diclofenac (Rx)

Brand and Other Names:Cataflam, Voltaren-XR, more...Dyloject, Cambia, Zipsor, Zorvolex
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

diclofenac potassium

packet

  • 50mg/single-dose packet (generic, Cambia)
  • Delivers 50-mg dose when mixed in water

tablet

  • 50mg (generic)

capsule

  • 25mg (Zipsor)

diclofenac sodium

tablet, delayed release

  • 25mg (generic)
  • 50mg (generic)
  • 75mg (generic)

tablet, extended-release

  • 100mg (generic)

capsule

  • 18mg (Zorvolex)
  • 35mg (Zorvolex)

Rheumatoid Arthritis

Diclofenac potassium: 50 mg PO q8-12hr

Diclofenac sodium: 50 mg PO q8hr or 75 mg PO q12hr

Extended release: 100 mg PO once daily; may be increased to 100 mg PO q12hr

Osteoarthritis

Diclofenac potassium: 50 mg PO q8-12hr

Diclofenac sodium: 50 mg PO q8hr or 75 mg PO q12hr

Extended release: 100 mg PO once daily; may be increased to 100 mg PO q12hr

Zorvolex: 35 mg PO TID

Ankylosing Spondylitis

Diclofenac sodium: 25 mg PO 4 or 5 times daily

Diclofenac potassium: 50 mg PO q12hr

Dysmenorrhea

Immediate-release: 100 mg PO once, then 50 mg PO q8hr PRN

Acute Pain

Indicated for treatment of mild to moderate acute pain in adults

Immediate-release tablets: 100 mg PO once, then 50 mg PO q8hr PRN

Extended-release tablets

  • Zipsor: 25 mg PO QID PRN
  • Zorvolex: 18 mg or 35 mg PO TID

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goal

Acute Migraine

Indicated for acute treatment of migraine attacks with or without aura

Cambia: 50 mg (1 packet) in 30-60 mL of water, mixed well and drunk immediately

Not for prophylaxis

Use lowest effective dose for shortest duration consistent with individual patient treatment goals

Dosage Modifications

Renal impairment

  • Patients with renal impairment had AUC values and elimination rates that were comparable to healthy patients

Hepatic impairment

  • Hepatic metabolism accounts for almost 100% of diclofenac elimination
  • There is insufficient information available to support dosing recommendations
  • Start with the lowest dose; if efficacy is not achieved, consider using an alternant

Dosing Considerations

Limitations of use

  • Not indicated for the prophylactic therapy of migraine
  • Safety and effectiveness not established for cluster headache, which is present in an older, predominantly male population

Dosage Forms & Strengths

diclofenac potassium

capsule

  • 25mg (Zipsor)

Acute Pain

Zipsor only

Indicated for relief of mild-to-moderate pain in adult and pediatric patients aged ≥12 years

<12 years: Safety and efficacy not established

≥12 years: 25 mg PO QID PRN

Dosage Modifications

Renal impairment

  • Patients with renal impairment had AUC values and elimination rates that were comparable to healthy patients

Hepatic impairment

  • Hepatic metabolism accounts for almost 100% of diclofenac elimination
  • There is insufficient information available to support dosing recommendations
  • Start with the lowest dose; if efficacy is not achieved, consider using an alternant

Dosing Considerations

Limitations of use

  • Not indicated for the prophylactic therapy of migraine
  • Safety and effectiveness not established for cluster headache, which is present in an older, predominantly male population

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Interactions

Interaction Checker

and diclofenac

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            Adverse Effects

            >10%

            Zorvolex

            • Edema (33%)
            • Nausea (27%)
            • Headache (13%)

            Zipsor

            • Nausea (16.5%)
            • Headache (12.5%)

            1-10%

            Cambia

            • Nausea (3%)
            • Dizziness (1%)

            Diclofenac potassium tablets

            • Abdominal pain
            • Constipation
            • Diarrhea
            • Dyspepsia
            • Flatulence
            • Gross bleeding/perforation
            • Heartburn
            • Nausea
            • GI ulcers (gastric/duodenal)
            • Vomiting
            • Abnormal renal function
            • Anemia
            • Dizziness
            • Edema
            • Elevated liver enzymes
            • Headaches
            • Increased bleeding time
            • Pruritus
            • Rashes
            • Tinnitus

            Zorvolex

            • Dizziness (10%)
            • Vomiting (9%)
            • Constipation (8%)
            • Pruritus (7%)
            • Flatulence (3%)
            • Pain in extremity (3%)
            • Dyspepsia (2%)

            Zipsor

            • Abdominal pain (7%)
            • Vomiting (5.8%)
            • Dizziness (3.5%)
            • Constipation (3.2%)
            • Somnolence (2.6%)
            • Diarrhea (2.3%)
            • Pruritus (1.4%)
            • Dyspepsia (1.2%)
            • Sweating increased (1.2%)

            <1%

            Cambia

            • Urticaria (0.2%)
            • Flushing (0.2%)

            Postmarketing Reports

            Body as a whole: Fever, infection, sepsis, anaphylactic reactions, appetite changes, death

            Cardiovascular system: Congestive heart failure (CHF), hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis

            Digestive system: Dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice, colitis, eructation, liver failure, pancreatitis

            Hemic and lymphatic system: Ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia, agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia

            Metabolic and nutritional: Weight changes, hyperglycemia

            Nervous system: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo, convulsions, coma, hallucinations, meningitis

            Respiratory system: Asthma, dyspnea, respiratory depression, pneumonia

            Skin and appendages: Alopecia, photosensitivity, sweating increased, angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Steven Johnson syndrome, urticaria

            Special senses: Blurred vision, conjunctivitis, hearing impairment

            Urogenital system: Cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure

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            Warnings

            Black Box Warnings

            Cardiovascular risk

            • Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal
            • Risk may increase with duration of use
            • Patients with existing cardiovascular disease or risk factors for such disease may be at greater risk
            • Use of COX-2 selective NSAID for pain treatment in the first 10­14 days following CABG surgery increased incidence of MI and stroke; use of NSAIDS is contraindicated for perioperative pain in setting of coronary artery bypass graft (CABG) surgery

            Gastrointestinal risk

            • NSAIDs can increase risk of serious GI adverse events, including bleeding, ulceration, and gastric or intestinal perforation, which can be fatal
            • May occur at any time during use and without warning symptoms
            • Patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events

            Contraindications

            Hypersensitivity (eg, anaphylaxis, serious skin reactions) to diclofenac or any components of the product

            History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs

            In the setting of coronary artery bypass graft (CABG) surgery

            Zipsor capsules are contraindicated in patients with history of hypersensitivity to bovine protein

            Cautions

            Use caution in patients with bronchospasm, cardiac disease, CHF, hepatic porphyria, hypertension, fluid retention, severe renal impairment, smoking, systemic lupus erythematosus

            Platelet aggregation and adhesion may be decreased; may prolong bleeding time

            Use caution in blood dyscrasias or bone marrow depression; also with thrombocytopenia, agranulocytosis, and aplastic anemia

            Long-term administration of NSAIDs may result in renal papillary necrosis and other renal injury; patients at greatest risk include elderly individuals, those with impaired renal function, hypovolemia, heart failure, liver dysfunction, or salt depletion, and those taking diuretics, angiotensin-converting enzyme inhibitors, or angiotensin-receptor blockers

            Increase risk of hyperkalemia may occur, especially in renal disease, diabetics, the elderly, and concomitant use of agents that may induce hyperkalemia; monitor potassium closely

            May cause dizziness blurred vision and neurologic effects that may impair physical and mental abilities

            Risk of serious skin reactions, including Stevens Johnson syndrome and necrotizing enterocolitis

            Persistent urinary symptoms, including bladder pain and dysuria, hematuria or cystitis may occur after initiating therapy; discontinue therapy with symptom onset and evaluate cause

            May increase risk of aseptic meningitis (rare), especially in patients with systemic lupus erythrmatosus, and mixed connective tissue disorders

            Use caution if patient dehydrated before initiating therapy; rehydrate patient before initiating therapy and monitor renal function closely

            Avoid use of NSAIDs in pregnant women at about ≥30 weeks gestation

            Use of NSAIDs at about ≥20 weeks gestation in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment

            Overuse of acute migraine drugs (eg, ergotamine, triptans, opioids, nonsteroidal anti-inflammatory drugs or combination of these drugs for ≥10 days per month) may lead to exacerbation of headache (medication overuse headache); may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks; detoxification of patients, including withdrawal of overused drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary

            Different formulations not bioequivalent even if milligram strength the same; do not interchange products

            Withhold for at least 4-6 half-lives prior to surgical or dental procedures

            Drug reaction with eosinophilia and systemic symptoms (DRESS)

            • Drug reaction reported; some of these events have been fatal or life-threatening; DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling
            • Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis; sometimes symptoms of DRESS may resemble an acute viral infection
            • Eosinophilia is often present; disorder varies in presentation, other organ systems not noted here may be involved
            • Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident; if such signs or symptoms are present, discontinue therapy and evaluate the patient immediately
            • Heart failure risk H4
            • NSAIDS have the potential to trigger HF by prostaglandin inhibition that leads to sodium and water retention, increased systemic vascular resistance, and blunted response to diuretics
            • NSAIDS should be avoided or withdrawn whenever possible

            Gastrointestinal bleeding, ulceration, perforation

            • Risk factors for GI bleeding, ulceration, and perforation
              • Prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs Other
              • Patients treated with NSAIDs include longer duration of NSAID therapy
              • Coadministration of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRI)
              • Smoking
              • Alcohol use
              • Older age
              • Poor general health status
              • Elderly or debilitated patients
              • Patients with advanced liver disease and/or coagulopathy
            • Strategies to minimize the GI risk in NSAID-treated patients
              • Use the lowest effective dosage for the shortest possible duration
              • Avoid using more than 1 NSAID at a time
              • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding
              • Consider alternants for high-risk patients, as well as those with active GI bleeding
              • Monitor for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
              • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue therapy until a serious GI adverse event is ruled out
              • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, closely monitor for evidence of GI bleeding

            Hepatoxicity

            • Increase in transaminase levels reported within 2 months of therapy; may occur at any time
            • Monitor transaminase levels periodically beginning 4-8 weeks after initiation of therapy
            • Exercise caution when used with drugs that are known to be potentially hepatotoxic (eg, acetaminophen, certain antibiotics, antiepileptics)
            • Caution patients to avoid taking nonprescription acetaminophen-containing products while using diclofenac

            Hypertension

            • NSAIDs can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events.
            • Use with caution in patients with hypertension
            • Closely monitor blood pressure during initiation and during therapy
            • Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides, or loop diuretics may have impaired response to these therapies when taking NSAIDs

            Drug interaction overview

            • Drugs that interfere with hemostasis
              • Monitor for bleeding
              • Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. Use with anticoagulants have an increased risk of serious bleeding
              • Serotonin release by platelets plays an important role in hemostasis
              • Monitor for signs of bleeding in patients concomitantly using anticoagulants (eg, warfarin), antiplatelet agents (eg, aspirin), selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors
            • Salicylates
              • Not generally recommended
              • Diclofenac with other NSAIDs or salicylates (eg, diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy
              • ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers H5
              • Monitor for signs of worsening renal function in high-risk patients (eg, elderly patients, volume depleted, renal impaired patients)
              • NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or beta-blockers
            • Diuretics
              • Monitor patients to assure diuretic efficacy including antihypertensive effects
              • NSAIDs can reduce natriuretic effect of loop and thiazide diuretics
            • Digoxin
              • Monitor serum digoxin level
              • Diclofenac can increase serum concentration and prolong half-life of digoxin
            • Pemetrexed
              • Monitor for myelosuppression, renal, and GI toxicity during coadministration of NSAIDS with pemetrexed in renally impaired patients (CrCl 45-79 mL/min)
              • Avoid NSAIDs with short elimination half-lives (eg, diclofenac, indomethacin) for a period of 2 days before, the day of, and 2 days following administration of pemetrexed
              • Interrupt dosing of NSAIDs with longer half-lives (eg, meloxicam, nabumetone) for at least 5 days before, during, and 2 days following pemetrexed administration
              • Diclofenac may increase the risk of pemetrexed­-associated myelosuppression, renal, and GI toxicity
            • CYP2C9 inhibitors
              • Consider increasing duration of diclofenac doses for subsequent migraine attacks
              • CYP2C9 inhibitors may affect the pharmacokinetics of diclofenac
            • Cyclosporine
              • Monitor for signs of worsening renal function
              • Diclofenac may increase cyclosporine nephrotoxicity
            • Methotrexate
              • Monitor for methotrexate toxicity
              • NSAIDS may increase the risk for methotrexate toxicity (eg, neutropenia, thrombocytopenia, renal dysfunction)
            • Lithium
              • Monitor for signs of lithium toxicity
              • NSAIDs elevated plasma lithium levels and reduced renal lithium clearance
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            Pregnancy & Lactation

            Pregnancy

            There are no studies on effects of drug during labor or delivery

            Premature closure of fetal ductus arteriosus

            • Use of NSAIDs can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment
            • Limit dose and duration of use to ~20-30 weeks of gestation; avoid use at about 30 weeks of gestation and later in pregnancy
            • Use of NSAIDs at ≥30 weeks gestation in pregnancy increases risk of premature closure of fetal ductus arteriosus

            Oligohydramnios/neonatal renal impairment

            • Use of NSAIDs at about ≥20 weeks gestation in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment
            • Data from observational studies regarding other potential embryofetal risks of NSAID use in women in first or second trimesters of pregnancy are inconclusive
            • Avoid use of NSAIDs in women at about 30 weeks gestation in pregnancy, because NSAIDs can cause premature closure of fetal ductus arteriosus
            • If an NSAID is necessary at about ≥20 weeks gestation in pregnancy, limit use to lowest dose and shortest duration possible; if treatment extends beyond 48 hr, consider monitoring with ultrasound for oligohydramnios
            • If oligohydramnios occurs, discontinue therapy, and follow up according to clinical practice

            Animal data

            • NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth

            Infertility

            • Females
              • Based on mechanism of action, use of prostaglandin-mediated NSAIDs may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility
              • Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation
              • Consider withdrawal of NSAIDs in women who have difficulties conceiving or who are undergoing investigation of infertility

            Animal data

            • In published studies, administration of clinically relevant doses of diclofenac to pregnant rats produced adverse effects on brain, kidney, and testicular development
            • Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization
            • Administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre-and post-implantation loss; prostaglandins also have been shown to have an important role in fetal kidney development
            • Prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses

            Lactation

            Data from published literature reports with oral preparations of diclofenac indicate the presence of diclofenac in small amounts human milk

            There are no data on effects on breastfed infant, or on milk production

            Pregnancy Categories

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

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

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

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

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

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Inhibits cyclooxygenase (COX)-1 and COX-2, thereby inhibiting prostaglandin synthesis

            May also inhibit neutrophil aggregation/activation, inhibit chemotaxis, decrease proinflammatory cytokine level, and alter lymphocyte activity

            Absorption

            Absolute bioavailability

            • Diclofenac potassium: 55%

            Peak plasma concentration

            • Cambia: ~0.25 hr
            • Zipsor: 1,087 ng/mL (adults); 699 ng/mL (aged 12-17 years)

            Peak plasma time

            • Diclofenac potassium: 1 hr
            • Zipsor: 0.47 hr (adults); 0.94 hr (aged 12-17 years)

            AUC

            • Zipsor: 597 ng⋅hr/mL(adults); 659 ng·hr/mL (aged 12-17 years)

            Effect of food

            • Capsules: 60% lower peak plasma concentration, 11% lower AUC, and 2.32 hr delayed peak plasma time under fed conditions; effectiveness when taken with food has not been studied
            • High-fat meal
              • Diclofenac potassium: No significant on extent of diclofenac absorption, but reduction in peak plasma levels of ~70% after high-fat meal

            Distribution

            Diclofenac diffuses into and out of the synovial fluid; unknown whether diffusion into the joint plays a role in the effectiveness of diclofenac

            Vd

            • Diclofenac potassium: 1.3 L/kg

            Protein bound

            • Diclofenac potassium: >99%

            Metabolism

            Metabolites: 4’- hydroxy-, 5-hydroxy-, 3’-hydroxy-, 4’,5-dihydroxy- and 3’-hydroxy-4’-methoxy diclofenac

            Formation of 4’- hydroxy- diclofenac is primarily mediated by CYP2C9

            Diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion

            Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism

            CYP3A4 is responsible for formation of minor metabolites, 5-hydroxy and 3’-hydroxy- diclofenac

            Elimination

            Half-life

            • Unchanged diclofenac: ~2 hr
            • Mean: 1.9 hr
            • Zipsor: 1.07 hr (adults); 1.81 (aged 12-17 years)

            Excretion

            • As unchanged diclofenac and metabolites
            • Urine (~65%); bile (~35%)
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            Administration

            Oral preparation

            Cambia

            • Empty the contents of 1 packet into a cup containing 1-2 ounces or 2-4 tablespoons (30-60 mL) of water, mix well and drink immediately
            • Do not use liquids other than water

            Oral Administration

            • Different formulations of diclofenac not necessarily bioequivalent even if milligram strength is the same
            • Zorvolex, Cataflam, and Cambia

              • May be taken with food to decrease GI distress
              • However, food may reduce effectiveness
              • Effectiveness when taken with food has not been studied

            Storage

            Diclofenac potassium immediate-release tablets: Store at 20-25ºC (68-77ºF); dispense in a tight container

            Zipsor: Store at 20-25ºC (68-77ºF); dispense in a tight container; protect from moisture

            Cambia: Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)

            Zorvolex

            • Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)
            • Store in original container and keep bottle tightly closed to protect from moisture
            • Dispense in a tight container if package is subdivided
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            Images

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.