Ranitidine and Risk ofN-Nitrosodimethylamine (NDMA) Formation

Abstract

The US Food and Drug Administration (FDA) limits the amount of the probable carcinogen N-nitrosodimethylamine (NDMA) in a daily dose of medication to 96 ng. 1 Chronic NDMA exposure has been shown to induce liver and lung cancer in animals, while high-dose acute NDMA poisoning can damage the liver and induce gastrointestinal and hepatic bleeding. 2 Since 2019, NDMA exceeding this amount was found in numerous lots of several medications-such as angiotensin receptor blockers, sustained-release metformin, and ranitidine-and led to widespread recalls of several products and concern among patients and clinicians. 3 On April 1, 2020, based on an ongoing investigation of NDMA in ranitidine, the FDA requested manufacturers of ranitidine to remove all over-the-counter and prescription ranitidine products from the market. 4 The FDA meticulously evaluated sources of NDMA and other nitrosamine contamination during the manufacturing process and established new procedures that manufacturers can take to prevent this issue from occurring in the future. By March 31, 2021, all manufacturers of chemically synthesized active pharmaceutical ingredients and finished pharmaceutical products that are FDA approved or pending approval had to conduct initial risk assessments for nitrosamine contamination. 5 However, the manufacturing facility is not the only place NDMA can be introduced into medications. Ranitidine forms NDMA as the product degrades on the store shelf and in the medicine cabinet, especially when exposed to heat and humidity. 6,7 According to a laboratory study from 2011, several dimethylamine-containing drugs bound to an electronrich moiety (such as ranitidine, doxylamine and chlorpheniramine, sumatriptan, nizatidine, diltiazem, and tetracycline) form NDMA when exposed to chloramine, a commonly used drinking water disinfectant. 8 Of these, ranitidine produced the highest amounts of NDMA by far. 8 These alternate production sources bypass the safety procedures just enacted by the FDA to prevent excessive NDMA exposure.Before the middle of May 2021, the available literature suggested that ranitidine could be a potential source of NDMA creation in the body. 9,10 In 2016, a small unblinded study by Zeng and Mitch 9 found more than 40 000 ng of NDMA in the urine of 10 people taking ranitidine. In January 2021, an in vitro human stomach simulation study by Braunstein et al 10 found that 947 ng and 320 000 ng of NDMA were created when 100 mL of 1000 μmol/L and 50 000 μmol/L sodium nitrite, respectively, were inter-

Efficacy of Premedication Protocol without Ranitidine for Taxane Regimen: A Multicenter Non-Randomized Historical Controlled Study

“…In January 2020, the United States Food and Drug Administration (US FDA) announced the withdrawal of ranitidine from the market after the discovery of N-nitrosodimethylamine (NDMA) as an ingredient of ranitidine; NDMA is a harmful chemical to health (White and Hernandez, 2021). For this reason, ranitidine was withdrawn from the market and production was canceled.…”

Orthogonal Chemical Reporter Strategy Enables Sensitive and Specific SERS Detection of Hydrazine Derivatives

“…Over the past few years, NDMA has been recognized as a toxic agent widely found in multiple pharmaceuticals and fermented foods. 56 NDMA is a strong carcinogen with a low acceptable daily limit of the US Food and Drug Administration (0.096 μg or 0.32 ppm per day) and potentially exposes millions of people to a risk of cancer. 57 Therefore, there is a great need for a method for rapidly and sensitively detecting and quantifying NDMA.…”

“…Figure 6m shows that ocSERS could sensitively detect the hazard in the blood (1.3 × 10 −6 M) and urine (4.2 × 10 −5 M), indicating that ocSERS meets in vivo analysis requirements of NDMA (4.3 × 10 −6 M). 56 Taken together, the ocSERS assay provides a promising method for monitoring NDMA levels in a complex physiological environment, which may be useful for pharmaceutical quality control.…”

N ‐nitrosodimethylamine‐Contaminated Valsartan and Risk of Cancer: A Nationwide Study of 1.4 Million Valsartan Users

“…Furthermore, in a separate analysis, we adjusted on exposure to metformin and ranitidine that may potentially be contaminated with NDMA. 31 , 32 Further analysis taking into account death as competing event was conducted using Cox cause‐specific hazard method. 33 …”