Data Sheet
PREXIGE®
Lumiracoxib
100 mg Tablets
Qualitative and quantitative composition
The active substance is lumiracoxib.
100 mg tablets
Each 100 mg tablet contains 100 mg lumiracoxib.
For a full list of excipients, see List of excipients.
Pharmaceutical form
Film-coated tablets.
Clinical particulars
Therapeutic indications
Symptomatic treatment of osteoarthritis (OA).
The decision to prescribe a selective COX-2 inhibitor should only be made:
- if non-pharmcological interventions and simple analgesic therapy have been tried and found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient; and
- after assessment of the individual patient's overall risk factors for developing severe adverse events e.g. history of cardiovascular, renal, or gastrointestinal disease (See Contraindications and Special warnings and precautions for use).
As the cardiovascular risks of Prexige, like those of other selective COX-2 inhibitors, may increase with dose and duration of exposure, the shortest duration of treatment and the lowest effective daily dose should be used. Patients on long-term treatment should be reviewed regularly, such as every three months, with regards to efficacy, risk factors and ongoing need for treatment.
Liver function monitoring is recommended at baseline and monthly thereafter while on therapy. Patients with a baseline AST/ALT > 1.5xULN should not be commenced on lumiracoxib.
Dosage and method of administration
Prexige tablets are administered orally and may be taken with or without food.
As with other NSAIDs, the cardiovascular and hepatic risks of Prexige may increase with dose and duration of exposure. Therefore the shortest duration of treatment and the lowest effective daily dose should be used. The 100mg dose should not be exceeded as this does not provide any additional clinical benefit and may increase the risks of adverse effects. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically in patients with osteoarthritis.
Osteoarthritis
The recommended dose is 100 mg once daily with or without food, for the shortest duration consistent with individual patient treatment goals. The 100 mg dose should not be exceeded as this does not provide any additional benefit and may increase the risks of adverse events. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically.
Ethnic differences
Dosing recommendations are the same for Asians, Blacks and Caucasians (See Pharmacokinetic properties).
Hepatic impairment
Patients with hepatic impairment should not be treated with Prexige. (See Contraindications, Special warnings and precautions for use and Pharmacokinetic properties).
Renal insufficiency
No dosage adjustment is necessary for patients with creatinine clearance >30 mL/min (See Contraindications and Special warnings and precautions for use).
Elderly
As with other medicinal products used in the elderly, caution should be exercised in elderly patients (See Special warnings and precautions for use and Pharmacokinetic properties).
Paediatric use
Prexige has not been studied in children and adolescents. Thus it is not indicated for use in this population.
Contraindications
- Known hypersensitivity to the active substance or to any of the excipients.
- Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicyclic acid (ASA)/aspirin or NSAIDs.
- Patients with severe renal dysfunction (estimated creatinine clearance < 30 mL/min) (See Special warnings and precautions for use).
- Patients with hepatic impairment, or patients with a baseline AST/ALT 1.5xULN should not be commenced on lumiracoxib. (See Special warnings and precautions for use).
- Patients who have previously had a myocardial infarction or stroke.
- Patients with peri-operative pain in the setting of cardiac surgery or major vascular surgery.
- Patients with active peptic ulceration or gastrointestinal (GI) bleeding.
Special warnings and precautions for use
Gastrointestinal effects
Upper gastrointestinal complications (perforations, ulcers or bleedings [PUBs]), some of them resulting in a fatal outcome, have rarely occurred in patients treated with Prexige. In clinical studies, few patients (<0.4%) treated with Prexige developed perforations, obstruction or bleeds (POBs).
Caution is advised in patients most at risk of developing a gastrointestinal (GI) complication with NSAIDs: the elderly, patients using any other NSAID or ASA/aspirin concomitantly, or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding.
The use of Prexige in patients with active peptic ulceration, gastrointestinal bleeding or inflammatory bowel disease is not recommended.
There is an increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications) when Prexige is taken concomitantly with ASA/aspirin (even at low doses). A significant difference in GI safety between selective COX-2 inhibitors + ASA/aspirin vs. NSAIDs + ASA/aspirin has not been demonstrated in long-term clinical trials (See Pharmacodynamic properties).
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding.
Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding, or perforation caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for 1 year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
Studies have shown that patients with a prior history of peptic ulcer disease and/or GI bleeding and who use NSAIDs, have a greater than 10 fold increase in risk of developing a GI bleed than patients without these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiologic studies have identified several other co-therapies or co-morbid conditions that may increase the risk of GI bleeding, such as treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age and poor general health status.
Renal effects
Renal prostaglandins may play a compensatory role in the maintenance of renal perfusion. Under conditions of compromised renal perfusion, administration of Prexige may therefore cause a reduction in prostaglandin formation and, secondarily, in renal blood flow, and thereby impair renal function. Clinical trials with Prexige have shown renal effects similar to those observed with comparator NSAIDs.
Patients at greatest risk of renal effects are those with pre-existing renal dysfunction, uncompensated heart failure, or cirrhosis and those receiving diuretics or ACE inhibitors. Monitoring of renal function in such patients should be considered. Caution should be used when initiating treatment with Prexige in patients with dehydration. It is advisable to rehydrate patients prior to starting therapy with Prexige.
Hypertension and oedema
As with other drugs known to inhibit prostaglandin synthesis, fluid retention and oedema have been observed in patients taking Prexige in clinical trials. Prexige should therefore be used with caution in patients with a history of cardiac failure, left ventricular dysfunction or hypertension, and in patients with pre-existing oedema of any other cause. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures including discontinuation of Prexige should be taken.
Medically appropriate supervision should be maintained when using Prexige in the elderly and in patients with renal, hepatic, or cardiac dysfunction.
Hepatic effects
In placebo/active-controlled clinical studies up to one year, elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), greater than three times the upper limit of normal (>3 x ULN) have been reported in approximately 1.0% of patients with 100 mg and 1.4% of patients with 200 mg daily.
In one year studies with Prexige, marked elevations (> 8 x ULN) have been observed in 0.2% of patients with 100 mg once daily and 0.6% of patients with 200 mg daily. In one year studies with Prexige, 200 mg and 400 mg daily was associated with more frequent elevations in ALT/AST (2.6% of ALT/AST >3 x ULN), and rare cases of hepatitis have been reported.
As with other NSAIDs, severe hepatic reactions including jaundice, hepatitis, liver necrosis and hepatic failure, some of them with fatal outcome or liver transplantation, have been reported in patients treated with Prexige. Although most cases of serious hepatotoxicity have occurred at doses higher than Prexige 100 mg daily, patients should be advised to remain vigilant for any symptoms compatible with hepatic injury while on treatment with Prexige (e.g. dark urine, jaundice). Patients should stop taking Prexige if any such symptoms occur, and should seek medical advice urgently.
For patients to be treated chronically (See Dosage and method of administration), liver function monitoring is recommended at baseline, and monthly thereafter. Patients with a baseline AST/ALT >1.5xULN should not be commenced on lumiracoxib. If AST/ALT levels >3xULN develop, Prexige therapy should be discontinued immediately.
Prexige should be discontinued immediately if clinical or laboratory signs and/or symptoms consistent with liver disease develop (e.g., jaundice).
Cardiovascular effects
COX-2 selective inhibitors are not a substitute for ASA/aspirin for prophylaxis of cardiovascular thromboembolic diseases because of their lack of antiplatelet effect. Therefore antiplatelet therapies should not be discontinued (See Interactions with other medicinal products and other forms of interaction and Pharmacodynamic properties).
There is no evidence that concurrent use of aspirin decreases the risk of cardiovascular adverse events associated with COX-2 inhibitors, including Prexige.
Clinical trials suggest that the selective COX-2 inhibitor class of drugs may be associated with a risk of thrombotic events (especially myocardial infarction and stroke), relative to placebo and naproxen. As the cardiovascular risks of Prexige, like those of other selective COX-2 inhibitors, may increase with dose and duration of exposure, the shortest duration of treatment 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 (See Dosage and method of administration, Contraindications, Adverse effects and Pharmacodynamic properties).
Prescribers should inform the individual patient of the increased risks when prescribing Prexige for patients with high risk factors for cardiovascular adverse events (e.g. including patients with diabetes, ischaemic heart disease, cardiac failure,, hyperlipidaemia, hypertension or smokers).
Two large, controlled clinical trials of COX-2 selective inhibitors for the treatment of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery found an increased incidence f myocardial infarction and stroke. In the absence f comparable data with Prexige it may be assumed that patient at high risk of cardiovascular disease (including patients with diabetes, ischaemic heart disease, cardiac failure, hyperlipidaemia, hypertension or smokers) who are undergoing major surgery may face an increased risk of developing a cardiovascular event. Patients with significant risk factors for cardiovascular events should only be treated with Prexige after careful consideration of the patient's overall rsik (see Pharmacodynamic properties( and the potential risks and benefits of alternative analgesic therapies.
The use of Prexige in patients with congestive heart failure (NYHA II-IV), established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease is not recommended.
In a meta-analysis of all clinical trials with Prexige including all daily doses tested, the relative risk (95% CI) compared to placebo of myocardial infarction, cardiovascular death or stroke was 1.08 (0.41, 2.86) for the overall population (Prexige n = 7,011).
Skin reactions
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs and some selective COX-2 inhibitors during post-marketing surveillance. Patients appear to be at highest risk for these reactions early in the course of therapy, with the onset of the reaction occurring in the majority of cases within the first month of treatment. Some selective COX-2 inhibitors have been associated with an increased risk of skin reactions in patients with a history of any drug allergy. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving Prexige. Prexige should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
General
If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken and discontinuation of Prexige therapy should be considered.
The pharmacological activity of Prexige in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed non-infectious, painful conditions.
Prexige 100 mg tablets contain lactose (23.3 mg). Patients with rare hereditary problems of galactose intolerance, a severe lactase deficiency or glucose-galactose malabsorption therefore should not take Prexige 100 mg tablets..
Prexige should be avoided in the third trimester of pregnancy because, as with other drugs known to inhibit prostaglandin synthesis, it may cause premature closure of the ductus arteriosus (See Pregnancy and lactation).
Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions
Oral anticoagulants
In a drug interaction study in healthy volunteers, a clinically small but statistically significant increase in the prothrombin time was observed during co-administration of warfarin with Prexige. In line with good clinical practice, anticoagulant activity should be monitored carefully in patients taking warfarin or similar agents, particularly in the first few days after initiating or changing the dose of Prexige. However, co-administration of Prexige with the CYP2C9 substrate warfarin had no effect on the pharmacokinetics of R-warfarin or S-warfarin (See Pharmacokinetic interactions below).
Diuretics and antihypertensive drugs
NSAIDs may reduce the effect of diuretics and antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function), the co-administration of an ACE inhibitor or angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, possibly including acute renal failure, which is usually reversible. These interactions should be taken into consideration in patients taking Prexige concomitantly with ACE inhibitors and diuretics or angiotensin II antagonists. Such combinations should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.
Aspirin
In a drug interaction study in healthy volunteers, Prexige had no clinically relevant interaction with the antiplatelet activity of low-dose aspirin (75 to 100 mg/day). However, concomitant administration of low doses of aspirin with lumiracoxib results in an increase rate of GI ulceration or other compications, compared with the use of lumiracoxib alone.
Cyclosporin or tacrolimus
Although this interaction has not been specifically studied with Prexige, co-administration of cyclosporin or tacrolimus and any NSAID may increase the nephrotoxic effect of cyclosporin or tacrolimus. Renal function should be monitored when Prexige and either of these drugs are used in combination (See Special warnings and special precautions for use).
Pharmacokinetic interactions
The oxidative metabolism of lumiracoxib is mainly CYP2C9 mediated. In vitro studies indicate that lumiracoxib is not a significant inhibitor of other cytochrome P450 isoforms, including CYP1A2, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.
Based on in vitro studies, lumiracoxib appears to have low potential for interactions with compounds cleared by cytochrome P450, with the exception of CYP2C9, where there is a possibility of decreased clearance of concomitantly administrated substrates of CYP2C9. In vivo studies, however, suggest that lumiracoxib has low potential for interactions with other substrates of CYP2C9.
Based on in vitro studies, interactions involving plasma protein binding are not expected to have any clinically relevant effects on lumiracoxib or co-administered drugs.
Effects of other drugs on the pharmacokinetics of lumiracoxib
Fluconazole
Co-administration of lumiracoxib with the potent CYP2C9 inhibitor fluconazole had no clinically relevant effect on the pharmacokinetics of lumiracoxib.
Omeprazole
Omeprazole had no effect on the pharmacokinetics of lumiracoxib.
Antacids
Aluminium hydroxide/magnesium hydroxide had no relevant effect on the pharmacokinetics of lumiracoxib.
Effects of lumiracoxib on the pharmacokinetics of other drugs
Warfarin
Co-administration of lumiracoxib with the CYP2C9 substrate warfarin had no effect on AUC, Cmax or Tmax of R-warfarin or S-warfarin.
Methotrexate
Co-administration of lumiracoxib at 400 mg once daily (four times the recommended chronic daily dose), had no clinically significant effects on the plasma pharmacokinetics, plasma protein binding or urinary excretion of methotrexate or of the 7-hydroxy methotrexate metabolite.
Oral contraceptives
Co-administration of lumiracoxib did not affect the steady-state pharmacokinetics of ethinyloestradiol or levonorgestrel. Taking the pharmacokinetic and pharmacodynamic interaction data into consideration, no alteration in oral contraceptive medication is necessary when lumiracoxib is co-administered.
Lithium
NSAIDs, including selective COX-2 inhibitors such as lumiracoxib, have been known to produce elevation of plasma lithium levels and reduction in renal lithium clearance. Thus when lumiracoxib and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
Pregnancy and lactation
Pregnancy
The use of Prexige in pregnant women has not been studied. It should therefore not be used during the first two trimesters of pregnancy unless the potential benefit to the patient justifies the potential risk to the foetus.
Prexige should be avoided in the third trimester of pregnancy because, as with other drugs known to inhibit prostaglandin synthesis, it may cause uterine inertia and premature closure of the ductus arteriosus.
Prexige is not recommended in women attempting to conceive.
Lactation
It is not known whether lumiracoxib is excreted in human milk. Lumiracoxib is excreted in the milk of lactating rats. Women who use lumiracoxib should not breast-feed.
Effects on ability to drive and use machines
No studies on the effect of lumiracoxib on the ability to drive or use machines have been performed. However, patients who experience central nervous effects such as dizziness or visual disturbances while taking Prexige should refrain from driving or using machines.
Adverse effects
In clinical studies, Prexige was evaluated for safety in approximately 18,500 patients, including approximately 15,850 patients with OA and 2,650 patients with RA. Approximately 13,500 patients were treated for three months, approximately 9,640 patients were treated for 6 months, and approximately 6,650 patients were treated for 1 year.
In clinical studies the following adverse effects were reported at an incidence greater than placebo in patients with OA or RA treated with Prexige daily for up to one year.
Frequencies are defined as: common (>1/100, ≤1/10), uncommon (>1/1,000, ≤1/100), rare (>1/10,000, ≤1/1,000).
Table 1
| Infections | |
|---|---|
| Common | Influenza-like symptoms, respiratory tract infection (e.g bronchitis), urinary tract infection |
| Uncommon | Candidiasis, ear infection, herpes simplex, tooth infection |
| Blood and lymphatic system disorders | |
| Uncommon | Anaemia |
| Rare | Pancytopenia, thrombocythaemia |
| Psychiatric disorders | |
| Uncommon | Depression, insomnia, anxiety |
| Nervous system disorders | |
| Common | Dizziness, headache |
| Uncommon | Syncope, hypoaesthaesia, migraine, paraesthesia, dysgeusia, vertigo |
| Eye disorders | |
| Uncommon | Conjunctivitis, dry eye, visual disturbance (e.g. blurred vision) |
| Rare | Visual acuity reduced |
| Cardiac disorders | |
| Uncommon | Palpitations, myocardial infarction* |
| Rare | Atrioventricular block of first degree |
| Vascular disorders | |
| Uncommon | Hypotension, cerebrovascular accident* |
| Respiratory disorders | |
| Common | Cough, pharyngitis |
| Uncommon | Dyspnoea, epistaxis, rhinitis, sinus congestion |
| Gastrointestinal disorders | |
| Common | Abdominal pain, constipation, diarrhoea, dyspepsia, nausea, vomiting, flatulence |
| Uncommon | Gastroduodenal ulcer or erosions, gastritis, oesophagitis, abdominal distension, aphthous stomatitis, dry mouth, dysphagia, epigastric discomfort, eructation, gastrooesophageal reflux disease, gingivitis, hyperacidity, toothache |
| Rare | Gastrointestinal haemorrhage |
| Hepatobiliary disorders | |
| Rare | Cholecystitis, cholelithiasis, hepatitis |
| Skin and subcutaneous tissue disorders | |
| Uncommon | Contusion, exanthem, pruritus, rash urticaria |
| Musculoskeletal disorders | |
| Uncommon | Joint swelling, muscle cramps |
| Rare | Angioedema |
| Renal and urinary disorders | |
| Uncommon | Dysuria, urinary frequency |
| Rare | Chromaturia, renal failure |
| Reproductive system disorders | |
| Rare | Erectile dysfunction |
| General disorders | |
| Common | Fatigue, oedema (e.g. lower limb) |
| Uncommon | Chest pain, rigors, thirst |
| Rare | Anaphylaxis |
| Investigations | |
| Uncommon | Alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, blood creatinine increased, blood urea increased, gamma-glutamyltransferase (gamma-GT) increased, weight increased |
* Based on analyses of long-term placebo and active controlled clinical trials, some selective COX-2 inhibitors have been associated with an increased risk of serious thrombotic arterial events, including myocardial infarction and stroke. The absolute risk increase for such events is unlikely to exceed 1% per year based on existing data (uncommon).
The following rare serious adverse effects have been reported in association with the use of NSAIDs including Prexige: nephrotoxicity including interstitial nephritis, nephrotic syndrome and renal failure; cutaneo-mucosal adverse effects and severe skin reactions.
Post-marketing events of jaundice, hepatitis and hepatic failure (some of them resulting in a fatal outcome or liver transplantation) have been reported in patients treated with lumiracoxib, predominantly with doses higher than 100 mg per day and for chronic use (See also Special warnings and precautions for use).
In addition, the following post-marketing events have also been reported in patients treated with Prexige: tachycardia, hypertension, hypertension aggravated, severe hypertension, somnolence.
Overdose
There is limited post-marketing experience of overdose with lumiracoxib. In the event of suspected overdose, appropriate supportive medical care should be provided, e.g. elimination of the gastric contents, clinical supervision and, if necessary, the institution of symptomatic treatment.
Haemodialysis is unlikely to be an efficient method of drug removal due to high protein binding.
Pharmacological properties
Pharmacodynamic properties
Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, non-steroids, coxibs (ATC code: M01AH06)
Mode of Action
Lumiracoxib is an orally active, selective cyclo-oxygenase-2 (COX-2) inhibitor within the clinical dose range. Selective inhibition of COX-2 by lumiracoxib provides anti-inflammatory and analgesic effects with improved gastrointestinal safety over that seen with non-selective NSAIDs.
Cyclooxygenase catalyses the first steps in the generation of prostaglandins and is encoded by two genes. These gene products, COX-1 and COX-2, are distinct in their regulation of gene expression and subsequent physiological roles. COX-1 is constitutively expressed in most tissues, including stomach, intestine, kidney, and in platelets. Its physiological activities include gastric protection, renal filtration and platelet aggregation. COX-2 is induced by pro-inflammatory and mitogenic stimuli and is responsible for the synthesis of prostaglandins mediating the symptoms of pain, inflammation, and fever. COX-2 also promotes angiogenesis and, accordingly, is involved with tissue proliferation and remodelling. As such, COX-2 plays a role in oncogenesis as well as ovulation, implantation and closure of the ductus arteriosus. It may also play a role in tissue healing. COX-2 has been identified in tissue around gastric ulcers in man but its relevance to ulcer healing has not been established. COX-2 is constitutively expressed in the kidney (where it augments filtration) and central nervous system (where it modulates fever induction, pain perception and cognitive function).
In the vasculature prostacyclin, which is produced by both COX-1 and COX-2, prevents platelet activation and promotes vasodilation. Platelet COX-1-derived thromboxane has the opposite role - driving aggregation and vasoconstriction. The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical significance in patients at risk of thrombo-embolic reactions. COX-2 selective inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane. The clinical relevance of these observations has not been established.
Across clinical pharmacology studies, lumiracoxib produced dose and concentration-dependent inhibition of COX-2 in whole blood without inhibition of COX-1. Administration of 100 mg, 200 mg, 400 mg or 800 mg once daily leads to >90 % peak inhibition of COX-2 activity as assessed in an ex vivo assay for LPS-induced PGE2 production with an EC50 of 60 ng/mL. There was no significant inhibition of COX-1 (assessed as ex vivo inhibition of thromboxane B2) up to 800 mg and concentration of 34,400 ng/mL.
Across three different studies in healthy volunteers and osteoarthritis patients Prexige at doses of either 200 mg, 400 mg and 800 mg administered once daily for up to 7 days did not significantly reduce the daily urinary excretion of the thromboxane A2 metabolites, consistent with lack of COX-1 inhibition in vivo. Compared to placebo Prexige (200 mg and 400 mg once daily for up to 7 days) transiently reduced the urinary excretion of the prostacyclin metabolites over a dosing interval.
Prexige (400 mg for 7 days, and 800 mg and 1,200 mg for 4 weeks) had no effect on platelet aggregation following activation by either arachidonic acid or collagen. Prexige 800 mg daily (eight times the recommended chronic daily dose) did not lead to clinically meaningful inhibition of gastric prostaglandin E2 synthesis. Two 13-week endoscopy studies with Prexige at doses up to 800 mg once daily showed that the incidence of gastrointestinal ulcers was approximately 4 % with Prexige and approximately 16 % with ibuprofen 800 mg t.i.d.
Hypertensive patients
Prexige at daily doses of 100 mg and 200 mg did not affect blood pressure control in hypertensive patients compared with placebo. Administration of Prexige at 400 mg once daily for 12 months did not increase newly occurring hypertension relative to naproxen or ibuprofen, nor aggravate pre-existing hypertensive conditions.
Clinical studies on osteoarthritis
In patients with osteoarthritis, Prexige 100 mg once daily provided significant improvements in pain, stiffness, function, and patient assessments of disease status. These beneficial effects were maintained for up to 52 weeks.
Increasing the dose to above 100 mg daily is not recommended, as this does not provide any additional benefit and may increase the risks of adverse effects.
The Therapeutic lumiracoxib Arthritis Research and Gastrointestinal Event Trial (TARGET)
TARGET, a 12-month, double-blind, phase III study, included 18,325 OA patients randomized to Prexige 400 mg o.d. (four times the recommended OA dose), naproxen 500 mg b.i.d. or ibuprofen 800 mg t.i.d. TARGET included patients taking low-dose ASA/aspirin (75 to 100 mg daily) for primary or secondary prevention of coronary heart disease. Randomization was stratified by low-dose ASA/aspirin use (24 % of patients in the overall study population) and age.
Gastrointestinal Effect
The primary endpoint was time to event distribution of definite or probable upper gastrointestinal tract ulcer (UGIT) complications (POBs) in patients not receiving low-dose ASA/aspirin and in the overall population. The results are shown in Table 1 below. In the low dose ASA/aspirin group a lower incidence of GI events was observed with Prexige compared to both NSAIDs (21%), however the study was not powered to show a difference in this group and it did not reach statistical significance.
Table 1: TARGET: symptomatic and complicated upper GI tract ulcers (POBs, PUBs)
| Number at risk |
Number (%) with events |
Hazard ratio | 95 % CI | p-value* | |
|---|---|---|---|---|---|
| Upper GI tract ulcer complications (POBs) | |||||
| No low-dose ASA/aspirin | |||||
| Study 0117 | |||||
| Lumiracoxib | 3549 | 9 (0.25) | 0.24 | 0.12 - 0.50 | 0.0001 |
| Naproxen | 3537 | 36 (1.02) | |||
| Study 2332 | |||||
| Lumiracoxib | 3401 | 5 (0.15) | 0.17 | 0.07 - 0.45 | 0.0003 |
| Ibuprofen | 3431 | 28 (0.82) | |||
| Overall population | |||||
| Study 0117 | |||||
| Lumiracoxib | 4741 | 19 (0.40) | 0.37 | 0.22 - 0.63 | 0.0002 |
| Naproxen | 4730 | 50 (1.06) | |||
| Study 2332 | |||||
| Lumiracoxib | 4376 | 10 (0.23) | 0.29 | 0.14 - 0.59 | 0.0006 |
| Ibuprofen | 4397 | 33 (0.75) | |||
| Upper GI tract ulcer complications or symptomatic ulcers (PUBs) | |||||
| No low-dose /ASA/aspirin | |||||
| Study 0117 | |||||
| Lumiracoxib | 3549 | 34 (0.96) | 0.39 | 0.26 - 0.58 | <0.0001 |
| Naproxen | 3537 | 85 (2.40) | |||
| Study 2332 | |||||
| Lumiracoxib | 3401 | 21 (0.62) | 0.36 | 0.22 - 0.60 | <0.0001 |
| Ibuprofen | 3431 | 57 (1.66) | |||
| Overall population | |||||
| Study 0117 | |||||
| Lumiracoxib | 4741 | 54 (1.14) | 0.46 | 0.33 - 0.64 | <0.0001 |
| Naproxen | 4730 | 116 (2.45) | |||
| Study 2332 | |||||
| Lumiracoxib | 4376 | 34 (0.78) | 0.47 | 0.31 - 0.70 | 0.0003 |
| Ibuprofen | 4397 | 71 (1.61) | |||
Cardiovascular Effect
The primary cardiovascular (CV) endpoint studied was the Antiplatelet Trialists' Collaboration (APTC) endpoint: confirmed or probable myocardial infarction (clinical or silent), stroke (ischemic or haemorrhagic) and CV death. There were no significant differences in the total number of patients with confirmed or probable APTC events between Prexige (59 patients, 0.65%) and NSAIDs (50 patients, 0.55%) (See the results in Table 2).
There was no statistically significant difference between Prexige and NSAIDs for any individual CV endpoint (MI, stroke, CV death, transient ischaemic attacks, deep vein thrombosis and pulmonary embolism). For systolic blood pressure, mean change from baseline was +0.4 mmHg for Prexige and +2.1 mmHg for NSAIDs (p<0.0001).
For diastolic blood pressure, mean change from baseline was -0.1 mmHg for Prexige and +0.5 mmHg for NSAIDs (p<0.0001).
Table 2: TARGET:Confirmed or probable CV events: CV deaths, MIs, strokes (APTC endpoint)
| Number at risk | Number (%) with events |
Hazard ratio | 95 % CI | p-value | |
|---|---|---|---|---|---|
| Overall population | |||||
| Study 0117 | |||||
| Lumiracoxib | 4741 | 40 (0.84) | 1.46 | 0.89 - 2.37 | 0.1313 |
| Naproxen | 4730 | 27 (0.57) | |||
| Study 2332 | |||||
| Lumiracoxib | 4376 | 19 (0.43) | 0.76 | 0.41 - 1.40 | 0.3775 |
| Ibuprofen | 4397 | 23 (0.52) | |||
| No low-dose ASA/aspirin | |||||
| Study 0117 | |||||
| Lumiracoxib | 3549 | 22 (0.62) | 1.49 | 0.76 - 2.92 | 0.2417 |
| Naproxen | 3537 | 14 (0.40) | |||
| Study 2332 | |||||
| Lumiracoxib | 3401 | 13 (0.38) | 0.94 | 0.44 - 2.04 | 0.8842 |
| Ibuprofen | 3431 | 13 (0.38) | |||
| Low-dose ASA/aspirin | |||||
| Study 0117 | |||||
| Lumiracoxib | 1192 | 18 (1.51) | 1.42 | 0.70 - 2.90 | 0.3368 |
| Naproxen | 1193 | 13 (1.09) | |||
| Study 2332 | |||||
| Lumiracoxib | 975 | 6 (0.62) | 0.56 | 0.20 - 1.54 | 0.2603 |
| Ibuprofen | 966 | 10 (1.04) | |||
Pharmacokinetic properties
Absorption
Lumiracoxib is rapidly absorbed following oral administration. At 15 minutes post 400 mg dose, the plasma concentration reached 0.6 microgram/mL, which is sufficiently high to achieve over 90% inhibition of COX-2. Median Tmax is about 2 hours post dose. Over the range of 25 to 800 mg, extent of exposure (AUC) increases in a dose-proportional manner and the peak plasma concentration (Cmax) was roughly dose-proportional. Following 400 mg once daily dosing, Cmax was about 9 micrograms/mL and AUC was about 31 micrograms h/mL.
The absolute bioavailability of lumiracoxib is approximately 74%.
Distribution
Lumiracoxib is highly bound to plasma proteins (≥98 %), and binding is independent of concentration over a range of 0.1 to 100 micrograms/mL.
The volume of distribution (Vss) is 9 L.
Concentrations of lumiracoxib in human synovial fluid were higher than in plasma by about 5 hours post dose and remained substantially higher than the plasma level for the remainder of the dose interval (AUC12-24 in synovial fluid was 2.6 times higher). No difference was observed in the extent of lumiracoxib protein binding in synovial fluid compared to plasma.
Lumiracoxib crosses the placenta in rats and rabbits.
One hour after oral administration of [14C]-labeled lumiracoxib in a carrageenan-treated rat model of inflammation, the ratio of radioactivity detected at the site of inflammation versus that detected in control (saline-treated) rats was 2.7:1, and was 5.3:1 four hours post dose. The ratios were 2.4:1 and 3.6:1 at 1 hour and 4 hours post dose, respectively, comparing the carrageenan-treated versus untreated footpads in the same animal. This indicates lumiracoxib and/or its metabolites are preferentially retained in inflamed tissue.
Biotransformation
In humans lumiracoxib undergoes extensive hepatic metabolism. The oxidative metabolism of lumiracoxib is mainly CYP2C9 mediated. Of the total drug-related material in plasma, unchanged lumiracoxib is the major component. Three major metabolites were identified in plasma: 4'-hydroxy-lumiracoxib, 5-carboxy-lumiracoxib and 4'-hydroxy-5-carboxy-lumiracoxib. In addition various conjugates (glucuronides and sulfates) of these metabolites are formed. The 4'-hydroxy metabolite has potency and COX-2 selectivity that is one third of lumiracoxib.
The concentration of 4'-hydroxy metabolite in plasma and synovial fluid is low, thus it is unlikely to contribute to efficacy. Other metabolites are not active as COX-1 or COX-2 inhibitors.
Elimination
Lumiracoxib is eliminated predominantly via hepatic metabolism. After administration of a single dose of lumiracoxib 400 mg to healthy subjects, 54% of drug-related material was excreted in urine and 43% in faeces. Only about 5% of the administrated dose was recovered in excreta as unchanged lumiracoxib.
Plasma clearance is 7.7 L/h.
The mean plasma half-life of lumiracoxib is approximately 4 hours. Lumiracoxib does not accumulate in plasma under once or twice daily administration and steady state is achieved on the first day of administration with no increase in Cmax or AUC after extended dosing.
Population pharmacokinetics
There is no difference in exposure of lumiracoxib in men and women.
In elderly subjects (over 65 years old), a 15% increase in AUC was observed as compared to younger subjects. Dosage adjustment in the elderly is not necessary.
The pharmacokinetics of lumiracoxib are similar in Asians, Blacks and Caucasians.
CYP2C9 polymorphism
On the basis of both plasma exposures to lumiracoxib and pharmacogenetic analysis, no evidence has been found to suggest that exposure to lumiracoxib is increased in subjects with genotypes of CYP2C9 associated with reduced metabolic clearance. No dose adjustment is necessary in patients known to be poor metabolisers of CYP2C9.
Hepatic insufficiency
Compared to healthy subjects, exposure to lumiracoxib was not changed in patients with moderate hepatic impairment (Child-Pugh score 7-8). No difference in plasma protein binding was observed between the two groups. The pharmacokinetics of lumiracoxib have not been studied in patients with severe hepatic impairment (Child-Pugh >9). Patients with hepatic impairment should not be treated with Prexige (See Contraindications and Special warnings and precautions for use).
Renal insufficiency
Mild (estimated creatinine clearance between 50 to 65 mL/min) or moderate renal impairment (estimated creatinine clearance between 30 to 49 mL/min) had no effect on the pharmacokinetics of lumiracoxib. When lumiracoxib was administered to patients with end-stage renal disease, a 33% decrease in lumiracoxib Cmax and a 27% decrease in AUC were observed compared to healthy subjects.
Mild and moderate renal impairment affected the pharmacokinetics of the three major metabolites, 4'-hydroxy-lumiracoxib, 5-carboxy-lumiracoxib and 4'-hydroxy-5-carboxy-lumiracoxib, in a similar fashion. AUC increased two-fold and T1/2 increased about three-fold for each of the three metabolites measured compared to healthy subjects. While there was no significant increase in exposure to the active metabolite, 4'-hydroxy-lumiracoxib, in patient with end-stage renal disease, significant accumulation of 4'-hydroxy-5-carboxy-lumiracoxib occurred.
Plasma protein binding of lumiracoxib was similar in healthy subjects and in patients with end-stage renal disease. Dialysis has no effect on the exposure of patients to lumiracoxib or its active metabolite. While renal insufficiency does not significantly influence the pharmacokinetics of lumiracoxib and its active metabolite, use of Prexige in advance renal disease is not recommended (See Contraindications and Special warnings and precautions for use).
Paediatric patients
The pharmacokinetics of lumiracoxib in paediatric patients have not been studied.
Preclinical safety data
In preclinical studies, lumiracoxib has been demonstrated to be neither mutagenic nor carcinogenic. Chromosome aberrations were induced in V79 cells at high, cytotoxic concentrations of lumiracoxib, which are not considered to have biological relevance for humans. There was no indication of genotoxic potential in three in vivo rat studies (micronucleus tests in bone marrow and liver and liver comet assay.
In repeated-dose toxicity studies in rats and monkeys, target organs were the gastrointestinal tract and kidney. Systemic exposure at levels with no adverse effect for these targets in rats (26-week study) and monkeys (39-week study) were 6.5 and 22 times that in man following a 200 mg therapeutic dose, respectively.
Lumiracoxib was not teratogenic in reproductive toxicity studies conducted in rats and rabbits at doses representing systemic exposure 10.4 (rat) and 38 (rabbit) times greater than the human therapeutic level after a 200 mg dose. In rats the incidence of pre-implantation loss was increased at a dose of 100 mg/kg/day (10.4 times the human therapeutic exposure following a dose of 200 mg), which caused maternal toxicity. The incidence of resorption was increased in rabbits at approximately 9 times the human exposure following a 200 mg dose. At the level with no embryo/foetal effect, the systemic exposure was 8.6 (rat) and 2.2 (rabbit) times that in man following a 200 mg therapeutic dose. In a pre- and post-natal development study in rats, an increase in stillborn pups and reduced embryo/foetal survival was seen at maternally toxic doses of ≥3 mg/kg.
Pharmaceutical particulars
List of excipients
100 mg tablets
Tablet core: microcrystalline cellulose, croscarmellose sodium, lactose, povidone, titanium dioxide (E 171), magnesium stearate.
Tablet coating: hypromellose, polyethylene glycol, talc, iron oxide red (E 172), iron oxide black (E 172) and titanium dioxide (E 171).
Incompatibilities
Not applicable
Shelf life
3 years.
Special precautions for storage
Store at or below 30°C
Keep out of the reach and sight of children.
Nature and contents of container
100mg: Clear PVC/aluminium blister packs containing 30 tablets.
Instructions for use and handling
No specific instructions for use.
Medicine classification
Prescription Medicine
Name and address
Novartis New Zealand Limited
Private Bag 47909
Ponsonby
6-8 Mackelvie Street
Grey Lynn
Auckland
Telephone: 09 361 8100
Date of preparation
7 October 2007
(Ref BPI: 7 September 2007 + Medsafe requirements)