Arthrotec 50

Uterine Rupture, Abortion, Premature Birth, or Birth Defects with Misoprostol and Embryo-Fetal Toxicity with NSAIDs

• Misoprostol can cause uterine rupture, abortion, premature birth or birth defects.
• Arthrotec is contraindicated in pregnant patients and is not recommended in women of childbearing potential.
• Verify pregnancy status prior to initiation; use contraception during treatment.
• NSAIDs like diclofenac increase the risk of premature closure of the fetal ductus arteriosus at about 30 weeks gestation and later.
• Use of NSAIDs at about 20 weeks gestation or later may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment; these adverse events are seen, on average, after days or weeks of treatment. 
• Rarely, oligohydramnios has been reported 48 hours after NSAID initiation; oligohydramnios is often reversible with treatment discontinuation.

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke.

• Incidence of serious cardiovascular thrombotic events greater in patients with known cardiovascular disease or risk factors.
• Increased risk has been observed as early as the first weeks of treatment (based on observational studies).
• Higher doses have been linked to increased cardiovascular thrombotic risk.
• To minimize risk, use the lowest effective dose for the shortest time possible.
• Evidence regarding use of aspirin to mitigate risk has not been consistent; aspirin coadministered with diclofenac may increase the risk of serious GI adverse events.

NSAIDs are contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Based on findings from 2 large studies evaluating a COX-2 selective NSAID, use in the first 10-14 days after CABG resulted in an increased incidence of MI and stroke. 

Among patients treated with NSAIDs in the post-MI period, there was an increase in the risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment, according to observational studies. 

• Incidence of death in the first year in the NSAID cohort: 20 per 100 person years.
• Incidence of death in the first year in the non-NSAID cohort: 12 per 100 person years.
• The relative risk of death in NSAID users persisted over at least the next 4 years of follow up.

Avoid the use of Arthrotec in patients with recent MI unless the benefits are expected to outweigh the risk of recurrent cardiovascular thrombotic events. Monitor for signs of cardiac ischemia if used in patients with recent MI.

Hypertension

• NSAIDs can lead to new onset hypertension or worsening of pre-existing hypertension.
• Impaired responses to thiazides and loop diuretics possible when taken with NSAIDs.
• Use with caution in patients with hypertension; monitor BP.

Heart Failure and Edema

• Meta-analysis of randomized controlled trials showed ~2-fold increase in hospitalizations for heart failure in patients treated with COX-2 selective and nonselective NSAIDs compared with placebo.
• NSAID use was also associated with increased risk of MI, hospitalization for heart failure and death in a Danish National Registry study of patients with heart failure.
• Fluid retention and edema have been observed in some patients treated with NSAIDs.
• Diclofenac may blunt the cardiovascular effects of diuretics, ACE inhibitors, angiotensin receptor blockers (ARBs).
• Avoid use in patients with severe heart failure unless benefits outweigh risk of worsening heart failure.
• Monitor for signs of worsening heart failure if Arthrotec is used in patients with severe heart failure.

Gastrointestinal (GI) Effects

• NSAIDs can cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine.
• These can occur at any time, with or without warning symptoms (only 1 in 5 patients who develop a serious upper GI adverse event on NSAIDs is symptomatic),
• Incidence of upper GI ulcers, gross bleeding, or perforation with NSAIDs: ~1% of patients treated for 3-6 months and 2-4% of patients treated for 1 year.
• Prior history of ulcer disease or GI bleeding: Prescribe with caution; these patients have a >10-fold increased risk for developing GI bleed vs those without these risk factors.
• Other factors that increase risk of GI bleed in patients treated with NSAIDs: concomitant oral corticosteroids, anticoagulants; longer duration of NSAID use; smoking; alcohol; older age; and poor general health status.
• Use the lowest effective dose for the shortest possible duration to minimize the potential for GI adverse events.
• If a serious GI adverse event occurs, discontinue NSAID therapy.
• Monitor patients closely for GI bleeding in the setting of concomitant low-dose aspirin for cardiac prophylaxis.

Hepatic Effects

• Borderline elevations of 1 or more liver tests without any other signs and symptoms may occur in up to 15% of patients taking NSAIDs.
• For patients with symptoms/signs suggesting liver dysfunction, or in whom abnormal liver test has occurred, evaluate for more severe hepatic reaction.
• Measure transaminases at baseline and periodically thereafter (within 4 to 8 weeks after initiation) in patients receiving long-term diclofenac.
• Discontinue Arthrotec if abnormal liver tests persist or worsen, if clinical signs/symptoms of liver disease develop, or if systemic manifestations (eg, eosinophilia, rash) occur.

Renal Effects

• Long-term NSAID use has been associated with renal papillary necrosis and other renal injury.
• Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion; in these patients administration of NSAIDs may cause a dose-dependent reduction in prostaglandin formation and, secondarily in renal blood flow, which may result in overt renal decompensation.
• Patients with impaired renal function, heart failure, liver dysfunction, on diuretics or ACE inhibitors, those who are volume-depleted and the elderly are at greatest risk of this reaction.
• Discontinuing NSAID therapy usually leads to recovery.
• Correct volume status in dehydrated and hypovolemic patients prior to initiating Arthrotec.
• Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.
• Avoid use of Arthrotec in patients with advanced renal disease unless the benefits outweigh the risk of worsening renal function; monitor.

Hyperkalemia

• Increases in serum potassium concentration have been reported with NSAIDs.

Anaphylactic/Anaphylactoid Reactions

• Arthrotec should not be given to patients with the aspirin triad.
• This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs.
• Use with caution in patients with preexisting asthma.

Skin Reactions

• NSAIDs can cause serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
• Discontinue treatment at the first appearance of skin rash or any other sign of hypersensitivity.
• DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) has been reported in patients taking NSAIDs.
• Symptoms of DRESS: Fever, rash, lymphadenopathy, and/or facial swelling; may resemble acute viral infection.
• Other clinical manifestations of DRESS: Hepatitis, nephritis, hematological abnormalities, myocarditis, myositis.
• Discontinue treatment if signs/symptoms of DRESS develop.

Hematological Effects

• Anemia is sometimes seen in patients receiving NSAIDs.
• Check hemoglobin/hematocrit if patients exhibit signs/symptoms of anemia.