Lexib 100 & 200 100 mg, 200 mg Capsule

LEXIB is indicated for symptomatic treatment of inflammation and pain in osteoarthritis and rheumatoid arthritis. Treatment of pain post dental surgery. Treatment of mild to moderate post-operative pain. Treatment of mild to moderate musculoskeletal pain. Treatment of mild to moderate primary dysmenorrhoea. Relief of signs and symptoms of ankylosing spondylitis.

Posology
Use in adults:
As the cardiovascular risks of LEXIB may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used.
Osteoarthritis: The recommended daily dose is 200 mg, administered as a single dose or as two divided doses. Doses up to 400 mg per day have been studied.
Rheumatoid arthritis: The recommended daily dose is 100 mg or 200 mg twice per day.
Pain post dental surgery: The recommended dose is 100 mg to 200 mg, up to a maximum daily dose of 400 mg. Dosing intervals should not be less than 4 hours.
Mild to moderate post-operative pain: The recommended dose is 200 mg once daily. Some patients may benefit from an additional 200 mg dose.
Mild to moderate musculoskeletal pain: The recommended dose is 200 mg twice daily.
Mild to moderate primary dysmenorrhea: The recommended dose 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.
Ankylosing spondylitis: The recommended daily dose is 200 mg, administered as a single dose or as 100 mg twice per day. Some patients may benefit from a total daily dose of 400 mg.
Special populations
Elderly: No dosage adjustment is necessary. However, for elderly patients with a lower than average body weight (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. Introduce LEXIB at the lowest recommended dose in patients with moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment (see sections 4.3, 4.4 and 5.2).
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 (see sections 4.3, 4.4 and 5.2).
Paediatric population: LEXIB is not indicated for use in children.
Method of administration
For oral use

Hypersensitivity to celecoxib or any other ingredient of LEXIB listed in section 6.1
Known sulphonamide hypersensitivity.
Active peptic ulceration or gastrointestinal (GI) bleeding.
In pregnancy and in women of childbearing potential unless using an effective method of contraception (see section 4.6). Celecoxib has been shown to cause malformations in animal species studied (see sections 4.6). The potential for human risk in pregnancy is unknown but cannot be excluded.
Breast-feeding.
Severe impairment of hepatic function.
Severe impairment of renal function.
Asthma, urticaria or allergic-type reactions precipitated by aspirin or non-steroidal anti-inflammatory drugs, including other cyclooxygenase 2 (COX-2) specific inhibitors.
Inflammatory bowel disease.
Congestive heart failure (NYHA II-IV).
Established ischaemic heart disease and/or cerebrovascular disease (stroke) and peripheral arterial disease.
Peri-operative analgesia in the setting of coronary artery bypass surgery (CABG).

Gastrointestinal (GI) effects
Upper and lower gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them resulting in fatal outcome, have occurred in patients treated with celecoxib. Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; the elderly, patients using any other NSAID or acetylsalicylic acid or glucocorticoids concomitantly, patients using alcohol, or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding.
There is further increase in the risk of gastrointestinal adverse effects for celecoxib (gastrointestinal ulceration or other gastrointestinal complications), when celecoxib is taken concomitantly with acetylsalicylic acid (even at low doses). A significant difference in GI safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been demonstrated in long-term clinical trials (see section 5.1).
Concomitant NSAID use
The concomitant use of celecoxib and a non-aspirin NSAID should be avoided.
Cardiovascular effects
Increased number of serious cardiovascular (CV) events, mainly myocardial infarction, has been found in a long-term placebo-controlled study in subjects with sporadic adenomatous polyps treated with celecoxib at doses of 200 mg twice daily and 400 mg twice daily compared to placebo (see section 5.1).
As the cardiovascular risks of celecoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. NSAIDs, including COX-2 selective inhibitors, have been associated with increased risk of cardiovascular and thrombotic adverse events when taken long term. The exact magnitude of the risk associated with a single dose has not been determined, nor has the exact duration of therapy associated with increased risk. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis (see sections 4.2, 4.3, 4.8 and 5.1).
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with celecoxib after careful consideration (see section 5.1).
COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thrombo-embolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapies should not be discontinued (see section 5.1).
Fluid retention and oedema
Fluid retention and oedema have been observed in patients taking celecoxib. Therefore, celecoxib should be used with caution in patients with history of cardiac failure, left ventricular dysfunction or hypertension, and in patients with pre-existing oedema from any other reason, since prostaglandin inhibition may result in deterioration of renal function and fluid retention. Caution is also required in patients taking diuretic treatment or otherwise at risk of hypovolaemia.
Hypertension
Celecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events. Therefore, blood pressure should be monitored closely during the initiation of therapy with celecoxib and throughout the course of therapy.
Hepatic and renal effects
Compromised renal or hepatic function and especially cardiac dysfunction are more likely in the elderly and therefore medically appropriate supervision should be maintained. NSAIDs, including celecoxib, may cause renal toxicity. Clinical trials with celecoxib have shown renal effects similar to those observed with comparator NSAIDs. Patients at greatest risk for renal toxicity are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors, angiotensin II receptor antagonists, and the elderly (see section 4.5). Such patients should be carefully monitored while receiving treatment with celecoxib. Some cases of severe hepatic reactions, including fulminant hepatitis (some with fatal outcome), liver necrosis and, hepatic failure (some with fatal outcome or requiring liver transplant), have been reported with celecoxib. Among the cases that reported time to onset, most of the severe adverse hepatic events developed within one month after initiation of celecoxib treatment (see section 4.8). If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken and discontinuation of celecoxib therapy should be considered.
CYP2D6 inhibition
Celecoxib inhibits CYP2D6. Although it is not a strong inhibitor of this enzyme, a dose reduction may be necessary for individually dose-titrated medicinal products that are metabolised by CYP2D6 (see section 4.5).
CYP2C9 poor metabolisers
Patients known to be CYP2C9 poor metabolisers should be treated with caution (see section 5.2).
Skin and systemic hypersensitivity reactions
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with the use of celecoxib (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (including anaphylaxis, angioedema and drug rash with eosinophilia and systemic symptoms (DRESS), or hypersensitivity syndrome), have been reported in patients receiving celecoxib (see section 4.8). Patients with a history of sulfonamide allergy or any drug allergy may be at greater risk of serious skin reactions or hypersensitivity reactions (see section 4.3). Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
General
Celecoxib may mask fever and other signs of inflammation.
Use with oral anticoagulants
In patients on concurrent therapy with warfarin, serious bleeding events, some of them fatal, have been reported. Increased prothrombin time (INR) with concurrent therapy has been reported. Therefore, this should be closely monitored in patients receiving warfarin/coumarin-type oral anticoagulants, particularly when therapy with celecoxib is initiated or celecoxib dose is changed (see section 4.5). Concomitant use of anticoagulants with NSAIDS may increase the risk of bleeding. Caution should be exercised when combining celecoxib with warfarin or other oral anticoagulants, including novel anticoagulants (e.g. apixaban, dabigatran, and rivaroxaban).

Pharmacodynamic interactions
Anticoagulants
Anticoagulant activity should be monitored particularly in the first few days after initiating or changing the dose of celecoxib in patients receiving warfarin or other anticoagulants since these patients have an increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with celecoxib is initiated or the dose of celecoxib is changed (see section 4.4). Bleeding events in association with increases in prothrombin time have been reported, predominantly in the elderly, in patients receiving celecoxib concurrently with warfarin, some of them fatal.
Anti-hypertensives
NSAIDs may reduce the effect of anti-hypertensive medicinal products including ACE-inhibitors, angiotensin II receptor antagonists, diuretics and beta-blockers. As for NSAIDs, the risk of acute renal insufficiency, which is usually reversible, may be increased in some patients with compromised renal function (e.g. dehydrated patients, patients on diuretics, or elderly patients) when ACE-inhibitors, angiotensin II receptor antagonists, and/or diuretics are combined with NSAIDs, including celecoxib (see section 4.4). Therefore, the combination 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.
In a 28-day clinical study in patients with lisinopril-controlled Stage I and II hypertension, administration of celecoxib 200 mg twice daily 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 treated with celecoxib 200 mg twice daily, 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 treated with placebo; this difference was statistically significant.
Ciclosporin and tacrolimus
Co-administration of NSAIDs and ciclosporin or tacrolimus may increase the nephrotoxic effect of ciclosporin or tacrolimus, respectively. Renal function should be monitored when celecoxib and any of these medicinal products are combined.
Acetylsalicylic acid
Celecoxib can be used with low-dose acetylsalicylic acid but is not a substitute for acetylsalicylic acid for cardiovascular prophylaxis. An increased risk of gastrointestinal ulceration or other gastrointestinal complications compared to use of celecoxib alone was shown for concomitant administration of low-dose acetylsalicylic acid (see section 5.1).
Pharmacokinetic interactions
Effects of celecoxib on other medicinal products
CYP2D6 inhibition
Celecoxib is an inhibitor of CYP2D6. The plasma concentrations of medicinal products that are substrates of this enzyme may be increased when celecoxib is used concomitantly. Examples of medicinal products which are metabolised by CYP2D6 are antidepressants (tricyclics and SSRIs), neuroleptics, anti-dysrhythmic medicinal products, etc. The dose of individually dose-titrated CYP2D6 substrates may need to be reduced when treatment with celecoxib is initiated or increased if treatment with celecoxib is terminated.
Concomitant administration of celecoxib 200 mg twice daily resulted in 2.6-fold and 1.5-fold increases in plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates), respectively. These increases are due to celecoxib inhibition of the CYP2D6 substrate metabolism.
CYP2C19 inhibition
In vitro studies have shown some potential for celecoxib to inhibit CYP2C19 catalysed metabolism. The clinical significance of this in vitro finding is unknown. Examples of medicinal products which are metabolised by CYP2C19 are diazepam, citalopram and imipramine.
Methotrexate
In patients with rheumatoid arthritis celecoxib had no statistically significant effect on the pharmacokinetics (plasma or renal clearance) of methotrexate (in rheumatologic doses). However, adequate monitoring for methotrexate-related toxicity should be considered when combining these two medicinal products.
Lithium
In healthy subjects, co-administration of celecoxib 200 mg twice daily with 450 mg twice daily of lithium resulted in a mean increase in C max of 16 % and in AUC of 18 % of lithium. Therefore, patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn.
Oral contraceptives
In an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of oral contraceptives (1 mg norethisterone /35 micrograms ethinylestradiol).
Glibenclamide/tolbutamide
Celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrate), or glibenclamide to a clinically relevant extent.
Effects of other medicinal products on celecoxib
CYP2C9 poor metabolisers
In individuals who are CYP2C9 poor metabolisers and demonstrate increased systemic exposure to celecoxib, concomitant treatment with CYP2C9 inhibitors such as fluconazole could result in further increases in celecoxib exposure. Such combinations should be avoided in known CYP2C9 poor metabolisers (see sections 4.2 and 5.2).
CYP2C9 inhibitors and inducers
Since celecoxib is predominantly metabolised by CYP2C9 it should be used at half the recommended dose in patients receiving fluconazole. Concomitant use of 200 mg single dose of celecoxib and 200 mg once daily of fluconazole, a potent CYP2C9 inhibitor, resulted in a mean increase in celecoxib C max of 60% and in AUC of 130%. Concomitant use of inducers of CYP2C9 such as rifampicin, carbamazepine and barbiturates may reduce plasma concentrations of celecoxib.
Ketoconazole and antacids
Ketoconazole or antacids have not been observed to affect the pharmacokinetics of celecoxib.

Pregnancy
Studies in animals have shown reproductive toxicity, including malformations (see sections 4.3). Inhibition of prostaglandin syntheses might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. The potential for human risk in pregnancy is unknown but cannot be excluded. Celecoxib may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Celecoxib is contraindicated in pregnancy and in women who can become pregnant (see sections 4.3 and 4.4). If a woman becomes pregnant during treatment, celecoxib should be discontinued.
Breast-feeding
Celecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. Administration of celecoxib to a limited number of lactating women has shown a very low transfer of celecoxib into breast milk. Women who take celecoxib should not breastfeed.
Fertility
Based on the mechanism of action, the use of NSAIDs, including celecoxib, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women.

Patients who experience dizziness, vertigo or somnolence while taking celecoxib should refrain from driving or operating machinery.

Summary of the safety profile
The following side effects have been reported in patients on LEXIB treatment. Adverse reactions are listed by system organ class and ranked by frequency in Table 1.
Table 1. Adverse Drug Reactions
MedDRA system organ class Frequency Undesirable effect
Infections and infestations Frequent Sinusitis, upper respiratory tract infection, urinary tract infection
Blood and lymphatic system disorders Less frequent Anemia
Leucopenia, thrombocytopenia
Pancytopenia
Immune system disorders Frequent Allergy aggravated (hypersensitivity)
Less frequent Anaphylactic shock, anaphylaxis(anaphylactic reaction)
Metabolism and nutrition disorders Less frequent Hyperkaelemia
Psychiatric disorders Frequent Insomnia
Less frequent Anxiety, depression, tiredness
Confusion (confusional state), hallucinations
Nervous system disorders Frequent Dizziness, hypertonia, headache
Less frequent Cerebral infarction, paraesthesia, somnolence
Ataxia, taste alteration
Fatal intracranial haemorrhage, meningitis aseptic, aggravated epilepsy, ageusia, anosmia
Eye disorders Less frequent Blurred vision, conjunctivitis
Ocular haemorrhage
Retinal artery occlusion, retinal vein occlusion
Ear and labyrinth disorders Less frequent Tinnitus, hypoacusis
Cardiac disorders Frequent Myocardial infarction
Less frequent Heart failure, palpitations, tachycardia
Arrhythmia
Vascular disorders Frequent Hypertension (including aggravated hypertension)
Less frequent Pulmonary embolism, flushing
Vasculitis
Respiratory, thoracic and mediastinal disorders Frequent Pharyngitis, rhinitis, coughing (cough), dyspnoea
Less frequent Bronchospasm
Gastrointestinal disorders Frequent Nausea, abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting, dysphagia
Less frequent Constipation, gastritis, stomatitis, aggravation of gastrointestinal inflammation, eructation
Gastrointestinal haemorrhage, duodenal, gastric, oesophageal, intestinal, and colonic ulceration, intestinal perforation, oesophagitis, melaena, pancreatitis, colitis/colitis aggravated
Hepatobiliary disorders Less frequent Abnormal hepatic function, elevation of hepatic enzymes (including increased SGOT and SGPT)
Hepatitis
Hepatic failure (sometimes fatal or requiring liver transplant), fulminant hepatitis 4 (some with fatal outcome), liver necrosis, cholestasis, cholestatic hepatitis, jaundice
Skin and subcutaneous tissue disorders Frequent Rash, pruritus (includes pruritus generalised)
Less frequent Urticaria, ecchymosis
Angioedema, alopecia, photosensitivity
Exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS) or hypersensitivity syndrome, acute generalised exanthematous pustulosis (AGEP), bullous eruption (dermatitis bullous)
Musculoskeletal and connective tissue disorders Frequent Arthralgia
Less frequent Leg cramps
Myositis
Renal and urinary disorders Less frequent Increased creatinine, BUN increased
Acute renal failure, hyponatraemia
Interstitial nephritis, nephrotic syndrome, minimal change disease
Reproductive system and breast disorders Less frequent Menstrual disorder NOS
Frequency unknown Female fertility decreased
General disorders and administration site conditions Frequent Flu-like symptoms (influenze-like illness), peripheral oedema/ fluid retention
Less frequent Face oedema, chest pain
Injury, poisoning and procedural conditions Frequent Accidental injury (injury)
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

There is no clinical experience of overdose. Single doses up to 1200 mg and multiple doses up to 1200 mg twice daily have been administered to healthy subjects for nine days without clinically significant adverse effects. In the event of suspected overdose, appropriate supportive medical care should be provided and, if necessary, the institution of symptomatic treatment. Dialysis is unlikely to be an efficient method of medicinal product removal due to high protein binding.