Drug Updates: Citalopram hydrobromide, Statins, and More

Drug Safety

Citalopram hydrobromide, the racemic mixture of R- and S-isomers, is having its warning clarified based on an ongoing data evaluation from the U.S. Food and Drug Administration (FDA).¹ The original updated safety information was reported in August 2011 and warned of dysrhythmias related to high doses of citalopram hydrobromide. Additional, new label changes are related to the potential for QT interval prolongation and Torsade de Pointes, as well as new drug dosage and usage recommendations. These new recommendations recognize that citalopram should be avoided in people with certain conditions—such as those with congenital long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia; those who have had a recent acute myocardial infarction; or those with uncompensated heart failure—because of the risk of QT prolongation. The new label recommendation for patients with congenital long QT syndrome has been changed from “contraindicated” to “not recommended.”

Citalopram use is also not recommended in patients who are taking other potential QT-interval prolonging drugs. Additionally, the maximum recommended daily citalopram dose is 20 mg for patients with hepatic impairment, those who are older than 60 years of age, those who are CYP 2C19 poor metabolizers, or those who are taking concomitant cimetidine or other CYP2C19 inhibitors. This is because these can lead to increased citalopram blood levels leading to an increased risk of QT-interval prolongation and Torsade de Pointes. Electrocardiogram (ECG) and/or electrolyte monitoring should be performed if citalopram is going to be used in these patients. Other patients may also require ECG monitoring. Citalopram should be discontinued in patients who are found to have persistent QTc measurements greater than 500 milliseconds.

Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, recently underwent important label and safety changes.² Due to the unpredictability of serious hepatic injury in statin users, and the fact that monitoring more frequently does not seem to prevent hepatic injury, the labeling of all statins have been updated to reflect a change in this monitoring. This comes from an extensive review of statin data, carried out by the FDA. The review determined that all available statins are associated with a very low risk of serious hepatic injury, which is not averted by routine serum alanine aminotransferase monitoring. It is now recommended that physicians monitor liver enzymes before starting statins and as clinically indicated thereafter.

In addition, the effect of statins on cognition was evaluated by the FDA by reviewing its Adverse Event Reporting System (AERS) database as well as published medical literature and randomized clinical trials. The postmarketing adverse-event reports most commonly describe cognitive impairment in people older than age 50, whose memory impairment (e.g., loss or impairment) abated upon discontinue of the statin. No associations were noted between the impairment and any particular statin or statin dose, patient age, or other associated medication use. Occurrence was very variable, and could occur from one day following commencement of the statin through years of use. It was not connected to dementia. Information derived from observational studies and clinical studies did not indicate that cognitive changes are common or lead to progressive cognitive decline.

Finally, additions to the drug label for lovastatin have been added related to drug–drug interactions, contraindications, and dose limitations. This information was evaluated subsequent to the 2011 simvastatin label change, due to similarities in metabolism between both simvastatin and lovastatin. Strong CYP3A4 inhibitors can significantly increase lovastatin exposure leading to rhabdomyolysis. New drug interactions added to the label include hepatitis C virus protease inhibitors and posaconazole. In addition, prescribers should avoid prescribing, and patients should avoid taking, cyclosporine or gemfibrozil with lovastatin, and limit the daily lovastatin dose to 20 mg with danazol, diltiazem, and verapamil. Lovastatin dosing should be limited to 40 mg daily with amiodarone, and patients should avoid drinking more than one quart of grapefruit juice daily if taking lovastatin.

Skin products, mostly cosmetics such as skin lighteners and antiaging products, have been under scrutiny by the FDA due to potential mercury contamination.³ Products with toxic mercury levels have been identified in at least seven U.S. states. Consumers are being warned not to use skin creams, beauty and antiseptic soaps, or lotions which are being marketed to remove age spots, freckles, blemishes, and wrinkles. Most of these products are manufactured abroad and illegally sold in the U.S. in ethnic markets. These products may have also been purchased abroad and brought home for use. Dangerous mercury exposure can include renal failure and nervous system damage. Children can inhale mercury vapors from topically used skin products or ingest products and develop mercury toxicity. Some of the more than 35 products that have been identified have been tested and contain more than 100 times the allowable mercury level. Physicians and patients should be alert to any of these skin products which are likely to contain mercury and have the following ingredients: mercurous chloride, mercuric, mercurio, mercury, or calomel. They should stop using them immediately. You can always call your local poison control center with any questions related to any potential or actual mercury-containing products.

Strontium ranelate (Protelos/Osseor) has been issued a safety warning from the European Medicines Agency (EMEA).⁴ This agent is not FDA approved. This drug is now contraindicated in patients with venous thromboembolism (VTE) or those who are immobilized due to the increased risk of VTE. The VTE risk also is higher in elderly patients. Additionally, new warnings were updated regarding the development of serious skin reactions, including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Strontium ranelate is approved in Europe to treat postmenopausal osteoporosis.

Drug Approvals

Binosto (alendronate sodium) has been FDA approved as a strawberry-flavored, effervescent tablet for the treatment of postmenopausal osteoporosis.⁵ It was also FDA approved to increase bone mass in men with osteoporosis. It is available as a once-weekly 70-mg dosage form containing 70 mg alendronate sodium that rapidly dissolves in four ounces of plain, room temperature water, making a buffered solution. It will be available in the third quarter of 2012 and be available in one-month (#4) and 3-month (#12) packages.

Peppermint-flavored escitalopram oxalate oral solution (5 mg/5 mL) is the first generic form of this liquid product to be FDA approved.⁶ Additionally, Teva has been awarded 180-day exclusivity for marketing of generic escitalopram tablets.⁷ Both dosage forms are now available.

Ibandronate 150-mg tablets, the once-monthly tablet to prevent or treat osteoporosis in postmenopausal women, is now available as a generic.⁸ At least three companies received FDA approval of their generic products, therefore the price of this agent will most likely decrease significantly. This generic of Boniva will be available with a medication guide that explains serious reactions associated with its use, including esophageal problems such as inflammation, irritation, or ulcers; hypocalcemia; bone, joint, or muscle pain; osteonecrosis of the jaw; and atypical femur fractures.

LidoPatch (3.99% lidocaine and 1% menthol), an over-the-counter pain patch, was recently FDA approved.⁹

Pipeline

CCX354 is a selective and potent CCR1 antagonist, a chemokine receptor that drives recruitment of inflammatory cells, including monocytes, macrophages, and T cells, into the joints of rheumatoid arthritis (RA) patients.¹⁰ By selectively blocking the CCR1 receptor, CCX354 reduces inflammatory cell infiltration into RA patients’ joints, reducing inflammation, swelling, pain, and joint destruction. Recently, positive outcomes were reported from a phase II clinical trial that investigated the safety, tolerability, and clinical and biological activity CCX354 in patients with RA.

GLPG0634, a selective inhibitor of Janus kinase 1 (JAK1), achieved its primary endpoint of significant improvement in the signs and symptoms of RA, with 83% of patients showing improvement in ACR20 score at four weeks.¹¹ Additionally, half of the treated patients went into remission or showed a low-disease activity at Week Four. No anemia or increases in cholesterol or low-density lipoproteins were seen. No severe adverse events were reported in patients that received the agent.

Ixekizumab and brodalumab are two investigational interleukin (IL)-17 inhibitors being studied in patients with psoriasis.¹² In phase II clinical trials, there seemed to be a lack of significant side effects, which is a plus for many of these biologic agents. However, because they suppress the immune system, there is always the potential for an increased infection risk. If these agents continue to do well in clinical trials, patients may soon have biologic options in additional to tumor necrosis factor–α inhibitors.

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

References

1. FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses. Published March 28, 2012. Available at www.fda.gov/Drugs/DrugSafety/ucm297391.htm. Accessed March 29, 2012.
2. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. Published February 28, 2012. Available at www.fda.gov/Drugs/DrugSafety/ucm293101.htm#data. Accessed March 27, 2012.
3. Mercury poisoning linked to skin products. Published March 6, 2012. Available at www.fda.gov/ForConsumers/ConsumerUpdates/ucm294849.htm?source=govdelivery. Accessed March 27, 2012.
4. Brooks M. 2012 EMA recommends new warnings on bone drug. Published March 16, 2012. Available at www.medscape.com/viewarticle/760408. Accessed March 16, 2012.
5. FDA approves BINOSTO, first and only effervescent osteoporosis treatment in a buffered solution. Published March 14, 2012. Available at www.effrx.com/news/20120314. Accessed March 27, 2012.
6. Cerra A. Amneal launches liquid generic Lexapro. Published March 15, 2012. Available at http://drugstorenews.com/article/amneal-launches-liquid-generic-lexapro. Accessed March 27, 2012.
7. Cerra A. Teva launches generic Lexapro, awarded 180-day exclusivity. Published March 22, 2012. Available at http://drugstorenews.com/article/teva-launches-generic-lexapro-awarded-180-day-exclusivity. Accessed March 27, 2012.
8. Dane L. FDA approves first generic versions of Roche’s Boniva. Published March 19, 2012. Available at www.firstwordpharma.com/node/961550. Accessed March 27, 2012.
9. Johnsen M. JAR Labs launches OTC lidocaine pain patch. Published February 9, 2012. Available at http://drugstorenews.com/article/jar-labs-launches-otc-lidocaine-pain-patch. Accessed February 12, 2012.
10. GSK exercises option to license ChemoCentryx’s CCR1 Inhibitor, CCX354, for the treatment of rheumatoid arthritis. Published January 5, 2012. Available at http://ir.chemocentryx.com/releasedetail.
11. Galapagos’ GLPG0634 shows excellent efficacy and safety in rheumatoid arthritis Phase II study. Published November 22, 2011. Available at www.glpg.com/index.php/randd/pipeline/glpg0634-ra. Accessed March 27, 2012.
12. Storrs C. Two experimental drugs could improve psoriasis treatment. Published March 29, 2012. Available at http://consumer.healthday.com/printer.asp?AID=663196. Accessed March 29, 2012.