Linezolid (Page 4 of 8)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of linezolid. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia). Thrombocytopenia has been reported more often in patients with severe renal impairment and in patients with moderate to severe hepatic impairment [see Warnings and Precautions (5.1)] ; sideroblastic anemia.
Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision [see Warnings and Precautions (5.2)].
Lactic acidosis [see Warnings and Precautions (5.7)]. Although these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days, these events have also been reported in patients receiving shorter courses of therapy.
Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, and linezolid [see Warnings and Precautions (5.3)].
Convulsions [see Warnings and Precautions (5.8)].
Anaphylaxis, angioedema, bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome, and hypersensitivity vasculitis.
Superficial tooth discoloration and tongue discoloration have been reported with the use of linezolid. The tooth discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome.
Hypoglycemia, including symptomatic episodes [see Warnings and Precautions (5.9)].
Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) [see Warnings and Precautions (5.10)].

7 DRUG INTERACTIONS

7.1 Monoamine Oxidase Inhibitors

Linezolid is a reversible, nonselective inhibitor of monoamine oxidase [see Contraindications (4.2) and Clinical Pharmacology (12.3)].

7.2 Adrenergic and Serotonergic Agents

Linezolid has the potential for interaction with adrenergic and serotonergic agents [see Warnings and Precautions (5.3, 5.6) and Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from published and postmarketing case reports with linezolid use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. When administered during organogenesis, linezolid did not cause malformations in mice, rats, or rabbits at maternal exposure levels approximately 6.5 times (mice), equivalent to (rats), or 0.06 times (rabbits) the clinical therapeutic exposure, based on AUCs. However, embryo-fetal lethality was observed in mice at 6.5 times the estimated human exposure. When female rats were dosed during organogenesis through lactation, postnatal survival of pups was decreased at doses approximately equivalent to the estimated human exposure based on AUCs (see Data).

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

In mice, embryo-fetal toxicities were observed only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). An oral dose of 450 mg/kg/day given from Gestation Day (GD) 6 to 16 (6.5 times the estimated human exposure based on AUCs) correlated with increased postimplantational embryo death, including total litter loss, decreased fetal body weights, and an increased incidence of costal cartilage fusion. Neither maternal nor embryo-fetal toxicities were observed at doses up to 150 mg/kg/day. Fetal malformations were not observed.

In rats, fetal toxicity was observed at 15 and 50 mg/kg/day administered orally from GD 6 to 17 (exposures 0.22 times to approximately equivalent to the estimated human exposure, respectively, based on AUCs). The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights. Fetal malformations were not observed. Maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day.

In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) when administered at an oral dose of 15 mg/kg/day given from GD 6 to 20 (0.06 times the estimated human exposure based on AUCs). Fetal malformations were not observed.

When female rats were treated with 50 mg/kg/day (approximately equivalent to the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation (GD 6 through Lactation Day 20), survival of pups was decreased on postnatal days 1 to 4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss.

8.2 Lactation

Risk Summary

Linezolid is present in breast milk. Based on data from available published case reports, the daily dose of linezolid that the infant would receive from breastmilk would be approximately 6% to 9% of the recommended therapeutic infant dose (10 mg/kg every 8 hours). There is no information on the effects of linezolid on the breastfed infant; however, diarrhea and vomiting were the most common adverse reactions reported in clinical trials in infants receiving linezolid therapeutically [see Adverse Reactions (6.1)] and (see Clinical Considerations). There is no information on the effects of linezolid on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for linezolid and any potential adverse effects on the breastfed child from linezolid or from the underlying maternal condition.

Clinical Considerations

Advise lactating women to monitor a breastfed infant for diarrhea and vomiting.

8.3 Females and Males of Reproductive Potential

Infertility

Males

Based on findings from studies in rats, linezolid may reversibly impair fertility in male patients [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years [see Indications and Usage (1), Clinical Pharmacology (12.3) andClinical Studies (14)]:

nosocomial pneumonia
complicated skin and skin structure infections
community-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years)
vancomycin-resistant Enterococcus faecium infections

The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infection have been established in a comparator-controlled study in pediatric patients ranging in age from 5 through 17 years [see Clinical Studies (14)]:

uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes

Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.

The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid gradually decreases with increasing age of pediatric patients. However, in preterm (gestational age < 34 weeks) neonates < 7 days of age, linezolid clearance is often lower than in full-term neonates < 7 days of age. Consequently, preterm neonates < 7 days of age may need an alternative linezolid dosing regimen of 10 mg/kg every 12 hours [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with minimum inhibitory concentrations (MICs) of 4 mcg/mL treated with linezolid had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 mcg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response [see Clinical Pharmacology (12.3) and Dosage and Administration (2)].

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