Toprol XL vs. Generic Metoprolol Succinate
Extended-release (ER) Tablets Review Article
Choose the Best Blood
Pressure Medication. Find Out Why Some Generic Blood Pressure Medications
Are Not the Same as the Original & May Increase Blood
Pressure or Have Other Disturbing Side Effects.
Medically reviewed and
edited by Tod Cooperman, M.D. 
Last Updated
: 12/31/2008 | Initially Posted:
03/17/2008
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Table of Contents
Update
Updates:
ETHEX/KV (25 mg, 50 mg, 100 mg, and 200 mg): On January 28, 2009 KV
Pharmaceutical recalled all strengths of its Metoprolol Succinate ER because
"...the products may have been manufactured under conditions that did not
sufficiently comply with Good Manufacturing Practices (cGMPs)."
It also recalled, at the wholesale level, sixty other generic products.
See the recall announcement, which includes a list of all
affected products.
EON/Sandoz (25 mg and 50 mg): On August 12, 2008, the U.S. FDA sent a letter to
Sandoz Inc. warning of violations in its manufacture of
Metoprolol Succinate ER tablets and other drug products. Sandoz's Metoprolol
Succinate ER tablets are generic versions of Toprol XL. In its letter the
FDA stated that, based on an inspection of a North Carolina plant in March
2008, Sandoz failed to appropriately validate the manufacturing process for
Metoprolol Succinate (25 and 50 mg). Some lots were found to fail tests for
content uniformity or dissolution. The FDA noted that Sandoz's practices
represented a "moving target of quality." The FDA noted that Sandoz
did not conduct timely investigations of lots that failed dissolution testing.
In addition, Sandoz chose to continue to release product even after being
notified of violations.
The FDA concluded that Sandoz does "not provide a high level of
assurance" that its process is "capable of producing a product that
meets specifications." The FDA added, "We question the continued
distribution of this product until better process controls are implemented and
process validation is completed." The FDA requires that Sandoz take prompt
action to correct the violations. The Warning Letter to Sandoz is found
at www.fda.gov/foi/warning_letters/s6891c.pdf. In
September and November 2008, with little public announcement, Sandoz undertook
recalls of its metoprolol succinate products.
Shortages of generic metoprolol succinate ER, as well as Toprol XL, have been
reported in the U.S. as a result of the recalls. PharmacyChecker.com, an
affiliate of ConsumerLab.com, has reported that both remain available to
Americans from pharmacies in other countries, often at lower cost. More
information is available from PharmacyChecker.com.
Background:
Toprol XL is approved for the treatment of high blood pressure
and other cardiovascular disorders including angina pectoris and stable but
symptomatic forms of heart failure. Toprol XL is also used to reduce the
occurrence of migraine headache. It is a beta-1-selective (cardioselective)
adrenoreceptor blocker. Its generic form, metoprolol succinate extended-release
tablets, first became available in November of 2006 in the 25 mg strength,
followed by additional strengths (50 mg, 100 mg, and 200 mg) in July and August
2007. Toprol XL and its generic forms are expected to provide a controlled and
predictable release of metoprolol for once-daily administration. Shortly after
the generics became available, some consumers began experiencing problems when
switching from Toprol XL to a generic. Reports began to appear on www.PeoplesPharmacy.com. ConsumerLab.com also began
receiving such reports through its reporting form at https://www.consumerlab.com/GenericReport.asp.
Toprol XL has been one of the most popular medications for controlling blood
pressure and arrhythmias. Prior to the launch of generics, annualized sales of
the most popular strength -- 50 mg -- was $640 million; sales of the 25 mg
strength was about $300 million, and the 100 and 200
mg strengths together had sales of $778 million according to IMS Health.
Problems Reported with
Generic Versions of Metoprolol Succinate Extended-Release:
A large
number of complaints have been posted for generic versions of Toprol XL. These
complaints generally focus on one or more of the following:
·
a dramatic increase in blood pressure
·
an increase in heart rate and ectopic beats
·
side effects such as nausea, dizziness, hives and headaches
(including migraine)
Although there are known
side-effects with Toprol XL, these, other than dizziness and itching, differ
from those being reported after a switch to a generic. In particular, patients
taking the generic are reporting an increase in blood pressure and heart rate
while a known side-effect of Toprol XL is a slowing of the heart rate
(bradycardia). The common side effects of Toprol XL, as noted on its package
insert, are tiredness (10%), dizziness (10%), depression (5%), diarrhea (5%),
pruritus (itching) or rash (5%), shortness of breath (3%), and bradycardia
(slow heart rate) (3%).
Perhaps most striking about the consumer complaints is that problems generally
stopped when medication was switched back to Toprol XL. The increase in blood
pressure and heart rate reported by some suggest that the generics they used
are not as effective as the original, possibly not providing high enough drug
levels throughout the day.
Below are examples of complaints reported by users of generic metoprolol
succinate received by ConsumerLab.com or posted at www.PeoplesPharmacy.com:
"After being on
TOPROL XL for almost a year, I was switched to the generic [25 mg]… After being on it for less than two weeks, my BP
started fluctuating toward the high end at different times of the day. After
talking to my doctor, he wrote me a D.A.W. [Dispense as Written] order for
TOPROL XL, and though I had to pay more, my BP became balanced throughout the
day."
"My doctor
prescribed Toprol-XL several years ago to control hypertension. All went well.
Last week my pharmacist refilled my prescription with generic metoprolol
succinate. Within two days my blood pressure was sky high--190/100. This has
never happened before, so there may be a problem with this generic for
Toprol-XL."
"My employer's drug
service replaced Toprol XL with the generic equivalent in Jan 2007 and I used
it until July-Aug 2007. During that time I had a
number of blood pressure tests which showed my pressure rising for no apparent
reason. Not to life-threatening levels, but noticeable. Late in 2007, I
switched back to Toprol XL and the latest tests, after about 3 months, are back
to normal low readings."
"In 2004, my GP
prescribed Toprol XL (50 mg daily) for my stage 3 hypertension and migraine
headaches. It has worked perfectly; my headaches have been virtually
nonexistent and my BP has been in the normal range. Caremark refilled my last
prescription with Metoprolol Succinate (without checking with my physician),
which I have started taking. I am now experiencing terrible, unrelenting
headaches, but have not yet had an opportunity to have my BP checked."
The 50 mg and 25 mg
strengths have been most commonly mentioned in the complaints. Eon Labs or its
parent Sandoz, which specifically markets these two strengths, has also been
identified in several of the complaints. Other strengths and companies have not
been commonly mentioned.
If you would like to report a problem with a generic drug, please let us
know. Click here.
Different Pills — But
Called Equivalent:
The
active ingredient in Toprol XL (metoprolol succinate) is off-patent while the
method for delivering it in time-released tablets is still patent-protected. As
a result, companies wishing to market their own time-released generics have had
to use or develop tablets different from those sold as Toprol XL or obtain an
appropriate license. Different pills and ingredients
Among the products on the market, only products from Par Pharmaceutical are
identical to original Toprol XL. Par has a supply arrangement with AstraZeneca,
the maker of Toprol XL. Generics that are identical to the original drug are
known as "authorized generics."
Two other companies selling metoprolol succinate extended-release generics,
Eon/Sandoz and Ethex (a division of KV Pharmaceutical)
use tablets different from Toprol XL in their size and inactive ingredients.
All the products, including Toprol XL, are formulated as tablets containing
many tiny pellets. Each pellet contains a small amount of drug along with a
variety of compounds designed to release the drug slowly as the pellet passes
through the digestive tract — primarily the intestine. But while the products
share this basic design, the "Inactive Ingredients" that make up the
Eon/Sandoz and Ethex products differ from those in
Toprol XL. The Eon/Sandoz products include ingredients such as methacrylic acid
copolymer, magnesium stearate, polysorbate 80, sugar spheres, and talc. The Ethex products include calcium stearate, hydrogenated
vegetable oil, and vinyl acetate copolymer. None of these ingredients are in
Toprol XL. People with chemical sensitivities may have a reaction to an
ingredient found in a generic but not in the original product. It is wise to
read the "Inactive Ingredient" list carefully if you have chemical sensitivities.
(See the comparison table below.)
Different drug release (Dissolution):
Differences in pill design and inactive ingredients may affect how drug is
released from a tablet and the rate of that release. Information available from
the FDA and the manufacturers suggest that this may be the case with products
from both Eon/Sandoz and Ethex.
The FDA permits the dissolution of generic products to vary from the original
by a fairly wide range. For example, to meet the dissolution test for the
original Toprol XL, a generic may release anywhere from 20% to 40% of its
ingredient at four hours into the test. At the completion of such a test (after
twenty hours), the product may have released from 80% to 100% of its ingredient
and still be considered equivalent.
But going further, the FDA has apparently not required the metoprolol succinate
generics from Eon/Sandoz and Ethex to meet this
dissolution test. Instead, it seems to have accepted different dissolution
tests established by the manufacturers. Unfortunately, the details of these
dissolution tests have been partially removed from documents on the FDA
website. (See the FDA letters for Eon/Sandoz and Ethex (KV Pharmaceutical) generics).
The official USP dissolution test for Toprol XL is conducted at a pH of 6.8,
which is near neutral (7.0). This is also within the pH range of much of the
intestine where extended-release products are expected to slowly release their
drug. Oddly, the dissolution test for the Eon/Sandoz product, as partially
described on the FDA website, is conducted at a more acidic pH of 4.5. This is
about a hundred times more acidic than a pH of 6.8. It is curious that only the
Eon/Sandoz generic is tested at such a relatively acidic pH.
It is possible that if the Eon/Sandoz product were tested like Toprol XL at a
pH of 6.8, it might not release the same amount of drug as Toprol XL. In
addition, drugs that neutralize acid or inhibit the stomach's production of
acid, or foods that create more acid, might affect its dissolution in a
different way than Toprol XL or other generics are affected.
The Ethex generic also seems to dissolve differently
than Toprol XL. A section of its package insert notes, in fact, that it
"Does not comply with the dissolution test of the USP monograph for
metoprolol succinate extended-release tablets." Exactly how it differs is
not disclosed.
Misbranding?
According to the inserts from Eon/Sandoz and Ethex,
all of these generics are named "Metoprolol Succinate Extended-release
Tablets USP." Using the term "USP" in a product name generally
implies that it meets all monograph specifications established by the United
States Pharmacopeia. However, as noted above, the Ethex
product, according to its own published materials, does not meet the USP
dissolution standard, nor does it describe its own standard. And the
dissolution test described for the Sandoz generic in its FDA approval letter is
not the USP method. By including USP in their names, but apparently not meeting
this USP standard, both products appear to be misbranded — a legal violation.
Of greater concern is that such misbranding could lead pharmacists, physicians,
or others to believe that these drugs behave just like the original Toprol XL,
when that may not be the case.
Bioequivalence
The safety and efficacy of generic drugs, unlike their original counterparts,
are not clinically tested. Instead, the FDA relies on information from
manufacturers showing that, when administered to people, blood levels of their
drugs are approximately the same as those for the original drug. These
"bioequivalence" tests are considered more important than dissolution
tests because they show what really happens in the body. However, ConsumerLab.com's research into generic forms of Wellbutrin XL, an anti-depressant, suggests
that the bioequivalence results for a generic can vary in notable ways from
that of the original drug and still be acceptable to the FDA. Unfortunately,
the FDA does not make bioequivalence data for generic drugs available for
public review.
Comparison of Metoprolol
Succinate Extended-Release Products:
|
Distributor |
Same
as Original? |
|
||
|
Appearance |
Inactive Ingredients |
Dissolution |
Where Sold** |
|
|
25 MG: |
||||
|
AstraZeneca |
Size: 10mm |
Silicon dioxide, cellulose compounds, sodium stearyl
fumarate, polyethylene glycol, titanium dioxide, and paraffin. |
Complies with USP dissolution test. |
Widely available |
|
Eon Labs/Sandoz |
Different |
Different |
May be different. |
CVS |
|
Par Pharmaceutical |
Same |
Same |
Same |
Albertsons/ |
|
50 MG: |
||||
|
AstraZeneca |
Size: 9mm |
(See list for Toprol XL 25 mg above) |
Complies with USP dissolution test. |
Widely available |
|
Eon Labs/Sandoz |
Different |
Different |
May be different. |
CVS |
|
Par Pharmaceutical |
Same |
Same |
Same |
Albertsons/ |
|
100 MG: |
||||
|
AstraZeneca |
Size: 10mm |
(See list for Toprol XL 25 mg above) |
Complies with USP dissolution test. |
Widely available |
|
Ethex |
Different |
Different |
Different. |
CVS |
|
Par Pharmaceutical |
Same |
Same |
Same |
Albertsons/ |
|
200 MG: |
||||
|
AstraZeneca |
Size: 17mm |
(See list for Toprol XL 25 mg above) |
Complies with USP dissolution test. |
Widely available |
|
Ethex |
Different |
Different |
Different. |
CVS |
|
Par Pharmaceutical |
Same |
Same |
Same |
Albertsons/ |
|
* An "authorized generic" drug is the same as
the original drug but sold as a generic under a different brand name. |
||||
What This Could Mean to
You:
Consumer complaints about
some of the generic versions of Toprol XL (mainly the 25 and 50 mg strengths)
suggest that they may act differently than the original — at least for some
people. This is unlikely to be an issue with the authorized generic from Par
Pharmaceuticals, which is identical to Toprol XL. Concern is greatest with the
Eon/Sandoz version -- specifically referenced in some complaints. The
Eon/Sandoz version is known to have different ingredients and probably
dissolves differently, as suggested by the more acidic solution used in the
test described in its drug approval letter. If the drug dissolves more rapidly
than the original, it is possible that blood levels of the generic drug might
at first rise higher than with the original, potentially increasing the risk of
side-effects. As drug is eliminated over the rest of the day, the amount of
drug in the blood might then fall lower than with the original, potentially
making the generic less effective later on. Conversely, if it releases too
slowly at first, too little of the drug may be available early in the day and
too much may be available later. As noted earlier, because the Eon/Sandoz and Ethex products each contain multiple inactive ingredients
different from Toprol XL, keep in mind that chemical sensitivities may occur
that you would not have experienced with Toprol XL.
Strategies for Getting
the Right Drug:
Request Generics by Name:
If your current generic version is working but others have
not, make note of the distributor and the manufacturer on the label and try to
stick with that exact product. Ask your pharmacist to fill your prescriptions
with that specific version. Call around if you need to — different pharmacies
often carry different generic brands. The last column of the table above provides
examples of pharmacies known to carry specific generic brands. Be aware,
though, that a pharmacy may change the brand it carries and a generic brand
itself may change its product due to new licensing or manufacturing
arrangements.
If you find that a generic version of Toprol XL is not working,
consider the following:
·
Dispense as Written: Have your doctor prescribe the
brand-name version and indicate "Dispense as Written" or "Do Not
Substitute." If your insurance will not cover it, ask your doctor to make
a special request to your insurance company.
·
If your insurance still won't cover the original, you have other
options:
o Try a Different Generic: See if there is a
different generic equivalent — preferably one made by the same company that
makes the original drug (an "authorized generic"), as this is likely
to be identical to the original. Par Pharmaceutical distributes authorized
generic versions of Toprol XL.
o Get the Original at Low
Cost: The
price for original Toprol XL is not much greater (about 10%) than that for
generics — possibly due to competition. If you are paying out-of-pocket, the
difference may not be great. You can also try to save money by purchasing the
drug from a discount pharmacy or a licensed Canadian or other non-US pharmacy.
A good place to compare low prices from licensed pharmacies is www.PharmacyChecker.com, a site started by ConsumerLab.com
in 2002.
·
Switch Versions: Consider a different version of the
drug. If a once-a-day generic is not working, consider a twice-a-day (SR) or
three-times-a-day version that will yield the same total daily dose. You will
have to remember to take the medication on schedule.
ConsumerLab.com may
update or publish additional research about metoprolol succinate products in
the future. Stay up-to-date by checking back or reading ConsumerLab.com's
free e-newsletter, which you receive as a
subscriber. For a list of other popular time-released generic drugs, see Extended-Release Generics — Are They the Same as the
Original?
If you have had a problem when switched to a generic drug, please let us
know. Click here.
Information on this site
is provided for informational purposes only. It is not an endorsement of any
product nor is it meant to substitute for the advice provided by physicians or
other healthcare professionals. The information contained herein should not be
used for diagnosing or treating a health problem or disease. Consumers should
inform their healthcare providers of the dietary supplements they take.