Roticox

Roticox is a member of a class of arthritis/analgesia medications called Coxibs. Roticox is a highly selective inhibitor of cyclooxygenase-2 (COX-2).

Roticox tablets contain Roticox, which is described chemically as 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine. The empirical formula is C₁₈H₁₅ClN₂O₂S. The molecular weight is 358.84.

Roticox is a white to off-white powder. Roticox is freely soluble in methanol, tetrahydrofuran, dimethyl sulfoxide, methyl ethyl ketone, dimethyl formamide, and chloroform. Roticox is soluble in isopropyl acetate, ethanol and toluene, sparingly soluble in 2-propanol, and practically insoluble in water.

Roticox is indicated for: Acute and chronic treatment of the signs and symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA); treatment of ankylosing spondylitis (AS); treatment of acute gouty arthritis; relief of acute pain; treatment of primary dysmenorrhea; treatment of moderate to severe acute post-operative pain associated with dental surgery; treatment of moderate to severe acute post-operative pain associated with abdominal gynecological surgery.

The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks.

Roticox is used for the following:

• acute and chronic treatment of the signs and symptoms of osteoarthritis and rheumatoid arthritis
• management of ankylosing spondylitis
• relief of chronic musculoskeletal pain
• relief of acute pain
• to treat acute gouty arthritis

Your doctor will prescribe Roticox for you only after you have used other medicines for your condition and they have not been suitable for you.

Your doctor will want discuss your treatment with Roticox from time to time. It is important that you use the lowest dose that controls your pain and you should not take Roticox for longer than necessary. This is because the risk of heart attacks and strokes might increase after prolonged treatment, especially with high doses.

Osteoarthritis

Osteoarthritis is a joint disease. It results from the gradual breakdown of the cartilage that covers the joints and cushions the ends of bones.

Symptoms of osteoarthritis include pain, tenderness, stiffness of one or more joints, and physical disability. The hips and knees are the most commonly affected joints, but other joints such as those of the hands and spine may also be affected.

Osteoarthritis is more common in women than in men. Many factors can lead to the development of osteoarthritis including obesity and joint injury (eg. from sport).

Rheumatoid Arthritis

Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling and loss of function in the joints and inflammation in other body organs.

Ankylosing Spondylitis

Ankylosing spondylitis is an inflammatory disease of the spine and large joints.

Gout

Gout is a disorder characterised by sudden, recurring attacks of pain and inflammation in one or more joints.

Osteoarthritis (OA): Recommended Dose: 30 mg once daily. In some patients with insufficient relief from symptoms, an increased dose of 60 mg once daily may increase efficacy. In the absence of an increase in therapeutic benefit, other therapeutic options should be considered.

Rheumatoid Arthritis (RA) and Ankylosing Spondylitis (AS): Recommended Dose: 90 mg once daily.

Acute Gouty Arthritis: Recommended Dose: 120 mg once daily. Roticox 120 mg should be used only for the acute symptomatic period, limited to a maximum of 8 days treatment. In clinical trials for acute gouty arthritis, Roticox was given for 8 days.

Analgesia: Acute Pain, Including that Related to Primary Dysmenorrhea and Minor Dental Procedures: Recommended Dose: 90 or 120 mg once daily. Roticox 120 mg should be used only for the acute symptomatic period; limited to a maximum of 8 days treatment.

Doses greater than those recommended for each indication have either not demonstrated additional efficacy or have not been studied. Therefore, the dose for each OA should not exceed 60 mg daily.

The dose for RA and AS should not exceed 90 mg daily.

The dose for acute gout and acute pain should not exceed 120 mg daily.

As the CV risks of selective COX-2 inhibitors may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically.

Renal Insufficiency: No dosage adjustment is necessary for patients with creatinine clearance ≥30 mL/min. The use of Roticox in patients with creatinine clearance <30 mL/min is contraindicated.

Hepatic Insufficiency: In patients with mild hepatic insufficiency (Child-Pugh score 5-6), a dose of 60 mg once daily should not be exceeded. In patients with moderate hepatic insufficiency (Child-Pugh score 7-9), the recommended dose of 60 mg every other day should not be exceeded; administration of 30 mg once daily can be considered. Clinical experience is limited, particularly in patients with moderate hepatic insufficiency and caution is advised. There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9); therefore, its use is contraindicated in these patients.

Administration: Roticox is administered orally and may be taken with or without food. The onset of drug effect may be faster when Roticox is administered without food. This should be considered when rapid symptomatic relief is needed.

Known hypersensitivity to any excipients of Roticox; active peptic ulceration or gastrointestinal bleeding; severe hepatic dysfunction (Child-Pugh score >9); estimated CrCl <30 mL/min; developed signs of asthma, acute rhinitis, nasal polyps, angioneurotic oedema or urticaria following the administration of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs); inflammatory bowel disease; cardiovascular disease; congestive heart failure (NYHA II-IV); hypertension in which blood pressure has not been adequately controlled; established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease (including patients who have recently undergone coronary artery bypass graft surgery or angioplasty).

Use in pregnancy: The use of Roticox, as with any drug substance known to inhibit COX-2, is not recommended in women attempting to conceive.

No clinical data on exposed pregnancies are available for Roticox. Studies in animals have shown reproductive toxicity. The potential for human risk in pregnancy is unknown. Roticox, as with other medicinal products inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Roticox is contraindicated in pregnancy. If a woman becomes pregnant during treatment, Roticox must be discontinued.

Reproductive studies conducted in rats have demonstrated no evidence of developmental abnormalities at doses up to 15 mg/kg/day [approximately 1.5 times the human dose (90 mg) based on systemic exposure]. At doses approximately 2 times the adult human exposure (90 mg) based on systemic exposure, a low incidence of cardiovascular malformations and increases in post-implantation loss were observed in Roticox-treated rabbits. No developmental effects were seen at systemic exposure of approximately equal to or less than the daily human dosage (90 mg). However, there was a decrease in embryo/foetal survival at exposures ≥1.5 times the human exposure. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.

Use in lactation: It is not known whether Roticox is excreted in human milk. Roticox is excreted in the milk of lactating rats. Women who use Roticox must not breastfeed.

Use in children: Roticox is contraindicated in children <16 years. Safety and effectiveness of Roticox in pediatric patients have not been established and should not be given to them.

Roticox is used to treat the pain and swelling due to diseases affecting the muscles, joints and tendons, like strains, gout, ankylosing spondylitis or arthritis as well as mild to moderate pain during dental operations.

In patients stabilized on chronic warfarin therapy, administration of Roticox 120 mg daily was associated with an approximate 13% increase in the prothrombin time International Normalized Ratio (INR). Therefore, patients receiving warfarin and Roticox should have their prothrombin time INR closely monitored, particularly in the 1st few days when therapy with Roticox is initiated or the dose of Roticox is changed. NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (eg, dehydrated patients or elderly patients with compromised renal function), the co-administration of an ACE inhibitor and agents that inhibit cyclooxygenase may result in further deterioration of renal function, which is usually reversible. These interactions should be given consideration in patients taking Roticox concomitantly with ACE inhibitors.

Roticox can be used concomitantly with aspirin at doses used for cardiovascular prophylaxis (low-dose aspirin). However, concomitant administration of low-dose aspirin with Roticox may result in an increased rate of GI ulceration or other complications compared to use of Roticox alone. Concomitant administration of Roticox with doses of aspirin above those for cardiovascular prophylaxis or with other NSAIDs is not recommended.

Co-administration of cyclosporin or tacrolimus with any NSAID may increase the nephrotoxic effect of cyclosporin or tacrolimus. Renal function should be monitored when Roticox and either of these drugs is used in combination.

NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary, monitor blood lithium closely and adjust the lithium dosage while the combination is being taken and when the NSAID is withdrawn.

Adequate monitoring for methotrexate-related toxicity is recommended when Roticox and methotrexate are administered concomitantly.

Administration of Roticox 120 mg with an oral contraceptive containing 35 mcg ethinyl estradiol (EE) and 0.5-1 mg norethindrone for 21 days, either concomitantly or separated by 12 hrs, increased the steady-state AUC_0-24hr of EE by 50-60%; however, norethindrone concentrations generally did not increase to a clinically relevant degree. This increase in EE concentration should be considered when selecting an oral contraceptive for use with Roticox. An increase in EE exposure can increase the incidence of adverse events associated with oral contraceptives (eg, venous thromboembolic events in women at risk).

Roticox 120 mg administered once daily for 10 days to healthy volunteers did not alter the steady-state plasma AUC_0-24hr or renal elimination of digoxin. There was an increase in digoxin C_max (approximately 33%). This increase is not generally important for most patients. However, patients at high risk of digoxin toxicity should be monitored for this when Roticox and digoxin are administered concomitantly.

Roticox is an inhibitor of human sulfotransferase activity, particularly SULT1E1 and has been shown to increase the serum concentrations of ethinyl estradiol. It may be prudent to exercise care when administering Roticox concurrently with other drugs primarily metabolized by human sulfotransferases (eg, oral salbutamol and minoxidil).

Co-administration of Roticox with rifampicin, a potent inducer of CYP enzymes, produced a 65% decrease in Roticox plasma concentrations. This interaction may result in recurrence of symptoms when Roticox is co-administered with rifampicin. While this information may suggest an increase in dose, doses of Roticox greater than those listed for each indication have not been studied in combination with rifampicin and are therefore not recommended.

In drug interaction studies, Roticox did not have clinically important effects on the pharmacokinetics of prednisone/prednisolone. Ketoconazole, a potent inhibitor of CYP3A4, did not have any clinically important effect on the single-dose pharmacokinetics of 60-mg Roticox (43% increase in AUC). Antacids do not affect the pharmacokinetics of Roticox to a clinically relevant extent.

In clinical trials, Roticox was evaluated for safety in 7152 individuals, including 4488 patients with OA, RA or chronic low back pain (approximately 600 patients with OA or RA were treated for one year or longer).

The following drug-related adverse experiences were reported in clinical studies in patients with OA, RA, or chronic low back pain treated for up to 12 weeks. These occurred in ≥1% of patients treated with Roticox and at an incidence greater than placebo: Asthenia/fatigue, dizziness, lower extremity edema, hypertension, dyspepsia, heartburn, nausea, headache, ALT increased, AST increased.

The adverse experience profile was similar in patients with OA or RA treated with Roticox for one year or longer.

In the MEDAL Study, an endpoint driven CV outcomes trial involving 23,504 patients, the safety of Roticox 60 or 90 mg daily was compared to diclofenac 150 mg daily in patients with OA or RA (mean duration of treatment was 20 months). In this large trial, only serious adverse events and discontinuations due to any adverse events were recorded. The rates of confirmed thrombotic cardiovascular serious adverse events were similar between Roticox and diclofenac. The incidence of discontinuations for hypertension-related adverse events was less than 3% in each treatment group; however, Roticox 60 and 90 mg demonstrated significantly higher rates of discontinuations for these events than diclofenac. The incidence of congestive heart failure adverse events (discontinuations and serious events) and the incidence of discontinuations due to edema occurred at similar rates on Roticox 60 mg compared to diclofenac; however, the incidences for these events were higher for Roticox 90 mg compared to diclofenac. The incidence of discontinuations due to atrial fibrillation was higher for Roticox compared to diclofenac.

The EDGE and EDGE II studies compared the GI tolerability of Roticox 90 mg daily (1.5 to 3 times the doses recommended for OA) and diclofenac 150 mg daily in 7111 patients with OA (EDGE Study; mean duration of treatment 9 months) and 4086 patients with RA (EDGE II; mean duration of treatment 19 months). In each of these studies, the adverse experience profile on Roticox was generally similar to that reported in the phase IIb/III placebo-controlled clinical studies; however, hypertension and edema-related adverse experiences occurred at a higher rate on Roticox 90 mg than on diclofenac 150 mg daily. The rate of confirmed thrombotic cardiovascular serious adverse events occurring in the two treatment groups was similar.

In a combined analysis of phase IIb to V clinical studies of 4 weeks duration or longer (excluding the MEDAL Program Studies), there was no discernible difference in the rate of confirmed thrombotic cardiovascular serious adverse events between patients receiving Roticox ≥30 mg or non-naproxen NSAIDs. The rate of these events was higher in patients receiving Roticox compared with those receiving naproxen 500 mg twice daily.

In a clinical study for ankylosing spondylitis, patients were treated with Roticox 90 mg once daily for up to 1 year (N=126). The adverse experience profile in this study was generally similar to that reported in chronic studies in OA, RA and chronic low back pain.

In a clinical study for acute gouty arthritis, patients were treated with Roticox 120 mg once daily for eight days. The adverse experience profile in this study was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.

In initial clinical studies for acute analgesia, patients were treated with Roticox 120 mg once daily for one to seven days. The adverse experience profile in these studies was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.

In the additional clinical studies for acute post-operative pain associated with dental and abdominal gynecological surgeries including 1222 patients treated with Roticox (90 mg or 120 mg), the adverse experience profile was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.

In the combined studies for acute post-operative dental pain, the incidence of post-dental extraction alveolitis (dry socket) reported in patients treated with Roticox was similar to that of patients treated with active comparators.

Post-Marketing Experience: The following adverse reactions have been reported in post-marketing experience: Blood and Lymphatic System Disorders: Thrombocytopenia.

Immune System Disorders: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions including shock.

Metabolism and Nutrition Disorders: Hyperkalemia.

Psychiatric Disorders: Anxiety, insomnia, confusion, hallucinations, depression, restlessness.

Nervous System Disorders: Dysgeusia, somnolence.

Eye Disorders: Blurred vision.

Cardiac Disorders: Congestive heart failure, palpitations, angina, arrhythmia.

Vascular Disorders: Hypertensive crisis.

Respiratory, Thoracic and Mediastinal Disorders: Bronchospasm.

Gastrointestinal Disorders: Abdominal pain, oral ulcers, peptic ulcers including perforation and bleeding (mainly in elderly patients), vomiting, diarrhea.

Hepatobiliary Disorders: Hepatitis, jaundice, hepatic failure.

Skin and Subcutaneous Tissue Disorders: Angioedema, pruritus, erythema, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, fixed drug eruption.

Renal and Urinary Disorders: Renal insufficiency, including renal failure.