Celecoxib dosing

Non-opioid analgesics (NSAIDs, COX-2 inhibitors, APAP), including celecoxib, are part of the World Health Organization s (WHO) analgesic ladder for the treatment of mild to moderate cancer pain. There are no celecoxib dosing guidelines for the treatment of somatic pain associated with cancer. 

It follows that drugs that selectively inhibit COX-2 should cause fewer side effects than those that inhibit both COX-1 and COX-2. At therapeutic doses, all currently available NSAIDs, with the excqrtion of celecoxib, etoricoxib, lumiracoxib and parecoxib (the prodrug of valdecoxib), are non-selective and inhibit both COX isoforms. 

Jenkins C, Costello J, Hodge L Systematic review of prevalence of aspirin-induced asthma and its implications for clinical practice. BMJ 2004 328 434-437. Baldassarre S, Schandene L, Choufani G, Michils A Asthma attacks induced by low doses of celecoxib, aspirin and acetaminophen. J Allergy Clin Immunol 2006 117 215-217. 

Recent data suggest that COX-2 inhibitors, including rofe-coxib, valdecoxib, and celecoxib, may increase the risk for MI and stroke.47 There is also some evidence that the non-selective NSAIDs may increase the risk for cardiovascular events.47,48 Rofecoxib was withdrawn from the market in late 2004 because of safety concerns. The FDA requested the withdrawal of valdecoxib from the market in 2005. The FDA also asked the manufacturers of celecoxib and non-selective NSAIDs (prescription and over-the-counter) to include information about the potential adverse cardiovascular effects of these drugs in their product labeling. The cardiovascular risk with COX-2 inhibitors and NSAIDs may be greatest in patients with a history of, or with risk factors for, cardiovascular disease. The American Heart Association recommends that the use of COX-2 inhibitors be limited to low-dose, short-term therapy in patients for whom there is no appropriate alternative.48 Patients with cardiovascular disease should consult a clinician before using over-the-counter NSAIDs. 

Two large trials, the Vioxx Gastrointestinal Outcomes Research (VIGOR) study and the Celecoxib Long-term Arthritis Safety Study (CLASS), compared selective COX-2 inhibitors and traditional, non-selective NSAID therapy in terms of their ability to prevent clinical PUD (i.e., symptomatic ulcers and ulcer complications). VIGOR (9-month median follow-up) demonstrated that rofecoxib (50 mg daily) therapy was significantly more efficacious than naproxen.28 The CLASS study (6-month median follow-up) found that high-dose celecoxib (400 mg twice daily) was superior to non-selective NSAID therapy (either ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily).29... 

Anti-inflammatory in 100 and 200 mg doses Active ingredient Celecoxib... 

CELECOXiB Seek the lowest dose for each patient. Safety and efficacy in children younger than 18 years of age have not been evaluated. 

PAP - Continue usual medical care for FAR patients while on celecoxib. The recommended oral dose is 400 mg/day. Take with food. 

Selective COX-2 inhibitors are ideal agents to combine with chemoradiotherapy for several reasons. First, they have been shown to enhance the effect of various chemotherapeutic agents and radiation on cancer cells. Second, selective COX-2 inhibitors are relatively safe. They do not have severe gastrointestinal toxicity, which is common in many nonselective NSAIDs. For example, celecoxib, a selective COX-2 inhibitor which is currently being used for patients with arthritis, is 375-fold more selective for COX-2 compared to COX-1 (94), and in large randomized, multicenter, placebo-controlled, double-blind trials conducted in patients with rheumatoid arthritis, celecoxib proved to be less toxic than nonselective inhibitors of COX-1 and COX-2, and no more toxic than a placebo (95). Third, high-dose celecoxib (600 mg bid) has no effect on serum thromboxane or platelet function (96). This is obviously important in patients receiving... 

Indomethacin and sulindac are slightly selective for COX-1. Meclofenamate and ibuprofen are approximately equipotent on COX-1 and COX-2, whereas celecoxib = diclofenac < rofecoxib = lumiracoxib < etoricoxib in inhibition of COX-2 (listed in order of increasing average selectivity). Aspirin acetylates and inhibits both enzymes covalently. Low doses (< 100 mg/day) inhibit preferentially, but not exclusively, platelet COX-1, whereas higher doses inhibit both systemic COX-1 and COX-2. 

Selectivity for COX-1 versus COX-2 is variable and incomplete for the older NSAIDs, but many selective COX-2 inhibitors have been synthesized. The selective COX-2 inhibitors do not affect platelet function at their usual doses. In testing using human whole blood, aspirin, ibuprofen, indomethacin, piroxicam, and sulindac are somewhat more effective in inhibiting COX-1. The efficacy of -2-selective drugs equals that of the older NSAIDs, while gastrointestinal safety may be improved. On the other hand, selective COX-2 inhibitors may increase the incidence of edema and hypertension. As of December 2008, celecoxib and the less selective meloxicam are the only COX-2 inhibitors marketed in the USA. Rofecoxib and valdecoxib, two previously marketed, selective COX-2 inhibitors, have been withdrawn from the market due to their association with increased cardiovascular thrombotic events. Celecoxib has an FDA-initiated "black box" warning concerning cardiovascular risks. It has been recommended that all NSAID product labels be revised to include cardiovascular risks. 

Celecoxib is associated with fewer endoscopic ulcers than most other NSAIDs. Probably because it is a sulfonamide, celecoxib may cause rashes. It does not affect platelet aggregation at usual doses. It interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9. Adverse effects are the common toxicities listed above. 

Meloxicam is an enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as celecoxib and may be considered "preferentially" selective rather than "highly" selective. The drug is popular in Europe and many other countries for the treatment of most rheumatic diseases and approved for treatment of osteoarthritis in the USA. It is associated with fewer clinical gastrointestinal symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, even at supratherapeutic doses its blockade of thromboxane A2 does not reach levels that result in decreased in vivo platelet function (see common adverse effects above). 

Plasma peak concentrations are achieved within 2 h and the elimination half-life is about 12 h. Within the clinical dose range, there is high plasma protein binding ( 97%). Celecoxib is metabolized primarily via cytochrome P450 2C9 to three inactive main metabolites. It is excreted in faeces ( 57%) and urine ( 27%) as determined by administration of a single oral dose of radiolabeled drug. Celecoxib is given orally (200-400 mg/day). 

Celecoxib is approved for the treatment of rheumatoid arthritis at doses up to 200 mg twice daily. These doses produced elfects that were similar to naproxen 500 mg twice a day. In clinical development, rofecoxib has shown efficacy in the therapy of rheumatoid arthritis. Rofecoxib is currently in phase III for the therapy of rheumatoid arthritis. 

Rofecoxib is approved for the treatment of acute pain and dysmenorrhea at a dose of 50 mg for up to 5 days. The clinical studies indicate that rofecoxib shows efficacy similar to that produced by the maximum analgesic doses of naproxen and ibuprofen (Ehrich et al., 1999). The pain settings in which rofecoxib has been tested include acute postoperative dental pain, the pain of dysmenorrhea for up to 3 days, and postoperative pain for 5 days following surgical replacement of the knee or hip. In contrast, celecoxib is not approved in the United States for the treatment of acute pain, and it appears to be less effective when given acutely than rofecoxib, ibuprofen, or naproxen. The explanation for the differences between rofecoxib and celecoxib in acute pain is not known. 

Rheumatoid arthritis is a disease that involves inflammation in joints and causes severe pain and immobility. The worldwide scenario indicates that the elderly population suffers the most from this disease. The drugs of choice for treatment of this condition are nonsteroidal antiinflammatory drugs (NSAIDs), which include acetylsalicylic acid, diclofenac sodium, piroxicam, nimesulide, celecoxib, and refecoxib. Therapeutic doses, adverse effects, and precautions are given in the foifowing pages. 

In one study, there was a mean increase of only 17% in healthy volunteers taking celecoxib 200 mg bd (667). When celecoxib was co-administered with lithium, celecoxib concentrations were higher for the first 6 hours after the dose but the AUC was not altered significantly (668). In another review it was mentioned that clinically significant interactions with lithium (increased lithium concentrations) had been identified, but no detail was presented (669). Both celecoxib and naproxen reduced the renal clearance of lithium (used as a measure of proximal tubular sodium reabsorption) (670). 

A 78-year-old woman had auditory hallucinations while taking celecoxib for osteoarthritis (144). Her symptoms occurred after she had taken celecoxib 200 mg bd for 48 hours and progressed over the next 8 days. Celecoxib was withdrawn and her hallucinations gradually disappeared over the next 4 days. Rechallenge with a lower dose (100 mg bd) caused recurrence. 

An 81-year-old woman took celecoxib 100 mg/day, and over the next 2 weeks developed delirium and auditory and visual hallucinations (146). Celecoxib was withdrawn and her symptoms resolved over several days. She took a few doses of rofecoxib 12.5 mg/ day 6 months later without any problem. She began to take rofecoxib regularly again 2 months later, and after 1 month developed agitation, confusion, and hallucinations. Physical examination suggested no cause of the delirium other than rofecoxib. A CT scan was negative. The rofecoxib was withdrawn, and over the next 2 days her symptoms resolved... 

Psychiatric effects have been previously reported with celecoxib (SEDA-26, 123), and may represent a class effect of the COX-2 inhibitors, according to the Australian Adverse Reactions Advisory Committee (ADRAC), which has received 142 reports of acute neuropsychiatric reactions attributed to celecoxib and 49 to rofecoxib (214). The most common reactions associated with celecoxib were confusion (n = 23) somnolence (n = 22), and insomnia (n = 21), while those associated with rofecoxib were confusion (n = 18) and hallucinations (n = 11). In many cases the onset of the reaction occurred within 24 hours of the first dose of the drug. 

NS AIDs ANTIFUNGALS -FLUCONAZOLE Fluconazole T celecoxib and possibly parecoxib levels Fluconazole inhibits CYP2C9-mediated metabolism of celecoxib and parecoxib Halve the dose of celecoxib and start parecoxib at the lowest dose... 

NSAIDs - CELECOXIB DRUG DEPENDENCE THERAPIES-BUPROPION t plasma concentrations of these substrates, with risk of toxic effects Bupropion and its metabolite hydroxybupropion inhibit CYP2D6 Initiate therapy of these drugs at the lowest effective dose... 

Experimental evidence indicates that COX modulates BBB permeability in neuroinflammatory conditions, ischemia, and hemorrhage. The COX inhibitor, KBT-3022, prevented brain edema induced by bilateral carotid occlusion and recirculation in gerbils (Yamamoto et al., 1996). In the collagenase model of intracerebral hemorrhage, the brain water content of rats treated with the COX-2 inhibitor, celecoxib, decreased both in lesioned and nonlesioned hemispheres in a dose-dependent manner, which was accompanied with reduced perihematomal cell death (Chu et al., 2004). Delayed damage to the BBB and vasogenic edema, which follow ischemic stroke, were significantly diminished by administration of... 

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