Moxifloxacin Hydrochloride (Page 5 of 11)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available human data establishing a drug associated risk with the use of moxifloxacin.

Based on animal studies with moxifloxacin, moxifloxacin hydrochloride may cause fetal harm. Moxifloxacin did not cause fetal malformation when administered to pregnant rats (IV and oral), rabbits (IV), and monkeys (oral) at exposures that were 0.24 to 2.5 times of those at the human clinical dose (400 mg/day moxifloxacin hydrochloride). However, when moxifloxacin was administered to rats and rabbits during pregnancy and throughout lactation (rats only) at doses associated with maternal toxicity, decreased neonatal body weights, increased incidence of skeletal variations (rib and vertebra combined), and increased fetal loss were observed (see Data). Advise pregnant women of the potential risk to the fetus.

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.

Data

Animal Data

Animal reproductive and development studies were done in rats, rabbits and cynomolgus macaques. Moxifloxacin did not cause fetal malformations when administered to pregnant rats during organogenesis (gestation days 6 to 17) at oral doses as high as 500 mg/kg/day or 0.24 times the maximum recommended human dose based on systemic exposure (AUC), but decreased fetal body weights and slightly delayed fetal skeletal development were observed. Intravenous administration of 80 mg/kg/day (approximately 2 times the maximum recommended human dose based on body surface area) to pregnant rats resulted in maternal toxicity and a marginal effect on fetal and placental weights and the appearance of the placenta (Gestation days 6 to 17). Fetal malformations were not observed at intravenous doses as high as 80 mg/kg/day (approximately 2 times the maximum recommended human dose based on body surface area) in litters of pregnant rats that received moxifloxacin during organogenesis (Gestation days 6 to 17). Intravenous administration of 20 mg/kg/day (approximately equal to the maximum recommended human oral dose based upon systemic exposure) to pregnant rabbits during organogenesis (gestation days 6 to 20) resulted in decreased fetal body weights and delayed fetal skeletal ossification. When rib and vertebral malformations were combined, there was an increased fetal and litter incidence of these effects in rabbits. Signs of maternal toxicity in rabbits at this dose included mortality, abortions, marked reduction of food consumption, decreased water intake, body weight loss and hypoactivity. Fetal malformation were not observed when pregnant cynomolgus macaques were given oral doses as high as 100 mg/kg/day (2.5 times the maximum recommended human dose based upon systemic exposure) during organogenesis (gestation days 20 to 50). An increased incidence of smaller fetuses was observed at 100 mg/kg/day in macaques. In a pre- and postnatal development study conducted in rats given oral doses from Gestation day 6, throughout gestation and rearing to Postpartum day 21, effects observed at 500 mg/kg/day (0.24 times the maximum recommended human dose based on systemic exposure (AUC)) included slight increases in duration of pregnancy and prenatal loss, reduced pup birth weight and decreased neonatal survival. Treatment-related maternal mortality occurred during gestation at 500 mg/kg/day in this study.

8.2 Lactation

Risk Summary

It is not known if moxifloxacin is present in human milk. Based on animal studies in rats, moxifloxacin may be excreted in human milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for moxifloxacin hydrochloride and any potential adverse effects on the breastfed child from moxifloxacin hydrochloride or from the underlying maternal condition.

Data

In lactating rats given a single oral dose of 4.59 mg/kg moxifloxacin (approximately 9 times less than the recommended human dose based on body surface area) 8 days postpartum, there was very low excretion of substance-related radioactivity into the milk, amounting to approximately 0.03% of the dose.

8.4 Pediatric Use

Effectiveness in pediatric patients and adolescents less than 18 years of age has not been established. Moxifloxacin causes arthropathy in juvenile animals. Limited information on the safety of moxifloxacin in 301 pediatric patients is available from the cIAI trial [see Boxed Warning, Warnings and Precautions ( 5.11) and Nonclinical Toxicology ( 13.2)].

Active Controlled Trial in Complicated Intra-Abdominal Infection (cIAI)

The safety and efficacy of moxifloxacin in pediatric patients for the treatment of cIAI has not been demonstrated.

Pediatric patients 3 months to <18 years of age (mean age of 12 ± 4 years) were enrolled in a single randomized, double-blind, active controlled trial in cIAI including appendicitis with perforation, abscesses and peritonitis.

Pediatric patients were randomized (2:1) to receive either moxifloxacin or comparator. This study enrolled 451 patients who received study medication, 301 treated with moxifloxacin, and 150 with comparator. Of the 301 pediatric patients treated with moxifloxacin, 15 were below the age of 6 years and 286 were between the ages of 6 to <18 years.

Patients received sequential intravenous/oral moxifloxacin or comparator (intravenous ertapenem followed by oral amoxicillin/clavulanate) for 5 to 14 days (mean duration was 9 days with a range of 1 to 24 days).

The overall adverse reaction profile in pediatric patients was comparable to that of adult patients. The most frequently occurring adverse reactions in pediatric patients treated with moxifloxacin were QT prolongation 9.3% (28/301), vomiting, 6.6% (20/301) diarrhea 3.7% (11/301), arthralgia 3.0% (9/301), and phlebitis 2.7% (8/301) (see Table 5). Discontinuation of study drug due to an adverse reaction was reported in 5.3% (16/301) of moxifloxacin-treated patients versus 1.3% (2/150) of comparator-treated patients. The adverse reaction profile of moxifloxacin or comparator was similar across all age groups studied.

Musculoskeletal adverse reactions were monitored and followed up to 5 years after the end of study treatment. The rates of musculoskeletal adverse reactions were 4.3% (13/301) in the moxifloxacin-treated group versus 3.3% (5/150) in the comparator-treated group. The majority of musculoskeletal adverse reactions were reported between 12 and 53 weeks after start of study treatment with complete resolution at the end of the study [see Warnings and Precautions ( 5.11) and Nonclinical Toxicology ( 13.2)].

Table 5 Incidence (%) of Selected Adverse Reactions in ≥2.0% of Pediatric Patients Treated with Moxifloxacin in cIAI Clinical Trial
System Organ Class Adverse Reactions Moxifloxacin N = 301 (%) Comparator N = 150 (%)

Gastrointestinal disorders

Abdominal pain

Diarrhea

Vomiting

8 (2.7)

11 (3.7)

20 (6.6)

3 (2.0)

1 (0.7)

12 (8.0)

General disorders and administration site conditions Pyrexia 6 (2.0) 4 (2.7)
Investigations Aspartate aminotransferase increased 2 (0.7) 3 (2.0)
Electrocardiogram QT prolonged 28 (9.3) 4 (2.7)
Musculoskeletal and connective tissue disorders Arthralgia 9 (3.0) 2 (1.3)
Nervous system disorders Headache 6 (2.0) 2 (1.3)
Vascular disorders Phlebitis 8 (2.7) 0 (0)

Clinical response was assessed at the test-of-cure visit (28 to 42 days after end of treatment). The clinical response rates observed in the modified intent to treat population were 83.9% (208/248) for moxifloxacin and 95.5% (127/133) for comparator; see Table 6.

Table 6: Clinical Response Rates at 28 to 42 Days After End of Treatment in Pediatric Patients with cIAI

1 The modified intent-to-treat (mITT) population is defined as all subjects who were treated with at least one dose of study medication and who have at least one pre-treatment causative organism from the intra-abdominal site of infection or from blood cultures.

2 Difference in clinical cure rates (Moxifloxacin -Comparator) and 95% confidence intervals, presented as percentages, are based on stratified analysis by age group using Mantel-Haenszel methods.

Moxifloxacin n (%) Comparator n (%) Difference 2 (95% CI)
mITT Population 1 N=248 N=133
Cure 208 (83.9) 127 (95.5) -12.2 (-17.9, -6.4)
Failure 17 (6.9) 3 (2.3)
Indeterminate 21 (8.5) 3 (2.3)
Missing 2 (0.8) 0

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