Cancer-causing Chemical in Blood Pressure Medication

Let’s talk about Valsartan. Sold under the trade name Diovan (among others), Valsartan is a medication frequently used to treat high blood pressure (hypertension), heart failure, and diabetic kidney disease. Valsartan can also come packaged with other drugs if it’s not enough to treat hypertension:

• Valsartan + Hydrochlorothiazide, trade name Co-Diovan (among others) is a combination of the Angiotensin-receptor blocker Valsartan with the diuretic Hydrochlorothiazide. Diuretics get rid of extra fluid build-up in order to help lower one’s blood pressure (Wright, Musini, & Gill, 2018).  The problem is diuretics are dehydrating and cause the loss of critical water-soluble vitamins (a possible reason for elevated blood pressure).

• Valsartan + Amlodipine, brand name Exforge:  the combination of Valsartan and Amlodipine, a calcium channel blocker, is usually well tolerated and more effective in reducing blood pressure (Eckert et al., 2013). The World Health Organization defines Amlodipine as one of the most effective and safe medicines needed in a health system. Because of this, there is a combination of Valsartan + Hydrochlorothiazide + Amlodipine, for patients who need a three-drug regimen to manage their blood pressure.

• Valsartan + Sacubitril, brand name Entresto (among others): the combination of Valsartan and Sacubitril is used for patients with a reduced ejection fraction of the heart especially when an ACE inhibitor cannot be taken (Yancy et al., 2016).

The goal of these combinations is to offer a single pill to increase effectiveness.

Just so you know, Valsartan doesn’t work for everybody. Among individuals with impaired glucose tolerance and cardiovascular disease (or associated risk factors), the use of Valsartan for 5 years--along with lifestyle modification--led to a 14% reduction in the incidence of diabetes but did not reduce the rate of cardiovascular events (NSG, 2010). For many people, Valsartan may be harmful causing common side effects such as dizziness, low blood pressure (hypotension), diarrhea, fatigue, and back/joint pain (US NLM, 2015).

Furthermore, Valsartan falls in FDA pregnancy category D and hence, requires a black box warning on its packaging warning customers of its toxicity to fetus.   The warning signifies that enough medical studies have indicated that Valsartan and other ARB drugs carry significant risk of serious or even life-threatening adverse effects (US FDA, 2011). From the Valsartan (Diovan) prescribing information sheet, the following warning is given:

“Diovan can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Diovan as soon as possible.”

Immediately after detection of pregnancy, an alternative medication should be started. Interestingly, the US labeling makes no recommendation regarding continuation or discontinuation of Valsartan for breast-feeding mothers, while Canadian labeling does not recommend use by nursing women.

This summer, Bloomberg reported even more bad news for Valsartan, a drug made by Swiss drugmaker Novartis and other pharmaceutical companies. According to a filing from the federal agency, Valisure, an online pharmacy company based in Connecticut, warned the Food and Drug Administration that it found cancer-causing impurities in Valsartan from at least five companies’ final pill batch. Valisure independently analyzed Valsartan from manufacturers like Novartis AG and several generic manufacturers. 

The chemical detected in Valsartan was Dimethylformamide (DMF), which the World Health Organization classifies as a Group 2A carcinogen, a human carcinogen(US NLM, 2014). DMF is a derivative of Formamide, the amide of formic acid, which is used (1) in the production of sulfa drugs, other pharmaceuticals, herbicides and pesticides, (2) in the manufacturing of hydrocyanic acid, (3) as a softening agent for paper and fiber, and (4) as a solvent for plasticizers and resins (Hohn, 1999). Because DMF is so widely used in the synthesis of active ingredients for medicine, as a class 2 solvent DMF must be “limited in pharmaceutical products because of its inherent toxicity”.

While U.S. regulators said that the amount of DMF in Valsartan was below levels deemed to be potentially harmful, Valisure asked that it still be recalled in the meantime. They also requested that the FDA review and significantly lower the acceptable intake of DMF from its current level of 8.8 milligrams (or 8,800,000 nanograms) to less than 1,000 nanograms per day. (You can read the Citizen Petition that Valisure used to inform the U.S. Food and Drug Administration here.)

The FDA noted that it would review Valisure’s petition, but that it was important to recognize that the amounts of DMF reported was “more than 100 times less than those determined by international standards as the level of concern to patients.” The FDA is missing the point. Valisure is explicitly stating that our standard upper threshold limits are too high and that “acceptable limits” have to be significantly reduced. 

The concentration of DMF found ranged from 8 nanograms per pill to over 100,000 nanograms per pill, Valisure said. But because these values are significantly below the current permissible level of 8.8 milligrams per day, it’s likely nothing will be done despite how alarmingly high DMF has increased. Valisure asked regulators to reduce the acceptable intake limit for DMF to match that of other probable carcinogens found in Valsartan, mainly N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA).

This is the first time that DMF has been connected to the pills. It is also the first time an impurity has been connected to Diovan, the branded version of Valsartan. A generic version of Valsartan has been recalled by several companies in the past, including Teva Pharmaceutical Industries, Ltd and Mylan NV, after a bulk manufacturer in China recalled the drug from the U.S. market after finding NDMA.

A handful of other blood pressure drugs have already been recalled due to concerns about other cancer-causing chemicals. Israel-based Teva Pharmaceuticals said it was going to expand a recall of its heart medication, Losartan Potassium, after a carcinogen known as N-Nitrosodimethylamine  (NMBA) was detected. Torrent Pharmaceuticals and Camber Pharmaceutical also said they were going to be recalling Losartan, too.

What Should I Do If My Blood Pressure Medicine Has Been Recalled?

You should discuss with your doctor how to taper off of your blood pressure medicine and define a better alternative treatment. Abruptly discontinuing a blood pressure medication is risky, so you want to work with a trained expert in this area. The good news is that Dr. Bhandari MD is here to support your in effectively normalizing blood pressure and prevent any unnecessary side effects or complications.  

Dr. Bhandari MD works to help patients improve their cardiovascular potential, supporting the human frame, and thereby allowing them to live healthier lives. We can test patients’ toxicant levels, and provide a personalized approach on how to effectively detoxify.  Our expertise and two decades of clinical experience is proactively reversing many chronic conditions like heart disease. Our team is always ready to share our expertise. 

To book an appointment, contact Advanced Health or call 1-415-506-9393.

References

Eckert, S., Freytag, S. B., Müller, A., & Klebs, S. H. (2013). Meta-analysis of three observational studies of amlodipine/valsartan in hypertensive patients with additional risk factors. Blood pressure, 22(sup1), 11-21.

"DIOVAN Product Monograph". Health Canada Drug Product Database. Novartis Pharmaceuticals Canada Inc. Retrieved 5 November 2015.

Hohn, A. (1999). "Formamide". In Kroschwitz, Jacqueline I. (ed.). Kirk-Othmer Concise Encylclopedia of Chemical Technology (4th ed.). New York: John Wiley & Sons, Inc. pp. 943–944.

NAVIGATOR Study Group. (NSG, 2010). Effect of valsartan on the incidence of diabetes and cardiovascular events. New England Journal of Medicine, 362(16), 1477-1490.

U.S. Food & Drug Administration (US FDA, 2011). “Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products — Content and Format.” Retrieved from https://www.fda.gov/regulatory-information/search-fda-guidance-documents/warnings-and-precautions-contraindications-and-boxed-warning-sections-labeling-human-prescription on Aug 24 2019.

U.S. National Library of Medicine (US NLM, 2015). “DailyMed - VALSARTAN - valsartan tablet”. Retrieved from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6e2cd953-88bf-4094-8ba8-2c9ba020f4d7 on Aug 24 2019.

U.S. National Library of Medicine (US NLM, 2014). "N,N-Dimethylformamide." Retrieved from https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+78 on Aug 24 2019.

"Valsartan prescribing sheet." Retrieved from https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/diovan.pdf on Aug 24 2019.

Wright, J. M., Musini, V. M., & Gill, R. (2018). First‐line drugs for hypertension. Cochrane Database of systematic reviews, (4).

Yancy, C. W., Jessup, M., Bozkurt, B., Butler, J., Casey, D. E., Colvin, M. M., ... & Hollenberg, S. M. (2016). 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Journal of the American College of Cardiology, 68(13), 1476-1488.

AUTHOR

Dr. Payal Bhandari M.D. is one of U.S.'s top leading integrative functional medical physicians and the founder of SF Advanced Health. She combines the best in Eastern and Western Medicine to understand the root causes of diseases and provide patients with personalized treatment plans that quickly deliver effective results. Dr. Bhandari specializes in cell function to understand how the whole body works. Dr. Bhandari received her Bachelor of Arts degree in biology in 1997 and Doctor of Medicine degree in 2001 from West Virginia University. She the completed her Family Medicine residency in 2004 from the University of Massachusetts and joined a family medicine practice in 2005 which was eventually nationally recognized as San Francisco’s 1st patient-centered medical home. To learn more, go to www.sfadvancedhealth.com.