daptomycin (Rx)

1-10%

Insomnia (9.0%)

Pharyngolaryngeal pain (8.0%)

Chest pain (7.0%)

Elevated blood creatine phosphokinase (7.0%)

Edema (7.0%)

Abdominal pain (6.0%)

Hypertension (6.0%)

Pruritus (6.0%)

Headache (5.4%)

Diarrhea (5.2%)

Sweating (5.0%)

Bacteremia (5.0%)

Sepsis (5.0%)

Rash (4.3%)

Abnormal LFTs (3.0%)

UTI (2.4%)

Hypotension (2.4%)

Dizziness (2.2%)

Dyspnea (2.1%)

Postmarketing Reports

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; consider treatment with systemic steroids

Infections and infestations: Clostridium difficile–associated diarrhea

Musculoskeletal disorders: myoglobin increased; rhabdomyolysis;

Respiratory, thoracic, and mediastinal disorders: Cough, eosinophilic pneumonia, organizing pneumonia

Nervous system disorders: Peripheral neuropathy

Skin and subcutaneous tissue disorders: Serious skin reactions, including Stevens-Johnson syndrome and vesiculobullous rash

Gastrointestinal disorders: Nausea, vomiting

Special senses: Visual disturbances

Blood and lymphatic system disorders: Anemia, thrombocytopenia

General and administration site conditions: Pyrexia

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

Skin and Subcutaneous Tissue Disorders: Acute generalized exanthematous pustulosis, epidermal necrolysis

Tubulointerstitial nephritis

Toxic epidermal necrolysis

Contraindications

Hypersensitivity

Cautions

Anaphylaxis/hypersensitivity reactions have been reported and may be life-threatening; discontinue the drug and institute appropriate therapy if allergic reaction occurs

May cause eosinophilic pneumonia characterized by fever, cough, shortness of breath, and difficulty breathing; may result in progressive respiratory failure and is potentially fatal; prompt medical evaluation, and treatment should be discontinued immediately if signs/symptoms develop; treatment with systemic steroids is recommended

Prolonged use may result in fungal or bacterial superinfection Perform susceptibility testing and rule out sequestered foci of infection if persisting or relapsing S. aureus bacteremia/endocarditis occurs

Avoid use in pediatric patients <12 months; potential nervous system or muscular system effects

Decreased efficacy reported in patients with moderate baseline renal impairment

Fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates or organizing pneumonia

Drug reaction with eosinophilia and systemic symptoms (DRESS) reported postmarketing; patients who develop skin rash, fever, peripheral eosinophilia, and systemic organ (for example, hepatic, renal, pulmonary) impairment while receiving therapy should undergo medical evaluation; if DRESS suspected, discontinue therapy promptly and institute appropriate treatment

Tubulointerstitial nephritis (TIN) reported post-marketing experience; patients who develop new or worsening renal impairment while receiving therapy should undergo medical evaluation; if TIN suspected, discontinue therapy promptly and institute appropriate treatment

Cases of peripheral neuropathy have been reported during the daptomycin postmarketing experience; monitor and consider discontinuation

Clinically relevant plasma concentrations of daptomycin reported 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

Prescribing in absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit and increases risk of development of drug-resistant bacteria

Clostridium difficile-associated diarrhea (CDAD)

• CDAD has been reported and may range in severity from mild diarrhea to fatal; CDAD must be considered in all patients who present with diarrhea following antibacterial use
• Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents
• Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, since these infections can be refractory to antimicrobial therapy and may require colectomy; CDAD must be considered in all patients who present with diarrhea following antibacterial use; careful medical history is necessary because CDAD has been reported to occur more than 2 months after administration of antibacterial agents
• If CDAD is suspected/confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued
• Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated

Myopathy and rhabdomyolysis

• Use cautiously in patients with peripheral neuropathies and myopathy; monitor for neuropathy and consider discontinuation
• Discontinue with symptoms of myopathy and CPK >1000 U/L (>5x ULN), or no symptoms and CPK >2000 U/L (>10x ULN)
• CPK elevations more prevalent if dosed more frequently than q24hr
• Consider suspending statins during daptomycin therapy; theoretical risk of additive myopathy
• Renal function and CPK should be monitored more frequently than once weekly in adult patients with renal impairment

Pregnancy

Limited published data on use in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage; no evidence of adverse developmental outcomes observed in animal reproduction studies

Lactation

Limited published data report that daptomycin is present in human milk at infant doses of 0.1% of maternal dose; there is no information on effects of daptomycin on breastfed infant or effects of daptomycin on milk production; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Cyclic lipopeptide: Binds to bacterial membranes and causes rapid depolarization of membrane potential; causes inhibition of protein, DNA, RNA synthesis, and bacterial cell death

Absorption

Peak plasma time

• 0.5-0.8 hr

Peak plasma concentration

• 4 mg/kg dose: 58 mcg/mL
• 6 mg/kg dose: 94 mcg/mL

AUC

• 4 mg/kg dose: 494 mcg•hr/mL
• 6 mg/kg dose: 632 mcg•hr/mL

Distribution

Protein bound: 92%

Vd: 0.1 L/kg

Elimination

Half-life: 8 hr

Dialyzable: 11-15% of dose removed by continuous ambulatory peritoneal dialysis/hemodialysis

Renal clearance: 3.7-4.8 mL/hr/kg

Total body clearance: 8-9 mL/hr/kg

Excretion: Urine (78%)

IV Incompatibilities

Solution: Dextrose-containing diluents

Do not admix with other drugs

IV Compatibilities

Solution: 0.9% NaCl, LR

IV Preparation

There are 3 formulations of daptomycin that have differences concerning storage and reconstitution; carefully follow the reconstitution and storage procedures in labeling

Reconstitution

• Cubicin

  • To minimize foaming, avoid vigorous agitation or shaking of the vial during or after reconstitution
  • Slowly transfer 10 mL of 0.9% NaCl into vial; use beveled sterile transfer needle that is 21-gauge or smaller in diameter, or a needleless device is used, pointing transfer needle toward vial wall
  • Gently rotate the vial to ensure all the lyophilized powder is wet; allow wetted product to stand undisturbed for 10 minutes
  • Gently rotate or swirl vial contents for a few minutes, as needed, to obtain a completely reconstituted solution
  • Do not use in conjunction with ReadyMED elastomeric infusion pumps in adult patients

• Cubicin RF or Dapzura RT

  • Do not use 0.9% NaCl (saline) based diluents for reconstituting vial because this will result in a hyperosmotic solution that may result in infusion-site reactions administered as an IV injection over a period of 2 minutes (adults)
  • Transfer 10 mL of sterile water for injection or bacteriostatic water for injection; use a beveled sterile transfer needle that is 21-gauge or smaller in diameter, pointing transfer needle toward vial wall
  • Rotate or swirl vial contents for a few minutes, as needed, to obtain a completely reconstituted solution

Further dilute for IV infusion

• Adults and children aged 7-17 years: Add calculated dose from reconstituted vial to IV bag containing 50 mL 0.9% NaCl
• Children aged 1-6 years: Add calculated dose from reconstituted vial to IV bag containing 25 mL 0.9% NaCl

IV Administration

Adults

• On hemodialysis days, administer after hemodialysis
• IV push: Administer reconstituted solution IV over 2 min (in adults only)
• IV infusion: Infuse diluted solution IV over 30 min

Pediatrics

• See section on IV preparation for appropriate concentrations of dilution for each age group
• 1-6 years: Infuse diluted IV solution at rate of 0.42 mL/min over a 60-min period
• 7-17 years: Infuse diluted IV solution at rate of 1.67 mL/min over a 30-min period
• Unlike adults, do not administer any formulation by injection over 2 minutes to children aged 1-17 yr

Storage

Unopened vials

Cubicin: Refrigerate in original packages at 2-8ºC (36-46ºF)

Cubicin RF and Dapzura RT: Store in original packages at controlled room temperature of 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

Daptomycin 350 mg vials: Store in original packages at refrigerated temperatures at 2-8ºC (36-46ºF); avoid excessive heat

Reconstituted or diluted solution (Cubicin)

Store in room temperature at 20-25ºC (68-77ºF) for up to 12 hr

Store in refrigerator at 2-8ºC (36-46ºF) for up to 48 hr

Reconstituted solution (Cubicin RF)

• Sterile water diluent

  • Vial or polypropylene syringe: 1 day (controlled room temperature) or 3 days (refrigerated at 2-8ºC [36-46ºF])

• Bacteriostatic water for injection diluent

  • Vial: 2 days (controlled room temperature) or 3 days (refrigerated at 2-8ºC [36-46ºF])
  • Polypropylene syringe: 2 days (controlled room temperature) or 5 days (refrigerated at 2-8ºC [36-46ºF])

Diluted solution in IV bag (Cubicin RF)

• Reconstituted and immediately diluted further with 0.9% NaCl
• Reconstituted with sterile water for injection: 19 hr (room temperature) or 3 days (refrigerated)
• Reconstituted with bacteriostatic water for injection: 2 days (room temperature) or 5 days (refrigerated)

Reconstituted solution (Dapzura RT)

• Sterile water diluent

  • Vial or polypropylene syringe: 18 hr (room temperature) or 3 days (refrigerated at 2-8°C [36-46°F])

• Bacteriostatic water for injection diluent

  • Vial: 2 days (controlled room temperature) or 5 days (refrigerated at 2-8°C [36-46°F])
  • Polypropylene syringe: 2 days (room temperature) or 5 days (refrigerated at 2-8°C [36-46°F])

Diluted solution in IV bag (Dapzura RT)

• Reconstituted and immediately diluted further with 0.9% NaCl
• Reconstituted with sterile water for injection: 1 day (room temperature) or 3 days (refrigerated)
• Reconstituted with bacteriostatic water for injection: 2 days (room temperature) or 5 days (refrigerated)