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= 5.8 -13.5 L

•85-95% protein bound

Metabolism • None

Excretion•Elimination t1/2= 5.8 – 8.7 hrs

•33 - 67% 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 Outcome Secondary 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 eventsLancet 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 mortality 1.26 [1.08 – 1.49] p=0.005

Secondary Outcomes

Clinical failure

Microbiological failure

Superinfections

Adverse events

NS (0.98 [0.93 -1.03])

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 Classof Highly Active Anti-Retroviral

Therapy (HAART)…

Integrase Inhibitors

Timeline of HAART

Nucleoside Reverse

Transcriptase Inhibitors (NRTIs)1987

1995Protease

Inhibitors (PIs)

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

1996

2003Fusion Inhibitors

Integrase Inhibtors2007

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 t1/2= 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)- 10-20%– 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???