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Review of widely used ranitidine medicines to treat conditions such as heartburn and stomach ulcers due to detection of impurity, N-nitrosodimethylamine (NDMA), a probable human carcinogen!

  • 23 сентября 2019
  • 4-(methyl)(nitroso)amino)butanoic acid, acceptable intake, active substance, AI, API, Article 31, benefit-risk balance, cancer, candesartan, carcinogen, CEP, detection, DIPNA, drug product, EC, EDQM, EIPNA, EMA, European Commission, FDA, finished product, HCl, heartburn, histamine receptors blocker, human, hydrochloride, ICH M7, impurity, irbesartan, LC-MS, limit, losartan, MA, MAH, medicinal product, medicines, method, N-nitrosodiethylamine, N-nitrosodiisopropylamine, N-nitrosodimethylamine, N-nitrosoethylisopropylamine, NDEA, NDMA, nitrosamine, NMBA, olmesartan, OTC, ranitidine, referral procedure, review, root cause, sartans, specific ring structure, stomach, tetrazole, ulcers, valsartan,

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ASE Pharma Solutions

EMA is to start a review of ranitidine medicines after tests showed that some of these products contained an impurity called N-nitrosodimethylamine (NDMA) at levels which raise concerns according to the principles of the ICH M7 guideline.

The results on a limited sample of products showed that for the majority of both ranitidine APIs and finished products, NDMA was above the acceptable intake established during the referral procedure under Article 31 of Directive 2001/83/EC for sartans with tetrazole ring (considering the maximum daily dose authorized in the EU, and long-term use in 50 kg adult), please refer to the table below.


         NDMA, NMBA

  NDEA, DIPNA, EIPNA

Active substance

Maximum daily
dose [mg]

Acceptable Intake [ng/day]

Limit [ppm]

Acceptable Intake [ng/day]

Limit [ppm]

Candesartan

32

96.0

3.000

26.5

0.820

Irbesartan

300

96.0

0.320

26.5

0.088

Losartan

150

96.0

0.640

26.5

0.177

Olmesartan

40

96.0

2.400

26.5

0.663

Valsartan

320

96.0

0.300

26.5

0.082


NDMA – N-nitrosodimethylamine
NDEA – N-nitrosodiethylamine,
NMBA – 4-(methyl)(nitroso)amino)butanoic acid
DIPNA – N-nitrosodiisopropylamine
EIPNA – N-nitrosoethylisopropylamine
 


toxicity lab

 
 

NDMA is classified as a probable human carcinogen (a substance that could cause cancer) on the basis of animal studies. It is present in some foods and in water supplies but is not expected to cause harm when ingested in very low levels.

The review of ranitidine medicines was initiated on 12 September 2019 at the request of the European Commission, under Article 31 of Directive 2001/83/EC, to evaluate the relevance of the findings, the potential root causes and their impact on the benefit-risk balance of medicinal products containing ranitidine.

Ranitidine belongs to a class of medicines known as H2 (histamine-2) blockers, which work by blocking histamine receptors in the stomach and reducing the production of stomach acid.

It is used to treat and prevent conditions caused by excess acid in the stomach such as heartburn and stomach ulcers. Ranitidine-containing medicines are authorised by national authorities and are available as tablets and injectable formulations.

Ranitidine hydrochloride



chemical labr

The LC-MS method for the detection of NDMA in ranitidine drug substance and drug products published by FDA is available here.

This method should be validated by the user if the resulting data are used to support a required quality assessment of the API or drug product, or if the results are used in a regulatory submission.


Patients who have any questions about their current treatment can speak to their doctor or pharmacist. There are several other medicines used for the same conditions as ranitidine that could be used as an alternative.

It should be noted here that ranitidine is an over-the-counter (OTC) and prescription drug.

patient nd doctor

 
Sources: EMA, EC, FDA
 

Related entries:

Review of common medicines used to treat hypertension – valsartan – due to detection of impurity, N-nitrosodimethylamine (NDMA), a probable human carcinogen! (Part VIII)

(Q)SAR models – important tool of risk assessment to support practical implementation of ICH M7 guideline