Side Effects of Arthrotec (diclofenac and misoprostol)

Arthrotec(diclofenac and misoprostol) is acombination of anonsteroidal anti-inflammatory drug(NSAID)used to treat inflammation,pain, andfeverand asynthetic (man-made) prostaglandinthat helps protect the stomach fromNSAIDs.

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, andfever. 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 andCox-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.

Misoprostolis a synthetic prostaglandin that stimulates secretion of粘液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/心burn,
• nausea, and
• gas(flatulence).

Serious side effects of Arthrotec include

• gastrointestinal ulcers and bleeding,
• liverdysfunction,
• severe skin reactions,
• allergicreactions,
• kidney failure,
• severe bronchospasms (in patients withaspirin-sensitiveasthma),
• 心attacksandstrokes,
• accumulation of fluid that can worsen心failure, and
• hypertension.

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

• Patients takinglithiumcan develop toxic blood levels of lithium because diclofenac may inhibit the elimination of lithium from the body by the kidney.
• Side effects frommethotrexateandcyclosporinealso may be increased by diclofenac.
• Diclofenac may reduce the effectiveness of官网地址bwin-loweringdrugs.
• 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-associateddiarrhea.
• 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, includingkidney failure.
• Diclofenac may increase blood levels ofdigoxinand lead to digoxin toxicity.

Sincemisoprostol can cause abortions,Arthrotec should not be used by women who arepregnant. Women also should avoidpregnancyfor one month or onemenstrual cycleafter discontinuing.

Both drugs in Arthrotec are secreted inbreast milk. Arthrotec is not recommended for use bybreastfeedingmothers.

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

• 胃疼,
• diarrhea,
• dyspepsia,
• nausea, and
• flatulence.

Diarrhea andabdominal painmay 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-sensitiveasthma. Like other NSAIDS, Arthrotec may cause心attacksand strokes; accumulation of fluid and worsen心failure; cause or worsenhypertensionand 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
• 心Failure andEdema
• Renal Toxicity andHyperkalemia
• Anaphylactic Reactions
• Serious Skin Reactions
• Hematologic Toxicity

Clinical Trials Experience

Becauseclinical trialsare 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.

GI disorder	Arthrotec	Diclofenac
Abdominal pain	21%	15%
Diarrhea	19%	11%
Dyspepsia	14%	11%
Nausea	11%	6%
Flatulence	9%	4%

• Arthrotec can cause moreabdominal 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 severedehydrationhave been reported in patients receiving misoprostol.
• Patients with an underlying condition such asinflammatory bowel disease, or those in whomdehydration, 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

• 妇科疾病之前报道与misoprostol use have also been reported for women receiving Arthrotec (seebelow).Postmenopausalvaginal bleedingmay 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,
• 痛经,
• menstrual disorder,
• menorrhagia,
• vaginal hemorrhage.

Hemic and lymphatic system

• epistaxis,
• leukopenia,
• melena,
• purpura,
• decreasedhematocrit.

代谢和营养

• alanine aminotransferase increased,
• alkaline phosphataseincreased,
• 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,
• sweatingincreased,
• 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,
• 心burn,
• 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,
• aplasticanemia,
• 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.

代谢和营养

• 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,
• 保留了ned placenta,
• amniotic fluidembolism,
• incomplete abortion,
• premature birth,
• fetal death.

Psychiatric

• confusion,
• disorientation,
• dream abnormalities,
• hallucinations,
• nervousness,
• paranoia,
• psychotic reaction.

Reproductive system and breast disorders

• femalefertilitydecreased.

Respiratory system

• dyspnea,
• pneumonia,
• respiratorydepression.

Skin and appendages

• acne,
• bruising,
• erythema multiforme,
• exfoliativedermatitis,
• 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,
• nightblindness,
• vision abnormal.

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

Table 1: Clinically Significant Drug Interactions with Diclofenac/Misoprostol

Drugs That Interfere with Hemostasis
Clinical Impact:	Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of Arthrotec with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding.
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone.
Intervention:	Concomitant use of Arthrotec and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding. Arthrotec is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	The concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter. 在浓缩的omitant use of Arthrotec and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. 在浓缩的omitant use of Arthrotec and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function.
Diuretics
Clinical Impact:	临床研究,以及上市后observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	在浓缩的omitant use of Arthrotec with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects.
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	在浓缩的omitant use of Arthrotec and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	在浓缩的omitant use of Arthrotec and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	在浓缩的omitant use of Arthrotec and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	在浓缩的omitant use of Arthrotec and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy.
Intervention:	The concomitant use of Arthrotec with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	在浓缩的omitant use of Arthrotec and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids
Clinical Impact:	Antacids reduce the bioavailability of misoprostol acid. Antacids may also delay absorption of diclofenac. Magnesium-containing antacids exacerbate misoprostol-associated diarrhea.
Intervention:	Concomitant use of Arthrotec and magnesium-containing antacids is not recommended.
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with diclofenac may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of Arthrotec with corticosteroids for signs of bleeding.
CYP2C9 Inhibitors or Inducers
Clinical Impact:	Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconzaole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of diclofenac.
Intervention:	CYP 2C9 inhibitors: When concomitant use of CYP2C9 inhibitors is necessary, the total daily dose of diclofenac should not exceed the lowest recommended dose of Arthrotec 50 twice daily. CYP2C9 inducers: A dosage adjustment may be warranted when Arthrotec is administered with CYP2C9 inducers. Administer the separate products of misoprostol and diclofenac if a higher dose of diclofenac is deemed necessary.