Diclofenac (Systemic)

Pharmacologic Category

Analgesic, Nonopioid; Nonsteroidal Anti-inflammatory Drug (NSAID); Nonsteroidal Anti-inflammatory Drug (NSAID), Oral

Dosing: Adult

Note: Use the lowest effective dose for the shortest duration of time, consistent with individual patient treatment goals. Due to an increased risk of cardiovascular events, use should generally be avoided in patients with established cardiovascular disease or risk factors for cardiovascular disease. Use should also be avoided in those with heart failure (Chan 2018; Schmidt 2016). Of note, Dyloject (diclofenac injection) has been discontinued in the United States for >1 year.

Note: For all indications, it has been recommended to not exceed 100 mg/day based on increased risk of vascular events (eg, stroke, nonfatal myocardial infarction) (Bhala 2013; Health Canada communication 2014).

Ankylosing spondylitis: Oral: Delayed-release tablet: 25 mg 4 times daily and 25 mg at bedtime as needed.

Gout, treatment (acute flares) (alternative agent) (off-label use): Oral: IR tablets or delayed-release tablets: 50 mg twice daily; initiate within 24 to 48 hours of flare onset preferably; discontinue 2 to 3 days after resolution of clinical signs; usual duration: 5 to 7 days (Becker 2019).

Migraine: Oral: Powder for oral solution: 50 mg (one packet) as a single dose; safety and efficacy of a second dose have not been established.

Osteoarthritis:

Oral:

Immediate-release tablet: 50 mg 2 to 3 times daily; Delayed-release tablet: 50 mg 2 to 3 times daily or 75 mg twice daily; Extended-release tablet: 100 mg once daily.

Immediate-release capsule: Zorvolex (diclofenac acid): 35 mg 3 times daily.

Rectal suppository [Canadian product]: Insert 50 mg or 100 mg rectally as single dose to substitute for final oral daily dose (maximum combined dose [rectal and oral]: 100 mg/day).

Pain:

Oral:

Immediate-release tablet: 50 mg 3 times daily; may administer 100 mg as an initial dose, followed by 50 mg 3 times daily.

Immediate-release capsule:

Zipsor (diclofenac potassium): 25 mg 4 times daily.

Zorvolex (diclofenac acid): 18 mg or 35 mg 3 times daily.

IV: 37.5 mg every 6 hours as needed; adjust frequency according to patient response (maximum: 150 mg/day).

Primary dysmenorrhea: Oral: Immediate-release tablet: 50 mg 3 times daily; may administer 100 mg as an initial dose, followed by 50 mg 3 times daily.

Rheumatoid arthritis:

Oral: Immediate-release tablet: 50 mg 3 to 4 times daily; Delayed-release tablet: 50 mg 3 to 4 times daily or 75 mg twice daily; Extended-release tablet: 100 mg once daily; may increase to 100 mg twice daily.

Rectal suppository [Canadian product]: Insert 50 mg or 100 mg rectally as single dose to substitute for final oral daily dose (maximum combined dose [rectal and oral]: 100 mg/day.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing. Use with caution; initiate using lowest recommended dose and frequency.

Dosing: Renal Impairment: Adult

Oral:

Mild or moderate impairment: No dosage adjustment necessary.

Significant impairment or advanced renal disease: Use is not recommended.

Injection:

Mild impairment: There are no dosage adjustments provided in the manufacturer's labeling.

Moderate to severe impairment: Use is not recommended; contraindicated in patients in the perioperative period and who are at risk for volume depletion.

KDIGO 2012 guidelines provide the following recommendations for NSAIDs:

eGFR 30 to <60 mL/minute/1.73 m2: Temporarily discontinue in patients with intercurrent disease that increases risk of acute kidney injury.

eGFR <30 mL/minute/1.73 m2: Avoid use.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; however, may require dosage adjustment due to extensive hepatic metabolism. Additional product-specific recommendations:

Cambia: Use the lowest effective dose for the shortest duration possible.

Zipsor/Zorvolex: Initial: Initiate treatment at the lowest dose; if efficacy is not achieved with the lowest dose, discontinue use.

Injection:

Mild impairment: No dosage adjustment necessary.

Moderate to severe impairment: Use is not recommended (has not been studied).

Dosing: Pediatric

Note: Different oral formulations are not bioequivalent; do not interchange products. Rectal formulation not available in the US.

Juvenile idiopathic arthritis:

Oral: Limited data available: Children and Adolescents: Immediate-release tablet: 2 to 3 mg/kg/day in divided doses 2 to 4 times/day; maximum daily dose: 150 mg/day (Haapasaari 1983; Hashkes 2005; Leak 1988; Petty 2016).

Rectal: Limited data available: Children: Rectal suppository (12.5 mg or 25 mg suppository, product not available in US): 1 to 3 mg/kg/day in divided doses 2 to 3 times daily (Voltarol UK prescribing information 2017).

Migraine: Oral: Adolescents ≥18 years: Oral solution: 50 mg (1 packet) as a single dose at the time of migraine onset; safety and efficacy of a second dose have not been established.

Osteoarthritis: Rectal [Canadian product]: Adolescents ≥16 years: Rectal suppository: Insert 50 or 100 mg suppository at bedtime as a substitute for the last daily oral dose; maximum daily dose: 100 mg/day (oral and rectal) (Voltaren Canadian product monograph 2019).

Postoperative pain: Limited data available: Rectal: Children and Adolescents: Rectal suppository (12.5, 25, or 50 mg; not available in US): Initial dose: 1 to 2 mg/kg/dose once followed by 1 mg/kg/dose 3 times daily; round dose to nearest available suppository size; maximum single dose: 50 mg/dose; maximum daily dose: 3 mg/kg/day; treatment should not exceed 4 days duration (Voltarol UK prescribing information 2017; Voltaren Australia product monograph 2019).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Renal Impairment: Pediatric

Children and Adolescents: There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling; some experts have suggested the following:

KDIGO 2012 guidelines provide the following recommendations for NSAIDs (KDIGO 2013):

eGFR 30 to <60 mL/minute/1.73 m2: Temporarily discontinue in patients with intercurrent disease that increases risk of acute kidney injury

eGFR <30 mL/minute/1.73 m2: Avoid use.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; however, may require dosage adjustment due to extensive hepatic metabolism.

Use: Labeled Indications

Ankylosing spondylitis (delayed-release tablets only): Acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis.

Dysmenorrhea (immediate-release tablets only): Treatment of primary dysmenorrhea.

Migraine (powder for oral solution only): Acute treatment of migraine attacks with or without aura in adults.

Osteoarthritis (immediate-release, extended-release, and delayed-release tablets; capsules [Zorvolex]; and suppositories [Canadian product] only): Relief of signs and symptoms of osteoarthritis.

Pain

Capsules/immediate-release tablets only: Relief of mild to moderate acute pain.

Injection only: Management of mild to moderate pain and moderate to severe pain (alone or in combination with opioid analgesics) in adults.

Rheumatoid arthritis (immediate-release, extended-release, and delayed-release tablets; and suppositories [Canadian product] only): Relief of signs and symptoms of rheumatoid arthritis.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

​Gout, treatment (acute flares)Level of Evidence [B, G]

Data from a limited number of trials support the efficacy of diclofenac in the treatment of acute gout flares Ref. Clinical experience also suggests the utility of diclofenac as an alternative agent for acute gout flares, particularly in younger adults (<60 years of age) without renal or cardiovascular comorbidities and active GI disease Ref.

Based on the 2020 American College of Rheumatology guidelines for the management of gout, nonsteroidal anti-inflammatory drugs are effective and recommended agents in the treatment of acute gout flares Ref.

Class and Related Monographs

Nonsteroidal Anti-Inflammatory Agents

Comparative Efficacy

• DICLOFENAC SODIUM INJECTABLE

Clinical Practice Guidelines

Ankylosing Spondylitis:

ACR/SAA/SPARTAN, "2019 Update of the Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis," August 2019

Gout:

ACR, "Guideline for the Management of Gout," June 2020

Heart Failure:

ACCF/AHA, “2013 ACCF/AHA Guideline for the Management of Heart Failure,” June 2013

Juvenile idiopathic arthritis:

American College of Rheumatology, “2013 Update of the 2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis” 2013

Osteoarthritis:

ACR/AF, “Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee,” February 2020

Other:

“The Use of Antiplatelet Therapy in the Outpatient Setting: Canadian Cardiovascular Society Guidelines,” 2011

Administration: IV

Administer as an IV bolus over 15 seconds.

Administration: Oral

Do not crush delayed-release or ER tablets. May administer IR formulations with food or milk to avoid gastric distress.

Cambia, Zorvolex: Administering with food may cause a reduction in effectiveness.

Bariatric surgery: Tablet, delayed and extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Do not cut, crush, or chew. Nonsteroidal anti-inflammatory drugs are generally not recommended for regular use post–bariatric surgery.

Administration: Pediatric

Oral:

Immediate release: Administer with milk or food to decrease GI upset; take with full glass of water to enhance absorption

Oral solution: Empty contents of packet into 1 to 2 ounces (30 to 60 mL) of water (do not use other liquids); mix well and administer right away. Food may reduce effectiveness.

Rectal: Suppository (products not available in US): Remove plastic film prior to insertion; insert well into the rectum; for best results, bowels should be empty prior to insertion (Voltaren Canadian product monograph 2019).

Dietary Considerations

Oral immediate-release formulations may be taken with food to decrease GI distress. However, food may reduce effectiveness of oral solution and diclofenac acid (capsule). Some products may contain phenylalanine.

Storage/Stability

Capsule, tablet: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.

Injection: Store at 20°C to 25°C (68°F to 77°F). Do not freeze. Protect from light.

Powder for oral solution: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Suppository [Canadian product]: Store at 15°C to 30°C (59°F to 86°F); protect from heat.

Preparation for Administration: Adult

Powder for oral solution: Empty contents of one packet into 30 to 60 mL of water (do not use other liquids); mix well and administer immediately.

Preparation for Administration: Pediatric

Oral solution: Empty contents of packet into 1 to 2 ounces (30 to 60 mL) of water (do not use other liquids); mix well and administer immediately.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to ease pain.

• It is used to treat some types of arthritis.

• It is used to ease painful period (menstrual) cycles.

• It is used to treat migraine headaches.

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Nausea

• Constipation

• Heartburn

• Abdominal pain

• Vomiting

• Diarrhea

• Passing gas

• Fatigue

• Common cold symptoms

• Injection site pain

• Sweating a lot

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Abdominal ulcers like severe abdominal or back pain; black, tarry, or bloody stools; vomiting blood or vomit that looks like coffee grounds; or weight gain or abnormal swelling.

• High potassium like abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, or numbness or tingling feeling.

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.

• Shortness of breath

• Severe dizziness

• Passing out

• Excessive weight gain

• Swelling of arm or leg

• Chest pain

• Fast heartbeat

• Severe headache

• Vision changes

• Severe loss of strength and energy

• Painful urination

• Blood in the urine

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Medication Safety Issues

​Sound-alike/look-alike issues:

​Geriatric Patients: High-Risk Medication:

​International issues:

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Cambia: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022165s012lbl.pdf#page=19

Cataflam: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM135935.pdf

NSAID: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206976s000lbl.pdf#page=22

Voltaren-XR: https://www.fda.gov/media/98046/download

Zipsor: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM243355.pdf

Zorvolex: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM372061.pdf

Contraindications

Hypersensitivity to diclofenac (eg, anaphylactoid reactions, serious skin reactions) or bovine protein (Zipsor only) or any component of the formulation; history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs; use in the setting of CABG surgery; patients with moderate to severe renal impairment in the perioperative period and who are at risk for volume depletion (injection only).

Canadian labeling: Additional contraindications (not in US labeling): Severe uncontrolled heart failure; active gastric/duodenal/peptic ulcer; active GI bleed or perforation, regional ulcer or enteritis, gastritis, ulcerative colitis, or recurrent ulceration; cerebrovascular bleeding or other bleeding disorders; inflammatory bowel disease; severe hepatic impairment; active hepatic disease; severe renal impairment (CrCl <30 mL/minute) or deteriorating renal disease; known hyperkalemia; patients <16 years of age (suppository, tablet) or <18 years of age (packet only); breastfeeding; pregnancy (third trimester); recent history of bleeding or inflammatory lesions of rectum/anus (suppository only)

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid reactions: Even in patients without prior exposure anaphylactoid reactions may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Contraindicated in patients who experience bronchospasm, asthma, rhinitis, or urticaria with nonsteroidal anti-inflammatory drug (NSAID) or aspirin therapy.

• Cardiovascular events: [US Boxed Warning]: NSAIDs cause an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including MI and stroke. Risk may occur early during treatment and may increase with duration of use. Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of serious cardiovascular thrombotic events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors and in those receiving higher doses. New onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to ACE inhibitors, thiazide diuretics, or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention; use with caution in patients with edema. Avoid use in heart failure (ACCF/AHA [Yancy 2013]). Avoid use in patients with recent MI unless benefits outweigh risk of cardiovascular thrombotic events. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.

• CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Discontinue use with blurred or diminished vision and perform ophthalmologic exam. Periodically evaluate vision in all patients receiving long term therapy.

• GI events: [US Boxed Warning]: NSAIDs cause an increased risk of serious gastrointestinal inflammation, ulceration, bleeding, and perforation (may be fata); elderly patients and patients with history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. These events may occur at any time during therapy and without warning. Avoid use in patients with active GI bleeding. In patients with a history of acute lower GI bleeding, avoid use of non-aspirin NSAIDs, especially if due to angioectasia or diverticulosis (Strate 2016). Use caution with a history of GI ulcers, concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), advanced hepatic disease, coagulopathy, smoking, use of alcohol, or in elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of gastrointestinal complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (Bhatt 2008).

• Hematologic effects: Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Anemia may occur; patients on long-term NSAID therapy should be monitored for anemia. Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, thrombocytopenia, aplastic anemia).

• Hepatic effects: Transaminase elevations have been reported with use; closely monitor patients with any abnormal LFT. Rare, sometimes fatal severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue immediately if clinical signs or symptoms of liver disease develop or if systemic manifestations occur.

• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in the elderly, diabetics, renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE inhibitors). Monitor potassium closely.

• Renal effects: NSAID use may compromise existing renal function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow which may cause renal decompensation (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, hepatic impairment, those taking diuretics and ACE inhibitors, and elderly patients are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Long-term NSAID use may result in renal papillary necrosis and other renal injury.

• Skin reactions: NSAIDs may cause potentially fatal serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN); may occur without warning; discontinue use at first sign of skin rash (or any other hypersensitivity).

Disease-related concerns:

• Aseptic meningitis: May increase the risk of aseptic meningitis (rarely), especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders.

• Asthma: Contraindicated in patients with aspirin-sensitive asthma; severe, potentially fatal bronchospasm may occur. Use caution in patients with other forms of asthma.

• Bariatric surgery: Gastric ulceration: Avoid chronic use of oral nonselective NSAIDs after bariatric surgery; development of anastomotic ulcerations/perforations may occur (Bhangu 2014; Mechanick 2013). Short-term use of celecoxib or IV ketorolac are recommended as part of a multimodal pain management strategy for postoperative pain (Chou 2016; Horsley 2019; Thorell 2016).

• Coronavirus disease 2019 (COVID-19): Clinical or population-based data regarding the risks of NSAIDs in the setting of COVID-19 are limited (FDA Safety Communication 2020; Kim 2020). Some experts recommend the use of acetaminophen as the preferred antipyretic agent, when possible, and if NSAIDs are needed, to use the lowest effective dose and shortest duration (EMA 2020; Kim 2020). In general, for patients already taking an NSAID for a comorbid condition, it is recommended to continue the NSAID as directed by their health care provider (EMA 2020; NIH 2020; WHO 2020).

• Coronary artery bypass graft surgery: [US Boxed Warning]: Use is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Risk of MI and stroke may be increased with use following CABG surgery.

• Hepatic impairment: Use with caution in patients with hepatic impairment; reduced doses may be required due to extensive hepatic metabolism. Patients with advanced hepatic disease are at an increased risk of GI bleeding with NSAIDs.

• Renal impairment: Avoid use in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function; monitor closely if therapy must be initiated. Injection is not recommended in patients with moderate to severe renal impairment and is contraindicated in patients with moderate to severe renal impairment in the perioperative period and who are at risk for volume depletion.

Special populations:

• Elderly: Elderly patients are at greater risk for serious GI, cardiovascular, and/or renal adverse events.

Dosage form specific issues:

• Injection: Not indicated for long-term use.

• Oral solution: May contain phenylalanine.

• Zipsor: Contains gelatin; use is contraindicated in patients with history of hypersensitivity to bovine protein.

Other warnings/precautions:

• Appropriate use: Oral solution: Indicated only for the acute treatment of migraine (not indicated for migraine prophylaxis or cluster headache). Acute migraine agents (eg, NSAIDs, triptans, opioids, ergotamine, or a combination of the agents) used for 10 or more days per month may lead to worsening of headaches (medication overuse headache); withdrawal treatment may be necessary in the setting of overuse.

• Bioequivalence: Different formulations of oral diclofenac are not bioequivalent, even if the milligram strength is the same; do not interchange products.

• Surgical/dental procedures: Withhold for at least 4 to 6 half-lives prior to surgical or dental procedures.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Elderly patients are at high-risk for adverse effects from NSAIDs. Up to 60% of elderly patients can develop an asymptomatic peptic ulcer and/or hemorrhage. Using the lowest effective dose for the shortest period possible is recommended. Use of NSAIDs can compromise existing renal function especially when CrCl is <30 mL/minute. CNS adverse effects such as confusion, agitation, and hallucination may occur even with lower doses in elderly patients.

Reproductive Considerations

The chronic use of NSAIDs, including diclofenac, in women of reproductive age may be associated with infertility that is reversible upon discontinuation of the medication. Consider discontinuing use in women having difficulty conceiving or those undergoing investigation of fertility.

Pregnancy Considerations

Diclofenac crosses the placenta. Birth defects have been observed following in utero NSAID exposure in some studies; however, data is conflicting (Bloor 2013). Nonteratogenic effects, including prenatal constriction of the ductus arteriosus, persistent pulmonary hypertension of the newborn, oligohydramnios, necrotizing enterocolitis, renal dysfunction or failure, and intracranial hemorrhage have been observed in the fetus/neonate following in utero NSAID exposure. In addition, nonclosure of the ductus arteriosus postnatally may occur and be resistant to medical management (Bermas 2014; Bloor 2013). Because they may cause premature closure of the ductus arteriosus, product labeling for diclofenac specifically states use should be avoided starting at 30 weeks' gestation.

Use of NSAIDs can be considered for the treatment of mild rheumatoid arthritis flares in pregnant women; however, use should be minimized or avoided early and late in pregnancy (Bermas 2014; Saavedra Salinas 2015). If treatment of migraine is needed in pregnant women, agents other than diclofenac are preferred (Amundsen 2015).

Breast-Feeding Considerations

Diclofenac may be present in breast milk.

The milk concentration of a woman treated with oral diclofenac 150 mg/day was reported to be 100 mcg/L (equivalent to an infant dose of ~0.03 mg/kg/day). Diclofenac was not detected in breast milk when 100 mg/day orally was administered to 12 women for 7 days or as a single dose of 50 mg IM immediately postpartum.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. In general, NSAIDs may be used in postpartum women who wish to breastfeed; however, agents other than diclofenac may be preferred (ABM [Reece-Stremtan 2017]; Amundsen 2015) and use should be avoided in women breastfeeding infants with platelet dysfunction, thrombocytopenia (Bloor 2013; Sammaritano 2014), or ductal-dependent cardiac lesions (ABM [Reece-Stremtan 2017]).

Lexicomp Pregnancy & Lactation, In-Depth

• Diclofenac (Systemic)

Briggs' Drugs in Pregnancy & Lactation

• Diclofenac

Adverse Reactions

Injection: Frequency not always defined.

Cardiovascular: Edema (≤10%), cerebrovascular accident, hypertension, myocardial infarction, significant cardiovascular event

Central nervous system: Headache (≤10%), dizziness (8%)

Dermatologic: Pruritus (≤10%), skin rash (≤10%), exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis

Endocrine & metabolic: Fluid retention

Gastrointestinal: Constipation (13%), abdominal pain (≤10%), diarrhea (≤10%), dyspepsia (≤10%), esophageal perforation (≤10%), flatulence (≤10%), gastrointestinal ulcer (≤10%; including gastric/duodenal), heartburn (≤10%), intestinal perforation (≤10%), nausea (≤10%), vomiting (≤10%)

Hematologic & oncologic: Anemia (≤10%), hemorrhage (≤10%), prolonged bleeding time (≤10%)

Hepatic: Increased liver enzymes (≤10%), increased serum transaminases (15%), increased serum ALT (≤4%; >8X ULN: ≤1%), increased serum AST (2% to ≤4%; >8X ULN: ≤1%)

Hypersensitivity: Anaphylactoid reaction

Local: Infusion site reaction (10%), extravasation (3%)

Otic: Tinnitus (≤10%)

Renal: Renal insufficiency (≤10%)

Miscellaneous: Wound healing impairment (8%), gastrointestinal inflammation

<1%, postmarketing, and/or case reports : Abnormal Dreams, agranulocytosis, alopecia, anaphylaxis, angioedema, anxiety, aplastic anemia, asthma, auditory impairment, blurred vision, cardiac arrhythmia, cardiac failure, change in appetite, colitis, coma, confusion, conjunctivitis, convulsions, cystitis, depression, diaphoresis, drowsiness, dyspnea, dysuria, ecchymoses, eosinophilia, eructation, erythema multiforme, esophagitis, exfoliative dermatitis, fever, fulminant hepatitis, gastritis, gastrointestinal hemorrhage, glossitis, hallucination, hematemesis, hematuria, hemolytic anemia, hepatic failure, hepatic necrosis, hepatitis, hepatotoxicity, hyperglycemia, hypertension, hypotension, infection, insomnia, interstitial nephritis, jaundice, leukopenia, lymphadenopathy, malaise, melena, meningitis, nervousness, oliguria, palpitations, pancreatitis, pancytopenia, paresthesia, pneumonia, polyuria, proteinuria, purpura, rectal hemorrhage, renal failure, respiratory depression, sepsis, skin photosensitivity, stomatitis, syncope, tachycardia, thrombocytopenia, toxic epidermal necrolysis, tremor, urticaria, vasculitis, vertigo, weakness, weight changes

Oral: Frequency not always defined.

>10%:

Cardiovascular: Edema (33%)

Hepatic: Increased serum transaminases (≤3 x ULN; 15%)

1% to 10%:

Cardiovascular: Hypertension (2% to 3%)

Central nervous system: Headache (4% to 8%), procedural pain (3%), dizziness (2%), falling (2%)

Dermatologic: Pruritus (7%), skin rash

Gastrointestinal: Constipation (5% to 8%), nausea (6% to 7%), diarrhea (6%), GI adverse effects (gastric ulcer, hemorrhage, and perforation; ≤4%, risk increases with therapy duration), abdominal pain (2% to 3%), vomiting (3%), dyspepsia (2% to 3%), flatulence (2% to 3%), heartburn, abdominal discomfort (2%), duodenal ulcer

Genitourinary: Urinary tract infection (7%)

Hematologic & oncologic: Bruise (3%), anemia, prolonged bleeding time

Hepatic: Increased serum ALT (>3 x ULN: ≤4%; >8 x ULN: ≤1%), increased serum AST (>3 x ULN; ≤4%; >8 x ULN: ≤1%)

Infection: Influenza (3%)

Neuromuscular & skeletal: Osteoarthritis (5%), arthralgia (3%), back pain (3%), limb pain (3%)

Renal: Renal function abnormality

Otic: Tinnitus

Renal: Increased serum creatinine (2%), renal function abnormality

Respiratory: Upper respiratory tract infection (8%), nasopharyngitis (6%), sinusitis (3% to 5%), cough (4%), bronchitis (3%)

<1%, postmarketing, and/or case reports: Abnormal dreams, agranulocytosis, alopecia, anaphylactoid reaction, anaphylaxis, angioedema, anxiety, aplastic anemia, aseptic meningitis, asthma, auditory impairment, azotemia (Gurwitz, 1990), blurred vision, cardiac arrhythmia, cardiac failure, cerebrovascular accident, change in appetite, chest pain, colitis, coma, confusion, conjunctivitis, cystitis, decreased hemoglobin (Goldstein, 2011), depression, diaphoresis, diplopia, disorientation, drowsiness, dyspnea, dysuria, ecchymoses, eosinophilia, eructation, erythema multiforme, esophageal ulcer, esophagitis, exfoliative dermatitis, fever, fluid retention, fulminant hepatitis, gastritis, glossitis, hallucination, hearing loss, hematemesis, hematuria, hemolytic anemia, hepatic failure, hepatic necrosis, hepatitis, hepatotoxicity, hyperglycemia, hypotension, infection, insomnia, interstitial nephritis, intestinal perforation, jaundice, leukopenia, lymphadenopathy, malaise, melena, memory impairment, meningitis, myocardial infarction, nephrotic syndrome, nervousness, oliguria, palpitations, pancreatitis, pancytopenia, paresthesia, peptic ulcer, pneumonia, polyuria, proteinuria, psychotic reaction, purpura, rectal hemorrhage, renal failure, renal papillary necrosis, respiratory depression, seizure, sepsis, skin photosensitivity, Stevens-Johnson syndrome, stomatitis, syncope, tachycardia, taste disorder, thrombocytopenia, toxic epidermal necrolysis, tremor, urticaria, vasculitis, vertigo, weakness, weight changes, xerostomia

Rectal suppository [Canadian product]:

Also refer to adverse reactions associated with oral formulations.

<1%, postmarketing, and/or case reports: Hemorrhoids (exacerbation), local hemorrhage, proctitis, rectal irritation

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Nonsteroidal Anti-inflammatory Drug (NSAID) Allergy

Toxicology

• Nonsteroidal Anti-inflammatory Drugs

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2B6 (minor), CYP2C19 (minor), CYP2C8 (minor), CYP2C9 (major), CYP2D6 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits UGT1A6

Drug Interactions Open Interactions

5-Aminosalicylic Acid Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of 5-Aminosalicylic Acid Derivatives. Risk C: Monitor therapy

Acalabrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Acemetacin: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Risk C: Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of GI bleeding may be increased with this combination. Risk C: Monitor therapy

Aliskiren: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Aliskiren. Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Aliskiren. Risk C: Monitor therapy

Aminoglycosides: Nonsteroidal Anti-Inflammatory Agents may decrease the excretion of Aminoglycosides. Data only in premature infants. Risk C: Monitor therapy

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy

Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Risk C: Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Exceptions: Bemiparin; Enoxaparin; Heparin. Risk C: Monitor therapy

Apixaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Apixaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of apixaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Artesunate: Diclofenac (Systemic) may increase serum concentrations of the active metabolite(s) of Artesunate. Risk C: Monitor therapy

Bemiparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin and nonsteroidal anti-inflammatory agents (NSAIDs) due to the increased risk of bleeding. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Bemiparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Beta-Blockers: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy

Bisphosphonate Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Risk C: Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy

Corticosteroids (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor therapy

CycloSPORINE (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (eg, hypertension) during concomitant therapy with NSAIDs. Risk D: Consider therapy modification

CYP2C9 Inducers (Moderate): May decrease the serum concentration of Diclofenac (Systemic). Risk C: Monitor therapy

CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Diclofenac (Systemic). Risk C: Monitor therapy

Dabigatran Etexilate: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of dabigatran and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk C: Monitor therapy

Deferasirox: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy

Deferiprone: UGT1A6 Inhibitors may increase the serum concentration of Deferiprone. Risk X: Avoid combination

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy

Desmopressin: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Digoxin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Digoxin. Risk C: Monitor therapy

Drospirenone: Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Drospirenone. Risk C: Monitor therapy

Edoxaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of edoxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Enoxaparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue nonsteroidal anti-inflammatory agents (NSAIDs) prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Enoxaparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Eplerenone: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Eplerenone. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Eplerenone. Risk C: Monitor therapy

Fat Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Heparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or nonsteroidal anti-inflammatory agents (NSAIDs) if coadministration is required. Risk D: Consider therapy modification

Heparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required. Risk D: Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Management: Avoid combination when possible. If used, monitor more closely for evidence of bleeding. Discontinue herbal products with anticoagulant or antiplatelet actions 2 weeks prior to surgical, dental, or invasive procedures. Risk D: Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Management: Concomitant treatment with these agents should generally be avoided. If used concomitantly, increased diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds) must be employed. Risk D: Consider therapy modification

HydrALAZINE: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of HydrALAZINE. Risk C: Monitor therapy

Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Icosapent Ethyl: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Ketorolac (Nasal): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Lithium: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Lithium. Management: Consider reducing the lithium dose when initiating a NSAID. Monitor for increased lithium therapeutic/toxic effects if a NSAID is initiated/dose increased, or decreased effects if a NSAID is discontinued/dose decreased. Risk D: Consider therapy modification

Loop Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the diuretic effect of Loop Diuretics. Loop Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Monitor for evidence of kidney injury or decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding concurrent use in CHF or cirrhosis. Concomitant use of bumetanide with indomethacin is not recommended. Risk D: Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy

Macimorelin: Nonsteroidal Anti-Inflammatory Agents may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination

MetFORMIN: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of MetFORMIN. Risk C: Monitor therapy

Methotrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Methotrexate. Management: Alternative anti-inflammatory therapy should be considered whenever possible, especially if the patient is receiving higher, antineoplastic doses of methotrexate. Risk D: Consider therapy modification

Mifamurtide: Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Mifamurtide. Risk X: Avoid combination

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Naftazone: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy

Nalmefene: Diclofenac (Systemic) may increase the serum concentration of Nalmefene. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of other Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk for gastrointestinal toxicity is increased. Risk X: Avoid combination

Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of gastrointestinal (GI) toxicity is increased. Management: Coadministration of systemic nonsteroidal anti-inflammatory drugs (NSAIDs) and topical NSAIDs is not recommended. If systemic NSAIDs and topical NSAIDs, ensure the benefits outweigh the risks and monitor for increased NSAID toxicities. Risk D: Consider therapy modification

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy

Omacetaxine: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Risk C: Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Phenylbutazone: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy

Potassium-Sparing Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Potassium-Sparing Diuretics. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy

PRALAtrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of PRALAtrexate. More specifically, NSAIDS may decrease the renal excretion of pralatrexate. Management: Avoid coadministration of pralatrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). If coadministration cannot be avoided, closely monitor for increased pralatrexate serum levels or toxicity. Risk D: Consider therapy modification

Probenecid: May increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Prostaglandins (Ophthalmic): Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic). Risk C: Monitor therapy

Quinolones: Nonsteroidal Anti-Inflammatory Agents may enhance the neuroexcitatory and/or seizure-potentiating effect of Quinolones. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Quinolones. Risk C: Monitor therapy

Resveratrol: May increase the serum concentration of Diclofenac (Systemic). Risk C: Monitor therapy

Rivaroxaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of rivaroxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Salicylates: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Management: Nonselective NSAIDs may reduce aspirin's cardioprotective effects. Administer ibuprofen 30-120 minutes after immediate-release aspirin, 2 to 4 hours after extended-release aspirin, or 8 hours before aspirin. Exceptions: Choline Magnesium Trisalicylate. Risk D: Consider therapy modification

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider alternatives to NSAIDs. Monitor for evidence of bleeding and diminished antidepressant effects. It is unclear whether COX-2-selective NSAIDs reduce risk. Risk D: Consider therapy modification

Selumetinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification

Sodium Phosphates: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with NSAIDs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification

Tacrolimus (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tacrolimus (Systemic). Risk C: Monitor therapy

Tenofovir Products: Diclofenac (Systemic) may enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to this combination whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Risk D: Consider therapy modification

Tenoxicam: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid combination

Thiazide and Thiazide-Like Diuretics: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Tolperisone: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Tolperisone. Specifically, the risk of hypersensitivity reactions may be increased. Tolperisone may enhance the therapeutic effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy

Tricyclic Antidepressants (Tertiary Amine): May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Risk X: Avoid combination

Vancomycin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Vancomycin. Risk C: Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising. Risk D: Consider therapy modification

Voriconazole: May increase the serum concentration of Diclofenac (Systemic). Risk C: Monitor therapy

Zanubrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Test Interactions

May lead to false-positive aldosterone/renin ratio (ARR) (Funder 2016).

Genes of Interest

• CYP2C8 - Diclofenac
• CYP2C9 - Diclofenac
• Leukotriene C4 Synthase

Monitoring Parameters

Monitor CBC, chemistry profile, weight gain, edema, liver function tests (baseline and periodically during chronic therapy), renal function (serum BUN, serum creatinine, urine output); occult blood loss; blood pressure; observe for bleeding, bruising; GI effects (abdominal pain, bleeding, dyspepsia); mental confusion, disorientation

Advanced Practitioners Physical Assessment/Monitoring

Evaluate cardiac risk and potential for GI bleeding prior to prescribing this medication. Monitor blood pressure at the beginning of therapy and periodically during use. Schedule ophthalmic evaluations for patients who develop eye complaints during long-term NSAID therapy.

Nursing Physical Assessment/Monitoring

Monitor blood pressure at the beginning of therapy and periodically during use. Schedule ophthalmic evaluations for patients who develop eye complaints during long-term NSAID therapy.

Product Availability

Dyloject (diclofenac injection) has been discontinued in the US for more than 1 year.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, as base:

Zorvolex: 18 mg, 35 mg [contains brilliant blue fcf (fd&c blue #1), fd&c blue #2 (indigotine)]

Generic: 35 mg

Capsule, Oral, as potassium:

Zipsor: 25 mg [contains gelatin (bovine)]

Packet, Oral, as potassium:

Cambia: 50 mg (1 ea, 9 ea) [anise-mint flavor]

Cambia: 50 mg (1 ea [DSC], 9 ea [DSC]) [contains aspartame, saccharin sodium]

Solution, Intravenous, as sodium:

Dyloject: 37.5 mg/mL (1 mL [DSC])

Tablet, Oral, as potassium:

Generic: 50 mg

Tablet Delayed Release, Oral, as sodium:

Generic: 25 mg, 50 mg, 75 mg

Tablet Extended Release 24 Hour, Oral, as sodium:

Generic: 100 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Packet, Oral, as potassium:

Cambia: 50 mg (1 ea, 3 ea, 9 ea) [contains aspartame, saccharin sodium]

Suppository, Rectal:

Voltaren: 50 mg (30 ea); 100 mg (30 ea)

Generic: 50 mg (30 ea); 100 mg (30 ea)

Tablet, Oral, as potassium:

Voltaren Rapide: 50 mg

Generic: 50 mg

Tablet Delayed Release, Oral, as sodium:

Voltaren: 50 mg [contains corn starch]

Generic: 25 mg, 50 mg

Tablet Extended Release 24 Hour, Oral:

Voltaren SR: 75 mg [contains polysorbate 80]

Generic: 75 mg

Tablet Extended Release 24 Hour, Oral, as sodium:

Voltaren SR: 100 mg

Generic: 100 mg

Anatomic Therapeutic Chemical (ATC) Classification

• M01AB05

Generic Available (US)

May be product dependent

Pricing: US

Capsules (Diclofenac Oral)

35 mg (per each): $8.93

Capsules (Zipsor Oral)

25 mg (per each): $9.36

Capsules (Zorvolex Oral)

18 mg (per each): $9.52

35 mg (per each): $9.52

Pack (Cambia Oral)

50 mg (per each): $99.73

Tablet, 24-hour (Diclofenac Sodium ER Oral)

100 mg (per each): $2.70 - $2.81

Tablet, EC (Diclofenac Sodium Oral)

25 mg (per each): $1.42

50 mg (per each): $0.95 - $1.47

75 mg (per each): $1.12 - $11.50

Tablets (Diclofenac Potassium Oral)

50 mg (per each): $2.76

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties

Other proposed mechanisms not fully elucidated (and possibly contributing to the anti-inflammatory effect to varying degrees), include inhibiting chemotaxis, altering lymphocyte activity, inhibiting neutrophil aggregation/activation, and decreasing proinflammatory cytokine levels.

Pharmacodynamics/Kinetics

Absorption: Oral: ~50% (systemically available)

Distribution: Oral: ~1.3 to 1.4 L/kg

Protein binding: >99%, primarily to albumin

Metabolism: Hepatic; undergoes first-pass metabolism; forms several metabolites (1 with weak activity)

Bioavailability: 55%

Half-life elimination: Oral: ~2 hours; ~1 hour (liquid filled capsule [Zipsor]); Injection: ~1.4 hours

Time to peak, serum: Note: Fasted values reported for oral products; may be delayed with food

Cambia: ~0.25 hours

Cataflam, Zorvolex: ~1 hour

Zipsor: ~0.47 ± 0.17 hour

Injection: ~5 minutes

Tablet, delayed release (diclofenac sodium): 2.3 hours

Tablet, extended release (diclofenac sodium): 5.3 hours

Excretion: Urine (~65%); bile (~35%)

Pharmacodynamics/Kinetics: Additional Considerations

Body weight: Injection: Increased volume of distribution and clearance with increased body weight (>95 kg).

Dental Use

Immediate-release tablets: Acute treatment of mild-to-moderate pain

* See Uses in AHFS Essentials for additional information.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

The dentist should be aware of the potential of abnormal coagulation. Caution should also be exercised in the use of NSAIDs in patients already on anticoagulant therapy with drugs such as warfarin (Coumadin®). See Effects on Bleeding.

Effects on Bleeding

Nonselective NSAIDs such as diclofenac (systemic) inhibit platelet aggregation and prolong bleeding time in some patients. Unlike aspirin, the NSAID effect on platelet function is quantitatively less, of shorter duration, and reversible. Normal platelet function should occur in ~5 elimination half-lives or in <10 hours after discontinuation of diclofenac (systemic). Concomitant use of other NSAIDs should be avoided.

Dental Usual Dosing

Pain: Adults: Oral: Starting dose: 50 mg 3 times/day; maximum dose: 150 mg/day

Related Information

• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Nonsteroidal Anti-inflammatory Drugs
• Oral Medications That Should Not Be Crushed or Altered
• Relative Infant Dose

Index Terms

Cataflam; Diclofenac Potassium; Diclofenac Sodium; Voltaren; Zorvolex

FDA Approval Date

July 28, 1988

References

2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi: 10.1111/jgs.15767[PubMed 30693946]

Amundsen S, Nordeng H, Nezvalová-Henriksen K, Stovner LJ, Spigset O. Pharmacological treatment of migraine during pregnancy and breastfeeding. Nat Rev Neurol. 2015;11(4):209-219.[PubMed 25776823]

Arnold MM, McKenna F. A Double Blind Comparison of the Endoscopic and Clinical Effects of Tenoxicam and Diclofenac in Rheumatoid Arthritis. Br J Rheumatol. 1995;34(suppl 1):95.[PubMed 7704474]

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Brand Names: International

Abitren (IL); Actifen CR (PH); Adiflam (ET); Allvoran (DE); Almiral (AE, BF, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, SA, SC, SD, SL, SN, SY, TN, TW, TZ, UG, YE, ZM, ZW); Anterin (TW); Anuva (ID); Arcanafenac (ZA); Artimed (ET); Artrites (CO); Berifen (CR, DO, GT, HN, NI, PA, SV); Betaren (IL); Bi Su Fu (CN); Bioran (ZW); Catafast (SA); Catafen (PH); Cataflam (AE, BE, BH, CL, CY, EC, EE, EG, ET, HK, ID, IL, IQ, IR, JO, KW, LB, LK, LT, LU, LV, LY, MT, NL, NO, OM, PE, PT, QA, SA, SY, TR, TW, UY, VE, VN, YE, ZW); Cataflam D (ID); Cataflam Drops (MY); Catanac (TH); Catas (KR); Cencenac (TH); Clofec (TH); Clofen (AE, JO, KW, LB, QA, SA); Clofen Retard (AE, KW); Clofenex-50 (HK); Clonac (AU); Cordralan (PE); Curafen (PH); D-Fiam (TH); Declophen (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, SA, SY, YE); Depain (KR); Diclac (CN, IE); Diclax SR (NZ); Dicloas (ET); Diclobene (AT); Diclofen (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, SA, SY, TW, YE); Diclofen Cremogel (BH); Diclofenac (CO); Dicloflam (ZA); Diclomax (IN, ZW); Diclon (DK, MY); Dicloran (MY); Diclosan SR (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, SA, SY, YE); Diclosian (TH); Diclowal (CR, DO, GT, HN, NI, PA, SV); Dicofen (PH); Difelene (VN); Difena (TW); Difene (IE); Diflosid (PH); Dioxaflex (DO, GT, HN, NI, PA, SV); Dioxaflox (CR); Disflam (EC); Divoltar (ID); Divon CR (LK); Doflex (IN); Dolotren (CR, DO, ES, GT, HN, NI, PA, SV); Dolpasse (AT); Dosanac (SG); E (GR); Ecofenac (CH); Epifenac (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, SA, SY, YE); Eurofenac (HK); Fenac (AU); Flamquit (TW); Flector (FR, LB); Flexagen (ZA); Flexy (TH); Flogozan (CR, DO, GT, HN, NI, PA, SV); Fortfen SR (ZA); Globanac 50 (PH); Inac (SG); Inflamac (CH); Inflanac (HK, LK, MY, TH); Joflam (QA); Kadiflam (ID); Lesflam (SG); Maxit (LK); Merflam (ID); Mioclof (PH); Mobifen (BD); Monoflam (CZ, DE); Neodolpasse (AT); Nepenthe (PH); Novarin (BD); Ofenac (KR); Olfen (AE, BB, BM, BS, BZ, GY, HK, JM, JO, LB, MY, PR, QA, SR, TT); Olfen-75 SR (MY); Osteoflam (IN); Panamor (ZA, ZW); Potaflam (ID); Profenac (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, SA, SY, YE); Raost (ID); Remafen (MY); Remethan (DE, ET, HK, MY, SG, ZW); Ren (HK); Rewodina (DE, MY, RU); Rhemofenax (MY); Soproxen (TH); Swiss Relief Dual Release (IL); Taks (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, SA, SY, YE); Troflam (ID); Tromax (ET); Ultrafen (SG); Vartelon (HK); Vesconac (TH); Vivian (ZW); Volcan (BD); Voldic (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, SA, SY, YE); Voldick-K (ET); Volna-K (TW); Volta (TH); Voltaflam (PK); Voltaflex (BR); Voltaren (AE, AR, AT, BB, BE, BF, BG, BH, BJ, BR, CH, CI, CL, CO, CY, CZ, DE, DK, EE, EG, ET, FI, GH, GM, GN, HK, HR, HU, ID, IL, IQ, IR, IS, IT, JO, KE, KW, LB, LR, LT, LU, LV, LY, MA, ML, MR, MU, MW, MY, NE, NG, NL, NO, NZ, OM, PH, PL, PT, PY, QA, RO, RU, SA, SC, SD, SE, SI, SK, SL, SN, SY, TH, TN, TR, TW, TZ, UA, UG, UY, VE, VN, YE, ZA, ZM, ZW); Voltaren Acti-Go (IL); Voltaren Dolo (FR); Voltaren Rapid (AU, NZ, UA); Voltaren SR (BH, CY, EG, HK, LB, MT, NZ, PH, SA); Voltarene (FR, GR); Voltarol (IE); Voltfast (ET, SG, TH); Voltine (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, SA, SY, YE); Volton-CR (HK); Voren (PH, TW); Votalin (CN); Votan (PH); Votan SR (PH); Votrex (AE); Voveran (IN); Vurdon (AE, BF, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, SA, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZM, ZW); Yingtaiqing (CN); Yuren (TW); Zobid (MY); Zobid D (LK); Zolterol (MY); Zolterol SR (LK, SG); Zorvolex (ID)

Last Updated 10/14/20