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Eravacycline (Monograph)

Brand name: Xerava
Drug class: Fluorocyclines
Chemical name: (4S,4aS,5aR,12aR)-4-(dimethylamino)-7-fluoro-1,10,11,12a-tetrahydroxy-3,12-dioxo-9-[(2-pyrrolidin-1-ylacetyl)amino]-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide;dihydrochloride
Molecular formula: C27H31FN4O8•2HCl
CAS number: 1334714-66-7

Medically reviewed by Drugs.com on Jan 24, 2024. Written by ASHP.

Introduction

Antibacterial; fluorocycline; tetracycline.1 6 7 21

Uses for Eravacycline

Intra-abdominal Infections

Treatment of complicated intra-abdominal infections caused by susceptible Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, K. oxytoca, Enterococcus faecalis, E. faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides, and Parabacteroides distasonis.1 2 3

Urinary Tract Infections

Not labeled by FDA for treatment of complicated urinary tract infections [off-label];1 efficacy in such infections not demonstrated in clinical studies.1

Eravacycline Dosage and Administration

Administration

Administer by IV infusion.1

For solution and drug compatibility information, see Compatibility under Stability.

IV Administration

Must be reconstituted and diluted prior to IV infusion.1

Infuse IV through a dedicated IV line or a Y-site.1 If same IV line used for sequential infusion of several drugs, flush with 0.9% sodium chloride before and after infusion of eravacycline.1

Do not admix with or add to solutions containing other drugs.1

Reconstitution

Reconstitute appropriate number of single-dose vials containing 50 mg of eravacycline by adding 5 mL of sterile water for injection or 0.9% sodium chloride injection to each vial;1 swirl gently until contents are dissolved.1 To avoid foaming, do not shake or rapidly move vial.1 Reconstituted solution contains 10 mg of eravacycline per mL.1

Dilution

Prior to IV infusion, reconstituted solutions must be further diluted.1 To prepare the indicated dose, withdraw appropriate volume of reconstituted solution from vial(s) and add to 0.9% sodium chloride to achieve target concentration of 0.3 mg/mL (range 0.2–0.6 mg/mL).1 Do not shake diluted solutions.1

Solutions should appear clear and range from light yellow to orange in color.1 Discard if cloudy or contains particulates.1

Discard unused portions of reconstituted and diluted solution.1

Rate of Administration

Administer by IV infusion over approximately 60 minutes.1

Dosage

Available as eravacycline dihydrochloride; dosage expressed in terms of eravacycline.1

Adults

Intra-abdominal Infections
IV

1 mg/kg every 12 hours for 4–14 days.1

Base treatment duration on severity and location of infection and clinical response.1

Increase dosage to 1.5 mg/kg every 12 hours for 4–14 days in those receiving a potent CYP3A inducer (e.g., phenytoin, rifampin) concomitantly.1 (See Interactions.)

Special Populations

Hepatic Impairment

Intra-abdominal Infections
IV

Mild or moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustments not needed.1

Severe hepatic impairment (Child-Pugh class C): 1 mg/kg every 12 hours on day 1, followed by 1 mg/kg once every 24 hours starting on day 2 of treatment and continued for total treatment duration of 4–14 days.1

Renal Impairment

Intra-abdominal Infections
IV

Dosage adjustments not needed.1

Cautions for Eravacycline

Contraindications

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Life-threatening hypersensitivity reactions, including anaphylaxis, reported.1 Because eravacycline is structurally similar to other tetracyclines, it is contraindicated in patients with known hypersensitivity to any tetracycline.1

Discontinue eravacycline if allergic reaction occurs.1

Tooth Discoloration and Enamel Hypoplasia

Use of tetracycline, including eravacycline, during tooth development (i.e., last half of pregnancy, infancy, childhood up to 8 years of age) may cause permanent discoloration of the teeth (yellow-grey-brown).1 Occurs more commonly with long-term use of tetracyclines, but has been observed following repeated short-term use.1 Enamel hypoplasia also reported with tetracyclines.1

Inhibition of Bone Growth

Use of tetracyclines, including eravacycline, during second or third trimester of pregnancy, infancy, or childhood up to 8 years of age may cause reversible inhibition of bone growth.1 Tetracyclines form stable calcium complex in any bone-forming tissue.1 Decreased fibula growth rate observed in premature infants receiving oral tetracycline;1 this effect was reversible when the drug was discontinued.1

Tetracycline-class Effects

Because eravacycline is structurally similar to conventional tetracyclines, adverse effects reported with tetracyclines (e.g., photosensitivity, pseudotumor cerebri, anti-anabolic action leading to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, abnormal liver function tests) may occur.1 Discontinue eravacycline if any of these adverse effects are suspected.1

Superinfection/C. difficile-associated Diarrhea and Colitis (CDAD)

Possible emergence and overgrowth of nonsusceptible bacteria or fungi.1 Institute appropriate therapy if superinfection occurs.1

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly known as Clostridium difficile).1 12 14 15 C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including eravacycline, and may range in severity from mild diarrhea to fatal colitis.1 12 14 15 C. difficile produces toxins A and B which contribute to development of CDAD;1 12 14 15 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.1 12 Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.1

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile as soon as possible.1 12 Initiate appropriate anti-infective therapy directed against C. difficile (e.g., vancomycin, fidaxomicin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.1 12 14 15

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of eravacycline and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.1 Prescribing eravacycline in absence of proven or strongly suspected bacterial infection unlikely to provide benefit to the patient and increases risk of development of drug-resistant bacteria.1

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1

Information on test methods and quality control standards for in vitro susceptibility testing of antibacterial agents and specific interpretive criteria for such testing recognized by FDA is available at [Web].1

Specific Populations

Pregnancy

Eravacycline, like other tetracyclines, may cause permanent discoloration of deciduous teeth and reversible inhibition of bone growth if administered during second or third trimester of pregnancy.1 (See Tooth Discoloration and Enamel Hypoplasia and see Inhibition of Bone Growth under Cautions.)

Insufficient data regarding use in pregnant women to inform a drug-associated risk of major birth defects and miscarriages.1

Animal studies indicate tetracyclines, including eravacycline, cross the placenta, are found in fetal plasma, and can have toxic effects on the developing fetus.1 In rats and rabbits receiving the drug during the period of organogenesis, decreased ossification, decreased fetal body weight, and/or increased post-implantation loss observed.1

Advise patients of potential risks to the fetus if eravacycline used during second or third trimester of pregnancy.1 (See Advice to Patients.)

Lactation

Eravacycline and its metabolites distributed into milk in lactating rats.1 Not known if distributes into human milk, affects breast-fed infant, or affects milk production.1

Because other antibacterial options are available to treat complicated intra-abdominal infections in lactating women and because of the potential for serious adverse effects in the breast-fed infant (See Tooth Discoloration and Enamel Hypoplasia and see Inhibition of Bone Growth under Cautions.), breast-feeding not recommended during eravacycline treatment and for 4 days after last dose of the drug.1

Fertility

Although human data not available, animal studies indicate eravacycline can impair spermiation and sperm maturation resulting in abnormal sperm morphology and poor motility.1

In fertility studies in male rats, eravacycline did not affect mating or fertility at IV dosages resulting in exposures approximately 1.5 times higher than human exposures; however, higher doses were associated with adverse effects on fertility and spermatogenesis (impaired spermiation and sperm maturation, decreased sperm counts, abnormal sperm morphology, reduced sperm motility).1 These effects appeared to be reversible.1

Fertility studies in female rats have not revealed evidence of adverse effects on mating or fertility.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1

Use in pediatric patients <8 years of age not recommended because of adverse effects of tetracyclines on tooth development and bone growth.1 (See Tooth Discoloration and Enamel Hypoplasia and see Inhibition of Bone Growth under Cautions.)

Geriatric Use

No overall differences in safety or efficacy observed between geriatric and younger adults.1

Hepatic Impairment

Adjust dosage in patients with severe hepatic impairment (Child-Pugh class C);1 dosage adjustments not needed in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Renal Impairment

Dosage adjustments not needed in patients with renal impairment.1

Common Adverse Effects

Infusion site reactions,1 3 nausea,1 3 vomiting,1 3 diarrhea,1 3 hypotension,1 wound dehiscence,1 anemia.3

Drug Interactions

Metabolized by CYP3A4.1

In vitro, does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5 and does not induce CYP1A2, 2B6, or 3A4.1

Not a substrate of P-glycoprotein (P-gp) transport system, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transport polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multi-drug and toxin extrusion transporter (MATE) 1, or MATE2-K.1

Does not inhibit BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inducers: Possible decreased eravacycline exposure and reduced eravacycline efficacy.1 8 If used concomitantly, increase eravacycline dosage to 1.5 mg/kg every 12 hours.1 8

Weak or moderate CYP3A inducers: Eravacycline dosage adjustments not needed.1

Specific Drugs

Drug

Interaction

Comments

Antibacterials

No in vitro evidence of antagonistic antibacterial effects between eravacycline and other antibacterials commonly used for indicated pathogens1

Anticoagulants

Tetracyclines decrease plasma prothrombin activity1

Decreased anticoagulant dosage may be needed1

Antifungals, azoles (itraconazole)

Itraconazole (potent CYP3A inhibitor): Increased eravacycline peak plasma concentrations and AUC;1 decreased eravacycline clearance1 8

Phenytoin

Potent CYP3A inducers (e.g., phenytoin) may decrease eravacycline exposures and reduce eravacycline efficacy8

Increase eravacycline dosage to 1.5 mg/kg every 12 hours8

Rifampin

Rifampin (potent CYP3A inducer) decreases eravacycline AUC and increases eravacycline clearance;1 8 may reduce eravacycline efficacy1

Increase eravacycline dosage to 1.5 mg/kg every 12 hours8

Eravacycline Pharmacokinetics

Absorption

Plasma Concentrations

Following single IV doses of eravacycline ranging from 1–3 mg/kg, AUC and peak plasma concentrations increase in an approximately dose-proportional manner.1 Peak plasma concentrations attained by end of a 60-minute IV infusion.8

When dosage of 1 mg/kg IV every 12 hours used, approximately 45% accumulation occurs following multiple doses1 5 and steady-state concentrations are attained on day 5.5

Special Populations

Hepatic impairment: In individuals with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment, peak plasma concentrations approximately 14, 16, or 20% higher, respectively, and AUC approximately 23, 38, or 110% higher, respectively, compared with healthy individuals.1

Renal impairment: In individuals with end-stage renal disease, peak plasma concentrations and AUC increased by 8.8 and 4%, respectively, compared with healthy individuals.1

Geriatric patients: No clinically relevant age-related differences in pharmacokinetics in adults 18–86 years of age.1

Distribution

Extent

Volume of distribution approximately 4 L/kg, which suggests extensive tissue distribution;5 8 9 distributed into bone and lungs.8 9

Plasma Protein Binding

79–90% with increasing plasma concentrations ranging from 100–10,000 ng/mL;1 concentration dependent.1 4

Elimination

Metabolism

Primarily metabolized by CYP3A4 and flavin-containing monooxygenase.1

Elimination Route

Following single IV dose, approximately 34% is eliminated in urine and 47% eliminated in feces as unchanged drug and metabolites;1 8 20% in urine and 17% in feces is unchanged drug.1 8

Half-life

20 hours.1

Stability

Storage

Parenteral

Powder for Infusion

Single-dose vials: 2–8°C;1 keep vial in carton until use.1

Reconstituted solutions containing 10 mg/kg are stable for 1 hour at room temperature (not exceeding 25°C); discard if not further diluted within 1 hour after reconstitution.1

Following reconstitution and dilution, use within 24 hours if stored at room temperature (not exceeding 25°C) or use within 7 days if stored under refrigeration (2–8°C).1 Do not freeze.1

Compatibility

Parenteral

Solution Compatibility1

Compatible

Sodium chloride 0.9%

Actions and Spectrum

Advice to Patients

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Eravacycline Dihydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

50 mg (of eravacycline)

Xerava

Tetraphase

AHFS DI Essentials™. © Copyright 2024, Selected Revisions February 3, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Tetraphase Pharmaceuticals. Xerava (eravacycline) for injection, for intravenous use prescribing information. 2019 Oct.

2. Solomkin J, Evans D, Slepavicius A et al. Assessing the Efficacy and Safety of Eravacycline vs Ertapenem in Complicated Intra-abdominal Infections in the Investigating Gram-Negative Infections Treated With Eravacycline (IGNITE 1) Trial: A Randomized Clinical Trial. JAMA Surg. 2017; 152:224-232. http://www.ncbi.nlm.nih.gov/pubmed/27851857?dopt=AbstractPlus

3. Solomkin JS, Gardovskis J, Lawrence K et al. IGNITE4: Results of a Phase 3, Randomized, Multicenter, Prospective Trial of Eravacycline vs. Meropenem in the Treatment of Complicated Intra-Abdominal Infections. Clin Infect Dis. 2018; http://www.ncbi.nlm.nih.gov/pubmed/30561562?dopt=AbstractPlus

4. Thabit AK, Monogue ML, Nicolau DP. Eravacycline Pharmacokinetics and Challenges in Defining Humanized Exposure In Vivo. Antimicrob Agents Chemother. 2016; 60:5072-5. http://www.ncbi.nlm.nih.gov/pubmed/27353264?dopt=AbstractPlus

5. Newman JV, Zhou J, Izmailyan S et al. Randomized, Double-Blind, Placebo-Controlled Studies of the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Eravacycline. Antimicrob Agents Chemother. 2018; 62 http://www.ncbi.nlm.nih.gov/pubmed/30150464?dopt=AbstractPlus

6. Zhanel GG, Cheung D, Adam H et al. Review of Eravacycline, a Novel Fluorocycline Antibacterial Agent. Drugs. 2016; 76:567-88. http://www.ncbi.nlm.nih.gov/pubmed/26863149?dopt=AbstractPlus

7. Xiao XY, Hunt DK, Zhou J et al. Fluorocyclines. 1. 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent. J Med Chem. 2012; 55:597-605. http://www.ncbi.nlm.nih.gov/pubmed/22148514?dopt=AbstractPlus

8. Newman JV, Zhou J, Izmailyan S et al. Mass Balance and Drug Interaction Potential of IV Eravacycline Administered to Healthy Subjects. Antimicrob Agents Chemother. 2018; http://www.ncbi.nlm.nih.gov/pubmed/30559132?dopt=AbstractPlus

9. Connors KP, Housman ST, Pope JS et al. Phase I, open-label, safety and pharmacokinetic study to assess bronchopulmonary disposition of intravenous eravacycline in healthy men and women. Antimicrob Agents Chemother. 2014; 58:2113-8. http://www.ncbi.nlm.nih.gov/pubmed/24468780?dopt=AbstractPlus

10. Sutcliffe JA, O'Brien W, Fyfe C et al. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Agents Chemother. 2013; 57:5548-58. http://www.ncbi.nlm.nih.gov/pubmed/23979750?dopt=AbstractPlus

11. Goldstein EJC, Citron DM, Tyrrell KL. In vitro activity of eravacycline and comparator antimicrobials against 143 recent strains of Bacteroides and Parabacteroides species. Anaerobe. 2018; 52:122-124. http://www.ncbi.nlm.nih.gov/pubmed/30018028?dopt=AbstractPlus

12. McDonald LC, Gerding DN, Johnson S et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018; 66:987-994. http://www.ncbi.nlm.nih.gov/pubmed/29562266?dopt=AbstractPlus

13. Zhang F, Bai B, Xu GJ et al. Eravacycline activity against clinical S. aureus isolates from China: in vitro activity, MLST profiles and heteroresistance. BMC Microbiol. 2018; 18:211. http://www.ncbi.nlm.nih.gov/pubmed/30545293?dopt=AbstractPlus

14. Surawicz CM, Brandt LJ, Binion DG et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013; 108:478-98; quiz 499. http://www.ncbi.nlm.nih.gov/pubmed/23439232?dopt=AbstractPlus

15. Debast SB, Bauer MP, Kuijper EJ et al. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014; 20 Suppl 2:1-26. http://www.ncbi.nlm.nih.gov/pubmed/24118601?dopt=AbstractPlus

16. Snydman DR, McDermott LA, Jacobus NV et al. Evaluation of the Activity of Eravacycline against a Broad Spectrum of Recent Clinical Anaerobic Isolates. Antimicrob Agents Chemother. 2018; 62 http://www.ncbi.nlm.nih.gov/pubmed/29483114?dopt=AbstractPlus

17. Seifert H, Stefanik D, Sutcliffe JA et al. In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii. Int J Antimicrob Agents. 2018; 51:62-64. http://www.ncbi.nlm.nih.gov/pubmed/28705668?dopt=AbstractPlus

18. Livermore DM, Mushtaq S, Warner M et al. In Vitro Activity of Eravacycline against Carbapenem-Resistant Enterobacteriaceae and Acinetobacter baumannii. Antimicrob Agents Chemother. 2016; 60:3840-4. http://www.ncbi.nlm.nih.gov/pubmed/27044556?dopt=AbstractPlus

19. Zhang Y, Lin X, Bush K. In vitro susceptibility of β-lactamase-producing carbapenem-resistant Enterobacteriaceae (CRE) to eravacycline. J Antibiot (Tokyo). 2016; 69:600-4. http://www.ncbi.nlm.nih.gov/pubmed/27353166?dopt=AbstractPlus

20. Zheng JX, Lin ZW, Sun X et al. Overexpression of OqxAB and MacAB efflux pumps contributes to eravacycline resistance and heteroresistance in clinical isolates of Klebsiella pneumoniae. Emerg Microbes Infect. 2018; 7:139. http://www.ncbi.nlm.nih.gov/pubmed/30068997?dopt=AbstractPlus

21. Rodvold KA. Eravacycline. In: Grayson ML, ed. Kucers' the use of antibiotics: a clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs. 7th ed. Boca Raton, FL: CRC Press; 2018:1273-89.

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