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

  • 29 мая 2019
  • 4-(methyl)(nitroso)amino)butanoic acid, active substance, angiotensin-II-receptor antagonists, angiotensin-II-receptor blockers, API, ARBs, Article 31, azilsartan, cancer, candesartan, carcinogen, CEP, conditions to MA, diabetes, DIPNA, drug product, EC, EDQM, EIPNA, EMA, eprosartan, European Commission, Hetero Labs, human, hypertension, impurity, interim, investigation, irbesartan, legally binding decision, limit, losartan, MA, MAH, manufacturer, manufacturing, manufacturing process, manufacturing site, marketing authorisation holder, medicinal product, medicines, N-nitrosodiethylamine, N-nitrosodiisopropylamine, N-nitrosodimethylamine, N-nitrosoethylisopropylamine, NDEA, NDMA, nitrosamine, NMBA, olmesartan, pioglitazone, review, root cause, sartans, scientific conclusion, specific ring structure, suspension, telmisartan, temporary, tetrazole, valsartan, Zhejiang Huahai Pharmaceuticals,

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On 31 January 2019, EMA recommended that companies making sartan blood pressure medicines (also known as angiotensin II receptor blockers, ARBs) review their manufacturing processes so that they do not produce nitrosamine impurities.

An initial investigation report on the root cause of the presence of N-nitrosodimethylamine (NDMA) provided by Zhejiang Huahai Pharmaceutical, China upon request from the supervisory authority in Italy (AIFA), indicated that NDMA is formed at the tetrazole ring-forming step in ZH’s valsartan API manufacturing process, and the level of NDMA present may depend on the reaction conditions used.

It should be reminded here, that the review of valsartan medicines was triggered by the European Commission on 5 July 2018 under Article 31 of Directive 2001/83/EC. On 20 September 2018, the review was extended to include medicines containing candesartan, irbesartan, losartan and olmesartan.

Angiotensin-II-receptor antagonists/blockers subject to the procedure (tetrazole group circled in red at the example of losartan):

 
 
 
 
 
 

Scientific conclusions related to the procedure are presented in Annex I while Conditions to the marketing authorisation(s) in Annex II.

It should be noted however, that there are additional ARBs not containing a tetrazole group authorised in the EU, and hence these are not subject to this procedure:


  • Azilsartan,

  • Eprosartan,

  • Telmisartan.


Temporary limits for NDMA, NDEA as well as for NMBA, DIPNA and EIPNA impurities have been set in line with current ICH M7(R1) guidelines and are given in 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
 

EMA’s recommendations for NDMA and NDEA were sent to the European Commission, which issued a legally binding decisions.

We have already informed on our website about the ongoing review of valsartan and other ‘sartan’ medicines due to the detection of impurity N-nitrosodimethylamine (NDMA) as well as suspensions of CEPs by EDQM in Part I, Part II, Part III, Part IV, Part V, Part VI and Part VII entries.

 

In addition, as part of strengthened monitoring of manufacturing, EMA and national authorities are also requesting as precaution that companies using certain reagents to manufacture the diabetes medicine pioglitazone test their products and check their processes to rule out the presence of nitrosamine impurities, in particular nitrosodimethylamine (NDMA).

The request follows the detection of low levels of NDMA in a few batches of pioglitazone manufactured by Hetero Labs in India, which were within strict limits previously set for sartans (refer to Annex I above) and are considered acceptably safe.

To check the current status of CEP for pioglitazone hydrochloride please click here.

 
Sources: EMA, EDQM
 
Updated: 2019-06-28
 

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