diclofenac (Rx)

Frequency Not Defined

Abdominal distention and flatulence

Abdominal pain or cramps

Constipation

Diarrhea

Dizziness

Dyspepsia

Edema

Fluid retention

Headache

Nausea

Peptic ulcer or GI bleeding

Pruritus

Rash

Tinnitus

Acute hepatitis

Agranulocytosis

Asthma

Aplastic anemia

Asymptomatic hepatitis

Blood urea nitrogen (BUN) >40 mg/dL (>14.3 mmol/L)

Cholestasis

Chronic active hepatitis

Congestive heart failure (CHF)

Decreased hemoglobin

Epistaxis

Fatal fulminant hepatitis

Hemolytic anemia (may be autoimmune)

Hepatocellular necrosis

Hypertension

Jaundice

Leukopenia

Nephrotoxicity

Purpura

Serum creatinine >2 mg/dL (>177 μmol/L)

Thrombocytopenia

Contraindications

Absolute: Hypersensitivity to diclofenac, history of aspirin triad, treatment of perioperative pain associated with CABG; active gastrointestinal bleeding

IV: Moderate-to severe renal insufficiency in the perioperative period and patients who are at risk for volume depletion

Zipsor capsules are contraindicated in patients with history of hypersensitivity to bovine protein

Cautions

Use caution in patients with bronchospasm, cardiac disease, CHF, hepatic porphyria, hypertension, fluid retention, severe renal impairment, smoking, systemic lupus erythematosus

Platelet aggregation and adhesion may be decreased; may prolong bleeding time

Use caution in blood dyscrasias or bone marrow depression; also with thrombocytopenia, agranulocytosis, and aplastic anemia

Long-term administration of NSAIDs may result in renal papillary necrosis and other renal injury; patients at greatest risk include elderly individuals, those with impaired renal function, hypovolemia, heart failure, liver dysfunction, or salt depletion, and those taking diuretics, angiotensin-converting enzyme inhibitors, or angiotensin-receptor blockers

Therapy may increase risk of hyperkalemia, especially in renal disease, diabetics, the elderly, and concomitant use of agents that may induce hyperkalemia; monitor potassium closely

May cause dizziness blurred vision and neurologic effects that may impair physical and mental abilities

Risk of serious skin reactions, including Stevens Johnson syndrome and necrotizing enterocolitis

Persistent urinary symptoms, including bladder pain and dysuria, hematuria or cystitis may occur after initiating therapy; discontinue therapy with symptom onset and evaluate cause

Increase in transaminase levels reported within 2 months of therapy; may occur at any time; monitor transaminase levels periodically beginning 4-8 weeks after initiation of therapy

May increase risk of aseptic meningitis (rare), especially in patients with systemic lupus erythrmatosus, and mixed connective tissue disorders

Use caution if patient dehydrated before initiating therapy; rehydrate patient before initiating therapy and monitor renal function closely

Injectable dosage form not recommended for long-term use

Overuse of acute migraine drugs (eg, ergotamine, triptans, opioids, nonsteroidal anti-inflammatory drugs or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache); may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks; detoxification of patients, including withdrawal of overused drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary

Different formulations not bioequivalent even if milligram strength the same; do not interchange products

Withhold for at least 4-6 half-lives prior to surgical or dental procedures

Heart failure 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

Published literature reports that use of NSAIDs after 30 weeks’ gestation increases risk of premature closure of fetal ductus arteriosus; data from observational studies regarding potential embryofetal risks of NSAID use, including diclofenac, in women in first or second trimester of pregnancy are inconclusive; avoid use of NSAIDs in pregnant women starting at 30 weeks of gestation (third trimester)

Infertility

• Based on mechanism of action, the use of prostaglandin-mediated NSAIDs, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women; published animal studies have shown that administration of prostaglandin synthesis inhibitors has potential to disrupt prostaglandin- mediated follicular rupture required for ovulation; small studies in women treated with NSAIDs have also shown reversible delay in ovulation; consider withdrawal of NSAIDs in women who have difficulties conceiving or who are undergoing investigation of infertility

Lactation

Data from published literature reports with oral preparations of diclofenac indicate presence of small amounts of diclofenac in human milk; there are no data on effects on breastfed infant, or on milk production; consider developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from treatment or from underlying maternal condition

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.

Mechanism of Action

Inhibits cyclooxygenase (COX)-1 and COX-2, thereby inhibiting prostaglandin synthesis

May also inhibit neutrophil aggregation/activation, inhibit chemotaxis, decrease proinflammatory cytokine level, and alter lymphocyte activity

Absorption

~100% absorbed

Bioavailability: 50-60%

Peak plasma time: Oral solution, 10-30 min; prompt-release tablet/capsule, 1 hr; extended-release tablet, 2-3 hr

Peak plasma concentration (50 mg dose): 1-1.5 mcg/mL

Onset of action: potassium salt faster acting than sodium salt (dissolves in stomach instead of duodenum)

Distribution

Protein bound: 99-99.8%

Vd: 1.3-1.4 L/kg

Metabolism

Metabolized in liver by hydroxylation and conjugation with glucuronic acid, taurine amide, sulfuric acid, and other biogenic ligands, as well as conjugation of unchanged drug

Metabolites: 3'-hydroxydiclofenac, 4'-hydroxydiclofenac (3'-hydroxy-4'-methoxydiclofenac), 5-hydroxydiclofenac, 4',5-dihydroxydiclofenac

Enzymes inhibited: COX-1, COX-2

Elimination

Half-life: 1.2-2 hr

Clearance: 263-350 mL/min

Excretion: Urine (50-70%), feces (30-35%)