Features October 2019 Issue

Generic Drugs: Are You Sure the Ones You Take Are Safe and Effective?

There's disturbing evidence that some generics are not equivalent to brand-name drugs or may be unsafe. Here's what you should know.

Americans have a love affair with generic drugs. At only a fraction of the cost of their brand-name counterparts, generics make medications more affordable for all.

Millions of people have no problems with the generic drugs they take. But a growing number of disturbing patient experiences and drug recalls have made it clear that some generics are not being manufactured according to the high standards set by the U.S. Food & Drug Administration (FDA).

The processes and raw materials that allow generics to be made overseas and sold so cheaply in the U.S. are often substandard, leading to medications that can be contaminated or fail to work like they should.

What Is a Generic Drug?

In 1984, the U.S. enacted a law that allows generic companies to win FDA approval with limited tests proving their drugs are bioequivalent to the brand-name drug and perform similarly. It may not have exactly the same chemical composition, but it must act the same way in the body and produce the same results. It also must be made in the same format: pill, capsule or liquid. This is why, in theory, generics are considered equivalent to their brand-name counterparts.

Location Matters


© kali9 | Getty Images

The vast majority of generic drugs are manufactured overseas in India, China and other countries where labor is cheap. Despite FDA assurances these companies are adhering to strict standards, the market is being flooded with drugs that do not perform as expected, are made in filthy plants or are contaminated with potentially deadly toxins. When your life depends on a medication, taking a generic could have tragic consequences.

Some generic drug manufacturers are private corporations or family businesses. Others are owned by major pharmaceutical companies. Plants located in the U.S. are subject to frequent FDA inspections and must adhere to rigorous manufacturing standards.

About 40% of generic drugs are made in India, however, and 80% of the ingredients in all drugs, both generic and brand name, come from India and China. As detailed in a recent exposé of the generic drug industry by Katherine Eban called Bottle of Lies, seemingly insurmountable problems inherent in policing overseas plants that supply these ingredients and manufacture these drugs, coupled with U.S. political pressure to make cheap drugs widely available, has caused the volume of ineffective, sometimes tainted, generic drugs to skyrocket.

Cleveland Clinic cardiologists and pharmacists have been aware of this issue for more than a decade. Over the years, they have badgered U.S. legislators and the FDA to ramp up inspections and institute laws that better protect the American public. But the wheels of the government turn slowly, so these patient advocates have developed an independent system for evaluating generic drugs and their manufacturers.

The complex story of the generic drug industry goes beyond the scope of this newsletter. However, we present the experience of two Cleveland Clinic physicians, along with their advice on what you can do to help ensure the generics drugs you take are safe and effective.

Not as Promised

Cardiologist Harry Lever, MD, was one of the first Cleveland Clinic physicians to learn he could not assume the drugs his patients were taking would work as expected.

In 2008, some of his patients with hypertrophic cardiomyopathy, a disease of the heart muscle that causes it to thicken, suddenly began going downhill after years of being stable. When their pharmacies switched them from the beta-blocker Toprol XL® to a generic version of metoprolol succinate, their heart-failure symptoms returned. Dr. Lever researched his patients' pills and noted the switch. He ordered their drugs be obtained from the original manufacturer, and his patients improved.

Shortly thereafter, the scenario was repeated with several different drugs: generic versions of the diuretic furosemide, the statin Pravachol® and the beta-blocker Coreg®. In all cases, when Dr. Lever switched patients back to the brand-name version or to a different generic, they got better.

A dedicated patient advocate, Dr. Lever was deeply concerned. He asked Cleveland Clinic pharmacists to check how well the generics used in their hospital worked. They used the results to compile a list of drugs and drug companies banned from Cleveland Clinic. Most were from India.

When Lifesaving Drugs Fail

Most patients recover when a medication failure is caught early and an effective drug is reinstated. When a drug requires precise dosing to prevent life-threatening complications, however, the situation can be more dangerous. One of these is tacrolimus, a drug that prevents the body from rejecting a transplanted organ.

Around 2014, some heart failure patients began being readmitted to Cleveland Clinic with signs of organ rejection. All had been discharged earlier on the brand-name version of tacrolimus, Prograf®, or a trusted generic. Heart transplant cardiologist Randall Starling, MD, discovered their local pharmacies had switched them to a generic version of tacrolimus made in India. He ordered the patients take only the original drug prescribed-an order that remains in effect today.

The Indian generic is now on Cleveland Clinic's list of banned drugs. Fortunately, all patients but one survived the harrowing experience without losing their new heart.

Common Heart Drugs Affected

At the same time Dr. Lever's eyes were being opened, Joe and Terry Graedon were being swamped with stories from unhappy patients. The couple authored a syndicated newspaper column and weekly show on National Public Radio called The People's Pharmacy. They had been staunch supporters of generic drugs until they began being deluged with complaints about serious complications that began immediately after starting a generic drug. The complaints centered on about 20 drugs for a variety of diseases, including Toprol XL®.

When Graedon looked into the issue, he found these drugs were far less bioequivalent than expected. The FDA's formula allows a generic to differ from the brand name by as much as 45%, which renders some drugs useless. Time-release formulations may release their active ingredients at a different pace. This was causing peaks and valleys resulting in side effects that included hair loss, hives, vivid nightmares and pounding hearts.

Tainted Products

While ineffective drugs are one problem, tainted drugs are another. FDA inspectors have found ground glass in pills and potentially lethal metal particles in insulin. Lack of sterility in plants where intravenous drugs are made has caused a variety of life-threatening complications. In 2008, contaminated batches of the bloodthinner heparin made in China caused the deaths of more than 200patients.

As late as July 2018, N-nitrosodimethylamine (NDMA), a potential carcinogen used in rocket fuel, was found in generic versions of the angiotensin receptor blocker (ARB) valsartan made in China. The FDA recalled the drug.

Recalls of the generic versions of the ARBs losartan and irbesartan followed, when a second related carcinogen was discovered. A third contaminant was found in June. All products were made in China by different manufacturers-some for American-based pharmaceutical companies.

The ban severely restricted access to generic ARBs, causing a financial hardship for Americans who could not afford brand-name drugs. In March 2019 the FDA responded by announcing it would permit tainted losartan to be sold in the U.S. until the supply of carcinogen-free losartan could be replenished.

Who Bears Responsibility?

Katherine Eban and her journalist colleagues from the New York Times, Bloomberg News and other media outlets are among those trying to discern how patients in the U.S. can be sold ineffective and dangerous drugs when the FDA's manufacturing standards are considered the best in the world. What they have uncovered and written about is a web of deceit based in greed and facilitated by politics, international law, customs and conditions in third-worldcountries.

After a decade of fighting to bring about reform, Cleveland Clinic refuses to accept excuses. Dr. Lever has joined with Joe Gradeon, a Harvard-based scientist named Preston Mason and several others to raise public awareness that the U.S. drug supply has been compromised.

Taking Action

Cleveland Clinic protects patients through a rigorous process for vetting generic drugs. They monitor FDA recalls, warning letters and inspection reports. They confirm FDA sources for therapeutic equivalence, research drug recall history, review available data and request input from Cleveland Clinic physicians who use the drug. Each proposed drug goes before the Formulary Panel and medical staff and is reviewed by the Pharmacy and Therapeutics Committee before being added to the hospital's formulary or sold in Cleveland Clinic pharmacies.

"When I specify a generic, I specify the manufacturer," says Dr. Lever.

But after patients leave the Cleveland Clinic, the situation can change. Health plans and pharmacies dictate which drugs they will approve and dispense, and their decisions generally favor companies that provide the lowest prices.

"Unfortunately, the lowest price can also mean the lowest quality," says Dr. Lever.

8 Ways To Protect Yourself

When your life or quality of life depends on a medication, here's what you can do to help ensure your drug works as expected and is safe to take:

1. Check the manufacturer listed on the bottle or the pharmacy's label and Google the name of the company to see if its products have been recalled.
2. Check FDA.gov for names of recalled drugs and companies.
3. If you take an ARB, call your pharmacy and ask if there has been a recall on the batch. "They should tell you, but they will not always volunteer this information," says Dr. Lever.
4. If you are stable on a drug, do not let your pharmacy change manufacturers.
5. Check the bottle each time your prescription is refilled to make sure the pills are identical to the last batch. If the color is different, the drug smells bad (often like fish or cat urine), or something you can't pinpoint seems "off," return it immediately and ask for a drug made by a different company. "Keep in mind that the quality can change with each batch. We are pushing for batch testing," says Dr. Lever.
6. Ask your doctor to make a list of pharmaceutical companies that are known to make safe drugs.
7. Contact your health insurance company and demand that they not require pharmacies to dispense potentially dangerous drugs, simply because they are the least expensive.
8. Contact your legislators and demand they make laws to protect us all from dangerous generic drugs.

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