Tigecycline

Dosage Forms

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

Solution Reconstituted, Intravenous [preservative free]:

Tygacil: 50 mg (1 ea) [contains lactose]

Generic: 50 mg (1 ea)

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: Children (8 to 11 years): 2.84 L/kg (range: 0.397 to 11.2 L/kg) (Purdy 2012); Adults: 7 to 9 L/kg; extensive tissue distribution; distributes into gallbladder, lung, and colon

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)

Clearance: Reduced by 25% in patient with moderate hepatic impairment and 55% in severe hepatic impairment.

Half-Life Elimination

Single dose: 27 hours; following multiple doses: 42 hours; increased by 23% in moderate hepatic impairment and 43% in severe hepatic impairment

Protein Binding

71% to 89%

Use: Labeled Indications

Pneumonia, community-acquired bacterial:

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

Intra-abdominal infections, complicated: 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.

Skin and skin structure infections, complicated: Treatment of complicated 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 and Administration

Dosing: Adult

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

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

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

General dosing, susceptible infection: Limited data available: Note: Use should be reserved for situations when no effective alternative therapy is available; should not be used in pediatric patients <8 years due to adverse effects on tooth development, unless no alternatives are available (Red Book [AAP 2018]). Duration of therapy dependent on severity/site of infection and clinical status and response to therapy.

Infants and Children <8 years: Dosing based on small studies and case series in pediatric patients (age range: 36 days to 15 years); should only be used if potential benefits of use outweigh risks of uncertain dosing and impact on tooth development (Lin 2018; Ye 2018; Zeng 2017; Zhu 2016):

Loading dose (optional): IV: 1.5 to 3 mg/kg once

Maintenance dose: IV: 1 to 2 mg/kg/dose every 12 hours; maximum dose: 50 mg/dose; if no loading dose, a maintenance dose of 2 mg/kg every 12 hours has been used

Children ≥8 years and Adolescents: Dosing based on data from pharmacokinetic trials (Purdy 2012) and on small studies and case series in pediatric patients (age range: 36 days to 15 years) (Lin 2018; Ye 2018; Zeng 2017; Zhu 2016)

8 to 11 years: IV: 1.2 to 2 mg/kg/dose every 12 hours; maximum dose: 50 mg/dose

≥12 years: IV: 50 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

IV: Infuse over 30 to 60 minutes through dedicated line or via Y-site. If the same IV line is used for sequential infusion of several drugs, flush line with NS, D5W, or LR before and after tigecycline administration.

Storage

Store intact vials 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 NS, D5W, or LR. Alternatively, may be stored 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

>10%: Gastrointestinal: Nausea (24% to 35%), vomiting (16% to 20%), diarrhea (12%)

1% to 10%:

Cardiovascular: Localized phlebitis (≤3%), septic shock (<2%), thrombophlebitis (<2%)

Central nervous system: Headache (6%), dizziness (3%), chills (<2%)

Dermatologic: Skin rash (3%), pruritus (<2%)

Endocrine & metabolic: Increased amylase (3%), hyponatremia (2%), hypocalcemia (<2%), hypoglycemia (<2%)

Gastrointestinal: Abdominal pain (6%), dyspepsia (2%), abnormal stools (<2%), anorexia (<2%), dysgeusia (<2%)

Genitourinary: Leukorrhea (<2%), vaginitis (<2%), vulvovaginal candidiasis (<2%)

Hematologic & oncologic: Anemia (5%), hypoproteinemia (5%), eosinophilia (<2%), increased INR (<2%), prolonged partial thromboplastin time (<2%), prolonged prothrombin time (<2%), thrombocytopenia (<2%)

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

Hypersensitivity: Hypersensitivity reaction (<2%)

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

Local: Inflammation at injection site (<2%), injection site reaction (<2%), pain at injection site (<2%), swelling at injection site (<2%)

Neuromuscular & skeletal: Weakness (3%)

Renal: Increased blood urea nitrogen (3%), increased serum creatinine (<2%)

Respiratory: Pneumonia (2%)

<1%, postmarketing, and/or case reports: Acute pancreatitis, allergic skin reaction, anaphylactoid reaction, anaphylaxis, Clostridioides (formerly Clostridium) difficile-associated diarrhea, hepatic dysfunction, hepatic failure, hypersensitivity reaction, hypoglycemia signs and symptoms (diabetic and nondiabetic patients), intrahepatic cholestasis, Stevens-Johnson syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactic/hypersensitivity reactions: May cause life-threatening anaphylaxis. Due to structural similarity with tetracyclines, avoid use in patients with known hypersensitivity to tetracycline-class antibiotics (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: [US Boxed Warning]: In a meta analysis of Phase 3 and 4 clinical trials, an increase in all-cause mortality has been observed in tigecycline-treated patients versus comparator-treated patients. The cause of the mortality 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 suitable. 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: Avoid use as monotherapy (Canadian labeling recommends using with caution) 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:

• Pediatric: Safety and efficacy in children and adolescents <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.

Monitoring Parameters

Monitor hepatic function periodically. Observe for signs and symptoms of anaphylaxis during administration.

Pregnancy

Pregnancy Considerations

Tigecycline crosses the placenta.

Tetracyclines accumulate in developing teeth and long tubular bones (Mylonas 2011). Permanent discoloration of teeth (yellow, gray, brown) can occur following in utero exposure and is more likely to occur following long-term use or short-term repeated exposure. In addition, tetracycline use has been associated with reversible retardation of skeletal development and reduced bone growth.

Patient Education

What is this drug used for?

• It is used to treat bacterial infections.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Lactic acidosis like fast breathing, fast heartbeat, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps
• Severe loss of strength and energy
• Headache
• Blurred vision
• Double vision
• Blindness
• Not able to pass urine
• Change in amount of urine passed
• Clostridioides (formerly Clostridium) difficile (C. diff)-associated diarrhea like abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools
• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.