Side Effects of Arthrotec (diclofenac and misoprostol)

Arthrotec (diclofenac and misoprostol) is a combination of a nonsteroidal anti-inflammatory drug (NSAID) used to treat inflammation, pain, and fever and a synthetic (man-made) prostaglandin that helps protect the stomach from NSAIDs. 

Diclofenac, like other NSAIDs works by inhibiting the production of prostaglandins. Prostaglandins are a family of chemicals produced by the cells of the body that promote inflammation, pain, and fever. In addition, they support the function of platelets that are necessary for the clotting of blood, and protect the lining of the stomach from the damaging effects of acid. 

Prostaglandins are produced by the enzyme cyclooxygenase (Cox). There actually are two Cox enzymes, Cox-1 and Cox-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever. However, only Cox-1 produces prostaglandins that support platelets and protect the stomach. Diclofenac blocks both Cox enzymes and reduces prostaglandins throughout the body. 

As a consequence, ongoing inflammation, pain, and fever are reduced. Since prostaglandins that protect the stomach and support platelets and blood clotting also are reduced, NSAIDs can cause ulcers in the stomach and promote bleeding. 

Misoprostol is a synthetic prostaglandin that stimulates secretion of mucus in the gastrointestinal tract. Mucus protects the lining of the stomach from acid. Misoprostol has been shown to reduce the frequency of ulcers of the stomach caused by NSAIDs.

Common side effects of Arthrotec include

• stomach/abdominal pain,
• diarrhea,
• indigestion/heartburn,
• nausea, and
• gas (flatulence).

Serious side effects of Arthrotec include

• gastrointestinal ulcers and bleeding,
• liver dysfunction,
• severe skin reactions,
• allergic reactions,
• kidney failure,
• severe bronchospasms (in patients with aspirin-sensitive asthma),
• heart attacks and strokes,
• accumulation of fluid that can worsen heart failure, and
• hypertension.

Drug interactions of Arthrotec include blood thinners (anticoagulants), such as warfarin, because of the increased risk of bleeding when combined with diclofenac.

• Patients taking lithium can develop toxic blood levels of lithium because diclofenac may inhibit the elimination of lithium from the body by the kidney.
• Side effects from methotrexate and cyclosporine also may be increased by diclofenac.
• Diclofenac may reduce the effectiveness of blood pressure-lowering drugs.
• Since prostaglandins are important in the control of blood pressure. Antacids reduce the absorption of misoprostol and may delay absorption of diclofenac.
• Magnesium-containing antacids worsen misoprostol-associated diarrhea.
• Combining NSAIDs with angiotensin receptor blockers (ARBs) or angiotensin converting enzyme (ACE) inhibitors in patients who are elderly, volume-depleted (including those on diuretic therapy), or with poor kidney function may result in reduced kidney function, including kidney failure.
• Diclofenac may increase blood levels of digoxin and lead to digoxin toxicity. 

Since misoprostol can cause abortions, Arthrotec should not be used by women who are pregnant. Women also should avoid pregnancy for one month or one menstrual cycle after discontinuing. 

Both drugs in Arthrotec are secreted in breast milk. Arthrotec is not recommended for use by breastfeeding mothers.

Arthrotec has the side effects of diclofenac and misoprostol. The most common side effects are:

• stomach pain,
• diarrhea,
• dyspepsia,
• nausea, and
• flatulence.

Diarrhea and abdominal pain may resolve after 2-7 days. Magnesium containing antacids worsen diarrhea caused by misoprostol. Taking Arthrotec with food and avoiding antacids containing magnesium may reduce the occurrence of diarrhea.

Other important side effects include

• gastrointestinal ulcers and bleeding;
• liver dysfunction;
• severe skin reactions,
• allergic reactions, and
• kidney failure.

Severe bronchospasms may occur in patients with aspirin-sensitive asthma. Like other NSAIDS, Arthrotec may cause heart attacks and strokes; accumulation of fluid and worsen heart failure; cause or worsen hypertension and kidney failure.

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

• Cardiovascular Thrombotic Events
• GI Bleeding, Ulceration and Perforation
• Hepatotoxicity
• Hypertension
• Heart Failure and Edema
• Renal Toxicity and Hyperkalemia
• Anaphylactic Reactions
• Serious Skin Reactions
• Hematologic Toxicity

Clinical Trials Experience

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 Arthrotec is derived from Phase III multinational controlled clinical trials in over 2,000 patients receiving Arthrotec 50 or Arthrotec 75, as well as from blinded, controlled trials of diclofenac delayed-release tablets and misoprostol tablets.

Gastrointestinal

GI disorders had the highest reported incidence of adverse events for patients receiving Arthrotec. These events were generally minor, but led to discontinuation of therapy in 9% of patients on Arthrotec and 5% of patients on diclofenac. For GI ulcer rates, see prescribing information.

• Arthrotec can cause more abdominal pain, diarrhea, and other GI symptoms than diclofenac alone.
• Diarrhea and abdominal pain developed early in the course of therapy, and were usually self-limited (resolved after 2 to 7 days).
• Rare instances of profound diarrhea leading to severe dehydration have been reported in patients receiving misoprostol.
• Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if Arthrotec is prescribed.
• The incidence of diarrhea can be minimized by administering Arthrotec with food and by avoiding coadministration with magnesium-containing antacids.

Gynecological

• Gynecological disorders previously reported with misoprostol use have also been reported for women receiving Arthrotec (see below). Postmenopausal vaginal bleeding may be related to administration of Arthrotec. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology.

Elderly

• Overall, there were no significant differences in the safety profile of Arthrotec in over 500 patients 65 years of age or older compared with younger patients.
• Other adverse experiences reported occasionally with Arthrotec, diclofenac or other NSAIDs, or misoprostol are:

Body as a whole:

• asthenia,
• fatigue,
• malaise.

Central and peripheral nervous system

• dizziness,
• drowsiness,
• headache,
• insomnia,
• paresthesia,
• vertigo.

Digestive

• anorexia,
• appetite changes,
• constipation,
• dry mouth,
• dysphagia,
• esophageal ulceration,
• oesophagitis,
• eructation,
• gastritis,
• gastroesophageal reflux,
• GI neoplasm benign,
• peptic ulcer,
• tenesmus,
• vomiting.

Female reproductive disorders

• breast pain,
• dysmenorrhea,
• menstrual disorder,
• menorrhagia,
• vaginal hemorrhage.

Hemic and lymphatic system

• epistaxis,
• leukopenia,
• melena,
• purpura,
• decreased hematocrit.

Metabolic and nutritional

• alanine aminotransferase increased,
• alkaline phosphatase increased,
• aspartate aminotransferase increased,
• dehydration, hyponatremia.

Musculoskeletal system

• arthralgia,
• myalgia.

Psychiatric

• anxiety,
• concentration impaired,
• depression,
• irritability.

Respiratory system

• asthma,
• coughing,
• hyperventilation.

Skin and appendages

•  alopecia,eczema,
• pemphigoid reaction,
• photosensitivity,
• sweating increased,
• pruritus.

Special senses

•  taste perversion,
• tinnitus.

Renal and urinary disorders

• dysuria,
• nocturia,
• polyuria,
• proteinuria,
• urinary tract infection.

Vision

• diplopia.

Postmarketing Experience

The following adverse reactions have been identified during post approval of Arthrotec, diclofenac or misoprostol. Because these reactions are reported voluntarily from a population of uncertain 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 CPK,
• increased 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

• 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,
• glomerulohephritis.

Vision

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

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

Table 1: Clinically Significant Drug Interactions with Diclofenac/Misoprostol