The Institute for Safe Medication Practices (ISMP) has recently issued several alerts regarding medication errors resulting from confusion of four different products (Celebrex, Celexa, Cerebyx, and Cerebra). Celebrex, Celexa and Cerebyx are all KUMC formulary products. Please refer to the following table for clarification of the use of these products:

Suggestions to reduce the likelihood of medication errors includes
                    Include the indication on prescriptions written for these drugs
                    Separate these drugs in all storage areas
                    Closely check the appearance of all new drugs
                    Closely review all labels against the prescribed medication.

Nonsteroidal anti-inflammatory agents (NSAIDs) work by blocking cyclooxygenase (COX-1 and –2) and thus, are useful in preventing the production of inflammatory prostaglandins and treating pain. Celecoxib is a COX-2 selective inhibitor, which decreases the production of inflammatory prostaglandins produced by COX-2 without decreasing the production of the prostaglandins produced by COX-1. COX-2 selective inhibitors have little effect on platelet function. Peak plasma levels occur within 3 hours after oral administration. Protein binding is high (97%). Celecoxib is extensively metabolized by the CYP 2C9 enzyme system with a half-life of approximately 11.2 hours in patients with normal CYP 2C9 activity. If an individual is a poor metabolizer, is receiving a CYP 2C9 inhibitor, or has hepatic impairment, the elimination half-life may be prolonged.

Celecoxib is contraindicated in patients with a history of allergic reactions to the drug or the product ingredients. Also, celecoxib is contraindicated in patients with a documented allergic-type reaction to sulfonamides. Aspirin and NSAIDs may cause severe bronchospasm, which can be fatal, in patients with aspirin-sensitive asthma. The safety of celecoxib in this patient group is unknown; therefore, should be avoided in patients with aspirin sensitivity and used with caution in patients with asthma. Celecoxib should be avoided during late pregnancy to avoid premature closure of the ductus arteriosus.

The most common adverse effects reported with celecoxib are headache, diarrhea, rhinitis, nausea, sinusitis, dyspepsia, and abdominal pain. Because COX-2 inhibitors were designed to cause less gastrointestinal adverse effects, several endoscopy studies were conducted to determine the impact of celecoxib on the gastroduodenal mucosa and tissue (detection of the development of erosions and ulceration). Based on the results of these studies, it would appear that celecoxib is a safer agent for patients at risk of gastroduodenal ulceration (e.g. elderly, high-dose therapy, history of GI problems, concomitant glucocorticoids or anticoagulant therapy). However, the FDA has required celecoxib to include the same gastrointestinal warnings as the NSAIDs, with modifications, until more studies are conducted to document the gastrointestinal safety of the COX-2 selective inhibitors. COX-2 inhibitors should be avoided in patients with advanced renal dysfunction due to the potential further reduction in renal function due to a decreased production in prostaglandins. The incidence of borderline liver function elevations with celecoxib was 6% and 5% with placebo, while 0.2% of celecoxib-treated patients experienced an elevation of greater than three times the upper limit of normal compared to 0.3% with placebo therapy.

Celecoxib does not affect the pharmacokinetics or pharmacodynamics of glyburide, tolbutamide, ketoconazole, phenytoin, methotrexate and warfarin, nor does it affect prothrombin time or partial thromboplastin time in patients receiving warfarin therapy. In vitro studies indicate that celecoxib may inhibit CYP 2D6. It is unknown whether celecoxib will alter the plasma levels of drugs metabolized by CYP 2D6. Drugs that inhibit CYP 2C9 (e.g. fluconazole) may decrease the metabolism of celecoxib. Fluconazole can increase the plasma concentrations of celecoxib two-fold. Several drug interactions listed in the celecoxib product labeling (e.g. angiotensin enzyme inhibitors [ACEIs] and diuretics) are based on experience with the NSAIDs. It is unknown what effect celecoxib therapy has on these medicinal agents. Low-dose aspirin can be used with celecoxib to prevent cardiovascular events because celecoxib has no effect on platelet function. However, concomitant use of aspirin with celecoxib may increase the rate of gastrointestinal ulceration or other complications. Celecoxib can increase the plasma concentrations of lithium. Administration with aluminum- and magnesium-containing antacids can decrease the total amount of drug that is absorbed.

The recommended dose for the treatment of rheumatoid arthritis is celecoxib 100 mg twice daily. This dose can be increased to 200 mg twice daily, if necessary. Osteoarthritis can be treated with celecoxib 200 mg once daily or 100 mg twice daily. The dose of celecoxib should be reduced in patients with moderate or higher hepatic impairment.

Abacavir is a nucleoside analogue HIV-1 reverse transcriptase inhibitor (RTI) with greater potency and apparently slower acquisition of resistance. Abacavir resistance requires several RT gene mutations and these gene mutations appear to develop more slowly than with 3TC. In vitro studies have demonstrated additive effects with lamivudine, didanosine, stavudine and zalcitabine. Synergistic effects have been seen with zidovudine and nevirapine. The oral bioavailability of a 300 mg tablet is approximately 83%. Central nervous system penetration is very good, with CSF to plasma ratios in the range of 30% to 44%. Abacavir requires intracellular triphosphorylation for activation, but it uses a unique pathway and is not thought to compete with other drugs. Two major metabolites are formed when the drug is metabolized by alcohol dehydrogenase and 5’glucuronyl transferase.

Dosage for adults (16 years of age and older) is abacavir 300mg tablets given orally twice daily. For pediatric patients (3 months to 16 years), the dose is abacavir 8 mg/kg orally twice daily with a maximum of 300 mg orally twice daily. No dosing adjustments are currently recommended in hepatic or renal insufficiency. However, studies are continuing to evaluate the drug in patients with renal dysfunction.

Alcohol decreases abacavir clearance, producing a 40% increase in the area-under-the-concentration time curve. No abacavir dose change is recommended and occasional moderate alcohol intake is currently considered acceptable. Abacavir is not metabolized by the cytochrome P-450 system and has not been shown to have interactions with drug metabolized by this route.

Rash has been a common reaction reported with abacavir therapy. The majority of patients with rash alone with no other symptoms have continued to take abacavir. Some side effects were more common on the 3-drug regimen (nausea, 18% vs. 10%), others such as anemia and neutropenia were comparable to those seen with the AZT + 3TC regimen. A potentially severe hypersensitivity reaction is associated with abacavir use. Estimated frequency is about 3 – 5%, with onset typically within the first 6 weeks on the drug. The syndrome involves multiple organ systems and is characterized by several of the following features: fever, nausea and vomiting, malaise, and a maculopapular or uticarial rash. Symptoms typically worsen with continued dosing but resolve promptly in several days when the drug is withheld. Patients who develop hypersensitivity to abacavir should NOT be rechallenged. Recurring symptoms have been more severe than the initial reaction, and life-threatening hypotension and death have been reported. Laboratory abnormalities have included lymphopenia, liver function test (LFT) increases, and occasionally elevated creatine kinase (CK) levels or thrombocytopenia.

Etanercept is approved for the treatment of moderately to severely active rheumatoid arthritis in patients who have failed disease-modifying antirheumatic drugs (DMARDs). It can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone. Etanercept is a soluble recombinant human tumor necrosis factor (TNF) receptor p75 Fc fusion protein that binds and neutralizes TNF biological activity. Etanercept can prevent inflammation by binding the soluble TNFa and TNFb, a proinflammatory cytokine. If the TNF is allowed to bind to cell-surface binding sites, it induces the proliferation of synoviocytes and enhances the production of prostaglandins, metalloproteinases, and cytokines. By decreasing the amount of soluble TNF, the drug decreases joint swelling, tenderness and morning stiffness, and lowers the levels of C-reactive protein, erythrocyte sedimentation rate and blood cytokines.

Etanercept is contraindicated in patients who are allergic to the drug, other product ingredients (mannitol, sucrose, tromethamine) or benzyl alcohol. Etanercept treatment should be discontinued if a patient develops a serious infection, with or without hypotension, which suggests impending sepsis syndrome. Etanercept should be discontinued if the child develops a varicella infection or has a significant exposure to varicella virus. In addition, treatment with Varicella Zoster Immune Globulin should be considered if the exposure was significant. Antibodies to etanercept have been detected in the sera of 16% of the rheumatoid arthritis patients treated with etanercept. However, none of these antibodies were neutralizing antibodies and did not decrease the drug’s effectiveness or cause adverse effects. Etanercept can be used during pregnancy (Category B) but no studies have been conducted in pregnant women. So the drug should only be used during pregnancy if clearly needed. Use of etanercept during nursing is discouraged since it is unknown if etanercept is excreted in breast milk. The manufacturer recommends that either the nursing or drug be discontinued.

The most common adverse reactions reported with etanercept were injection site reactions (37%). These reactions were classified as mild-to-moderate injection site reactions (erythema, erythema plus discomfort, itching or swelling). The injection site reactions do not occur with each dose, occur most frequently in the first month of therapy and decrease in frequency with continued therapy. The reaction generally resolved within 3 to 5 days.

Etanercept does not affect immune function. It is unknown if etanercept will affect the immune response to vaccines, so all scheduled vaccinations should be completed prior to starting etanercept therapy. Live vaccines should not be given concurrently with etanercept therapy. No specific drug interaction studies have been conducted with etanercept. However, patients enrolled in clinical studies were allowed to receive methotrexate, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, analgesics and/or hormone replacement therapy and no adverse effects were associated with the concomitant use of these agents with etanercept.

The most effective dose of etanercept used in the treatment of adults is 25 mg subcutaneously twice weekly. Although etanercept is not currently FDA approved for the treatment of juvenile rheumatoid arthritis, the dose of etanercept used in the treatment of juvenile rheumatoid arthritis is 0.4 mg/kg, with a maximum dose of 25 mg subcutaneously twice weekly. Safety in children less than 4 years has not been evaluated. Preferred subcutaneous injection sites include the thigh, abdomen, and upper arm. The injection site should be rotated with each dose. The new injection should be given at least 1 inch from previously used injection site. If the skin is tender, bruised, red or hard, then that area should be avoided.

Colestipol is a high molecular weight basic anion exchange resin composed of secondary and tertiary amines that is unlike cholestyramine, which contains quarternary ammonium groups. Colestipol binds bile acids in the intestine, forming a complex that is excreted in the feces Increased bile acid excretion causes increased cholesterol catabolism to replace the bile acid.

Colestipol is indicated as an adjunct to dietary therapy directed at decreasing elevated serum cholesterol and low-density lipoproteins in primary hyper-cholesterolemia. In hypercholesterolemia a number of studies have demonstrated that colestipol with diet therapy is more effective than diet alone or placebo. Colestipol (10 grams twice daily) in combination with gemfibrozil (600 milligrams twice daily) was effective for treating familial combined hyperlipidemia. Colestipol has also been used in combination with niacin, clofibrate, probucol, bezafibrate, fenofibrate, simvastatin, and lovastatin for synergy.

Colestipol can interfere with normal fat absorption and prevent absorption of fat soluble vitamins such as vitamin K. Vitamin K deficiency may cause bleeding tendencies due to hypoprothrombinemia which responds promptly to parenteral Vitamin K. Recurrences can be prevented by oral vitamin K(1). There is the possibility that prolonged use of colestipol may lead to hyperchloremic acidosis. Hypothyroidism especially in patients with limited thyroid reserve is theoretically possible. Colestipol combined with niacin was implicated in the reduction of thyroxine-binding globulin levels.

Gastrointestinal effects secondary to colestipol therapy include abdominal distention, constipation, nausea, vomiting, flatulence and diarrhea. Perianal pruritis has also been reported. This product should also not be taken in dry form to avoid accidental inhalation or esophageal distress. Always mix with water or fluids before ingesting.

Since colestipol is an anion exchange resin, it may have a strong affinity for anions other than bile acids. In vitro studies have indicated that colestipol binds a number of drugs including, tetracycline, furosemide, penicillin G, hydrochlororthiazide and gemfibrozil. The interval between administration between colestipol and other concomitant medications should be as long as possible. Patients should take other drugs at least one hour before or four hours after colestipol administration to avoid impeding drug absorption.

One dose (1 packetful or 1 level scoopful) contains 7.5 gm of flavored Colestid and 5 gm of colestipol hydrochloride. The recommended daily dose is one to six packets or level scoopfuls given once or in divided doses daily.

Citalopram appears to have comparable efficacy and tolerability with sertraline, and similar efficacy, but better tolerability to fluoxetine, amitriptyline and maprotiline in the treatment of depression. Citalopram exhibited similar efficacy and tolerability when compared to clomipramine for the treatment of panic disorder. Both citalopram and fluvoxamine therapies showed a greater rate of abstinence from alcohol compared to cognitive-behavioral therapy alone, but only citalopram showed an effect on craving thoughout a 16-week trial. Citalopram also exhibited comparable efficacy to fluvoxamine in the treatment of obsessive-compulsive disorder.

Citalopram is a weak inhibitor of CYP1A2, CYP2D6 and CYP2C19 however these effects have not been clinically significant. Inhibitors of CYP3A4 (e.g. Ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin) and CYP2C19 (eg. Omeprazole) may reduce the clearance of citalopram. Administration with cimetidine resulted in increased citalopram levels, but dosage adjustments are not necessary when these agents are given concomitantly. Citalopram coadministration with imipramine and desipramine resulted in an approximately 50% increase in single dose AUC of desipramine. Administration with metoprolol resulted in a two-fold increase in metoprolol levels. Citalopram should be given concomitantly with lithium only with caution.

Citalopram is contraindicated within 14 days of monoamine oxidase inhibitor therapy. It should be used with caution in patients with a history of hyponatremia and SIADH, seizure disorders and suicide ideation. It should also be used with caution in patients with hepatic or renal dysfunction. Citalopram is excreted in the breast milk of nursing mothers and has been detected in the serum of a breast-fed infant. The most common adverse events associated with citalopram include dry mouth, nausea, somnolence, insomnia, increased sweating, tremor, diarrhea, and sexual dysfunction. In general, these side effects are similar to those occurring with the other SSRIs.