Understanding the molecular-pharmaceutical basis of sartan recalls focusing on valsartan.

Avik Ray,Balakrishnan Sadasivam,Shubham Atal

doi:10.21542/gcsp.2020.25

Abstract

Angiotensin receptor blockers (ARBs) or the ‘sartans’ are widely used for the management of hypertension and heart failure. There have been a series of recent incidents where drug formulations containing different ARBs as active pharmaceutical ingredients have been recalled by various pharmaceutical firms. This article addresses valsartan as well as other sartan recalls besides discussing the recent recalls of ranitidine and metformin, giving insights into the molecular-pharmaceutical basis of the recalls. A thorough literature search of PubMed/Medline and Google Scholar databases was performed to identify all relevant articles and information published up to 29th April 2020 using Medical Subject Headings (MeSH terms) and Boolean operators. We also searched for relevant information on the web using web-browsers and reference lists from original research papers and review articles. The main impurity found was N-nitrosodimethylamine (NDMA) which was thought to be formed due to a change in the manufacturing process of valsartan. Besides, other impurities such N-nitrosodiethylamine (NDEA) and N-nitroso-N-methyl-4-aminobutyric acid (NMBA) were found in batches of other sartans, such as losartan and irbesartan. All of these are carcinogens and harmful if consumed at a level beyond a certain acceptable daily limit. Ranitidine, and more recent metformin recalls, have also been linked with valsartan in view of the presence of NDMA, the same impurity. Safety of ARBs is a major concern among healthcare professionals after the recalls of valsartan in the recent years. Periodic quality assessment of the manufacturing process and the drugs is key to ensure safe, effective and high-quality drugs for the global population. Additionally, practising physicians need to be vigilant in reporting adverse events in their patients receiving treatments.

Highlights

Valsartan, an angiotensin II receptor antagonist, is primarily used for the treatment of hypertension and heart failure, both as a monotherapy and in combination with other drugs[1,2]
In July 2018, the United States Food and Drug Administration (USFDA) alerted the world regarding the voluntary recalls of many drug formulations containing valsartan as an active ingredient
As evident from the valsartan recall, this practice can lead to formation of impurities in other drugs as well

Summary

INTRODUCTION

An angiotensin II receptor antagonist, is primarily used for the treatment of hypertension and heart failure, both as a monotherapy and in combination with other drugs[1,2]. USP, United States Pharmacopeia; NDMA, N-nitrosodimethylamine; LLC, Limited liability company; HCTZ, Hydrochlorothiazide; NDEA, N-nitrosodiethylamine; API, Active Pharmaceutical Ingredient; NMBA, N-Nitroso-N-Methyl-4 amino butyric acid. On 1st April 2020, the USFDA requested the removal of all ranitidine products from the US market in view of NDMA concentration increasing over time, especially when stored at higher than room temperature, exposing the consumers to unacceptable levels of the impurity[62] This goes onto to show how periodic quality and safety testing by the manufacturing firms are important in identifying a potential carcinogenic impurity in the medicines produced. A few pharmaceutical firms have recalled back batches of extended-release formulations of metformin due to the presence of the same impurity beyond acceptable limits[64], highlighting the importance of stringent monitoring of NDMA levels in all probable drugs . The NDMA levels in the recalled tablets ranged from 0.3 to 16 ppm per valsartan 320 mg tablets, clearly highlighting the reason for their recalls[67]

LIMITATIONS

CONCLUSIONS

Findings

Key Points