DICLOFENAC SODIUM-MISOPROSTOL (diclofenac sodium/misoprostol)

There are 7 contraindications. Absolute contraindication.

Contraindication List
Aspirin exacerbated respiratory disease
Cerebrovascular accident
Drug-induced hepatitis
History of roux-en-Y gastric bypass
Post-operative from CABG surgery
Pregnancy
Renal transplant

There are 22 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Acute myocardial infarction
Alcohol use disorder
Chronic heart failure
Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
Chronic kidney disease stage 5 (failure) GFr<15 ml/min
Disease of liver
Gastrointestinal hemorrhage
Gastrointestinal perforation
Gastrointestinal ulcer
Hepatic porphyria
History of kidney donation
Hypertension
Increased risk of bleeding
Increased risk of bleeding due to coagulation disorder
Inflammatory bowel disease
Kidney disease with likely reduction in glomerular filtration rate (GFr)
Nephrectomy
Non-infective meningitis
Systemic mastocytosis
Thrombotic disorder
Tobacco smoker
Uterine rupture in pregnancy

There are 6 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Anemia
Asthma
Dehydration
Edema
Previous cesarean section
Uterine scar present

There are 77 severe adverse reactions.

More Frequent	Less Frequent
None.	Abnormal hepatic function tests Body fluid retention Edema Esophageal ulcer Gastrointestinal ulcer Increased alanine transaminase Peptic ulcer Skin rash Tinnitus

Rare/Very Rare

Abnormal hepatic function tests Abnormal vaginal bleeding Acute eruptions of skin Acute myocardial infarction Acute pancreatitis Agranulocytosis Allergic dermatitis Anaphylaxis Anemia Angioedema Aplastic anemia Black tarry stools Bloody stools Bloody vomit Bronchospastic pulmonary disease Bullous dermatitis Cardiac arrhythmia Cerebrovascular accident CNS toxicity Colitis Cystitis DRESS syndrome Dyspnea Eosinophilia Epistaxis Erythema multiforme Esophagitis Exfoliative dermatitis Gastric ulcer Gastrointestinal hemorrhage Gastrointestinal perforation Gout Hearing loss Heart failure Hematuria Hemolytic anemia Hemorrhage Hepatic failure Hepatic necrosis Hepatitis Hyperkalemia Hypertension Infection Interstitial nephritis Jaundice Kidney disease with reduction in glomerular filtration rate (GFr) Leukopenia Memory impairment Nephrotic syndrome Nephrotoxicity Non-infective meningitis Oliguria Pancytopenia Pneumonia Proteinuria Purpura Renal failure Renal papillary necrosis Respiratory depression Seizure disorder Stevens-johnson syndrome Tachycardia Thrombocytopenic disorder Thromboembolic disorder Thrombotic disorder Toxic epidermal necrolysis Urticaria Uterine rupture in pregnancy

There are 83 less severe adverse reactions.

More Frequent	Less Frequent
Abdominal pain with cramps Acute abdominal pain Constipation Diarrhea Dizziness Drowsy Dyspepsia Headache disorder Hyperhidrosis Insomnia Nausea Pruritus of skin Vomiting	Constipation Dyspepsia Flatulence Headache disorder Heartburn Nausea Vomiting

Rare/Very Rare

Abnormal vaginal bleeding Acute cognitive impairment Agitation Alopecia Appetite changes Arthralgia Asthma Back pain Chest pain Chills Conjunctivitis Cramps Depression Dizziness Dream disorder Drowsy Dysgeusia Dysmenorrhea Dysphagia Dyspnea Dysuria Earache Ecchymosis Edema Epistaxis Erectile dysfunction Eructation Fatigue Fever Flushing General weakness Gingivitis Hearing loss Hematuria Hyperglycemia Hyperhidrosis Hypertension Hypotension Irritability Lymphadenopathy Mastalgia Medication overuse headache Menstrual disorder Myalgia Pallor Palpitations Phlebitis Polyuria Purpura Skin inflammation Skin photosensitivity Skin rash Stomatitis Symptoms of anxiety Syncope Tachycardia Tinnitus Tremor Upper respiratory infection Uterine cramps Visual changes Weight loss Xerostomia

Misoprostol exhibits abortifacient activity and therefore can cause serious fetal harm when administered to pregnant women. A boxed warning about this risk is included in the prescribing information for the drug. Misoprostol should not be used in pregnant women for reducing the risk of NSAIA-induced gastric ulcers.

The drug also should not be used for reducing the risk of NSAIA-induced gastric ulcers in women of childbearing potential unless the woman is at high risk of developing gastric ulcers or of complications resulting from NSAIA-induced gastric ulcers; such women should not receive misoprostol until pregnancy is excluded and other necessary precautions are ensured. Misoprostol has been reported to produce uterine contractions and to stimulate uterine bleeding and total or partial expulsion of the products of conception in pregnant women. Spontaneous abortions induced by the drug may be incomplete, may require hospitalization and/or surgery, and can result in dangerous uterine bleeding, premature birth, or birth defects.

Intravaginal use of misoprostol may result in hyperstimulation of the uterus, which may progress to uterine tetany with marked impairment of uteroplacental blood flow, uterine rupture (requiring surgical repair, hysterectomy, and/or salpingo-oophorectomy), or amniotic fluid embolism. Pelvic pain, retained placenta, severe genital bleeding, shock, fetal bradycardia, and fetal and maternal death have been reported. Use of intravaginal misoprostol dosages exceeding 25 mcg may be associated with an increased risk of uterine tachysystole, uterine rupture, meconium passage, meconium staining of amniotic fluid, and cesarean delivery resulting from uterine hyperstimulation.

The risk of uterine rupture increases with advancing gestational age, prior uterine surgery (including cesarean delivery), and grand multiparity; the American College of Obstetricians and Gynecologists (ACOG) states that intravaginal use of misoprostol for cervical ripening or labor induction is not recommended in patients with a previous cesarean delivery or prior major uterine surgery. Serious, sometimes fatal, bacterial (e.g., Clostridium sordellii) infection and sepsis or prolonged heavy vaginal bleeding have been reported following spontaneous, surgical, and medical abortions, including in patients receiving mifepristone and misoprostol for termination of pregnancy; a causal relationship to the regimen has not been established. Congenital abnormalities, sometimes associated with fetal death, have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient.

Some data indicate that use of misoprostol during the first trimester of pregnancy has been associated with skull defects, cranial nerve palsies, facial malformations, and limb defects; however, the precise mechanism(s) for these teratogenic effects has not been fully elucidated. Effects of misoprostol on later growth, development, and functional maturation of the child whose mother received the drug for cervical ripening or labor induction have not been established. The effects of misoprostol on the need for forceps delivery or other intervention are not known.

Currently, it is recommended that misoprostol be used for reducing the risk of NSAIA-induced gastric ulcers in women of childbearing potential only if they are at high risk of complications resulting from NSAIA-induced gastric ulceration or are at high risk of developing gastric ulceration. Such therapy should be initiated in such women only after determining that they are reliable and able to comply with effective contraceptive measures and ensuring that they have received both oral and written warnings concerning the hazards associated with misoprostol therapy, the risk of possible contraceptive failure, and the danger to other women of childbearing potential should the drug be taken by them. In addition, a reliable, blood pregnancy test must be performed within 2 weeks prior to beginning misoprostol therapy and the drug should not be provided to the patient until the pregnancy test is reported as negative, initiating therapy on the second or third day of the next normal menstrual cycle.

If misoprostol is inadvertently administered during pregnancy or if the patient becomes pregnant while receiving the drug for reducing the risk of NSAIA-induced gastric ulcer, misoprostol should be discontinued and the patient informed of the potential hazard to the fetus. Reproduction studies in rats and rabbits using oral misoprostol dosages up to 10 and 1 mg/kg (625 and 63 times the usual human dosage), respectively, have not revealed evidence of fetotoxicity or teratogenicity. However, increased fetal resorption occurred in rabbits, suggesting possible embryotoxicity.

Use of NSAIAs during pregnancy at about >=30 weeks' gestation can cause premature closure of the fetal ductus arteriosus, and use at about >=20 weeks' gestation has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, use of NSAIAs should be avoided in pregnant women at about >=30 weeks' of gestation; if NSAIA therapy is necessary between about 20-30 weeks' gestation, the lowest effective dosage and shortest possible duration of treatment should be used. Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.

Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20-30 weeks of gestation. Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy. Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy.

Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation. A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios. Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.

Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use. Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.

There are no studies evaluating the effects of diclofenac on labor and delivery in humans. In animal studies, NSAIAs, including diclofenac, inhibit prostaglandin synthesis, delay parturition, and increase the incidence of stillbirth. Diclofenac sodium in fixed combination with misoprostol is contraindicated in women who are pregnant because misoprostol exhibits abortifacient activity and can cause serious fetal harm. In addition, it is recommended that diclofenac in fixed combination with misoprostol be used in women of reproductive potential only if they require NSAIA therapy and are considered at high risk of complications resulting from NSAIA-induced gastric or duodenal ulceration or at high risk of developing gastric or duodenal ulceration.

It is not known whether misoprostol and/or misoprostol acid cross the placenta. The drug is metabolized rapidly to the free acid following oral administration, which is biologically active and distributed into breast milk. There are no published reports of adverse effects associated with misoprostol in breast-fed infants.

Caution is advised if the drug is used during breast-feeding. Diclofenac may be distributed into human milk. While diclofenac was not detectable in breast milk in 12 women who received diclofenac 100 mg orally daily for 7 days or a single 50-mg IM dose administered in the immediate postpartum period, the drug was detected in breast milk at a concentration of 100 mcg/L (equivalent to an infant dose of about 0.03 mg/kg daily) in one woman receiving a diclofenac salt at a dosage of 150 mg daily. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for diclofenac and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Geriatric patients are at increased risk for NSAIA-associated serious adverse cardiovascular, GI, and renal effects. The risk of these adverse effects may be increased in geriatric patients with renal impairment or receiving concomitant ACE inhibitor or angiotensin II receptor antagonist therapy. Many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals.

If the anticipated benefits of diclofenac therapy outweigh the potential risks, diclofenac should be initiated at the lower end of the dosing range and patients should be monitored for adverse effects. Diclofenac sodium in fixed combination with misoprostol should be avoided in geriatric patients with cardiovascular and/or renal risk factors. In clinical trials of diclofenac sodium in fixed combination with misoprostol, 25.5%

of patients were >=65 years of age. No overall differences in efficacy were observed between geriatric patients and younger adults. Other clinical experience has not identified differences in response compared to younger adults, although a greater sensitivity to the drug cannot be ruled out in older individuals.

No clinically meaningful differences in diclofenac and misoprostol pharmacokinetics were observed in geriatric patients compared to younger adults. In phase 3 clinical trials of diclofenac sodium 1.5% topical solution, 49% of patients receiving the drug were >=65 years of age.

In an open-label, long-term safety study, 42% of patients receiving diclofenac sodium 1.5% topical solution were >=65 years of age, while 13% were >=75 years of age. No age-related differences in the incidence of adverse effects were observed in these studies.

Clinical trials of diclofenac epolamine transdermal system or diclofenac potassium oral solution did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently than younger adults. Other clinical experience has not identified differences in response between geriatric and younger patients. Diclofenac is substantially excreted by the kidneys, and the risk of toxicity may be greater in patients with renal impairment. Because geriatric patients are more likely to have decreased renal function, diclofenac should be used with caution; it may be useful to monitor renal function in such patients.