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Eravacycline Injection

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Eravacycline is a synthetic tetracycline-class antibacterial agent for intravenous administration. Chemically, eravacycline is a C7-, C9-substituted sancycline derivative. The chemical name of eravacycline dihydrochloride is [(4S,4aS,5aR,12aS)-4-(dimethylamino)-7- fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[2-(pyrrolidin-1-yl) acetamido]- 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide] dihydrochloride.

The following represents the chemical structure of eravacycline dihydrochloride:

Empirical formula: C27H31FN4O8•2HCl - Molecular weight: 631.5 g/mol

Eravacycline is a sterile, preservative-free, yellow to orange, lyophilized powder in a glass single-dose vial for intravenous infusion after reconstitution and dilution. Each vial of eravacycline contains 50 mg of eravacycline (equivalent to 63.5 mg of eravacycline dihydrochloride) and the excipient, mannitol (150 mg). Sodium hydroxide and hydrochloric acid are used as needed for pH adjustment to 5.5 to 7.0.

2. INDICATIONS AND USAGE

2.1 Complicated Intra-abdominal Infections

Eravacycline is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasonis in patients 18 years or older [see Microbiology and Clinical Studies].

Limitations of Use

Eravacycline is not indicated for the treatment of complicated urinary tract infections (cUTI) [see Clinical Studies].

2.2 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of eravacycline and other antibacterial drugs, eravacycline should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Adult Dosage

The recommended dose regimen of eravacycline is 1 mg/kg every 12 hours. Administer intravenous infusions of eravacycline over approximately 60 minutes every 12 hours.

The recommended duration of treatment with eravacycline for cIAI is 4 to 14 days. The duration of therapy should be guided by the severity and location of infection and the patient’s clinical response.

3.2 Dosage Modifications in Patients with Hepatic Impairment

In patients with severe hepatic impairment (Child Pugh C), administer eravacycline 1 mg/kg every 12 hours on Day 1 followed by eravacycline 1 mg/kg every 24 hours starting on Day 2 for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B) [see Use in Specific Populations (8.6) and Clinical Pharmacology].

3.3 Dosage Modifications in Patients with Concomitant Use of a Strong Cytochrome P450 Isoenzymes (CYP) 3A Inducer

With concomitant use of a strong CYP3A inducer, administer eravacycline 1.5 mg/kg every 12 hours for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with concomitant use of a weak or moderate CYP3A inducer [see Drug Interactions (7.1) and Clinical Pharmacology].

3.4 Preparation and Administration

Eravacycline is for intravenous infusion only. Each vial is for a single dose only.

Preparation

Eravacycline is supplied as a sterile yellow to orange dry powder in a single-dose vial that must be reconstituted and further diluted prior to intravenous infusion as outlined below. Eravacycline does not contain preservatives. Aseptic technique must be used for reconstitution and dilution as follows:

1. Calculate the dose of eravacycline based on the patient weight; 1 mg/kg actual body weight. Prepare the required dose for intravenous infusion, by reconstituting the appropriate number of vials needed. Reconstitute each vial of eravacycline with 5 mL of Sterile Water for Injection, USP. When the eravacycline vial content is reconstituted with 5 mL sterile Water for Injection, USP it will deliver 50 mg (10 mg/mL) of eravacycline (free base equivalents).

2. Swirl the vial gently until the powder has dissolved entirely. Avoid shaking or rapid movement as it may cause foaming. The reconstituted eravacycline solution should be a clear, pale yellow to orange solution. Do not use the solution if you notice any particles or the solution is cloudy. Reconstituted solution is not for direct injection.

3. The reconstituted eravacycline solution is further diluted for intravenous infusion to a target concentration of 0.3 mg/mL, in a 0.9% Sodium Chloride Injection, USP infusion bag before intravenous infusion. To dilute the reconstituted solution, withdraw the full or partial reconstituted vial content from each vial and add it into the infusion bag to generate an infusion solution with a target concentration of 0.3 mg/mL (within a range of 0.2 to 0.6 mg/mL). Do not shake the bag.

4. The reconstituted and diluted solutions must be infused within 6 hours if stored at room temperature (not to exceed 25°C/77°F) or within 24 hours if stored refrigerated at 2 °C to 8 ºC (36 ºF to 46ºF). Reconstituted eravacycline solutions and diluted eravacycline infusion solutions should not be frozen.

5. Visually inspect the diluted eravacycline solution for particulate matter and discoloration prior to administration (the eravacycline infusion solution for administration is clear and ranges from light yellow to orange). Discard unused portions of the reconstituted and diluted solution.

Administration of the Intravenous Infusion

The diluted eravacycline solution is administered as an intravenous infusion over approximately 60 minutes.

Eravacycline 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 eravacycline with 0.9% Sodium Chloride Injection, USP.

3.5 Drug Compatibilities

Eravacycline is compatible with 0.9% Sodium Chloride Injection, USP. The compatibility of eravacycline with other drugs and infusion solutions has not been established. Eravacycline should not be mixed with other drugs or added to solutions containing other drugs.

4. CONTRAINDICATIONS

Eravacycline is contraindicated for use in patients with known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or to any of the excipients [see Warnings and Precautions (5.1) and Adverse Reactions (6)].

5. WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Life-threatening hypersensitivity (anaphylactic) reactions have been reported with eravacycline [see Adverse Reactions (6.1)]. Eravacycline is structurally similar to other tetracycline-class antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracyclineclass antibacterial drugs. Discontinue eravacycline if an allergic reaction occurs.

5.2 Tooth Discoloration and Enamel Hypoplasia

The use of eravacycline during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-grey-brown). This adverse reaction is more common during long-term use of the tetracycline class drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported with tetracycline class drugs. Advise the patient of the potential risk to the fetus if eravacycline is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)].

5.3 Inhibition of Bone Growth

The use of eravacycline during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Advise the patient of the potential risk to the fetus if eravacycline is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)].

5.4 Clostridium difficile-Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.5 Tetracycline Class Adverse Reactions

Eravacycline is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti-anabolic action which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests, have been reported for other tetracycline-class antibacterial drugs, and may occur with eravacycline. Discontinue eravacycline if any of these adverse reactions are suspected.

5.6 Potential for Microbial Overgrowth

Eravacycline use may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue eravacycline and institute appropriate therapy.

5.7 Development of Drug-Resistant Bacteria

Prescribing eravacycline in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage (2.2)].

6. ADVERSE REACTIONS

The following clinically significant adverse reactions are described in greater detail in the Warnings and Precautions section:

• Hypersensitivity Reactions [Warning and Precautions (5.1)]

• Tooth Discoloration [Warning and Precautions (5.2)]

• Inhibition of Bone Growth [Warning and Precautions (5.3)]

• Clostridium difficile-Associated Diarrhea [Warning and Precautions (5.4)]

• Tetracycline Class Adverse Reactions [Warning and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Eravacycline was evaluated in 3 active-controlled clinical trials (Trial 1, Trial 2 and Trial 3) in adults with cIAI. These trials included two Phase 3 trials (Trial 1and Trial 2) and one Phase 2 trial (Trial 3, NCT01265784). The Phase 3 trials included 520 patients treated with eravacycline and 517 patients treated with comparator antibacterial drugs (ertapenem or meropenem). The median age of patients treated with eravacycline was 56 years, ranging between 18 and 93 years old; 30% were age 65 years and older. Patients treated with eravacycline were predominantly male (57%) and Caucasian (98%). The eravacycline- treated population included 31% obese patients (BMI ≥ 30 kg/m2) and 8% with baseline moderate to severe renal impairment (calculated creatinine clearance 15 to less than 60 mL/min). Among the trials, 66 (13%) of patients had baseline moderate hepatic impairment (Child Pugh B); patients with severe hepatic impairment (Child Pugh C) were excluded from the trials.

Adverse Reactions Leading to Discontinuation

Treatment discontinuation due to an adverse reaction occurred in 2% (11/520) of patients receiving eravacycline and 2% (11/517) of patients receiving the comparator. The most commonly reported adverse reactions leading to discontinuation of eravacycline were related to gastrointestinal disorders.

Most Common Adverse Reactions

Adverse reactions occurring at 3% or greater in patients receiving eravacycline were infusion site reactions, nausea and vomiting.

Table 1 lists adverse reactions occurring in ≥ 1% of patients receiving eravacycline and with incidences greater than the comparator in the Phase 3 cIAI clinical trials. A similar adverse reaction profile was observed in the Phase 2 cIAI clinical trial (Trial 3).

Table 1. Selected Adverse Reactions Reported in ≥ 1% of Patients Receiving Eravacycline in the Phase 3 cIAI Trials (Trial 1 and Trial 2)

Abbreviations: IV=intravenous

a Eravacycline dose equals 1 mg/kg every 12 hours IV.

b Comparators include ertapenem 1 g every 24 hours IV and meropenem 1 g every 8 hours IV.

c Infusion site reactions include: catheter/vessel puncture site pain, infusion site extravasation, infusion site hypoaesthesia, infusion/injection site phlebitis, infusion site thrombosis, injection site/vessel puncture site erythema, phlebitis, phlebitis superficial, thrombophlebitis, and vessel puncture site swelling.

Other Adverse Reactions of Eravacycline

The following selected adverse reactions were reported in eravacycline-treated patients at a rate of less than 1% in the Phase 3 trials:

Cardiac disorders: palpitations

Gastrointestinal System: acute pancreatitis, pancreatic necrosis

General Disorders and Administrative Site Conditions: chest pain

Immune system disorders: hypersensitivity

Laboratory Investigations: increased amylase, increased lipase, increased alanine aminotransferase, prolonged activated partial thromboplastin time, decreased renal clearance of creatinine, increased gamma-glutamyltransferase, decreased white blood cell count, neutropenia

Metabolism and nutrition disorders: hypocalcemia

Nervous System: dizziness, dysgeusia

Psychiatric disorders: anxiety, insomnia, depression

Respiratory, Thoracic, and Mediastinal System: pleural effusion, dyspnea

Skin and subcutaneous tissue disorders: rash, hyperhidrosis

7. DRUG INTERACTIONS

7.1 Effect of Strong CYP3A Inducers on Eravacycline

Concomitant use of strong CYP3A inducers decreases the exposure of eravacycline, which may reduce the efficacy of eravacycline [see Clinical Pharmacology]. Increase eravacycline dose in patients with concomitant use of a strong CYP3A inducer [see Dosage and Administration (3.3)].

7.2 Anticoagulant Drugs

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Eravacycline, like other tetracycline-class antibacterial drugs, may cause discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy [see Warnings and Precautions (5.1, 5.2), Data, Use in Specific Populations (8.4)]. The limited available data with eravacycline use in pregnant women are insufficient to inform drug-associated risk of major birth defects and miscarriages. Animal studies indicate that eravacycline crosses the placenta and is found in fetal plasma; doses greater than approximately 3- and 2.8- times the clinical exposure, based on AUC in rats and rabbits, respectively, administered during the period of organogenesis, were associated with decreased ossification, decreased fetal body weight, and/or increased post-implantation loss [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Embryo-fetal development studies in rats and rabbits reported no treatment-related effects at approximately 3 and 2.8 times the clinical exposure (based on AUC). Dosing was during the period of organogenesis, i.e. gestation days 7-17 in rats and gestation days 7-19 in rabbits. Higher doses, approximately 8.6 and 6.3 times the clinical exposure (based on AUC) in rats and rabbits, respectively, were associated with fetal effects including increased post-implantation loss, reduced fetal body weights, and delays in skeletal ossification in both species, and abortion in the rabbit.

A peri-natal and post-natal rat toxicity study demonstrated that eravacycline crosses the placenta and is found in fetal plasma following intravenous administration to the dams. This study did not demonstrate anatomical malformations, but there were early decreases in pup weight that were later comparable to controls and a non-significant trend toward increased stillbirths or dead pups during lactation. F1 males from dams treated with 10 mg/kg/day eravacycline that continued to fertility testing had decreased testis and epididymis weights at approximately Post- Natal Day 111 that may have been at least partially related to lower body weights in this group.

Tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy.

8.2 Lactation

Risk Summary

It is not known whether eravacycline is excreted in human breast milk. Eravacycline (and its metabolites) is excreted in the milk of lactating rats (see Data). Tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including eravacycline, by the breastfed infant is not known. There are no data on the effects of eravacycline on the breastfed infant, or the effects on milk production. Because there are other antibacterial drug options available to treat cIAI in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with eravacycline and for 4 days (based on half-life) after the last dose.

Data

Animal Data

Eravacycline (and its metabolites) was excreted in the milk of lactating rats on post-natal day 15 following intravenous administration of 3, 5, and 10 mg/kg/day eravacycline.

8.3 Females and Males of Reproductive Potential

Infertility

Based on animal studies, eravacycline can lead to impaired spermiation and sperm maturation, resulting in abnormal sperm morphology and poor motility. The effect is reversible in rats. The long-term effects of eravacycline on male fertility have not been studied [see Nonclinical Toxicology].

8.4 Pediatric Use

The safety and effectiveness of eravacycline in pediatric patients have not been established.

Due to the adverse effects of the tetracycline-class of drugs, including eravacycline on tooth development and bone growth, use of eravacycline in pediatric patients less than 8 years of age is not recommended [see Warnings and Precautions (5.1, 5.2)].

8.5 Geriatric Use

Of the total number of patients with cIAI who received eravacycline in Phase 3 clinical trials (n = 520), 158 subjects were ≥ 65 years of age, while 59 subjects were ≥ 75 years of age. No overall differences in safety or efficacy were observed between these subjects and younger subjects.

No clinically relevant differences in the pharmacokinetics of eravacycline were observed with respect to age in a population pharmacokinetic analysis of eravacycline [see Clinical Pharmacology].

8.6 Hepatic Impairment

No dosage adjustment is warranted for eravacycline in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Adjust eravacycline dosage in patients with severe hepatic impairment (Child Pugh C) [see Dosage and Administration (3.2) and Clinical Pharmacology].

8.7 Renal Impairment

No dosage adjustment is necessary for eravacycline in patients with renal impairment [see Clinical Pharmacology].

9. OVERDOSAGE

No reports of overdose were reported in clinical trials. In the case of suspected overdose, eravacycline should be discontinued and the patient monitored for adverse reactions. Hemodialysis is not expected to remove significant quantities of eravacycline [see Clinical Pharmacology].

10. MECHANISM OF ACTION

Eravacycline is an antibacterial drug.

Mechanism of Action

Eravacycline is a fluorocycline antibacterial within the tetracycline class of antibacterial drugs. Eravacycline disrupts bacterial protein synthesis by binding to the 30S ribosomal subunit thus preventing the incorporation of amino acid residues into elongating peptide chains.

In general, eravacycline is bacteriostatic against gram-positive bacteria (e.g., Staphylococcus aureus and Enterococcus faecalis); however, in vitro bactericidal activity has been demonstrated against certain strains of Escherichia coli and Klebsiella pneumoniae.

Resistance

Eravacycline resistance in some bacteria is associated with upregulated, non-specific intrinsic multidrug-resistant (MDR) efflux, and target-site modifications such as to the 16s rRNA or certain 30S ribosomal proteins (e.g., S10).

The C7 and C9 substitutions in eravacycline are not present in any naturally occurring or semisynthetic tetracyclines and the substitution pattern imparts microbiological activities including in vitro activity against gram-positive and gram-negative strains expressing certain tetracycline-specific resistance mechanism(s) [i.e., efflux mediated by tet(A), tet(B), and tet(K); ribosomal protection as encoded by tet(M) and tet(Q)].

Activity of eravacycline was demonstrated in vitro against Enterobacteriaceae in the presence of certain beta-lactamases, including extended spectrum β-lactamases, and AmpC. However, some beta-lactamase-producing isolates may confer resistance to eravacycline via other resistance mechanisms.

The overall frequency of spontaneous mutants in the gram-positive organisms tested was in the range of 10-9 to 10-10 at 4 times the eravacycline Minimum Inhibitory Concentration (MIC). Multistep selection of gram-negative strains resulted in a 16- to 32-times increase in eravacycline MIC for one isolate of Escherichia coli and Klebsiella pneumoniae, respectively. The frequency of spontaneous mutations in K. pneumoniae was 10-7 to 10-8 at 4 times the eravacycline MIC.

Interaction with Other Antimicrobials

In vitro studies have not demonstrated antagonism between eravacycline and other commonly used antibacterial drugs for the indicated pathogens.

Antimicrobial Activity

Eravacycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (2)]:

Aerobic bacteria

Gram-positive bacteria

Enterococcus faecalis

Enterococcus faecium

Staphylococcus aureus

Streptococcus anginosus group

Gram-negative bacteria

Citrobacter freundii

Enterobacter cloacae

Escherichia coli

Klebsiella oxytoca

Klebsiella pneumoniae

Anaerobic bacteria

Gram-positive bacteria

Clostridium perfringens

Gram-negative bacteria

Bacteroides caccae

Bacteroides fragilis

Bacteroides ovatus

Bacteroides thetaiotaomicron

Bacteroides uniformis

Bacteroides vulgatus

Parabacteroides distasonis

11. PHARMACODYNAMICS

The AUC divided by the MIC of eravacycline has been shown to be the best predictor of activity. Based on the flat exposure-response relationship observed in clinical studies, eravacycline exposure achieved with the recommended dosage regimen appears to be on the plateau of the exposure-response curve.

Cardiac Electrophysiology

The effect of eravacycline on the QTc interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, single-dose, crossover thorough QTc study in 60 healthy adult subjects. At the 1.5 mg/kg single dose (1.5 times the maximum approved recommended dose), eravacycline did not prolong the QTc interval to any clinically relevant extent.

12. PHARMACOKINETICS

Following single-dose intravenous administration, eravacycline AUC and Cmax increase approximately dose-proportionally over doses from 1 mg/kg to 3 mg/kg (3 times the approved dose).

The mean exposure of eravacycline after single and multiple intravenous infusions (approximately 60 minutes) of 1 mg/kg administered to healthy adults every 12 hours is presented in Table 2.

There is approximately 45% accumulation following intravenous dosing of 1 mg/kg every 12 hours.

Table 2: Mean (%CV) Plasma Exposure of Eravacycline After Single and Multiple Intravenous Dose in Healthy Adults

Abbreviations: Cmax = maximum observed plasma concentration, CV = coefficient of variation;

AUC0-12 = area under the plasma concentration-time curve from time 0 to 12 hours.

a AUC of day 1 equals AUC0-12 after the first dose of eravacycline.

b AUC of day 10 equals steady state AUC0-12.

Distribution

Protein binding of eravacycline to human plasma proteins increases with increasing plasma concentrations, with 79% to 90% (bound) at plasma concentrations ranging from 100 to 10,000 ng/mL. The volume of distribution at steady-state is approximately 321 L.

Elimination

The mean elimination half-life is 20 hours.

Metabolism

Eravacycline is metabolized primarily by CYP3A4- and FMO-mediated oxidation.

Excretion

Following a single intravenous dose of radiolabeled eravacycline 60 mg, approximately 34% of the dose is excreted in urine and 47% in feces as unchanged eravacycline (20% in urine and 17% in feces) and metabolites.

Specific Populations

No clinically significant differences in the pharmacokinetics of eravacycline were observed based on age (18-86 years), sex, and race.

Patients with Renal Impairment

The geometric least square mean Cmax for eravacycline was increased by 8.8% for subjects with end stage renal disease (ESRD) versus healthy subjects with 90% CI -19.4, 45.2. The geometric least square mean AUC0-inf for eravacycline was decreased by 4.0% for subjects with ESRD versus healthy subjects with 90% CI -14.0, 12.3 [see Use in Specific Populations (8.7)].

Patients with Hepatic Impairment Eravacycline Cmax was 13.9%, 16.3%, and 19.7% higher in subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), and severe (Child-Pugh Class C) hepatic impairment versus healthy subjects, respectively. Eravacycline AUC0-inf was 22.9%, 37.9%, and 110.3% higher in subjects with mild, moderate, and severe hepatic impairment versus healthy subjects, respectively [see Dosage and Administration (3.2) and Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

Concomitant use of rifampin (strong CYP3A4/3A5 inducer) decreased eravacycline AUC by 35% and increased eravacycline clearance by 54% [see Dosage and Administration (3.3) and Drug Interactions (7.1)].

Concomitant use of itraconazole (strong CYP3A inhibitor) increased eravacycline Cmax by 5% and AUC by 32%, and decreased eravacycline clearance by 32%.

In Vitro Studies

Eravacycline is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Eravacycline is not an inducer of CYP1A2, 2B6, or 3A4.

Eravacycline is not a substrate for P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter peptide (OATP)1B1, OATP1B3, organic ion transporter (OAT)1, OAT3, OCT1, OCT2, multidrug and toxin extrusion (protein) (MATE)1, or MATE2-K transporters.

Eravacycline is not an inhibitor of BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K transporters.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

XERAVA for injection, 50 mg/vial, is a yellow to orange, sterile, preservative-free powder for reconstitution in single-dose 10-mL clear glass vials with a rubber stopper and an aluminum overseal. Each vial contains 50 mg of eravacycline (equivalent to 63.5 mg of eravacycline dihydrochloride). XERAVA is supplied in two packaging configurations:

Single-vial carton containing one 50 mg single-dose vial: NDC 71773-050-05.

Twelve-vial carton containing twelve 50 mg single-dose vial cartons: NDC 71773-050-12.

Storage and Handling:

Prior to reconstitution, XERAVA should be stored at 2°C to 8°C (36°F to 46°F) [see Dosage and Administration 3.4]. Keep vial in carton until use.

Rx only

Rev 08/18