Drug theft: more products affected (additionally Avastin and MabThera)

Situation Austria: currently only parallel distributed Italian Herceptin, Alimta, Avastin and Mabthera are affected (as of 19.08.2014);

Product purchased directly from the marketing authorization holder is not affected Situation EU: currently, parallel distributed Herceptin, Alimta, Remicade, Avastin and MabThera are affected (as of 08/19/2014).

The drug Herceptin is approved throughout Europe for the treatment of early breast cancer, metastatic breast cancer and metastatic gastric cancer. It is used primarily in hospitals, contains the active ingredient trastuzumab, and is available as 150 mg powder for the preparation of an infusion solution concentrate for intravenous administration or as 600 mg/5 ml injection solution for subcutaneous administration. Suspicions of counterfeiting are currently limited to the intravenous dosage form only. The drug Alimta is approved throughout Europe for the treatment of lung cancer. It is used under the supervision of physicians experienced in the use of antineoplastic drugs. Alimta is a powder prepared for infusion and administered intravenously. It contains the active ingredient pemetrexed. Remicade is approved throughout Europe as an anti-inflammatory drug and is used to treat rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis. It contains the active ingredient infliximab and is a powder prepared for infusion. It is used by qualified physicians who are experienced in the diagnosis and treatment of the above diseases. The preparation Avastin is used throughout Europe for the treatment of metastatic colon or rectal cancer, metastatic breast carcinoma, unresectably advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology, advanced and/or metastatic renal cell carcinoma, and advanced epithelial ovarian carcinoma, fallopian tube carcinoma or primary peritoneal carcinoma. It is used primarily in hospitals, contains the active ingredient bevacizumab and is available as a 25 mg/ml concentrate for the preparation of an infusion solution. MabThera is approved throughout Europe for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis and granulomatosis with polyangiitis and microscopic polyangiitis. It is used primarily in hospitals, under the supervision of physicians experienced in the use of antineoplastic drugs. It contains the active ingredient rituximab and is available as a 100 mg concentrate for the preparation of an infusion solution and as a 500 mg concentrate for the preparation of an infusion solution.

Measures at EU level

The European Medicines Agency (EMA) is adding to previous publications regarding vials of Herceptin (trastuzumab), Alimta (pemetrexed), and Remicade (infliximab) stolen in Italy other affected products, namely Avastin (bevacizumab) and MabThera (rituximab). The additional products identified were illegally distributed from Italy and introduced into the legal distribution chain. Italian law enforcement authorities are currently investigating the theft, but the incident affects the entire EU. These are exceptional circumstances, caused by criminal activity, which require special measures and require close cooperation between all EU health authorities.

National health authorities have been working as quickly as possible to identify the batches affected so far in their countries and have already taken appropriate steps to avoid any health risk to patients. Therefore, in addition to the theft investigation, all piercing vials of previously identified products and batches have been recalled. In addition to Herceptin (trastuzumab), Alimta (pemetrexed) and Remicade (infliximab ), which were affected by the theft, there is now also such confirmation for the products Avastin (bevacizumab) and MabThera (rituximab). Samples of the batches affected by the theft are currently being analyzed. According to current information, apart from falsifications of the transport documents, tampering with the drug itself was only found in the case of Herceptin. It is assumed that also in the case of Herceptin only a small number of vials are affected by this manipulation and there have been no reports of patients being harmed so far. The precautionary recall actions initiated will not lead to a restriction of distribution and the supply of Austrian patients is therefore further ensured.

Users and pharmacists are asked to pay special attention to the affected drugs before use/preparation. If one of the products mentioned appears suspicious, the BASG / AGES Medizinmarktaufsicht should be informed as soon as possible. Furthermore, users and pharmacists are requested to report any suspicious packages of the affected products that were returned to wholesalers/parallel distributors last year or this year to the BASG / AGES Medizinmarktaufsicht at enforcement@ages.at immediately, if this has not already been done.

It is again pointed out to check the following characteristics to be able to detect possibly counterfeit vials of Herceptin, Alimta, Remicade, Avastin and MabThera:

• Lot number and expiration date on the vials do not match the information on the outer packaging.

• Some vials contained a liquid (only Herceptin confirmed to date; Herceptin is a white to faint yellow lyophilized powder).

• Tampered rubber stoppers, crimp caps, and caps (confirmed only for Herceptin to date).

• The counterfeit vials are likely to be circulating in Italian presentation.

Counterfeit drugs should not be used under any circumstances, as it must be considered that they are not safe and/or effective.

The following information regarding the affected batches that were not legally introduced into the distribution chain is currently available across the EU:

Situation in Austria

The following proprietary medicinal products are approved in Austria:

• Herceptin 150 mg powder for the preparation of an infusion solution concentrate (EU approval number EU/1/00/145/001).
• Herceptin 600 mg/5 ml solution for injection (EU marketing authorization number EU/1/00/145/002)
• Alimta 100 mg powder for the preparation of a concentrate for solution for infusion (EU marketing authorization number EU/1/04/290/002)
• Alimta 500 mg powder for preparation of a concentrate for solution for infusion (EU marketing authorization number EU/1/04/290/001)
• Remicade 100 mg powder for a concentrate for solution for infusion (EU marketing authorization number EU/1/99/116/001-005)
• Avastin 25 mg/ml concentrate for solution for infusion (EU marketing authorization number EU/1/04/300/001-002)
• MabThera 100 mg concentrate for solution for infusion (EU marketing authorization number EU/1/98/067/001)
• MabThera 500 mg concentrate for solution for infusion (EU marketing authorization number EU/1/98/067/002)

Please note that to date, counterfeits have only been identified for "Herceptin 150 mg powder for the preparation of a solution for infusion". So far, no evidence of adulterated vials has been found for Alimta, Remicade, Avastin and MabThera, but they are also affected by the theft in Italy.

Batches marketed directly by the marketing authorization holders in Austria are not affected.

In Austria, Italian Herceptin has been distributed exclusively by the two parallel distributors "HAEMATO PHARM GmbH" and "INOPHA GmbH". The recall of the batches affected in Austria has already been carried out.

In Austria, Italian Alimta has been distributed exclusively through the two parallel distributors "HAEMATO PHARM GmbH" and "INOPHA GmbH" . The recall of the batches affected in Austria has already been carried out.

According to current information, no Italian Remicade of the mentioned batches has been distributed in Austria via parallel distribution, so that no recall has been initiated here so far.

In Austria, Italian Avastin has been distributed exclusively through the two parallel distributors "HAEMATO PHARM GmbH" and "INOPHA GmbH". A recall of the batches affected in Austria(Avastin 100 mg: B7100B18, B7101B12, B7102B04, B7102B21, B7103B09, B7103B14, H0113B29, H0115B17; Avastin 400 mg: B7107B07 , B7108B01, B7109B11, B7110B11, B7111B06, B7112B05) has been initiated.

In Austria, Italian MabThera has been distributed exclusively through the two parallel distributors "HAEMATO PHARM GmbH" and "INOPHA GmbH". A recall of the batches affected in Austria(MabThera 100 mg: H0101B03, H0111B03, H0115B05, H0121B10, H0122B03, H0122B07, H0128B01, H0136B03; MabThera 500 mg: H0634B01, H0637B01, H0656B01, H0698B01, N3610B02) has been initiated.

The BASG received a total of 26 adverse event reports for Herceptin, 7 for Alimta, 70 for Avastin, and 52 for MabThera from Austria in the period from January 2013 to May 2014. However, no conclusion can be drawn regarding a connection with the use of adulterated "Herceptin 150 mg powder for the preparation of an infusion concentrate" or any of the other affected products. BASG recommendations Recommend ations for users and pharmacists:

• Please check the counterfeit characteristics listed above before using/preparing the above products.

• Please check your stock for the mentioned products with origin Italy and compare them with the affected batch numbers already identified for Austria as well as those identified throughout Europe and do not use them anymore.

• Please quarantine all affected batches and notify BASG / AGES Medizinmarktaufsicht at enforcement@ages.at for sampling.
• If a possible counterfeit is detected, notification to BASG / AGES Medizinmarktaufsicht at enforcement@ages.at is also requested.

Recommendations for patients:

• If you have any questions, please contact your physician

Further information: European Medicines Agency press release (03.06.2014):

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/06/news_detail_002113.jsp&mid=WC0b01ac058004d5c1

Safety release of the BASG (04.06.2014): see below "Files".

Queries (technical): Dr. Christoph Baumgärtel, Tel.: 050555/36004 E-mail: christoph.baumgaertel@ages.at Queries (for media): Communications Management, Tel.: 050555/25000 E-Mail: presse@ages.at

Further inquiry note

basg_anfragen@basg.gv.at