Warning~Low Mag assoc. with long term PPI use

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FDA Drug Safety Communication: Low magnesium levels can be associated with

long-term use of Proton Pump Inhibitor drugs (PPIs)

Safety Announcement

Additional Information for Patients

Additional Information for Healthcare Professionals

Data Summary

Safety Announcement [3-2-2011] The

U.S. Food and Drug Administration (FDA) is informing the public that

prescription proton pump inhibitor (PPI) drugs may cause low serum

magnesium levels (hypomagnesemia) if taken for prolonged periods of time

(in most cases, longer than one year). In approximately one-quarter of

the cases reviewed, magnesium supplementation alone did not improve low

serum magnesium levels and the PPI had to be discontinued.PPIs

work by reducing the amount of acid in the stomach and are used to treat

conditions such as gastroesophageal reflux disease (GERD), stomach and

small intestine ulcers, and inflammation of the esophagus. In 2009,

approximately 21 million patients filled PPI prescriptions at outpatient

retail pharmacies in the United States.23 Patients who take prescription PPIs

usually stay on therapy for an average of about 180 days (6 months).Prescription

PPIs include Nexium (esomeprazole magnesium), Dexilant

(dexlansoprazole), Prilosec (omeprazole), Zegerid (omeprazole and sodium

bicarbonate), Prevacid (lansoprazole), Protonix (pantoprazole sodium),

and AcipHex (rabeprazole sodium). Vimovo is a prescription combination

drug product that contains a PPI (esomeprazole magnesium and naproxen).

Over-the-counter (OTC) PPIs include Prilosec OTC (omeprazole), Zegerid

OTC (omeprazole and sodium bicarbonate), and Prevacid 24HR

(lansoprazole).In contrast to prescription PPIs, OTC PPIs are

marketed at low doses and are only intended for a 14 day course of

treatment up to 3 times per year. FDA believes that there is very little

risk of hypomagnesemia when OTC PPIs are used according to the

directions on the OTC label.Low serum magnesium levels can result

in serious adverse events including muscle spasm (tetany), irregular

heartbeat (arrhythmias), and convulsions (seizures); however, patients

do not always have these symptoms. Treatment of hypomagnesemia generally

requires magnesium supplements. Treatment in patients taking a PPI and

who have hypomagnesemia may also require stopping the PPI.Healthcare

professionals should consider obtaining serum magnesium levels prior to

initiation of prescription PPI treatment in patients expected to be on

these drugs for long periods of time, as well as patients who take PPIs

with medications such as digoxin, diuretics or drugs that may cause

hypomagnesemia. For patients taking digoxin, a heart medicine, this is

especially important because low magnesium can increase the likelihood

of serious side effects. Healthcare professionals should consider

obtaining magnesium levels periodically in these patients.Information

about the potential risk of low serum magnesium levels from PPIs will

be added to the WARNINGS AND PRECAUTIONS sections of the labels for all

the prescription PPIs.Today's communication is in keeping with

FDA's commitment to inform the public about its ongoing safety review of

drugs. FDA is continuing to review reports of possible adverse events

and drug interactions with PPI drugs submitted to our Adverse Event

Reporting System. [see Data Summary]

 Additional Information for PatientsSeek

immediate care if you (or your child) experience an abnormal heart rate

or rhythm, or symptoms such as a racing heartbeat, palpitations, muscle

spasm, tremor or convulsions while taking a PPI drug. In children,

abnormal heart rates may cause fatigue, upset stomach, dizziness and

lightheadedness.Tell your healthcare professional

if you have ever been told you have low magnesium levels in your blood,

or if you take the drug digoxin, diuretics, or other drugs that may

cause hypomagnesemia.Your healthcare professional

may occasionally check your serum magnesium level (a blood test) while

you are taking your prescription PPI drug.Do not stop taking your prescription

PPI drug without talking to your healthcare professional.Discuss any questions

or concerns about your PPI drug with your healthcare professional.If you take an

over-the-counter (OTC) PPI drug, follow the directions on the package

carefully.Make sure your healthcare professional knows if you have been taking

an OTC PPI drug for a long period of time.Report

any side effects you experience to the FDA MedWatch program using the

information in the " Contact Us " box at the bottom of the page.

 Additional Information for Healthcare ProfessionalsConsider

obtaining serum magnesium levels prior to initiation of prescription

PPI treatment and checking levels periodically thereafter for patients

expected to be on prolonged treatment or who take PPIs with medications

such as digoxin or drugs that may cause hypomagnesemia (e.g.,

diuretics).Hypomagnesemia occurs with both loop

diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid) and

thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and

metolazone). These agents can cause hypomagnesemia when used as a

single agent or when combined with other anti-hypertensives (e.g.,

beta-blockers, angiotensin receptor blockers and/or ACE inhibitors).Advise

patients to seek immediate care from a healthcare professional if they

experience arrhythmias, tetany, tremors, or seizures while taking PPIs.

These may be signs of hypomagnesemia.Consider PPIs as a possible cause of

hypomagnesemia, particularly in patients who are clinically symptomatic.Patients

who develop hypomagnesemia may require PPI discontinuation in addition to

magnesium replacement.Be

aware that consumers either on their own, or based on a healthcare

professional's recommendation, may take OTC PPIs for periods of time

that exceed the directions on the OTC label. This is considered an

off-label (unapproved) use. Healthcare professionals should communicate

the risk of hypomagnesemia to patients if they are recommending

prolonged use of an OTC PPIs.Report adverse events

involving PPIs to the FDA MedWatch program, using the information in the

" Contact Us " box at the bottom of the page.

 Data SummaryFDA

has reviewed reports from the Adverse Event Reporting System (AERS),

medical literature, and periodic safety update reports for cases of

hypomagnesemia in patients undergoing prolonged treatment with PPI

medications. FDA's review focused on 38 cases in AERS and 23 cases

reported in the literature (which include at least 8 cases of the

identified AERS cases).4,5,6,7,8,9,10,11 The AERS case series

excluded patients who were on diuretics. The cases from the literature

included patients on diuretics when either (a) change in diuretic was

not associated with an improvement in serum magnesium level, or ( when

increase in serum magnesium level occurred with documented PPI

discontinuation. The FDA review suggests an association between

hypomagnesemia-related serious adverse events and prolonged PPI use.

However, because hypomagnesemia is likely under-recognized and

under-reported, the available data are insufficient to quantify an

incidence rate for hypomagnesemia with PPI therapy.Hypomagnesemia

has been reported in adult patients taking PPIs for at least three

months, but most cases occurred after a year of treatment. Approximately

one-quarter of these cases required discontinuation of PPI treatment in

addition to magnesium supplementation. Some cases cited both positive

dechallenge as well as positive rechallenge (i.e., resolution of

hypomagnesemia with PPI cessation and recurrent hypomagnesemia with PPI

resumption). After discontinuing the PPI, the median time required for

the magnesium to normalize was one week. After restarting the PPI, the

median time to develop hypomagnesemia again was two weeks. In most cases

reviewed the patients did not continue on PPIs after the hypomagnesemia

was treated.Examples of positive dechallenge in two patients

include a 63-year-old woman and a 67-year-old man who were both treated

with PPIs for 6 and 11 years, respectively. Both patients presented with

seizures and hypomagnesemia. Although both patients' hypomagnesemia

partially resolved with intravenous replacement, in both cases

discontinuation of PPI treatment was necessary to stop ongoing symptoms

and to stop magnesium loss.Clinically serious adverse events were

consistent with commonly reported signs and symptoms of hypomagnesemia,

which are similar to the signs and symptoms reported with hypocalcemia.

The serious events included tetany, seizures, tremors, carpo-pedal

spasm, atrial fibrillation, supraventricular tachycardia, and abnormal

QT interval. Hypomagnesemia also produces impaired parathyroid hormone

secretion which may lead to hypocalcemia. In cases where comprehensive

clinical laboratory data were available, most patients had concomitant

hypocalcemia and normal parathyroid hormone levels. Therefore, these

findings confirm hypomagnesemia as the primary deficit.The

mechanism responsible for hypomagnesemia associated with long term PPI

use is unknown; however, long term use of PPIs may be associated with

changes in intestinal absorption of magnesium.5OTC

PPIs are marketed for the treatment of frequent heartburn under the

brand names Prilosec OTC, Zegerid OTC, and Prevacid 24 HR. OTC PPIs are

labeled for 14 days of use, and this treatment course may be repeated

every 4 months, up to 3 times per year. FDA acknowledges that consumers,

either on their own, or based on a healthcare professional's

recommendation, may take these products for periods of time that exceed

the directions on the OTC label. This is considered an off-label

(unapproved) use, based on the directions of use for OTC PPIs.

Healthcare professionals should be aware of the risk of hypomagnesemia

if they are recommending use of OTC PPIs for longer periods of time than

in the OTC PPI label. FDA believes that OTC PPIs carry very little risk

of hypomagnesemia when used according to the package directions, and

therefore the Drug Facts box for the OTC PPIs will not be changed to

include the risk of hypomagnesemia. SDI, Vector One®: National (VONA). 2002-

2010. Data extracted 3-12-10.SDI, Vector One®: Total Patient Tracker (TPT).

2002-2009. Data extracted 3-24-10.IMS Health, IMS Health Plan Claims

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