Cubicin

Cubicin

daptomycin

Manufacturer:

Merck Sharp & Dohme

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Daptomycin.
Description
CUBICIN contains daptomycin, a cyclic lipopeptide antibacterial agent.
Freshly reconstituted solutions of CUBICIN range in color from pale yellow to light brown.
CUBICIN is a sterile product contained in a single-use vial.
Excipients/Inactive Ingredients: Sodium hydroxide.
Action
Pharmacology: Pharmacokinetics: General Characteristics: Daptomycin pharmacokinetics were generally linear (dose-proportional) and time-independent at CUBICIN doses of 4 to 12 mg/kg administered by IV infusion over a 30-minute period as a single daily dose for up to 14 days. Steady-state concentrations were achieved by the third daily dose.
Distribution: Daptomycin is reversibly bound to human plasma proteins (mean binding range of 90 to 93%) in a concentration-independent manner, and serum protein binding trended lower (mean binding range of 84 to 88%) in subjects with significant renal impairment (CLCR <30 mL/min or on dialysis). The protein binding of daptomycin in subjects with mild to moderate hepatic impairment (Child-Pugh Class B) was similar to that in healthy adult subjects.
The volume of distribution at steady-state of daptomycin in healthy adult subjects was approximately 0.1 L/kg and was independent of dose. Tissue distribution studies in rats showed that daptomycin appears to penetrate the blood-brain barrier and the placental barrier only minimally following single and multiple doses.
Metabolism: In in vitro studies, daptomycin was not metabolized by human liver microsomes. In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the P450 system.
After infusion of 14C-daptomycin in healthy adults, the plasma radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference between total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma, and minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.
Elimination: Daptomycin is excreted primarily by the kidneys. There is minimal to no active tubular secretion of daptomycin. In a mass balance study using radiolabeled daptomycin, 78% of the administered dose was recovered from the urine based on total radioactivity, while urinary recovery of unchanged daptomycin was approximately 52% of the dose. About 6% of the administered dose was excreted in the feces based on total radioactivity. Plasma clearance of daptomycin is approximately 7 to 9 mL/h/kg, and its renal clearance is 4 to 7 mL/h/kg.
Specific Populations: Elderly: The pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (≥75 years of age) and 11 healthy young controls (18 to 30 years of age). Following administration of a single 4 mg/kg dose of CUBICIN by IV infusion over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC was approximately 58% higher in elderly subjects than in healthy young subjects. There were no differences in Cmax.
Renal Impairment: Following administration of a single 4 mg/kg or 6 mg/kg dose of CUBICIN by IV infusion over a 30-minute period to subjects with various degrees of renal impairment, total daptomycin clearance was lower and systemic exposure (AUC) was higher than in subjects with normal renal function. The mean AUC for patients with CLCR <30 mL/min and for patients on dialysis (CAPD and hemodialysis dosed post-dialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function.
Hepatic Impairment: The pharmacokinetics of daptomycin were evaluated in 10 subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with those in healthy volunteers (N=9) matched for gender, age, and weight. The pharmacokinetics of daptomycin were not altered in subjects with moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh Class C) have not been evaluated.
Pediatric: The pharmacokinetics of daptomycin after a single 4 mg/kg dose of CUBICIN were evaluated in three groups of pediatric patients with Gram-positive infections. The pharmacokinetic profile in adolescents 12 to 17 years old was similar to that in healthy adults, although exposure was lower. In the two younger age groups (7 to 11 years and 2 to 6 years), total clearance was higher than in adolescents, resulting in lower exposure (AUC and Cmax) and elimination half-life. After a single dose of 8 or 10 mg/kg in children 2 to 6 years old, clearance and elimination half-life were similar to those in the same age group who received a 4 mg/kg dose. In a single-dose study in infants 3 to 12 months old (4 mg/kg) and 13 to 24 months old (6 mg/kg), the clearance and elimination half-life of daptomycin were similar to those in children 2 to 6 years old who received a single dose of 4, 8, or 10 mg/kg. The results of these studies show that exposures (AUC) in pediatric patients across all doses are lower than those in adults at comparable doses. Efficacy was not assessed in these single-dose studies. (See Pharmacology: Toxicology: Nonclinical Toxicology and Animal Pharmacology under Actions.)
Gender: No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed.
Obesity: The pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m2) and 6 extremely obese (BMI ≥40 kg/m2) subjects. The AUC was approximately 30% higher in moderately obese subjects and 31% higher in extremely obese subjects than in nonobese controls.
Toxicology: Nonclinical Toxicology and Animal Pharmacology: In rats and dogs, daptomycin administration has been associated with effects on skeletal muscle. However, there were no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by microscopic degenerative/regenerative changes and variable elevations in CPK. No fibrosis or rhabdomyolysis was observed. All muscle effects, including microscopic changes, were fully reversible within 30 days following the cessation of dosing.
In adult rats and dogs, effects on peripheral nerve (characterized by axonal degeneration and frequently accompanied by functional changes) were observed at daptomycin doses higher than those associated with skeletal myopathy. Reversal of both the microscopic and functional effects was essentially complete within 6 months post-dose.
Target organs of daptomycin-related effects in 7-week-old juvenile dogs were skeletal muscle and nerve, the same target organs as in adult dogs. In juvenile dogs, nerve effects were noted at lower daptomycin blood concentrations than in adult dogs following 28 days of dosing. In contrast to adult dogs, juvenile dogs also showed evidence of effects in nerves of the spinal cord as well as peripheral nerves after 28 days of dosing. Following a 28-day recovery phase, microscopic examination revealed full recovery of the skeletal muscle and the ulnar nerve effects, and partial recovery of the sciatic nerve and spinal cord effects. No nerve effects were noted in juvenile dogs following 14 days of dosing.
Effects of daptomycin were assessed in neonatal dogs following once-daily IV administration for 28 consecutive days from postnatal days (PND) 4 through 31 at nominal dosage levels of 10 [no observed adverse effect level (NOAEL)], 25, 50, and 50/75 mg/kg/day.
At dose levels of 50 and 75 mg/kg/day with associated Cmax and AUCinf values of ≥321 μg/mL and ≥1470 μg·h/mL, respectively, marked clinical signs of twitching, muscle rigidity in the limbs, and impaired use of limbs were observed. Resulting decreases in body weights and overall body condition at doses ≥50 mg/kg/day necessitated early discontinuation by PND19. At the dose level of 25 mg/kg/day with associated Cmax and AUCinf values of 147 μg/mL and 717 μg·h/mL, respectively, mild clinical signs of twitching and one incidence of muscle rigidity were observed without any effects on body weight and were reversible over a 28-day recovery period. These data indicate a limited margin between doses associated with mild versus marked adverse clinical signs. Histopathological assessment did not reveal any daptomycin-related changes in the peripheral and central nervous system tissue, as well as in the skeletal muscle or other tissues assessed, at any dose level. No adverse clinical signs for these target organs of toxicity were observed in the dogs that received daptomycin at 10 mg/kg/day, the NOAEL, with associated Cmax and AUCinf values of 62 μg/mL and 247 μg·h/mL, respectively.
Carcinogenesis/Mutagenesis: Long-term carcinogenicity studies in animals have not been conducted. Daptomycin was not mutagenic or clastogenic in a battery of in vivo and in vitro genotoxicity tests.
Reproduction: Reproductive studies performed in rats revealed no effect of daptomycin on fertility or reproductive performance.
Microbiology: Daptomycin belongs to the cyclic lipopeptide class of antibacterials. Daptomycin is a natural product that has clinical utility in the treatment of infections caused by aerobic, Gram-positive bacteria. The in vitro spectrum of activity of daptomycin encompasses most clinically relevant Gram-positive pathogenic bacteria. Daptomycin retains potency against Gram-positive bacteria that are resistant to other antibacterials, including isolates resistant to methicillin, vancomycin, and linezolid.
Mechanism of Action: The mechanism of action of daptomycin is distinct from that of any other antibacterial. Daptomycin binds to bacterial cell membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death.
Mechanism of Resistance: The mechanism(s) of daptomycin resistance is not fully understood. There are no known transferable elements that confer resistance to daptomycin.
There is no cross-resistance due to resistance mechanisms that are specific for another class of antibacterials.
Emergent decreases in susceptibility have been observed in both S. aureus and enterococcal isolates following CUBICIN therapy.
PK/PD Relationship: Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive bacteria in vitro and in in vivo animal models.
Interactions with Other Antibacterials: In vitro studies have investigated daptomycin interactions with other antibacterials. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, β-lactam antibacterials, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates).
Indications/Uses
CUBICIN is indicated for the treatment of the infections listed as follows.
Complicated Skin and Skin Structure Infections: Complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following Gram-positive bacteria: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only).
Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible and Methicillin-Resistant Isolates: Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates.
Limitations of Use: CUBICIN is not indicated for the treatment of pneumonia.
CUBICIN is not indicated for the treatment of left-sided infective endocarditis due to S. aureus. The clinical trial of CUBICIN in patients with S. aureus bloodstream infections included limited data from patients with left-sided infective endocarditis; outcomes in these patients were poor. CUBICIN has not been studied in patients with prosthetic valve endocarditis.
Usage: Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to daptomycin.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CUBICIN and other antibacterial drugs, CUBICIN should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.
When culture and susceptibility information is available, it should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Empiric therapy may be initiated while awaiting test results.
Dosage/Direction for Use
Administration Duration: CUBICIN should be administered intravenously by infusion over a thirty (30) minute period.
Complicated Skin and Skin Structure Infections: CUBICIN 4 mg/kg should be administered intravenously in 0.9% sodium chloride injection once every 24 hours for 7 to 14 days.
Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible and Methicillin-Resistant Isolates: CUBICIN 6 mg/kg should be administered intravenously in 0.9% sodium chloride injection 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 patients who were treated with CUBICIN for more than 28 days.
Patients with Renal Impairment: The recommended dosage regimen for patients with creatinine clearance (CLCR) <30 mL/min, including those 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 1). When possible, CUBICIN should be administered following the completion of hemodialysis on hemodialysis days (see Pharmacology under Actions, Use in Specific Populations under Precautions). (See Table 1.)

Click on icon to see table/diagram/image

Preparation of CUBICIN for Administration: CUBICIN is supplied in single-use vials, each containing 500 mg daptomycin as a sterile, lyophilized powder. The contents of a CUBICIN vial should be reconstituted, using aseptic technique, to 50 mg/mL as follows: Note: To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.
Remove the polypropylene flip-off cap from the CUBICIN vial to expose the central portion of the rubber stopper.
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.
Slowly transfer 10 mL of 0.9% sodium chloride injection through the center of the rubber stopper into the CUBICIN vial, pointing the transfer needle toward the wall of the vial. It is recommended that a beveled sterile transfer needle that is 21 gauge or smaller in diameter, or a needleless device is used, pointing the transfer needle toward the wall of the vial.
Ensure that all of the CUBICIN powder is wetted by gently rotating the vial.
Allow the wetted product to stand undisturbed for 10 minutes.
Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted solution.
Slowly remove reconstituted liquid (50 mg daptomycin/mL) from the vial using a beveled sterile needle that is 21 gauge or smaller in diameter.
For IV infusion over a period of 30 minutes, the appropriate volume of the reconstituted CUBICIN (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.
Parenteral drug products should be inspected visually for particulate matter prior to administration.
No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the preparation of final IV solution. Stability studies have shown that the reconstituted solution is stable in the vial for 12 hours at room temperature and up to 48 hours if stored under refrigeration at 2 to 8°C (36 to 46°F).
The diluted solution is stable in the infusion bag for 12 hours at room temperature and 48 hours if stored under refrigeration. The combined storage time (reconstituted solution in vial and diluted solution in infusion bag) should not exceed 12 hours at room temperature or 48 hours under refrigeration.
CUBICIN vials are for single use only.
Compatible Intravenous Solutions: CUBICIN is compatible with 0.9% sodium chloride injection and lactated Ringer's injection.
Method/Route of Administration: CUBICIN is given by intravenous (IV) administration.
Overdosage
In the event of overdose, supportive care is advised. Daptomycin is cleared slowly from the body by hemodialysis (approximately 15% of the administered dose is removed over 4 hours) and by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours).
Contraindications
CUBICIN is contraindicated in patients with known hypersensitivity to daptomycin.
Special Precautions
Anaphylaxis/Hypersensitivity Reactions: Anaphylaxis/hypersensitivity reactions have been reported with the use of antibacterial agents, including CUBICIN. If an allergic reaction to CUBICIN occurs, discontinue the drug and institute appropriate therapy.
Pneumonia: CUBICIN should not be used for the treatment of pneumonia. It has been demonstrated in clinical studies that CUBICIN is not effective in the treatment of community-acquired pneumonia, due to binding to pulmonary surfactant and consequent inactivation.
Skeletal Muscle Effects: Increases in plasma CPK levels, muscular pains, weakness, and/or rhabdomyolysis have been reported during therapy with CUBICIN.
It is recommended that: Patients receiving CUBICIN be monitored for the development of muscle pain or weakness, particularly of the distal extremities.
In patients who receive CUBICIN, CPK levels be measured at baseline and at regular intervals (at least weekly), and more frequently in patients who received recent prior or concomitant therapy with an HMG-CoA reductase inhibitor or in whom elevations in CPK occur during treatment with CUBICIN.
In patients with renal impairment, both renal function and CPK be monitored more frequently than once weekly.
CUBICIN be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevations to levels greater than 1000 U/L (approximately 5 times upper limit of normal [ULN]) and in patients without reported symptoms who have marked elevations in CPK, with levels greater than 2000 U/L (≥10× ULN).
Consideration be given to suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, temporarily in patients receiving CUBICIN.
Peripheral Neuropathy: Physicians should be alert to signs and symptoms of peripheral neuropathy in patients receiving CUBICIN.
Pediatric patients one year old and younger should not be given CUBICIN due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs. (See Pharmacology: Toxicology: Nonclinical Toxicology and Animal Pharmacology under Actions.)
Eosinophilic Pneumonia: 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. In general, patients developed eosinophilic pneumonia 2 to 4 weeks after starting CUBICIN and improved when CUBICIN was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving CUBICIN should undergo prompt medical evaluation, and CUBICIN should be discontinued immediately. Treatment with systemic steroids is recommended.
Clostridium difficile-Associated Diarrhea: Clostridium difficile-associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including CUBICIN. If CDAD is suspected or confirmed, CUBICIN may need to be discontinued and appropriate treatment instituted as clinically indicated.
Persisting or Relapsing S. aureus Bacteremia/Endocarditis: Patients with persisting or relapsing S. aureus bacteremia/endocarditis or poor clinical response should have repeat blood cultures. If a blood culture is positive for S. aureus, minimum inhibitory concentration (MIC) susceptibility testing of the isolate should be performed using a standardized procedure, and diagnostic evaluation of the patient should be performed to rule out sequestered foci of infection. Appropriate surgical intervention (e.g., debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibacterial regimen may be required.
Drug-Laboratory Test Interactions: False prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) have been observed when certain recombinant thromboplastin reagents are utilized for the assay (see Adverse Reactions, Drug-Laboratory Test Interactions under Interactions).
Non-Susceptible Microorganisms: The use of antibacterials may promote the overgrowth of non-susceptible microorganisms. If superinfection occurs during therapy, take appropriate measures.
Use in Specific Populations: Renal Impairment: Daptomycin is eliminated primarily by the kidneys; therefore, an adjustment of CUBICIN dosage interval is recommended for patients with CLCR <30 mL/min, including patients receiving hemodialysis or CAPD. The recommended dosing regimen for these patients is 4 mg/kg (cSSSI) or 6 mg/kg (S. aureus bloodstream infections) once every 48 hours. Alternatively, patients on hemodialysis can be dosed three times per week. When possible, administer CUBICIN following the completion of hemodialysis on hemodialysis days. In patients with renal impairment, monitor both renal function and CPK more frequently than once weekly.
No dosage interval adjustment is required for patients with CLCR ≥30 mL/min.
Hepatic Impairment: No dosage adjustment is warranted when CUBICIN is administered to patients with mild to moderate hepatic impairment (Child-Pugh Class B). The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh Class C) have not been evaluated.
Gender: No dosage adjustment is warranted based on gender when CUBICIN is administered.
Obesity: No adjustment of CUBICIN dosage is warranted in obese patients.
Use in Pregnancy & Lactation: Teratogenic Effects: Pregnancy Category B.
Embryo/fetal development and teratology studies performed in rats and rabbits at doses of up to 75 mg/kg (2 and 4 times the 6 mg/kg human dose, respectively, on a body surface area basis) revealed no evidence of harm to the fetus due to daptomycin. Daptomycin can cross the placenta in pregnant rats. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, CUBICIN should be used during pregnancy only if the potential benefit outweighs the possible risk.
Excretion of daptomycin into milk of lactating animals has not been studied. In a single human case study, CUBICIN was administered daily for 28 days to a nursing mother at an IV dose of 6.7 mg/kg/day, and samples of the patient's breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 μg/mL, which is a low concentration. Until more experience is gained, women should be instructed to avoid breast-feeding while receiving CUBICIN.
Use in Children: Safety and effectiveness of CUBICIN in patients under the age of 18 years have not been established. (Also see Pharmacology: Toxicology: Nonclinical Toxicology and Animal Pharmacology under Actions).
Pediatric patients one year old and younger should not be given CUBICIN due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs. (See Pharmacology: Toxicology: Nonclinical Toxicology and Animal Pharmacology under Actions).
Use in Elderly: No adjustment of CUBICIN dosage is warranted for elderly patients with CLCR ≥30 mL/min.
Use In Pregnancy & Lactation
Teratogenic Effects: Pregnancy Category B.
Embryo/fetal development and teratology studies performed in rats and rabbits at doses of up to 75 mg/kg (2 and 4 times the 6 mg/kg human dose, respectively, on a body surface area basis) revealed no evidence of harm to the fetus due to daptomycin. Daptomycin can cross the placenta in pregnant rats. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, CUBICIN should be used during pregnancy only if the potential benefit outweighs the possible risk.
Excretion of daptomycin into milk of lactating animals has not been studied. In a single human case study, CUBICIN was administered daily for 28 days to a nursing mother at an IV dose of 6.7 mg/kg/day, and samples of the patient's breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 μg/mL, which is a low concentration. Until more experience is gained, women should be instructed to avoid breast-feeding while receiving CUBICIN.
Adverse Reactions
Undesirable Effects Identified during Clinical Trials: During clinical trials of CUBICIN, the following adverse drug reactions were reported during therapy and during follow-up. The adverse drug reactions are organized by system organ class, and the frequency categories for these adverse drug reactions are reported in the table as follows: Very common: ≥1/10 (≥10%), Common: ≥1/100 and <1/10 (≥1% and <10%), Uncommon: ≥1/1000 and <1/100 (≥0.1% and <1%), Rare: ≥1/10,000 and <1/1000 (≥0.01% and <0.1%), Very rare: <1/10,000 (<0.01%). (See Table 2.)

Click on icon to see table/diagram/image

Undesirable Effects Reported Post-Marketing: The following adverse drug reactions, not listed previously, have been reported during worldwide post-marketing experience: Immune system disorders: Hypersensitivity reactions, including, but not limited to, anaphylaxis, angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), and pulmonary eosinophilia.
Infections and infestations: Clostridium difficile-associated diarrhea.
Investigations: Myoglobin increased.
Musculoskeletal, connective tissue, and bone disorders: Rhabdomyolysis.
Nervous system disorders: Peripheral neuropathy.
Respiratory, thoracic, and mediastinal disorders: Cough, Eosinophilic pneumonia, Organizing pneumonia.
Skin and subcutaneous tissue disorders: Vesiculobullous rash with or without mucous membrane involvement; Acute generalized exanthematous pustulosis.
Drug Interactions
Interactions with Other Medicinal Products: CUBICIN was studied in human drug-drug interaction studies with aztreonam, tobramycin, warfarin, simvastatin, and probenecid. Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these drugs alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam.
Experience with the concomitant administration of CUBICIN and warfarin is limited. Studies of CUBICIN with anticoagulants other than warfarin have not been conducted. Monitor anticoagulant activity in patients receiving CUBICIN and warfarin for the first several days after therapy with CUBICIN is initiated.
Experience with the coadministration of HMG-CoA reductase inhibitors and CUBICIN in patients is limited; therefore, consider suspending use of HMG-CoA reductase inhibitors temporarily in patients receiving CUBICIN.
Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during coadministration by IV infusion over a 30-minute period using a CUBICIN dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with a clinical dose of CUBICIN is unknown. Caution is warranted when CUBICIN is coadministered with tobramycin.
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, it is recommended that clinicians: Repeat the assessment of PT/INR, requesting that the specimen be drawn just prior to the next CUBICIN 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.
Evaluate for other causes of abnormally elevated PT/INR results.
Caution For Usage
Incompatibilities: CUBICIN is not compatible with dextrose-containing diluents.
CUBICIN should not be used in conjunction with ReadyMED elastomeric infusion pumps (Cardinal Health, Inc.). 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 with other IV substances, additives and other medications should not be added to CUBICIN single-use vials or infusion bags, or infused simultaneously 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.
Storage
Store original packages at refrigerated temperatures, 2 to 8°C (36 to 46°F); avoid excessive heat.
Shelf-Life: Three years from the date of manufacture. After reconstitution: Chemical and physical stability of the reconstituted solution in the vial has been demonstrated for 12 hours at 25°C and up to 48 hours if stored under refrigeration (2 to 8°C). Chemical and physical stability of the diluted solution in infusion bags has been established as 12 hours at 25°C and 48 hours if stored under refrigeration at 2 to 8°C. The combined storage time (reconstituted solution in vial and diluted solution in infusion bag) must not exceed 12 hours at 25°C or 48 hours at 2 to 8°C.
MIMS Class
ATC Classification
J01XX09 - daptomycin ; Belongs to the class of other antibacterials. Used in the systemic treatment of infections.
Presentation/Packing
Powd for infusion (pale yellow to light brown lyophilized cake in a vial) 500 mg x 10 mL x 1's.
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