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TGA Laboratories testing of ranitidine medicines

22 October 2019

Ranitidine is a medicine marketed in Australia and overseas to treat heartburn by reducing stomach acid. It is also used in the treatment and prevention of gastric reflux and ulcers.

In response to reports of contamination of ranitidine medicines with an impurity called N-nitrosodimethylamine (NDMA), which is associated with an increased risk of cancer, the TGA Laboratories have tested samples of these products currently marketed in Australia.

The purpose of this testing was to determine if NDMA was present in these medicines and to quantify the amounts present. The testing report is available below.

The report identifies batches tested that contained levels of NDMA above the internationally agreed limit of 0.3 parts per million (ppm) and those with levels below this limit. All products with levels of NDMA at or above 0.3 ppm have been recalled and removed from retailer shelves, while all batches with levels below 0.3 ppm are still available for sale.

The 0.3 ppm limit has been calculated in line with international guidance (ICH M7 guideline: Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk). This guideline was adopted by the TGA in 2016. The limit is derived from animal carcinogenicity data to ensure the additional risk from a genotoxic/carcinogenic impurity does not increase the life-time (70 year) risk of cancer for an individual by more than 1:100,000. The specific ppm limit is calculated from the acceptable daily intake of the impurity, adjusted for the maximum daily dose of the medicine.

The TGA reiterates the advice that the additional risk of cancer posed by the levels of NDMA identified to date in ranitidine products is considered to be very low. However, the TGA sets very high standards for safety in medicines and the levels of contamination observed through our laboratory testing are considered unacceptable. The TGA is also introducing new requirements for ranitidine products to ensure that they do not contain unacceptable levels of NDMA. Additionally, the TGA is considering suspending the registration for products which cannot demonstrate adequate safety and quality.

For further information about this issue, including information for consumers and health professionals, see the TGA's latest safety advisory.


Contamination of ranitidine medicines with the nitrosamine NDMA

Version 1.0, 22 October 2019

Ranitidine is a medicine marketed in Australia and overseas to treat heartburn by reducing stomach acid. It is also used in the treatment and prevention of gastric reflux and ulcers. Following international reports of contamination of ranitidine medicines with an impurity called N-nitrosodimethylamine (NDMA), the TGA published an alert on our website in September 2019, which was updated in October. NDMA belongs to a class of chemicals called nitrosamines and is classified as a probable human carcinogen.

As part of the TGA's response to this issue, the TGA Laboratories have tested samples of the ranitidine medicines available on the Australian market. The purpose of this testing was to determine if NDMA was present in these medicines and to quantify the amounts present.

Sponsors of ranitidine medicines on the Australian market provided batch samples for TGA testing. Ten sponsors provided samples of the 34 products of ranitidine medicines on the market. The TGA Laboratories analysed a selection of the batch samples provided by sponsors in order to assess the extent of the problem.

Results are reported as parts per million NDMA in the ranitidine active ingredient rather than as content per tablet. Thus, for example, a result of 1 ppm NDMA in a 300 mg ranitidine tablet corresponds to 300 nanograms of NDMA per tablet.

The TGA Laboratories adapted a publically available US Food and Drug Administration test method using LC-HRMS (liquid chromatography with high resolution mass spectrometric detection) to test for NDMA in the samples. This method has a limit of quantitation of 0.1 parts per million (ppm) NDMA, equivalent to 0.1 microgram of NDMA per gram of ranitidine active ingredient. There is an internationally agreed limit of 0.3 ppm NDMA in the ranitidine active ingredient.

A total of 135 batch samples of ranitidine medicines have being tested by the TGA Laboratories. The nitrosamine contents of the ranitidine batches tested are shown in the Tables below. All of the products with levels of NDMA at or above 0.3 ppm (Table 1) have been recalled and removed from pharmacy shelves. The batches of ranitidine products with levels of NDMA below the 0.3 ppm limit (Table 2) are still available for sale. Please note that NDMA values above 3 ppm are considered to be estimates only. The method does not give a fully linear response above 3 ppm, hence there is greater uncertainty associated with these higher results.

Table 1: Ranitidine medicine batches with levels of NDMA at or above the acceptable limit (0.3ppm)
ARTG No Product Name Sponsor Batch No* Expiry Date* Result (ppm NDMA)
285693 RANI 2 ranitidine 300mg (as hydrochloride) tablet blister pack Alphapharm Pty Ltd 370653 Jun-20 3.7
370654 Jun-20 5.4
830251 Feb-21 1.2
830412 Mar-21 2.5
830411 Mar-21 4.1
830656 May-21 1.4
830914 Aug-21 1.7
831277 Nov-21 3.0
831374 Nov-21 3.1
831373 Nov-21 3.2
930189 Jan-22 0.4
930376 Mar-22 0.8
930377 Mar-22 0.9
930480 Apr-22 0.3
930481 Apr-22 0.3
930597 Apr-22 0.4
285696 RANI 2 ranitidine 150mg (as hydrochloride) tablet blister pack Alphapharm Pty Ltd 370651 Jun-20 7.7
370652 Jun-20 14
830246 Feb-21 1.0
830409 Mar-21 1.0
830410 Mar-21 1.1
830408 Mar-21 1.2
830509 Apr-21 0.9
830610 May-21 1.2
830609 May-21 1.4
831275 Nov-21 0.5
831276 Nov-21 1.1
831274 Nov-21 1.2
930374 Mar-22 0.5
930375 Mar-22 0.6
930478 Apr-22 0.6
930479 Apr-22 0.7
122013 APO-RANITIDINE ranitidine 150 mg (as hydrochloride) tablet blister pack Apotex Pty Ltd NW5096 Aug-21 1.1
NW5098 Aug-21 2.0
PV2244 Aug-21 2.0
NW5097 Aug-21 2.1
NW5095 Aug-21 2.2
PJ8132 Sep-21 1.0
RF0005 Jun-22 0.4
RF0006 Jun-22 0.4
122014 APO-RANITIDINE ranitidine 300mg (as hydrochloride) tablet blister pack Apotex Pty Ltd NW5121 Aug-21 2.1
NW5122 Sep-21 0.9
PJ8126 Sep-21 1.0
NW5123 Sep-21 1.2
PZ3423& Jan-22 1.1
PZ3422 Jan-22 1.6
RF0038 Jun-22 0.5
254412 APOHEALTH RANITIDINE ACID & HEARTBURN RELIEF 150 mg (as hydrochloride) tablet blister pack Apotex Pty Ltd 831050 Sep-21 1.6
930112 Jan-22 0.3
930409 Mar-22 0.7
930704 May-22 0.6
254413 APOHEALTH RANITIDINE ACID & HEARTBURN RELIEF EXTRA STRENGTH 300 mg (as hydrochloride) tablet blister pack Apotex Pty Ltd 830342 Feb-21 5.3
831258 Nov-21 1.9
930114 Jan-22 0.3
930705 May-22 0.3
97354 AUSRAN ranitidine 150mg (as hydrochloride) tablet blister pack Arrow Pharma Pty Ltd 7701349A Feb-20 1.5
CK807 Feb-20 2.2
CM029 May-20 3.9
7702666A Dec-20 2.9
97355 AUSRAN ranitidine 300mg (as hydrochloride) tablet blister pack Arrow Pharma Pty Ltd CK719 Dec-19 0.4
7701350A Feb-20 1.0
CL712 May-20 3.8
123658 CHEMISTS' OWN RANITIDINE FORTE ranitidine 300mg (as hydrochloride) tablet blister pack Arrow Pharma Pty Ltd CK361 Dec-19 0.4
CL713 May-20 3.4
123670 CHEMISTS' OWN RANITIDINE 150mg (as hydrochloride) tablet blister pack Arrow Pharma Pty Ltd CK852 Feb-20 2.3
CK853 Feb-20 2.4
CL956 May-20 3.0
CL957 May-20 3.4
12536 ZANTAC ranitidine 50mg/2mL (as hydrochloride) injection ampoule Aspen Pharmacare Australia Pty Ltd CA2L Oct-20 0.3
2U3U-B Nov-20 0.3
35188 ZANTAC ranitidine 150mg/10mL (as hydrochloride) oral liquid bottle Aspen Pharmacare Australia Pty Ltd 17N001 Dec-19 1.0
18M001 Nov-20 0.6
19B001 Feb-21 3.2
45993 ZANTAC ranitidine 150mg (as hydrochloride) effervescent tablet tube Aspen Pharmacare Australia Pty Ltd 1601908301 Nov-19 1.1
190007038 Apr-22 1.1
190007039 Apr-22 1.2
53323 ZANTAC ranitidine 300mg (as hydrochloride) tablet blister pack Aspen Pharmacare Australia Pty Ltd AJF6004A Jun-19 5.1
AJF9003A Feb-22 0.7
53324 ZANTAC ranitidine 150mg (as hydrochloride) tablet blister pack Aspen Pharmacare Australia Pty Ltd AJE8021A Nov-21 0.5
AJE9005A Feb-22 0.7
71786 ZANTAC ranitidine 150mg (as hydrochloride) tablet blister pack Aspen Pharmacare Australia Pty Ltd AJE8021B Nov-21 0.5
AJE8020A Nov-21 2.0
AJE9001A Dec-21 0.5
AJE9002A Dec-21 0.6
AJE9003A Jan-22 0.7
AJE9004A Jan-22 0.9
AJE9006A Mar-22 0.6
AJE9007A May-22 0.9
95076 ZANTAC DOUBLE STRENGTH ranitidine 300mg (as hydrochloride) tablet blister pack Aspen Pharmacare Australia Pty Ltd AJF8012A Oct-21 2.7
AJF9001A Dec-21 0.9
AJF9002A Feb-22 0.8
AJF9005A Mar-22 0.6
AJF9004A Mar-22 0.8
AJF9006A May-22 0.9
219924 AMCAL HEARTBURN RELIEF EXTRA STRENGTH ranitidine (as hydrochloride) 300mg tablet strip pack Cipla Australia Pty Ltd EC90535 May-22 3.6
191837 PHARMACY ACTION Heartburn & Acid Indigestion Relief ranitidine 150mg tablets (as hydrochloride) blister pack Generic Health Pty Ltd 830102 Dec-20 1.2
830779 Jun-21 1.0
191838 PHARMACY ACTION Heartburn & Acid Indigestion Relief Forte ranitidine (as hydrochloride) 300mg tablet blister pack Generic Health Pty Ltd 830232 Jan-21 1.6
210000 MEDIX HEARTBURN & ACID INDIGESTION ranitidine hydrochloride 167.5 mg tablets blister pack Nova Pharmaceuticals Pty Ltd JQ8003 Nov-21 0.5
281344 COLES HEARTBURN & ACID INDIGESTION ranitidine 150 mg (as hydrochloride) tablet blister pack Nova Pharmaceuticals Pty Ltd JQ9001 Mar-22 0.8
70356 RANITIDINE SANDOZ ranitidine 300mg (as hydrochloride) tablet blister pack Sandoz Pty Ltd JK8814 Oct-21 0.3
JP7293 Jan-22 0.3
219142 RANITIDINE GH ranitidine (as hydrochloride) 300 mg film-coated tablet blister pack Sandoz Pty Ltd JE8892 Jul-21 0.4
298409 PHARMACY HEALTH REFLUX RELIEF EXTRA STRENGTH ranitidine (as hydrochloride) 300 mg tablet blister pack Soul Pattinson Manufacturing Pty Ltd 830435 Apr-21 1.4
298410 PRICELINE PHARMACY REFLUX RELIEF EXTRA STRENGTH ranitidine (as hydrochloride) 300 mg tablet blister pack Soul Pattinson Manufacturing Pty Ltd 830436 Apr-21 1.0
930113 Jan-22 0.4
303346 TERRYWHITE CHEMMART HEARTBURN RELIEF EXTRA STRENGTH ranitidine (as hydrochloride) 300 mg tablet blister pack Soul Pattinson Manufacturing Pty Ltd 831052 Sep-21 1.8
192601 PHARMACY CHOICE ACID & HEARTBURN RELIEF ranitidine (as hydrochloride) 150mg tablets blister pack Symbion Pty Ltd 831372 Nov-21 3.1
194056 PHARMACY CHOICE ACID & HEARTBURN RELIEF EXTRA STRENGTH ranitidine (as hydrochloride) 300 mg tablet blister pack Symbion Pty Ltd 930593 Apr-22 0.4

* Batch number and expiry date information is usually printed or embossed on the end flaps of the tablet cartons.

Table 2: Ranitidine medicine batches with levels of NDMA within the acceptable limit (0.3ppm)
ARTG No Product Name Sponsor Batch No* Expiry Date* Result (ppm NDMA)
97354 AUSRAN ranitidine 150mg (as hydrochloride) tablet blister pack Arrow Pharma Pty Ltd CJ603 Oct-19 0.1
CJ923 Oct-19 0.1
7702729A Jan-21 <0.1
7702826B Feb-21 <0.1
7702932B Feb-21 <0.1
5900022 Mar-21 <0.1
5900045 Nov-21 0.2
5900046 Nov-21 0.2
7704325A Dec-21 <0.1
97355 AUSRAN ranitidine 300mg (as hydrochloride) tablet blister pack Arrow Pharma Pty Ltd 7702667A Dec-20 <0.1
7702730A Jan-21 <0.1
5900023 Mar-21 <0.1
7703045A Apr-21 <0.1
7704367A Dec-21 <0.1
7705633A May-22 <0.1
7705645A May-22 <0.1
123658 CHEMISTS' OWN RANITIDINE FORTE ranitidine 300mg (as hydrochloride) tablet blister pack Arrow Pharma Pty Ltd 7703045B Apr-21 <0.1
7704367B Dec-21 <0.1
7705645B May-22 <0.1
123670 CHEMISTS' OWN RANITIDINE 150mg (as hydrochloride) tablet blister pack Arrow Pharma Pty Ltd CJ602 Oct-19 0.1
CJ601 Oct-19 0.1
7702826A Feb-21 <0.1
7702932A Feb-21 <0.1
7704325B Dec-21 <0.1
75771 RANITIDINE SANDOZ ranitidine 50mg/5mL (as hydrochloride) concentrated injection ampoules Sandoz Pty Ltd JL6422 Oct-20 <0.1
JN4108 Oct-20 <0.1

* Batch number and expiry date information is usually printed or embossed on the end flaps of the tablet cartons.