Baxdela (Page 4 of 9)

7 DRUG INTERACTIONS

7.1 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 [see Dosage and Administration (2.1)].

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 [see Dosage and Administration (2.1)].

8 USE IN SPECIFIC POPULATIONS

8.1 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 [see Data].

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.

Data

Animal Data

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).

8.2 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 [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BAXDELA and any potential adverse effects on the breast-fed child from BAXDELA or from the underlying maternal condition.

Data

After single oral dose of 20 mg/kg (approximately 194 mg for a 60 kg patient) 14 C-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.

8.4 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.

8.5 Geriatric Use

Of the 754 adult ABSSSI patients treated with BAXDELA, in Trials 1 and 2, 111/754 (15%) were 65 years of age and older. The clinical response rates at 48-72 hours for the BAXDELA-treated and comparator-treated patients were 84/111 (75.7%) and 72/101 (71.3%), respectively in ABSSSI patients aged 65 years and older compared to patients aged less than 65 years of age 529/643 (82.3%) and 538/655 (82.1%), respectively. In the safety population, of the 741 adult patients treated with BAXDELA, 18/110 (16.4%) patients aged 65 years and older and 146/631 (23.1%) patients aged less than 65 years had at least one adverse drug reaction.

Of the 431 adult CABP patients treated with BAXDELA, in Trial 3, 203/431 (47.1%) were 65 years of age and older, while 85/431 (19.7%) were 75 and over. The clinical response rates at 72-120 hours for the BAXDELA-treated and moxifloxacin-treated patients were 177/203 (87.2%) and 161/179 (89.9%), respectively in the CABP patients aged 65 years and older compared to patients aged less than 65 years old (206/228 (90.4%) and 220/249 (88.4%), respectively). In the safety population, of the 429 adult patients treated with BAXDELA, 10/84 (11.9%) patients aged 75 and older, 27/202 (13.4%) patients aged 65 years and older and 38/227 (16.7%) patients aged less than 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 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 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 [see Warnings and Precautions (5.1)].

Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients [see Warnings and Precautions (5.8)].

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 [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

No dosage adjustment is necessary for BAXDELA in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 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 450 mg orally every 12 hours. BAXDELA is not recommended in patients with End Stage Renal Disease [ESRD] (eGFR of < 15 mL/min/1.73 m2) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

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 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.

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