Infectious Disease: Update on FDA Notices in 2007 Valerie A. Bush, PharmD Clinical Pharmacy Specialist- Internal Medicine Greenville Hospital System University Medical Center Affiliate Clinical Assistant Professor South Carolina College of Pharmacy

Ceftriaxone Warning FDA ALERT (5/07) –“…The drug must not be mixed or administered simultaneously with calcium- containing solutions or products, even via different infusion lines. Additionally, calcium- containing solutions or products must not be administered within 48 hours of the last administration of ceftriaxone.”

Ceftriaxone Details 5 case reports of neonatal death reported by manufacturer –4 deaths due to ceftriaxone and calcium in the same infusion –1 death seen when ceftriaxone and calcium gluconate administered by different routes at different times Crystalline precipitates seen in IV tubing, pulmonary, or renal vasculature FDA also received 4 post-marketing results in patients <1yo (3 fatalities)

Ceftriaxone FDA ALERT (9/07) –“Ceftriaxone and calcium-containing solutions, including continuous calcium-containing infusions such as parenteral nutrition, should not be mixed or co-administered to any patient irrespective of age, even via different infusion lines at different sites…Ceftriaxone and IV calcium-containing solutions should not be administered within 48 hours of each other in any patient.”

Ceftriaxone Pharmacokinetics Absorption Not absorbed orally Bioavailability is 100% when dosed intramuscularly or intravenously Distribution Vd= L 85-95% protein bound Metabolism None Excretion Elimination t 1/2 = 5.8 – 8.7 hrs % of drug eliminated in the urine with remainder secreted into bile and excreted in the stool

Ceftriaxone Recommendations Neonates –contraindicated Pediatrics (<18yo) –No ceftriaxone and calcium-containing products (PN, electrolyte boluses, lactated ringers) within 48hrs –Contact physician Adults –Clinical judgment

Cefepime Warning FDA ALERT (11/07) –“early communication” on an ongoing safety review –Recent meta-analysis raised question of increased mortality when using cefepime –FDA currently reviewing safety data and requested additional data to further evaluate

Efficacy and safety of cefepime: a systematic review and meta- analysis Lancet Infect Dis 2007;7:338-48

Methods 57 randomized controlled trials comparing cefepime with different  -lactam antibiotic Primary OutcomeSecondary Outcomes -30-day all-cause mortality OR -Mortality at end of study follow-up -Clinical failure -Microbiological failure -Bacterial, fungal, or any other superinfections -Adverse events Lancet Infect Dis 2007;7:338-48

Methods Included Infections: –Febrile neutropenia –Pneumonia –UTI –Sepsis –Bacteremia –Skin and soft tissue infections Compared  -lactams: –Ceftazidime –Imipenem-cilastatin –Meropenem –Piperacillin-tazobactam –Cefotaxime –Ceftriaxone –Cefoparazone-sulbactam Lancet Infect Dis 2007;7:338-48

Results Primary Outcome All-cause mortality1.26 [1.08 – 1.49] p=0.005 Secondary Outcomes Clinical failure Microbiological failure Superinfections Adverse events NS (0.98 [ ]) NS (0.92 [0.82 – 1.23]) NS (1.01 [0.77 – 1.38]) NS (0.99 [0.94 – 1.04]) Lancet Infect Dis 2007;7:338-48

All-Cause Mortality by Comparator Drug Lancet Infect Dis 2007;7:338-48

Problems with Meta-Analyses Heterogeneous data Inconsistency in patient demographics Variability of susceptibilities Measured outcomes Limited to strength of individual trials

Introduction of a New Class of Highly Active Anti-Retroviral Therapy (HAART)… Integrase Inhibitors

Timeline of HAART Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Protease Inhibitors (PIs) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Fusion Inhibitors Integrase Inhibtors 2007

Mechanism of HAART

Raltegravir (Isentress®) Indication: combination treatment of HIV in treatment-experienced adults who have multi-drug resistance and active replication Dosage: 400mg po BID

Ongoing Phase III Trials BNCHMARK-1 and –2 –Triple blind, randomized –Treatment groups (all patients resistant to 3 classes of HAART and failing therapy) Raltegravir 400mg po BID + optimized background therapy (OBT) Placebo + OBT –Primary outcomes CD4 increases from baseline % patients with viral load reduction to <400 copies/mL % patients with viral load reduction to <50 copies/mL Isentress® package insert, Merck ; 2007

Interim Analysis- 24 Weeks Isentress® package insert, Merck ; 2007

Raltegravir Pharmacokinetics Absorption AUC increased by 19% with high fat meal Distribution 83% protein bound Metabolism hepatic glucuronidation mediated by uridine diphosphate glucuronosyltransferase (UGT1A1) Excretion Elimination t 1/2 = 9 hrs Feces (51%, as unchanged drug) and urine (32%)

Raltegravir Dose Adjustments: –None required in renal or hepatic dysfunction Adverse Events: –Gastrointestinal (diarrhea, nausea) % –Headache –Pruritis Drug Interactions: –Rifampin (uridine diphosphate glucuronosyltransferase inducer)- may  plasma levels of raltegravir (??)

Raltegravir- Take Home Points Salvage therapy only! Promising early results No long-term safety or efficacy therapy

Questions???