Introduction

Antibacterial; fluoroquinolone.

Uses for Delafloxacin

Skin and Skin Structure Infections

Treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA] and methicillin-susceptible S. aureus), S. haemolyticus, S. lugdunensis, Streptococcus pyogenes (group A β-hemolytic streptococci, GAS), S. agalactiae (group B streptococci, GBS), S. anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), Enterococcus faecalis, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, or Pseudomonas aeruginosa.

Delafloxacin Dosage and Administration

Administration

Administer orally or by slow IV infusion.

Oral Administration

Administer tablets orally without regard to meals. (See Food under Pharmacokinetics.)

Administer orally at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, metal cations (e.g., iron), sucralfate, multivitamins or dietary supplements containing iron or zinc, or buffered didanosine preparations. (See Specific Drugs under Interactions.)

IV Infusion

Must be reconstituted and further diluted prior to IV infusion. Observe strict aseptic technique when preparing IV solutions.

Do not infuse simultaneously through same tubing with other drugs. Do not administer with any solution containing multivalent cations (e.g., calcium, magnesium).

If common IV line used to administer other drugs, flush with 0.9% sodium chloride injection or 5% dextrose injection before and after each delafloxacin infusion.

Vials of lyophilized powder for injection are for single use only.

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute vial containing 300 mg of delafloxacin by adding 10.5 mL of 0.9% sodium chloride injection or 5% dextrose injection to provide a solution containing 25 mg/mL.

Shake vial vigorously until contents completely dissolved. Reconstituted solution should appear clear yellow to amber in color.

Dilution

To prepare a 300-mg dose of delafloxacin in a 250-mL infusion bag containing 0.9% sodium chloride injection or 5% dextrose injection, remove 12 mL of the diluent from infusion bag, then inject 12 mL of reconstituted delafloxacin solution into the bag. Concentration of final infusion solution is 1.2 mg/mL.

To prepare a 200-mg dose of delafloxacin in a 250-mL infusion bag containing 0.9% sodium chloride injection or 5% dextrose injection, remove 8 mL of the diluent from infusion bag, then inject 8 mL of reconstituted delafloxacin solution into the bag. Concentration of final infusion solution is 0.8 mg/mL.

Rate of Administration

Administer by IV infusion over 1 hour.

Dosage

Available as delafloxacin meglumine; dosage expressed in terms of delafloxacin.

Adults

Skin and Skin Structure Infections

Oral

450 mg every 12 hours for 5–14 days.

IV

300 mg every 12 hours for 5–14 days.

IV therapy may be switched to oral therapy at discretion of clinician. Total duration of IV and oral therapy is 5–14 days.

Special Populations

Hepatic Impairment

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C): Dosage adjustments not needed.

Renal Impairment

Oral

Mild, moderate, or severe renal impairment (estimated GFR [eGFR] of 15–89 mL/minute per 1.73 m²): Dosage adjustments not needed.

End-stage renal disease (eGFR <15 mL/minute per 1.73 m²): Not recommended.

IV

Mild or moderate renal impairment (eGFR of 30–89 mL/minute per 1.73 m²): Dosage adjustments not needed.

Severe renal impairment (eGFR of 15–29 mL/minute per 1.73 m²): 200 mg every 12 hours.

End-stage renal disease (eGFR <15 mL/minute per 1.73 m²): Not recommended.

Geriatric Patients

No dosage adjustments except those related to renal impairment. (See Renal Impairment under Dosage and Administration.)

Contraindications

• Known hypersensitivity to delafloxacin, any component of the preparation, or other fluoroquinolones.

Warnings/Precautions

Warnings

Disabling and Potentially Irreversible Serious Adverse Reactions

Systemic fluoroquinolones are associated with disabling and potentially irreversible serious adverse reactions (e.g., tendinitis and tendon rupture, peripheral neuropathy, CNS effects) that can occur together in the same patient. May occur within hours to weeks after a systemic fluoroquinolone is initiated; have occurred in all age groups and in patients without preexisting risk factors for such adverse reactions.

Immediately discontinue at first signs or symptoms of any serious adverse reactions.

Avoid systemic fluoroquinolones, including delafloxacin, in patients who have experienced any serious adverse reactions associated with fluoroquinolones.

Tendinitis and Tendon Rupture

Systemic fluoroquinolones are associated with an increased risk of tendinitis and tendon rupture in all age groups.

Risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in older adults (usually those >60 years of age), individuals receiving concomitant corticosteroids, and kidney, heart, or lung transplant recipients. (See Geriatric Use under Cautions.)

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 been reported in patients receiving fluoroquinolones who did not have any risk factors for such adverse reactions.

Fluoroquinolone-associated tendinitis and tendon rupture most frequently involve the Achilles tendon; also reported in the rotator cuff (shoulder), hand, biceps, thumb, and other tendon sites.

Tendinitis and tendon rupture can occur within hours or days after therapy initiated or as long as several months after completion of therapy; can occur bilaterally.

Immediately discontinue delafloxacin if pain, swelling, inflammation, or rupture of a tendon occurs. (See Advice to Patients.)

Avoid systemic fluoroquinolones, including delafloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture.

Peripheral Neuropathy

Systemic fluoroquinolones are associated with an increased risk of peripheral neuropathy.

Sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias, and weakness reported with fluoroquinolones, including delafloxacin. Symptoms may occur soon after initiation of the drug and, in some patients, may be irreversible.

Immediately discontinue delafloxacin if symptoms of peripheral neuropathy (e.g., pain, burning, tingling, numbness, and/or weakness) occur or if there are other alterations in sensations (e.g., light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength).

Avoid systemic fluoroquinolones, including delafloxacin, in patients who have experienced peripheral neuropathy.

CNS Effects

Systemic fluoroquinolones are associated with an increased risk of adverse psychiatric effects, including toxic psychosis, hallucinations, paranoia, depression, suicidal thoughts or acts, delirium, disorientation, confusion, disturbances in attention, anxiety, agitation, nervousness, insomnia, nightmares, and memory impairment. These adverse effects may occur after first dose.

Systemic fluoroquinolones are associated with increased risk of convulsions (seizures), increased intracranial pressure (including pseudotumor cerebri), dizziness, and tremors. Use delafloxacin in patients with known or suspected CNS disorders (e.g., severe cerebral arteriosclerosis, epilepsy) or other risk factors that predispose to seizures or lower seizure threshold only if potential benefits outweigh risks.

If psychiatric or other CNS effects occur, immediately discontinue delafloxacin and institute appropriate measures. (See Advice to Patients.)

Exacerbation of Myasthenia Gravis

Fluoroquinolones have neuromuscular blocking activity and may exacerbate muscle weakness in myasthenia gravis patients; death or need for ventilatory support reported.

Avoid use in patients with known history of myasthenia gravis. (See Advice to Patients.)

Sensitivity Reactions

Hypersensitivity

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions reported in patients receiving fluoroquinolones. These reactions may occur with first or subsequent doses.

Some hypersensitivity reactions reported with fluoroquinolones have been accompanied by cardiovascular collapse, loss of consciousness, tingling, edema (pharyngeal or facial), dyspnea, urticaria, or pruritus.

Hypersensitivity and urticaria reported in patients receiving delafloxacin.

Immediately discontinue delafloxacin at first appearance of rash or any other sign of hypersensitivity. (See Advice to Patients.)

Photosensitivity

No evidence of phototoxic potential.

Other Warnings and Precautions

Risk of Aortic Aneurysm and Dissection

Rupture or dissection of aortic aneurysms reported in patients receiving systemic fluoroquinolones. Epidemiologic studies indicate an increased risk of aortic aneurysm and dissection within 2 months following use of systemic fluoroquinolones, particularly in elderly patients. Cause for this increased risk not identified.

Unless there are no other treatment options, do not use systemic fluoroquinolones, including delafloxacin, in patients who have an aortic aneurysm or are at increased risk for an aortic aneurysm. This includes elderly patients and patients with peripheral atherosclerotic vascular disease, hypertension, or certain genetic conditions (e.g., Marfan syndrome, Ehlers-Danlos syndrome).

If patient reports adverse effects suggestive of aortic aneurysm or dissection, immediately discontinue the fluoroquinolone. (See Advice to Patients.)

Hypoglycemia or Hyperglycemia

Systemic fluoroquinolones are associated with alterations in blood glucose concentrations, including symptomatic hypoglycemia and hyperglycemia. Blood glucose disturbances during fluoroquinolone therapy usually have occurred in patients with diabetes mellitus receiving an oral antidiabetic agent (e.g., glyburide) or insulin.

Severe cases of hypoglycemia resulting in coma or death reported with some systemic fluoroquinolones. Although most reported cases of hypoglycemic coma involved patients with risk factors for hypoglycemia (e.g., older age, diabetes mellitus, renal insufficiency, concomitant use of antidiabetic agents [especially sulfonylureas]), some involved patients receiving a fluoroquinolone who were not diabetic and not receiving an oral antidiabetic agent or insulin.

Carefully monitor blood glucose concentrations when systemic fluoroquinolones, including delafloxacin, used in diabetic patients receiving antidiabetic agents.

If hypoglycemic reaction occurs, discontinue the fluoroquinolone and immediately initiate appropriate therapy. (See Advice to Patients.)

C. difficile-associated Diarrhea and Colitis

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly known as Clostridium difficile). C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including delafloxacin, and may range in severity from mild diarrhea to fatal colitis. C. difficile produces toxins A and B which contribute to development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.

Consider CDAD if diarrhea develops during or after therapy and manage accordingly. Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile as soon as possible. Manage using appropriate anti-infective therapy directed against C. difficile (e.g., vancomycin, fidaxomicin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of delafloxacin and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.

Information on test methods and quality control standards for in vitro susceptibility testing of antibacterial agents and specific interpretive criteria for such testing recognized by FDA is available at [Web].

Specific Populations

Pregnancy

Available data regarding use in pregnant women insufficient to inform any drug-associated risk for miscarriages or major birth defects.

When administered orally to pregnant rats, no malformations or fetal deaths observed at delafloxacin concentrations 7 times estimated clinical exposure. Maternal toxicity and reduced fetal body weight observed at highest dosage (1.6 g/kg daily); fetal ossification delays observed at all doses. Following IV administration to rats in late pregnancy through lactation, no adverse effects on offspring observed at clinically relevant concentrations.

Lactation

Distributed into milk in lactating rats; not known if distributes into human milk, affects breast-fed infant, or affects milk production.

Consider developmental and health benefits of breast-feeding along with the mother's clinical need for delafloxacin; also consider potential adverse effects on breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in children or adolescents <18 years of age; use in pediatric patients not recommended.

Quinolones cause arthropathy in juvenile animals.

Manufacturer states clinical trials evaluating delafloxacin for treatment of bacterial skin and skin structure infections did not include patients <18 years of age because risks versus benefits do not support use of the drug for such infections in this age group.

AAP states use of a systemic fluoroquinolone may be justified in children <18 years of age in certain specific circumstances when there are no safe and effective alternatives and the drug is known to be effective.

Geriatric Use

About 15% of patients receiving delafloxacin in clinical studies were ≥65 years of age. Clinical response rate at 48–72 hours was about 76% in patients ≥65 years of age compared with about 82% in those <65 years of age.

Risk of severe tendon disorders, including tendon rupture, is increased in older adults (usually those >60 years of age). This risk is further increased in those receiving concomitant corticosteroids. (See Tendinitis and Tendon Rupture under Cautions.) Use caution in geriatric adults, especially those receiving concomitant corticosteroids.

Risk of aortic aneurysm and dissection may be increased in geriatric patients. (See Risk of Aortic Aneurysm and Dissection under Cautions.)

Hepatic Impairment

No clinically important differences in pharmacokinetics in adults with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C); dosage adjustments not needed in such patients.

Renal Impairment

Severe renal impairment (eGFR of 15–29 mL/minute per 1.73 m²): Accumulation of the IV delafloxacin vehicle, sulfobutylether-β-cyclodextrin (SBECD), occurs. Reduce dosage (see Renal Impairment under Dosage and Administration) and closely monitor S_cr and eGFR in patients receiving IV delafloxacin. Consider switching to oral delafloxacin if S_cr increases during IV delafloxacin treatment. If eGFR decreases to <15 mL/minute per 1.73 m², discontinue delafloxacin.

End-stage renal disease (eGFR <15 mL/minute per 1.73 m²): Accumulation of IV delafloxacin vehicle (SBECD) occurs. Use of delafloxacin (oral or IV) not recommended.

Common Adverse Effects

GI effects (nausea, diarrhea, vomiting), headache, elevated aminotransferase concentrations.

Administration

Administer orally or by slow IV infusion.

Oral Administration

Administer tablets orally without regard to meals. (See Food under Pharmacokinetics.)

Administer orally at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, metal cations (e.g., iron), sucralfate, multivitamins or dietary supplements containing iron or zinc, or buffered didanosine preparations. (See Specific Drugs under Interactions.)

IV Infusion

Must be reconstituted and further diluted prior to IV infusion. Observe strict aseptic technique when preparing IV solutions.

Do not infuse simultaneously through same tubing with other drugs. Do not administer with any solution containing multivalent cations (e.g., calcium, magnesium).

If common IV line used to administer other drugs, flush with 0.9% sodium chloride injection or 5% dextrose injection before and after each delafloxacin infusion.

Vials of lyophilized powder for injection are for single use only.

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute vial containing 300 mg of delafloxacin by adding 10.5 mL of 0.9% sodium chloride injection or 5% dextrose injection to provide a solution containing 25 mg/mL.

Shake vial vigorously until contents completely dissolved. Reconstituted solution should appear clear yellow to amber in color.

Dilution

To prepare a 300-mg dose of delafloxacin in a 250-mL infusion bag containing 0.9% sodium chloride injection or 5% dextrose injection, remove 12 mL of the diluent from infusion bag, then inject 12 mL of reconstituted delafloxacin solution into the bag. Concentration of final infusion solution is 1.2 mg/mL.

To prepare a 200-mg dose of delafloxacin in a 250-mL infusion bag containing 0.9% sodium chloride injection or 5% dextrose injection, remove 8 mL of the diluent from infusion bag, then inject 8 mL of reconstituted delafloxacin solution into the bag. Concentration of final infusion solution is 0.8 mg/mL.

Rate of Administration

Administer by IV infusion over 1 hour.

Dosage

Available as delafloxacin meglumine; dosage expressed in terms of delafloxacin.

Adults

Skin and Skin Structure Infections

Oral

450 mg every 12 hours for 5–14 days.

IV

300 mg every 12 hours for 5–14 days.

IV therapy may be switched to oral therapy at discretion of clinician. Total duration of IV and oral therapy is 5–14 days.

Special Populations

Hepatic Impairment

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C): Dosage adjustments not needed.

Renal Impairment

Oral

Mild, moderate, or severe renal impairment (estimated GFR [eGFR] of 15–89 mL/minute per 1.73 m²): Dosage adjustments not needed.

End-stage renal disease (eGFR <15 mL/minute per 1.73 m²): Not recommended.

IV

Mild or moderate renal impairment (eGFR of 30–89 mL/minute per 1.73 m²): Dosage adjustments not needed.

Severe renal impairment (eGFR of 15–29 mL/minute per 1.73 m²): 200 mg every 12 hours.

End-stage renal disease (eGFR <15 mL/minute per 1.73 m²): Not recommended.

Geriatric Patients

No dosage adjustments except those related to renal impairment. (See Renal Impairment under Dosage and Administration.)

Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5 in vitro at clinically relevant concentrations; shows no potential for induction of CYP1A2, 2B6, 2C19, or 2C8. Mild induction of CYP2C9 and 3A4 in vitro.

Drugs Affecting or Affected by Membrane Transporters

Substrate of P-glycoprotein (P-gp) transport and breast cancer resistance protein (BCRP) in vitro; clinical importance of concomitant use with P-gp inhibitors and/or BCRP inhibitors not known.

Does not inhibit multidrug-resistance gene (MDR) 1, BCRP, organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, bile salt export pump (BSEP), or organic cation transporter (OCT) 1 or OCT2 at clinically relevant concentrations.

Not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3.

Specific Drugs