Cubicin RF

Dosage Forms And Strengths

For Injection: 500 mg daptomycin as a sterile, pale yellow to light brown lyophilized powder for reconstitution in a single-dose vial.

Storage And Handling

CUBICIN RF (daptomycin for injection) is supplied as a sterile pale yellow to light brown lyophilized powder in a single-dose 10 mL vial containing 500 mg of daptomycin: Package of 1 (NDC 67919-012-01).

Store original packages at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] [see DOSAGE AND ADMINISTRATION].

Distributed by : Merck Sharp 7 Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA.  Revised: Sep 2017

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]
• 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.

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

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

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

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

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 AND USAGE].

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

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

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.

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.

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

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

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.

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

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

General and administration site conditions: pyrexia

Immune System Disorders: anaphylaxis; hypersensitivity reactions, including angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]

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

Musculoskeletal Disorders: myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with CUBICIN and HMG-CoA 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 Stevens-Johnson syndrome and vesiculobullous rash (with or without mucous membrane involvement), acute generalized exanthematous pustulosis

Gastrointestinal Disorders: nausea, vomiting

Renal and urinary disorders: acute kidney injury, renal insufficiency, and renal failure

Special Senses: visual disturbances

Included as part of the PRECAUTIONS section.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Daptomycin is injected into a vein through an IV. You may be shown how to use an IV at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of needles, IV tubing, and other items used.

Daptomycin must be given slowly, and the IV infusion can take 2 to 30 minutes to complete. When giving this medicine to a child or teenager, the infusion is even slower (30 to 60 minutes).

Use this medicine for the full prescribed length of time. Some infections must be treated for up to 6 weeks. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Daptomycin will not treat a viral infection such as the flu or a common cold.

Call your doctor if your symptoms do not improve, or if they get worse.

Daptomycin is a powder medicine that must be mixed with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medication.

Do not shake the medication bottle or you may ruin the medicine. Gently swirl the medicine when mixing. Prepare your dose only when you are ready to give an injection. Do not use if the medicine has changed colors or has particles in it. Call your pharmacist for new medicine.

Each single-use vial (bottle) of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

While using daptomycin, you may need frequent blood and urine tests.

This medicine can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using daptomycin.

Store daptomycin powder in the refrigerator, do not freeze. After mixing daptomycin with a diluent, store in the refrigerator and use it within 48 hours. Do not freeze.

Mixed medicine must be used within 12 hours if you keep it at room temperature.

Important Administration Duration Instructions

Adults

Administer the appropriate volume of the reconstituted Cubicin RF (concentration of 50 mg/mL) to adult patients intravenously either by injection over a two (2) minute period or by intravenous infusion over a thirty (30) minute period. [see Dosage and Administration (2.2, 2.4, 2.7)].

Pediatric Patients (1 to 17 Years of Age)

Unlike in adults, do NOT administer Cubicin RF by injection over a two (2) minute period to pediatric patients.

• Pediatric Patients 7 to 17 years of Age: Administer Cubicin RF intravenously by infusion over a 30-minute period [see Dosage and Administration (2.3, 2.5, 2.7)].
• Pediatric Patients 1 to 6 years of Age: Administer Cubicin RF intravenously by infusion over a 60-minute period [see Dosage and Administration (2.3, 2.5, 2.7)].

Dosage in Adults for cSSSI

Administer Cubicin RF 4 mg/kg to adult patients intravenously once every 24 hours for 7 to 14 days.

Dosage in Pediatric Patients (1 to 17 Years of Age) for cSSSI

The recommended dosage regimens based on age for pediatric patients with cSSSI are shown in Table 1. Administer Cubicin RF intravenously once every 24 hours for up to 14 days.

Dosage in Adult Patients with Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible and Methicillin-Resistant Isolates

Administer Cubicin RF 6 mg/kg to adult patients intravenously once every 24 hours for 2 to 6 weeks. There are limited safety data for the use of CUBICIN for more than 28 days of therapy. In the Phase 3 trial, there were a total of 14 adult patients who were treated with CUBICIN for more than 28 days.

Dosage in Pediatric Patients (1 to 17 Years of Age) with Staphylococcus aureus Bloodstream Infections (Bacteremia)

The recommended dosage regimens based on age for pediatric patients with S. aureus bloodstream infections (bacteremia) are shown in Table 2. Administer Cubicin RF intravenously in 0.9% sodium chloride injection once every 24 hours for up to 42 days.

Dosage in Patients with Renal Impairment

Adult Patients:

No dosage adjustment is required in adult patients with creatinine clearance (CLCR) greater than or equal to 30 mL/min. The recommended dosage regimen for Cubicin RF in adult patients with CLCR less than 30 mL/min, including adult patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), is 4 mg/kg (cSSSI) or 6 mg/kg (S. aureus bloodstream infections) once every 48 hours (Table 3). When possible, Cubicin RF should be administered following the completion of hemodialysis on hemodialysis days [see Warnings and Precautions (5.2, 5.8), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Pediatric Patients:

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

Preparation and Administration of Cubicin RF

There are two formulations of daptomycin that have differences concerning storage and reconstitution. Carefully follow the reconstitution and storage procedures in labeling.

Reconstitution of Cubicin RF Vial

Cubicin RF must be reconstituted within the vial only with either Sterile Water for Injection or Bacteriostatic Water for Injection.

Do NOT use saline based diluents for the reconstitution in the vial because this will result in a hyperosmotic solution that may result in infusion site reactions if the reconstituted product is administered as an intravenous injection over a period of 2 minutes.

Cubicin RF is supplied in single-dose vials, each containing 500 mg daptomycin as a sterile, lyophilized powder. The contents of a Cubicin RF vial should be reconstituted, using aseptic technique, to 50 mg/mL as follows:

1. Remove the polypropylene flip-off cap from the Cubicin RF vial to expose the central portion of the rubber stopper.
2. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface.
3. Transfer 10 mL of Sterile Water for Injection or Bacteriostatic Water for Injection through the center of the rubber stopper into the Cubicin RF vial. Use a beveled sterile transfer needle that is 21 gauge or smaller in diameter, pointing the transfer needle toward the wall of the vial.
4. Rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted solution.

Administration Instructions

Parenteral drug products should be inspected visually for particulate matter prior to administration.

Slowly remove reconstituted liquid (50 mg daptomycin/mL) from the vial using a beveled sterile needle that is 21 gauge or smaller in diameter. Administer as an intravenous injection or infusion as described below:

Adults

Intravenous Injection over a period of 2 minutes

• For intravenous (IV) injection over a period of 2 minutes in adult patients only: Administer the appropriate volume of the reconstituted Cubicin RF (concentration of 50 mg/mL).

Intravenous Infusion over a period of 30 minutes

• For IV infusion over a period of 30 minutes in adult patients: The appropriate volume of the reconstituted Cubicin RF (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into a 50 mL IV infusion bag containing 0.9% sodium chloride injection.

Pediatric Patients (1 to 17 Years of Age)

Intravenous Infusion over a period of 30 or 60 minutes

• Unlike in Adults, do NOT administer Cubicin RF by injection over a two (2) minute period to pediatric patients [see Dosage and Administration (2.1)].
• For Intravenous infusion over a period of 60 minutes in pediatric patients 1 to 6 years of age: The appropriate volume of the reconstituted Cubicin RF (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into an intravenous infusion bag containing 25 mL of 0.9% sodium chloride injection. The infusion rate should be maintained at 0.42 mL/minute over the 60-minute period.
• For Intravenous infusion over a period of 30 minutes in pediatric patients 7 to 17 years of age: The appropriate volume of the reconstituted Cubicin RF (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into a 50 mL IV infusion bag containing 0.9% sodium chloride injection. The infusion rate should be maintained at 1.67 mL/minute over the 30-minute period.

No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the preparation of final IV solution. Table 4 below provides in-use storage conditions for reconstituted Cubicin RF in acceptable intravenous diluents in the syringe, vial and intravenous bag (for reconstitution and dilution). Do not exceed the listed shelf-life of reconstituted and diluted solutions of Cubicin RF. Discard unused portions of Cubicin RF.

Compatible Intravenous Solutions

Reconstituted Cubicin RF is compatible with Sterile Water for Injection, Bacteriostatic Water for Injection, and 0.9% sodium chloride injection. [See Dosage and Administration (2.7).]

Incompatibilities

Cubicin RF is not compatible with dextrose-containing diluents.

Cubicin RF should not be used in conjunction with ReadyMED® elastomeric infusion pumps. Stability studies of CUBICIN solutions stored in ReadyMED® elastomeric infusion pumps identified an impurity (2-mercaptobenzothiazole) leaching from this pump system into the CUBICIN solution.

Because only limited data are available on the compatibility of Cubicin RF with other IV substances, additives and other medications should not be added to Cubicin RF single-dose vials or infusion bags, or infused simultaneously with Cubicin RF through the same IV line. If the same IV line is used for sequential infusion of different drugs, the line should be flushed with a compatible intravenous solution before and after infusion with Cubicin RF.

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 (12.3)].

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 (6.1)]. 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.

Pregnancy

Risk Summary

Limited published data on use of Cubicin RF 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.

Lactation

Risk Summary

Limited published data report that daptomycin is present in human milk at infant doses 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 RF or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of Cubicin RF 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 RF 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 infections [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

Safety and effectiveness in pediatric patients below the age of one year have not been established. Avoid use of Cubicin RF 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 [see Warnings and Precautions (5.5) and Nonclinical Toxicology (13.2)].

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

Cubicin RF has not been studied in pediatric patients with other bacterial infections.

Geriatric Use

Of the 534 adult patients treated with CUBICIN in Phase 3 controlled clinical trials of complicated skin and skin structure infections (cSSSI), 27% were 65 years of age or older and 12% were 75 years of age or older. Of the 120 adult patients treated with CUBICIN in the Phase 3 controlled clinical trial of S. aureus bacteremia/endocarditis, 25% were 65 years of age or older and 16% were 75 years of age or older. In Phase 3 adult clinical trials of cSSSI and S. aureus bacteremia/endocarditis, clinical success rates were lower in patients ≥65 years of age than in patients <65 years of age. In addition, treatment-emergent adverse events were more common in patients ≥65 years of age than in patients <65 years of age.

The exposure of daptomycin was higher in healthy elderly subjects than in healthy young adult subjects. However, no adjustment of Cubicin RF dosage is warranted for elderly patients with creatinine clearance (CLCR) ≥30 mL/min [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

Patients with Renal Impairment

Daptomycin is eliminated primarily by the kidneys; therefore, a modification of Cubicin RF dosage interval is recommended for adult patients with CLCR <30 mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). In adult patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently than once weekly [see Dosage and Administration (2.6), Warnings and Precautions (5.2, 5.8), and Clinical Pharmacology (12.3)].

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

NDC 67919-012-02

Cubicin® RF
(daptomycin for injection)
500 mg per vial

For Intravenous Use

Reconstitute vial only with
Sterile Water for Injection or
Bacteriostatic Water for Injection.

Single-dose vial –
Discard Unused Portion

Rx only

PREMIERProRx®

Applies to daptomycin: intravenous powder for solution

Along with its needed effects, daptomycin (the active ingredient contained in Cubicin RF) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking daptomycin:

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• fever
• rapid weight gain
• tingling of the hands or feet
• unusual weight gain or loss

• Abdominal or stomach pain
• agitation
• black, tarry stools
• bladder pain
• bloody or cloudy urine
• blurred vision
• chest pain or discomfort
• chills
• coma
• confusion
• convulsions
• cough
• decreased frequency or amount of urine
• decreased urine output
• depression
• diarrhea
• difficult or labored breathing
• difficult, burning, or painful urination
• dilated neck veins
• dizziness
• dry mouth
• extreme fatigue
• fainting
• faintness or lightheadedness when getting up suddenly from a lying or sitting position
• fast heartbeat
• frequent urge to urinate
• headache
• hostility
• increased blood pressure
• increased thirst
• irregular breathing
• irregular heartbeat
• irritability
• itching in the genital or other skin areas
• itching, pain, redness, swelling, tenderness, or warmth on the skin
• lethargy
• lightheadedness
• loss of appetite
• lower back or side pain
• mood changes
• muscle pain or cramps
• muscle twitching
• nausea
• nervousness
• numbness or tingling in the hands, feet, or lips
• pale skin
• pounding in the ears
• rapid weight gain
• rapid, shallow breathing
• scaling
• seizures
• slow or fast heartbeat
• sneezing
• sore throat
• stupor
• sweating
• swelling of the face, fingers, ankles, or hands
• tightness in the chest
• troubled breathing with exertion
• unusual bleeding or bruising
• usual tiredness or weakness
• vomiting of blood or material that looks like coffee grounds
• weight gain

• Bleeding gums
• blood in the urine or stools
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• clay-colored stools
• dark urine
• difficulty with moving
• drowsiness
• eye pain
• feeling of warmth
• feeling unusually cold
• general feeling of illness
• headache
• hives, itching, or rash
• hoarseness
• increase in bone pain
• irritation
• joint pain, stiffness, or swelling
• loss of appetite
• mood or mental changes
• muscle aching or cramping
• muscle spasms (tetany) or twitching
• no blood pressure or pulse
• pain in the joints
• pinpoint red spots on the skin
• rapid or irregular heartbeat
• redness of the face, neck, arms, and occasionally, upper chest
• redness of the skin
• redness, blistering, peeling, or loosening of the skin
• shivering
• skin rash, encrusted, scaly and oozing
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stopping of heart
• swelling of the eyelids, face, lips, hands, or feet
• swollen glands
• swollen joints
• swollen, painful, or tender lymph glands in the neck, armpit, or groin
• trembling
• troubled breathing or swallowing
• twitching, twisting, uncontrolled repetitive movements of the tongue, lips, face, arms, or legs
• unconsciousness
• unpleasant breath odor
• unusual bleeding or bruising
• vomiting of blood
• yellow eyes or skin

• Abdominal or stomach cramps
• abdominal or stomach tenderness
• diarrhea, watery, and severe, which may also be bloody
• difficulty with swallowing
• dry cough
• pain
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• unusual weight loss

Some side effects of daptomycin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
• diarrhea, mild
• difficulty having a bowel movement (stool)

• Anxiety
• back pain
• blurred vision
• cold sweats
• coma
• cool, pale skin
• decreased appetite
• depression
• flushed, dry skin
• fruit-like breath odor
• increased hunger
• increased urination
• itching of the vagina or outside genitals
• lack or loss of strength
• limb pain
• nervousness
• nightmares
• pain during sexual intercourse
• shakiness
• slurred speech
• sweating
• thick, white, curd-like vaginal discharge without odor or with mild odor
• trouble sleeping
• unexplained weight loss

• Acid or sour stomach
• bad, unusual, or unpleasant (after) taste
• belching
• change in taste
• continuing ringing or buzzing or other unexplained noise in the ears
• excess air or gas in the stomach or intestines
• feeling of constant movement of self or surroundings
• full feeling
• hearing loss
• heartburn
• indigestion
• pain or discomfort in the chest, upper stomach, or throat
• passing gas
• pressure in the stomach
• red, sore eyes
• seeing, hearing, or feeling things that are not there
• sensation of spinning
• sore mouth or tongue
• swelling of the abdominal or stomach area
• swelling or inflammation of the mouth
• weakness
• white patches in the mouth or on the tongue

Applies to daptomycin: intravenous powder for injection

General

In phase 3 complicated skin and skin structure infection trials, this drug was discontinued in 2.8% of patients due to a side effect, while comparator was discontinued in 3% of patients. In the Staphylococcus aureus bacteremia/endocarditis trial, this drug was discontinued in 16.7% of patients due to a side effect, while comparator was discontinued in 18.1% of patients.

In phase 3 community-acquired pneumonia trials, the death rate and rates of serious cardiorespiratory side effects were higher with this drug than comparator due to lack of therapeutic efficacy.[Ref]

Musculoskeletal

Common (1% to 10%): Elevated creatine phosphokinase (CPK), limb pain
Uncommon (0.1% to 1%): Myalgia, muscle cramps, myositis, increased myoglobin, muscle weakness, muscle pain, arthralgia, muscle pain/weakness symptoms associated with CPK elevations to greater than 4 times the upper limit of normal (4 x ULN)
Frequency not reported: Pain in extremity, back pain, osteomyelitis, muscle twitching, myopathy (with minor increases in CPK), rhabdomyolysis (with secondary acute renal failure), severe myopathy (with possible hepatotoxicity)
Postmarketing reports: Rhabdomyolysis (some cases involved coadministration with HMG-CoA reductase inhibitors)[Ref]

In clinical studies, 0.2% of patients had symptoms of muscle pain or weakness associated with CPK elevations to greater than 4 x ULN. After discontinuation of this drug, CPK returned to normal within 7 to 10 days and symptoms resolved within 3 days.

A 45-year-old female with refractory acute myeloid leukemia was admitted to the blood and marrow transplant unit for a second attempt to induce remission with myeloablative chemotherapy of high-dose cytarabine. Two months prior, the patient's first course of induction therapy was complicated by neutropenic fever and vancomycin- resistant Enterococcus faecium (VRE) bacteremia that was treated with linezolid for 14 days. The patient was also receiving aztreonam, levofloxacin, acyclovir, amphotericin B lipid complex, and azithromycin. Once her clinical status stabilized, she was transferred from the intensive care unit (ICU) back to the blood and marrow transplant unit. After receiving 8 of 12 scheduled doses of cytarabine, the patient required readmission to the medical ICU due to a decrease in mental status, supraventricular tachycardia, and hypotension. Cultures of blood and urine samples at the time of her transfer showed VRE with intermediate resistance to linezolid. The patient, who was neutropenic at this time, was started on IV daptomycin 550 mg (6 mg/kg) every 24 hours. The patient's baseline CPK was 108 units/L and serum creatinine level was 0.8 mg/dL. Over the following 7 days, the patient's CPK level gradually increased, and on day 10 of daptomycin therapy, her CPK level was 996 units/L, BUN was 73 mg/dL, and serum creatinine level was 1.9 mg/dL. To evaluate for rhabdomyolysis, urine myoglobin was measured and reported at 30,890 ng/mL. Rhabdomyolysis was diagnosed based on increased CPK and urine myoglobin level in a patient with acute renal failure. Daptomycin was discontinued and the patient was started on treatment for rhabdomyolysis. Despite aggressive hydration and diuresis, CPK and urine myoglobin levels continued to increase up to 5350 units/L and 47,166 ng/mL, respectively. Over 2 weeks, the patient's CPK and urine myoglobin levels slowly resolved. The final CPK and urine myoglobin levels measured were 3395 units/L and 451 ng/mL, respectively.

In another case, a 53-year-old African-American female with a history of hypertension, diabetes mellitus, and peripheral vascular disease was admitted to the hospital and an MRI revealed L5-S1 discitis and osteomyelitis. After an 8-week course of empirical antibiotic therapy with vancomycin and levofloxacin, an open biopsy was performed. Specimens from the biopsy cultured positive for Torulopsis glabrata, VRE, and methicillin-resistant S aureus (MRSA) and the patient was started on daptomycin 360 mg (6 mg/kg) IV as a single daily dose and voriconazole 250 mg twice daily. Ten days after starting this drug, the patient developed generalized muscular weakness that progressed to the point she was unable to get out of bed. The patient then developed nonoliguric acute renal failure with a serum creatinine of 27 mg/mL up from baseline of 9 mg/mL. A CPK level drawn was elevated to 21,243 units/L and was associated with elevated levels: AST 375 units/L, ALT 219 units/L, and LDH 666 units/L. Urinalysis was positive for hemoglobin, myoglobin, and RBCs which conferred a diagnosis of acute renal failure secondary to drug-induced rhabdomyolysis. After this drug was discontinued and IV fluid was administered to alkalinize the urine, renal function, CPK, and liver function tests returned to baseline as well as dissipation of muscular weakness. Myoglobin, hemoglobin, and RBCs disappeared from urine as well.

In another similar case, a 52-year-old male with a history hepatitis C, IV drug abuse, idiopathic thrombocytopenia, and hyperlipidemia was admitted to the hospital and an MRI revealed findings compatible with L3-L4 discitis and osteomyelitis. He was started on vancomycin but it was discontinued after a rash developed. Daptomycin was started at 500 mg (6.5 mg/kg) IV as a single daily dose. The patient was also on simvastatin; however, it was discontinued prior to starting this drug. After 9 days of therapy, the patient developed generalized muscle weakness progressing to the point where he was unable to get out of bed. The patient's CPK rose to 20,771 units/L from a baseline of 102 units/L. AST 239 units/L and ALT 40 units/L were elevated from baseline and alkaline phosphatase was elevated to 118 units/L. This drug was discontinued and the patient was admitted to the ICU for close monitoring and hydration. The patient slowly improved and recovered all muscle strength and within 2 weeks his enzymes returned to baseline.

Increased myoglobin has also been reported during postmarketing experience.[Ref]

Psychiatric

Common (1% to 10%): Insomnia, anxiety
Uncommon (0.1% to 1%): Mental status change
Frequency not reported: Hallucination, confusion[Ref]

Other

Common (1% to 10%): Pyrexia, asthenia, serious gram-negative infections (including bloodstream infections, cholangitis, alcoholic pancreatitis, sternal osteomyelitis/mediastinitis, bowel infarction, recurrent Crohn's disease, recurrent line sepsis, recurrent urosepsis), chest pain, edema, sepsis, bacteremia, fungal infections, candidal infection
Uncommon (0.1% to 1%): Fatigue, weakness, rigors, flushing, taste disturbance, fungemia, pain, chills
Frequency not reported: Discomfort, jitteriness, pneumonia, chapped lips, peripheral edema
Postmarketing reports: Infusion reactions (including tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope, metallic taste)[Ref]

Serious gram-negative infections (including bloodstream infections) were reported in 10/120 daptomycin-treated patients in the S aureus bacteremia/endocarditis trial compared to 0/115 in comparator-treated patients. Gram-negative infections included cholangitis, alcoholic pancreatitis, sternal osteomyelitis/mediastinitis, bowel infarction, recurrent Crohn's disease, recurrent line sepsis, and recurrent urosepsis.

One patient developed S aureus endocarditis with a 2 cm mitral vegetation, bowel infarction, and polymicrobial bacteremia that ultimately lead to death following mitral valve repair complicated by sternal osteomyelitis.

Pyrexia has also been reported during postmarketing experience.[Ref]

Respiratory

Common (1% to 10%): Pharyngolaryngeal pain, dyspnea
Frequency not reported: Pleural effusions, sore throat, adenoviral upper respiratory infection, upper respiratory tract infection (not otherwise specified), dyspnea with hypoxic respiratory insufficiency, diffuse pulmonary infiltrates
Postmarketing reports: Cough, eosinophilic pneumonia, organizing pneumonia[Ref]

Symptoms of eosinophilic pneumonia have included fever, dyspnea with hypoxic respiratory insufficiency, diffuse pulmonary infiltrates, cough, shortness of breath, and difficulty breathing.[Ref]

Gastrointestinal

Common (1% to 10%): Abdominal pain, diarrhea, gastrointestinal and abdominal pain, nausea, vomiting, constipation, flatulence, bloating and distension
Uncommon (0.1% to 1%): Abdominal distention, stomatitis, dyspepsia, glossitis
Frequency not reported: Dry mouth, epigastric discomfort, gingival pain, oral candidiasis, oral hypoesthesia, loose stools, gastrointestinal hemorrhage, abnormal bowel sounds, aphthous stomatitis
Postmarketing reports: Clostridium difficile-associated diarrhea[Ref]

Nausea and vomiting have also been reported during postmarketing experience.[Ref]

Dermatologic

Common (1% to 10%): Pruritus, increased sweating, rash
Uncommon (0.1% to 1%): Eczema, urticaria
Frequency not reported: Heat rash, generalized pruritus, vesicular rash, erythema, cellulitis, papular rash
Postmarketing reports: Serious skin reactions (including Stevens-Johnson syndrome, vesiculobullous rash [with or without mucous membrane involvement]), acute generalized exanthematous pustulosis[Ref]

Cardiovascular

Common (1% to 10%): Hypertension, hypotension
Uncommon (0.1% to 1%): Supraventricular arrhythmia, supraventricular tachycardia, extrasystole
Frequency not reported: Atrial fibrillation, atrial flutter, cardiac arrest, cardiac failure, cardiac disorders (unspecified)[Ref]

Nervous system

Common (1% to 10%): Headache, dizziness
Uncommon (0.1% to 1%): Vertigo, paresthesia, taste disorder, tremor
Frequency not reported: Peripheral nervous system events (such as paresthesias, dysesthesias, peripheral neuropathies), tinnitus, dyskinesia
Postmarketing reports: Peripheral neuropathy[Ref]

Hepatic

Common (1% to 10%): Abnormal liver function tests (increased ALT, increased AST, increased alkaline phosphatase)
Rare (less than 0.1%): Jaundice
Frequency not reported: Hepatobiliary disorder[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infections
Uncommon (0.1% to 1%): Vaginitis
Frequency not reported: Vaginal candidiasis, fungal urinary tract infection, proteinuria, vaginal discharge, asymptomatic foamy urine[Ref]

Hematologic

Anemia has also been reported during postmarketing experience.[Ref]

Common (1% to 10%): Anemia
Uncommon (0.1% to 1%): Leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased INR, thrombocythemia
Rare (less than 0.1%): Prolonged prothrombin time
Frequency not reported: Lymphadenopathy[Ref]

Local

Common (1% to 10%): Infusion site reactions
Frequency not reported: Injection site reactions, injection site erythema, injection site phlebitis[Ref]

Metabolic

Uncommon (0.1% to 1%): Hypomagnesemia, increased serum bicarbonate, electrolyte imbalance/disturbance, decreased appetite, hyperglycemia, increased serum lactate dehydrogenase (LDH)
Frequency not reported: Increased blood phosphorous, elevated alkaline phosphatase, hypoglycemia, hypokalemia, hyperkalemia[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Hypersensitivity
Postmarketing reports: Anaphylaxis, hypersensitivity reactions (including angioedema, drug rash with eosinophilia and systemic symptoms [DRESS], pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, pulmonary eosinophilia, vesiculobullous rash with mucous membrane involvement, sensation of oropharyngeal swelling)[Ref]

Ocular

Uncommon (0.1% to 1%): Eye irritation
Frequency not reported: Blurred vision
Postmarketing reports: Visual disturbances[Ref]

Renal

Renal insufficiency and renal failure have also been reported during postmarketing experience.[Ref]

Uncommon (0.1% to 1%): Renal impairment (including renal failure, renal insufficiency), increased serum creatinine
Frequency not reported: Renal impairment (including interstitial nephritis, toxic nephropathy, acute prerenal failure, acute or chronic renal failure, renal impairment, renal tubular necrosis), worsening CrCl/decreased renal function
Postmarketing reports: Acute kidney injury[Ref]

Oncologic

Frequency not reported: Benign and malignant neoplasms (unspecified)[Ref]

Some side effects of Cubicin RF may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.