diclofenac (Rx)

>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

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

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.

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%)

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