Pr TYGACIL(r) Tigecycline for Injection Sterile, lyophilized powder for Intravenous use 50 mg/vial Professed Tetracycline Antibiotic (glycylcycline derivative)

Submission Control Number: 117145

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY OF PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

TYGACIL (tigecycline) is indicated for the treatment of the following infections when caused by susceptible strains of the designated microorganisms in patients 18 years of age and older:

Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible strains only), Staphylococcus aureus (methicillin

-susceptible and -resistant strains), Streptococcus agalactiae, Streptococcus anginosus, Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis. Patients with severe underlying disease, such as those who were immunocompromised, patients with decubitus ulcer infections, or patients who had infections requiring longer than 14 days of treatment (for example, necrotizing fasciitis), were not enrolled in clinical trials. Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible strains only), Staphylococcus aureus (methicillin-susceptible only), 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 pneumonia (mild to moderate infections only) caused by Haemophilus influenzae, Streptococcus pneumoniae (penicillin-susceptible isolates only), Mycoplasma pneumoniae, and Chlamydia pneumoniae.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to tigecycline. Once these results are available, antimicrobial therapy should be adjusted if necessary. TYGACIL may be initiated as empiric therapy before results of these tests are known. Tigecycline has decreased in vitro activity against Proteus spp., Providencia spp., and Morganella spp. Pseudomonas aeruginosa is inherently resistant to TYGACIL. Geriatrics (>= 65 years of age): Evidence from clinical studies suggests that use in the geriatric population is not associated with differences in safety or effectiveness. A brief discussion can be found in WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics. Pediatrics (< 18 years of age): No data is available. (See WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics).

CONTRAINDICATIONS

TYGACIL (tigecycline) is contraindicated for use in patients who have known hypersensitivity to tigecycline or tetracycline class of antibiotics.

WARNINGS AND PRECAUTIONS

Anaphylaxis/anaphylactoid reactions have been reported with TYGACIL, and may be life- threatening. Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics and may have similar adverse events. 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 tigecycline. Tigecycline may be associated with permanent tooth discoloration in humans during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years). Results of studies in rats with tigecycline have shown bone discoloration. During antibiotic therapy, colonization or superinfection with Candida, Proteus or Pseudomonas spp may occur in the GI, genitourinary, and respiratory tracts. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken. TYGACIL is not indicated for the treatment of severe community acquired pneumonia. Safety and efficacy of TYGACIL in severe community acquired pneumonia have not been studied. (See CLINICAL TRIALS). TYGACIL has not been evaluated in clinical trials for use against suspected or documented multiple drug resistant pathogens in pneumonia. TYGACIL is not indicated for treatment of hospital acquired pneumonia. The safety and efficacy of TYGACIL in patients with hospital acquired pneumonia have not been established. In a study of hospital acquired pneumonia patients, 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) and greater mortality (25/131 [19.1%] versus 15/122 [12.3%]) than the comparator. Caution should be exercised when considering TYGACIL monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. (See ADVERSE REACTIONS). In Phase 3 cIAI studies (n=1642), 6 patients treated with TYGACIL and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with TYGACIL had higher APACHE II scores (median = 13) vs 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.

An effect on cardiac repolarization following tigecycline administration cannot be definitively excluded from the clinical data. (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Cardiovascular). There is limited clinical experience using tigecycline in patients with known prolongation of the QTc interval, patients with hypokalemia, patients receiving Class IA (e.g. quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents, or in other pro- arrhythmic conditions. Pharmacokinetic studies between tigecycline and drugs that prolong the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants have not been performed. The effect of tigecycline has also not been studied in patients with congenital prolongation of the QT interval. It is expected that these individuals may be more susceptible to drug-induced QT prolongation. The magnitude of QTc prolongation may increase with increasing concentrations of drugs; therefore, the recommended dose and the recommended infusion rate for TYGACIL should not be exceeded. (see DOSAGE AND ADMINISTRATION). Patients should be instructed to contact their physician if they experience palpitations or fainting spells while taking TYGACIL.

Clostridium difficile-associated disease

-associated disease (CDAD) has been reported with use of many antibacterial agents, including TYGACIL. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy. If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases. (see ADVERSE REACTIONS).

Based on pharmacokinetic data, in patients with severe hepatic impairment (Child Pugh C), the dose of TYGACIL should be reduced to 100 mg followed by 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response. (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency and DOSAGE AND ADMINISTRATION). Cases of pancreatitis have been reported.

Pregnant Women:

There are no adequate and well-controlled studies of TYGACIL in pregnant women. TYGACIL should not be used unless the potential benefit to the mother outweighs any possible risk to the fetus.

TYGACIL may cause fetal harm when administered to a pregnant woman. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Tigecycline was not teratogenic in the rat or rabbit. Decreased fetal weights and increased incidence of minor skeletal anomalies in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline. (See TOXICOLOGY). TYGACIL has not been studied for use during labor and delivery. Nursing Women: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and there is the potential risk of permanent discoloration of the teeth/bones (yellow gray- brown) of the child, TYGACIL should not be administered to a nursing woman unless the potential benefit to the mother outweighs any possible risk to the child. (See WARNINGS AND PRECAUTIONS, General). Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline there was little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.

Pediatrics (< 18 years of age):

TYGACIL should not be used in children under 8 years of age because of the risk of teeth discoloration. Safety and effectiveness in pediatric patients below the age of 18 have not been established. Therefore, use in patients under 18 years of age is not recommended.

Geriatrics (>= 65 years of age):

Of the total number of subjects who received TYGACIL in Phase 3 clinical studies (n=2514), 664 were 65 years of age and over, while 288 were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events in some older individuals cannot be ruled out.

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

Driving a vehicle or operating machinery

Tigecycline can cause dizziness which may impair the ability to drive and/or operate machinery.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The overall incidence of drug-related adverse reactions with TYGACIL (tigecycline) was 41.0%. The most common adverse drug reactions, as judged by investigators, in patients treated with TYGACIL (tigecycline) were nausea at 18.9% (11.6% mild; 6.4% moderate; 0.9% severe) and vomiting 12.4% (7.4% mild; 4.3% moderate; 0.6% severe). In general, nausea and vomiting occurred early in treatment (days 1 - 2) and on average over 2 to 4 days. Tigecycline was discontinued due to an adverse event in 6.7% of subjects. Discontinuation from tigecycline was most frequently associated with nausea (1.1%) and vomiting (1.1%).

Clinical Trial Adverse Drug Reactions

Because clinical studies are conducted under varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates

In Phase 3 clinical studies, 2514 patients were treated with TYGACIL. These patients received at least 1 dose of TYGACIL. In the active controlled studies that employed a 1:1 randomization, 2274 patients with complicated intra-abdominal infections, complicated skin and skin structure infections, community acquired pneumonia, and hospital acquired pneumonia were treated with TYGACIL for up to 14 days (see CLINICAL TRIALS). In resistant pathogen clinical studies which were uncontrolled or employed a randomization of 3:1, 184 patients were treated for up to 14 days and 56 patients up to 28 days. Table 1 shows the incidence (%) of treatment-emergent adverse drug reactions reported in >=1% of patients treated with TYGACIL in Phase 3 clinical studies.

Table 1: Incidence (%) of Adverse Drug Reactions Reported in >=1% of Patients Treated with TYGACIL in Phase 3 Clinical Studies

Adverse Events TYGACILa

(N=2514)

Comparator (N=2307)

Any adverse event 41.0 32.4

Body as a whole 6.2 6.1

Abdominal pain 1.2 0.6

Headache 1.2 1.7

Cardiovascular system 3.7 5.0

Phlebitis 1.5 2.3

Digestive system 27.2 14.9

Nausea 18.9 7.8

Vomiting 12.4 4.2

Diarrhea 6.2 4.9

Anorexia 1.1 0.2

Liver function tests abnormal 1.0 0.8

Hemic and lymphatic system 6.0 5.0

Thrombocythemia 2.1 1.8

Activated partial thromboplastin time prolonged

1.0 0.4

Metabolic and nutritional 8.7 7.5

Lactic dehydrogenase increased 1.4 1.0

Alkaline phosphatase increased 1.9 1.5

SGPT increasedb 2.5 3.4

SGOT increasedb 2.2 3.3

Amylase increased 1.4 1.0

Bilirubinemia 1.3 0.2

Skin and appendages 2.7 3.8

Rash 1.2 1.7

Urogenital system 1.4 0.8

Vaginal moniliasis 1.0 0.6

100 mg initially, followed by 50 mg every 12 hours.

Liver function test abnormalities in TYGACIL-treated patients were reported more frequently in the posttherapy period than those in comparator-treated patients, which occurred more often on therapy.

Abbreviations: SGPT=serum glutamic pyruvic transaminase; SGOT=serum glutamic oxaloacetic transaminase.

Less Common Clinical Trial Adverse Drug Reactions (<1%) The following adverse drug reactions as judged by the investigators were reported infrequently (<1% and >=0.1%) in patients receiving TYGACIL in Phase 3 clinical studies:

Body as a whole

: infection, fever, asthenia, septic shock, injection site inflammation, injection site pain, injection site reaction, chills, injection site edema, injection site phlebitis, pain, moniliasis, chest pain, chills and fever, malaise, peritonitis, allergic reaction

Cardiovascular system

: thrombophlebitis, hypertension, hypotension, bradycardia, vasodilatation, tachycardia, atrial fibrillation, AV block first degree, congestive heart failure, electrocardiogram abnormal, palpitation, QT interval prolonged, sinus bradycardia, syncope, tachycardia sinus, ventricular extrasystoles

Digestive system

: dyspepsia, oral moniliasis, constipation, dry mouth, jaundice, stools abnormal, abdominal distension, fecal incontinence, flatulence, gastroesophageal reflux disease, glossitis, hepatic failure, liver damage, mucositis, pancreatitis, pseudomembranous colitis

Hemic and lymphatic system

: eosinophilia, prothrombin time prolonged, anemia, leukocytosis, leukopenia, international normalized ratio increased, thrombocytopenia, coagulation disorder, ecchymosis, hemolysis, neutropenia, prothrombin decreased, prothrombin time shortened

Metabolic and nutritional

: BUN increased, hypoproteinemia, creatinine increased, hypocalcemia, hyperkalemia, hyponatremia, peripheral edema, hypoglycemia, hypokalemia, creatine phosphokinase increased, healing abnormal, hyperglycemia, hyperphosphatemia, hypophosphatemia

Musculoskeletal system

: myalgia

Nervous system

: dizziness, somnolence, insomnia, nervousness, tremor, twitching, vertigo

Respiratory system

: cough increased, dyspnea, hiccup, pleural effusion, pneumonia, pulmonary physical finding, pharyngitis, sputum increased

Skin and appendages

: pruritus, sweating, urticaria, fungal dermatitis, herpes simplex, maculopapular rash, pruritic rash, skin discoloration

Special senses

: taste perversion, abnormal vision

Urogenital system

: vaginitis, kidney function abnormal, urinary tract infection, creatinine clearance decreased, leukorrhea, polyuria, scrotal edema, vulvovaginal disorder, vulvovaginitis

Adverse events associated with miscellaneous factors

: local reaction to procedure, device malfunction

In addition to those noted above, the following adverse reactions judged as related as determined by the investigator were noted in Phase 2 studies in complicated skin and skin structure infections and complicated intra-abdominal infections: hypomagnesemia, confusion. Adverse reactions for the Phase 1 clinical pharmacology studies are similar to those reported in Phase 3 and Phase 2 clinical trials. The most common adverse reactions in these trials were nausea, vomiting, headache, dizziness, and diarrhea.

Abnormal Hematologic and Clinical Chemistry Findings

See Table 1.

Adverse events with outcome of Death

In Phase 3 studies, which included controlled and uncontrolled studies, death occurred in 5.4% (137/2514) of patients receiving TYGACIL and 3.8% (87/2307) of patients receiving comparator drugs. In Phase 3 studies that included a comparator and employed a 1:1 randomization, death occurred in 4.7% (107/2274) of patients receiving TYGACIL and 3.8% (85/2264) of patients receiving comparator drugs. Generally, deaths represented complications of the underlying disease or progression of disease, and relationship to treatment cannot be established.

Infection-related serious adverse events

In Phase 3 clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with TYGACIL (6.7%) vs comparators (5.5%). Serious adverse events of sepsis/septic shock were more frequently reported for subjects treated with TYGACIL (1.8%) vs comparators (1.2%). 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). Other events included abscess (1.4% vs 1.2%), infections, including wound infections (1.2% vs 0.9%) and pneumonia (1.1% vs 1.2%) for TYGACIL vs comparators, respectively.

Post Marketing Adverse Reactions

The following adverse reactions have been identified during postapproval use of tigecycline: acute pancreatitis, anaphylaxis/anaphylactoid reactions. There has been one case of ventricular arrhythmia (with positive dechallenge and rechallenge) associated with TYGACIL administration.

DRUG INTERACTIONS

studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome (CYP) P450 isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. There has been no specific study conducted to examine the effects of tigecycline on microsomal enzyme induction. The exposure and safety data did not show any evidence of increased liver weight during multiple dosing which typically is associated with enzyme induction. Therefore, 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.

Concurrent use of antibiotics with oral contraceptives may render oral contraceptives less effective. Tigecycline (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg 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 is necessary when tigecycline is administered with digoxin. Concomitant administration of 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%, 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.

DOSAGE AND ADMINISTRATION

Based on pharmacokinetic data in patients with severe hepatic impairment (Child Pugh C), the dose of TYGACIL (tigecycline) should be altered (See Recommended Dose and Dosage Adjustment).

The recommended dosage regimen of TYGACIL is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous (IV) infusions of TYGACIL should be administered over approximately 30 to 60 minutes every 12 hours. The recommended duration of treatment with TYGACIL 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 for community acquired pneumonia (mild to moderate infections only) 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.

No dosage adjustment of TYGACIL is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency). Patients with Severe Hepatic Impairment: Based on the pharmacokinetic profile of tigecycline in patients with severe hepatic impairment (Child Pugh C), the dose of TYGACIL should be altered to 100 mg followed by 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response. (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency and WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Based on the pharmacokinetic data, no dosage adjustment of TYGACIL is necessary in patients with renal impairment or in patients undergoing hemodialysis. (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).

No dosage adjustment of TYGACIL is necessary based on age, gender or race. (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Intravenous (IV) infusions of TYGACIL should be administered over approximately 30 to 60 minutes every 12 hours. TYGACIL may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of TYGACIL with either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. Injection should be made with an infusion solution compatible with TYGACIL and with any other drug(s) administered via this common line.

Reconstitution:

Parenteral Products:

Each Vial of TYGACIL should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose 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.

Dilution

Withdraw 5 mL of the reconstituted solution from the vial and add to a 100 mL IV bag for infusion (for a 100 mg dose, reconstitute two vials; for a 50 mg dose, reconstitute one vial). The maximum concentration in the IV 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, whenever solution and container permit. Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, and 5% Dextrose Injection USP. Once reconstituted, TYGACIL may be stored at room temperature for up to 24 hours (up to 6 hours in the vial and the remaining time in the IV bag). Alternatively, TYGACIL may be stored refrigerated at 2deg to 8degC (36deg to 46degF) for up to 48 hours following immediate transfer of the reconstituted solution into the IV bag. (See STORAGE AND STABILITY). The concentration of the admixture solution is 1 mg/mL (100 mg loading dose/100 mL) or 0.5 mg/mL (50 mg dose in 100 mL). When administered through a Y-site, TYGACIL is compatible with the following drugs or diluents:

Figure 1: A generic schematic diagram for the Y-site co-administration is provided below.

OVERDOSAGE

No specific information is available on the treatment of overdosage with TYGACIL (tigecycline). Intravenous administration of 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 IV 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. For the management of suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Tigecycline, a glycylcycline, acts by inhibiting protein synthesis at the level of the bacterial ribosome by blocking the binding of amino-acyl tRNA to the A site of the ribosome. Tigecycline has in vivo and in vitro antibacterial activity against a broad-spectrum of pathogens. (see MICROBIOLOGY). Tigecycline is active against bacterial strains that carry classical tetracycline resistant genes encoding either ribosomal protection or a tetracycline efflux pump. Several efflux-related resistance mechanisms have been identified that provide decreased activity (Proteus spp., Providencia spp., & Morganella spp.) or no activity (P. aeruginosa spp. ).

The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses are summarized in Table 2. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes.

Table 2: Mean (CV%) Pharmacokinetic Parameters of Tigecycline

Absorption:

Tigecycline is administered intravenously and therefore has 100% bioavailability.

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 mg/mL). Animal and human pharmacokinetic studies have demonstrated that tigecycline readily distributes to tissues. In rats receiving single or multiple doses of 14C-tigecycline, radioactivity was well distributed to most tissues, with the highest overall exposure observed in bone, bone marrow, thyroid gland, kidney, spleen and salivary gland. In humans, 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 of humans. Two studies examined the steady-state pharmacokinetic profile of tigecycline in specific tissues or fluids of healthy subjects receiving tigecycline 100 mg followed by 50 mg every 12 hours. In a bronchoalveolar lavage study, the tigecycline AUC0-12h (134 mg *hr/mL) in alveolar cells was approximately 77.5-fold higher than the AUC0-12h in the serum of these subjects, and the AUC0-12h (2.28 mg *hr/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12h in serum. In a skin blister study, the AUC0-12h (1.61 mg *hr/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12h in the serum of these subjects. In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Tissue concentrations at 4 hours after tigecycline administration were measured in the following tissue and fluid samples: gallbladder, lung, colon, synovial fluid and bone. Tigecycline attained higher concentrations in tissues versus serum in gallbladder (38-fold, n=6), lung (8.6-fold, n=1), and colon (2.1-fold, n=5). 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.

Excretion:

The recovery of total radioactivity in feces and urine following administration of

C-tigecycline indicates that 59% of the dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.

Pediatrics: The pharmacokinetics of tigecycline in patients less than 18 years of age have not been established. (See WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics). Geriatrics: No overall 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 tigecycline. Therefore, no dosage adjustment is necessary based on age. (See WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics). 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 (22.8+-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. Hepatic Insufficiency: 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 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). In addition, systemic clearance of tigecycline was reduced by 55%, and the half-life of tigecycline is prolonged by 43% in patients with severe hepatic impairment (Child-Pugh C). Based on the pharmacokinetic profile of tigecycline, no dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). However, in patients with severe hepatic impairment (Child Pugh C), the dose of tigecycline should be reduced to 100 mg followed by 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response. (See DOSAGE AND ADMINISTRATION, Patients with Severe Hepatic Impairment). Renal Insufficiency: A single dose study compared 6 subjects with severe renal impairment (creatinine clearance <=30 mL/min), 4 end stage renal disease patients receiving tigecycline 2 hours before hemodialysis, 4 end stage renal disease patients receiving tigecycline after hemodialysis, and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not altered in any of the renally impaired patient groups nor was tigecycline removed by hemodialysis. No dosage adjustment of tigecycline is necessary in patients with renal impairment or in patients undergoing hemodialysis. (See DOSAGE AND ADMINISTRATION).

Cardiovascular:

In a phase 2 study, ECG results are available from 88 subjects treated with tigecycline. Median change from baseline for QT corrected using the Fridericia formula (QTc(F)) and using a log-linear method (QTc(L)) were 8.5 msec and -4.9 msec, respectively. The upper bounds of a 2-sided 95% confidence interval (CI) were 14.0 and 0.6 msec, respectively. No apparent clinically important effects on cardiac repolarization were seen in subjects treated with tigecycline in this trial. Categorical analyses of QTc(F) and QTc(L) changes

60 msec from baseline occurred in 6.8% and 1.1% of the subjects, respectively. However, interpretation of these results is limited because of the relatively small sample size and lack of a control group in this trial.

The results from phase 3 studies involving ECGs from 773 subjects showed that the median changes from baseline for QTc(F) and QTc(L) were 6.0 and 3.3 msec, respectively, with an upper bound of a 2-sided 95% CI of 7 and 5 msec, respectively. Comparable median change values from subjects treated with comparator agents (n=788) were 3.0 and 1.2 msec, with upper bounds of the 95% CI of 5 and 3 msec, respectively. Categorical analyses of QTc(F) and QTc(L) changes >= 60 msec from baseline occurred, respectively, in 1.8% and 1.3% of tigecycline-treated subjects and in 0.8% and 0.6% of comparator subjects. The differences between the tigecycline and comparator groups were statistically significant for the QTc(F) analysis. QTc(F) and QTc(L) absolute values > 500 msec occurred in 0.4% of tigecycline-treated subjects and in none of the comparator subjects. These differences between the tigecycline and comparator groups were not statistically significant. Although an effect on cardiac repolarization following administration of tigecycline cannot be absolutely excluded, the overall median changes from baseline in the phase 3 studies were generally small, with the upper bounds of the 95% CI <=10 msec, without associated drug-related adverse cardiac events being reported in concert with any significant changes in QTc.

STORAGE AND STABILITY

Prior to reconstitution, TYGACIL (tigecycline) lyophilized powder should be stored at a controlled room temperature 20deg-25degC (68deg-77degF), excursions permitted to 15deg-30degC (59deg-86degF) for up to the expiration date specified on the label. Once reconstituted, TYGACIL may be stored at room temperature for up to 24 hours (up to 6 hours in the vial and the remaining time in the IV bag). Alternatively, TYGACIL may be stored refrigerated at 2deg to 8degC (36deg to 46degF) for up to 48 hours following immediate transfer of the reconstituted solution into the IV bag. 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. The following drugs should not be administered simultaneously through the same Y-site as TYGACIL: amphotericin B and diazepam.

DOSAGE FORMS, COMPOSITION AND PACKAGING

TYGACIL (tigecycline) for injection is supplied in a single-dose 5 mL Type I glass vial. TYGACIL is an orange lyophilized powder or cake. Each TYGACIL vial contains 50 mg tigecycline lyophilized powder 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. Supplied 10 vials/box.

Route of Administration	Dosage Form/Strength	Clinically Relevant Nonmedicinal Ingredients *
Intravenous infusion	Sterile, lyophilized powder 50 mg tigecycline per vial	Lactose

Vial Size	Volume of Diluent to be Added to Vial	Approximate Available Volume	Nominal Concentration per mL
5 mL	5.3 mL	5 mL	10 mg/mL *

	Single Doses 100 mg	Multiple Doses a 50 mg q12h
C max (mg/mL) b	1.45 (22%)	0.87 (27%)
C max (mg/mL) c	0.90 (30%)	0.63 (15%)
AUC (mg *hr/mL)	5.19 (36%)	- -
AUC 0-24h (mg *hr/mL)	- -	4.70 (36%)
C min (mg/mL)	- -	0.13 (59%)
t 1/2 (hr)	27.1 (53%)	42.4 (83%)
CL (L/h)	21.8 (40%)	23.8 (33%)
CL r (mL/min)	38.0 (82%)	51.0 (58%)

PRODUCT MONOGRAPH