Valsartan is a type of high blood pressure and heart failure medicine that belongs to the class of medications know as angiotensin II receptor blockers (ARBs). It is a generic version of Diovan and is manufactured by several companies. It is manufactured as a single medication and in combination with other active ingredients. Other generic brands of this class of medicine include Losartan and Irebesartan.
Angiotensin II receptor blockers (ARBs) have been used for more than 35 years and work by preventing blood vessels from narrowing, thereby reducing blood pressure. The most common side effects associated with valsartan are dizziness, hypotension, high levels of potassium in the blood (hyperkalemia) and increased blood creatinine. Valsartan does carry a black-box warning for fetal toxicity, so pregnant women or women planning to become pregnant should not take the medication.
Since July, 2018, the FDA has recalled more than 1150 lots of ARB medications (mainly Valsartan) from more than 25 manufacturers and have issued more than 45 statements and updates concerning the presence of probable cancer-causing contaminants, nitrosamines, in angiotensin II receptor blockers (ARBs). These contaminants include N- Nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and N-Methylnitrosobutyric (NMBA).
In July, 2018, The European Medicine Agency (EMA) began the first recalls of lots of Valsartan that were manufactured by Zhejiang Huahai Pharmaceuticals in China. The EMA stated that changes in the company’s manufacturing processes “introduced in 2012 are believed to have produced NDMA as a side product”. It is important to note that not all ARBs have been contaminated. However, due to multiple recalls, doctors and patients have experienced a shortage of medications that contained Valsartan as an active ingredient. In March 2019, in order to address the shortage, the FDA granted approval to Alkem Laboratories Limited to manufacture the new generic of Diovan.
The FDA has created a web page to share an overview of the problem and provide guidance to patients that includes the following information:
Beginning in Summer 2018, FDA learned and reported that some generic versions of the angiotensin II receptor blocker (ARB) medicines contain nitrosamine impurities that don’t meet the agency’s safety standards.
- Nitrosamine impurities, including N-Nitrosodimethylamine (NDMA), and N-Nitrosodiethylamine (NDEA), are probable human carcinogens (a substance that could cause cancer), and N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) is a potential human carcinogen.
- Nitrosamines are known environmental contaminants and found in water and foods, including meats, dairy products and vegetables.
- The presence of these nitrosamine impurities in ARB medicines was unexpected. Our ongoing effort has determined that these impurities may be generated when specific chemicals and reaction conditions are present in the manufacturing process of the drug’s API (active pharmaceutical ingredient), and may also result from the reuse of materials, such as solvents.
Not all valsartan, losartan, and irbesartan-containing medications are affected and being recalled.
Not all lots of valsartan, irbesartan, and losartan from a manufacturer involved in a recall are affected and being recalled. FDA has posted a list of currently available ARBs and the status of our assessment of those medications.
Medications containing only amlodipine or hydrochlorothiazide (HCTZ) are not being recalled.
Some manufacturers are recalling some medications containing amlodipine in combination with valsartan or losartan, and some medications containing hydrochlorothiazide HCTZ in combination with valsartan or losartan are also being recalled.
To find out if your medication has been recalled, you need the following information:
- Manufacturer or labeler name
- National Drug Code (NDC)
- Lot number
- Active ingredient(s)
Following is an example of an ARB medication label to help you identify the information on your medication:
- Note the manufacturer may be different from the distributor or labeler of your medication.
- If the lot number is on the medication bottle, it is usually imprinted on the label and is normally found next to the expiration date. It will also be printed on the back of a blister pack.
Contact your pharmacist to get this information if you cannot find it or if you have questions about your medication being recalled.
If you have medicine included in a recall, contact your pharmacist. The pharmacist may be able to provide you with an unaffected ARB made by another company.
If the pharmacist cannot provide this, contact your doctor to discuss other treatment options.
The FDA has also posted a list of ARB medications that have been recalled.
Report any unexpected side effects with ARB-containing medicines, to FDA’s MedWatch program to help the agency better understand the scope of the problem:
- Complete and submit the report online at www.fda.gov/medwatch/report.htm
- Download and complete the appropriate form, then submit it via fax at 1-800-FDA-0178
Health Studies
According to the CDC tox profile for N-Methylnitrosobutyric (NMBA), poisoning in humans can cause liver damage and death. The CDC also found that “when rats, mice, hamsters, and other animals ate food, drank water, or breathed air containing lower levels of NDMA for periods more than several weeks, liver cancer and lung cancer as well non-cancerous liver damage occurred.” (11)
According to a Danish nationwide cohort study reported in the British Medical Journal (BMJ), increased risk for colorectal and ovarian cancers was seen in users of valsartan that was contaminated with N-Nitrosodimethylamine (NDMA). However, the study also concluded that “the results do not imply a markedly increased short term overall cancer risk”. Additionally, the study reported that “longer follow-up are needed to assess long term cancer risk”. (10)
After a preliminary evaluation in 2018, the European Medical Agency (EMA) estimated “that there could be one extra case of cancer for every 5,000 patients taking the affected medicines at the highest valsartan dose (320 mg) every day for 7 years. This was based on average levels of this impurity detected in the active substance from Zhejiang Huahai Pharmaceuticals (60 parts per million)”. (8)
In May of 2019, the FDA published the following estimated risks of the contaminated valsartan products:
The
FDA NDMA ESTIMATED RISK:
FDA
estimated that if 8,000 people took the highest valsartan dose (320
mg) containing NDMA from the recalled batches daily for four years,
there may be one additional case of cancer over the lifetimes of the
8,000 people. (9)
NDEA
ESTIMATED RISK:
FDA
scientists estimate that if 18,000 people took valsartan at the
highest dose (320 mg) containing NDEA from recalled batches daily for
four years, there may be one additional case of cancer over the
lifetime of these 18,000 people. NDEA has a marginally lower cancer
risk estimate than NDMA because NDEA levels were lower than levels of
NDMA in drug samples. (9)
Medical References
1.
https://www.fda.gov/drugs/drug-safety-and-availability/recalls-angiotensin-ii-receptor-blockers-arbs-including-valsartan-losartan-and-irbesartan
2.
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan
3. https://www.fda.gov/news-events/press-announcements/fda-provides-update-its-ongoing-investigation-valsartan-products-and-reports-finding-additional
4. https://www.fda.gov/drugs/drug-safety-and-availability/search-list-recalled-angiotensin-ii-receptor-blockers-arbs-including-valsartan-losartan-and
5. https://www.fda.gov/news-events/press-announcements/fda-statement-agencys-list-known-nitrosamine-free-valsartan-and-arb-class-medicines-part-agencys
6. https://www.fda.gov/drugs/drug-safety-and-availability/fdas-assessment-currently-marketed-arb-drug-products
7. https://www.ema.europa.eu/en/documents/press-release/update-review-valsartan-medicines-following-detection-impurity-active-substance_en.pdf
8. https://www.ema.europa.eu/en/news/update-review-recalled-valsartan-medicines-preliminary-assessment-possible-risk-patients
9. https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-analysis-valsartan-products
10. https://www.bmj.com/content/362/bmj.k3851
11. https://www.atsdr.cdc.gov/toxprofiles/tp141-c1.pdf
12. https://www.fda.gov/drugs/drug-safety-and-availability/transcript-angiotensin-ii-receptor-blockers-arbs-message-patients
13. https://www.fda.gov/news-events/press-announcements/fda-approves-new-generic-valsartan
14. https://medlineplus.gov/druginfo/meds/a697015.html