Cubicin RF

SIDE EFFECTS

The following adverse reactions are described, or described in greater detail, in other sections:

• Anaphylaxis/hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
• Myopathy and rhabdomyolysis [see WARNINGS AND PRECAUTIONS]
• Eosinophilic pneumonia [see WARNINGS AND PRECAUTIONS]
• Drug reaction with eosinophilia and systemic symptoms [see WARNINGS AND PRECAUTIONS]
• Tubulointerstitial nephritis [see WARNINGS AND PRECAUTIONS]
• Peripheral neuropathy [see WARNINGS AND PRECAUTIONS]
• Increased International Normalized Ratio (INR)/prolonged prothrombin time [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trial Experience In Adult Patients

Clinical trials enrolled 1,864 adult patients treated with CUBICIN and 1,416 treated with comparator.

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 in 15/534 (2.8%) patients due to an adverse reaction, while comparator was discontinued in 17/558 (3.0%) patients.

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 7.

Table 7: Incidence of Adverse Reactions that Occurred in ≥2% of Adult Patients in the CUBICIN Treatment Group and ≥ the Comparator Treatment Group in Phase 3 cSSSI Trials

Adverse Reaction	Adult Patients (%)
	CUBICIN 4 mg/kg (N=534)	Comparator* (N=558)
Gastrointestinal disorders
Diarrhea	5.2	4.3
Nervous system disorders
Headache	5.4	5.4
Dizziness	2.2	2.0
Skin/subcutaneous disorders
Rash	4.3	3.8
Diagnostic investigations
Abnormal liver function tests	3.0	1.6
Elevated CPK	2.8	1.8
Infections
Urinary tract infections	2.4	0.5
Vascular disorders
Hypotension	2.4	1.4
Respiratory disorders
Dyspnea	2.1	1.6
* Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g/day IV in divided doses).

Drug-related adverse reactions (possibly or probably drug-related) that occurred in <1% of adult patients receiving CUBICIN in the cSSSI trials are as follows:

Body as a Whole: fatigue, weakness, rigors, flushing, hypersensitivity

Blood/Lymphatic System: leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased International Normalized Ratio (INR)

Cardiovascular System: supraventricular arrhythmia

Dermatologic System: eczema

Digestive System: abdominal distension, stomatitis, jaundice, increased serum lactate dehydrogenase

Metabolic/Nutritional System: hypomagnesemia, increased serum bicarbonate, electrolyte disturbance

Musculoskeletal System: myalgia, muscle cramps, muscle weakness, arthralgia

Nervous System: vertigo, mental status change, paresthesia

Special Senses: taste disturbance, eye irritation

S. aureus Bacteremia/Endocarditis Trial in Adults

In the S. aureus bacteremia/endocarditis trial involving adult patients, CUBICIN was discontinued in 20/120 (16.7%) patients due to an adverse reaction, while comparator was discontinued in 21/116 (18.1%) patients.

Serious Gram-negative infections (including bloodstream infections) were reported in 10/120 (8.3%) CUBICIN-treated patients and 0/115 comparator-treated patients. Comparator-treated patients received dual therapy that included initial gentamicin for 4 days. Infections were reported during treatment and during early and late follow-up. Gram-negative infections included cholangitis, alcoholic pancreatitis, sternal osteomyelitis/mediastinitis, bowel infarction, recurrent Crohn's disease, recurrent line sepsis, and recurrent urosepsis caused by a number of different Gram-negative bacteria.

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 8.

Table 8: Incidence of Adverse Reactions that Occurred in ≥5% of Adult Patients in the CUBICIN Treatment Group and ≥ the Comparator Treatment Group in the S. aureus Bacteremia/Endocarditis Trial

Adverse Reaction*	Adult Patients n (%)
	CUBICIN 6 mg/kg (N=120)	Comparator† (N=116)
Infections and infestations
Sepsis NOS	6 (5%)	3 (3%)
Bacteremia	6 (5%)	0 (0%)
Gastrointestinal disorders
Abdominal pain NOS	7 (6%)	4 (3%)
General disorders and administration site conditions
Chest pain	8 (7%)	7 (6%)
Edema NOS	8 (7%)	5 (4%)
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	10 (8%)	2 (2%)
Skin and subcutaneous tissue disorders
Pruritus	7 (6%)	6 (5%)
Sweating increased	6 (5%)	0 (0%)
Psychiatric disorders
Insomnia	11 (9%)	8 (7%)
Investigations
Blood creatine phosphokinase increased	8 (7%)	1 (1%)
Vascular disorders
Hypertension NOS	7 (6%)	3 (3%)
* NOS, not otherwise specified. † Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 2 g IV q4h), each with initial low-dose gentamicin.

The following reactions, not included above, were reported as possibly or probably drug-related in the CUBICIN-treated group:

Blood and Lymphatic System Disorders: eosinophilia, lymphadenopathy, thrombocythemia, thrombocytopenia

Cardiac Disorders: atrial fibrillation, atrial flutter, cardiac arrest

Ear and Labyrinth Disorders: tinnitus

Eye Disorders: vision blurred

Gastrointestinal Disorders: dry mouth, epigastric discomfort, gingival pain, hypoesthesia oral

Infections and Infestations: candidal infection NOS, vaginal candidiasis, fungemia, oral candidiasis, urinary tract infection fungal

Investigations: blood phosphorous increased, blood alkaline phosphatase increased, INR increased, liver function test abnormal, alanine aminotransferase increased, aspartate aminotransferase increased, prothrombin time prolonged

Metabolism and Nutrition Disorders: appetite decreased NOS

Musculoskeletal and Connective Tissue Disorders: myalgia

Nervous System Disorders: dyskinesia, paresthesia

Psychiatric Disorders: hallucination NOS

Renal and Urinary Disorders: proteinuria, renal impairment NOS

Skin and Subcutaneous Tissue Disorders: pruritus generalized, rash vesicular

Other Trials in Adults

In Phase 3 trials of community-acquired pneumonia (CAP) in adult patients, the death rate and rates of serious cardiorespiratory adverse events were higher in CUBICIN-treated patients than in comparator-treated patients. These differences were due to lack of therapeutic effectiveness of CUBICIN in the treatment of CAP in patients experiencing these adverse events [see INDICATIONS].

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 of 4 mg/kg, elevations in CPK were reported as clinical adverse events in 15/534 (2.8%) CUBICIN-treated patients, compared with 10/558 (1.8%) comparator-treated patients. Of the 534 patients treated with CUBICIN, 1 (0.2%) had symptoms of muscle pain or weakness associated with CPK elevations to greater than 4 times the upper limit of normal (ULN). The symptoms resolved within 3 days and CPK returned to normal within 7 to 10 days after treatment was discontinued [see WARNINGS AND PRECAUTIONS]. Table 9 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI adult trials.

Table 9: 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

Change in CPK	All Adult Patients				Adult Patients with Normal CPK at Baseline
	CUBICIN 4 mg/kg (N=430)		Comparator* (N=459)		CUBICIN 4 mg/kg (N=374)		Comparator* (N=392)
	%	n	%	n	%	n	%	n
No Increase	90.7	390	91.1	418	91.2	341	91.1	357
Maximum Value >1× ULN†	9.3	40	8.9	41	8.8	33	8.9	35
>2× ULN	4.9	21	4.8	22	3.7	14	3.1	12
>4× ULN	1.4	6	1.5	7	1.1	4	1.0	4
>5× ULN	1.4	6	0.4	2	1.1	4	0.0	0
>10× ULN	0.5	2	0.2	1	0.2	1	0.0	0
Note: Elevations in CPK observed in adult patients treated with CUBICIN or comparator were not clinically or statistically significantly different. * Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g/day IV in divided doses). † ULN (Upper Limit of Normal) is defined as 200 U/L.

S. aureus Bacteremia/Endocarditis Trial in Adults

In the S. aureus bacteremia/endocarditis trial in adult patients, at a dose of 6 mg/kg, 11/120 (9.2%) CUBICIN-treated patients, including two patients with baseline CPK levels >500 U/L, had CPK elevations to levels >500 U/L, compared with 1/116 (0.9%) comparator-treated patients. Of the 11 CUBICIN-treated patients, 4 had prior or concomitant treatment with an HMG-CoA reductase inhibitor. Three of these 11 CUBICIN-treated patients discontinued therapy due to CPK elevation, while the one comparator-treated patient did not discontinue therapy [see WARNINGS AND PRECAUTIONS].

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 < 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 [see Clinical Studies]. 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 10.

Table 10: Adverse Reactions that Occurred in ≥2% of Pediatric Patients in the CUBICIN Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the cSSSI Pediatric Trial

Adverse Reaction	CUBICIN (N = 256)	Comparator* (N = 133)
	n (%)	n (%)
Gastrointestinal disorders
Diarrhea	18 (7.0)	7 (5.3)
Vomiting	7 (2.7)	1 (0.8)
Abdominal Pain	5 (2.0)	0
Skin and subcutaneous tissue disorders
Pruritus	8 (3.1)	2 (1.5)
General disorders and administration site conditions
Pyrexia	10 (3.9)	4 (3.0)
Investigations
Blood CPK increased	14 (5.5)	7 (5.3)
Nervous system disorders
Headache	7 (2.7)	3 (2.3)
* Comparators included intravenous therapy with either vancomycin, clindamycin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin)

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

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 <6 years, 9 mg/kg for 7 to 11 years and 7 mg/kg for 12 to 17 years of age [see Clinical Studies]. Patients treated with CUBICIN were (69%) male and (31%) female. No patients 1 to <2 years of age were enrolled.

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 11.

Table 11: Incidence of Adverse Reactions that Occurred in ≥5% of Pediatric Patients in the CUBICIN Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the Pediatric Bacteremia Trial

Adverse Reaction	CUBICIN (N = 55)	Comparator (N = 26)
	n (%)	n (%)
Gastrointestinal disorders
Vomiting	6 (10.9)	2 (7.7)
Investigations
Blood CPK increased	4 (7.3)	0
* Comparators included intravenous therapy with either vancomycin, cefazolin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin)

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of CUBICIN. 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.

Blood and lymphatic system disorders: anemia, thrombocytopenia

General and administration site conditions: pyrexia

Immune System Disorders: anaphylaxis; hypersensitivity reactions, including angioedema, pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]

Infections and Infestations: Clostridioides difficile–associated diarrhea [see WARNINGS AND PRECAUTIONS]

Laboratory Investigations: platelet count decreased

Musculoskeletal Disorders: myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with CUBICIN and HMGCoA reductase inhibitors) [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY]

Respiratory, Thoracic, and Mediastinal Disorders: cough, eosinophilic pneumonia, organizing pneumonia [see WARNINGS AND PRECAUTIONS]

Nervous System Disorders: peripheral neuropathy [see WARNINGS AND PRECAUTIONS]

Skin and Subcutaneous Tissue Disorders: serious skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), vesiculobullous rash (with or without mucous membrane involvement, including Stevens-Johnson syndrome [SJS] or toxic epidermal necrolysis [TEN]), and acute generalized exanthematous pustulosis [see WARNINGS AND PRECAUTIONS]

Gastrointestinal Disorders: nausea, vomiting

Renal and urinary disorders: acute kidney injury, renal insufficiency, renal failure, and tubulointerstitial nephritis (TIN) [see WARNINGS AND PRECAUTIONS]

Special Senses: visual disturbances

DRUG INTERACTIONS

HMG-CoA Reductase Inhibitors

In healthy adult subjects, concomitant administration of CUBICIN and simvastatin had no effect on plasma trough concentrations of simvastatin, and there were no reports of skeletal myopathy [see CLINICAL PHARMACOLOGY].

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 trial, some patients who received prior or concomitant treatment with an HMG-CoA reductase inhibitor developed elevated CPK [see ADVERSE REACTIONS]. Experience with the coadministration of HMG-CoA reductase inhibitors and CUBICIN in patients is limited; therefore, consideration should be given to suspending use of HMG-CoA reductase inhibitors temporarily in patients receiving CUBICIN RF.

Drug-Laboratory Test Interactions

Clinically relevant plasma concentrations of daptomycin have been observed to cause a significant concentration-dependent false prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay. The possibility of an erroneously elevated PT/INR result due to interaction with a recombinant thromboplastin reagent may be minimized by drawing specimens for PT or INR testing near the time of trough plasma concentrations of daptomycin. However, sufficient daptomycin concentrations may be present at trough to cause interaction.

If confronted with an abnormally high PT/INR result in a patient being treated with CUBICIN RF, it is recommended that clinicians:

1. Repeat the assessment of PT/INR, requesting that the specimen be drawn just prior to the next CUBICIN RF dose (i.e., at trough concentration). If the PT/INR value obtained at trough remains substantially elevated above what would otherwise be expected, consider evaluating PT/INR utilizing an alternative method.
2. Evaluate for other causes of abnormally elevated PT/INR results.

Read the entire FDA prescribing information for Cubicin RF (Daptomycin Injection)