Sivextro™ (tedizolid phosphate) Manufacturer: Cubist Pharmaceuticals FDA Approval Date: June 20, 2014

Sivextro™ - tedizolid phosphate Clinical Application Indications: Acute bacterial skin and skin structure infections Susceptible Gram-positive organisms Place in therapy: First line against gram positives? Think good antimicrobial stewardship

Sivextro™ - tedizolid phosphate Clinical Application Contraindications: None Warnings and Precautions: Neutropenia (<1000 cells/mm3) Bacterial or Fungal Super-infections

Sivextro™ - tedizolid phosphate Clinical Application Pregnancy: Category C Adverse event noted in animal studies Lactation: Not known if it enters breast milk

Sivextro™ - tedizolid phosphate Drug Facts Pharmacology: Prodrug (tedizolid phosphate  tedizolid) Binds to the 50S bacterial ribosomal subunit Bacteriostatic against Enterococci Staphylococci Streptococci This prevents the formation of a functional 70S initiation complex that is essential for the bacterial translation process and subsequently inhibits protein synthesis.

Sivextro™ - tedizolid phosphate Drug Facts Pharmacokinetics A Well absorbed F= 91% Cmax: ~ 3 hour D Vd = 67 to 80 L, 70 to 90% protein bound Tissue penetration similar to plasma free drug concentration M No significant metabolite E Feces 82%, Urine 18% Most occurs within 96 hours

Sivextro™ - tedizolid phosphate Drug Interactions Drug Interactions – Object Drugs: No known drug interactions Drug interactions – Precipitant Drugs:

Sivextro™ - tedizolid phosphate Adverse Effects Sivextro (200 mg) vs non-placebo (linezolid 600 mg) Nausea 8% (12%) Headache 6% (6%) Diarrhea 4% (5%) Vomiting 3% (6%) Dizziness 2% (2%)

Sivextro™ - tedizolid phosphate Monitoring Parameters Efficacy Monitoring: Signs of clinical improvement Toxicity Monitoring: Reduction in circulation RBCs, WBCs, and platelets

Sivextro™ - tedizolid phosphate Prescription Information Dosing: 200 mg Oral or Intravenous Infusion time 1 hour Daily for six days IV to oral – no dose adjustment

Sivextro™ - tedizolid phosphate Prescription Information Cost: Brand (generic) Dose(s) Cost Sivextro (tedizolid phosphate) Oral – 200 mg tablets #6 $2124.00 IV – 200 mg vial #10 $2820.00 Lexi-Comp via UpToDate; Accessed 10/16/2014

Sivextro™ - tedizolid phosphate Literature Review Study Design (ESTABLISH-1) Phase 3, randomized, double blind, double dummy, non-inferiority trial 81 study centers from North America, Latin American and Europe Interventions Tedizolid 200 mg daily for 6 days Linezolid 600 mg twice daily for 10 days Prokocimer et al., JAMA. 2013;309(6):559-569

Sivextro™ - tedizolid phosphate Literature Review Endpoints Primary Early clinical response (48-72hr) Temp ≤ 37.6°C Cessation of primary lesion spread Classified as responders, non-responders, and indeterminate Prokocimer et al., JAMA. 2013;309(6):559-569

Sivextro™ - tedizolid phosphate Literature Review (n = 332) Linezolid (n = 335) Absolute difference (95% CI) 48- to 72-h assessment (ITT) No. (%) [95% CI] 264 (79.5) [74.8 to 83.7] 266 (79.4) [74.7 to 83.6] 0.1 (-6.1 to 6.2) Sustained at EOT assessment (ITT) No. (%) [95% CI] 230 (69.3) [64.0 to 74.2] 241 (71.9) [66.8 to 76.7] -2.6 (-9.6 to 4.2) Prokocimer et al., JAMA. 2013;309(6):559-569

Sivextro™ - tedizolid phosphate Summary Sivextro is a new oxazolidinone for acute bacterial skin and skin structure infections for gram positive organisms. IV or oral 200 mg once daily dosing. It has a simple metabolism and does not interfere with other medications Sivextro should be used as a second line medication for ABSSSI. More uses could become available.

Sivextro™ - tedizolid phosphate References http://sivextro.com/. 10/14. Sivextro package insert. Cubist. October 2014. Prokocimer et al., Tedizolid Phosphate vs Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infections. JAMA. 2013;309(6):559-569