Dorex

Each 100 mg capsule contains 100 mg Dorex.

Each 200 mg capsule contains 200 mg Dorex.

Each 400 mg capsule contains 400 mg Dorex.

Excipients/Inactive Ingredients: 100 mg, 200 mg and 400 mg capsules contain lactose monohydrate, sodium lauryl sulphate, polyvidone K30, croscarmellose sodium and magnesium stearate. Capsule shells contain gelatin, titanium dioxide, and ink gold SB-3002 (200 mg capsule) or ink blue SB-6018 (100 mg capsule) or ink green SB-4027 (400 mg capsule).

Carefully consider the potential benefits and risks of Dorex and other treatment options before deciding to use Dorex. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals

Osteoarthritis (OA)

Dorex is indicated for relief of the signs and symptoms of OA

Rheumatoid Arthritis (RA)

Dorex is indicated for relief of the signs and symptoms of RA

Juvenile Rheumatoid Arthritis (JRA)

Dorex is indicated for relief of the signs and symptoms of JRA in patients 2 years and older

Ankylosing Spondylitis (AS)

Dorex is indicated for the relief of signs and symptoms of AS

Acute Pain (AP)

Dorex is indicated for the management of AP in adults

Primary Dysmenorrhea (PD)

Dorex is indicated for the treatment of PD

Dorex is a nonsteroidal anti-inflammatory drug (NSAID) used to treat mild to moderate pain and help relieve symptoms of arthritis (e.g., osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis), such as inflammation, swelling, stiffness, and joint pain. However, Dorex does not cure arthritis and will help you only as long as you continue to take it.

Dorex is also used to treat ankylosing spondylitis, which is a type of arthritis that affects the joints in the spine. Dorex may also be used to treat acute pain and menstrual cramps.

Dorex is available only with your doctor's prescription.

Dorex capsules at doses up to 200 mg twice per day can be taken with or without food.

As the cardiovascular risks of Dorex may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used.

Adults: Symptomatic Treatment of Osteoarthritis (OA): The recommended dose of Dorex 200 mg administered as a single dose or as 100 mg twice per day.

Symptomatic Treatment of Rheumatoid Arthritis (RA): The recommended dose of Dorex is 100 or 200 mg twice per day.

Ankylosing Spondylitis (AS): The recommended dose of Dorex is 200 mg administered as a single dose or as 100 mg twice a day. Some patients may benefit from a total daily dose of 400 mg.

Management of Acute Pain: The recommended dose of Dorex is 400 mg, initially, followed by an additional 200 mg dose, if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily or 400 mg once daily, as needed.

Primary Dysmenorrhea: The recommended dose of Dorex is 400 mg, initially, followed by an additional 200 mg dose, if needed on the 1st day. On subsequent days, the recommended dose is 200 mg twice daily, as needed.

CYP2C9 Poor Metabolizers: Patients who are known, or suspected to be CYP2C9 poor metabolizers based on previous history/experience with other CYP2C9 substrates should be administered Dorex with caution. Consider starting treatment at half the lowest recommended dose..

Co-administration with Fluconazole: Dorex should be introduced at half the recommended dose in patients receiving fluconazole, a CYP2C9 inhibitor.

Elderly: No dosage adjustment is generally necessary. However, for elderly patients weighing less than 50 kg, it is advisable to initiate therapy at the lowest recommended dose.

Hepatic Impairment: No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A). Introduce Dorex at half the recommended dose in arthritis or pain patients with moderate hepatic impairment (Child-Pugh Class B).

Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied.

Renal Impairment: No dosage adjustment is necessary in patients with mild or moderate renal impairment. There is no clinical experience in patients with severe renal impairment.

Administration: For patients who have difficulty swallowing capsules, the contents of a Dorex capsule can be added to applesauce, rice gruel, yogurt or mashed banana. To do so, the entire capsule contents must be carefully emptied onto a level teaspoon of cool or room temperature applesauce, rice gruel, yogurt or mashed banana and should be ingested immediately with water. The sprinkled capsule contents on applesauce, rice gruel or yogurt are stable for up to 6 hours under refrigerated conditions (2°C-8°C or 35°F-45°F). The sprinkled capsule contents on mashed banana should not be stored under refrigerated conditions and should be ingested immediately.

See also:
What is the most important information I should know about Dorex?

Hypersensitivity to Dorex, sulfonamide or to any of the excipients of Dorex.

Patients who have experienced asthma, urticaria or allergic-type reactions after taking acetylsalicylic acid [aspirin (ASA)] or other NSAIDs, including other COX-2-specific inhibitors.

Treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

Use in pregnancy: There are no studies in pregnant women. Studies in animals have shown reproductive toxicity. The relevance of these data for humans is unknown.

Dorex, as with other drugs inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus and should be avoided during the 3rd trimester of pregnancy.

Dorex should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. In animals, administration of prostaglandin synthesis inhibitors has been shown to result in increased pre- and post-implantation loss.

Use in lactation: Studies in rats show that Dorex is excreted in milk at concentrations similar to those in plasma. Administration of Dorex to lactating women has shown very low transfer of Dorex into breast milk. Because of the potential for adverse reactions in nursing infants from Dorex, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the expected benefit of the drug to the mother.

Use in children: Dorex has not been studied in subjects <18 years.

Use Dorex as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Dorex comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Dorex refilled.
• Take Dorex by mouth. It may be taken with food if it upsets your stomach. Taking it with food may not lower the risk of stomach or bowel problems (eg, bleeding, ulcers). Talk with your doctor or pharmacist if you have persistent stomach upset.
• Some doses of Dorex should be taken with food. Ask your doctor if you have questions about how to take Dorex.
• Take Dorex with a full glass of water (8 oz/240 mL) as directed by your doctor.
• Do not lie down for 30 minutes after taking Dorex.
• If you miss a dose of Dorex and you are taking it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Dorex.

Use: Labeled Indications

Acute pain: Management of acute pain.

Ankylosing spondylitis: Relief of the signs/symptoms of ankylosing spondylitis.

Juvenile idiopathic arthritis: Relief of the signs/symptoms of juvenile idiopathic arthritis (JIA) in patients 2 years and older.

Osteoarthritis: Relief of the signs/symptoms of osteoarthritis.

Primary dysmenorrhea: Treatment of primary dysmenorrhea.

Rheumatoid arthritis: Relief of the signs/symptoms of rheumatoid arthritis.

Off Label Uses

Gout, acute flares

Data from a multinational, randomized, double-blind, controlled trial demonstrate efficacy of Dorex for the treatment of acute gout flares.

Based on the American College of Rheumatology guidelines for the management of acute gout flares, Dorex is an effective and recommended treatment option for patients with GI contraindications or intolerance to nonselective NSAIDs.

See also:
What other drugs will affect Dorex?

Interactions with Other Medicinal Products and Other Forms of Interaction: General: Dorex metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered Dorex with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Consider starting treatment at half the lowest recommended dose.

Concomitant administration of Dorex with inhibitors of CYP2C9 can lead to increases in plasma concentrations of Dorex. Therefore, a dose reduction of Dorex may be necessary when Dorex is co-administered with CYP2C9 inhibitors.

Concomitant administration of Dorex with inducers of CYP2C9 such as rifampicin, carbamazepine and barbiturates can lead to decreases in plasma concentrations of Dorex. Therefore, a dose increase of Dorex may be necessary when Dorex is co-administered with CYP2C9 inducers.

In Clinical pharmacokinetics study and in vitro studies indicate that Dorex, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6.

Drug Specific: Interaction of Dorex with warfarin or similar agents:.

Lithium: In healthy subjects, lithium plasma levels increased approximately 17% in subjects receiving lithium together with Dorex. Patients on lithium treatment should be closely monitored when Dorex is introduced or withdrawn.

Aspirin: Dorex does not interfere with the antiplatelet effect of low-dose aspirin. Because of its lack of platelet effects, Dorex is not a substitute for aspirin in the prophylactic treatment of cardiovascular disease.

Antihypertensives including Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II Antagonists (also known as Angiotensin Receptor Blockers, ARBs), Diuretics and Beta-blockers: Inhibition of prostaglandins may diminish the effect of antihypertensives including (ACEIs and/or ARBs, diuretics and beta-blockers. This interaction should be given consideration in patients taking Dorex concomitantly with ACEIs and/or ARBs, diuretics and beta-blockers.

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, angiotensin II antagonists or diuretics, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.

Results from Lisinopril Study: In a 28-day clinical study in patients with lisinopril-controlled Stage I and II hypertension, administration of Dorex 200 mg BID resulted in no clinically significant increases, when compared to placebo treatment, in mean daily systolic or diastolic blood pressure as determined using 24-hour ambulatory blood pressure monitoring. Among patients co-administered with Dorex 200 mg BID, 48% were considered unresponsive to lisinopril at the final clinic visit (defined as either cuff diastolic blood pressure >90 mmHg or cuff diastolic blood pressure increased >10% compared to baseline), compared to 27% of patients co-administered with placebo; this difference was statistically significant.

Cyclosporine: Because of their effect on renal prostaglandins, NSAIDs may increase the risk of nephrotoxicity with cyclosporine.

Fluconazole and Ketoconazole: Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in Dorex plasma concentration. This increase is due to the inhibition of Dorex metabolism via CYPP450 2C9 by fluconazole. Dorex should be introduced at half the recommended dose in patients receiving the CYP2C9 inhibitor fluconazole. Ketoconazole, a CYP3A4 inhibitor, showed no clinically relevant inhibition in the metabolism of Dorex.

Dextromethorphan and Metoprolol: Concomitant administration of Dorex 200 mg twice daily resulted in a 2.6-fold and a 1.5-fold increases in plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates), respectively. These increases are due to Dorex inhibition to the CYP2D6 substrate metabolism via CYP2D6. Therefore, the dose of drugs as CYP2D6 substrate may need to be reduced when treatment with Dorex is initiated or increased when treatment with Dorex is terminated.

Diuretics: Clinical studies have shown that NSAIDs, in some patients, can reduce the natriuretic effect of furosemide and thiazides by inhibition of renal prostaglandin synthesis.

Methotrexate: No pharmacokinetic and clinically important interactions have been observed in a clinical study between Dorex and methotrexate.

Oral Contraceptives:

Other Drugs: No clinically important interactions have been observed with Dorex and antacids (aluminum and magnesium), omeprazole, glibenclamide (glyburide), phenytoin, or tolbutamide.

See also:
What are the possible side effects of Dorex?

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiovascular Thrombotic Events
• GI Bleeding, Ulceration and Perforation
• Hepatotoxicity
• Hypertension
• Heart Failure and Edema
• Renal Toxicity and Hyperkalemia
• Anaphylactic Reactions
• Serious Skin Reactions
• Hematologic Toxicity

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Of the Dorex-treated patients in the pre-marketing controlled clinical trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients received a total daily dose of Dorex of 200 mg (100 mg twice daily or 200 mg once daily) or more, including more than 400 treated at 800 mg (400 mg twice daily). Approximately 3,900 patients received Dorex at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more.

Pre-marketing Controlled Arthritis Trials

Table 1 lists all adverse events, regardless of causality, occurring in ≥ 2% of patients receiving Dorex from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence.

Table 1: Adverse Events Occurring in > 2% of Dorex Patients from Pre-marketing Controlled Arthritis Trials

In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving Dorex and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the Dorex treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of Dorex patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain.

The following adverse reactions occurred in 0.1 - 1.9% of patients treated with Dorex (100 - 200 mg twice daily or 200 mg once daily):

Gastrointestinal: Constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, vomiting

Cardiovascular: Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction

General: Hypersensitivity, allergic reaction, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain

Central, peripheral Leg cramps, hypertonia, hypoesthesia, nervous system: migraine, paresthesia, vertigo

Hearing and vestibular: Deafness, tinnitus

Heart rate and rhythm: Palpitation, tachycardia

Liver and biliary: Hepatic enzyme increased (including SGOT increased, SGPT increased)

Metabolic and nutritional: BUN increased, CPK increased, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increased, creatinine increased, alkaline phosphatase increased, weight increased

Musculoskeletal : Arthralgia, arthrosis, myalgia, synovitis, tendinitis

Platelets (bleeding or clotting): Ecchymosis, epistaxis, thrombocythemia, Psychiatric: Anorexia, anxiety, appetite increased, depression, nervousness, somnolence

Hemic: Anemia

Respiratory: Bronchitis, bronchospasm, bronchospasm aggravated, cough, dyspnea, laryngitis, pneumonia

Skin and appendages: Alopecia, dermatitis, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria

Application site disorders: Cellulitis, dermatitis contact

Urinary: Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus

The following serious adverse events (causality not evaluated) occurred in < 0.1% of patients:

Cardiovascular: Syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis

Gastrointestinal: Intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, ileus

General: Sepsis, sudden death

Liver and biliary: Cholelithiasis

Hemic and lymphatic: Thrombocytopenia

Nervous: Ataxia, suicide

Renal: Acute renal failure

The Dorex Long-Term Arthritis Safety Study

Hematological Events: The incidence of clinically significant decreases in hemoglobin ( > 2 g/dL) was lower in patients on Dorex 400 mg twice daily (0.5%) compared to patients on either diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower incidence of events with Dorex was maintained with or without aspirin use.

Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for Dorex, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., causing hospitalization or felt to be life-threatening or otherwise medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and 8%, respectively).

Juvenile Rheumatoid Arthritis Study

In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were treated with Dorex or naproxen; 77 JRA patients were treated with Dorex 3 mg/kg twice daily, 82 patients were treated with Dorex 6 mg/kg twice daily, and 83 patients were treated with naproxen 7.5 mg/kg twice daily. The most commonly occurring ( ≥ 5%) adverse events in Dorex treated patients were headache, fever (pyrexia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea and vomiting. The most commonly occurring ( ≥ 5%) adverse experiences for naproxen-treated patients were headache, nausea, vomiting, fever, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 2). Compared with naproxen, Dorex at doses of 3 and 6 mg/kg twice daily had no observable deleterious effect on growth and development during the course of the 12-week double-blind study. There was no substantial difference in the number of clinical exacerbations of uveitis or systemic features of JRA among treatment groups.

In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were treated with Dorex 6 mg/kg twice daily. The incidence of adverse events was similar to that observed during the double-blind study; no unexpected adverse events of clinical importance emerged.

Table 2: Adverse Events Occurring in ≥ 5% of JRA Patients in Any Treatment Group, by System Organ Class (% of patients with events)

Other Pre-Approval Studies

Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with Dorex in placebo- and active-controlled AS studies. Doses up to 400 mg once daily were studied. The types of adverse events reported in the AS studies were similar to those reported in the OA/RA studies.

Adverse Events from Analgesia and Dysmenorrhea Studies: Approximately 1,700 patients were treated with Dorex in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose of study medication. Doses up to 600 mg/day of Dorex were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only additional adverse event reported was post-dental extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies.

The APC and PreSAP Trials

Adverse reactions from long-term, placebo-controlled polyp prevention studies: Exposure to Dorex in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years.

Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing trials (treatment durations up to 12 weeks; see Adverse events from Dorex pre-marketing controlled arthritis trials, above). The adverse reactions for which these differences in patients treated with Dorex were greater as compared to the arthritis pre-marketing trials were as follows:

The following additional adverse reactions occurred in ≥ 0.1% and < 1% of patients taking Dorex, at an incidence greater than placebo in the long-term polyp prevention studies, and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in the long-term, placebo-controlled polyp prevention studies:

Nervous system disorders: Cerebral infarction

Eye disorders: Vitreous floaters, conjunctival hemorrhage

Ear and labyrinth: Labyrinthitis

Cardiac disorders: Angina unstable, aortic valve incompetence, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy

Vascular disorders: Deep vein thrombosis

Reproductive system and breast disorders: Ovarian cyst

Investigations: Blood potassium increased, blood sodium increased, blood testosterone decreased

Injury, poisoning and procedural complications: Epicondylitis, tendon rupture

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Dorex. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure

Cardiovascular: Vasculitis, deep venous thrombosis

General: Anaphylactoid reaction, angioedema

Liver and biliary: Liver necrosis, hepatitis, jaundice, hepatic failure

Hemic and lymphatic: Agranulocytosis, aplastic anemia, pancytopenia, leucopenia

Metabolic: Hypoglycemia, hyponatremia

Nervous: Aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage

Renal: Interstitial nephritis