Drug Safety-related Labeling Changes (SrLC)

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CUBICIN (NDA-021572)

(DAPTOMYCIN)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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08/26/2020 (SUPPL-63)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

(Newly added section)

DRESS has been reported in post-marketing experience with CUBICIN [see Adverse Reactions (6.2)]. Patients who develop skin rash, fever, peripheral eosinophilia, and systemic organ (for example, hepatic, renal, pulmonary) impairment while receiving CUBICIN should undergo medical evaluation. If DRESS is suspected, discontinue CUBICIN promptly and institute appropriate treatment.

5.5 Tubulointerstitial Nephritis (TIN)

(Newly added information)

TIN has been reported in post-marketing experience with CUBICIN [see Adverse Reactions (6.2)]. Patients who develop new or worsening renal impairment while receiving CUBICIN should undergo medical evaluation. If TIN is suspected, discontinue CUBICIN promptly and institute appropriate treatment.

5.8 Clostridioides difficile-Associated Diarrhea

(Section title revised)

(Additions and/or revisions underlined)

Clostridioides difficile–associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including CUBICIN, and may range in severity from mild diarrhea to fatal colitis [see Adverse Reactions (6.2)].

6 Adverse Reactions

(Newly added information)

  • Drug reaction with eosinophilia and systemic symptoms [see Warnings and Precautions (5.4)]

  • Tubulointerstitial nephritis [see Warnings and Precautions (5.5.)]

6.2 Post-Marketing Experience

(Additions and/or revisions underlined)

Infections and Infestations: Clostridioides difficile–associated diarrhea [see Warnings and Precautions (5.8)]

Skin and Subcutaneous Tissue Disorders: serious skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome and vesiculobullous rash (with or without mucous membrane involvement), acute generalized exanthematous pustulosis [see Warnings and Precautions (5.4)]

Renal and urinary disorders: acute kidney injury, renal insufficiency, renal failure, and tubulointerstitial nephritis (TIN) [see Warnings and Precautions (5.5)]

12/03/2018 (SUPPL-61)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Post-Marketing Experience

(additions  underlined)

...

Blood and lymphatic system disorders: anemia, thrombocytopenia

Laboratory Investigations: platelet count decreased

09/01/2017 (SUPPL-57)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Clinical Trial Experience in Pediatric Patients

Addition of the following:

S. aureus Bacteremia Trial in Pediatric Patients

The safety of CUBICIN was evaluated in one clinical trial (in S. aureus bacteremia), which treated 55 pediatric patients with intravenous CUBICIN and 26 patients with comparator agents. Patients were given age-dependent doses once daily for a treatment period of up to 42 days (mean duration of IV treatment was 12 days). The doses by age group were as follows: 12 mg/kg for 1 to less than 6 years, 9 mg/kg for 7 to 11 years and 7 mg/kg for 12 to 17 years of age. Patients treated with CUBICIN were (69%) male and (31%) female. No patients 1 to less than 2 years of age were enrolled.

Additions and/or revisions underlined:

Adverse Reactions Leading to Discontinuation

In the bacteremia study, CUBICIN was discontinued in 3/55 (5.5%) patients due to an adverse reaction, while comparator was discontinued in 2/26 (7.7%) patients.

Most Common Adverse Reactions

The rates of the most common adverse reactions, organized by body system, observed in these pediatric patients with bacteremia are displayed in Table 10.

Table 10: Incidence of Adverse Reactions that Occurred in greater than or equal to 5% of Pediatric Patients in the CUBICIN Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the Pediatric Bacteremia Trial Newly added table; please refer to label for full information.

*Comparators included intravenous therapy with either vancomycin, cefazolin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of CUBICIN in the treatment of cSSSI and S. aureus bloodstream infections (bacteremia) have been established in the age groups 1 to 17 years of age. Use of CUBICIN in these age groups is supported by evidence from adequate and well-controlled studies in adults, with additional data from pharmacokinetic studies in pediatric patients, and from safety, efficacy and PK studies in pediatric patients with cSSSI and S. aureus bloodstream infection ….

06/09/2017 (SUPPL-59)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Eosinophilic Pneumonia

(Additions and/or revisions are underlined)

Eosinophilic pneumonia has been reported in patients receiving CUBICIN. In reported cases associated with CUBICIN, patients developed fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates or organizing pneumonia.

5.8 Decreased Efficacy in Patients with Moderate Baseline Renal Impairment

(Additions and/or revisions are underlined)

Limited data are available from the two Phase 3 complicated skin and skin structure infection (cSSSI) trials regarding clinical efficacy of CUBICIN treatment in adult patients with creatinine clearance (CLCR) less than 50 mL/min; only 31/534 (6%) patients treated with CUBICIN in the intent-to-treat (ITT) population had a baseline CLCR less than 50 mL/min. Table 4 shows the number of adult patients by renal function and treatment group who were clinical successes in the Phase 3 cSSSI trials.

In a subgroup analysis of the ITT population in the Phase 3 S. aureus bacteremia/endocarditis trial, clinical success rates, as determined by a treatment-blinded Adjudication Committee [see Clinical Studies (14.2)], in the CUBICIN-treated adult patients were lower in patients with baseline CLCR <50 mL/min (see Table 5). A decrease of the magnitude shown in Table 5 was not observed in comparator-treated patients.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions to Table numbering are underlined)

The rates of the most common adverse reactions, organized by body system, observed in adult patients with cSSSI (receiving 4 mg/kg CUBICIN) are displayed in Table 6.

S. aureus Bacteremia/Endocarditis Trial in Adults

The rates of the most common adverse reactions, organized by System Organ Class (SOC), observed in adult patients with S. aureus bacteremia/endocarditis (receiving 6 mg/kg CUBICIN) are displayed in Table 7.

Laboratory Changes in Adults

…Table 8 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI adult trials.

Most Common Adverse Reactions

The rates of the most common adverse reactions, organized by body system, observed in these pediatric patients with cSSSI are displayed in Table 9.

6.2 Post-Marketing Experience

(Additions and/or revisions are underlined)

Respiratory, Thoracic, and Mediastinal Disorders: cough, eosinophilic pneumonia, organizing pneumonia

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

The safety and effectiveness of CUBICIN RF in the treatment of cSSSI has been established in the age groups 1 to 17 years of age. Use of CUBICIN RF in these age groups is supported by evidence from adequate and well-controlled studies with CUBICIN

03/29/2017 (SUPPL-55)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Myopathy and Rhabdomyolysis

… In adult patients with renal impairment, both renal function and CPK should be monitored more frequently than once weekly.

In Phase 1 studies and Phase 2 clinical trials in adults, CPK elevations …

5.4 Peripheral Neuropathy

… Therefore, physicians should be alert to signs and symptoms of peripheral neuropathy in patients receiving CUBICIN. Monitor for neuropathy and consider discontinuation.

5.8 Decreased Efficacy in Patients with Moderate Baseline Renal Impairment

Limited data are available from the two Phase 3 complicated skin and skin structure infection (cSSSI) trials regarding clinical efficacy of CUBICIN treatment in adult patients with creatinine clearance (CLCR) <50 mL/min; only 31/534 (6%) patients treated with CUBICIN in the intent-to-treat (ITT) population had a baseline CLCR <50 mL/min. Table 3 shows the number of adult patients by renal function and treatment group who were clinical successes in the Phase 3 cSSSI trials.

Table 3: Clinical Success Rates by Renal Function and Treatment Group in Phase 3 cSSSI Trials in Adult Patients (Population: ITT)

… Adjudication Committee, in the CUBICIN-treated adult patients were lower in patients with baseline CLCR less than 50 mL/min (see Table 4) ...

Table 4: Adjudication Committee Clinical Success Rates at Test of Cure by Baseline Creatinine Clearance and Treatment Subgroup in the S. aureus Bacteremia/Endocarditis Trial in Adult Patients (Population: ITT)

Consider these data when selecting antibacterial therapy for use in adult patients with baseline moderate to severe renal impairment.

5.10 Non-Susceptible Microorganisms

The use of antibacterials may promote the overgrowth of non-susceptible microorganisms. If  these infections occur during therapy …

6 Adverse Reactions

Additions and/or revisions underlined:

6.1 Clinical Trials Experience

Clinical Trial Experience in Adult Patients

Clinical trials enrolled 1,864 adult patients

Complicated Skin and Skin Structure Infection Trials in Adults

In Phase 3 complicated skin and skin structure infection (cSSSI) trials in adult patients, CUBICIN was discontinued …

The rates of the most common adverse reactions, organized by body system, observed in adult patients with cSSSI (receiving 4 mg/kg CUBICIN) patients are displayed in Table 5.

Table 5: Incidence of Adverse Reactions that Occurred in greater than or equal to 2% of Adult Patients in the CUBICIN Treatment Group and greater than or equal to the Comparator Treatment Group in Phase 3 cSSSI Trials

Drug-related adverse reactions (possibly or probably drug-related) that occurred in less than 1% of adult patients receiving …

S. aureus Bacteremia/Endocarditis Trial in Adults

In the S. aureus bacteremia/endocarditis trial involving adult patients, CUBICIN was discontinued …

The rates of the most common adverse reactions, organized by System Organ Class (SOC), observed in  adult patients with S. aureus bacteremia/endocarditis (receiving 6 mg/kg CUBICIN) are displayed in Table 6.

Table 6: Incidence of Adverse Reactions that Occurred in greater than or equal to 5% of Adult Patients in the CUBICIN Treatment Group and greater than or equal to  the Comparator Treatment Group in the S. aureus Bacteremia/Endocarditis Trial

Other Trials in Adults

In Phase 3 trials of community-acquired pneumonia (CAP) in adult patients, the death rate …

Laboratory Changes in Adults

Complicated Skin and Skin Structure Infection Trials in Adults

In Phase 3 cSSSI trials of adult patients receiving CUBICIN at a dose … within 7 to 10 days after treatment was discontinued. Table 7 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI adult trials.

Table 7: Incidence of CPK Elevations from Baseline during Therapy in Either the CUBICIN Treatment Group or the Comparator Treatment Group in Phase 3 cSSSI Adult Trials

S. aureus Bacteremia/Endocarditis Trial in Adults

In the S. aureus bacteremia/endocarditis trial in adult patients, at a dose …

Addition of the following:

Clinical Trial Experience in Pediatric Patients

Complicated Skin and Skin Structure Infection Trial in Pediatric Patients

The safety of CUBICIN was evaluated in one clinical trial (in cSSSI), which included 256 pediatric patients (1 to 17 years of age) treated with intravenous CUBICIN and 133 patients treated with comparator agents. Patients were given age- dependent doses once daily for a treatment period of up to 14 days (median treatment period was 3 days). The doses given by age group were as follows: 10mg/kg for 1 to less than 2 years, 9 mg/kg for 2 to 6 years, 7mg/kg for 7 to 11 years and 5 mg/kg for 12 to 17 years of age. Patients treated with CUBICIN were (51%) male, (49%) female and (46 %) Caucasian and (32 %) Asian.

Adverse Reactions Leading to Discontinuation

In the cSSSI study, CUBICIN was discontinued in 7/256 (2.7%) patients due to an adverse reaction, while comparator was discontinued in 7/133 (5.3%) patients.

Most Common Adverse Reactions

The rates of the most common adverse reactions, organized by body system, observed in these pediatric patients with cSSSI are displayed in Table 8.

Table 8: Adverse Reactions that Occurred in greater than or equal to 2% of Pediatric Patients in the CUBICIN Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the cSSSI Pediatric Trial

The safety profile in the clinical trial of cSSSI pediatric patients was similar to that observed in the cSSSI adult patients.

7 Drug Interactions

7.1 HMG-CoA Reductase Inhibitors

Additions and/or revisions underlined:

In healthy adult subjects, concomitant administration of CUBICIN and simvastatin had no effect …

However, inhibitors of HMG-CoA reductase may cause myopathy, which is manifested as muscle pain or weakness associated with elevated levels of creatine phosphokinase (CPK). In the adult Phase 3 S. aureus bacteremia/endocarditis …

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion, as below:

Risk Summary

Limited published data on use of CUBICIN in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies performed in rats and rabbits daptomycin was administered intravenously during organogenesis at doses 2 and 4-times, respectively, the recommended 6 mg/kg human dose (on a body surface area basis). No evidence of adverse developmental outcomes was observed.

The 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 2-4% and 15-20%, respectively.

Data

Animal Data

In pregnant rats, daptomycin was administered intravenously at doses of 5, 20, or 75 mg/kg/day during the gestation days 6 to 18. Maternal body weight gain was decreased at 75 mg/kg/day.

No embryo/fetal effects were noted at the highest dose of 75 mg/kg/day, a dose approximately 2-fold higher than in humans at the recommended maximum dose of 6mg/kg (based on body surface area).

In pregnant rabbits, daptomycin was administered intravenously at doses of 5, 20, or 75 mg/kg/day during the gestation days 6 to 15. Maternal body weight gain and food consumption were decreased at 75 mg/kg/day. No embryo/fetal effects were noted at the highest dose of 75 mg/kg/day, a dose approximately 4-fold higher than in humans at the maximum recommended dose of 6mg/kg (based on body surface area).

In a combined fertility and pre/postnatal development study, daptomycin was administered intravenously to female rats at doses of 2, 25, 75 mg/kg/day from 14-days pre-mating through lactation/postpartum day 20). No effects on pre/postnatal development were observed up to the highest dose of 75 mg/kg/day, a dose approximately 2-fold higher than the maximum recommended human dose of 6 mg/kg (based on body surface area)1.

8.2 Lactation

PLLR conversion; as below:

Risk Summary

 published data report that daptomycin is present in human milk at infant  150 mL/kg/ddoses of 0.1% of the maternal dose [see Data]2,3,4. There is no information on the effects of daptomycin on the breastfed infant or the effects of daptomycin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CUBICIN and any potential adverse effects on the breastfed infant from CUBICIN or from the underlying maternal condition.

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of CUBICIN in the treatment of cSSSI has been established in the age groups 1 to 17 years of age. Use of CUBICIN in these age groups is supported by evidence from adequate and well-controlled studies in adults, with additional data from pharmacokinetic studies in pediatric patients, and additional data from a safety, efficacy and PK study in pediatric patients 1 to 17 years of age with cSSSI. Safety and effectiveness in pediatric patients below the age of one year have not been established. Avoid use of CUBICIN in pediatric patients younger than  one year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs.

CUBICIN is not indicated in pediatric patients with renal impairment because dosage has not been established in these patients.

The safety and efficacy of CUBICIN has not been established in pediatric patients (below 18 years of age) with Staphylococcus aureus bloodstream infections (bacteremia). The safety and efficacy of CUBICIN has also not been established in pediatric patients with cSSSI associated with bloodstream infections. CUBICIN has also not been studied in pediatric patients with other bacterial infections.

8.5 Geriatric Use

Addition of the word adult before patients, clinical trials, and subjects throughout subsection.

8.6 Patients with Renal Impairment

Addition of the word adult prior to patients throughout this subsection.

Additions and/or revisions underlined:

The dosage regimen for CUBICIN in pediatric patients with renal impairment has not been established.

07/07/2016 (SUPPL-53)

Approved Drug Label (PDF)

6 Adverse Reactions

Post-Marketing Experience

Addition of the following adverse reactions:

  • Blood and lymphatic system disorders: anemia
  • General and administration site conditions: pyrexia
  • Renal and urinary disorders: acute kidney injury, renal insufficiency, and renal failure
  • Skin and Subcutaneous Tissue Disorders: acute generalized exanthematous pustulosis

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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