and Bacteroides fragilis.

Complicated Intra-abdominal Infections

Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiellapneumoniae, 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.

Community-Acquired Bacterial Pneumonia

Community-acquired bacterial pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of TYGACIL (tigecycline) and other antibacterial drugs, TYGACIL (tigecycline) should be used only to treat or prevent 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. TYGACIL (tigecycline) may be initiated as empiric monotherapy before results of these tests are known.

DOSAGE AND ADMINISTRATION

General Dosage and Administration

The recommended dosage regimen for TYGACIL (tigecycline) is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous infusions of TYGACIL (tigecycline) should be administered over approximately 30 to 60 minutes every 12 hours.

The recommended duration of treatment with TYGACIL (tigecycline) for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 to 14 days. The recommended duration of treatment with TYGACIL (tigecycline) for community-acquired bacterial pneumonia is 7 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.

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 (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 Use in Specific Populations].

Preparation and Handling

Each vial of TYGACIL (tigecycline) 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. 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 (tigecycline) may be stored at room temperature for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag). Alternatively, TYGACIL (tigecycline) mixed with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into the intravenous bag.

TYGACIL (tigecycline) 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 (tigecycline) 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.

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 (tigecycline) 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 HC1, gentamicin, haloperidol, Lactated Ringer's, lidocaine HC1, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HC1, theophylline, and tobramycin.

Incompatibilities

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

HOW SUPPLIED

Dosage Forms And Strengths

Each single-dose 5 mL glass vial and 10 mL glass vial contain 50 mg of tigecycline as an orange lyophilized powder for reconstitution.

TYGACIL (tigecycline) for injection is supplied in a single-dose 5 mL glass vial or 10 mL glass vial, each containing 50 mg tigecycline lyophilized powder for reconstitution.

Supplied:

5 mL - 10 vials/box. NDC 0008-4990-02
10 mL - 10 vials/box. NDC 0008-4990-20

Prior to reconstitution, TYGACIL (tigecycline) should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Once reconstituted, TYGACIL (tigecycline) may be stored at room temperature for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag). Alternatively, TYGACIL (tigecycline) mixed with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into the intravenous bag. Reconstituted solution must be transferred and further diluted for intravenous infusion.

Manufactured for: Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101. Manufactured By: Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101 Or Patheon Italia S.p.A. 20052 Monza, Italy. Revised: 07/2010

Last reviewed on RxList: 8/5/2010
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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 (tigecycline) . TYGACIL (tigecycline) was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of treatment-emergent 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
TYGACIL
(N=2514)
Comparatorsa
(N=2307)
Body as a Whole
  Abdominal pain 6 4
  Abscess 3 3
  Asthenia 3 2
  Headache 6 7
  Infection 8 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 4 5
Metabolic and Nutritional
  Alkaline Phosphatase 4 3
Increased
  Amylase Increased 3 2
  Bilirubinemia 2 1
  BUN Increased 3 1
  Healing Abnormal 4 3
  Hypoproteinemia 5 3
  SCOT Increasedb 4 5
  SGPT Increasedb 5 5
Nervous System
  Dizziness 3 3
Skin and Appendages
  Rash 3 4
a Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid.
b LFT abnormalities in TYGACIL (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 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 (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 bv Infection Tvne

Infection Type TYGACIL
n/N
% Comparator
n/N
% Risk Difference*
% (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-VAPa 41/336 12.2 42/345 12.2 0.0 (-4.9, 4.9)
  VAPa 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)
DPI 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; DPI = Diabetic foot infections.
* The difference between the percentage of patients who died in TYGACIL (tigecycline) and comparator treatment groups. The 95% CI for each infection type was calculated using the normal approximation method without continuity correction.
** Overall adjusted (random effects model by trial weight) risk difference estimate and 95% CI. a These are subgroups of the HAP population. Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRS A or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DPI with and without osteomyelitis).

In comparative clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with TYGACIL (tigecycline) (7%) versus comparators (6%). Serious adverse events of sepsis/septic shock were more frequently reported for subjects treated with TYGACIL (tigecycline) (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 [see WARNINGS AND PRECAUTIONS].

The most common treatment-emergent 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 (tigecycline) and comparators were either mild or moderate in severity. In patients treated with TYGACIL (tigecycline) , nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).

In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for TYGACIL (tigecycline) and 9% for vancomycin/aztreonam; vomiting incidence was 20% for TYGACIL (tigecycline) and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for TYGACIL (tigecycline) and 21% for imipenem/cilastatin; vomiting incidence was 20% for TYGACIL (tigecycline) and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for TYGACIL (tigecycline) and 8% for levofloxacin; vomiting incidence was 16% for TYGACIL (tigecycline) and 6% for levofloxacin.

Discontinuation from tigecycline 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 infrequently ( < 2%) in patients receiving TYGACIL (tigecycline) 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, hyponatremia

Special Senses: taste perversion

Hemic and Lymphatic System: 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

Post-Marketing Experience

The following adverse reactions have been identified during postapproval use of TYGACIL (tigecycline) . 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.

  • anaphylaxis/anaphylactoid reactions
  • acute pancreatitis
  • hepatic cholestasis, and jaundice

Read the Tygacil (tigecycline) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Warfarin

Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin [see CLINICAL PHARMACOLOGY].

Oral Contraceptives

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

Last reviewed on RxList: 8/5/2010
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

All-Cause Mortality

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

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.

Hepatic 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. 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).

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].

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].

Tooth Development

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.

Tetracycline-Class Effects

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) .

Superinfection

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.

Nonclinical Toxicology

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

Pregnancy

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.

Nursing Mothers

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.

Pediatric Use

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.

Geriatric Use

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].

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 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.

OVERDOSE

No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of TYGACIL (tigecycline) at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. In single-dose intravenous toxicity studies conducted with tigecycline in mice, the estimated median lethal dose (LD50) was 124 mg/kg in males and 98 mg/kg in females. In rats, the estimated LD50 was 106 mg/kg for both sexes. Tigecycline is not removed in significant quantities by hemodialysis.

CONTRAINDICATIONS

TYGACIL (tigecycline) is contraindicated for use in patients who have known hypersensitivity to tigecycline.

Last reviewed on RxList: 8/5/2010
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

Tigecycline is an antibacterial drug.

Pharmacokinetics

The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses based on pooled data from clinical pharmacology studies are summarized in Table 3. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes.

Table 3. Mean (CV%) Pharmacokinetic Parameters of Tieecvcline

  Single Dose
100 mg
(N=224)
Multiple Dosea
50 mg every 12h
(N=103)
Cmax (mcg/mL)b 1.45 (22%) 0.87 (27%)
Cmax (mcg/mL)c 0.90 (30%) 0.63 (15%)
AUC (mcg-h/mL) 5.19 (36%) --
AUC0-24h (mcg-h/mL) -- 4.70 (36%)
Cmin (mcg/mL) -- 0.13 (59%)
t½ (h) 27.1 (53%) 42.4 (83%)
CL (L/h) 21.8 (40%) 23.8 (33%)
CLr (mL/min) 38.0 (82%) 51.0(58%)
Vss (L) 568 (43%) 639 (48%)
a 100 mg initially, followed by 50 mg every 12 hours
b 30-minute infusion
c 60-minute infusion

Distribution

The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mcg/mL). The steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues.

Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to 33 healthy volunteers, the tigecycline AUC0-12h (134 mcg-h/mL) in alveolar cells was approximately 78-fold higher than the AUC0-12h in the serum, and the AUC0-12h (2.28 mcg-h/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12h in serum. The AUC0-12h (L61 mcg-h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12h in the serum of 10 healthy subjects.

In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at 4 hours after tigecycline administration were higher in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6), and lower in synovial fluid (0.58-fold, n=5), and bone (0.35-fold, n=6) relative to serum. The concentration of tigecycline in these tissues after multiple doses has not been studied.

Metabolism

Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers receiving 14C-tigecycline, tigecycline was the primary 14C-labeled material recovered in urine and feces, but a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.

Elimination

The recovery of total radioactivity in feces and urine following administration of 14C-tigecycline indicates that 59% of the dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Approximately 22% of the total dose is excreted as unchanged tigecycline in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline and its metabolites. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.

Specific Populations

Patients with Hepatic Impairment

In a study comparing 10 patients with mild hepatic impairment (Child Pugh A), 10 patients with moderate hepatic impairment (Child Pugh B), and 5 patients with severe hepatic impairment (Child Pugh C) to 23 age and weight matched healthy control subjects, the single-dose pharmacokinetic disposition of tigecycline was not altered in patients with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25% and the half-life of tigecycline was prolonged by 23% in patients with moderate hepatic impairment (Child Pugh B). Systemic clearance of tigecycline was reduced by 55%, and the half-life of tigecycline was prolonged by 43% in patients with severe hepatic impairment (Child Pugh C). Dosage adjustment is necessary in patients with severe hepatic impairment (Child Pugh C) [see Use in Specific Populations and DOSAGE AND ADMINISTRATION].

Patients with Renal Impairment

A single dose study compared 6 subjects with severe renal impairment (creatinine clearance < 30 mL/min), 4 end stage renal disease (ESRD) patients receiving tigecycline 2 hours before hemodialysis, 4 ESRD patients receiving tigecycline 1 hour after hemodialysis, and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not significantly altered in any of the renally impaired patient groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of TYGACIL (tigecycline) is necessary in patients with renal impairment or in patients undergoing hemodialysis.

Geriatric Patients

No significant differences in pharmacokinetics were observed between healthy elderly subjects (n=15, age 65-75; n=13, age > 75) and younger subjects (n=18) receiving a single 100-mg dose of TYGACIL (tigecycline) . Therefore, no dosage adjustment is necessary based on age [see Use In Specific Populations].

Gender

In a pooled analysis of 38 women and 298 men participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance between women (20.7+6.5 L/h) and men (22.8+8.7 L/h). Therefore, no dosage adjustment is necessary based on gender.

Race

In a pooled analysis of 73 Asian subjects, 53 Black subjects, 15 Hispanic subjects, 190 White subjects, and 3 subjects classified as "other" participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance among the Asian subjects (28.8+8.8 L/h), Black subjects (23.0+7.8 L/h), Hispanic subjects (24.3+6.5 L/h), White subjects (22.1+8.9 L/h), and "other" subjects (25.0+4.8 L/h). Therefore, no dosage adjustment is necessary based on race.

Drug Interactions

TYGACIL (tigecycline) (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg, orally, every 24 hours) were coadministered to healthy subjects in a drug interaction study. Tigecycline slightly decreased the Cmax of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in Cmax did not affect the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. In addition, digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment of either drug is necessary when TYGACIL (tigecycline) is administered with digoxin.

Concomitant administration of TYGACIL (tigecycline) (100 mg followed by 50 mg every 12 hours) and warfarin (25 mg single-dose) to healthy subjects resulted in a decrease in clearance of R-warfarin and S-warfarin by 40% and 23%, an increase in Cmax by 38% and 43% and an increase in AUC by 68% and 29%, respectively. Tigecycline did not significantly alter the effects of warfarin on INR. In addition, warfarin did not affect the pharmacokinetic profile of tigecycline. However, prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.

In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Therefore, TYGACIL (tigecycline) is not expected to alter the metabolism of drugs metabolized by these enzymes. In addition, because tigecycline is not extensively metabolized, clearance of tigecycline is not expected to be affected by drugs that inhibit or induce the activity of these CYP450 isoforms.

Microbiology

Mechanism of Action

Tigecycline, a glycylcycline, inhibits protein translation in bacteria by binding to the 308 ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. Tigecycline carries a glycylamido moiety attached to the 9-position of minocycline. The substitution pattern is not present in any naturally occurring or semisynthetic tetracycline and imparts certain microbiologic properties to tigecycline. In general, tigecycline is considered bacteriostatic; however, TYGACIL (tigecycline) has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.

Mechanism(s) of Resistance

To date there has been no cross-resistance observed between tigecycline and other antibacterials. Tigecycline is not affected by the two major tetracycline-resistance mechanisms, ribosomal protection and efflux. Additionally, tigecycline is not affected by resistance mechanisms such as beta-lactamases (including extended spectrum beta-lactamases), target-site modifications, macrolide efflux pumps or enzyme target changes (e.g. gyrase/topoisomerases). Tigecycline resistance in some bacteria (e.g. Acinetobacter calcoaceticus-Acinetobacter baumannii complex) is associated with multi-drug resistant (MDR) efflux pumps.

Interaction with Other Antimicrobials

In vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibacterials.

Tigecycline has been shown to be active against most of the following bacteria, both in vitro and in clinical infections [see INDICATIONS].

Facultative Gram-positive bacteria

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 pneumoniae
(penicillin-susceptible isolates)
Streptococcus pyogenes

Facultative Gram-negative bacteria

Citrobacter freundii
Enterobacter cloacae

Escherichia coli
Haemophilus influenzae
(beta-lactamase negative isolates)
Klebsiella oxytoca

Klebsiella pneumoniae

Legionella pneumophila

Anaerobic bacteria

Bacteroides fragilis

Bacteroides thetaiotaomicron

Bacteroides uniformis

Bacteroides vulgatus

Clostridium perfringens
Peptostreptococcus micros

At least 90% of the following bacteria exhibit in vitro minimum inhibitory concentrations (MICs) that are at concentrations that are achievable using the prescribed dosing regimens. However, the clinical significance of this is unknown because the safety and effectiveness of tigecycline in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Facultative Gram-positive bacteria

Enterococcus avium
Enterococcus casseliflavus

Enterococcus faecalis
(vancomycin-resistant isolates)
Enterococcus faecium
(vancomycin-susceptible and -resistant isolates)
Enterococcus gallinarum

Listeria monocytogenes

Staphylococcus epidermidis
(methicillin-susceptible and -resistant isolates)
Staphylococcus haemolyticus

Facultative Gram-negative bacteria

Acinetobacter baumannii*
Aeromonas hydrophila

Citrobacter koseri

Enterobacter aerogenes

Haemophilus influenzae
(ampicillin-resistant)
Haemophilus parainfluenzae

Pasteurella multocida

Serratia marcescens

Stenotrophomonas maltophilia

Anaerobic bacteria

Bacteroides distasonis

Bacteroides ovatus

Peptostreptococcus
spp.
Porphyromonas
spp.
Prevotella
spp.

Other bacteria

Mycobacterium abscessus
Mycobacterium fortuitum


*There have been reports of the development of tigecycline resistance in Acinetobacter infections seen during the course of standard treatment. Such resistance appears to be attributable to an MDR efflux pump mechanism. While monitoring for relapse of infection is important for all infected patients, more frequent monitoring in this case is suggested. If relapse is suspected, blood and other specimens should be obtained and cultured for the presence of bacteria. All bacterial isolates should be identified and tested for susceptibility to tigecycline and other appropriate antimicrobials.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure based on dilution methods (broth, agar, or microdilution)1,3,4 or equivalent using standardized inoculum and concentrations of tigecycline. For broth dilution tests for aerobic organisms, MICs must be determined in testing medium that is fresh ( < 12h old). The MIC values should be interpreted according to the criteria provided in Table 4.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standardized procedure2,4 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 meg tigecycline to test the susceptibility of bacteria to tigecycline. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for tigecycline. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 meg tigecycline disk should be interpreted according to the criteria in Table 4.

Anaerobic Techniques

Anaerobic susceptibility testing with tigecycline should be done by the agar dilution method3 since quality control parameters for broth-dilution are not established.

Table 4. Susceptibility Test Result Interpretive Criteria for Tigecycline

  Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm)
Pathogen S I R S I R
Staphylococcus aureus (including methicillin-resistant isolates) ≤ 0.5a - - ≥ 19 - -
Streptococcus spp. other than S. pneumoniae ≤ 0.25a - - ≥ 19 - -
Streptococcus pneumoniae ≤ 0.06a - - ≥ 19 - -
Enterococcus faecalis (vancomycin- susceptible isolates) ≤ 0.25a - - ≥ 19 - -
Enterobacteriaceaeb ≤ 2 4 ≥ 8 ≥ 19 15-18 ≤ 14
Haemophilus influenzae ≤ 0.25a - - ≥ 19 - -
Anaerobesc ≤ 4 8 ≥ 16 n/a n/a n/a
a The current absence of resistant isolates precludes defining any results other than "Susceptible." Isolates yielding MIC results suggestive of "Nonsusceptible" category should be submitted to reference laboratory for further testing.
b Tigecycline has decreased in vitro activity against Morganella spp., Proteus spp. and Providencia spp.
c Agar dilution

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; other therapy should be selected.

Quality Control

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures.1,2,3,4 Standard tigecycline powder should provide the MIC values provided in Table 5. For the diffusion technique using the 15 meg tigecycline disk the criteria provided in Table 5 should be achieved.

Table 5. Acceptable Quality Control Ranges for Susceptibility Testing

QC organism Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm)
Staphylococcus aureus ATCC 25923 Not Applicable 20-25
Staphylococcus aureus ATCC 29213 0.03-0.25 Not Applicable
Escherichia coli ATCC 25922 0.03-0.25 20-27
Enterococcus faecalis ATCC 29212 0.03-0.12 Not Applicable
Streptococcus pneumoniae ATCC 49619 0.016-0.12 23-29
Haemophilus influenzae ATCC 49247 0.06-0.5 23-31
Bacteroides fragilisa ATCC 25285 0.12-1 Not Applicable
Bacteroides thetaiotaomicrora ATCC 29741 0.5-2 Not Applicable
Eubacterium lentuma ATCC 43055 0.06-0.5 Not Applicable
Clostridium difficilea ATCC 70057 0.12-1 Not Applicable
ATCC = American Type Culture Collection
a Agar dilution

Animal Toxicology and/or Pharmacology

In two week studies, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8 times and 10 times the human daily dose based on AUC in rats and dogs, (AUC of approximately 50 and 60 mcg-hr/mL at doses of 30 and 12 mg/kg/day) respectively. These alterations were shown to be reversible after two weeks of dosing.

Clinical Studies

Complicated Skin and Skin Structure Infections

TYGACIL (tigecycline) was evaluated in adults for the treatment of complicated skin and skin structure infections (cSSSI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 300 and 305). These studies compared TYGACIL (tigecycline) (100 mg intravenous initial dose followed by 50 mg every 12 hours) with vancomycin (1 g intravenous every 12 hours)/aztreonam (2 g intravenous every 12 hours) for 5 to 14 days. Patients with complicated deep soft tissue infections including wound infections and cellulitis ( ≥ 10 cm, requiring surgery/drainage or with complicated underlying disease), major abscesses, infected ulcers, and burns were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See Table 6. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 7.

Table 6. Clinical Cure Rates from Two Studies in Complicated Skin and Skin Structure Infections after 5 to 14 Days of Therapy

  TYGACILa
n/N (%)
Vancomycin/Aztreonamb
n/N (%)
Study 300
  CE 165/199 (82.9) 163/198 (82.3)
  c-mITT 209/277 (75.5) 200/260 (76.9)
Study 305
  CE 200/223 (89.7) 201/213 (94.4)
  c-mITT 220/261 (84.3) 225/259 (86.9)
a 100 mg initially, followed by 50 mg every 12 hours
b Vancomycin (1 g every 12 hours)/Aztreonam (2 g every 12 hours)

Table 7. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Skin and Skin Structure Infectionsa

Pathogen TYGACIL
n/N (%)
Vancomycin/Aztreonam
n/N (%)
Escherichia coli 29/36 (80.6) 26/30 (86.7)
Enterobacter cloacae 10/12 (83.3) 15/15 (100)
Enterococcus faecalis (vancomycin- susceptible only) 15/21 (71.4) 19/24 (79.2)
Klebsiella pneumoniae 12/14 (85.7) 15/16 (93.8)
Methicillin-susceptible Staphylococcus aureus (MSSA) 124/137 (90.5) 113/120(94.2)
Methicillin-resistant Staphylococcus aureus (MRSA) 79/95 (83.2) 46/57 (80.7)
Streptococcus agalactiae 8/8 (100) 11/14(78.6)
Streptococcus anginosus grp.b 17/21 (81.0) 9/10 (90.0)
Streptococcus pyogenes 31/32 (96.9) 24/27 (88.9)
Bacteroides fragilis 7/9 (77.8) 4/5 (80.0)
a Two cSSSI pivotal studies and two Resistant Pathogen studies
b Includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus

Complicated Intra-abdominal Infections

TYGACIL (tigecycline) was evaluated in adults for the treatment of complicated intra-abdominal infections (cIAI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 301 and 306). These studies compared TYGACIL (tigecycline) (100 mg intravenous initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg intravenous every 6 hours) for 5 to 14 days. Patients with complicated diagnoses including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis were enrolled in the studies. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the microbiologically evaluable (ME) and the microbiologic modified intent-to-treat (m-mITT) patients. See Table 8. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 9.

Table 8. Clinical Cure Rates from Two Studies in Complicated Intra-abdominal Infections after 5 to 14 Days of Theranv

  TYGACILa
n/N (%)
Imipenem/Cilastatinb
n/N (%)
Study 301
  ME 199/247 (80.6) 210/255 (82.4)
  m-mITT 227/309 (73.5) 244/312 (78.2)
Study 306
  ME 242/265 (91.3) 232/258 (89.9)
  m-mITT 279/322 (86.6) 270/319 (84.6)
a 100 mg initially, followed by 50 mg every 12 hours
b Imipenem/Cilastatin (500 mg every 6 hours)

Table 9. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Intra-abdominal Infectionsa

Pathogen TYGACILn/N (%) Imipenem/Cilastatin n/N (%)
Citrobacter freundii 12/16 (75.0) 3/4 (75.0)
Enterobacter cloacae 15/17 (88.2) 16/17 (94.1)
Escherichia coli 284/336 (84.5) 297/342 (86.8)
Klebsiella oxytoca 19/20 (95.0) 17/19 (89.5)
Klebsiella pneumoniae 42/47 (89.4) 46/53 (86.8)
Enterococcus faecalis 29/38 (76.3) 35/47 (74.5)
Methicillin- susceptible Staphylococcus aureus (MSSA) 26/28 (92.9) 22/24 (91.7)
Methicillin-resistant Staphylococcus aureus (MRSA) 16/18 (88.9) 1/3 (33.3)
Streptococcus anginosus grp.b 101/119(84.9) 60/79 (75.9)
Bacteroides fragilis 68/88 (77.3) 59/73 (80.8)
Bacteroides thetaiotaomicron 36/41 (87.8) 31/36 (86.1)
Bacteroides uniformis 12/17 (70.6) 14/16 (87.5)
Bacteroides vulgatus 14/16 (87.5) 4/6 (66.7)
Clostridium perfringens 18/19 (94.7) 20/22 (90.9)
Peptostreptococcus micros 13/17 (76.5) 8/11 (72.7)
a Two cIAI pivotal studies and two Resistant Pathogen studies
b Includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus

Community-Acquired Bacterial Pneumonia

TYGACIL (tigecycline) was evaluated in adults for the treatment of community-acquired bacterial pneumonia (CABP) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 308 and 313). These studies compared TYGACIL (tigecycline) (100 mg intravenous initial dose followed by 50 mg every 12 hours) with levofloxacin (500 mg intravenous every 12 or 24 hours). In one study (Study 308), after at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms. Total therapy was 7 to 14 days. Patients with community-acquired bacterial pneumonia who required hospitalization and intravenous therapy were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See Table 10. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 11.

Table 10. Clinical Cure Rates from Two Studies in Community-Acquired Bacterial Pneumonia after 7 to 14 Days of Total Therapy

  TYGACILa
n/N (%)
Levofloxacinb
n/N (%)
95% CIc
Study 308d
  CE 125/138 (90.6) 136/156 (87.2) (-4.4, 11.2)
  c-mITT 149/191 (78) 158/203 (77.8) (-8.5, 8.9)
Study 313
  CE 128/144 (88.9) 116/136(85.3) (-5.0, 12.2)
  c-mITT 170/203 (83.7) 163/200 (81.5) (-5.6, 10.1)
a 100 mg initially, followed by 50 mg every 12 hours
b Levofloxacin (500 mg intravenous every 12 or 24 hours)
c 95% confidence interval for the treatment difference
d After at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 308.

Table 11. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Community-Acquired Bacterial Pneumoniaa

Pathogen TYGACIL
n/N (%)
Levofloxacin
n/N(%)
Haemophilus influenzae 14/17 (82.4) 13/16(81.3)
Legionella pneumophila 10/10 (100.0) 6/6 (100.0)
Streptococcus pneumoniae (penicillin-susceptible only)b 44/46 (95.7) 39/44 (88.6)
a Two CABP studies
b Includes cases of concurrent bacteremia [cure rates of 20/22 (90.9%) versus 13/18 (72.2%) for TYGACIL (tigecycline) and levofloxacin respectively]

To further evaluate the treatment effect of tigecycline, a post-hoc analysis was conducted in CABP patients with a higher risk of mortality, for whom the treatment effect of antibiotics is supported by historical evidence. The higher-risk group included CABP patients from the two studies with any of the following factors:

  • Age ≥ 50 years
  • PSI score ≥ 3
  • Streptococcus pneumoniae bacteremia

The results of this analysis are shown in Table 12. Age ≥ 50 was the most common risk factor in the higher-risk group.

Table 12. Post-hoc Analysis of Clinical Cure Rates in Patients with Community-Acquired Bacterial Pneumonia Based on Risk of Mortalitya

  TYGACIL
n/N (%)
Levofloxacin
n/N (%)
95% CIb
Study 308c
CE  
Higher risk  
  Yes 93/103 (90.3) 84/102 (82.4) (-2.3, 18.2)
  No 32/35 (91.4) 52/54 96.3) (-20.8, 7.1)
c-mITT  
Higher risk  
  Yes 111/142(78.2) 100/134 (74.6) (-6.9, 14)
  No 38/49 (77.6) 58/69 (84.1) (-22.8, 8.7)
Study 3 13
CE  
Higher risk  
  Yes 95/107 (88.8) 68/85 (80) (-2.2, 20.3)
  No 33/37 (89.2) 48/51 (94.1) (-21.1, 8.6)
c-mITT  
Higher risk  
  Yes 112/134(83.6) 93/120 (77.5) (-4.2, 16.4)
  No 58/69 (84.1) 70/80 (87.5) (-16.2, 8.8)
a Patients at higher risk of death include patients with any one of the following: ≥ 50 year of age; PSI score ≥ 3; or bacteremia due to Streptococcus pneumoniae
b 95% confidence interval for the treatment difference
c After at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 308.

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - 8th ed. Approved Standard, CLSI document M07-A8, CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898. January 2009.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests - 10th ed. Approved Standard, CLSI document M02-A10, CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898. January 2009.

3. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria - 7th ed. Approved Standard, CLSI document M11-A7, CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898. January 2007.

4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing - 19th Informational Supplement. Approved Standard, CLSI document M100-S19, CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898. January 2009.

Last reviewed on RxList: 8/5/2010
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

  • Patients should be counseled that antibacterial drugs including TYGACIL (tigecycline) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When TYGACIL (tigecycline) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by TYGACIL (tigecycline) or other antibacterial drugs in the future.
  • Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556.

Last reviewed on RxList: 8/5/2010
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

  • Patients should be counseled that antibacterial drugs including TYGACIL (tigecycline) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When TYGACIL (tigecycline) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by TYGACIL (tigecycline) or other antibacterial drugs in the future.
  • Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556.

Last reviewed on RxList: 8/5/2010
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Tygacil Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

TIGECYCLINE - INJECTION

(tye-geh-SYE-kleen)

COMMON BRAND NAME(S): Tygacil

USES: This medication is used to treat certain serious bacterial infections which may be resistant to other antibiotics. Discuss the risks and benefits of treatment with your doctor and if there are alternative medication options. This medication is known as a glycylcycline antibiotic. It works by stopping the growth of bacteria.

HOW TO USE: This medication is given by injection into a vein over 30-60 minutes by a healthcare professional. Doses are usually repeated every 12 hours or as directed by your doctor. The dose and length of treatment depend on your condition and response to therapy.

If you are giving this medication to yourself at home, learn all preparation and usage instructions from your health care professional. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Learn how to store and discard medical supplies safely.

Antibiotics work best when the amount of medicine in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals.

Continue to take this medication until the full-prescribed amount is finished even if symptoms disappear after a few days. Stopping the medication too early may allow bacteria to continue to grow, which may result in a relapse of the infection.

Inform your doctor if your condition worsens or has not improved within 14 days.

Disclaimer

Tygacil Consumer (continued)

SIDE EFFECTS: Nausea, vomiting, headache, dizziness, or pain/swelling at the injection site may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: sunburn (sun sensitivity), change in the amount of urine, unusual fatigue, severe stomach/abdominal pain, hearing changes (e.g., ringing in the ears, decreased hearing), persistent or severe headache, vision changes (e.g., blurred vision, double vision), irregular heartbeat, easy bleeding/bruising, yellowing of the eyes or skin, dark urine.

This medication may rarely cause a severe intestinal condition (Clostridium difficile-associated diarrhea) due to a resistant bacteria. This condition may occur weeks to months after treatment has stopped. Do not use anti-diarrhea products or narcotic pain medications if you have the following symptoms because these products may make them worse. Tell your doctor right away if you develop: persistent diarrhea, abdominal or stomach pain/cramping, or blood/mucus in your stool.

Use of this medication for prolonged or repeated periods may result in oral thrush or a new vaginal yeast infection (oral or vaginal fungal infection). Contact your doctor if you notice white patches in your mouth, a change in vaginal discharge or other new symptoms.

A very serious allergic reaction to this drug is unlikely, but get medical help right away if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Tygacil (tigecycline) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before using tigecycline, tell your doctor or pharmacist if you are allergic to it; or to tetracyclines (such as doxycycline, minocycline, tetracycline); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: severe liver disease.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths or sunlamps. Use a sunscreen and wear protective clothing when outdoors.

Before having surgery, tell your doctor or dentist that you are using this medication.

This medication should not be used in children younger than 8 years of age because it may cause permanent tooth discoloration and other problems. Tooth discoloration may also occur in older children and young adults. Consult your doctor for more information.

This medication is not recommended for use during pregnancy because of possible harm to an unborn baby. Women of child-bearing age should use effective birth control while using this medication. Consult your doctor for more details.

It is not known whether this drug passes into breast milk. Because of possible harm to a nursing infant, consult your doctor before breast-feeding.

Disclaimer

Tygacil Consumer (continued)

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: "blood thinners" (e.g., warfarin), live bacterial vaccines.

Although most antibiotics probably do not affect hormonal birth control such as pills, patch, or ring, some antibiotics may decrease their effectiveness. This could cause pregnancy. Examples include rifamycins such as rifampin or rifabutin. Be sure to ask your doctor or pharmacist if you should use additional reliable birth control methods while using this antibiotic.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in those cases.

Laboratory and/or medical tests (e.g., liver function tests, blood counts, cultures) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Consult the product instructions and your pharmacist for storage details. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

Information last revised September 2011. Copyright(c) 2011 First Databank, Inc.

Tygacil Patient Information Including Side Effects

Brand Names: Tygacil

Generic Name: tigecycline (Pronunciation: tye ge SYE kleen)

What is tigecycline (Tygacil)?

Tigecycline is an antibiotic that fights bacteria in the body.

Tigecycline is used to treat many different bacterial infections of the skin or the digestive system, as well as pneumonia.

Tigecycline may also be used for purposes not listed in this medication guide.

What are the possible side effects of tigecycline (Tygacil)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using tigecycline and call your doctor at once if you have a serious side effect such as:

  • diarrhea that is watery or bloody;
  • severe headache, ringing in your ears, dizziness, nausea, vision problems, pain behind your eyes;
  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or
  • severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate.

Less serious side effects may include:

  • headache; or
  • dizziness, sleep problems (insomnia);
  • vaginal itching or discharge.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Tygacil (tigecycline) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about tigecycline (Tygacil)?

Tigecycline can make birth control pills less effective. Ask your doctor about using a non hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while using tigecycline.

You should not use this medication if you are allergic to tigecycline.

Children should not use tigecycline. Tigecycline can cause permanent yellowing or graying of the teeth in children younger than 8 years old.

Before using tigecycline, tell your doctor if you are allergic to a tetracycline antibiotic such as demeclocycline (Declomycin), doxycycline (Adoxa, Doryx, Oracea, Vibramycin), minocycline (Dynacin, Minocin, Solodyn, Vectrin), or tetracycline (Brodspec, Panmycin, Sumycin, Tetracap). Also tell your doctor if you have liver disease or if you are using a blood thinner such as warfarin (Coumadin, Jantoven).

You may be shown how to use an IV at home. Do not self-inject this medicine if you do not fully understand how to give the injection, and how to properly mix and store the medication.

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics.

Avoid exposure to sunlight or tanning beds. Tigecycline can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Side Effects Centers

Tygacil Patient Information including How Should I Take

What should I discuss with my healthcare provider before using tigecycline (Tygacil)?

You should not use this medication if you are allergic to tigecycline.

To make sure you can safely take tigecycline, tell your doctor if you have any of these other conditions:

  • liver disease;
  • if you are using a blood thinner such as warfarin (Coumadin, Jantoven); or
  • if you are allergic to a tetracycline antibiotic such as demeclocycline (Declomycin), doxycycline (Doryx, Oracea, Periostat, Vibramycin), minocycline (Dynacin, Minocin, Solodyn), or tetracycline (Ala-Tet, Brodspec, Panmycin, Sumycin, Tetracap).

Tigecycline can make birth control pills less effective. Ask your doctor about using a non hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while using tigecycline.

It is not known whether tigecycline passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Children should not use tigecycline. Tigecycline can cause permanent yellowing or graying of the teeth in children younger than 8 years old.

How should I use tigecycline (Tygacil)?

Tigecycline is injected into a vein through an IV. You may be shown how to use an IV at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

Tigecycline must be given slowly, and the IV infusion can take up to 60 minutes to complete.

Tigecycline is a powder medicine that must be mixed with a liquid (diluent) in an IV bag before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medication.

Prepare your dose only when you are ready to give yourself an injection. After mixing, the liquid should appear as a yellow or orange color. Do not use the medication if it has changed to green or black, or if it has any particles in it. Call your doctor for a new prescription.

Use a disposable needle only once. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Tigecycline will not treat a viral infection such as the common cold or flu.

Store unmixed powder at room temperature away from moisture and heat.

Mixed medicine must be used within 24 hours if you keep it at room temperature.

Tigecycline mixed in an IV bag with sodium chloride or dextrose solution may be stored in a refrigerator and used within 48 hours.

Side Effects Centers

Tygacil Patient Information including If I Miss a Dose

What happens if I miss a dose (Tygacil)?

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose (Tygacil)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while using tigecycline (Tygacil)?

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or bloody, stop using tigecycline and call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.

Avoid exposure to sunlight or tanning beds. Tigecycline can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

What other drugs will affect tigecycline (Tygacil)?

  • amphotericin (Amphocin, Fungizone);
  • diazepam (Valium); or
  • amphotericin B lipid complex (Abelcet);
  • esomeprazole (Nexium I.V.).

This list is not complete and other drugs may interact with tigecycline. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about tigecycline.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 2.01. Revision date: 1/24/2011.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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