Diclofenac and misoprostol

Do not use if you are pregnant. Misoprostol can cause birth defects, miscarriage, premature labor, or rupture of the uterus. You must have a negative pregnancy test within 2 weeks before you start taking diclofenac and misoprostol. You may need to start taking this medicine only on the 2nd or 3rd day of a normal menstrual period. Use effective birth control while you are using diclofenac and misoprostol.

Diclofenac can increase your risk of fatal heart attack or stroke, especially if you use it long term or take high doses, or if you have heart disease. Do not use this medicine just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

Diclofenac may also cause stomach or intestinal bleeding, which can be fatal. These conditions can occur without warning while you are using diclofenac, especially in older adults. You should not use this medicine if you have active bleeding in your stomach or intestines.

Diclofenac can increase your risk of fatal heart attack or stroke, especially if you use it long term or take high doses, or if you have heart disease. Even people without heart disease or risk factors could have a stroke or heart attack while taking this medicine.

Do not use this medicine just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

Diclofenac may also cause stomach or intestinal bleeding, which can be fatal. These conditions can occur without warning while you are using diclofenac, especially in older adults.

You should not use this medicine if you are allergic to diclofenac or misoprostol, or:

• if you have active bleeding in your stomach or intestines;

• if you are pregnant; or

• if you have a history of asthma attack or severe allergic reaction after taking aspirin or an NSAID.

To make sure diclofenac and misoprostol is safe for you, tell your doctor if you have:

• heart disease, high blood pressure, high cholesterol, diabetes, or if you smoke;

• a history of heart attack, stroke, or blood clot;

• a history of stomach ulcers or bleeding;

• asthma;

• porphyria (a genetic enzyme disorder that causes symptoms affecting the skin or nervous system);

• liver or kidney disease; or

• fluid retention.

Do not use this medicine if you are pregnant. Diclofenac and misoprostol can cause birth defects, miscarriage, premature labor, or rupture of the uterus. Use an effective form of birth control to prevent pregnancy while you are using this medicine. Tell your doctor right away if you become pregnant during treatment.

You will need to have a pregnancy test within 2 weeks before you start taking diclofenac and misoprostol. You may need to start taking this medicine only on the 2nd or 3rd day of a normal menstrual period.

It is not known whether diclofenac and misoprostol passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Get emergency medical help if you have signs of an allergic reaction: sneezing, runny or stuffy nose; wheezing or trouble breathing; hives; swelling of your face, lips, tongue, or throat.

Get emergency medical help if you have signs of a heart attack or stroke: chest pain spreading to your jaw or shoulder, sudden numbness or weakness on one side of the body, slurred speech, feeling short of breath.

Stop using this medicine and call your doctor at once if you have:

• the first sign of any skin rash, no matter how mild;

• shortness of breath (even with mild exertion);

• swelling or rapid weight gain;

• signs of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

• liver problems--nausea, upper stomach pain, itching, tired feeling, flu-like symptoms, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• kidney problems--little or no urinating, painful or difficult urination, swelling in your feet or ankles, feeling tired or short of breath;

• low red blood cells (anemia)--pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• abnormal vaginal bleeding;

• heartburn, indigestion stomach pain, gas;

• nausea, vomiting;

• diarrhea, constipation; or

• dizziness.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Belly pain or heartburn.
• Upset stomach or throwing up.
• Loose stools (diarrhea).
• Gas.
• Dizziness.
• Hard stools (constipation).

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about diclofenac and misoprostol, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about diclofenac and misoprostol. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using diclofenac and misoprostol.

Review Date: October 4, 2017

• Arthrotec

This product contains diclofenac and misoprostol. The administration of misoprostol to women who are pregnant can cause abortion, premature birth, or birth defects.

Uterine rupture has been reported when misoprostol was administered to pregnant women to induce labor or to induce abortion beyond the eighth week of pregnancy. Diclofenac/misoprostol should not be taken by pregnant women.

Advise patients of the abortifacient property and warn them not to give the drug to others. Do not use 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 of developing complications from gastric or duodenal ulcers associated with the use of the NSAID. In such patients, this drug may be prescribed if the patient:

- 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, risk of possible contraception failure, and danger to other women of childbearing potential if the drug is taken by mistake; and

- will begin using this product only on the second or third day of the next normal menstrual period.

NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.

Diclofenac/misoprostol is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

NSAIDs cause an increased risk of serious GI adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

Applies to diclofenac / misoprostol: oral tablet, oral tablet enteric coated

Along with its needed effects, diclofenac / misoprostol may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking diclofenac / misoprostol:

• Black, tarry stools
• bleeding or crusting sores on the lips
• blood in the urine or stools
• bruises or red spots on the skin
• chest pain
• chills
• confusion
• continuing thirst
• convulsions (seizures)
• cough or hoarseness
• disorientation
• drowsiness
• fainting
• fever with or without chills
• fluid retention
• general feeling of illness
• heartburn or indigestion
• increased heart rate
• increased weight gain
• irregular heartbeat
• itching of the skin
• large, flat, blue or purplish patches on the skin
• lightheadedness or dizziness
• lower back or side pain
• mental depression
• muscle cramps
• nausea
• painful or difficult urination
• pounding heartbeat
• psychotic reaction
• rectal bleeding
• seeing, hearing, or feeling things that are not there
• severe headache
• severe liver reactions
• severe stomach pain, cramping, or burning
• skin rash
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stiff neck or back
• sudden decrease in the amount of urine
• swelling or tenderness in the upper stomach
• swelling of the face, fingers, feet, or lower legs
• troubled breathing, tightness in the chest
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of material that looks like coffee grounds
• yellow eyes or skin

• Changes in facial skin color
• fast or irregular breathing
• puffiness or swelling of the eyelids or around the eyes

Get emergency help immediately if any of the following symptoms of overdose occur while taking diclofenac / misoprostol:

• Diarrhea
• fever
• slow heartbeat
• stomach pain
• trembling or shaking

Some side effects of diclofenac / misoprostol may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Gas

• Abnormal vision
• acne
• change in sense of taste
• decreased appetite
• decrease in sexual ability
• dry mouth
• irritability or nervousness
• loss of hair
• muscle pain
• tingling, burning, or prickling sensations
• trouble with swallowing
• vaginal bleeding

Applies to diclofenac / misoprostol: oral tablet

General

The highest reported incidences of adverse events for this drug were gastrointestinal and included abdominal pain, diarrhea, dyspepsia, nausea, and flatulence.[Ref]

Gastrointestinal

NSAIDs including this drug, can cause serious gastrointestinal (GI) events which can occur at any time, with or without warning. For patients who develop a serious upper GI event, only about 20% were symptomatic. Upper GI ulcers, gross bleeding, or perforation occurred in approximately 1% of patients treated with NSAIDs for 3 to 6 months and 2% to 4% of patients treated for 1 year. Patients with a prior history of peptic ulcer disease and/or GI bleeding had a greater than 10-fold increased risk for developing a GI bleed than patients with neither of these risk factors.[Ref]

Diclofenac-misoprostol:
Very common (10% or more): Abdominal pain (21%), diarrhea (19%), dyspepsia (14%), nausea (11%)
Common (1% to 10%): Flatulence, gastritis, vomiting, eructation, constipation, peptic ulcer
Uncommon (0.1% to 1%): Stomatitis
Rare (less than 0.1%): Esophageal ulceration, esophagitis, gastroesophageal reflux, heartburn, hematemesis, melena, gall bladder disorder
Frequency not reported: Pancreatitis
Postmarketing reports: Gastrointestinal (GI) perforation, GI bleeding, melena, colitis, Crohn's disease, esophageal disorder, mouth ulceration, tongue edema, dry mouth

Diclofenac:
Very common (10% or more): Abdominal pain (15%), diarrhea (11%), dyspepsia (11%), nausea (11%)
Common (1% to 10%): Flatulence, nausea[Ref]

Cardiovascular

Uncommon (0.1% to 1%): Hypertension, chest pain, edema, palpitation, syncope
Rare (less than 0.1%): Arrhythmia, atrial fibrillation, hypotension, myocardial infarction, premature ventricular contractions, tachycardia, vasculitis, phlebitis
Frequency not reported: Cardiac failure, palpitations[Ref]

Clinical trials of several cyclooxygenase (COX)-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs appear to have a similar risk. There is no consistent evidence that concurrent use of aspirin mitigates this increased risk and may be associated with an increased risk of serious gastrointestinal events.[Ref]

Hepatic

Common (1% to 10%): Alanine aminotransferase increased, aspartate aminotransferase increased
Rare (less than 0.1%): Hepatitis, jaundice, abnormal hepatic function
Frequency not reported: Liver failure
Postmarketing reports: Hepatitis fulminant, blood bilirubin increased[Ref]

Elevations to greater than 3 x ULN of ALT occurred in about 1.6% (n=2184) of patients receiving diclofenac-misoprostol at some point during treatment. These increases were generally transient and returned to within normal range upon discontinuation of therapy. In an open-labeled trial among patients receiving NSAIDs, a higher incidence of transaminase elevations were observed in patients receiving diclofenac compared with other NSAIDs.[Ref]

Hypersensitivity

Rare (less than 0.1%): Allergic reactions
Frequency not reported: Angioedema, laryngeal/pharyngeal edema, urticaria
Postmarketing reports: Anaphylaxis[Ref]

Dermatologic

Common (1% to 10%): Erythema multiforme, rash, pruritus
Uncommon (0.1% to 1%): Purpura, urticaria
Rare (less than 0.1%): Angioedema, increased sweating, acne
Postmarketing reports: Toxic epidermal necrolysis, Stevens-Johnson syndrome, dermatitis exfoliative, dermatitis bullous, Henoch Schonlein purpura, mucocutaneous rash, rash vesicular, photosensitivity reaction, alopecia[Ref]

Renal

Frequency not reported: Renal failure, glomerulonephritis membranous, glomerulonephritis minimal lesion
Postmarketing reports: Acute renal failure, renal papillary necrosis, nephritis, interstitial nephrotic syndrome, proteinuria[Ref]

Hematologic

Uncommon (0.1% to 1%): Thrombocytopenia
Rare (less than 0.1%): Agranulocytosis, anemia, aplastic anemia, coagulation time increased, ecchymosis, eosinophilia, hemolytic anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, decreased hematocrit[Ref]

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, the NSAID effect on platelet function is quantitatively less, of shorter duration, and reversible.[Ref]

Metabolic

Rare (less than 0.1%): Anorexia, appetite changes, dehydration, hyperglycemia, hypoglycemia, hyponatremia, weight changes, gout, hypercholesterolemia, porphyria[Ref]

Nervous system

Common (1% to 10%): Headache, dizziness
Rare (less than 0.1%): Drowsiness, headache, hyperesthesia, hypertonia, hypoesthesia, insomnia, meningitis, migraine, neuralgia, paresthesia, somnolence, stroke, tremor, confusion
Frequency not reported: Coma
Postmarketing reports: Convulsions, memory disturbance, taste disturbance[Ref]

Psychiatric

Common (1% to 10%): Insomnia
Rare (less than 0.1%): Anxiety, impaired concentration, depression, dream abnormalities, hallucinations, irritability, nervousness, paranoia, psychotic reaction
Postmarketing reports: Mood changes, nightmares[Ref]

Other

Rare (less than 0.1%): Asthenia, fatigue, fever, malaise, chills, hearing impairment, tinnitus, speech disorder[Ref]

Genitourinary

Diclofenac-misoprostol:
Rare (less than 0.1%): Vaginitis, menstrual disorder, menorrhagia, dysmenorrhea, intermenstrual bleeding, cystitis, dysuria, nocturia
Frequency not reported: Impotence, perineal pain
Postmarketing reports: Intrauterine death, uterine rupture, incomplete abortion, abnormal uterine contractions, retained placenta, dysuria, urine abnormal

Misoprostol:
Frequency not reported: Hyperstimulation of the uterus, amniotic fluid embolism resulting in maternal and fetal death, severe vaginal bleeding, retained placenta, pelvic pain, uterine rupture[Ref]

Misoprostol may cause abortion. It has been used outside of its approved indications to ripen the cervix, to induce labor, and to treat postpartum hemorrhage, however a major adverse effect of these uses is hyperstimulation of the uterus. Uterine rupture, amniotic fluid embolism, and severe genital bleeding have been reported.[Ref]

Ocular

Rare (less than 0.1%): Amblyopia, blurred vision, conjunctivitis, diplopia, glaucoma, iritis, lacrimation abnormal, night blindness, abnormal vision, eye pain[Ref]

Respiratory

Rare (less than 0.1%): Coughing, dyspnea, hyperventilation, pneumonia, respiratory depression, pharyngitis, increased sputum
Postmarketing reports: Asthma, pneumonitis, dyspnea[Ref]

Immunologic

Frequency not reported: Infection, sepsis
Postmarketing reports: Aseptic meningitis[Ref]

Musculoskeletal

Rare (less than 0.1%): Arthralgia, myalgia, leg cramps[Ref]

Some side effects of diclofenac / misoprostol may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.