COVID -19 Has Blinded Us All to the Potential Risks to Our Drug Supply

“COVID-19 is a new disease and there is limited information regarding risk factors for severe disease. Based on currently available information and clinical expertise, older adults and people of any age who have serious underlying medical conditions might be at higher risk for severe illness from COVID-19.

Based on what we know now, those at high-risk for severe illness from COVID-19 are:

People 65 years and older
People who live in a nursing home or long-term care facility

People of all ages with underlying medical conditions, particularly if not well controlled, including:

People with chronic lung disease or moderate to severe asthma
People who have serious heart conditions
People who are immunocompromised

Many conditions can cause a person to be immunocompromised, including cancer treatment, smoking, bone marrow or organ transplantation, immune deficiencies, poorly controlled HIV or AIDS, and prolonged use of corticosteroids and other immune weakening medications

People with severe obesity (body mass index [BMI] of 40 or higher)
People with diabetes
People with chronic kidney disease undergoing dialysis
People with liver disease”

THE GOOD NEWS:

A recent study by the University of Minnesota was touted by the Minnesota Star Tribune – “University of Minnesota's large COVID-19 study finds new drug targets”:

“University of Minnesota researchers conducted one of the world’s largest observational studies of COVID-19 patients and found that diabetes and obesity increased death risks, but that a common diabetes drug protects women.

Metformin reduced COVID-19 death risks by 21 to 24% in women with COVID-19 who were already taking it to manage their blood-sugar levels and their diabetes, according to the U study results, which were posted online this weekend in advance of publication in a medical journal.”

The original study by the University of Minnesota can be found here:

“Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19”:

“Abstract Background Type 2 diabetes (T2DM) and obesity are significant risks for mortality in Covid19. Metformin has been hypothesized as a treatment for COVID19. Metformin has sex specific immunomodulatory effects which may elucidate treatment mechanisms in COVID-19. In this study we sought to identify whether metformin reduced mortality from Covid19 and if sex specific interactions exist.

Methods De-identified claims data from UnitedHealth were used to identify persons with at least 6 months continuous coverage who were hospitalized with Covid-19. Persons in the metformin group had at least 90 days of metformin claims in the 12 months before hospitalization. Unadjusted and multivariate models were conducted to assess risk of mortality based on metformin as a home medication in individuals with T2DM and obesity, controlling for pre-morbid conditions, medications, demographics, and state. Heterogeneity of effect was assessed by sex.

Results 6,256 persons were included; 52.8% female; mean age 75 years. Metformin was associated with decreased mortality in women by logistic regression, OR 0.792 (0.640, 0.979); mixed effects OR 0.780 (0.631, 0.965); Cox proportional-hazards: HR 0.785 (0.650, 0.951); and propensity matching, OR of 0.759 (0.601, 0.960). TNFα inhibitors were associated with decreased mortality in the 38 persons taking them, by propensity matching, OR 0.19 (0.0378, 0.983).

Conclusions: Metformin was significantly associated with reduced mortality in women with obesity or T2DM in observational analyses of claims data from individuals hospitalized with Covid-19. This sex-specific finding is consistent with metformin’s reduction of TNFα in females over males, and suggests that metformin conveys protection in Covid-19 through TNFα effects. Prospective studies are needed to understand mechanism and causality.”

This was exciting information for the diabetic community!

“Statistics About Diabetes”:

According to the American Diabetes Association:

“Overall numbers

Prevalence: In 2018, 34.2 million Americans, or 10.5% of the population, had diabetes.

Nearly 1.6 million Americans have type 1 diabetes, including about 187,000 children and adolescents

Undiagnosed: Of the 34.2 million adults with diabetes, 26.8 million were diagnosed, and 7.3 million were undiagnosed.
Prevalence in seniors: The percentage of Americans age 65 and older remains high, at 26.8%, or 14.3 million seniors (diagnosed and undiagnosed).
New cases: 1.5 million Americans are diagnosed with diabetes every year.
Prediabetes: In 2015, 88 million Americans age 18 and older had prediabetes.”

According to the Mayo Clinic:

Type 2 Diabetes:

“Diabetes medications and insulin therapy

Some people who have type 2 diabetes can achieve their target blood sugar levels with diet and exercise alone, but many also need diabetes medications or insulin therapy. The decision about which medications are best depends on many factors, including your blood sugar level and any other health problems you have. Your doctor might combine drugs from different classes to help you control your blood sugar in several different ways.

Examples of possible treatments for type 2 diabetes include:

Metformin (Glucophage, Glumetza, others).Generally, metformin is the first medication prescribed for type 2 diabetes. It works by lowering glucose production in the liver and improving your body's sensitivity to insulin so that your body uses insulin more effectively.”

The Bad News:

On December 19, 2019, this statement was made by “Director - Center for Drug Evaluation and Research Janet Woodcock M.D.”:” Statement from Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research, on impurities found in diabetes drugs outside the U.S.”:

“The U.S. Food and Drug Administration has been investigating the presence of genotoxic impurities, called nitrosamines, in some types of drugs. Over the past year and a half, several drug products including angiotensin II receptor blockers (ARBs) and ranitidine, commonly known as Zantac, have been found to contain small amounts of nitrosamines such as N-Nitrosodimethylamine (NDMA). During this time, there has been an ongoing investigation into the presence of nitrosamines in other drug products. This effort is focused on ensuring the drugs used by Americans continue to meet strict quality standards.

The FDA is aware that some metformin diabetes medicines in other countries were reported to have low levels of NDMA. Based on the information we have available, the levels of NDMA seen outside the U.S. are within the range that is naturally occurring in some foods and in water. While we are aware that some regulatory agencies outside the U.S. may be recalling some metformin drugs, there are no metformin recalls affecting the U.S. market at this time. The FDA is investigating whether metformin in the U.S. market contains NDMA, and whether it is above the acceptable daily intake limit of 96 nanograms. The agency will also work with companies to test samples of metformin sold in the U.S. and will recommend recalls as appropriate if high levels of NDMA are found. If as part of our investigation, metformin drugs are recalled, the FDA will provide timely updates to patients and health care professionals.

Metformin is a prescription drug used to control high blood sugar in patients with type 2 diabetes. Patients should continue taking metformin to keep their diabetes under control. It could be dangerous for patients with this serious condition to stop taking their metformin without first talking to their health care professional. The FDA recommends prescribers continue to use metformin when clinically appropriate, as the FDA investigation is still ongoing, and there are no alternative medications that treat this condition in the same way.

Today, we have better testing methods than ever before, and we know what to look for in products’ chemical structure and manufacturing processes that may increase the risk of forming low levels of nitrosamines. Improved technology enables us to detect even trace amounts of impurities in drug products and may be the reason why more products have been found to have low levels of NDMA. The agency has strict standards for safety, effectiveness and quality, and our staff makes every effort to help keep the U.S. drug supply as safe as possible. We also work closely with international drug regulatory agencies so that we leverage resources and testing done outside the U.S. which can help inform testing of the U.S. drug supply. As our investigations and testing continues, along with the investigations done by other drug regulatory agencies, we may find low levels of nitrosamines in additional drugs.

The FDA will continue to investigate the source of these impurities, but it is important to note that there are multiple reasons why NDMA can be present in drugs. Previously, we found the source of NDMA can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed. The FDA continues to test and research possible sources for the several drugs found to contain NDMA.

We are taking a systematic approach to identify medicines with nitrosamines above acceptable daily intake limits and remove them from the market. For example, yesterday we announced expanded testing requirements for ranitidine manufacturers to help give consumers confidence that the drugs on the market do not have NDMA above the acceptable daily intake limit.

Our investigations, including our current investigation of metformin, take into account the medical necessity of the drug, how many Americans may take it, and whether there may be alternative treatments available. The American public can expect that we will act quickly to address any issue as soon as we find out about it.

These investigations take time. We understand that these issues affect patients’ health and well-being in many ways, and the FDA’s goal is to provide patients and health care providers as much clarity and as many answers as possible to inform their health care decisions. The FDA will communicate any information we have scientifically confirmed to ensure the public knows as much as possible as soon as possible.

Protecting patients is the FDA’s highest priority, and Americans can be confident in the quality of the products the agency approves. We are patients too, and we’re committed to maintaining our high standards for quality, safety and efficacy for all drugs we, our families, friends, colleagues and millions of fellow Americans rely on for their health.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.”

QUESTIONS FOR CONGRESS AND THE FDA:

“The acceptable daily intake limit for NDMA in the U.S. is 96 nanograms.”

· If a patient is a Senior over 65 years of age, what are their chances that they take a blood pressure medication – an angiotensin II receptor blockers (ARBs)? ARBs include: Angiotensin II receptor blockers:

“Examples of angiotensin II receptor blockers include:

Azilsartan (Edarbi)
Candesartan (Atacand)
Eprosartan
Irbesartan (Avapro)
Losartan (Cozaar)
Olmesartan (Benicar)
Telmisartan (Micardis)
Valsartan (Diovan)”

If a patient is a Senior over the age of 65, what are their chances of being diabetic and that they take metformin?
If a patient is a Senior over 65, what are their chances that they take Zantac or Ranitidine?
If a patient therefore is a Senior over 65, what are the risks that they are taking three different medications all of which contain some level of NDMA?

In September 2019, I wrote a CityWatch article: “Urgent: Congress Needs to Mandate Our Meds be Made in the US!”:

Why is this article pertinent today?

In the past year, one of the medications referenced above by the Mayo Clinic for the treatment of diabetes – Glucophage XR is no longer manufactured. Why?

· Is it no longer being manufactured because there are so many generics that it is no longer profitable?

“Determination That GLUCOPHAGE (Metformin Hydrochloride) Oral Tablets, 500 Milligrams, 850 Milligrams, and 1 Gram, and GLUCOPHAGE XR (Metformin Hydrochloride) Oral Extended-Release Tablets, 500 Milligrams and 750 Milligrams, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness”

Recent news:

“FDA Alerts Patients and Health Care Professionals to Nitrosamine Impurity Findings in Certain Metformin Extended-Release Products”:

“For Immediate Release:

May 28, 2020

The U.S. Food and Drug Administration is announcing today that agency laboratory testing has revealed levels of the nitrosamine impurity N-Nitrosodimethylamine (NDMA) above the agency’s acceptable intake limit in several lots of the extended-release (ER) formulation of metformin, a prescription drug used to control high blood sugar in patients with type 2 diabetes. The agency is in contact with five firms to recommend they voluntarily recall their products. Company recall notices will be posted on FDA’s website. There are additional manufacturers of the metformin ER formulation that supply a significant portion of the U.S. market, and their products are not being recalled. The FDA is continuing to work closely with manufacturers to ensure appropriate testing. Assessments are underway to determine whether metformin ER recalls will result in shortages and the agency will work closely with manufacturers to prevent or reduce any impact of shortages.

“The FDA has strict standards for safety, effectiveness and quality, and the agency makes every effort based on science and data to help keep the U.S. drug supply safe. We understand that patients may have concerns about possible impurities in their medicines, and want to assure the public that we have been looking closely at this problem over many months in order to provide patients and health care professionals with clear and accurate answers,” said Patrizia Cavazzoni, M.D., acting director of the FDA’s Center for Drug Evaluation and Research. “Now that we have identified some metformin products that do not meet our standards, we’re taking action. As we have been doing since this impurity was first identified, we will communicate as new scientific information becomes available and will take further action, if appropriate.”

Patients should continue taking metformin tablets even after recalls occur, until they consult with their health care professional who can prescribe a replacement. Patients with type 2 diabetes could face dangerous health risks if they stop taking their prescribed metformin. The FDA recommends that health care professionals continue to prescribe metformin when clinically appropriate; FDA testing has not shown NDMA in immediate release (IR) metformin products (the most commonly prescribed type of metformin). The agency is working with manufacturers of the recalled tablets to identify the source of the NDMA impurity. At this time, the elevated levels of NDMA have been found in some finished-dose tablets of the ER formulation but have not been detected NDMA in samples of the metformin active pharmaceutical ingredient.

The agency is also asking all manufacturers of metformin containing ER products to evaluate the risk of excessive NDMA in their product and to test each batch before it is released into the U.S. market. If testing shows NDMA above the acceptable intake limit, the manufacturer should inform the agency and should not release the batch to the U.S. market.

In late 2019, the FDA announced it had become aware of NDMA in some metformin products in other countries. The agency immediately began testing to determine whether the metformin in the U.S. supply was at risk, as part of the ongoing investigation into nitrosamine impurities across medication types. By February 2020, the agency had identified very low levels of NDMA in some samples, but at that time, no FDA-tested sample of metformin exceeded the acceptable intake limit for NDMA. The FDA has maintained that it would continue with ongoing testing of metformin and other medications, and if any levels of NDMA or other impurities were identified, swift action would be taken.

Recently, the FDA became aware of reports of higher levels of NDMA in certain ER formulations of metformin via a citizen petition filed by a private laboratory. FDA laboratories tested the same metformin lots that the private laboratory found to contain NDMA above the acceptable intake limit. The agency confirmed unacceptable NDMA levels in some, but not all, of those lots. In other instances, our laboratory detected NDMA in lots that the private laboratory did not. The agency also found that the levels of NDMA, when present, were generally lower than reported by the private laboratory. Given FDA scientists’ deep experience quantifying these impurities in drugs, the agency is confident in the reliability of the FDA’s testing method and results and will continue to take action based on the latest scientific information. The results have also been consistent with the findings of other regulatory agencies’ laboratories around the world.

Additional Information

NDMA is a common contaminant found in water and foods including cured and grilled meats, dairy products and vegetables. Everyone is exposed to some level of NDMA. The FDA and the international scientific community do not expect it to cause harm when ingested at low levels. The FDA’s acceptable intake limit for NDMA in drug formulations is 96 nanograms per day. The FDA does not expect nitrosamines to cause harm when ingested at or below the acceptable intake limit levels (such low levels of nitrosamines are present in foods in low levels and ingested as part of usual diets) even over a long period of time (such as a 70-year lifespan). Nitrosamine impurities may increase the risk of cancer if people are exposed to them at above-acceptable levels over long periods of time, but we do not anticipate that shorter-term exposure at levels above the acceptable intake limit would lead to an increase in the risk of cancer. We are working to ensure medicines on the U.S. market do not exceed the acceptable intake limit.

The FDA has previously investigated the presence of nitrosamines in the U.S. drug supply. The investigation began with the blood pressure and heart failure medicines called angiotensin II receptor blockers (ARBs) and later expanded to include heartburn medicines, ranitidine and nizatidine, as well as diabetes medication, metformin and other medicines. In April 2020, the agency requested manufacturers withdraw all prescription and over-the-counter (OTC) ranitidine drug products from the market because of test results showing that NDMA in some ranitidine products increases over time and, when stored at higher than room temperatures, may result in consumer exposure to unacceptable levels of this impurity.

There are multiple reasons for the presence of NDMA in drugs. The FDA has previously found that the source of NDMA can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed.

The FDA is taking a systematic approach to identify medicines with nitrosamines above the acceptable intake limit and remove them from the market. Improved technology enables the detection of even trace amounts of impurities in drug products and may be the reason why more products have been found to have low levels of NDMA. Today, better testing methods exist, and the FDA better understands the specific manufacturing steps that may increase the risk of nitrosamine formation. The FDA works closely with international drug regulatory agencies, who have also been testing drug products for NDMA and are collaborating to investigate the sources of these impurities.

Link to the recalled metformin XR:

In conclusion: As Congress discusses COVID – 19 with the CDC and the FDA et al, and as they discuss the need for personal protective equipment stockpiles (PPE), when will we have a vaccine that works, how long do our communities have to be shut down, how long do students have to stay home from school, and what treatments do we have in the pipeline for COVID – 19, can’t they ask these questions please?

· Why can’t we manufacture Glucophage XR again in the United States?

· Why can’t we require drug manufacturers to put on their websites where their medications are manufactured for consumers to look for medications that are made in the United States or Canada or wherever the consumer feels safe in getting their medications?

· Why aren’t the manufacturers required to put on their bottles the “Country of Origin” rather than “Manufactured for” a country that may be based in the United States?

· Why can’t we determine which drugs are used most frequently by Americans, and try to get those manufactured in the United States?

· If drugs are imported from China or India, are they climate controlled on their way to the ship, on the ship, on the docks when they reach the United States, and are they climate controlled enroute to their destinations?

· When patients request that their medications be mailed – particularly during the COVID – 19 pandemic, are the medications from pharmacies transported via the US Mail in a climate controlled manner?

Los Angeles and other parts of the United States will go over 100 degrees many times throughout the year.

· Congress has to ask the FDA scientists how medications that are exposed in mail trucks to these temperatures and above impact the quality of our prescription and “Over the Counter” (OTC) medication supplies.

(Chris Rowe, a former health care employee who has worked at Northridge Hospital, Tarzana Medical Center, and West Hills Hospital has a B.S. in Health Education. She is a 42-year resident of West Hills. She has written for the Los Angeles Daily News, RonKayeLA.org; OurLA.org; and CityWatch. She has a blog on the USC/ Annenberg Center for Health Journalism website and can be reached at [email protected])

-cw