Celecoxib

Is celecoxib safe?

For most adults with arthritis, yes, at the doses on the label. Celecoxib, sold as Celebrex and as cheap generics, is the only coxib (COX-2 inhibitor) still sold in the US. It treats pain and inflammation like ibuprofen and naproxen, but it spares the enzyme that protects the stomach lining, so it causes fewer ulcers and bleeds.

The catch is the heart. Two of its relatives, rofecoxib (Vioxx) and valdecoxib (Bextra), were withdrawn in 2004 and 2005 after trials showed more heart attacks, and celecoxib carries the same boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary as every prescription NSAID. The best evidence now says that at a modest dose its heart risk is about the same as the older drugs, not lower and not clearly higher. We score it 74, level with ibuprofen and one point above naproxen.

What the PRECISION trial showed

PRECISION was set up after the Vioxx withdrawal to settle the heart question. It enrolled 24,081 people with osteoarthritis or rheumatoid arthritis who had heart disease or were at high risk of it, and gave them celecoxib, ibuprofen or naproxen for an average of 20 months. Everyone also got a stomach-protecting drug, esomeprazole.

Celecoxib met the trial's test of being no worse than either drug. Serious stomach and bowel events were significantly less common with celecoxib than with naproxen or ibuprofen, and kidney problems were less common than with ibuprofen. In a blood pressure substudy, celecoxib left 24-hour blood pressure unchanged while ibuprofen raised it by 3.7 mmHg.

There is an important limit. Most patients on celecoxib stayed at 100 mg twice a day, while more than half on the other drugs moved up to full doses. The US label says the trial cannot show how celecoxib at 200 mg twice a day compares.

Why dose matters for the heart

The worry about higher doses comes from the APC trial, which tested celecoxib for preventing bowel polyps. Over about three years, both 200 mg and 400 mg twice a day roughly tripled the rate of heart death, heart attack or stroke compared with placebo, the US label says. A similar trial at 400 mg once a day found no clear increase.

A 2013 Lancet analysis of 754 trials put coxibs as a group in the same bracket as high-dose diclofenac: about a third more major vascular events, or three extra events for every 1,000 people treated for a year. Heart failure risk roughly doubled with every NSAID studied. In 2005 the European Medicines Agency ruled that COX-2 inhibitors must not be used by people with established heart disease, a past stroke or peripheral arterial disease, and that rule still applies in the UK and EU.

The stomach advantage

Celecoxib's reason to exist is the gut. In the same Lancet analysis, coxibs raised serious upper stomach complications by about 80%, while high-dose ibuprofen and naproxen roughly quadrupled them. The label still gives the class figures, about 1% of NSAID users with an ulcer or bleed after 3 to 6 months, and warns that taking low-dose aspirin as well wipes out much of the advantage: in the CLASS trial, complicated or symptomatic ulcers rose from 0.78% to 2.19% at nine months in those also taking aspirin. The MHRA notes that an older NSAID plus a proton pump inhibitor such as omeprazole may bring stomach risk down to a similar level.

Allergies, liver and interactions

Celecoxib contains a sulfonamide group, and the label rules it out for anyone who has had an allergic reaction to sulfa drugs, or asthma, hives or other reactions after aspirin or another NSAID. Serious skin reactions, including Stevens-Johnson syndrome and fixed drug eruption, are rare but can be fatal; the label says to stop it at the first sign of a rash and get medical advice.

The liver enzyme CYP2C9CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary does most of the work of clearing it. Fluconazole doubles celecoxib levels, and people who are known poor CYP2C9 metabolisers, often found because warfarin or phenytoin built up in them, should start at half the lowest dose. The other interactions are the usual NSAID set: more bleeding with blood thinners, SSRIs and SNRIs; higher lithium levels; and weaker blood pressure tablets and diuretics, with a risk of kidney injury in older or dehydrated people.

Who should be careful

Talk to your doctor before starting or continuing celecoxib if you:

• have had a heart attack, stroke, heart failure or bypass surgery, or have poorly controlled blood pressure
• have had a stomach ulcer or bleed, or take a blood thinner, a steroid or low-dose aspirin
• have kidney or moderate to severe liver disease
• are allergic to sulfa drugs or react to aspirin
• are pregnant: the label says to limit NSAIDs from about 20 weeks and avoid them from 30 weeks

The label asks for the lowest dose that works for the shortest time. Do not take it with ibuprofen, naproxen or other NSAIDs, including those in cold remedies. An overdose is rarely life-threatening, but call Poison Control on 1-800-222-1222 in the US or NHS 111 in the UK.

How we scored it

Dependence (97), track record (90) and overdose marginOverdose marginHow far a normal dose is from a harmful one. A wide margin means an accidental extra dose is unlikely to cause serious harm.More in the glossary (87) are strong. Serious side effects (66) score a point above ibuprofen because of the lower stomach risk, held back by the dose-related heart signal. Regulatory warnings (42) sit a little below the older NSAIDs because of the extra EU heart contraindicationsContraindicationA situation in which a medicine should not be used, because the risk clearly outweighs any benefit, such as a known allergy to it.More in the glossary and the sulfa allergy rule. A lower score is no reason to stop a medicine your doctor prescribed.