DRUG INTERACTIONS-

 • Concomitant use of strong CYP3A inducers decreases the exposure of eravacycline. Increase XERAVA dose with concomitant use of a strong CYP3A inducer

• Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage 

U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  34

ADVERSE REACTIONS-

 Most common adverse reactions (incidence = 3%) are infusion site reactions, nausea, and vomiting.

CONTRAINDICATIONS-

 • Known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or any of the excipients in XERAVA

WARNINGS AND PRECAUTIONS-

 • Hypersensitivity Reactions:                                                                                            Life-threatening hypersensitivity (anaphylactic) reactions have been reported with tetracycline antibacterial drugs, including XERAVA. Avoid use in patients with known hypersensitivity to tetracyclines.

• Tooth Discoloration and Enamel Hypoplasia:                                                               The use of XERAVA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown) and enamel hypoplasia.

 • Inhibition of Bone Growth:                                                                                             The use of XERAVA 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.

 • Clostridium difficile-associated diarrhea:                                                                     Evaluate if diarrhea occurs.

 PATIENT COUNSELING INFORMATION-

 Serious Allergic Reactions-                                                                                                Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask patient about any previous hypersensitivity reactions to antibacterial drugs including tetracycline or other allergens.

 Tooth Discoloration and Inhibition of Bone Growth-                                                     Advise patients that XERAVA, like other tetracycline-class drugs, may cause permanent tooth discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy. 

Tell your healthcare provider right away if you become pregnant during treatment.

 Lactation-                                                                                                                            Advise women not to breastfeed during treatment with XERAVA and for 4 days after the last dose 

 Diarrhea  -                                                                                                                          Diarrhea is a common problem caused by antibacterial drugs, including XERAVA, which usually ends when the antibacterial drug is discontinued. 

 Sometimes after starting treatment with antibacterial drug, patients can develop watery and bloody stools (with or without stomach cramps and fever) which may be a sign of a more serious intestinal infection, even as late as 2 or more months after having taken the last dose of the antibacterial drug. 

If this occurs, instruct patients to contact their healthcare provider as soon as possible

Tetracycline Class Adverse Reactions -                                                                          Inform patients that XERAVA is similar to tetracycline-class antibacterial drugs and may have similar adverse reactions

Overgrowth of Non-susceptible Microorganisms-                                                           Inform patients that antibacterial drugs including XERAVA may promote the overgrowth of non-susceptible microorganisms, including fungi

Antibacterial Resistance-                                                                                                   Inform patients that antibacterial drugs including XERAVA should only be used to treat bacterial infections.  They do not treat viral infections (for example, the common cold). 

When XERAVA is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. 

Skipping doses or not completing the full course of therapy may                                 (1) decrease the effectiveness of the immediate treatment and                                           (2) increase the likelihood that bacteria will develop resistance and will not be treatable         by XERAVA or other antibacterial drugs in the future.

 Distributed by:                                                                                                        Tetraphase Pharmaceuticals, Inc. 480 Arsenal Way, Ste 110 Watertown, MA 02472 XERAVA™ is a trademark of Tetraphase Pharmaceuticals, Inc. ©2018, Tetraphase Pharmaceuticals, Inc.  All rights reserved.

 CLINICAL PHARMACOLOGY-

1.Mechanism of Action-                                                                                                      Eravacycline is an antibacterial drug

2. 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 XERAVA 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), XERAVA did not prolong the QTc interval to any clinically relevant extent.

3. 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).

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.

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.

Drug Interaction Studies-                                                                                                  Clinical Studies- Concomitant use of rifampin (strong CYP3A4/3A5 inducer) decreased eravacycline AUC by 35% and increased eravacycline clearance by 54%.

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

 USE IN SPECIFIC POPULATIONS-       

1. Pregnancy Risk Summary-                                                                                             XERAVA, 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.

The limited available data with XERAVA use in pregnant women are insufficient to inform drug-associated risk of major birth defects and miscarriages.

  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.

2. Lactation Risk Summary-                                                                                              It is not known whether XERAVA is excreted in human breast milk.  Eravacycline (and its metabolites) is excreted in the milk of lactating rats .

  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 XERAVA 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 XERAVA and for 4 days (based on half-life) after the last dose. 

3. Females and Males of Reproductive Potential Infertility-                                           Based on animal studies, XERAVA 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 XERAVA on male fertility have not been studied.

4. Pediatric Use-                                                                                                                The safety and effectiveness of XERAVA in pediatric patients have not been established.   

Due to the adverse effects of the tetracycline-class of drugs, including XERAVA on tooth development and bone growth, use of XERAVA in pediatric patients less than 8 years of age is not recommended.

5. Geriatric Use-                                                                                                                    Of the total number of patients with cIAI who received XERAVA 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.

6. Hepatic Impairment-                                                                                                       No dosage adjustment is warranted for XERAVA in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Adjust XERAVA dosage in patients with severe hepatic impairment (Child Pugh C)

7. Renal Impairment-                                                                                                            No dosage adjustment is necessary for XERAVA in patients with renal impairment.

 OVERDOSAGE-                                                                                                                  No reports of overdose were reported in clinical trials.  In the case of suspected overdose, XERAVA should be discontinued and the patient monitored for adverse reactions. Hemodialysis is not expected to remove significant quantities of XERAVA.