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Delafloxacin Meglumine

Class: Quinolones
Chemical Name: 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxoquinoline-3-carboxylic acid
Molecular Formula: C18H12ClF3N4O4
CAS Number: 1256037-58-7
Brands: Baxdela

Warning(s)

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.1

Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together), including:1

  • Tendinitis and tendon rupture1

  • Peripheral neuropathy1

  • Central nervous system effects1

Discontinue delafloxacin meglumine immediately and avoid the use of fluoroquinolones, including delafloxacin meglumine, in patients who experience any of these serious adverse reactions.1

Fluoroquinolones may exacerbate muscle weakness in patients with myasthenia gravis. Avoid delafloxacin meglumine in patients with known history of myasthenia gravis.1

Introduction

Delafloxacin meglumine is a fluoroquinolone anti-infective agent.1

Uses for Delafloxacin Meglumine

Delafloxacin meglumine has the following uses:

Delafloxacin meglumine is a fluoroquinolone antibacterial indicated in adults for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by designated susceptible bacteria.1

To reduce the development of drug-resistant bacteria and maintain the effectiveness of delafloxacin meglumine and other antibacterial drugs, delafloxacin meglumine should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.1

Delafloxacin Meglumine Dosage and Administration

General

Delafloxacin meglumine is available in the following dosage form(s) and strength(s):

  • 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.1

  • Oral Tablets: 450 mg delafloxacin (equivalent to 649 mg delafloxacin meglumine).1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Intravenous: Administer 300 mg of delafloxacin by intravenous infusion over 60 minutes every 12 hours for 5–14 days.1 Alternatively, administer 300 mg of delafloxacin by intravenous infusion over 60 minutes every 12 hours and then, at clinician's discretion, switch to 450 mg of oral delafloxacin as tablets every 12 hours for total duration of 5–14 days.1

  • Oral: Administer 450 mg of delafloxacin as tablets every 12 hours for 5–14 days.1

  • Dosage for patients with renal impairment is based on the estimated glomerular filtration rate (eGFR).1

Estimate of GFR based on a Modification of Diet in Renal Disease (MDRD) equation.

For a total treatment duration of 5 to 14 days.

All intravenous doses of delafloxacin meglumine are administered over 60 minutes.

Not recommended due to insufficient information to provide dosing recommendations.

Estimated Glomerular Filtration Rate (eGFR)(mL/min/1.73m2)

Recommended Dosage Regimen for Delafloxacin

Oral

Intravenous

30-89

No dosage adjustment

No dosage adjustment

15-29

No dosage adjustment

200 mg every 12 hours

End Stage Renal Disease (ESRD) (<15 including hemodialysis)

Not Recommended

Not Recommended

Cautions for Delafloxacin Meglumine

Contraindications

Known hypersensitivity to delafloxacin meglumine or other fluoroquinolones.1

Warnings/Precautions

Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy and Central Nervous System Effects

Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions could occur within hours to weeks after starting a fluoroquinolone. Patients of any age or without pre-existing risk factors have experienced these adverse reactions.1

Discontinue delafloxacin meglumine immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including delafloxacin meglumine, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.1

Tendinitis and Tendon Rupture

Fluoroquinolones have been associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur within hours or days of starting a fluoroquinolone or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally.1

This risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart, and lung transplant. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors.1

Discontinue delafloxacin meglumine immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Advise patients that, at the first sign of tendon pain, swelling, or inflammation, they should stop taking delafloxacin meglumine, avoid exercise and use of the affected area, and promptly contact their healthcare provider about changing to a non-quinolone antimicrobial drug.

Avoid delafloxacin meglumine in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture.1

Peripheral Neuropathy

Fluoroquinolones have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias, and weakness have been reported in patients receiving fluoroquinolones, including delafloxacin meglumine. Symptoms may occur soon after initiation of fluoroquinolones and may be irreversible in some patients.1

Discontinue delafloxacin meglumine immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation and/or motor strength in order to minimize the development of an irreversible condition.

Avoid fluoroquinolones, including delafloxacin meglumine, in patients who have previously experienced peripheral neuropathy.1

Central Nervous System Effects

Fluoroquinolones have been associated with an increased risk of central nervous system (CNS) reactions, including convulsions and increased intracranial pressure (including pseudotumor cerebri) and toxic psychosis. Fluoroquinolones, including delafloxacin meglumine, may also cause CNS reactions of nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and suicidal thoughts or acts. These adverse reactions may occur following the first dose. If these reactions occur in patients receiving delafloxacin meglumine, discontinue delafloxacin meglumine immediately and institute appropriate measures.

As with all fluoroquinolones, use delafloxacin meglumine when the benefits of treatment exceed the risks in patients with known or suspected CNS disorders (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold.1

Exacerbation of Myasthenia Gravis

Fluoroquinolones have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post-marketing serious adverse reactions, including death and requirement for ventilator support, have been associated with fluoroquinolone use in persons with myasthenia gravis.

Avoid delafloxacin meglumine in patients with known history of myasthenia gravis.1

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Hypersensitivity reactions have been reported in patients receiving delafloxacin meglumine. These reactions may occur after first or subsequent doses of delafloxacin meglumine.

Discontinue delafloxacin meglumine at the first appearance of a skin rash or any other sign of hypersensitivity.1

Clostridium difficile-associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported in users of nearly all systemic antibacterial drugs, including delafloxacin meglumine, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon, and may permit overgrowth of C. difficile.1

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 antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.1

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.1

Development of Drug-resistant Bacteria

Prescribing delafloxacin meglumine 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.1

Specific Populations

Pregnancy

The limited available data with delafloxacin meglumine 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.1

In embryo-fetal studies, oral administration of delafloxacin to pregnant rats during the period of major organogenesis resulted in maternal toxicity and reduced fetal body weights at the highest dose (1600 mg/kg/day) and fetal ossification delays at all doses. No malformations were reported up to the highest dose tested (approximately 7 times the estimated human plasma exposure based on AUC). The lowest dose, 200 mg/kg/day (approximately 2.5 times the estimated human plasma exposure based on AUC), was still toxic to the fetus, based on ossification delays. In rabbits, a species known to be extremely sensitive to maternal toxicity of antibacterial drugs, no embryo-fetal developmental toxicity was observed up to the highest dose which induced maternal toxicity (1.6 mg/kg/day, or approximately 0.01 times the estimated human plasma exposure based on AUC). In a pre-postnatal study in rats of IV administered delafloxacin, dams at the highest dose tested (120 mg/kg/day) exhibited slightly lower body weights and slightly longer gestation length than control animals. Exposure at that dose was estimated to be approximately 5 times human plasma exposure based on AUC, as determined in a separate shorter term study at an earlier stage of pregnancy. Effects on pups at that dose included increased mortality during lactation, small stature, and lower body weights, but no changes in learning and memory, sensory function, locomotor activity, developmental landmarks, or reproductive performance were reported. The No Adverse Effect Level (NOAEL) for maternal toxicity pup development in that study was 60 mg/kg/day (approximately 580 mg/day IV for a 60 kg patient, or just below the clinical IV dose).1

Lactation

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's clinical need for delafloxacin meglumine and any potential adverse effects on the breast-fed child from delafloxacin meglumine or from the underlying maternal condition.1

After single oral dose of 20 mg/kg (approximately 194 mg for a 60 kg patient) 14C labeled delafloxacin on post-natal day 11, the radioactivity was transferred into the milk of lactating rats. The mean milk/plasma radioactivity concentration ratios in dams at 4 and 8 hours after dosing were 8.5 and 4.0, respectively, and essentially background by 24 hours. The rate of elimination of radioactivity was similar in milk and plasma. Absorption of radioactive drug by rat pups following nursing was observed.1

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 delafloxacin meglumine for ABSSSI in this population. Fluoroquinolones cause arthropathy in juvenile animals.1

Geriatric Use

Of the 754 adults patients treated with delafloxacin meglumine in the Phase 3 ABSSSI trials, 111 (15%) were ≥ 65 years of age. The clinical response rates at 48-72 hours in the delafloxacin meglumine 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.1

In the safety population, of the 741 adult patients treated with delafloxacin meglumine, 110 (16.4%) patients aged ≥ 65 years old and 146 (23.1%) patients aged < 65 years old had at least one adverse drug reaction.1

Geriatric patients are at increased risk for developing severe tendon disorders, including tendon rupture, when being treated with a fluoroquinolone. 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 delafloxacin meglumine to elderly patients, especially those on corticosteroids. Patients should be informed of this potential adverse reaction and advised to discontinue delafloxacin meglumine and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur.1

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.1

Hepatic Impairment

No dosage adjustment is necessary for delafloxacin meglumine in patients with hepatic impairment. 1

Renal Impairment

No dosage adjustment of delafloxacin meglumine 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 intravenous delafloxacin in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) should be decreased to 200 mg every 12 hours; the dose of oral delafloxacin in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) is 450 mg orally every 12 hours. Delafloxacin meglumine is not recommended in patients with End Stage Renal Disease [ESRD] (eGFR of <15 mL/min/1.73 m2).1

In patients with severe renal impairment or ESRD (eGFR of < 15 mL/min/1.73 m2) accumulation of the intravenous vehicle, sulfobutylether-β-cyclodextrin (SBECD) occurs. Serum creatinine levels should be closely monitored in patients with severe renal impairment receiving intravenous delafloxacin meglumine. If serum creatinine level increases occur, consideration should be given to changing to oral delafloxacin meglumine. If eGFR decreases to <15 mL/min/1.73 m2, delafloxacin meglumine should be discontinued.1

Common Adverse Effects

Most common adverse reactions (incidence ≥2%) are nausea, diarrhea, headache, transaminase elevations, and vomiting.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions and Spectrum

Mechanism of Action

Delafloxacin meglumine belongs to the fluoroquinolone class of antibacterial drugs and is anionic in nature.1

The antibacterial activity of delafloxacin is due to the inhibition of both bacterial topoisomerase IV and DNA gyrase (topoisomerase II) enzymes which are required for bacterial DNA replication, transcription, repair, and recombination. Delafloxacin exhibits a concentration-dependent bactericidal activity against gram-positive and gram-negative bacteria in vitro.1

Spectrum

Delafloxacin meglumine has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.1

    Gram-positive Bacteria
  • Staphylococcus aureus (including methicillin-resistant and methicillin-sensitive strains)1

  • Staphylococcus haemolyticus1

  • Staphylococcus lugdunensis1

  • Streptococcus pyogenes1

  • Streptococcus agalactiae1

  • Streptococcus anginosus Group (including S. anginosus, S. intermedius, and S. constellatus)1

  • Enterococcus faecalis1

    Gram-negative Bacteria
  • Escherichia coli1

  • Klebsiella pneumoniae1

  • Enterobacter cloacae1

  • Pseudomonas aeruginosa1

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint of delafloxacin against isolates of similar genus or organism group. However, the efficacy of delafloxacin meglumine in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.1

    Gram-positive Bacteria
  • Streptococcus dysgalactiae1

    Gram-negative Bacteria
  • Enterobacter aerogenes1

  • Haemophilus parainfluenzae1

  • Klebsiella oxytoca1

  • Proteus mirabilis1

In vitro drug combination studies with delafloxacin and aztreonam, ceftazidime, colistin, daptomycin, linezolid, meropenem, tigecycline, trimethoprim/sulfamethoxazole and vancomycin demonstrated neither synergy nor antagonism.1

Resistance

Resistance to fluoroquinolones, including delafloxacin, can occur due to mutations in defined regions of the target bacterial enzymes topoisomerase IV and DNA gyrase referred to as Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux.1

Fluoroquinolones, including delafloxacin, have a different chemical structure and mechanism of action relative to other classes of antibacterial compounds (e.g., aminoglycosides, macrolides, β-lactams, glycopeptides, tetracyclines and oxazolidinones).1

In vitro resistance to delafloxacin develops by multiple step mutations in the QRDRs of gram-positive and gram-negative bacteria. Delafloxacin-resistant mutants were selected in vitro at a frequency of <10-9.1

Although cross-resistance between delafloxacin and other fluoroquinolone-class antibacterial agents has been observed, some isolates resistant to other fluoroquinolone-class antibacterial agents may be susceptible to delafloxacin meglumine.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).1

Serious Adverse Reactions

Advise patients to stop taking delafloxacin meglumine 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.1

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 delafloxacin meglumine immediately if they experience an adverse reaction and to call their healthcare provider.1

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 delafloxacin meglumine 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.1

Inform patients that peripheral neuropathies have been associated with delafloxacin meglumine 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 delafloxacin meglumine and contact their physician.1

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 delafloxacin meglumine 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.1

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.1

Inform patients that delafloxacin meglumine can cause hypersensitivity reactions, even following a single dose, and to discontinue delafloxacin meglumine 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.1

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.1

Inform patients that antibacterial drugs, including delafloxacin meglumine tablets and injection should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When delafloxacin meglumine tablets and delafloxacin meglumine 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 delafloxacin meglumine tablets and delafloxacin meglumine injection or other antibacterial drugs in the future.1

Administration with Food and Concomitant Medications

Inform patients that delafloxacin meglumine tablets may be taken with or without food and without any dietary restrictions.1

Inform patients that delafloxacin meglumine tablets should be taken at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, sucralfate, metal cations such as iron, multivitamin preparations containing zinc or iron, or didanosine buffered tablets for oral suspension or didanosine pediatric powder for oral solution.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

Delafloxacin Meglumine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

450 mg

Baxdela

Melinta

Parenteral

For Injection, for IV infusion

300 mg

Baxdela

Melinta

AHFS Drug Information. © Copyright 2017, Selected Revisions July 17, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Melinta Therapeutics, Inc. Baxdela (Delafloxacin meglumine) tablets and for injection for intravenous infusion prescribing information. 2017 Jun.

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