DICLOFENAC SODIUM (diclofenac sodium)

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 23 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Acute myocardial infarction
Alcohol use disorder
Cerebrovascular accident
Chronic heart failure
Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
Chronic kidney disease stage 5 (failure) GFr<15 ml/min
Debilitation
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
Kidney disease with likely reduction in glomerular filtration rate (GFr)
Nephrectomy
Non-infective meningitis
Peptic ulcer
Systemic mastocytosis
Thrombotic disorder
Tobacco smoker

There are 5 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
Hypertension

There are 78 severe adverse reactions.

More Frequent	Less Frequent
None.	Abnormal hepatic function tests Body fluid retention Dyspnea 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 Asthma Black tarry stools Bloody stools Bloody vomit Body fluid retention Bronchospastic pulmonary disease Bullous dermatitis Cerebrovascular accident Colitis Cystitis DRESS syndrome Dyspnea Eosinophilia Epistaxis Erythema multiforme Esophagitis Exfoliative dermatitis Gastric ulcer Gastroenteritis Gastrointestinal hemorrhage Gastrointestinal perforation Gastrointestinal ulcer 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 Maculopapular rash Memory impairment Nephrotic syndrome Nephrotoxicity Non-infective meningitis Oliguria Pancytopenia Platelet aggregation inhibition Pneumonia Proteinuria Rectal bleeding Renal failure Renal papillary necrosis Respiratory depression Seizure disorder Stevens-johnson syndrome Thrombocytopenic disorder Thrombotic disorder Tongue swelling Toxic epidermal necrolysis Urticaria

There are 88 less severe adverse reactions.

More Frequent	Less Frequent
Acute abdominal pain Acute pain at drug application site Constipation Dermatitis due to topical drug Diarrhea Dizziness Drowsy Dry skin Dyspepsia Headache disorder Hyperhidrosis Insomnia Nausea Pruritus of skin Skin rash Skin scaling Vomiting	Abdominal distension Abnormal desquamation Acute abdominal pain Bruising Conjunctivitis Contact dermatitis Diarrhea Drowsy Dysgeusia Dyspepsia Edema Flatulence Flu-like symptoms Headache disorder Heartburn Hyperesthesia Hypertension Myalgia Nausea Paresthesia Pruritus of skin Skin inflammation Skin rash Skin ulcer Stinging of skin Treatment site sequelae

Rare/Very Rare

Acute cognitive impairment Alopecia Appetite changes Asthma Cataracts Conjunctivitis Cramps in legs Depression Diarrhea Dizziness Dream disorder Ecchymosis Eczema Eructation Fever Flushing Gastritis General weakness Halitosis Hearing loss Hyperglycemia Hyperkinesis Hypertension Hypoesthesia Irritability Localized edema Lymphadenopathy Medication overuse headache Myalgia Palpitations Purpura Seborrhea Sinusitis Skin hypertrophy Skin photosensitivity Stomatitis Symptoms of anxiety Syncope Tachycardia Tremor Urinary tract infection Urticaria Visual changes Weight loss Xerostomia

Safety of diclofenac sodium 3% gel has not been established during pregnancy. Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later 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 or later; if NSAIA therapy is necessary between about 20 and 30 weeks of 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. (See Advice to Patients.) Known effects of NSAIAs on the human fetus during the third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis. 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 (generally within 3-6 days) 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. Deaths associated with neonatal renal failure have been reported. 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. Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.

In animal studies, inhibitors of prostaglandin synthesis, such as diclofenac, were associated with increased pre- and post-implantation losses. Prostaglandins also have an important role in fetal kidney development. In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.

No evidence of teratogenicity was observed in reproduction studies in mice, rats, or rabbits at diclofenac doses at least 15 times the maximum recommended human dose of diclofenac sodium 3% gel. In rats, maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, reduced fetal weight and growth, and reduced fetal survival. The effects of diclofenac on labor and delivery in pregnant women are unknown.

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.

Discontinue nursing or the drug because of potential risk in nursing infants. 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.

Individuals 65 years of age or older were included in clinical trials since actinic keratoses occur frequently in an older patient population. No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out. 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.