Celecoxib 100 mg/200 mg Capsules

• Symptomatic treatment of inflammation and pain in osteoarthritis and rheumatoid arthritis.
• Treatment of pain after 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 symptoms of ankylosing spondylitis.

Posology
As the cardiovascular risks of CELECOXIB BIOTECH may increase with dose and duration of exposure, the lowest effective daily dose should be used, for the shortest possible duration of treatment.

Osteoarthritis
The recommended daily dose is 200 mg, taken 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 dysmenorrhoea
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, taken 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
Hepatic impairment
No dosage adjustment is necessary in patients with mild hepatic impairment. Introduce CELECOXIB BIOTECH 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 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 and 5.2).

Elderly
No dosage adjustment is necessary. However for elderly patients with a body mass of 50 kg or less it is advisable to initiate therapy at the lowest recommended dose.

Children
As no data are available, CELECOXIB BIOTECH is not recommended in persons under 18 years old.

Method of administration
Oral use. CELECOXIB BIOTECH should be taken whole with a glass of water, with or without food.

• Hypersensitivity to celecoxib, or any other excipient of CELECOXIB BIOTECH (see section 6.1).
• Known hypersensitivity to sulphonamide.
• Severe hepatic impairment (serum albumin 10).
• Severe renal impairment with estimated creatinine clearance < 30 mL/min.
• Asthma, urticaria or allergic-type reactions precipitated by aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs), including other cyclooxygenase 2 (COX-2) specific inhibitors.
• Established ischaemic heart disease and/or cerebrovascular disease (stroke) and peripheral arterial disease.
• Perioperative analgesia against the background of coronary artery bypass surgery (CABG).
• Active peptic ulceration or gastrointestinal (GI) bleeding.
• Inflammatory bowel disease.
• In pregnancy and in women of childbearing potential unless using an effective method of contraception (see section 4.6). The potential for human risk in pregnancy is unknown but cannot be excluded.
• Breastfeeding (see section 4.6).

Safety and efficacy of CELECOXIB BIOTECH have not been established for treatment exceeding 12 weeks in osteoarthritis and 24 weeks in rheumatoid arthritis.

Cardiovascular effects
Increased number of serious cardiovascular (CV) events, mainly myocardial infarction, has been reported in patients with sporadic adenomatous polyps treated with celecoxib (as in CELECOXIB BIOTECH) 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 BIOTECH 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).

Caution is advised when CELECOXIB BIOTECH is prescribed to patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking). CELECOXIB BIOTECH is not a substitute for aspirin for prophylaxis of cardiovascular thromboembolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapies should not be discontinued.

Anaphylactoid reactions
As with NSAIDs in general, anaphylactoid reactions occurred in patients exposed to CELECOXIB BIOTECH (see sections 4.3).

Gastrointestinal (GI) effects
Upper and lower gastrointestinal complications (perforations, ulcers or bleedings (PUBs)), some resulting in fatalities, have occurred in patients treated with celecoxib (as in CELECOXIB BIOTECH). 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 antiplatelet medicine (such as aspirin) or glucocorticoids concomitantly, patients using alcohol, or patients with a prior history of or active gastrointestinal disease, such as ulceration and GI bleeding. When CELECOXIB BIOTECH is taken concomitantly with aspirin (even at low doses), there is further increase in the risk of gastrointestinal adverse effects for celecoxib (gastrointestinal ulceration or other gastrointestinal complications). A significant difference in GI safety between selective COX-2 inhibitors plus aspirin vs NSAIDs plus aspirin has not been demonstrated in long-term clinical trials.

Concomitant NSAID use
The concomitant use of CELECOXIB BIOTECH and a non-aspirin NSAID should be avoided.

Fluid retention and oedema
Fluid retention and oedema have been observed in patients taking celecoxib (as in CELECOXIB BIOTECH). Therefore, CELECOXIB BIOTECH 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. Patients with pre-existing congestive heart failure or hypertension should be closely monitored.

Hypertension
NSAIDS, including celecoxib (as in CELECOXIB BIOTECH) 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 BIOTECH 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 BIOTECH, may cause renal toxicity. Celecoxib has 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, angiotensin converting enzyme (ACE)-inhibitors, angiotensin II receptor antagonists, and the elderly (see section 4.5). Such patients should be carefully monitored while receiving treatment with CELECOXIB BIOTECH. 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 (contained in CELECOXIB BIOTECH. Among the cases that reported time to onset, most of the severe adverse hepatic events developed within one month after initiation of celecoxib (contained in CELECOXIB BIOTECH 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 BIOTECH therapy should be considered. Caution should be used when initiating treatment in patients with dehydration. It is advisable to first rehydrate patients and then commence with CELECOXIB BIOTECH therapy.

CYP2D6 inhibition
Celecoxib inhibits CYP2D6. Although it is not a strong inhibitor of this enzyme, a dose reduction of CELECOXIB BIOTECH may be necessary for individually dose-titrated medicines that are metabolised by CYP2D6 (see section 4.5).

CYP2C9 poor metabolisers
Patients known to be CYP2C9 poor metabolisers should be treated with caution.

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 very rarely in association with the use of celecoxib, (as in CELECOXIB BIOTECH) see section 4.8. Patients appear to be at highest risk for these events early in the course of therapy: the onset of the event 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 (as in CELECOXIB BIOTECH), see section 4.8. Patients with a history of sulphonamide allergy or any medicine allergy may be at greater risk of serious skin reactions or hypersensitivity reactions (see section 4.3). CELECOXIB BIOTECH should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as CELECOXIB BIOTECH. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue CELECOXIB BIOTECH and evaluate the patient immediately.

General
CELECOXIB BIOTECH may mask fever and other signs of inflammation.

Pharmacodynamic interactions
Anticoagulants
In patients on concurrent therapy with warfarin, increases in prothrombin time (INR) have been reported (see section 4.4). Anticoagulant activity should be monitored particularly in the first few days after initiating or changing the dose of CELECOXIB BIOTECH 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 BIOTECH is initiated or the dose is changed (see section 4.4). Bleeding events in association with increases in prothrombin time (INR) have been reported, predominantly in the elderly, in patients receiving celecoxib (as in CELECOXIB BIOTECH) concurrently with warfarin, some of them fatal.

Antihypertensives
NSAIDs, including CELECOXIB BIOTECH, may reduce the effect of antihypertensive medicines (including ACE-inhibitors, angiotensin II receptor antagonists, diuretics and beta-blockers). This interaction should be given consideration in patients taking CELECOXIB BIOTECH concomitantly with antihypertensive medicines. 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 or angiotensin II receptor antagonists, and/or diuretics are combined with NSAIDs, including CELECOXIB BIOTECH (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.

Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.

Ciclosporin and tacrolimus
Co-administration of NSAIDs (including CELECOXIB BIOTECH) and ciclosporin or tacrolimus may increase the nephrotoxic effect of ciclosporin or tacrolimus, respectively. Renal function should be monitored when CELECOXIB BIOTECH and any of these medicines are combined.

Aspirin
CELECOXIB BIOTECH can be used with low-dose aspirin. However, concomitant administration of aspirin with CELECOXIB BIOTECH may result in an increased risk of gastrointestinal ulceration or other gastrointestinal complications, compared to use of CELECOXIB BIOTECH alone. Because of its lack of platelet effects, CELECOXIB BIOTECH is not a substitute for aspirin for cardiovascular prophylaxis. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious cardiovascular thromboembolic events associated with CELECOXIB BIOTECH. An increased risk of gastrointestinal ulceration or other gastrointestinal complications compared to use of CELECOXIB BIOTECH alone was shown for concomitant administration of low-dose aspirin.

Pharmacokinetic interactions
Effects of CELECOXIB BIOTECH on other medicines
CYP2D6 inhibition
Celecoxib is an inhibitor of CYP2D6. The plasma concentrations of medicines that are substrates of this enzyme may be increased when CELECOXIB BIOTECH is used concomitantly. Examples of medicines which are metabolised by CYP2D6 are antidepressants (tricyclics and selective serotonin reuptake inhibitors (SSRIs)), neuroleptics, antidysrhythmic medicines, etc. The dose of individually dose-titrated CYP2D6 substrates may need to be reduced when treatment with CELECOXIB BIOTECH is initiated or increased if treatment with CELECOXIB BIOTECH 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 medicines 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 medicines.

Lithium
In healthy persons, 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 area under the curve (AUC) of 18 % of lithium. Therefore, patients on lithium treatment should be closely monitored when CELECOXIB BIOTECH is introduced or withdrawn.

Oral contraceptives
In an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of oral contraceptive (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.

Phenytoin
In specific studies in healthy volunteers with other medicines metabolised by CYP2C9, celecoxib was found to produce no clinically significant pharmacokinetic interaction with phenytoin.

Effects of other medicines on CELECOXIB BIOTECH
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 section 4.4).

CYP2C9 inhibitors and inducers
Since celecoxib is predominantly metabolised by CYP2C9, CELECOXIB BIOTECH 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.

Paediatric populations
Interaction studies have only been performed in adults.

Pregnancy
CELECOXIB BIOTECH is contraindicated in pregnancy (see section 4.3). Regular use of NSAIDs during pregnancy may result in:

First trimester
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/ or the embryo/ foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1 %, up to approximately 1,5 %. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

Second and Third trimester
During the third trimester of pregnancy, prostaglandin synthesis inhibitors, may expose the foetus to: cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); renal dysfunction, which may progress to renal failure with oligohydroamniosis. At the end of pregnancy, the mother and the neonate may be exposed to: possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; inhibition of uterine contractions resulting in delayed or prolonged labour.

Breastfeeding
Limited data indicate that CELECOXIB BIOTECH is excreted in breastmilk and therefore should not be used during lactation.

Fertility
Based on the mechanism of action, the use of NSAIDs, including CELECOXIB BIOTECH, 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 (see section 4.8) while taking CELECOXIB BIOTECH should refrain from driving or operating machinery.

Tabulated list of adverse reactions

Infections and infestations
Frequent: sinusitis, upper respiratory tract infection, pharyngitis, urinary tract infection, bronchitis
Less frequent: helicobacter infection, herpes zoster, erysipelas, bronchopneumonia, labyrinthitis, gingival infection

Blood and lymphatic system disorders
Less frequent: anaemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, ecchymosis

Immune system disorders
Frequent: hypersensitivity, allergy aggravated
Less frequent: anaphylactic shock, anaphylactic reaction, angioedema
Frequency unknown: anaphylaxis

Metabolism and nutrition disorders
Frequent: increased weight
Less frequent: hyperkalaemia, increased blood sodium

Psychiatric disorders
Frequent: insomnia
Less frequent: anxiety, depression, fatigue, confusional state, hallucinations

Nervous system disorders
Frequent: dizziness, hypertonia, headache
Frequency unknown: cerebral infarction (stroke), paraesthesia, somnolence, ataxia, dysguesia, intracranial haemorrhage (including fatal intracranial haemorrhage), aseptic meningitis, epilepsy (including aggravated epilepsy), ageusia, anosmia

Eye disorders
Less frequent: blurred vision, conjunctivitis, eye haemorrhage, retinal artery occlusion, retinal vein occlusion, vitreous floaters, conjunctival haemorrhage

Ear and labyrinth disorders
Less frequent: tinnitus, hypoacusis, dysphonia

Cardiac disorders
Frequent: myocardial infarction, angina pectoris
Less frequent: cardiac failure, palpitations, tachycardia, dysrhythmia
Frequency unknown: cardiovascular thrombotic incidents

Vascular disorders
Frequent: hypertension (including aggravated hypertension)
Less frequent: pulmonary embolism, flushing, vasculitis, deep vein thrombosis

Respiratory, thoracic and mediastinal disorders
Frequent: rhinitis, cough, dyspnoea
Less frequent: bronchospasm, pneumonitis

Gastrointestinal disorders
Frequent: nausea, abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting, dysphagia, irritable bowel syndrome, tooth disorder
Less frequent: constipation, gastritis, stomatitis, gastrointestinal inflammation (including aggravation of gastrointestinal inflammation), eructation, gastrointestinal haemorrhage, duodenal ulcer, gastric ulcer, oesophageal ulcer, intestinal ulcer, large intestinal ulcer, intestinal perforation, oesophagitis, melaena, pancreatitis, colitis, haemorrhoidal haemorrhage, frequent bowel movements, mouth ulceration

Hepatobiliary disorders
Less frequent: abnormal hepatic function, increased hepatic enzymes (including increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), hepatitis, hepatic failure (sometimes fatal or requiring liver transplant), fulminant hepatitis (some with fatal outcome), hepatic necrosis, cholestasis, cholestatic jaundice

Skin and subcutaneous tissue disorders
Frequent: rash, pruritis (includes pruritis generalised)
Less frequent: urticaria, ecchymosis, alopecia, photosensitivity, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP), bullous dermatitis, lipoma, allergic dermatitis, ganglion

Musculoskeletal and connective tissue disorders
Frequent: arthralgia
Less frequent: muscle spasms (leg cramps), myositis, lower limb fracture

Renal and urinary disorders
Less frequent: increased blood creatinine, increased blood urea, acute renal failure, hyponatraemia, tubulointerstitial nephritis, nephrotic syndrome, glomerulonephritis minimal lesion, nephrolithiasis, nocturia

Reproductive system and breast disorders
Less frequent: menstrual disorder
Frequency unknown: female infertility (female fertility decreased), vaginal haemorrhage, breast tenderness

General disorders and administration site conditions
Frequent: influenza-like illness, peripheral oedema/fluid retention
Less frequent: face oedema, chest pain

Injury, poisoning and procedural complications
Frequent: accidental injury

Description of selected adverse reactions
In final data (adjudicated) from the APC and PreSAP trials in patients treated with celecoxib 400 mg daily for up to 3 years (pooled data from both trials), the excess rate over placebo for myocardial infarction was 7,6 events per 1 000 patients (less frequent) and there was no excess rate for stroke (types not differentiated) over placebo.

Drug reaction with eosinophillia and systemic symptoms (DRESS) (see section 4.4).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions 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 1 200 mg and multiple doses up to 1 200 mg twice daily have been administered to healthy persons without clinically significant adverse effects. In the event of a suspected overdose, appropriate supportive medical care should be provided. Dialysis is not likely to be an efficient method of medicine removal.