diclofenac/misoprostol (Rx)

>10%

Rash including erythematous, rash macular and maculo-papular (18%)

Pyrexia (15%)

Urticaria (13%)

Flushing (13%)

1-10%

Hypertension (10%)

Hyperhydrosis (8%)

Decreased oxygen saturation (8%)

Cough (8%)

Tachypnea (8%)

Tachycardia (8%)

Urticaria (8%)

Anaphylaxis (7%

Chest discomfort (7%)

Muscle twitching (7%)

Erythema (5%)

Vomiting (5%)

Rigors (5%)

Pallor (5%)

Cyanosis (5%)

Agitation (5%)

Tremor (5%)

Myalgia (5%)

Flushing (5%)

Peripheral edema (3%)

Pruritus (3%)

Rash, papular (3%)

Throat tightness (3%)

<1%

Fatigue

Malaise

Chills

Edema

Atrial fibrillation

Congestive heart failure

Myocardial infarction

Phlebitis

Vasculitis

Syncope

Dysphagia

Enteritis

Peptic ulcer

Vaginitis

Breast pain

Dysmenorrhea

Uterine cramping

Ulcerative stomatitis

Impotence

Perineal pain

Glycosuria

Alopecia

Postmarketing reports

Increased alanine aminotransferase

Increased alkaline phosphatase

Increased aspartate aminotransferase

Increased BUN

Dehydration

Glycosuria

Gout

Hypercholesterolemia

Hyperglycemia

Hyperuricemia

Hypoglycemia

Hyponatremia

Periorbital edema porphyria

Weight changes

Fluid retention

Contraindications

Hypersensitivity drugs or related products

Perioperative pain in the setting of coronary artery bypass graft (CABG) surgery; active gastrointestinal bleeding

Patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs

Cautions

Women of childbearing potential (see mfr's package insert for restrictions)

Avoid pregnancy during & for at least 1 month after treatment

May cause blurred vision, drowsiness, dizziness

Transaminase elevation observed with chronic use

Hypokalemia may occur when administered with drugs capable of inducing hyperkalemia; risk may increase in diabetics, renal disease, the elderly

NSAIDs reported to cause serious skin reactions including exfoliative dermatitis, Stevens-Johnson syndrome

May increase risk of aseptic meningitis especially in patients with mixed connective tissue disorders and systemic lupus erythematous

Severe bronchospasm may occur in patients with asthma

Use caution in hepatic impairment, porphyria (avoid if possible), hypertension, renal impairment

Avoid use of diclofenac/misoprostol with concomitant NSAIDs including COX inhibitors

Use lowest effective dose in patients with known cardiovascular (CV) disease or risk factors for CV

Concurrent use of aspirin with NSAIDs in mitigating CV thrombotic events not shown conclusively; increased risk of serious GI adverse reactions likely

Use caution in patients with hypertension; monitor blood pressure closely during initiation of NSAID treatment and throughout the course of therapy

Fluid retention and edema may occur with therapy; use with caution in patients with heart failure

Serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and perforation of stomach, small intestine, or large intestine, which can be fatal may occur

Renal papillary necrosis and other renal injury reported with NSAID long-term therapy

Toxic epidermal necrolysis, reported with NSAID use, especially within first month of therapy; discontinue use at first appearance of skin rash

Use of NSAIDs may diminish ability to diagnose conditions associated with pain or inflammation

Anemia reported with NSAID use; monitor

Use caution in patients with coagulation disorders or receiving anticoagulants; NSAIDs inhibit platelet aggregation

Not for administration to patients with aspirin-sensitive asthma; use caution in patients with preexisting asthma

NSAIDs may diminish antihypertensive effect of ACE-inhibitors

Not recommended in patients with advanced renal disease

Drug-induced hepatotoxicity reported in first month, and may occur within 1-6 months, but can occur at any time during therapy

Drug reaction with eosinophilia and systemic symptoms (DRESS)

• Drug Reaction reported in patients taking NSAIDs; 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
• 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 therapy and evaluate the patient immediately

Pregnancy

Drug combination is contraindicated in pregnant women; there are no adequate and well-controlled studies in pregnant women; however, there is information available about the active drug components diclofenac sodium and misoprostol

Administration of misoprostol to pregnant women can cause abortion, premature birth, birth defects or uterine rupture; congenital anomalies sometimes associated with fetal death have been reported subsequent to unsuccessful use of misoprostol as an abortifacient, but the drug’s teratogenic mechanism has not been demonstrated

Use of NSAIDS, including diclofenac can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment

There are clinical considerations when misoprostol and diclofenac are used in pregnant women In reproduction studies with pregnant rabbits, there were no skeletal or visceral malformations when the combination of diclofenac sodium and misoprostol was administered during organogenesis at doses less than the maximum recommended human doses (MRHD); however, embryotoxicity was observed at this exposure

Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization

In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre-and post-implantation loss; if a woman becomes pregnant while taking drug combination, discontinue drug and advise the woman of the potential risks to her and to a fetus

Maternal adverse reactions

• Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception; misoprostol has been used to ripen the cervix, to induce labor, and to treat postpartum hemorrhage, outside of its approved indication
• A major adverse effect of these uses is hyperstimulation of the uterus; uterine rupture, amniotic fluid embolism, severe bleeding, shock, and maternal death have been reported when misoprostol was administered to pregnant women to induce labor to induce abortion beyond the eighth weeks of pregnancy
• Higher doses of misoprostol, including the 100 mcg tablet, may increase the risk of complications from uterine hyperstimulation; the drug combination, which contains 200 mcg of misoprostol, is likely to have a greater risk of uterine hyperstimulation than the 100 mcg tablet of misoprostol
• Abortions caused by misoprostol may be incomplete; cases of amniotic fluid embolism, which resulted in maternal and fetal death, have been reported with use of misoprostol during pregnancy
• Severe vaginal bleeding, retained placenta, shock, and pelvic pain have also been reported; these women were administered misoprostol vaginally and/or orally over a range of doses; if a woman is or becomes pregnant while taking this drug, the drug should be discontinued and the patient apprised of the potential hazard to the fetus
• Drug combination is contraindicated in pregnant women

Fetal toxicity

• Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman; use of misoprostol for the induction of labor in the third trimester was associated with uterine hyperstimulation with resulting changes in the fetal heart rate (fetal bradycardia) and fetal death
• NSAIDs can cause premature closure of the fetal ductus arteriosus at about 30 weeks gestation and later in pregnancy and at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment
• If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue treatment and follow up according to clinical practice

Labor or delivery

• There are no studies on the effects of drug combination or diclofenac during labor or delivery; in animal studies, NSAIDS, including diclofenac, are known to inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth;
• In humans, some case reports and studies have associated misoprostol with risk of stillbirth, uterine hyperstimulation, perineal tear, amniotic fluid embolism, severe bleeding, shock, uterine rupture and death
• The risk of uterine rupture associated with misoprostol use in pregnancy may occur at any gestational age, and increases with advancing gestational ages and with prior uterine surgery, including cesarean delivery; grand multiparity also appears to be a risk factor for uterine rupture

Infertility

• Based on mechanism of action, NSAIDs, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women
• Animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation; small studies in women have also shown a reversible delay in ovulation in women treated with NSAIDs; consider withdrawal of NSAIDs, in women who have difficulties conceiving or who are undergoing investigation of infertility

Animal data

• In reproduction studies with pregnant rabbits, there were no skeletal or visceral malformations when drug combination was administered during organogenesis at doses less than maximum recommended human doses (MRHD); however, embryotoxicity was observed at this exposure
• Based on animal data, prostaglandins have been shown to have important role in endometrial vascular permeability, blastocyst implantation, and decidualization; in animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre-and post-implantation loss; if a woman becomes pregnant while receiving therapy, discontinue drug and advise woman of potential risks to her and to a fetus
• In animal studies, NSAIDs are known to inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth

Lactation

No lactation studies conducted; however, limited published literature reports that diclofenac and active metabolite of misoprostol are present in breast milk; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Diclofenac: Inhibits cyclooxygenase-1 (COX-1) & -2 (COX-2), thereby inhibiting prostaglandin synthesis; has anti-inflammatory, antipyresis, and analgesic properties

Misoprostol: Replaces protective prostaglandins consumed by prostaglandin-inhibiting therapies (NSAID-induced ulcers)