Diclofenac

Diclofenac is a medication that is primarily used to treat Ankylosing spondylitis, Dysmenorrhea, Migraine, Osteoarthritis, Pain, Rheumatoid arthritis. It is also used to treat Gout and acute flares.

Diclofenac is Absorbed from the gastrointestinal tract, skin. Decreased absorption rate with food. Bioavailability: 55%. Time to peak plasma concentration (under fasted conditions): Approx 1 hour (conventional tablet or capsule, suppositories); 2-3 hours (delayed-release tablet); approx 4-5 hours (extended-release tablet or capsule); approx 0.25 hour (powder for oral solution); approx 5 minutes (IV); approx 20 minutes (IM); 10-20 hours (transdermal).

It Crosses the placenta and enters breastmilk. Volume of distribution: Approx 1.3-1.4 L/kg. Plasma protein binding: >99% mainly to albumin and Undergoes first-pass metabolism in the liver via hydroxylation and methoxylation into metabolites including 4'-hydroxydiclofenac (major), 3'-hydroxydiclofenac, 5-hydroxydiclofenac, 4',5-dihydroxydiclofenac and 3'-hydroxy-4’-methoxydiclofenac; further metabolised via glucuronidation.It excreted Mainly via urine (approx 60% as metabolites including glucuronide conjugates; <1% as unchanged drug); bile (approx 35%). Terminal elimination half-life: Approx 1-2 hours (tablet, capsule, inj, suppositories); approx 12 hours (transdermal patch).

The Tmax is approximately 2-3 hours after administration.

Cmax of Diclofenac after a single oral dose 5-7 ng/mL.

Diclofenac shows common side effects like Headache, Dry mouth, Fatigue or drowsiness, Nausea, Stomach upset, Nervousness, Difficulty sleeping and Skin rash or itching.

Diclofenac is available in Tablets, Capsule and Powders, Solution

Diclofenac is available in India, Germany, Canada, France.

Diclofenac inhibits cyclooxygenase-1 and -2, the enzymes responsible for production of prostaglandin (PG) G₂ which is the precursor to other PGs. These molecules have broad activity in pain and inflammation and the inhibition of their production is the common mechanism linking each effect of diclofenac.

Diclofenac is available in the form of Tablets, Capsule and Powders, Solution.

Oral: Administer with water 1 hour before or 2 hours after intake of food or fruit juices.

Diclofenac reduces inflammation and by extension reduces nociceptive pain and combats fever. It also increases the risk of developing a gastrointestinal ulcer by inhibiting the production of protective mucus in the stomach.

Diclofenac is approved for use in the following clinical indications

Ankylosing spondylitis: Acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis.

Dysmenorrhea: Treatment of primary dysmenorrhea.

Migraine, acute treatment: Acute treatment of migraine attacks with or without aura in adults.

Osteoarthritis: Relief of signs and symptoms of osteoarthritis.

Pain, acute: Relief of mild to moderate acute pain in pediatric patients ≥12 years of age and adults.

Rheumatoid arthritis: Relief of signs and symptoms of rheumatoid arthritis.

It is also used to treat Gout and acute flares.

Acute pain (monotherapy or as adjunctive agent):

Oral: Diclofenac potassium or sodium formulations: 100 to 150 mg/day in divided doses as needed or scheduled (may choose immediate release [given in 2 to 4 divided doses], delayed release [given in 2 to 4 divided doses], or extended release [given once daily]); may administer 100 mg as an initial loading dose followed by a maintenance dose; maximum dose (after day 1): 150 mg/day .

Oral: Diclofenac acid: 18 mg or 35 mg 3 times daily as needed or scheduled; maximum dose: 105 mg/day.

Ankylosing spondylitis:

Oral: Diclofenac potassium or sodium formulations: 100 to 150 mg/day in divided doses (may choose immediate release [given in 2 to 4 divided doses], delayed release [given in 2 to 4 divided doses], or extended release [given once daily]); maximum dose: 150 mg/day

Dysmenorrhea:

Oral: Diclofenac potassium or sodium formulations: 150 mg/day in divided doses (may choose immediate release [given in 2 to 4 divided doses] or delayed release [given in 2 to 4 divided doses]); may administer 75 to 100 mg as an initial loading dose followed by a maintenance dose; maximum dose (after day 1): 150 mg/day. Begin at menses onset or 1 to 2 days prior to onset of menses for severe symptoms; usual duration: 1 to 5 days

Gout, treatment (acute flares) (off-label use):

Note: Some experts reserve use for patients who are not candidates for intra-articular glucocorticoids or when intra-articular glucocorticoid administration is not feasible

Migraine, acute treatment:

Note: For use as monotherapy in mild to moderate attacks not associated with vomiting or severe nausea; may be used in combination with triptans for severe migraine.

Osteoarthritis:

Oral: Diclofenac potassium or sodium formulations: 100 to 150 mg/day in divided doses (may choose immediate release [given in 2 to 4 divided doses], delayed release [given in 2 to 4 divided doses], or extended release [given once daily]); maximum dose: 150 mg/day.

Oral: Diclofenac acid: 35 mg 3 times daily; maximum dose: 105 mg/day.

Rectal (Canadian product): Substitute for the final oral daily dose: Insert 50 mg or 100 mg suppository as a single dose.

Rheumatoid arthritis:

Oral: Diclofenac potassium or sodium formulations: 100 mg/day in divided doses (may choose immediate release [given in 2 to 4 divided doses], delayed release [given in 2 to 4 divided doses], or extended release [given once or twice daily]); if needed, may increase to a maximum dose of 200 mg/day in divided doses .

Note: For the ER formulation, the maximum dose should be given in 2 divided doses according to the manufacturer.

Rectal (Canadian product): Substitute for the final oral daily dose: Insert 50 mg or 100 mg suppository as a single dose.

Diclofenac is available in the dosage strength of

• 25 mg ,50 mg ,75 mg, 100 mg ,18 mg ,35 mg, 37.5mg/mL

Diclofenac is available in the form of tablets, capsules and oral packets.

Dosage Adjustment in Kidney Patient

• Oral, rectal:
• Altered kidney function:
• CrCl ≥60 mL/minute: No dosage adjustment necessary .
• CrCl >30 to <60 mL/minute: No dosage adjustment necessary.
• However, use of analgesics other than nonsteroidal anti-inflammatory drugs may be preferred. If necessary, use the lowest effective dose for the shortest duration possible; avoid in patients at high risk for acute kidney injury (ie, volume depleted, hypotensive, older adults, or taking concurrent nephrotoxic medications).
• CrCl ≤30 mL/minute: Avoid use due to increased risk of acute kidney injury .
• Hemodialysis, intermittent (thrice weekly): Not expected to be significantly dialyzable (highly protein bound): No dosage adjustment necessary. Avoid use in patients with residual kidney function .
• Peritoneal dialysis: No dosage adjustment necessary. Avoid use in patients with residual kidney function .
• CRRT: Avoid use .
• PIRRT (eg, sustained, low-efficiency defiltration): Avoid use

Dosage Adjustment in Hepatic impairment Patient

● No Dosage Adjustment is necessary .

Dosage Adjustment for Pediatric Patients

• Acute pain (mild to moderate): Children ≥12 years and Adolescents: Immediate-release capsule : Oral: 25 mg 4 times daily
• Juvenile idiopathic arthritis: Limited data available: Children and Adolescents: Immediate-release tablet: Oral: 2 to 3 mg/kg/day in divided doses 2 to 3 times daily; maximum daily dose: 150 mg/day
• Migraine: Limited data available: Children ≥12 years and Adolescents: Powder for oral solution : Oral: 50 mg (1 packet) as a single dose at onset of migraine
• Osteoarthritis: Limited data available: Adolescents ≥16 years: Suppository (50 mg or 100 mg): Rectal: 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)

Postoperative pain: Limited data available: Rectal suppository (12.5, 25, or 50 mg): Children and Adolescents: Suppository (12.5 mg, 25 mg, or 50 mg): Rectal: 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.

Take after eating and with a full glass of water to decrease gastric upset.

Diclofenac is contraindicated in patients with:

Hypersensitivity to diclofenac or other NSAIDs. Aspirin-sensitive asthma, risk factors for volume depletion (inj). Moderate to severe heart failure, ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, gastrointestinal ulceration, perforation or haemorrhage, proctitis (rectal). Treatment in the setting of CABG. Concomitant use of other NSAIDs, antiplatelets, anticoagulants. Severe hepatic or renal impairment. Pregnancy (3rd trimester).

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: 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 (FDA 2015). 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.

• Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.

• GI events: 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/hypersensitivity: NSAIDs may cause potentially fatal serious skin adverse events, including drug reaction with eosinophilia and systemic symptoms, 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).

Diclofenac may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Diclofenac is present in breast milk.

There are no known food interactions with Diclofenac. However, it is recommended to avoid drinking alcohol while taking Diclofenac, as it can increase the risk of drowsiness and dizziness.

• Common Adverse effects:

Eye irritation or burning (when used as eye drops), Headache ,Taste disturbances, Dry mouth, Fatigue or drowsiness, Dizziness, Nausea

• Less Common Adverse effects:

Cardiovascular effects such as increased heart rate, palpitations, and high blood pressure.

Respiratory effects such as thickening of bronchial secretions, which can make it difficult to breathe, especially in patients with asthma or COPD.

Skin reactions such as rash, hives, and itching.

Allergic reactions such as anaphylaxis, which is a severe and potentially life-threatening allergic reaction.

Gastrointestinal effects such as abdominal pain and diarrhea.

Fatigue, weakness, and headache.

• Rare Adverse effects

Allergic reactions: In rare cases, Diclofenac may cause an allergic reaction, which can be life-threatening. Symptoms of an allergic reaction may include difficulty breathing, swelling of the face, lips, tongue or throat, or a skin rash.

Liver injury: There have been rare reports of liver injury associated with the use of Diclofenac, including cases of hepatitis and elevated liver enzymes.

Seizures: Diclofenac may lower the seizure threshold in some people, especially those with a history of seizures or epilepsy.

Cardiac events: There have been rare reports of cardiac events associated with the use of Diclofenac, including tachycardia, palpitations, and QT prolongation.

Increased risk of gastrointestinal ulceration, perforation or haemorrhage with other corticosteroids, SSRIs. Increased risk CV-related adverse reactions with cardiac glycosides. Increased risk of hyperkalaemia and renal toxicity with ACE inhibitors, diuretics, ciclosporin, tacrolimus. Increased risk of haematological toxicity with zidovudine. Increased levels and risk of toxicity with digoxin, lithium, methotrexate, pemetrexed, phenytoin. Decreased effect with colestipol, cholestyramine. Decrease effect of mifepristone. Increased peak plasma concentration with CYP2C9 inhibitors e.g. voriconazole.

Potentially Fatal: Increased risk of gastrointestinal ulceration, perforation or haemorrhage with other NSAIDs (e.g. aspirin), antiplatelets, anticoagulants (e.g. warfarin).

The common side effects of Diclofenac include the following :

Headache, Taste disturbances, Dry mouth, Fatigue or drowsiness, Dizziness and Nausea.

Symptoms: Lethargy, tinnitus, headache, drowsiness, nausea, vomiting, diarrhoea, dizziness, disorientation, excitation, epigastric pain, gastrointestinal bleeding, convulsions; rarely, anaphylactoid reactions, hypertension, respiratory depression, acute renal failure, coma.

Management: Symptomatic and supportive treatment. Maintain a clear airway. Administration of activated charcoal within 1 hour of ingestion or perform gastric lavage. May perform osmotic cathartic within 4 hours of ingestion.

• Pharmacodynamic

Diclofenac primarily exerts its pharmacodynamic effects by inhibiting the enzyme cyclooxygenase (COX), which is responsible for the synthesis of prostaglandins. Prostaglandins are chemical messengers involved in inflammation, pain, and fever. By inhibiting COX, diclofenac reduces the production of prostaglandins, resulting in analgesic (pain-relieving), anti-inflammatory, and antipyretic (fever-reducing) effects.

Diclofenac's inhibition of COX is nonselective, meaning it affects both COX-1 and COX-2 enzymes. COX-1 is constitutively expressed in various tissues and plays a role in maintaining normal physiological functions, such as protecting the stomach lining and promoting kidney function. COX-2, on the other hand, is induced during inflammation and contributes to the production of prostaglandins that mediate pain and inflammation. By inhibiting both COX-1 and COX-2, diclofenac can effectively reduce pain, inflammation, and fever.

• Pharmacokinetics

Absorption: diclofenac is well-absorbed from the gastrointestinal tract, although its absorption may be slower when taken with food. Diclofenac is also available as enteric-coated tablets, which help protect the stomach from irritation. The oral bioavailability of diclofenac is approximately 50%.

Distribution: Once absorbed, diclofenac binds extensively to plasma proteins, primarily albumin. The drug has a relatively large volume of distribution, indicating that it distributes well into various tissues. Diclofenac crosses the blood-brain barrier, and small amounts are excreted into breast milk.

Metabolism: Diclofenac undergoes extensive hepatic metabolism. The primary metabolic pathway involves cytochrome P450 enzymes, mainly CYP2C9 and CYP2C8. These enzymes convert diclofenac into several metabolites, including 4'-hydroxydiclofenac, 5-hydroxydiclofenac, and 3'-hydroxydiclofenac. Some of these metabolites are pharmacologically active but to a lesser extent than the parent compound.

Excretion: Diclofenac and its metabolites are eliminated primarily through the kidneys. Less than 1% of an oral dose is excreted unchanged in urine. The major metabolites are eliminated through renal excretion as glucuronide or sulfate conjugates. The elimination half-life of diclofenac is approximately 1-2 hours.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
2. https://reference.medscape.com/drug/colestid-Diclofenac -342452
3. https://go.drugbank.com/drugs/DB00375
4. https://www.sciencedirect.com/topics/medicine-and-dentistry/Diclofenac
5. https://europepmc.org/article/med/6988203