DRUG INTERACTIONS

 

1. Chelation Agents: 

 Antacids, Sucralfate, Metal Cations, Multivitamins

 Fluoroquinolones form chelates with alkaline earth and transition metal cations. 

 Oral administration of BAXDELA with antacids containing aluminum or magnesium,

 with sucralfate, with metal cations such as iron, or with multivitamins containing

 iron or zinc, or with formulations containing divalent and trivalent cations such

 as didanosine buffered tablets for oral suspension or the pediatric powder 

 for oral solution, may substantially interfere with the absorption of BAXDELA, 

 resulting in systemic concentrations considerably lower than desired. 

 

Therefore, BAXDELA should be taken at least 2 hours before or 6 hours 

 after these agents 

 

There are no data concerning an interaction of intravenous BAXDELA with 

 oral antacids, sucralfate,multivitamins, didanosine, or metal cations. 

 

However, BAXDELA should not be co-administered with any solution 

 containing multivalent cations, e.g., magnesium, through the same 

 intravenous line 

U.S. FDA APPROVED  DRUGS DURING 2017

 

Sr.No-  22

  

Name of the  Drug-        Baxdela

 

Active Ingredient-         Delafloxacin                                                                                                                                                                                                                                Pharmacological Classification- 

 

                       To treat patients with acute bacterial skin infections                  

                                                                                                                                                             

Date of Approval-          06-19-2017

 

 (Ref- FDA approved List 2017)

 

                                                                                         

 HIGHLIGHTS OF PRESCRIBING INFORMATION 

 

These highlights do not include all the information needed 

to use BAXDELA. safely and effectively.

 See full prescribing information for BAXDELA.

 

BAXDELA (delafloxacin) tablets, for oral use 

BAXDELA (delafloxacin) for injection, for intravenous use 

Initial U.S. Approval: 2017

 

WARNING: 

 SERIOUS ADVERSE REACTIONS

 INCLUDING TENDINITIS, TENDON RUPTURE,

 PERIPHERAL NEUROPATHY, CENTRAL NERVOUS

 SYSTEM EFFECTS, and EXACERBATION OF

 MYASTHENIA GRAVIS

 

See full prescribing information for complete boxed warning.

 

 Fluoroquinolones have been associated with disabling and potentially 

 irreversible serious adverse reactions that have occurred together,including:

Tendinitis and tendon rupture .

 Peripheral neuropathy .

 Central nervous system effects 

 

 Discontinue BAXDELA immediately and avoid the use of fluoroquinolones, 

 including BAXDELA, in patients who experience any of these serious 

 adverse reactions. 

.

 Fluoroquinolones may exacerbate muscle weakness in patients with 

 myasthenia gravis. Avoid BAXDELA in patients with known history

 of myasthenia gravis. 

 

                                                                                                                                                 INDICATIONS AND USAGE

 

 BAXDELA is a fluoroquinolone antibacterial indicated in adults 

 for the treatment of acute bacterial skin and skin structure infections

  (ABSSSI) caused by designated susceptible bacteria.

 

 To reduce the development of drug-resistant bacteria and maintain 

 the effectiveness of BAXDELA and other antibacterial drugs,

  BAXDELA should be used only to treat infections that are proven 

 or strongly suspected to be caused by bacteria                                                           

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               

 

ADVERSE REACTIONS 

 

Most common adverse reactions (incidence . 2%) are nausea, diarrhea, 

headache, transaminase elevations and vomiting.

 

 CONTRAINDICATIONS 

 

 Known hypersensitivity to BAXDELA or other fluoroquinolones.

 

 WARNINGS AND PRECAUTIONS.

 

 Hypersensitivity Reactions: 

 May occur after first or subsequent doses of BAXDELA. 

 Discontinue BAXDELA at the first sign of a skin rash or any other sign 

 of hypersensitivity. 

 

 Clostridium difficile-associated diarrhea: 

 Evaluate if diarrhea occurs. 

INDICATIONS AND USAGE

 

 BAXDELA is a fluoroquinolone antibacterial indicated in adults 

 for the treatment of acute bacterial skin and skin structure infections

  (ABSSSI) caused by designated susceptible bacteria.

 

 To reduce the development of drug-resistant bacteria and maintain 

 the effectiveness of BAXDELA and other antibacterial drugs,

  BAXDELA should be used only to treat infections that are proven 

 or strongly suspected to be caused by bacteria. 

 

 DOSAGE AND ADMINISTRATION.

 

Administer BAXDELA for injection 300 mg by intravenous infusion 

 over 60 minutes, every 12 hours, or a 450-mg BAXDELA tablet 

 orally every 12 hours for 5 to 14 days total duration. 

.

Dosage for patients with renal impairment is based on the estimated 

glomerular filtration rate (eGFR) 

 

                                     Table

 

Estimated Glomerular Filtration Rate        Recommended Dosage Regimen for 

 (eGFR)(mL/min/1.73m2).a                              for BAXDELA.c

 

                                                                    Oral                    Intravenous.b

 

 30-89                                      No dosage adjustment        No dosage adjustment

 

15-29                                       No dosage adjustment       200 mg every 12 hours

 

End Stage Renal Disease          Not Recommended.d     Not Recommended.d

(ESRD) (<15 including hemodialysis).

 

 Estimate of GFR based on 

a Modification of Diet in Renal Disease (MDRD) equation.

 b. All intravenous doses of BAXDELA are administered over 60 minutes. 

c. For a total treatment duration of 5 to 14 days. 

d. Not recommended due to insufficient information to provide dosing recommendations.

 

DOSAGE FORMS AND STRENGTHS 

 For Injection: 300 mg of delafloxacin (equivalent to 433 mg 

delafloxacin meglumine) as a lyophilized powder 

in a single dose vial for reconstitution and further dilution before 

intravenous infusion. 

.

Oral Tablets: 

450 mg delafloxacin (equivalent to 649 mg delafloxacin meglumine). 

 

 PATIENT COUNSELING INFORMATION

 

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

 

 Serious Adverse Reactions

 Advise patients to stop taking BAXDELA if they experience an adverse reaction

 and to call their healthcare provider for advice on completing the full course of

 treatment with another antibacterial drug.

 

 Inform patients of the following serious adverse reactions that have been 

 associated with BAXDELA or other fluoroquinolone use:

 

 Disabling and Potentially Irreversible Serious Adverse Reactions that may

 occur together: 

 

Inform patients that disabling and potentially irreversible serious adverse 

reactions, including tendinitis and tendon rupture, peripheral neuropathies, 

and central nervous system effects, have been associated with use of 

 fluoroquinolones and may occur together in the same patient. 

 

 Inform patients to stop taking BAXDELA immediately if they experience

  an adverse reaction and to call their healthcare provider.

 

  Tendinitis and Tendon Rupture: 

  Instruct patients to contact their healthcare provider if they experience pain, 

  swelling, or inflammation of a tendon, or weakness or inability to use one 

  of their joints; rest and refrain from exercise; and discontinue BAXDELA

  treatment. 

 

 Symptoms may be irreversible. The risk of severe tendon disorder with

  fluoroquinolones is higher in older patients usually over 60 years of age,

  in patients taking corticosteroid drugs, and in patients with kidney, 

 heart or lung transplants.

 

 Peripheral Neuropathy: 

 Inform patients that peripheral neuropathies have been associated with 

 BAXDELA use, symptoms may occur soon after initiation of therapy and 

 may be irreversible. 

 

If symptoms of peripheral neuropathy including pain, burning, tingling, 

 numbness and/or weakness develop, immediately discontinue 

 BAXDELA and tell them to contact their physician.

 

 Central Nervous System Effects:  (for example, convulsions, dizziness, 

 lightheadedness, increased  intracranial pressure): 

 

 Inform patients that convulsions have been reported in patients receiving

  fluoroquinolones, Instruct patients to notify their physician before 

 taking this drug if they have a history of convulsions. 

 

 Inform patients that they should know how they react to BAXDELA

  before they operate an automobile or machinery or engage in other

  activities requiring mental alertness and coordination. 

 

 Instruct patients to notify their physician if persistent headache with

 or without blurred vision occurs.

 

 Exacerbation of Myasthenia Gravis:

 Instruct patients to inform their physician of any history of myasthenia gravis. 

 Instruct patients to notify their physician if they experience any symptoms

 of muscle weakness, including respiratory difficulties.

 

 Hypersensitivity Reactions: 

 Inform patients that BAXDELA can cause hypersensitivity reactions, 

 even following a single dose, and to discontinue BAXDELA at the first sign

 of a skin rash, hives or other skin reactions, a rapid heartbeat, 

 difficulty in swallowing or breathing, any swelling suggesting angioedema 

 (for example, swelling of the lips, tongue, face, tightness of the throat, 

 hoarseness), or other symptoms of an allergic reaction.

 

 Diarrhea: 

 Diarrhea is a common problem caused by antibiotics which usually ends

  when the antibiotic is discontinued. Sometimes after starting treatment with

  antibiotics, patients can develop watery and bloody stools

  (with or without stomach cramps and fever) even as late as two or more 

 months after having taken the last dose of the antibiotic. 

 

 If this occurs, instruct patients to contact their physician as soon as possible.

 

 Antibacterial Resistance: 

 Inform patients that antibacterial drugs including BAXDELA Tablets and 

 Injection should only be used to treat bacterial infections. 

 They do not treat viral infections (for example, the common cold). 

 

 When BAXDELA Tablets and BAXDELA Injection are 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 BAXDELA Tablets and BAXDELA Injection or other 

 antibacterial drugs in the future.

 

 Administration with Food and Concomitant Medications

 Inform patients that BAXDELA Tablets may be taken with or without food 

 and without any dietary restrictions..

 

 Inform patients that BAXDELA Tablets should be taken at least 2 hours 

 before or 6 hours after antacids containing magnesium, or aluminum,

  with sucralfate, with metal cations such as iron, or with multivitamin

 preparations containing zinc or iron, or with didanosine buffered tablets

 for oral suspension or the pediatric powder for oral solution.

 

Distributed by:

Melinta Therapeutics, Inc. 300 Tri-State International Lincolnshire, Illinois, USA

Trademarks depicted herein are the property of their respective owners.

©2017 Melinta Therapeutics, Inc. All rights reserved.

 CLINICAL PHARMACOLOGY

 

1. Mechanism of Action

 BAXDELA is an antibacterial drug.

 

2. Pharmacodynamics

 The antibacterial activity of delafloxacin appears to best correlate with the 

 ratio of area under the concentration-time curve of free delafloxacin to 

 minimal inhibitory concentration (fAUC/MIC) for Gram-positive organisms

 such as Staphylococcus aureus and Gram-negative organisms such as

  Escherichia coli based on animal models of infection.

 

 Cardiac Electrophysiology

 In a randomized, positive-and placebo-controlled, thorough QT/QTc study,

  51 healthy subjects received BAXDELA 300 mg IV, BAXDELA 900 mg IV,

 oral moxifloxacin 400 mg, or placebo. 

 Neither BAXDELA 300 mg nor BAXDELA 900 mg (three times the intravenous

 therapeutic dose) had any clinically relevant adverse effect on 

 cardiac repolarization.

 

 Photosensitivity Potential

 A study of photosensitizing potential to ultraviolet (UVA and UVB) and

 visible radiation was conducted in 52 healthy volunteers 

 (originally 13 subjects per treatment group). 

 

 BAXDELA, at 200 mg/day  and 400 mg/day (0.22 and 0.44 times the approved 

 recommended daily   oral dosage, respectively) for 7 days, and placebo 

 did not demonstrate  clinically significant phototoxic potential at any 

 wavelengths tested  (295 nm to 430 nm), including solar simulation. 

 

3. Pharmacokinetics

 The pharmacokinetic parameters of delafloxacin following single-and 

  multiple-dose (every 12 hours) oral (450 mg) and intravenous (300 mg) 

  administration are estimated. 

 

 Steady-state was achieved within approximately three days with accumulation 

 of approximately 10% and 36% following IV and oral administration, respectively.

 

 Absorption

The absolute bioavailability for BAXDELA 450 mg oral tablet administered 

 as a single dose was 58.8%. The AUC of delafloxacin following administration 

 of a single 450 mg oral (tablet) dose was comparable to that following 

 a single 300 mg intravenous dose. The Cmax of delafloxacin was achieved 

 within about 1 hour after oral administration under fasting condition. 

 

 Food (kcal:917, Fat: 58.5%, Protein: 15.4%, Carbohydrate: 26.2%). 

 did not affect the bioavailability of delafloxacin.

 

  Distribution

 The steady state volume of distribution of delafloxacin is 30.48 L which

  approximates total body water. The plasma protein binding of delafloxacin 

  is approximately 84%; delafloxacin primarily binds to albumin.

 

 Plasma protein binding of delafloxacin is not significantly affected by 

 renal impairment.

 

 Elimination

 In a mass balance study, the mean half-life for delafloxacin was 3.7 hours

 (SD 0.7 hour) after a single dose intravenous administration. 

 

 The mean half-life values for delafloxacin ranged from 4.2 to 8.5 hours

 following multiple oral administrations. Following administration of a 

 single 300 mg intravenous dose of BAXDELA, the mean clearance (CL)

 of delafloxacin was 16.3 L/h (SD 3.7 L/h), and the renal clearance (CLr)

 of delafloxacin accounts for 35-45% of the total clearance.

 

 Metabolism

 Glucuronidation of delafloxacin is the primary metabolic pathway with

 oxidative metabolism representing about 1% of an administered dose. 

 The glucuronidation of delafloxacin is mediated mainly by UGT1A1, 

 UGT1A3, and UGT2B15.

 

 Unchanged parent drug is the predominant component in plasma. 

There are no significant circulating metabolites in humans.

 

 Excretion

 After single intravenous dose of 14C-labeled delafloxacin, 65% of the 

 radioactivity was excreted in urine as unchanged delafloxacin and 

 glucuronide metabolites and 28% was excreted in feces as unchanged 

 delafloxacin. 

 

 Following a single oral dose of 14C-labeled delafloxacin, 50% of the 

 radioactivity was excreted in urine as unchanged delafloxacin and 

 glucuronide metabolites and 48% was excreted in feces as 

 unchanged delafloxacin.

 

 Specific Populations

 Based on a population pharmacokinetic analysis, the pharmacokinetics 

 of delafloxacin were not significantly impacted by age, sex, race, weight,

  body mass index, and disease state (ABSSSI).

 

 Patients with Hepatic Impairment

 No clinically meaningful changes in delafloxacin Cmax and AUC were 

 observed, following administration of a single 300-mg intravenous dose of

 BAXDELA to patients with mild, moderate or severe hepatic impairment

 (Child-Pugh Class A, B, and C) compared to matched healthy control subjects.

 

 Patients with Renal Impairment

 Following a single intravenous (300 mg) administration of delafloxacin to 

 subjects with mild (eGFR = 51-80 mL/min/1.73 m2), moderate 

 (eGFR = 31.50 mL/min/1.73 m2), severe (eGFR = 15-29 mL/min/1.73 m2) 

 renal impairment, and ESRD on hemodialysis receiving intravenous 

 delafloxacin within 1 hour before and 1 hour after hemodialysis, 

 mean total exposure (AUCt) of delafloxacin was 1.3, 1.6, 1.8, 2.1, and

  2.6-fold higher, respectively than that for matched normal control subjects. 

 

 The mean dialysate clearance (CLd) of delafloxacin was 4.21 L/h (SD 1.56 L/h). 

 After about 4 hours of hemodialysis, the mean fraction of administered 

 delafloxacin recovered in the dialysate was about 19% .

 

 Following a single oral (400 mg) administration of delafloxacin to subjects 

 with mild (eGFR = 51-80 mL/min/1.73 m2), moderate (eGFR = 31-50mL/min/1.73m2),

 or severe (eGFR = 15-29 mL/min/1.73m2) renal impairment, the mean total 

 exposure (AUCt) of delafloxacin was about 1.5-fold higher for subjects with 

 moderate and severe renal impairment compared with healthy subjects, 

 whereas total systemic exposures of delafloxacin in subjects with mild 

 renal impairment were comparable with healthy subjects.

 

 In patients with moderate (eGFR = 31.50 mL/min/1.73 m2), or severe 

 (eGFR = 15.29 mL/min/1.73 m2) renal impairment or ESRD on hemodialysis, 

 accumulation of the intravenous vehicle SBECD occurs. 

 

 The mean systemic exposure (AUC) increased 2-fold, 5-fold, 7.5-fold, 

 and 27-fold for patients with moderate impairment, severe impairment, 

 ESRD on hemodialysis receiving intravenous delafloxacin within

 1 hour before, and 1 hour after hemodialysis respectively, compared 

 to the healthy control group. In subjects with ESRD undergoing 

 hemodialysis, SBECD is dialyzed with a clearance of 4.74 L/h. 

 

 When hemodialysis occurred 1 hour after the BAXDELA infusion in subjects 

 with ESRD, the mean fraction of SBECD recovered in the dialysate 

 was 56.1% over approximately 4 hours.

 

 Geriatric Patients

 Following single oral administration of 250 mg delafloxacin (approximately

  0.6 times the approved recommended oral dose), the mean delafloxacin 

 Cmax and AUC‡ values in elderly subjects (. 65 years) were about 

 35% higher compared to values obtained in young adults (18 to 40 years). 

 

This difference is not considered clinically relevant. 

 

A population pharmacokinetic analysis of patients with ABSSSI showed 

 no significant impact of age on delafloxacin pharmacokinetics.

 

 Male and Female Patients

 Following single oral administration of 250 mg delafloxacin 

 (approximately 0.6 times the approved recommended oral dose), 

 the mean delafloxacin Cmax and AUC‡ values in male subjects were 

 comparable to female subjects.

 

 Results from a population pharmacokinetic analysis showed that females 

 have a 24% lower AUC than males.

 

 USE IN SPECIFIC POPULATIONS

 

1. Pregnancy

 Risk Summary

 The limited available data with BAXDELA use in pregnant women are insufficient

 to inform a drug-associated risk of major birth defects and miscarriages. 

 

 When delafloxacin (as the N-methyl glucamine salt) was administered orally

 to rats during the period of organogenesis, no malformations or fetal death

 were observed at up to 7 times the estimated clinical exposure based on AUC. 

 

 When rats were dosed intravenously in late pregnancy and through lactation,

 there were no adverse effects on offspring at exposures approximating the 

 clinical intravenous (IV) exposure based on AUC .

The background risk of major birth defects and miscarriage for the indicated 

 population is unknown. 

 

  In the U.S. general population, the estimated background risk of major birth

 defects and miscarriage in clinically recognized pregnancies is 2.4% and

 15.20%, respectively.

 

2. Lactation

 Risk Summary

 There are no data available on the presence of delafloxacin in human milk, 

 the effects on the breast-fed infant, or the effects on milk production. 

 Delafloxacin is excreted in the breast milk of rats.

 

 The developmental and health benefits of breastfeeding should be considered

 along with the motherfs clinical need for BAXDELA and any potential adverse

 effects on the breast-fed child from BAXDELA or from the underlying maternal condition.

 

 

3. Pediatric Use

 Use in patients under 18 years of age is not recommended. 

 Safety and effectiveness in pediatric patients below the age of 18 years have 

 not been established. 

 

 Pediatric studies were not conducted because risk-benefit considerations 

 do not support the use of BAXDELA for ABSSSI in this population. 

 Fluoroquinolones cause arthropathy in juvenile animals.

 

4. Geriatric Use

 Of the 754 adults patients treated with BAXDELA in the Phase 3 ABSSSI trials,

 111 (15%) were . 65 years of age. The clinical response rates at 48-72 hours 

 in the BAXDELA group (ITT Population) in patients aged . 65 years old 

 were 75.7% and 82.3% in patients aged < 65 years old; comparator response 

 rates were 71.3% in patients aged . 65 years old and 82.1% in patients

 aged < 65 years old.

 

 In the safety population, of the 741 adult patients treated with BAXDELA, 

 110 (16.4%) patients aged . 65 years old and 146 (23.1%) patients 

 aged < 65 years old had at least one adverse drug reaction.

 

 Geriatric patients are at increased risk for developing severe tendon 

 disorders including tendon rupture when being treated with a

  fluoroquinolones. 

 

 This risk is further increased in patients receiving concomitant

  corticosteroid therapy. Tendinitis or tendon rupture can involve the 

  Achilles, hand, shoulder, or other tendon sites and can occur during 

  or after completion of therapy; cases occurring up to several months

  after fluoroquinolone treatment have been reported. 

 

  Caution should be used when prescribing BAXDELA to elderly patients

  especially those on corticosteroids. 

 

 Patients should be informed of this potential adverse reaction and advised 

 to discontinue BAXDELA and contact their healthcare provider 

 if any symptoms of tendinitis or tendon rupture occur.

 

 In elderly subjects (. 65 years), the mean Cmax and AUC‡ of delafloxacin 

 were about 35% higher compared with young adults, which is not 

 considered clinically significant..

 

 5. Hepatic Impairment

 No dosage adjustment is necessary for BAXDELA in patients with hepatic 

 impairment .

 

6. Renal Impairment

 No dosage adjustment of BAXDELA is necessary in patients with mild

  (eGFR 60-89 mL/min/1.73 m2) or moderate (eGFR 30-59 mL/min/1.73 m2)

  renal impairment. 

 

 The dose of BAXDELA intravenous IV infusion in patients with severe 

 renal impairment (eGFR 15-29 mL/min/1.73 m2) should be decreased 

 to 200 mg intravenously every 12 hours; the dose of oral BAXDELA 

 in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) 

 is 450mg orally every 12 hours. 

 

 BAXDELA is not recommended in patients with End Stage Renal Disease 

 [ESRD] (eGFR of <15 mL/min/1.73 m2) 

 

 In patients with severe renal impairment or ESRD (eGFR of < 15 mL/min/1.73 m2), 

 accumulation of the intravenous vehicle, sulfobutylether-ƒÀ-cyclodextrin 

 (SBECD) occurs. 

 

 Serum creatinine levels should be closely monitored in patients with severe 

 renal impairment receiving intravenous BAXDELA. 

 

 If serum creatinine level increases occur, consideration should be given to

  changing to oral BAXDELA. If eGFR decreases to <15 mL/min/1.73 m2, 

 BAXDELA should be discontinued.

 

 OVERDOSAGE

 Treatment of overdose with BAXDELA should consist of observation and

  general supportive measures. 

 

 Hemodialysis removed about 19% of delafloxacin and 56% of SBECD 

 (Sulfobutylether ƒÀ cyclodextrin) after intravenous administration of BAXDELA.