Dosing and uses of Ddiflunisal
Adult dosage forms and strengths
tablet
- 500mg
Pain
500-1000 mg PO first dose, THEn
250-500 mg PO q8-12hr; not to exceed 1.5 g/day
Osteoarthritis
500-1000 mg PO daily divided q12hr
Maximum dose: 1500 mg/day
Rheumatoid Arthritis
500-1000 mg PO daily divided q12hr
Maximum dose: 1500 mg/day
Renal Impairment
Initiate at lower dose, monitor for ADRs
CrCl<50 mL/min: 50% of regular dose
Hepatic Impairment
Initiate at lower dose, monitor for ADRs
Administration
Take with food or 8-12 oz water to avoid GI effects
Other Indications & Uses
Off-label: Vascular headache
Pediatric dosage forms and strengths
<12 years old: Safety & efficacy not established
Geriatric dosage forms and strengths
Pain
500-1000 mg PO first dose, THEn
250-500 mg PO q8-12hr; not to exceed 1.5 g/day
Osteoarthritis
500-1000 mg PO daily divided q12hr
Maximum dose: 1500 mg/day
Rheumatoid Arthritis
500-1000 mg PO daily divided q12hr
Maximum dose: 1500 mg/day
Ddiflunisal adverse (side) effects
>10%
Increased liver function test (up to 15%)
1-10%
Body fluid retention
Rash
Abdominal pain
Constipation
Diarrhea
Flatulence
Indigestion
Nausea
Dizziness
Headache
Insomnia
Tinnitus
<1%
Edema (<1%)
Hypertension
Myocardial infarction
Vasculitis (<1%)
Erythema multiforme (<1%)
Scaling eczema, Stevens-Johnson syndrome (<1%)
Toxic epidermal necrolysis (<1%)
Gastrointestinal hemorrhage (<1%)
Gastrointestinal perforation (<1%)
Inflammatory disorder of digestive tract
Agranulocytosis (<1%)
Anemia (<1%)
Thrombocytopenia (<1%)
Hepatitis (<1%)
Jaundice (<1%)
Anaphylactoid reaction (<1%)
Immune hypersensitivity reaction (<1%)
Cerebrovascular accident
Impaired renal function disorder (<1%)
Interstitial nephritis (<1%)
Renal failure (<1%)
Bronchospasm
Warnings
Black box warnings
Cardiovascular Risk
- NSAIDs may increase risk of serious cardiovascular thrombotic events, myocardial infarction (MI), & stroke, which can be fatal
- Risk may increase with duration of use
- Patients with risk factors for or existing cardiovascular disease may be at greater risk
- NSAIDs are contraindicated for perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (increased risk of MI & stroke)
Gastrointestinal Risk
- NSAIDs increase risk of serious GI adverse events including bleeding, ulceration, & perforation of the stomach or intestines, which can be fatal
- GI adverse events may occur at any time during use & without warning symptoms
- Elderly patients are at greater risk for serious GI events
Contraindications
Absolute: hypersensitivity to diflunisal, ASA allergy, history of aspirin triad, CABg
Relative: bleeding disorders, duodenal/gastric/peptic ulcer, renal impairment, stomatitis, ulcerative colitis, upper GI dz, late pregnancy (risk of premature closure of ductus arteriosus)
Cautions
Use caution in bronchospasm, cardiac disease, CHF, hepatic/renal impairment, HTN, SLE, fluid retention, >65 years
Potential risk of cardiovascular damage
Long-term administration of NSAIDs may result in renal papillary necrosis and other renal injury; patients at greatest risk include the elderly, or those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, and individuals taking diuretics, ACE inhibitors, or ARBs
Risk of serious skin reactions
Heart Failure (HF) risk
- NSAIDS have the potential to trigger HF by prostaglandin inhibition that leads to sodium and water retention, increased systemic vascular resistance, and blunted response to diuretics
- NSAIDS should be avoided or withdrawn whenever possible
- AHA/ACC Heart Failure Guidelines; Circulation. 2016; 134
Pregnancy and lactation
Pregnancy category: C (avoid in late pregnancy; may cause premature closure of ductus arteriosus)
The Quebec Pregnancy Registry identified 4705 women who had spontaneous abortions by 20 weeks' gestation; each case was matched to 10 control subjects (n=47,050) who had not had spontaneous abortions; exposure to nonaspirin NSAIDs during pregnancy was documented in approximately 7.5% of cases of spontaneous abortions and in approximately 2.6% of controls. (CMAJ, September 6, 2011; DOI:10.1503/cmaj.110454)
Lactation: enters breast milk/not recommended
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.
Pharmacology of Ddiflunisal
Mechanism of action
Inhibits cyclooxygenase-1 (COX-1) & -2 (COX-2), thereby inhibiting prostaglandin synthesis
Pharmcokinetics
Bioavailability: 80-100%
Peak Plasma Time: within 2-3 hr
Protein Bound: at least 98-99%
Vd: 0.11 L/kg
Metabolism: Liver (to glucuronide conjugates, not to salicylic acid)
Metabolites: salicylurate, salicyl phenolic glucuronide, salicyl acyl glucuronide, 2,5-dihydroxybenzoic acid (gentisic acid), 2,3-dihydroxybenzoic acid, 2,3,5-trihydroxybenzoic acid, gentisuric acid (active)
Enzymes inhibited: Prostaglandin synthesis (insignificant)
Half-life: 8-12 hr
Excretion: Urine ~90%; feces <5%
Renal Clearance: 80-100% in 24-72 hr
Dialyzable: Yes
