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Takeda Statement Regarding Distribution of Counterfeit ICLUSIG® (ponatinib) in Multiple Regions Outside the U.S.

Cambridge, Mass. and Osaka, Japan, Mar. 14, 2019 – At Takeda, patient safety is our highest priority. We are aware that counterfeit ICLUSIG® (ponatinib) has been identified outside of the U.S. and are working closely with health authorities, local law enforcement and authorized distribution partners to address this matter. Following identification of falsified batches of ICLUSIG in Turkey, laboratory analyses have confirmed two batches of product do not contain the ponatinib Active Pharmaceutical Ingredient (API). A third falsified batch is suspected based upon expert assessment of the product packaging and labelling but has not yet been analyzed by a laboratory.

To date, the counterfeit product has been distributed to wholesalers online and in multiple regions, including Turkey, Argentina and Malaysia. At this time, no U.S. product has been found to be counterfeit. Some units of the falsified product and batch numbers have also been purchased by international traders with intent for distribution.

In cooperation with health authorities, local law enforcement and authorized distribution partners, Takeda’s Global Product Protection is working to recover and quarantine suspicious falsified ICLUSIG in the affected regions and continues to actively investigate the issue. We are closely monitoring the situation and working to minimize any potential supply disruption to patients and healthcare professionals.

The World Health Organization (WHO) Global Surveillance & Monitoring Unit issued a global alert on January 31, 2019, regarding the counterfeit product in which they confirmed falsified versions of ICLUSIG 15mg and 45mg tablets circulating in the WHO Region of Europe and the WHO Region of the Americas, specifically South America. An updated global alert was issued on February 22, 2019, which confirmed falsified versions of ICLUSIG 45mg are also circulating in the WHO Region of the Western Pacific.

Specific batch and lot numbers for confirmed and suspected falsified batches of ICLUSIG are as follows:

  • ICLUSIG 15mg with batch number 25A19E09, UK/Ireland pack, does not contain ponatinib and instead contains paracetamol (commonly known as acetaminophen and is used to treat minor aches and pain).
  • ICLUSIG 45mg with batch number PR072875, UK/Ireland pack, does not contain ponatinib and instead contains paracetamol. The same batch number exists in Germany, however German pack, batch number PR072875 is genuine.
  • ICLUSIG 45mg with batch number PR0834170, German pack, is awaiting forensic/laboratory analysis.

Currently, neither Takeda nor our partners are aware of additional counterfeit product bearing different batch numbers.

Takeda does not sell ICLUSIG directly over the internet. Patients, caregivers and healthcare providers should only acquire their medicines from established and credible channels, which are validated and reliable sources able to demonstrate authenticity of origin. We discourage patients who have been prescribed ICLUSIG from purchasing their medicine from the internet, or any other non-validated source.

We urge anyone who has concerns related to falsified ICLUSIG or the WHO alert to verify the authenticity of the product lot and batch numbers. The counterfeit product should not be clinically administered or taken by any patient, and appropriate professional medical support is being offered to patients who have received falsified product. Batch and lot numbers can be confirmed on ICLUSIG packaging. If a patient has any questions or concerns related to ICLUSIG, please contact Takeda Medical Information:

In addition to contacting Global Medical Information, we urge patients to speak to their physicians and align on a path forward based on their personal treatment plan.

Inquiries specifically related to the investigation regarding ICLUSIG, or to verify authenticity of product, can be made to Takeda Global Product Protection at GlobalProductProtection@takeda.com, +1 866-9-TAKEDA (866-982-5332) or +1 224-554-5050.

ICLUSIG authorized distribution partners

ICLUSIG is currently marketed by Takeda only in the United States. Outside of the U.S., ICLUSIG is marketed in 60 markets by the following authorized distribution partners:

  • Incyte Biosciences International Sàrl has development and commercialization rights in in the European Union and 28 other countries, including Switzerland, Norway, Turkey, Israel and Russia.
  • Otsuka Pharmaceutical Co. Ltd. has exclusive rights to co-develop and commercialize ICLUSIG in Japan, China, Indonesia, South Korea, Malaysia, the Philippines, Singapore, Taiwan, Thailand and Vietnam.
  • Paladin Labs Ltd. has exclusive rights to co-develop and commercialize ICLUSIG in Canada.
  • Specialised Therapeutics Australia Pty Ltd. has exclusive rights to co-develop and commercialize ICLUSIG in Australia.
  • PINT Pharma International SA has exclusive rights to co-develop and commercialize ICLUSIG in Brazil, Mexico, Argentina, Colombia and Chile.
  • BIOLOGIX FZCO has exclusive rights to co-develop and commercialize ICLUSIG in Bahrain, Egypt, Kingdom of Saudi Arabia, Kuwait, Lebanon, Oman, Qatar, United Arab Emirates, Jordan, Algeria, Morocco, Tunisia and Iraq.

About Takeda’s position on counterfeit, falsified and illegal trading of healthcare products

Takeda’s mission is to strive towards better health for people worldwide through leading innovation in medicine. In carrying out our mission, we prioritize patients, trust with society, our reputation and our business, in that order.

Counterfeit, falsified and other illegally traded medicines present significant threats to consumers and patients around the globe. With the growing trend of illegal operations targeting medicines used to treat and prevent complex diseases, the industry faces increasing challenges to safeguard patient health and its products.

Takeda is proactively taking a holistic, risk-based approach to identify and mitigate the risk of falsified, illegal, and other types of suspect products to ensure patient safety. A dedicated Global Product Protection team employs a strategic approach by collaborating with internal functions and external agencies to carry out this mission.

The following principles guide Takeda's approach to counterfeit, falsified and illegal trading of healthcare products.

  • We proactively partner with international and local law enforcement, regulatory agencies, other pharmaceutical companies and industry organizations to combat counterfeiting and illegal trading, while also educating patients, supply chain partners and customers on the dangers associated with these activities. Through partnerships, such as IFPMA “Fight the Fakes” Campaign and Alliance for Safe On Line Pharmacies (ASOP), we do contribute to grass roots education to patients.
  • We routinely set high security standards and requirements for supply chain partners worldwide, perform due diligence and audit against these requirements.
  • We evaluate, develop and implement innovative anti-counterfeiting solutions for products and packaging to deter and detect counterfeiting, theft, diversion and tampering.
  • We detect, investigate and collect evidence against entities suspected of engaging in illegal trade of Takeda product on a continuous basis, which includes active monitoring and disruption of illegal online pharmacies and other illicit Internet trading.

The counterfeiting, falsification and illegal trade of healthcare products is not a problem that Takeda can tackle alone. Takeda strives to form strong partnerships and promote innovation to protect patient safety.

About ICLUSIG® (ponatinib) tablets

ICLUSIG is a kinase inhibitor primarily targeting BCR-ABL1, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR-ABL1 and its mutations. ICLUSIG targets native BCR-ABL1, as well as BCR-ABL1 treatment-resistant mutations, including the most resistant T315I mutation. ICLUSIG is the only approved TKI that demonstrates activity against the T315I gatekeeper mutation of BCR-ABL1. This mutation has been associated with resistance to all other approved TKIs. ICLUSIG which received full approval from the FDA in November 2016, is also approved in the EU, Australia, Switzerland, Israel, Canada and Japan.

In the U.S., ICLUSIG is indicated for:

  • Treatment of adult patients with chronic-phase, accelerated-phase or blast-phase CML (CP-CML, AP-CML or BP-CML) or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
  • Treatment for adult patients with T315I-positive CML (CP, AP or BP) or T315I-positive Ph+ ALL.

Limitations of Use: ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

ICLUSIG (ponatinib) IMPORTANT SAFETY INFORMATION (U.S.)

WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY
See full prescribing information for complete boxed warning.

  • Arterial occlusion has occurred in at least 35% of ICLUSIG® (ponatinib)-treated patients including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Interrupt or stop ICLUSIG immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart ICLUSIG.
  • Venous Thromboembolism has occurred in 6% of ICLUSIG-treated patients. Monitor for evidence of thromboembolism. Consider dose modification or discontinuation of ICLUSIG in patients who develop serious venous thromboembolism.
  • Heart Failure, including fatalities occurred in 9% of ICLUSIG treated patients. Monitor cardiac function. Interrupt or stop ICLUSIG for new or worsening heart failure.
  • Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor hepatic function. Interrupt ICLUSIG if hepatotoxicity is suspected.

WARNINGS AND PRECAUTIONS

Arterial Occlusions: Arterial occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease have occurred in at least 35% of ICLUSIG-treated patients from the phase 1 and phase 2 trials. In the phase 2 trial, 33% (150/449) of ICLUSIG-treated patients experienced a cardiac vascular (21%), peripheral vascular (12%), or cerebrovascular (9%) arterial occlusive event; some patients experienced more than 1 type of event. Fatal and life-threatening events have occurred within 2 weeks of starting treatment, with doses as low as 15 mg per day. ICLUSIG can also cause recurrent or multi-site vascular occlusion. Patients have required revascularization procedures. The median time to onset of the first cardiac vascular, cerebrovascular, and peripheral vascular arterial occlusive events was 193, 526, and 478 days, respectively. Patients with and without cardiovascular risk factors, some age 50 years or younger, experienced these events. The most common risk factors observed with these events were hypertension, hyperlipidemia, and history of cardiac disease. Arterial occlusive events were more frequent with increasing age and in patients with a history of ischemia, hypertension, diabetes, or hyperlipidemia. In patients suspected of developing arterial occlusive events, interrupt or stop ICLUSIG.

Venous Thromboembolism: Venous thromboembolic events occurred in 6% (25/449) of ICLUSIG-treated patients with an incidence rate of 5% (13/270 CP-CML), 4% (3/85 AP-CML), 10% (6/62 BP-CML) and 9% (3/32 Ph+ ALL). Events included: deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with vision loss. Consider dose modification or discontinuation of ICLUSIG in patients who develop serious venous thromboembolism.

Heart Failure: Fatal or serious heart failure or left ventricular dysfunction occurred in 6% of ICLUSIG-treated patients (29/449). Nine percent of patients (39/449) experienced any grade of heart failure or left ventricular dysfunction. The most frequently reported heart failure events were congestive cardiac failure and decreased ejection fraction (14 patients each; 3%). Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of ICLUSIG. Consider discontinuation if serious heart failure develops.

Hepatotoxicity: ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in a patient within one week of starting ICLUSIG. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts, with 11% (50/449) experiencing grade 3 or 4 hepatotoxicity. The most common forms of hepatotoxicity were elevations of AST or ALT (54% all grades, 8% grade 3 or 4, 5% not reversed at last follow-up), bilirubin, and alkaline phosphatase. Hepatotoxic events were observed in 29% of patients. The median time to onset of hepatotoxicity event was 3 months. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue ICLUSIG as clinically indicated.

Hypertension: Treatment-emergent elevation of systolic or diastolic blood pressure (BP) occurred in 68% (306/449) of ICLUSIG-treated patients. Fifty-three patients (12%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90 mm Hg, 80% (229/285) experienced treatment-emergent hypertension; 44% (124/285) developed Stage 1 hypertension, 37% developed Stage 2 hypertension. In 132 patients with Stage 1 hypertension at baseline, 67% (88/132) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during ICLUSIG use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.

Pancreatitis: Pancreatitis occurred in 7% (31/449, 6% serious or grade 3/4) of ICLUSIG-treated patients. The incidence of treatment-emergent lipase elevation was 42% (16% grade 3 or greater). Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (26/449). The median time to onset of pancreatitis was 14 days. Twenty-three of the 31 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with ICLUSIG and evaluate patients for pancreatitis. Do not consider restarting ICLUSIG until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first-line treatment of newly diagnosed patients with chronic phase (CP) CML, single agent ICLUSIG 45 mg once-daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once-daily. The median exposure to treatment was less than 6 months. The trial was halted for safety in October 2013. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib-treated patients, ICLUSIG-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

Neuropathy: Peripheral and cranial neuropathy have occurred in ICLUSIG-treated patients. Overall, 20% (90/449) of ICLUSIG-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). The most common peripheral neuropathies reported were paresthesia (5%, 23/449), neuropathy peripheral (4%, 19/449), hypoesthesia (3%, 15/449), dysgeusia (2%, 10/449), muscular weakness (2%, 10/449) and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 2% (10/449) of ICLUSIG-treated patients (<1%, 3/449 - grade 3/4). Of the patients who developed neuropathy, 26% (23/90) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting ICLUSIG and evaluate if neuropathy is suspected.

Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in ICLUSIG-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 2% of ICLUSIG-treated patients. Conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye pain occurred in 14% of patients. Visual blurring occurred in 6% of patients. Other ocular toxicities include cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperaemia, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Serious hemorrhage events including fatalities, occurred in 6% (28/449) of patients treated with ICLUSIG. Hemorrhage occurred in 28% (124/449) of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most commonly reported serious bleeding events occurring in 1% (4/449) each. Most hemorrhagic events, but not all, occurred in patients with grade 4 thrombocytopenia. Interrupt ICLUSIG for serious or severe hemorrhage and evaluate.

Fluid Retention: Fluid retention events judged as serious occurred in 4% (18/449) of patients treated with ICLUSIG. One instance of brain edema was fatal. For fluid retention events occurring in >2% of the patients (treatment-emergent), serious cases included: pleural effusion (7/449, 2%), pericardial effusion (4/449, 1%), and edema peripheral (2/449, <1%).

In total, fluid retention occurred in 31% of the patients. The most common fluid retention events were peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%) and peripheral swelling (3%).

Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue ICLUSIG as clinically indicated.

Cardiac Arrhythmias: Arrhythmias occurred in 19% (86/449) of ICLUSIG-treated patients, of which 7% (33/449) were grade 3 or greater. Arrhythmia of ventricular origin was reported in 3% (3/86) of all arrhythmias, with one case being grade 3 or greater. Symptomatic bradyarrhythmias that led to pacemaker implantation occurred in 1% (3/449) of ICLUSIG-treated patients.

Atrial fibrillation was the most common arrhythmia and occurred in 7% (31/449) of patients, approximately half of which were grade 3 or 4. Other grade 3 or 4 arrhythmia events included syncope (9 patients; 2.0%), tachycardia and bradycardia (2 patients each 0.4%), and electrocardiogram QT prolonged, atrial flutter, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction (1 patient each 0.2%). For 27 patients, the event led to hospitalization.

In patients with signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness), interrupt ICLUSIG and evaluate.

Myelosuppression: Myelosuppression was reported as an adverse reaction in 59% (266/449) of ICLUSIG-treated patients and grade 3/4 myelosuppression occurred in 50% (226/449) of patients. The incidence of these events was greater in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML.

Severe myelosuppression (Grade 3 or 4) was observed early in treatment, with a median onset time of 1 month (range <1-40 months). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%, one with AP-CML and one with BP-CML) treated with ICLUSIG developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (31/449) of patients. Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with ICLUSIG.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Postmarketing cases of reversible posterior leukoencephalopathy syndrome (RPLS—also known as Posterior Reversible Encephalopathy Syndrome (PRES)) have been reported in ICLUSIG-treated patients. RPLS is a neurological disorder that can present with signs and symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. Hypertension is often present and diagnosis is made with supportive findings on magnetic resonance imaging (MRI) of the brain. If RPLS is diagnosed, interrupt ICLUSIG treatment and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of RPLS.

Compromised Wound Healing and Gastrointestinal Perforation: Since ICLUSIG may compromise wound healing, interrupt ICLUSIG for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, ICLUSIG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at exposures lower than human exposures at the recommended human dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose.

ADVERSE REACTIONS

Most Common Adverse Reactions: Overall, the most common non-hematologic adverse reactions (≥20%) were abdominal pain, rash, constipation, headache, dry skin, arterial occlusion, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda at 1-844-T-1POINT (1-844-817-6468) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid concurrent use or reduce ICLUSIG dose if co-administration cannot be avoided.

Strong CYP3A Inducers: Avoid concurrent use.

Use in Specific Populations

Females and Males of Reproductive Potential: ICLUSIG can cause fetal harm when administered to pregnant women. Advise females to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose. Ponatinib may impair fertility in females and it is not known if these effects are reversible. Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG.

Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for six days after last dose.

For US Prescribing Information: http://www.iclusig.com/pi

About Takeda Pharmaceutical Company

Takeda Pharmaceutical Company Limited (TSE: 4502) is a global, research and development-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its R&D efforts on oncology, gastroenterology and neuroscience therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. Innovative products, especially in oncology and gastroenterology, as well as Takeda’s presence in emerging markets, are currently fueling the growth of Takeda. Approximately 30,000 Takeda employees are committed to improving quality of life for patients, working with Takeda’s partners in health care in more than 70 countries.

For more information, visit https://www.takeda.com/newsroom/.

Additional information about Takeda is available through its corporate website, www.takeda.com, and additional information about Takeda Oncology, the brand for the global oncology business unit of Takeda Pharmaceutical Company Limited, is available through its website, www.takedaoncology.com.

CONTACTS:

Takeda Pharmaceutical Company Limited

Japanese Media
Kazumi Kobayashi
kazumi.kobayashi@takeda.com
+81 (0) 3-3278-2095

Media outside Japan
Victoria von Rinteln
victoria.vonrinteln@takeda.com
+1-617-444-4391