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.

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.

Urinary Tract Infections

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

Eravacycline Dosage and Administration

Administration

Administer by IV infusion.

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

IV Administration

Must be reconstituted and diluted prior to IV infusion.

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

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

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; swirl gently until contents are dissolved. To avoid foaming, do not shake or rapidly move vial. Reconstituted solution contains 10 mg of eravacycline per mL.

Dilution

Prior to IV infusion, reconstituted solutions must be further diluted. 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). Do not shake diluted solutions.

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

Discard unused portions of reconstituted and diluted solution.

Rate of Administration

Administer by IV infusion over approximately 60 minutes.

Dosage

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

Adults

Intra-abdominal Infections

IV

1 mg/kg every 12 hours for 4–14 days.

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

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. (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.

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.

Renal Impairment

Intra-abdominal Infections

IV

Dosage adjustments not needed.

Cautions for Eravacycline

Contraindications

• Known hypersensitivity to eravacycline, other tetracyclines, or excipients in the preparation.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

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

Discontinue eravacycline if allergic reaction occurs.

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). Occurs more commonly with long-term use of tetracyclines, but has been observed following repeated short-term use. Enamel hypoplasia also reported with tetracyclines.

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. Tetracyclines form stable calcium complex in any bone-forming tissue. Decreased fibula growth rate observed in premature infants receiving oral tetracycline; this effect was reversible when the drug was discontinued.

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. Discontinue eravacycline if any of these adverse effects are suspected.

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

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

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly known as Clostridium difficile). 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. C. difficile produces toxins A and B which contribute to development of CDAD; 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.

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

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile as soon as possible. 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.

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. 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.

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

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].

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. (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.

Animal studies indicate tetracyclines, including eravacycline, cross the placenta, are found in fetal plasma, and can have toxic effects on the developing fetus. 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.

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

Lactation

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

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.

Fertility

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

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). These effects appeared to be reversible.

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

Pediatric Use

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

Use in pediatric patients <8 years of age not recommended because of adverse effects of tetracyclines on tooth development and bone growth. (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.

Hepatic Impairment

Adjust dosage in patients with severe hepatic impairment (Child-Pugh class C); dosage adjustments not needed in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). (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.

Common Adverse Effects

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

Drug Interactions

Metabolized by CYP3A4.

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

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.

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

Drugs Affecting Hepatic Microsomal Enzymes

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

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

Specific Drugs

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. Peak plasma concentrations attained by end of a 60-minute IV infusion.

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

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.

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

Distribution

Extent

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

Plasma Protein Binding

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

Elimination

Metabolism

Primarily metabolized by CYP3A4 and flavin-containing monooxygenase.

Elimination Route

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

Half-life

20 hours.

Stability

Storage

Parenteral

Powder for Infusion

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

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.

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). Do not freeze.

Compatibility

Parenteral

Solution Compatibility1

Actions and Spectrum

• Fluorocycline; tetracycline anti-infective.

• Like other tetracyclines, eravacycline disrupts protein synthesis in susceptible organisms by binding to the 30S ribosomal subunit, which prevents incorporation of amino acid residues into peptide chains.

• Usually bacteriostatic against susceptible gram-positive bacteria (e.g., S. aureus, E. faecalis); in vitro bactericidal activity reported against certain strains of E. coli and K. pneumoniae.

• Has expanded spectrum of activity compared with conventional tetracyclines (doxycycline, minocycline, tetracycline) because of certain structural differences (fluorine at C-7 and pyrrolidinoacetamido at C-9 of tetracycline core D-ring) that result in activity against some bacteria that possess certain tetracycline-specific resistance mechanisms that can inactivate conventional tetracyclines.

• Gram-positive aerobes: Active in vitro and in clinical infections against S. aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA] and methicillin-susceptible S. aureus), S. anginosus group, E. faecalis, and E. faecium. Although clinical importance not known, also active in vitro against S. epidermidis, S. agalactiae, S. pneumoniae, S. pyogenes, S. salivarius group, and Bacillus anthracis; efficacy for treatment of clinical infections caused by these gram-positive bacteria not established.

• Gram-negative aerobes: Active in vitro and in clinical infections against C. freundii, E. cloacae, E. coli, K. oxytoca, and K. pneumoniae. Although clinical importance not known, also active in vitro against Acinetobacter baumannii, C. koseri, E. aerogenes, Francisella tularensis, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Proteus vulgaris, Salmonella, Shigella, Strenotrophomonas maltophilia, and Yersinia pestis; efficacy for treatment of clinical infections caused by these gram-negative bacteria not established.

• Gram-positive anaerobes: Active in vitro and in clinical infections against C. perfringens.

• Gram-negative anaerobes: Active in vitro and in clinical infections against Bacteroides (B. caccae, B. fragilis, B. ovatus, B. thetaiotaomicron, B. uniformis, B. vulgatus ) and P. distasonis.

• Not active against Pseudomonas aeruginosa or Burkholderia cenocepacia.

• Resistance to tetracyclines usually occurs as the result of tetracycline-specific resistance mechanisms such as efflux pumps, ribosomal protection proteins (RPPs), tetracycline degradation, and mutations in the rRNA target.

• Eravacycline not affected, or only minimally affected, by common tetracycline-resistance mechanisms involving efflux pumps mediated by tet(A), tet(B), tet(L), and tet(K) and RPPs encoded by tet(M) and tet(Q).

• Active in vitro against some Enterobacteriaceae that produce certain β-lactamases, including extended-spectrum β-lactamases (ESBLs) and AmpC. However, some β-lactamase-producing isolates may be resistant to eravacycline because of other resistance mechanisms, including upregulated, nonspecific, intrinsic, multidrug-resistant (MDR) efflux or target-site modifications (e.g., 16s rRNA or certain 30S ribosomal proteins [S10]).

Advice to Patients

• Advise patients that antibacterials, including eravacycline, should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).

• Importance of completing the full course of therapy, even if feeling better after a few days.

• Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with eravacycline or other antibacterials in the future.

• Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Inquire about any previous hypersensitivity reactions to tetracyclines, other antibiotics, or other allergens.

• Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued. Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.

• Advise patients that eravacycline is similar to other tetracyclines and may have similar adverse effects.

• Importance of women informing their clinician if they are or plan to become pregnant. Advise patients that eravacycline, like other tetracyclines, may cause permanent tooth discoloration of deciduous teeth and reversible inhibition of bone growth if administered during the second or third trimester of pregnancy.

• Importance of women informing their clinician if they plan to breast-feed. Advise women not to breast-feed during eravacycline treatment and for 4 days after the last dose of the drug.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.

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Frequently asked questions

• What type of drug is Xerava?

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