24/19. Lefamulin-(XENLETA)-@- (Aug-2019)- Anti-bacterial drug
Drug Name:24/19. Lefamulin-(XENLETA)-@- (Aug-2019)- Anti-bacterial drug
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS
Summary-
XENLETA Injection
Strong or moderate CYP3A inducers or P-gp inducers
Avoid XENLETA unless the benefit outweighs the risk. Monitor for reduced efficacy.
XENLETA Tablets
Strong or moderate CYP3A inducers or P-gp inducers
Avoid XENLETA unless the benefit outweighs the risk. Monitor for reduced efficacy.
Strong CYP3A inhibitors or P-gp inhibitors
Avoid XENLETA.
Moderate CYP3A inhibitors or P-gp inhibitors
Monitor for adverse reactions.
CYP3A substrates that prolong the QT interval
Concomitant use is contraindicated.
Midazolam and other sensitive CYP3A substrates
Monitor for adverse reactions.
Dertails-
1. Effect of Other Drugs on XENLETA
Strong and Moderate CYP3A Inducers or P-gp Inducers
Concomitant use of oral or intravenous XENLETA with strong CYP3A4 inducers or P-gp inducers decreases lefamulin AUC and Cmax ,which may reduce the efficacy of XENLETA.
Avoid concomitant use of XENLETA Injection and XENLETA Tablets with strong and moderate CYP3A4 inducers or P-gp inducers unless the benefit outweighs the risks.
Strong and Moderate CYP3A Inhibitors or P-gp Inhibitors
Concomitant use of XENLETA Tablets with strong CYP3A inhibitors or P-gp inhibitors increases lefamulin AUC, which may increase the risk of adverse reactions with XENLETA Tablets.
Avoid concomitant use of XENLETA Tablets with strong CYP3A inhibitors or P-gp inhibitors. Monitor for adverse effects of XENLETA Tablets when administered concomitantly with moderate CYP3A inhibitors or P-gp inhibitors.
2. Effect of XENLETA on Other Drugs
CYP3A4 Substrates
Concomitant use of XENLETA Tablets with sensitive CYP3A4 substrates increases the AUC and Cmax of CYP3A4 substrates , which may increase the risk of toxicities associated with cardiac conduction.
Concomitant use with CYP3A substrates known to prolong the QT interval is contraindicated
Concomitant use of sensitive CYP3A substrates with XENLETA Tablets requires close monitoring for adverse effects of these drugs (for example, alprazolam, diltiazem, verapamil, simvastatin, vardenafil).
Concomitant use of XENLETA Injection with CYP3A4 substrates does not affect the exposure of CYP3A4 substrates.
3. Drugs that Prolong QT
The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between XENLETA and other drugs that effect cardiac conduction is unknown.
Therefore, avoid concomitant use of XENLETA Injection and XENLETA Tablets with such drugs (for example, Class IA and III antiarrhythmics, antipsychotics, erythromycin, moxifloxacin, tricyclic antidepressants).
Indication:
BRIEF SUMMARY
LEFAMULIN- (Aug 2019)
Indn- To treat adult with comminity -acquired bacterial pneumonia
Comp- Tablets • 600 mg of lefamulin. It is a pleuromutilin antibacterial indicated for the treatment of adults with community-acquired bacterial pneumonia (CABP) caused by susceptible microorganisms.
ADR- Most common adverse reactions (incidence =2%) are:•
Injection: administration site reactions, hepatic enzyme elevation, nausea, hypokalemia, insomnia, headache.
• Tablets: diarrhea, nausea, vomiting, hepatic enzyme elevation.
CI- is contraindicated in patients with known hypersensitivity to lefamulin, pleuromutilin class drugs, or any of the components
•Concomitant use of tablets with CYP3A substrates that prolong the QT interval is contraindicated.
WARNINGS-
•QT Prolongation: Avoid use in patients with known QT prolongation, ventricular arrhythmias including torsades de pointes, and patients receiving drugs that prolong the QT interval such as antiarrhythmic agents.
Pat Infm-
Diarrhea
Advise patients that diarrhea is a common problem caused by antibacterial drugs, including A, which usually ends when the antibacterial drug is discontinued.
Sometimes after starting treatment with an antibacterial drug, patients can develop watery 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.
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U.S. FDA APPROVED DRUGS DURING 2019
Sr.No.24.
Name of the Drug- XENLETA
Active Ingredient - Lefamulin
Pharmacological Classification-
To treat adult with comminity -acquired bacterial pneumonia
Date of Approval - 8/19/2019
(Ref- FDA approved List 2019
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use XENLETATM safely and effectively.
See full prescribing information for XENLETA. XENLETA (lefamulin) injection, for intravenous use XENLETA (lefamulin) tablets, for oral use
Initial U.S. Approval: 2019
INDICATIONS AND USAGE
XENLETA is a pleuromutilin antibacterial indicated for the treatment of adults with community-acquired bacterial pneumonia (CABP) caused by susceptible microorganisms.
To reduce the development of drug resistant bacteria and maintain the effectiveness of XENLETA and other antibacterial drugs, XENLETA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
Adverse Reaction:
ADVERSE REACTIONS
Most common adverse reactions (incidence =2%) are:
•
XENLETA Injection: administration site reactions, hepatic enzyme elevation, nausea, hypokalemia, insomnia, headache.
•
XENLETA Tablets: diarrhea, nausea, vomiting, hepatic enzyme elevation.
Contra-Indications:
CONTRA-INDICATIONS
• XENLETA is contraindicated in patients with known hypersensitivity to lefamulin, pleuromutilin class drugs, or any of the components of XENLETA.
•Concomitant use of XENLETA tablets with CYP3A substrates that prolong the QT interval is contraindicated.
WARNINGS AND PRECAUTIONS
•QT Prolongation: Avoid use in patients with known QT prolongation, ventricular arrhythmias including torsades de pointes, and patients receiving drugs that prolong the QT interval such as antiarrhythmic agents.
•Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception.
•Clostridium difficile-associated Diarrhea (CDAD): Evaluate patients who develop diarrhea.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
XENLETA is a pleuromutilin antibacterial indicated for the treatment of adults with community-acquired bacterial pneumonia (CABP) caused by susceptible microorganisms.
To reduce the development of drug resistant bacteria and maintain the effectiveness of XENLETA and other antibacterial drugs, XENLETA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.2)
DOSAGE AND ADMINISTRATION
• For treatment of adults with CABP, the recommended dosage of XENLETA is as follows:
Dosage Treatment Duration 150 mg every 12 hours by intravenous infusion over 60 minutes* 5 to 7 days
600 mg orally every 12 hours. 5 days *With the option to switch to XENLETA Tablets 600 mg every 12 hours to complete the treatment course.
• Patients with Hepatic Impairment:
Reduce the dosage of XENLETA Injection to 150 mg infused over 60 minutes every 24 hours in patients with severe hepatic impairment (Child-Pugh Class C).
XENLETA Tablets have not been studied in and are not recommended for patients with moderate (Child-Pugh Class B) or severe hepatic impairment
Administration Instruction for XENLETA Tablets:
Take at least 1 hour before a meal or 2 hours after a meal. Swallow XENLETA Tablets • • whole with water (6 to 8 ounces).
Administration Instruction for XENLETA Injection:
Infuse over 60 minutes.
See Full Prescribing Information for additional information on the administration and preparation of XENLETA Tablets and Injection.
DOSAGE FORMS AND STRENGTHS
Injection • A single-dose clear glass vial containing 150 mg of lefamulin in 15 mL of 0.9% sodium chloride for further dilution prior to intravenous infusion.
Tablets • 600 mg of lefamulin.
Patient Information:
PATIENT COUNSELING INFORMATION
Diarrhea
Advise patients that diarrhea is a common problem caused by antibacterial drugs, including XENLETA, which usually ends when the antibacterial drug is discontinued.
Sometimes after starting treatment with an antibacterial drug, patients can develop watery 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
Nausea and Vomiting
Advise patients that nausea and vomiting are common adverse reactions to XENLETA
Drug Interactions
Advise patients of the potential interaction other medications can have with XENLETA or the effect XENLETA may have on other medications, as these interactions may result in decreased effectiveness or increased toxicities of either XENLETA or the other medications.
Patients should alert their physician if they are currently taking any medication(s) (including herbal or nutritional supplements) or are prescribed new medication(s) during treatment with XENLETA
Allergic Reactions
Advise patients that allergic reactions, including serious allergic reactions, could occur with XENLETA and that serious allergic reactions require immediate treatment. Ask the patient about any previous hypersensitivity reactions to XENLETA, or other pleuromutilin class antibacterial drugs
Administration with Food
Advise patients that XENLETA should be taken at least 1 hour before a meal or 2 hours after a meal and should be swallowed whole with water (6 to 8 ounces). XENLETA should not be crushed or divided
Embryo-Fetal Toxicity
Advise pregnant women and females of reproductive potential of the potential risk to a fetus, and to inform their healthcare provider of a known or suspected pregnancy.
Advise patients to avoid becoming pregnant while receiving this drug
Advise females of reproductive potential to use effective contraception during treatment with XENLETA and for 2 days after the final dose
Inform patients that Nabriva Therapeutics has a surveillance program for pregnant women who have inadvertently taken XENLETA during pregnancy.
Lactation
Advise lactating women to pump and discard human milk for the duration of treatment with XENLETA and for 2 days after the final dose
Antibacterial Resistance
Patients should be counseled that antibacterial drugs including XENLETA should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).
When XENLETA is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of treatment, 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 XENLETA or other antibacterial drugs in the future
Distributed by:
Nabriva Therapeutics US, Inc. Nabriva Therapeutics is a trademark of Nabriva Therapeutics Ireland DAC XENLETA is a trademark of Nabriva Therapeutics Ireland DAC For patent information: www.nabriva.com/patents Copyright © 2019 Nabriva Therapeutics US, Inc., an affiliate of Nabriva Therapeutics Ireland
DAC. All rights reserved
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
XENLETA is an antibacterial drug [see Microbiology
2. Pharmacodynamics
The 24 h free-drug AUC to minimal inhibitory concentration (MIC) ratio has been shown to be the best Pharmacokinetic-Pharmacodynamic (PK-PD) index for the antibacterial activity of lefamulin in animal infection models of Streptococcus pneumoniae and Staphylococcus aureus pneumonia.
Cardiac Electrophysiology
The QTcF interval prolongation risk of XENLETA was evaluated using 2 randomized, double-blind, double-dummy, active controlled (moxifloxacin 400 mg once daily), parallel group, trials (Trials 1 and 2) in adult patients with CABP.
3. Pharmacokinetics
Following single-dose intravenous administration, the AUC of lefamulin increased approximately dose-proportionally while the Cmax of lefamulin increased less than dose-proportionally over a dose range of 25 mg (0.17 times the approved dose) to 400 mg (2.67 times the approved dose).
Absorption
The mean oral bioavailability of XENLETA Tablets is approximately 25% and peak lefamulin plasma concentration occurred 0.88 to 2 hours after administration to healthy subjects.
Effect of Food
The concomitant administration of a single oral dose of 600 mg XENLETA Tablets with a high fat (approximately 50% of total calories from fat), high calorie breakfast (approximately 800-1000 calories) slightly reduced bioavailability.
The mean relative reduction for oral XENLETA (fasted vs. fed) was on average 22.9% [90% CI: 12.2; 32.3] for the Cmax and 18.43% [90% CI: 11.7; 24.7] for the AUC0-inf.
Distribution
Mean plasma protein binding of lefamulin ranges from 94.8% at 2.35 mcg/mL to 97.1% at 0.25 mcg/mL in healthy adults.
The mean (min to max) steady state volume of distribution of lefamulin is 86.1 L (34.2 to 153 L) in patients with CABP after administration of XENLETA Injection.
Elimination
The mean (min to max) total body clearance of lefamulin is 11.9 L/h (2.94 to 30.0 L/h) in patients with CABP after XENLETA Injection administration.
The mean (min to max) elimination half-life of lefamulin is approximately 8 hours (3 to 20 h) in patients with CABP.
Metabolism
Lefamulin is primarily metabolized by CYP3A4.
Excretion
In healthy adult subjects, the mean % of total radioactivity excreted in feces was 77.3% (4.2% to 9.1% unchanged) and 88.5% (7.8% to 24.8% unchanged), and in urine was 15.5% (9.6% to 14.1% unchanged) and 5.3% (unchanged not determined) following 150 mg IV or 600 mg oral XENLETA, respectively.
Specific Populations
No clinically significant differences in the pharmacokinetics of XENLETA were observed based on age, sex, race, weight, or renal impairment including patients receiving hemodialysis.
Patients with Hepatic Impairment
The disposition of lefamulin was evaluated in non-infected subjects with normal hepatic function and with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment following administration of XENLETA Injection.
The half-life of lefamulin is prolonged in subjects with severe hepatic impairment compared to that in subjects with normal hepatic function (17.5 h versus 11.5 h).
Drug Interaction Studies
Clinical Studies
Effect of Other Drugs on the Pharmacokinetics of Lefamulin
Strong CYP3A inducers or P-gp inducers: oral rifampin (strong inducer) reduced the mean lefamulin AUC0-inf and Cmax by 28% and 8%, respectively, when administered concomitantly with XENLETA Injection.
Additionally, oral rifampin reduced the mean lefamulin AUC0-inf and Cmax by 72% and 57%, respectively, when administered concomitantly with XENLETA Tablets.
Strong CYP3A inhibitors or P-gp inhibitors:
oral ketoconazole (strong inhibitor) increased the mean lefamulin AUC0-inf and Cmax by 31% and 6%, respectively, when administered concomitantly with XENLETA Injection.
Additionally, oral ketoconazole (strong inhibitor) increased the lefamulin AUC0-inf and Cmax by 165% and 58%, respectively, when administered concomitantly with XENLETA tablets.
Effect of Lefamulin on the Pharmacokinetics of Other Drugs
CYP3A Substrates: No clinically significant differences in the pharmacokinetics of midazolam were observed when administered concomitantly with XENLETA Injection.
P-gp substrates:
No clinically significant differences in the pharmacokinetics of digoxin (P-gp substrate) were observed when administered concomitantly with XENLETA Tablets.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Risk Summary
Based on findings from animal studies, lefamulin may cause fetal harm when administered to pregnant women.
There are no available data on the use of XENLETA in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.
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
There are no data on the presence of XENLETA in human milk, its effects on the breastfed infant, or its effects on milk production.
Animal studies indicate that lefamulin was concentrated in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.
Because of the potential for serious adverse reactions, including QT prolongation, a woman should pump and discard human milk for the duration of treatment with XENLETA and for 2 days after the final dose.
3. Females and Males of Reproductive Potential
Pregnancy Testing Verify pregnancy status in females of reproductive potential. Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with XENLETA and for 2 days after the final dose. XENLETA may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
4. Pediatric Use
The safety and effectiveness of XENLETA in patients less than 18 years of age has not yet been established.
5. Geriatric Use
Of the 646 patients randomized to XENLETA in Trials 1 and 2, 268 (41.5%) were =65 years of age. Early clinical response (ECR) rates in the subgroup of patients =65 were similar to ECR rates in subjects <65 years of age and comparable across treatment groups (XENLETA versus moxifloxacin).
The adverse reaction profiles in patients =65 years and in patients <65 years of age were similar. The percentage of patients in the XENLETA group who had at least one adverse reaction was 30% in patients =65 years and 38% in patients <65 years.
6. Hepatic Impairment
XENLETA Injection
Dosage of XENLETA Injection should be reduced by extending the dosing interval for patients with severe hepatic impairment (Child-Pugh Class C).
No dosage adjustment of XENLETA Injection is needed for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
XENLETA Tablets:
XENLETA Tablets have not been studied in patients with hepatic impairment.
It is not recommended to use XENLETA Tablets for patients with moderate or severe hepatic impairment
7. Renal Impairment
No dosage adjustment of XENLETA is warranted in patients with renal impairment, including those on hemodialysis.
OVERDOSAGE
Treatment of overdose with XENLETA should consist of observation and general support measures. Lefamulin and its primary metabolite are not dialyzable.
