Rivaroxaban

Class and Mechanism of Action

• Goodman & Gilman's Pharmacological Basis of Therapeutics, p. 739
• Goldman-Cecil Medicine, p. 70-6

Pharmacokinetics (ADME)

Dosing by Indication

Clinical Indications

1. Non-valvular atrial fibrillation - non-inferior or superior to warfarin for stroke/systemic embolism prevention (ROCKET-AF trial)
2. Acute DVT and PE treatment
3. Secondary prevention of VTE (after completed treatment course)
4. Post-surgical thromboprophylaxis after total hip or knee arthroplasty
5. Stable coronary artery disease - rivaroxaban 2.5 mg twice daily + aspirin reduces major vascular events (COMPASS trial)
6. Peripheral arterial disease - combination with aspirin also reduces adverse limb events (VOYAGER PAD trial)
7. Medically ill patients - extended post-discharge prophylaxis (10 mg daily x 45 days) in selected patients; data from MAGELLAN and MARINER trials

• Not suitable for patients with prosthetic cardiac valves (DOACs inferior to warfarin in this setting)
• Less effective than warfarin in high-risk antiphospholipid syndrome (triple aPL-positive) - the TRAPS trial demonstrated inferiority
• Used off-label for heparin-induced thrombocytopenia (HIT)

Drug Interactions

• Strong CYP3A4/P-gp inhibitors: ketoconazole, itraconazole, ritonavir, dronedarone, clarithromycin, erythromycin, cyclosporine

• Strong CYP3A4/P-gp inducers: carbamazepine, phenytoin, rifampin, St. John's wort

Adverse Effects

• Major adverse effect: Bleeding (as with all anticoagulants)
• Intracranial bleeding rates are at least 50% lower than with warfarin
• GI bleeding is higher than warfarin (unlike apixaban, which does not share this risk) - possibly due to unabsorbed drug in the gut promoting bleeding from preexisting GI lesions
• Rates of life-threatening and fatal bleeding are still lower than warfarin overall

Monitoring

Reversal

• Low-dose: 400 mg IV bolus at ~30 mg/min, then 4 mg/min infusion x 120 min
• High-dose: 800 mg IV bolus at ~30 mg/min, then 8 mg/min infusion x 120 min

Special Populations

• Renal impairment: Dose reduce to 15 mg once daily (AF) if CrCl 15-50 mL/min; avoid if CrCl <15-30 mL/min depending on indication
• Hepatic impairment: Avoid in severe hepatic dysfunction (increased drug exposure)
• Pregnancy: Avoid - safety not established; use LMWH instead
• Bariatric surgery: Absorption may be impaired after gastric bypass (stomach-dependent absorption)
• Cancer-associated VTE: Effective, more effective than LMWH but associated with somewhat more bleeding

Key Landmark Trials

Probenecid

Class and Chemistry

Mechanism of Action

1. Uricosuric Effect (Primary)

Key interaction: Salicylates (aspirin) blunt the uricosuric action of probenecid. Low-dose aspirin (<2.6 g/day) causes net retention of uric acid by inhibiting the secretory transporter, so it should not be used for analgesia in gout patients.

2. Inhibition of Organic Acid Transport (Secondary)

• Beta-lactam antibiotics (penicillin G, cephalosporins) - exploited therapeutically to prolong dwell time
• Methotrexate
• NSAIDs (naproxen, ketoprofen, indomethacin - via their inactive glucuronide metabolites)
• Zidovudine (AZT)
• Acyclovir, furosemide, lorazepam, theophylline, rifampin

Pharmacokinetics (ADME)

Therapeutic Indications

1. Gout / Chronic Hyperuricemia

• Used in patients with underexcretion of uric acid (the more common cause of hyperuricemia)
• Appropriate when allopurinol or febuxostat is contraindicated or not tolerated
• Can be used as monotherapy or combined with a xanthine oxidase inhibitor (allopurinol or febuxostat) for refractory cases
• Among patients failing allopurinol monotherapy, 86% achieved target serum uric acid <5 mg/dL after addition of probenecid 1000 mg/day
• Long-term benefits include: softening and resorption of tophi, remineralization of bone, functional improvement, reduced gout flares

• Patients who overproduce uric acid (24-hour urine uric acid >800 mg)
• Patients with nephrolithiasis (uric acid stones)
• Active gout attack - wait 2 to 3 weeks after the acute attack before starting

2. Adjuvant to Beta-Lactam Antibiotics

• Higher doses (1 to 2 g/day) used to prolong penicillin plasma levels - historically important for gonorrhea treatment with single-dose amoxicillin

3. Used with Cidofovir

• Probenecid is co-administered with IV cidofovir (antiviral) to reduce its nephrotoxicity by blocking its tubular secretion

Dosing

• After 6 months with normal serum uric acid and no gout attacks, the dose can be tapered by 500 mg every 6 months
• Maintain high urine volume throughout therapy to minimize uric acid stone risk
• Urine should be alkalinized (pH >6.0) especially early in treatment to improve urate solubility

Contraindications and Cautions

• Renal insufficiency: Ineffective (and should be avoided) when CrCl <50 mL/min - requires functioning tubular secretion to work
• Overproducers of uric acid: Uricosurics increase urinary urate and raise stone risk
• Active gout attack: Can precipitate or worsen flare
• Nephrolithiasis (existing uric acid/calcium oxalate stones)
• Do not use low-dose aspirin concomitantly for pain - will antagonize uricosuric effect

Adverse Effects

Important Drug Interactions Summary

Place in Gout Therapy