Misoprostol - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity.

Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop • Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs.

Monitor blood pressure ( 5.4 , 7 ) • Heart Failure and Edema : Avoid use of diclofenac sodium and misoprostol delayed-release tablets in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure • Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.

Avoid use of diclofenac sodium and misoprostol delayed-release tablets in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function • Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs • Exacerbation of Asthma Related to Aspirin Sensitivity : Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in patients with aspirin-sensitive asthma.

Monitor patients with preexisting asthma (without aspirin sensitivity) • Serious Skin Reactions : Discontinue diclofenac sodium and misoprostol delayed-release tablets at first appearance of skin rash or other signs of hypersensitivity • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically • Fetal Toxicity : Use of NSAIDs, including diclofenac in women at about 30 weeks gestation and later in pregnancy may cause oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus ( 4 , 5.11 , 8.1 ) • Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.12 , 7 ) 5.1 Cardiovascular Thrombotic Events Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal.

Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs.

The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease.

However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate.

Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment.

The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible.

Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms.

Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions ] .

Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.

NSAIDs are contraindicated in the setting of CABG [see Contraindications ] .

Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment.

In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients.

Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of diclofenac sodium and misoprostol delayed-release tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events.

If diclofenac sodium and misoprostol delayed-release tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal.

These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic.