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Tigecycline

Pronunciation

Pronunciation

(tye ge SYE kleen)

Index Terms

  • GAR-936

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Tygacil: 50 mg (1 ea)

Brand Names: U.S.

  • Tygacil

Pharmacologic Category

  • Antibiotic, Glycylcycline

Pharmacology

A glycylcycline antibiotic that binds to the 30S ribosomal subunit of susceptible bacteria, thereby, inhibiting protein synthesis. Generally considered bacteriostatic; however, bactericidal activity has been demonstrated against isolates of S. pneumoniae and L. pneumophila. Tigecycline is a derivative of minocycline (9-t-butylglycylamido minocycline), and while not classified as a tetracycline, it may share some class-associated adverse effects. Tigecycline has demonstrated activity against a variety of gram-positive and -negative bacterial pathogens including methicillin-resistant staphylococci.

Distribution

Vd: 7-9 L/kg; extensive tissue distribution

Metabolism

Hepatic, via glucuronidation, N-acetylation, and epimerization to several metabolites, each <10% of the dose

Excretion

Feces (59%, primarily as unchanged drug); urine (33%, with 22% of the total dose as unchanged drug)

Half-Life Elimination

Single dose: 27 hours; following multiple doses: 42 hours

Protein Binding

71% to 89%

Special Populations: Hepatic Function Impairment

Systemic Cl reduced 25% and half-life prolonged 23% in patients with moderate hepatic impairment (Child-Pugh class B); systemic Cl reduced 55% and half-life prolonged 43% in patients with severe hepatic impairment (Child-Pugh class C).

Use: Labeled Indications

Community-acquired bacterial pneumonia:

US labeling: Treatment of community-acquired pneumonia in patients 18 years and older caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila.

Canadian labeling: Treatment of mild or moderate community-acquired pneumonia in patients 18 years and older caused by S. pneumoniae (penicillin-susceptible isolates), H. influenzae, Mycoplasma pneumoniae, and Chlamydia pneumoniae.

Complicated intra-abdominal infections: Treatment of complicated intra-abdominal infections in patients 18 years and older caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates [US labeling] or methicillin-susceptible isolates [Canadian labeling]), Streptococcus anginosus group (includes S. anginosus, Streptococcus intermedius, and Streptococcus constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.

Complicated skin and skin structure infections: Treatment of skin and skin structure infections in patients 18 years and older caused by E. coli, E. faecalis (vancomycin-susceptible isolates), S. aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus agalactiae, S. anginosus group (includes S. anginosus, S. intermedius, and S. constellatus) [US labeling] or S. anginosus [Canadian labeling], Streptococcus pyogenes, E. cloacae, K. pneumoniae, and B. fragilis.

Contraindications

Hypersensitivity to tigecycline or any component of the formulation

Documentation of allergenic cross-reactivity for tetracyclines is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to tetracycline class of antibiotics

Dosage

Children ≥8 years and Adolescents: Limited data available: Note: Use should be reserved for situations when no effective alternative therapy is available.

General dosing, susceptible infection: IV: Dosing based on data from pharmacokinetic trials.

Children 8 to 11 years: 1.2 mg/kg/dose every 12 hours; maximum dose: 50 mg

Children ≥12 years and Adolescents: 50 mg every 12 hours

Adults: Note: Duration of therapy dependent on severity/site of infection and clinical status and response to therapy.

Intra-abdominal infections, complicated (cIAI): IV: Initial: 100 mg as a single dose; Maintenance dose: 50 mg every 12 hours for 5 to 14 days; Note: 2010 IDSA guidelines recommend a treatment duration of 4 to 7 days (provided source controlled) for community-acquired, mild to moderate IAI

Pneumonia, community-acquired: IV: Initial: 100 mg as a single dose; Maintenance dose: 50 mg every 12 hours for 7 to 14 days

Skin/skin structure infections, complicated: IV: Initial: 100 mg as a single dose; Maintenance dose: 50 mg every 12 hours for 5 to 14 days

Dosage adjustment in renal impairment: No dosage adjustment necessary.

Poorly dialyzed; no supplemental dose or dosage adjustment necessary, including patients on intermittent hemodialysis, peritoneal dialysis, or continuous renal replacement therapy (eg, CVVHD).

Dosage adjustment in hepatic impairment:

Mild to moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe hepatic impairment (Child-Pugh class C): Initial: 100 mg single dose; Maintenance: 25 mg every 12 hours

Reconstitution

Add 5.3 mL NS, D5W, or LR to each 50 mg vial. Swirl gently to dissolve. Resulting solution is 10 mg/mL. Reconstituted solution must be further diluted to allow IV administration. Transfer to 100 mL IV bag for infusion (final concentration should not exceed 1 mg/mL). Reconstituted solution should be yellow-orange; discard if not this color.

Administration

Infuse over 30-60 minutes through dedicated line or via Y-site

Compatibility

Stable in NS, D5W, or LR.

Y-site administration: Incompatible: Amiodarone, amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole, nicardipine, omeprazole, phenytoin sodium.

Storage

Prior to reconstitution, store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Reconstituted solution may be stored at room temperature (not to exceed 25°C [77°F]) for up to 6 hours in the vial or up to 24 hours if further diluted in a compatible IV solution. Alternatively, may be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into NS or D5W.

Drug Interactions

Warfarin: Tigecycline may increase the serum concentration of Warfarin. Monitor therapy

Adverse Reactions

Note: Frequencies relative to placebo are not available; some frequencies are lower than those experienced with comparator drugs.

>10%: Gastrointestinal: Nausea (26%; severe: 1%), vomiting (18%; severe: 1%), diarrhea (12%)

2% to 10%:

Cardiovascular: Localized phlebitis (3%)

Central nervous system: Headache (6%), dizziness (3%)

Dermatologic: Skin rash (3%)

Endocrine & metabolic: Hyponatremia (2%), increased amylase (3%)

Gastrointestinal: Abdominal pain (6%), dyspepsia (2%)

Hematologic & oncologic: Anemia (5%), hypoproteinemia (5%)

Hepatic: Increased serum ALT (5%), increased serum AST (4%), increased serum alkaline phosphatase (3%), hyperbilirubinemia (2%)

Infection: Infection (7%), abscess (2%)

Neuromuscular & skeletal: Weakness (3%)

Renal: Increased blood urea nitrogen (3%)

Respiratory: Pneumonia (2%)

Miscellaneous: Abnormal healing (3%)

<2% (Limited to important or life-threatening): Acute pancreatitis, allergic skin reaction, anaphylactoid reaction, anaphylaxis, anorexia, Clostridium difficile associated diarrhea, dysgeusia, eosinophilia, hepatic insufficiency, hepatic failure, hypocalcemia, hypoglycemia, increased INR, increased serum creatinine, increased serum transaminases, increased INR, increased serum creatinine, increased serum transaminases, prolonged partial thromboplastin time, prolonged prothrombin time, pruritus, septic shock, Stevens-Johnson syndrome, swelling at injection site, thrombocytopenia, thrombophlebitis, vaginal moniliasis, vaginitis

ALERT: U.S. Boxed Warning

Mortality:

An increase in all-cause mortality has been observed in a meta-analysis of phase 3 and 4 clinical trials in tigecycline-treated patients versus comparator. The cause of this mortality risk difference of 0.6% (95% confidence interval [CI], 0.1 to 1.2) has not been established. Tigecycline should be reserved for use in situations when alternative treatments are not suitable.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid/hypersensitivity reactions: May cause life-threatening anaphylaxis/anaphylactoid reactions. Due to structural similarity with tetracyclines, use with caution in patients with prior hypersensitivity and/or severe adverse reactions associated with tetracycline use (Canadian labeling contraindicates use in patients with hypersensitivity to tetracyclines).

• Antianabolic effects: May be associated with antianabolic effects observed with the tetracycline class (including increased BUN, azotemia, acidosis, and hyperphosphatemia).

• Hepatotoxicity: Abnormal liver function tests (increased total bilirubin, prothrombin time, transaminases) have been reported. Isolated cases of significant hepatic dysfunction and hepatic failure have occurred. Closely monitor for worsening hepatic function in patients who develop abnormal liver function tests during therapy. Adverse hepatic effects may occur after drug discontinuation.

• Pancreatitis: Acute pancreatitis (including fatalities) has been reported, including patients without known risk factors; discontinue use when suspected.

• Photosensitivity: May be associated with photosensitivity due to structural similarities with tetracyclines.

• Pseudotumor cerebri: May be associated with pseudotumor cerebri due to structural similarities with tetracyclines.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

• Treatment-related mortality: [U.S. Boxed Warning]: In a meta analysis of Phase 3 and 4 clinical trials, an increase in all-cause mortality was observed in patients treated with tigecycline compared to those treated with comparator antibiotics The cause of the risk difference (0.6% [95% CI 0.1, 1.2]) has not been established. Use should be reserved for situations in which alternative treatments are not appropriate. In general, deaths were the result of worsening infection, complications of infection, or underlying comorbidity.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment recommended in severe hepatic impairment.

• Intra-abdominal infections: Use with caution if using as monotherapy for patients with intestinal perforation (in the small sample of available cases, sepsis/septic shock occurred more frequently than patients treated with imipenem/cilastatin comparator).

Special populations:

• Children: Safety and efficacy in children <18 years of age have not been established due to increased mortality observed in trials of adult patients. Use only if no alternative antibiotics are available. Because of effects on tooth development (yellow-gray-brown discoloration), use in patients <8 years is not recommended.

Other warnings/precautions:

• Appropriate use: Do not use for diabetic foot infections; non-inferiority was not demonstrated in studies. Do not use for healthcare-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP); increased mortality and decreased efficacy have been reported in HAP and VAP trials.

Pregnancy Risk Factor

D

Pregnancy Considerations

Because adverse effects were observed in animals and because of the potential for permanent tooth discoloration, tigecycline is classified pregnancy category D. Tigecycline frequently causes nausea and vomiting and, therefore, may not be ideal for use in a patient with pregnancy-related nausea.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, diarrhea, or dyspepsia. Have patient report immediately to prescriber signs of hepatic impairment, severe injection site irritation, considerable asthenia, significant headache, vision changes, ophthalmalgia, intolerable eye irritation, urinary retention, oliguria, vaginal yeast infection, signs of pseudomembranous colitis (rare), or signs of pancreatitis (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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