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New Drug Interaction With Widely Used Antibacterial Drug and Common Diuretic

Worst Pills, Best Pills Newsletter article December, 2011

Elderly patients prescribed trimethoprim-sulfamethoxazole (SEPTRA, SEPTRA DS), a widely used antibacterial drug for urinary tract infections, in combination with the diuretic spironolactone (ALDACTONE) have a much higher risk of being hospitalized for increased blood levels of potassium (hyperkalemia), according to a new study.

On Sept. 13, 2011, the British Medical Journal (BMJ) released the results of important research showing this effect in elderly patients. The risk for...

Elderly patients prescribed trimethoprim-sulfamethoxazole (SEPTRA, SEPTRA DS), a widely used antibacterial drug for urinary tract infections, in combination with the diuretic spironolactone (ALDACTONE) have a much higher risk of being hospitalized for increased blood levels of potassium (hyperkalemia), according to a new study.

On Sept. 13, 2011, the British Medical Journal (BMJ) released the results of important research showing this effect in elderly patients. The risk for hospitalization due to hyperkalemia for elderly patients, all of whom were also taking spironolactone, was much greater for those taking trimethoprim-sulfamethoxazole than for those taking either amoxicillin (AMOXIL) or nitrofurantoin (FURADANTIN, MACROBID).

This research identified a new drug interaction with the two above-mentioned drugs. In 2010, prescriptions for spironolactone and trimethoprim-sulfamethoxazole exceeded 9.2 and 21.3 million, respectively.

Hyperkalemia and the elderly

Elderly patients are at an increased risk of developing elevated potassium levels as a consequence of aging. Potassium is eliminated through the kidneys, and with age, kidney function declines, leading to decreased ability to eliminate potassium.

Hyperkalemia often has no symptoms. Patients may experience irregular heartbeat, nausea and slow, weak or absent pulse. Emergency symptoms include absent or weak heartbeat, changes in breathing pattern, loss of consciousness, nausea and weakness.

Other causes of elevated potassium levels in the blood, besides this new drug interaction, include kidney disease, other drugs, dietary supplements and potassium from dietary sources (see the table; a number of drugs in the list are most commonly available by their generic names.)

Selected Drugs Causing Elevated Potassium Levels

Generic Name Brand Name
acebutolol SECTRAL
amiloride MIDAMOR
atenolol TENORMIN
benazepril** LOTENSIN
betaxolol (for the heart) KERLONE
bisoprolol ZEBETA
candesartan** ATACAND
captopril** CAPOTEN
carvedilol COREG
celecoxib* CELEBREX
cyclosporine NEORAL, SANDIMMUNE
diclofenac** CATAFLAM, VOLTAREN
dietary sources (ba¬nanas, melon and orange juice)  
digoxin LANOXIN (at toxic blood levels)
enalapril** VASOTEC
eplerenone** INSPRA
eprosartan** TEVETEN
ethinyl estradiol and drospirenone* YASMIN
etodolac** ETOGESIC, LODINE
fenoprofen** NALFON
fluconazole DIFLUCAN 
flurbiprofen ANSAID, OCUFEN
fosinopril** MONOPRIL
herbal remedies with digitalis-like effect
(milkweed, lily of the valley, Siberian ginseng*, hawthorn berries or preparations from dried toad skin [Bufo, Chan Su, Senso])
 
herbs containing high potassium levels
(e.g., Noni juice*, alfalfa, dan¬delion, horsetail and nettle)
 
ibuprofen ADVIL, MOTRIN
indomethacin* INDOCI
irbesartan** AVAPRO
itraconazole* SPORANOX
ketoconazole NIZORAL
lisinopril** PRINIVIL, ZESTRIL
losartan** COZAAR
meclofenamate** MECLOMEN
mefenamic acid** PONSTEL
meloxicam* MOBIC
metoprolol succinate TOPROL XL
metoprolol tartrate LOPRESSOR
moexipril** UNIVASC
nabumetone** RELAFEN
nadolol  CORGARD
naproxen ALEVE, ANAPROX, NAPROSYN
olmesartan** BENICAR
oxaprozin** DAYPRO
penicillin G potassium  
pentamidine NEBUPENT, PENTAM 300
perindopril** ACEON
piroxicam* FELDENE
posaconazole NOXAFIL 
potassium supplements   
propranolol INDERAL, INDERAL LA
quinapril ACCUPRIL
ramipril** ALTACE
salt substitutes  
spironolactone** ALDACTONE
sulindac** CLINORIL
tacrolimus PROGRAF, PROTOPIC
telmisartan** MICARDIS
tolmetin** TOLECTIN
trandolapril** MAVIK
triamterene* DYRENIUM
trimethoprim PROLOPRIM, TRIMPEX
valsartan** DIOVAN
voriconazole VFEND 

Note: The list was compiled from various sources, beginning with an article appearing in the Jan. 15, 2006, American Family Physician medical journal.
* Do Not Use ** Limited Use (offers limited benefit or benefits certain people or conditions)

BMJ study results

The study was conducted in Ontario, Canada, and included all residents aged 66 and over treated with spironolactone between April 1992 and March 2010. This was an observational study, not a gold-standard, randomized, controlled trial, which is the best evidence for showing a cause-and-effect relationship. However, observational studies, especially those based on an entire population (like the BMJ study), have provided most of what we know about the adverse effects of drugs.

The researchers were intrigued by the fact that the trimethoprim portion of the trimethoprim-sulfamethoxazole combination has negative effects similar to those of another diuretic, amiloride (MIDAMOR), known to reduce the elimination of potassium by as much as 40 percent.

To assess this effect in the study, the researchers identified patients on chronic spironolactone treatment who were admitted to the hospital with a diagnosis of hyperkalemia within 14 days of starting one of four study antibiotics: trimethoprim-sulfamethoxazole, amoxicillin, norfloxacin (NOROXIN) or nitrofurantoin.

From these 6,903 patients, the researchers calculated the risks for hospitalization for hyperkalemia with the use of each antibiotic drug in those already taking spironolactone. Of the 6,903 patients admitted to the hospital, 10.8 percent received at least one prescription for trimeth-oprim-sulfamethoxazole. Regarding the duration of treatment, 306 of the admissions occurred within 14 days of starting one of the four drugs for urinary tract infection.

Compared to amoxicillin, the use of trimethoprim-sulfamethoxazole along with spironolactone was associated with a 12.4-fold risk ofhospitalization for hyperkalemia.
Those taking spironolactone and nitrofurantoin had an increased risk of hospitalization for hyperkalemia of 2.4-fold, and those on spironolac¬tone and norfloxacin experienced an increased risk of 1.6-fold. There was no increased risk with amoxicillin.

What You Can Do

You should alert your physician to the risk of this drug interaction if you take long-term spironolactone treatment and develop a urinary tract infection.

The study’s authors stated, “treatment with trimethoprim-sulfamethoxazole was associated with a major increase in the risk of admission to hospital for hyperkalaemia,” and that “[t]his drug combination should be avoided when possible.”

You should seek medical attention immediately if you are taking drugs or dietary supplements that elevate blood potassium levels and you experience the symptoms of elevated blood potassium listed above.

Consumers may report serious adverse events with drugs or product quality problems to the Food and Drug Administration’s (FDA) MedWatch Adverse Event Reporting program.

  • Online: www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
  • Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
  • Fax: (800) FDA-0178
  • Phone: (800) FDA-1088