These Highlights Do Not Include All The Information Needed To Use Diclofenac Sodium And Misoprostol Delayed-release Tablets Safely And Effectively. See Full Prescribing Information For Diclofenac Sodium And Misoprostol Delayed-release Tablets.

Cardiovascular Thrombotic Events

• •
  NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)].
• •
  Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4), and Warnings and Precautions (5.1)].

Store in a dry area at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

The toxic dose of diclofenac sodium and misoprostol delayed-release tablets has not been determined. However, signs of overdosage from the components of the product have been described.

Diclofenac sodium and misoprostol delayed-release tablets, USP are a combination product containing diclofenac sodium, an NSAID with analgesic properties, and misoprostol, a gastrointestinal (GI) mucosal protective prostaglandin-1 (PGE1) analog. Diclofenac sodium and misoprostol delayed-release tablets, USP are white to off-white, round, biconvex, and approximately 12.7 mm in diameter. Each 50 mg/200 mcg tablet consists of an enteric-coated core containing 50 mg diclofenac sodium surrounded by an outer mantel containing 200 mcg misoprostol. Each 75 mg/200 mcg tablet consists of an enteric-coated core containing 75 mg diclofenac sodium surrounded by an outer mantle containing 200 mcg misprostol.

Diclofenac sodium is a phenylacetic acid derivative that is a white to off-white, virtually odorless, crystalline powder. Diclofenac sodium is freely soluble in methanol, soluble in ethanol, and practically insoluble in chloroform and in dilute acid. Diclofenac sodium is sparingly soluble in water. Its chemical formula and name are:

C₁₄H₁₀Cl₂NO₂Na [M.W. = 318.14] 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. Misoprostol is a water-soluble, viscous liquid that contains approximately equal amounts of two diastereomers. Its chemical formula and name are:

C₂₂H₃₈O₅ [M.W. = 382.54] (±) methyl 11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate.

Inactive ingredients in diclofenac sodium and misoprostol delayed-release tablets include: colloidal silicon dioxide; crospovidone; hypromellose; lactose; magnesium stearate; methacrylic acid copolymer; microcrystalline cellulose; polyethylene glycol (400); povidone (polyvidone) K-30; starch (corn); titanium dioxide; triethyl citrate; Carnauba wax.

NSAIDs, including diclofenac, a component of diclofenac sodium and misoprostol delayed-release tablets, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

Safety and effectiveness of diclofenac sodium and misoprostol delayed-release tablets in pediatric patients have not been established.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)].

Of the more than 2,100 subjects in clinical studies with diclofenac sodium and misoprostol delayed-release tablets, 25% were 65 and over, while 6% were 75 and over. In studies with diclofenac, 31% of subjects were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Diclofenac is known to be substantially excreted by the kidney, and the risk of toxic reactions to diclofenac sodium and misoprostol delayed-release tablets may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)].

Based on studies in the elderly, no adjustment of the dose of diclofenac sodium and misoprostol delayed-release tablets is necessary in the elderly for pharmacokinetic reasons [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14) and Clinical Pharmacology (12.3)], although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging.

In clinical trials with diclofenac sodium and misoprostol delayed-release tablets, meaningful elevation of alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT], more than 3 times the upper limit of the normal range [ULN]) occurred in 1.6% of 2,184 patients treated with diclofenac sodium and misoprostol delayed-release tablets and in 1.4% of 1,691 patients treated with diclofenac sodium. These increases were generally transient, and enzyme levels returned to within the normal range upon discontinuation of therapy with diclofenac sodium and misoprostol delayed-release tablets. The misoprostol component of diclofenac sodium and misoprostol delayed-release tablets does not appear to exacerbate the hepatic effects caused by the diclofenac sodium component.

In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies).

In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.

Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium and misoprostol delayed-release tablets should be discontinued immediately.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue diclofenac sodium and misoprostol delayed-release tablets immediately, and perform a clinical evaluation of the patient.

To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium and misoprostol delayed-release tablets, the lowest effective dose should be used for the shortest duration possible. Exercise caution when prescribing diclofenac sodium and misoprostol delayed-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in the following patients:

• •
  Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac sodium and misoprostol, other prostaglandins, or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]
• •
  History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]
• •
  In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]
• •
  Pregnancy. Use of diclofenac sodium and misoprostol delayed-release tablets during pregnancy can result in maternal and fetal harm, including abortion, premature birth, birth defects, and uterine rupture [see Use in Specific Populations (8.1)]
• •
  Active gastrointestinal bleeding [see Warnings and Precautions (5.2)]

Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women. Advise pregnant women of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiation of diclofenac sodium and misoprostol delayed-release tablets. Advise females of reproductive potential to use effective contraception during treatment with diclofenac sodium and misoprostol delayed-release tablets [see Contraindications (4) , Use in Specific Populations (8.1 , 8.3) ] .

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• •
  Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
• •
  GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
• •
  Hepatotoxicity [see Warnings and Precautions (5.3)]
• •
  Hypertension [see Warnings and Precautions (5.4)]
• •
  Heart Failure and Edema [see Warnings and Precautions (5.5)]
• •
  Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
• •
  Anaphylactic Reactions [see Warnings and Precautions (5.7)]
• •
  Serious Skin Reactions [see Warnings and Precautions (5.9)]
• •
  Hematologic Toxicity [see Warnings and Precautions (5.12)]

See Table 1 for clinically significant drug interactions with diclofenac and misoprostol.

A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse during long-term toxicology studies with misoprostol. No such increase has been observed in humans administered misoprostol for up to 1 year. An apparent response of the female mouse to misoprostol in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with misoprostol.

Diclofenac sodium and misoprostol delayed-release tablets are indicated for treatment of the signs and symptoms of osteoarthritis or rheumatoid arthritis in patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications. For a list of factors that may increase the risk of NSAID-induced gastric and duodenal ulcers and their complications [see Warnings and Precautions (5.2)].

Diclofenac sodium and misoprostol delayed-release tablets are a combination product containing diclofenac sodium, an NSAID with analgesic, anti-inflammatory and antipyretic properties, and misoprostol, a GI mucosal protective prostaglandin-1 (PGE1) analog.

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with diclofenac sodium and misoprostol delayed-release tablets has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including diclofenac sodium and misoprostol delayed-release tablets, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet drugs (e.g., aspirin), and SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

• •
  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 (5.3)
• •
  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 (5.5)
• •
  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 (5.6)
• •
  Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7)
• •
  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) (5.8)
• •
  Serious Skin Reactions: Discontinue diclofenac sodium and misoprostol delayed-release tablets at first appearance of skin rash or other signs of hypersensitivity (5.9)
• •
  Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10)
• •
  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)

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a complete blood count (CBC) and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.6)].

Diclofenac sodium and misoprostol delayed-release tablets have been associated with anaphylactic reactions in patients with and without known hypersensitivity to the individual components of diclofenac sodium and misoprostol and in patients with aspirin-sensitive asthma [see Contraindications (4) and Error! Hyperlink reference not valid. ]. Seek emergency help if an anaphylactic reaction occurs.

NSAIDs, including diclofenac, a component of diclofenac sodium and misoprostol delayed-release tablets, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diclofenac sodium and misoprostol delayed-release tablets at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].

Carefully consider the potential benefits and risks of diclofenac sodium and misoprostol delayed-release tablets and other treatment options before deciding to use diclofenac sodium and misoprostol delayed-release tablets. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

After observing the response to initial therapy with diclofenac sodium and misoprostol delayed-release tablets, the dose and frequency should be adjusted to suit an individual patient's needs. For the relief of rheumatoid arthritis and osteoarthritis, the dosage is given below.

Diclofenac sodium and misoprostol delayed-release tablets are administered as diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg (50 mg diclofenac sodium and 200 mcg misoprostol) or as diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg (75 mg diclofenac sodium and 200 mcg misoprostol).

Note: See Error! Hyperlink reference not valid. section below.

For osteoarthritis, the dosage for maximal GI mucosal protection is diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg three times a day. For patients who experience intolerance, diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg two times a day or diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg two times a day can be used, but are less effective in preventing ulcers. This fixed combination product, diclofenac sodium and misoprostol delayed-release tablets, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:

For rheumatoid arthritis, the dosage is diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg three or four times a day. For patients who experience intolerance, diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg two times a day or diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg two times a day can be used, but are less effective in preventing ulcers. This fixed combination product, diclofenac sodium and misoprostol delayed-release tablets, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:

The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)].

Avoid the use of diclofenac sodium and misoprostol delayed-release tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac sodium and misoprostol delayed-release tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Diclofenac sodium and misoprostol delayed-release tablets, USP:

• 1.
  50 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off-white tablet imprinted with "YSP 167".
• 2.
  75 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off-white tablet imprinted with "YSP 168".

The following adverse reactions have been identified during post approval of diclofenac sodium and misoprostol delayed-release tablets, diclofenac or misoprostol. Because these reactions are reported voluntarily from a population of unceritan size, it is not always possible to reliable estimate their frequency or establish a causal relationship to drug exposure.

Body as a whole: death, fever, infection, sepsis, chills, edema.

Cardiovascular system: arrhythmia, atrial fibrillation, congestive heart failure, hypertension, hypotension, increased creatine phosphokinase (CPK), increased lactate dehydrogenase (LDH), myocardial infarction, palpitations, phlebitis, premature ventricular contractions, syncope, tachycardia, vasculitis.

Central and peripheral nervous system: coma, convulsions, hyperesthesia, hypertonia, hypoesthesia, meningitis, migraine, neuralgia, somnolence, stroke, tremor.

Congenital, familial and genetic disorders: birth defects.

Digestive: enteritis, GI bleeding, glossitis, heartburn, hematemesis, hemorrhoids, intestinal perforation, stomatitis and ulcerative stomatitis.

Female reproductive disorders: intermenstrual bleeding, leukorrhea, vaginitis, uterine cramping, uterine hemorrhage.

Hemic and lymphatic system: agranulocytosis, anemia, aplastic anemia, coagulation time increased, ecchymosis, eosinophilia, hemolytic anemia, leukocytosis, lymphadenopathy, pancytopenia, pulmonary embolism, rectal bleeding, thrombocythemia, thrombocytopenia.

Hypersensitivity: angioedema, laryngeal/pharyngeal edema, urticaria.

Liver and biliary system: abnormal hepatic function, bilirubinemia, liver failure, pancreatitis, hepatitis, jaundice.

Male reproductive disorders: impotence, perineal pain.

Metabolic and nutritional: blood urea nitrogen (BUN) increased, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypoglycemia, periorbital edema, porphyria, weight changes, fluid retention.

Pregnancy, puerperium and perinatal conditions: abnormal uterine contractions, uterine rupture/perforation, retained placenta, amniotic fluid embolism, incomplete abortion, premature birth, fetal death.

Psychiatric: confusion, disorientation, dream abnormalities, hallucinations, nervousness, paranoia, psychotic reaction.

Reproductive system and breast disorders: female fertility decreased.

Respiratory system: dyspnea, pneumonia, respiratory depression.

Skin and appendages: acne, bruising, erythema multiforme, exfoliative dermatitis, pruritus ani, rash, skin ulceration, Stevens-Johnson syndrome, toxic epidermal necrolysis, cutaneous reactions (bullous eruption).

Special senses: hearing impairment, taste loss.

Renal and urinary disorders: cystitis, hematuria, interstitial nephritis, micturition frequency, nephrotic syndrome, oliguria, papillary necrosis, renal failure, glomerulonephritis membranous, glomerulonephritis minimal lesion, glomerulonephritis.

Vision: amblyopia, blurred vision, conjunctivitis, glaucoma, iritis, lacrimation abnormal, night blindness, vision abnormal.

Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of diclofenac sodium and misoprostol delayed-release tablets in women who have difficulties conceiving (8.3)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reaction information for diclofenac sodium and misoprostol delayed-release tablets is derived from multinational controlled clinical trials in over 2,000 patients receiving diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg or diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg, as well as from blinded, controlled trials of diclofenac sodium delayed-release tablets and misoprostol tablets.

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium and misoprostol delayed-release tablets and periodically during the course of ongoing therapy.

Diclofenac sodium and misoprostol delayed-release tablets, USP are supplied as:

• 1.
  50 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off-white tablet imprinted with "YSP 167".
• 2.
  75 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off-white tablet imprinted with "YSP 168".

The dosage strengths are supplied in:

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 (5.2)].

The pharmacological activity of diclofenac, a component of diclofenac sodium and misoprostol delayed-release tablets, in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

NDC 71205-865-30

Diclofenac Sodium and

Misoprostol Delayed-

Release Tablets, USP

50 mg/200 mcg

Pharmacist:

Dispense in this unit-of-use,

child-resistant container with

Medication Guide provided

separately.

Rx Only

30 Tablets

NDC 71205-866-30

Diclofenac Sodium and

Misoprostol Delayed-

Release Tablets, USP

75 mg/200 mcg

Pharmacist:

Dispense in this unit-of-use,

child-resistant container with

Medication Guide provided

separately.

Rx Only

30 Tablets

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, diclofenac sodium and misoprostol delayed-release tablets are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When diclofenac sodium and misoprostol delayed-release tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

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. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as diclofenac sodium and misoprostol delayed-release tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue diclofenac sodium and misoprostol delayed-release tablets and evaluate the patient immediately.

•  
  DICLOFENAC SODIUM AND MISOPROSTOL DELAYED-RELEASE TABLETS CONTAIN DICLOFENAC SODIUM AND MISOPROSTOL. ADMINISTRATION OF MISOPROSTOL TO WOMEN WHO ARE PREGNANT CAN CAUSE ABORTION, PREMATURE BIRTH, BIRTH DEFECTS, OR UTERINE RUPTURE. UTERINE RUPTURE HAS BEEN REPORTED WHEN MISOPROSTOL WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION. THE RISK OF UTERINE RUPTURE INCREASES WITH ADVANCING GESTATIONAL AGES AND WITH PRIOR UTERINE SURGERY, INCLUDING CESAREAN DELIVERY. DICLOFENAC SODIUM AND MISOPROSTOL DELAYED-RELEASE TABLETS SHOULD NOT BE TAKEN BY PREGNANT WOMEN [see Contraindications (4), Warnings and Precautions (5.11), and Use in Specific Populations (8.1)].

PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO OTHERS. Diclofenac sodium and misoprostol delayed-release tablets should not be used in women of childbearing potential unless the patient requires nonsteroidal anti-inflammatory drug (NSAID) therapy and is at high risk of developing gastric or duodenal ulceration or for developing complications from gastric or duodenal ulcers associated with the use of the NSAID. In such patients, diclofenac sodium and misoprostol delayed-release tablets may be prescribed if the patient:

• •
  has had a negative serum pregnancy test within 2 weeks prior to beginning therapy.
• •
  is capable of complying with effective contraceptive measures.
• •
  has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake.
• •
  will begin diclofenac sodium and misoprostol delayed-release tablets only on the second or third day of the next normal menstrual period [see Use in Specific Populations (8.3)] .

Cardiovascular Thrombotic Events

• •
  NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)].
• •
  Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4), and Warnings and Precautions (5.1)].

Store in a dry area at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

The toxic dose of diclofenac sodium and misoprostol delayed-release tablets has not been determined. However, signs of overdosage from the components of the product have been described.

Diclofenac sodium and misoprostol delayed-release tablets, USP are a combination product containing diclofenac sodium, an NSAID with analgesic properties, and misoprostol, a gastrointestinal (GI) mucosal protective prostaglandin-1 (PGE1) analog. Diclofenac sodium and misoprostol delayed-release tablets, USP are white to off-white, round, biconvex, and approximately 12.7 mm in diameter. Each 50 mg/200 mcg tablet consists of an enteric-coated core containing 50 mg diclofenac sodium surrounded by an outer mantel containing 200 mcg misoprostol. Each 75 mg/200 mcg tablet consists of an enteric-coated core containing 75 mg diclofenac sodium surrounded by an outer mantle containing 200 mcg misprostol.

Diclofenac sodium is a phenylacetic acid derivative that is a white to off-white, virtually odorless, crystalline powder. Diclofenac sodium is freely soluble in methanol, soluble in ethanol, and practically insoluble in chloroform and in dilute acid. Diclofenac sodium is sparingly soluble in water. Its chemical formula and name are:

C₁₄H₁₀Cl₂NO₂Na [M.W. = 318.14] 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. Misoprostol is a water-soluble, viscous liquid that contains approximately equal amounts of two diastereomers. Its chemical formula and name are:

C₂₂H₃₈O₅ [M.W. = 382.54] (±) methyl 11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate.

Inactive ingredients in diclofenac sodium and misoprostol delayed-release tablets include: colloidal silicon dioxide; crospovidone; hypromellose; lactose; magnesium stearate; methacrylic acid copolymer; microcrystalline cellulose; polyethylene glycol (400); povidone (polyvidone) K-30; starch (corn); titanium dioxide; triethyl citrate; Carnauba wax.

NSAIDs, including diclofenac, a component of diclofenac sodium and misoprostol delayed-release tablets, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

Safety and effectiveness of diclofenac sodium and misoprostol delayed-release tablets in pediatric patients have not been established.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)].

Of the more than 2,100 subjects in clinical studies with diclofenac sodium and misoprostol delayed-release tablets, 25% were 65 and over, while 6% were 75 and over. In studies with diclofenac, 31% of subjects were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Diclofenac is known to be substantially excreted by the kidney, and the risk of toxic reactions to diclofenac sodium and misoprostol delayed-release tablets may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)].

Based on studies in the elderly, no adjustment of the dose of diclofenac sodium and misoprostol delayed-release tablets is necessary in the elderly for pharmacokinetic reasons [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14) and Clinical Pharmacology (12.3)], although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging.

In clinical trials with diclofenac sodium and misoprostol delayed-release tablets, meaningful elevation of alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT], more than 3 times the upper limit of the normal range [ULN]) occurred in 1.6% of 2,184 patients treated with diclofenac sodium and misoprostol delayed-release tablets and in 1.4% of 1,691 patients treated with diclofenac sodium. These increases were generally transient, and enzyme levels returned to within the normal range upon discontinuation of therapy with diclofenac sodium and misoprostol delayed-release tablets. The misoprostol component of diclofenac sodium and misoprostol delayed-release tablets does not appear to exacerbate the hepatic effects caused by the diclofenac sodium component.

In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies).

In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.

Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium and misoprostol delayed-release tablets should be discontinued immediately.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue diclofenac sodium and misoprostol delayed-release tablets immediately, and perform a clinical evaluation of the patient.

To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium and misoprostol delayed-release tablets, the lowest effective dose should be used for the shortest duration possible. Exercise caution when prescribing diclofenac sodium and misoprostol delayed-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in the following patients:

• •
  Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac sodium and misoprostol, other prostaglandins, or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]
• •
  History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]
• •
  In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]
• •
  Pregnancy. Use of diclofenac sodium and misoprostol delayed-release tablets during pregnancy can result in maternal and fetal harm, including abortion, premature birth, birth defects, and uterine rupture [see Use in Specific Populations (8.1)]
• •
  Active gastrointestinal bleeding [see Warnings and Precautions (5.2)]

Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women. Advise pregnant women of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiation of diclofenac sodium and misoprostol delayed-release tablets. Advise females of reproductive potential to use effective contraception during treatment with diclofenac sodium and misoprostol delayed-release tablets [see Contraindications (4) , Use in Specific Populations (8.1 , 8.3) ] .

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• •
  Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
• •
  GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
• •
  Hepatotoxicity [see Warnings and Precautions (5.3)]
• •
  Hypertension [see Warnings and Precautions (5.4)]
• •
  Heart Failure and Edema [see Warnings and Precautions (5.5)]
• •
  Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
• •
  Anaphylactic Reactions [see Warnings and Precautions (5.7)]
• •
  Serious Skin Reactions [see Warnings and Precautions (5.9)]
• •
  Hematologic Toxicity [see Warnings and Precautions (5.12)]

See Table 1 for clinically significant drug interactions with diclofenac and misoprostol.

A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse during long-term toxicology studies with misoprostol. No such increase has been observed in humans administered misoprostol for up to 1 year. An apparent response of the female mouse to misoprostol in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with misoprostol.

Diclofenac sodium and misoprostol delayed-release tablets are indicated for treatment of the signs and symptoms of osteoarthritis or rheumatoid arthritis in patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications. For a list of factors that may increase the risk of NSAID-induced gastric and duodenal ulcers and their complications [see Warnings and Precautions (5.2)].

Diclofenac sodium and misoprostol delayed-release tablets are a combination product containing diclofenac sodium, an NSAID with analgesic, anti-inflammatory and antipyretic properties, and misoprostol, a GI mucosal protective prostaglandin-1 (PGE1) analog.

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with diclofenac sodium and misoprostol delayed-release tablets has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including diclofenac sodium and misoprostol delayed-release tablets, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet drugs (e.g., aspirin), and SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

• •
  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 (5.3)
• •
  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 (5.5)
• •
  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 (5.6)
• •
  Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7)
• •
  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) (5.8)
• •
  Serious Skin Reactions: Discontinue diclofenac sodium and misoprostol delayed-release tablets at first appearance of skin rash or other signs of hypersensitivity (5.9)
• •
  Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10)
• •
  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)

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a complete blood count (CBC) and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.6)].

Diclofenac sodium and misoprostol delayed-release tablets have been associated with anaphylactic reactions in patients with and without known hypersensitivity to the individual components of diclofenac sodium and misoprostol and in patients with aspirin-sensitive asthma [see Contraindications (4) and Error! Hyperlink reference not valid. ]. Seek emergency help if an anaphylactic reaction occurs.

NSAIDs, including diclofenac, a component of diclofenac sodium and misoprostol delayed-release tablets, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diclofenac sodium and misoprostol delayed-release tablets at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].

Carefully consider the potential benefits and risks of diclofenac sodium and misoprostol delayed-release tablets and other treatment options before deciding to use diclofenac sodium and misoprostol delayed-release tablets. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

After observing the response to initial therapy with diclofenac sodium and misoprostol delayed-release tablets, the dose and frequency should be adjusted to suit an individual patient's needs. For the relief of rheumatoid arthritis and osteoarthritis, the dosage is given below.

Diclofenac sodium and misoprostol delayed-release tablets are administered as diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg (50 mg diclofenac sodium and 200 mcg misoprostol) or as diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg (75 mg diclofenac sodium and 200 mcg misoprostol).

Note: See Error! Hyperlink reference not valid. section below.

For osteoarthritis, the dosage for maximal GI mucosal protection is diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg three times a day. For patients who experience intolerance, diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg two times a day or diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg two times a day can be used, but are less effective in preventing ulcers. This fixed combination product, diclofenac sodium and misoprostol delayed-release tablets, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:

For rheumatoid arthritis, the dosage is diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg three or four times a day. For patients who experience intolerance, diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg two times a day or diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg two times a day can be used, but are less effective in preventing ulcers. This fixed combination product, diclofenac sodium and misoprostol delayed-release tablets, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:

The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)].

Avoid the use of diclofenac sodium and misoprostol delayed-release tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac sodium and misoprostol delayed-release tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Diclofenac sodium and misoprostol delayed-release tablets, USP:

• 1.
  50 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off-white tablet imprinted with "YSP 167".
• 2.
  75 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off-white tablet imprinted with "YSP 168".

The following adverse reactions have been identified during post approval of diclofenac sodium and misoprostol delayed-release tablets, diclofenac or misoprostol. Because these reactions are reported voluntarily from a population of unceritan size, it is not always possible to reliable estimate their frequency or establish a causal relationship to drug exposure.

Body as a whole: death, fever, infection, sepsis, chills, edema.

Cardiovascular system: arrhythmia, atrial fibrillation, congestive heart failure, hypertension, hypotension, increased creatine phosphokinase (CPK), increased lactate dehydrogenase (LDH), myocardial infarction, palpitations, phlebitis, premature ventricular contractions, syncope, tachycardia, vasculitis.

Central and peripheral nervous system: coma, convulsions, hyperesthesia, hypertonia, hypoesthesia, meningitis, migraine, neuralgia, somnolence, stroke, tremor.

Congenital, familial and genetic disorders: birth defects.

Digestive: enteritis, GI bleeding, glossitis, heartburn, hematemesis, hemorrhoids, intestinal perforation, stomatitis and ulcerative stomatitis.

Female reproductive disorders: intermenstrual bleeding, leukorrhea, vaginitis, uterine cramping, uterine hemorrhage.

Hemic and lymphatic system: agranulocytosis, anemia, aplastic anemia, coagulation time increased, ecchymosis, eosinophilia, hemolytic anemia, leukocytosis, lymphadenopathy, pancytopenia, pulmonary embolism, rectal bleeding, thrombocythemia, thrombocytopenia.

Hypersensitivity: angioedema, laryngeal/pharyngeal edema, urticaria.

Liver and biliary system: abnormal hepatic function, bilirubinemia, liver failure, pancreatitis, hepatitis, jaundice.

Male reproductive disorders: impotence, perineal pain.

Metabolic and nutritional: blood urea nitrogen (BUN) increased, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypoglycemia, periorbital edema, porphyria, weight changes, fluid retention.

Pregnancy, puerperium and perinatal conditions: abnormal uterine contractions, uterine rupture/perforation, retained placenta, amniotic fluid embolism, incomplete abortion, premature birth, fetal death.

Psychiatric: confusion, disorientation, dream abnormalities, hallucinations, nervousness, paranoia, psychotic reaction.

Reproductive system and breast disorders: female fertility decreased.

Respiratory system: dyspnea, pneumonia, respiratory depression.

Skin and appendages: acne, bruising, erythema multiforme, exfoliative dermatitis, pruritus ani, rash, skin ulceration, Stevens-Johnson syndrome, toxic epidermal necrolysis, cutaneous reactions (bullous eruption).

Special senses: hearing impairment, taste loss.

Renal and urinary disorders: cystitis, hematuria, interstitial nephritis, micturition frequency, nephrotic syndrome, oliguria, papillary necrosis, renal failure, glomerulonephritis membranous, glomerulonephritis minimal lesion, glomerulonephritis.

Vision: amblyopia, blurred vision, conjunctivitis, glaucoma, iritis, lacrimation abnormal, night blindness, vision abnormal.

Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of diclofenac sodium and misoprostol delayed-release tablets in women who have difficulties conceiving (8.3)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reaction information for diclofenac sodium and misoprostol delayed-release tablets is derived from multinational controlled clinical trials in over 2,000 patients receiving diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg or diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg, as well as from blinded, controlled trials of diclofenac sodium delayed-release tablets and misoprostol tablets.

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium and misoprostol delayed-release tablets and periodically during the course of ongoing therapy.

Diclofenac sodium and misoprostol delayed-release tablets, USP are supplied as:

• 1.
  50 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off-white tablet imprinted with "YSP 167".
• 2.
  75 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off-white tablet imprinted with "YSP 168".

The dosage strengths are supplied in:

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 (5.2)].

The pharmacological activity of diclofenac, a component of diclofenac sodium and misoprostol delayed-release tablets, in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

NDC 71205-865-30

Diclofenac Sodium and

Misoprostol Delayed-

Release Tablets, USP

50 mg/200 mcg

Pharmacist:

Dispense in this unit-of-use,

child-resistant container with

Medication Guide provided

separately.

Rx Only

30 Tablets

NDC 71205-866-30

Diclofenac Sodium and

Misoprostol Delayed-

Release Tablets, USP

75 mg/200 mcg

Pharmacist:

Dispense in this unit-of-use,

child-resistant container with

Medication Guide provided

separately.

Rx Only

30 Tablets

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, diclofenac sodium and misoprostol delayed-release tablets are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When diclofenac sodium and misoprostol delayed-release tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

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. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as diclofenac sodium and misoprostol delayed-release tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue diclofenac sodium and misoprostol delayed-release tablets and evaluate the patient immediately.

•  
  DICLOFENAC SODIUM AND MISOPROSTOL DELAYED-RELEASE TABLETS CONTAIN DICLOFENAC SODIUM AND MISOPROSTOL. ADMINISTRATION OF MISOPROSTOL TO WOMEN WHO ARE PREGNANT CAN CAUSE ABORTION, PREMATURE BIRTH, BIRTH DEFECTS, OR UTERINE RUPTURE. UTERINE RUPTURE HAS BEEN REPORTED WHEN MISOPROSTOL WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION. THE RISK OF UTERINE RUPTURE INCREASES WITH ADVANCING GESTATIONAL AGES AND WITH PRIOR UTERINE SURGERY, INCLUDING CESAREAN DELIVERY. DICLOFENAC SODIUM AND MISOPROSTOL DELAYED-RELEASE TABLETS SHOULD NOT BE TAKEN BY PREGNANT WOMEN [see Contraindications (4), Warnings and Precautions (5.11), and Use in Specific Populations (8.1)].

PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO OTHERS. Diclofenac sodium and misoprostol delayed-release tablets should not be used in women of childbearing potential unless the patient requires nonsteroidal anti-inflammatory drug (NSAID) therapy and is at high risk of developing gastric or duodenal ulceration or for developing complications from gastric or duodenal ulcers associated with the use of the NSAID. In such patients, diclofenac sodium and misoprostol delayed-release tablets may be prescribed if the patient:

• •
  has had a negative serum pregnancy test within 2 weeks prior to beginning therapy.
• •
  is capable of complying with effective contraceptive measures.
• •
  has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake.
• •
  will begin diclofenac sodium and misoprostol delayed-release tablets only on the second or third day of the next normal menstrual period [see Use in Specific Populations (8.3)] .