Celecoxib Pharmacia 100 mg. 200 mg Hard capsules

• 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.

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

Posology

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 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, 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 CELECOXIB PHARMACIA at half the recommended dose in patients with moderate hepatic impairment. For pain post dental surgery, introduce CELECOXIB PHARMACIA at the lowest recommended dose. There is no clinical experience in patients with severe hepatic impairment (see section 4.3).

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 section 4.3).

CYP2C9 poor metabolisers
Patients who are known or suspected to be CYP2C9 poor metabolisers based on genotyping or previous history/experience with other CYP2C9 substrates should be administered CELECOXIB PHARMACIA with caution as the risk of dose-dependent adverse effects is increased. Consider reducing the dose to half the lowest recommended dose (see section 5.2).

Paediatric population
CELECOXIB PHARMACIA has not been studied in subjects under 18 years old.

Method of administration
For oral use. CELECOXIB PHARMACIA may be taken with or without food.

• Hypersensitivity to celecoxib or to any of the excipients of CELECOXIB PHARMACIA (listed in section 6.1).
• Known sulphonamide hypersensitivity.
• Severe impairment of hepatic function.
• Severe impairment of renal function.
• Asthma, urticaria or allergic-type reactions precipitated by aspirin or other non-steroidal 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.
• Peri-operative analgesia in the setting of coronary artery bypass surgery (CABG).
• Pregnancy.
• In women of childbearing potential unless using an effective method of contraception (see section 4.6). CELECOXIB PHARMACIA has been shown to cause malformations in the animal species studied (see section 4.6). The potential for human risk in pregnancy is unknown but cannot be excluded.

CELECOXIB PHARMACIA may predispose to cardiovascular events, cerebrovascular events, gastrointestinal events or cutaneous reactions which may be fatal. Safety and efficacy of CELECOXIB PHARMACIA have not been established for treatment exceeding 12 weeks in osteoarthritis and 24 weeks in rheumatoid arthritis.

Cardiovascular effects
There is insufficient data to assess cardiovascular safety beyond one year of continuous treatment. CELECOXIB PHARMACIA may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction and stroke, which can be fatal. There appears to be a higher risk for cardiovascular events with higher doses and longer duration of treatment. The shortest duration possible and the lowest effective dose should be used. Caution is advised when CELECOXIB PHARMACIA is prescribed to patients with cardiovascular risk factors e.g. hypertension, diabetes, smoking and hypercholesterolaemia. Medical practitioners and patients should remain alert for the development of such events, even in the absence of previous cardiovascular symptoms. Because of its lack of platelet effects, CELECOXIB PHARMACIA is not a substitute for aspirin for cardiovascular prophylaxis. Therefore, antiplatelet therapies should not be discontinued.

Hypertension
As with all NSAIDs, CELECOXIB PHARMACIA 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. Blood pressure should be monitored closely during the initiation of therapy with CELECOXIB PHARMACIA and throughout the course of therapy.

Gastrointestinal (GI) effects
Upper and lower gastrointestinal perforations, ulcers or bleeds have occurred in patients treated with CELECOXIB PHARMACIA. Patients most at risk of developing these types of GI complications with NSAIDs are the elderly, patients with cardiovascular disease, patients using concomitant glucocorticoids, antiplatelet medicines (such as aspirin), or other NSAIDs, patients using alcohol or patients with a prior history of, or active, gastrointestinal disease, such as ulceration, GI bleeding or inflammatory conditions. Most spontaneous reports of fatal gastrointestinal events have been in elderly or debilitated patients.

Serious 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 CELECOXIB PHARMACIA. 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. Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) has been reported in patients receiving CELECOXIB PHARMACIA. CELECOXIB PHARMACIA 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)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as CELECOXIB PHARMACIA. 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 PHARMACIA and evaluate the patient immediately.

CELECOXIB contains a sulphonamide moiety. In clinical trials CELECOXIB PHARMACIA did not induce bronchospasm in patients with asthma. However, CELECOXIB PHARMACIA has not been evaluated in patients in whom attacks of asthma, urticaria or acute rhinitis have been precipitated by aspirin or NSAIDs. Use in such patients should be avoided until further information is available.

Fluid retention and oedema
As with other medicines known to inhibit prostaglandin synthesis, fluid retention and oedema have been observed in patients taking CELECOXIB PHARMACIA, therefore CELECOXIB PHARMACIA should be used with caution in patients with compromised cardiac function, pre-existing oedema and other conditions predisposing to, or worsened by, fluid retention. Patients with pre-existing congestive heart failure or hypertension should be closely monitored.

Renal effects
NSAIDs, including CELECOXIB PHARMACIA may cause renal toxicity. Clinical trials with CELECOXIB PHARMACIA 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, and the elderly. Such patients should be carefully monitored while receiving treatment with CELECOXIB PHARMACIA. Caution should be used when initiating treatment in patients with dehydration. It is advisable to rehydrate patients first and then start therapy with CELECOXIB PHARMACIA. Renal function should be closely monitored in patients with advanced renal disease who are administered CELECOXIB PHARMACIA.

Hepatic effects
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 PHARMACIA. A patient with symptoms and/or signs of liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with CELECOXIB PHARMACIA.

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

Anaphylactoid reactions
As with NSAIDs in general, anaphylactoid reactions have occurred in patients exposed to CELECOXIB PHARMACIA (see section 4.3).

General
By reducing inflammation, CELECOXIB PHARMACIA may diminish the utility of diagnostic signs, such as fever, in detecting infections. The concomitant use of CELECOXIB PHARMACIA and a non-aspirin NSAID should be avoided.

Use with oral anticoagulants
In patients on concurrent therapy with warfarin or similar medicines, serious bleeding events, some of them fatal, have been reported. Because increases in prothrombin time (INR) have been reported, anticoagulant activity should be monitored in patients receiving warfarin/coumarin-type oral anticoagulants after initiating treatment with CELECOXIB PHARMACIA or changing the dose. Concomitant use of anticoagulants with NSAIDs may increase the risk of bleeding. Caution should be exercised when combining CELECOXIB PHARMACIA with warfarin or other oral anticoagulants including novel anticoagulants (e.g. apixaban, dabigatran and rivaroxaban).

Lactose intolerance
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

General
CELECOXIB PHARMACIA metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of CELECOXIB PHARMACIA with medicines that are known to inhibit CYP2C9 should be done with caution. Concomitant use of inducers of CYP2C9 such as rifampicin, carbamazepine and barbiturates may reduce plasma concentrations of CELECOXIB PHARMACIA.

In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo medicine interaction with medicines that are metabolised by CYP2D6.

Anti-hypertensives
Inhibition of prostaglandins may diminish the effect of anti-hypertensive medicines including angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, diuretics and beta-blockers. The risk of acute renal insufficiency, which is usually reversible, may be increased in some patients with compromised renal function (e.g. patients on diuretics or elderly patients) when ACE-inhibitors, angiotensin II receptor antagonists and/or diuretics are combined with NSAIDs, including CELECOXIB PHARMACIA. 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 PHARMACIA 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 PHARMACIA 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.

Aspirin
CELECOXIB PHARMACIA can be used with low dose aspirin. However, concomitant administration of aspirin with CELECOXIB PHARMACIA may result in an increased rate of GI ulceration or other complications, compared to use of CELECOXIB PHARMACIA alone. Because of its lack of platelet effects, CELECOXIB PHARMACIA 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 PHARMACIA.

Ciclosporin
Co-administration of NSAIDs and ciclosporin may increase the nephrotoxic effect of ciclosporin.

Fluconazole
Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in CELECOXIB PHARMACIA plasma concentration. This increase is due to the inhibition of CELECOXIB PHARMACIA metabolism via CYP2C9 by fluconazole. CELECOXIB PHARMACIA should be introduced at half the recommended dose in patients receiving the CYP2C9 inhibitor fluconazole.

Dextromethorphan and metoprolol
Concomitant administration of CELECOXIB PHARMACIA 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 PHARMACIA inhibition of the CYP2D6 substrate metabolism.

Diuretics
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.

Glibenclamide
CELECOXIB PHARMACIA does not affect the pharmacokinetics of glibenclamide to a clinically relevant extent.

Ketoconazole and antacids
Ketoconazole or antacids have not been observed to affect the pharmacokinetics of CELECOXIB PHARMACIA.

Lithium
In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17 % in subjects receiving lithium 450 mg twice daily with CELECOXIB PHARMACIA 200 mg twice daily as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when CELECOXIB PHARMACIA is introduced or withdrawn.

Methotrexate
In an interaction study of rheumatoid arthritis patients taking methotrexate, CELECOXIB PHARMACIA did not have a significant effect on the pharmacokinetics of methotrexate.

Other medicines
In specific studies in healthy volunteers with other medicines metabolised by CYP2C9, CELECOXIB PHARMACIA was found to produce no clinically significant pharmacokinetic interaction with phenytoin or tolbutamide.

Oral contraceptives
In an interaction study, CELECOXIB PHARMACIA had no clinically relevant effects on the pharmacokinetics of a prototype combination oral contraceptive (1 mg norethindrone/0,035 mg ethinyl estradiol).

Warfarin
In patients on concurrent therapy with warfarin, increases in prothrombin time (INR) have been reported (see section 4.4).

Fertility
Based on the mechanism of action, the use of NSAIDs, including CELECOXIB PHARMACIA, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women.

Pregnancy
Studies in animals have shown reproductive toxicity. Inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. CELECOXIB PHARMACIA, as with other medicines inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus and should be avoided during pregnancy. During the second or third trimester of pregnancy, NSAIDs including CELECOXIB PHARMACIA may cause foetal renal dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe cases. Such effects may occur shortly after treatment initiation and are usually reversible.

Breastfeeding
CELECOXIB PHARMACIA is excreted in the milk of lactating rats at concentrations similar to those in plasma. Limited data indicate that CELECOXIB PHARMACIA is excreted in breast milk and therefore should not be used during lactation.

The effect of CELECOXIB PHARMACIA on ability to drive or use machinery has not been studied but based on its pharmacodynamic properties and overall safety profile it is unlikely to have an effect.

Tabulated summary of adverse reactions
The following side effects have been reported in patients on CELECOXIB PHARMACIA treatment. Incidence rates are categorised as follows: Very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000).

Post-marketing experience
Reactions from post-marketing experience include the following:

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 subjects without clinically significant adverse effects. In the event of suspected overdose, appropriate supportive medical care should be provided. Dialysis is unlikely to be an efficient method of medicine removal.