5.1 Myelosuppression

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Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. Thrombocytopenia has been reported more often in patients with severe renal impairment, whether or not on dialysis, and in patients with moderate to severe hepatic impairment. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those with severe renal impairment or moderate to severe hepatic impairment, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibacterial drug therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression [see Adverse Reactions (6.2)].

6.2 Postmarketing Experience

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The following adverse reactions have been identified during postapproval use of ZYVOX. 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.

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(Newly added subsection)

Postmarketing cases of hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) have been observed in patients treated with linezolid. In reported cases, the signs and symptoms included confusion, somnolence, generalized weakness, and in severe cases led to respiratory failure and even death. Monitor serum sodium levels regularly in the elderly, in patients taking diuretics, and in other patients at risk of hyponatremia and/or SIADH while taking ZYVOX. If signs and symptoms of hyponatremia and/or SIADH occur, discontinue ZYVOX, and institute appropriate supportive measures.

(Addition of the following to the bulleted line listing)

• Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) [see Warnings and Precautions (5.10)].

(Additions and/or revisions underlined)

Important Administration Instructions

Advise patients that ZYVOX may be taken with or without food. Peripheral and Optic Neuropathy

Advise patients to inform their physician if they experience changes in vision while taking ZYVOX [see Warnings and Precautions (5.2)].

Serotonin Syndrome

Advise patients to inform their physician if taking serotonergic agents, including serotonin re-uptake inhibitors or other antidepressants and opioids [see Warnings and Precautions (5.3)].

Potential Interactions Producing Elevation of Blood Pressure

• Advise patients to inform their physician if they have a history of hypertension.

• Advise patients to avoid large quantities of foods or beverages with high tyramine content while taking ZYVOX. Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses, fermented or air-dried meats, sauerkraut, soy sauce, tap beers, and red wines. The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.

• Advise patients to inform their physician if taking medications containing pseudoephedrine HCl or phenylpropanolamine HCl, such as cold remedies and decongestants [see Warnings and Precautions (5.6)].

Lactic Acidosis

Advise patients to inform their physician if they experience repeated episodes of nausea or vomiting while receiving ZYVOX [see Warnings and Precautions (5.7)].

Convulsions

Advise patients to inform their physician if they have a history of seizures or convulsions [see Warnings and Precautions (5.8)].

Hypoglycemia

Advise patients to inform their physician if they have diabetes mellitus. Hypoglycemic reactions, such as diaphoresis and tremulousness, along with low blood glucose measurements may occur when treated with linezolid. If such reactions occur, patients should contact a physician or other health professional for proper treatment [see Warnings and Precautions (5.9)].

Hyponatremia and/or SIADH

Advise patients at risk for hyponatremia to inform their physician if they experience signs and symptoms of hyponatremia and/or SIADH, including confusion, somnolence, generalized weakness, and respiratory distress [see Warnings and Precautions (5.10)].

Phenylketonuria

Advise patients with phenylketonuria (PKU) that each 5 mL of the 100 mg/5 mL ZYVOX for Oral Suspension contains 20 mg phenylalanine. The other ZYVOX formulations do not contain phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria. Contact your physician or pharmacist when prescribed with ZYVOX for Oral Suspension [see Warnings and Precautions (5.11)].

Antibacterial Resistance

Patients should be counseled that antibacterial drugs including ZYVOX should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ZYVOX is 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 ZYVOX or other antibacterial drugs in the future.

Diarrhea

Diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, 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 antibacterial drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.5)].

Infertility

Advise male patients that ZYVOX may reversibly impair fertility [see Use in Specific Populations (8.3)].

Additions underlined

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Unless clinically appropriate and patients are carefully observed for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions, linezolid should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, bupropion, buspirone, serotonin 5-HT1 receptor agonists (triptans), and opioids, including meperidine [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

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• Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, and ZYVOX [see Warnings and Precautions (5.3)].

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Additions underlined

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Serotonin Syndrome

Advise patients to inform their physician if taking serotonergic agents, including serotonin re-uptake inhibitors or other antidepressants and opioids [see Warnings and Precautions (5.3)].

(Additions and/or revisions underlined)

The following adverse reactions have been identified during postapproval use of ZYVOX. 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) [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 ZYVOX [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)].

5.10         Risks in Patients with Phenylketonuria

(Newly added subsection)

Phenylalanine can be harmful to patients with phenylketonuria (PKU). ZYVOX for oral suspension contains phenylalanine, a component of aspartame. Each 5 mL of the 100 mg/5 mL oral suspension contains 20 mg of phenylalanine. Before prescribing ZYVOX for oral suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including ZYVOX for oral suspension. The other ZYVOX formulations do not contain phenylalanine.

8.1         Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

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 2-4% and 15-20%, 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) 6-16 (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 6-17 (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 6-20 (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

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

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

(Newly added subsection)

Infertility

Males

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

17         PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to label)

5.10         Risks in Patients with Phenylketonuria

(Newly added subsection)

Phenylalanine can be harmful to patients with phenylketonuria (PKU). ZYVOX for oral suspension contains phenylalanine, a component of aspartame. Each 5 mL of the 100 mg/5 mL oral suspension contains 20 mg of phenylalanine. Before prescribing ZYVOX for oral suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including ZYVOX for oral suspension. The other ZYVOX formulations do not contain phenylalanine.

8.1        Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

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 2-4% and 15-20%, 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) 6-16 (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 6-17 (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 6-20 (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

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

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

(Newly added subsection)

Infertility

Males

17          PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to label)

(“antibiotic use” revised to read “antibacterial drug use” throughout labeling)

(additions underlined)

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• Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia); sideroblastic anemia.

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• Anaphylaxis, angioedema, and bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome.

  …