Drug Safety Labeling Changes (SLC)

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ICLUSIG (NDA-203469)

(PONATINIB HYDROCHLORIDE)

Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

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11/28/2016 (SUPPL-22)

Approved Drug Label (PDF)

Boxed Warning

(additions and/or revisions are underlined)

WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY

Arterial Occlusion:

  • Arterial occlusions have occurred in at least 35% of Iclusig-treated patients. Some patients experienced more than 1 type of event. Events observed included 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 age 50 years or younger, experienced these events. Monitor for evidence of arterial occlusion. Interrupt or stop Iclusig immediately for arterial occlusion...

Venous Thromboembolism

  • Venous occlusive events have occurred in 6% of Iclusig-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism.

Heart Failure:

  • Heart failure, including fatalities, occurred in 9% of Iclusig-treated patients...

5 Warnings and Precautions

5.1 Arterial Occlusion

(additions and/or revisions are underlined)

Arterial occlusions, including fatal myocardial infarction...severe peripheral vascular disease have occurred in at least 35% of Iclusig-treated patients from the phase 1 and phase 2 trials. With a minimum of 48 months follow-up for ongoing patients (N=133) 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 arterial occlusive event.

Iclusig can cause fatal and life-threatening arterial occlusion within 2 weeks of starting treatment, and at dose levels as low as 15 mg per day. Iclusig can also cause recurrent or multi-site vascular occlusion. Patients have required revascularization procedures (coronary, cerebrovascular, and peripheral arterial).

In the phase 2 trial, the median time to onset of the first cardiac vascular, cerebrovascular, and peripheral vascular arterial occlusive events was 193 (range: 1 - 1355), 526 (range: 5 - 1339), and 478 (range: 3 - 1344) days, respectively.

Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. The most common risk factors observed in patients with arterial occlusive events were hypertension (62%; 93/150), hyperlipidemia (61%; 91/150), and history of cardiac disease (48%; 72/150). Arterial occlusion adverse events were more frequent with increasing age...

Table 4: Arterial Occlusion Incidence in Iclusig-Treated Patients in Phase 2 Trial According to Risk Categories: 4 year follow-up (Table title has been revised as has data; please refer to label)

5.10 Hemorrhage

(additions and/or revisions are underlined)

Serious hemorrhage events including fatalities, occurred in 6% (28/449) of patients treated with Iclusig in the phase 2 trial, with 48 months follow-up. Hemorrhage occurred in 28% (124/449) of patients… Gastrointestinal hemorrhage and subdural hematoma were the most commonly reported serious bleeding events occurring in 1% (4/449 and 4/449, respectively).

5.11 Fluid Retention

(additions and/or revisions are underlined)

Fluid retention events judged as serious occurred in 4% (18/449) of patients treated with Iclusig in the phase 2 trial (48 months follow-up). One instance of brain edema was fatal. For fluid retention events occurring in more than 2% of the patients (treatment-emergent), serious cases included: pleural effusion (7/449, 2%), pericardial effusion (4/449, 1%), and edema peripheral (2/449, less than 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%).

5.12 Cardiac Arrhythmias

(additions and/or revisions are underlined)

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.

5.13 Myelosuppression

(additions and/or revisions are underlined)

Myelosuppression was reported as an adverse reaction in 59% (266/449) of patients, and severe (grade 3 or 4) myelosuppression occurred in 50% (226/449) of patients treated with Iclusig. With 48 months of follow-up, the incidence of these events...

Severe myelosuppression (Grade 3 or 4) was observed early in treatment, with a median onset time of 1 month (range less than 1–40 months)...

5.14 Tumor Lysis Syndrome

(additions and/or revisions are underlined)

One case occurred in a patient with advanced AP-CML and one case occurred in a patient with BP-CML.  Hyperuricemia occurred in 7% (31/449) of patients...

5.15 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

(Newly added subsection)

Post marketing 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.

5.17 Embryo-Fetal Toxicity

(additions and/or revisions are underlined)

Based on its mechanism of action and findings from animals 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.

5.2 Venous Thromboembolism

(additions and/or revisions are underlined)

Venous thromboembolic events occurred in 6% (25/449) of Iclusig-treated patients, including deep venous thrombosis (10 patients), pulmonary embolism (7 patients), superficial thrombophlebitis (3 patients), and retinal vein thrombosis (2 patients) with vision loss.

In the phase 2 trial, the incidence of venous thromboembolism was 9% (3/32) in patients with Ph+ ALL, 10% (6/62) in patients with blast phase (BP) CML, 4% (3/85) in patients with AP-CML, and 5% (13/270) in patients with CP-CML.

5.3 Heart Failure

(additions and/or revisions are underlined)

Fatal or serious heart failure or left ventricular dysfunction occurred in 6% of Iclusig-treated patients (N=29/449) in the phase 2 trial (48 months follow-up). Nine percent of patients (N=39) 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 (in 14 patients each; 3%)...

5.4 Hepatotoxicity

(additions and/or revisions are underlined)

Two additional fatal cases of acute liver failure also occurred...The fatal cases occurred in patients with blast phase (BP) CML or Ph+ ALL. Severe (grade 3 or 4) hepatotoxicity occurred in all disease cohorts.

With 48 months follow-up, 11% (50/449) of Iclusig-treated patients experienced grade 3 or 4 hepatotoxicity in the phase 2 trial. The most common forms of hepatotoxicity were elevations of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), bilirubin, and alkaline phosphatase. The incidence of AST or ALT elevation was 54% (all grades) and 8% (grade 3 or 4)...

Hepatotoxic events were observed in 29% of patients. The median time to onset of hepatotoxicity event was 3 months, with a range of less than 1 month to 47 months...

5.5 Hypertension

(additions and/or revisions are underlined)

Treatment-emergent elevation of systolic or diastolic blood pressure (BP) occurred in 68% (306/449) of patients in the phase 2 clinical trial (48 months of follow-up). Fifty three patients (12%) treated with Iclusig in this clinical trial experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis…In patients with baseline systolic BP less than 140 mm Hg and baseline diastolic BP less than 90 mm Hg, 80% (229/285) experienced treatment-emergent hypertension; 44% (124/285) developed Stage 1 hypertension (defined as systolic BP greater than or equal to 140 mm Hg or diastolic BP greater than or equal to 90 mm Hg) while 37% developed Stage 2 hypertension (defined as systolic BP greater than or equal to 160 mm Hg or diastolic BP greater than or equal to 100 mm Hg). In 132 patients with Stage 1 hypertension at baseline, 67% (88/132) developed Stage 2 hypertension.

5.6 Pancreatitis

(additions and/or revisions are underlined)

Pancreatitis occurred in 7% (31/449, 6% serious or grade 3/4) of Iclusig-treated patients with 48 months of follow-up in the phase 2 trial. 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 (range: 3 - 1452). Twenty-three of the 31 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction...

5.8 Neuropathy

(additions and/or revisions are underlined)

Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 20% (90/449) of Iclusig-treated patients in the pivotal phase 2 trial experienced a peripheral neuropathy event of any grade (2%, grade 3/4) (48 months follow-up).  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 (less than 1%, 3/449 - grade 3/4).

Of the patients who developed neuropathy, 26% (23/90) developed neuropathy during the first month of treatment...

5.9 Ocular Toxicity

(additions and/or revisions are underlined)

Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients in the phase 2 trial (48 months follow-up). 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...

6 Adverse Reactions

6.1 Clinical Trial Experience

(Additions and/or revisions are underlined)

All patients received a starting dose of 45 mg Iclusig once daily ...  Interruptions and dose adjustments to 30 mg once daily or 15 mg once daily were allowed for the management of treatment toxicity. Additionally, after approximately 2 years of follow-up, patients who were still taking a 45 mg daily dose were recommended to undergo a dose reduction, in response to the continued occurrence of arterial occlusive events and venous thromboembolic events in the clinical trial.

At the time of analysis (48 months of follow-up), 133 patients (30%) were ongoing (110 CP-CML; 20 AP-CML; 3 BP- CML; 0 Ph+ ALL), and the median duration of treatment with Iclusig was 32.2 months in patients with CP-CML, 19.4 months in patients with AP-CML, 2.9 months in patients with BP-CML, and 2.7 months in patients with Ph+ ALL. The median dose intensity in patients with CP-CML was 29 mg /day or 64% of the 45 mg starting dose; median dose intensity was greater in patients with advanced disease patients. Seventy one percent (318/449) of patients experienced a dose interruption of more than three days and 68% (304/449) experienced a dose reduction.

The most common adverse reactions (greater than or equal to 5%) that led to dose modifications (interruption or dose reduction) include thrombocytopenia (31%), neutropenia (14%), lipase increased (13%), arterial occlusive events (13%), abdominal pain (12%), rash (9%), anemia (6%), pancreatitis (6%), ALT increased (5%) and hypertension (5%).

At the time of the analysis, 69% of the ongoing patients (92/133 patients) were reported to be receiving 15 mg; with 26% (35/133) and 5% (6/133) of Iclusig-treated patients receiving 30 mg and 45 mg, respectively.

… Overall, the most common non-hematologic adverse reactions (greater than or equal to 20%) were abdominal pain, rash, constipation, headache, dry skin, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity. The rates of treatment-emergent adverse reactions resulting in discontinuation were 19% in CP-CML, 12% in AP-CML … The most common adverse reactions that led to treatment …

Table 5: Adverse Reactions in greater than 10% of Patients in the Phase 2 Trial (N=449) (Revision to table title and table data; please refer to label)

Table 6: Serious Adverse Reactions Occurring in > 2% of Patients from the Phase 2 Trial (N=449) (Revision to table title and data text and data; please refer to label)

Table 7: Clinically Relevant Grade 3/4* Hematologic Laboratory Abnormalities in Patients from the Phase 2 Trial (N=449) (Revision to table title and table data; please refer to label)

Table 8: Clinically Relevant Non-Hematologic Laboratory Abnormalities (Data revised in table; please refer to label)

6.2 Postmarketing Experience

(Newly added subsection)

The following adverse reactions have been identified during post approval use of Iclusig. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Reversible posterior leukoencephalopathy syndrome (RPLS) – also known as Posterior Reversible Encephalopathy Syndrome - PRES)

7 Drug Interactions

7.4 Drugs that are Substrates of the P-gp or ABCG2 Transporter Systems

(Newly added subsection)

Ponatinib inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro.

8 Use in Specific Populations

8. 3 Females and Males of Reproductive Potential

(PLLR conversion)

Iclusig can cause fetal harm when administered to pregnant women.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Iclusig treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with Iclusig and for 3 weeks after the last dose.

Infertility

Based on animal data, ponatinib may impair fertility in females of reproductive potential. It is not known whether these effects on fertility are reversible.

8.1 Pregnancy

(PLLR conversion)

...There are no available data on Iclusig use in pregnant women. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at doses lower than human exposures at the recommended human dose. Advise pregnant women of the potential risk to a fetus.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data

Animal Data

Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis (25 rats per group)...

8.2 Lactation

(PLLR conversion)

Risk Summary

There is no data on the presence of ponatinib in human milk, the effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from ponatinib including arterial occlusion, venous thromboembolism, heart failure, and hepatotoxicity, advise women not to breastfeed during treatment with Iclusig and for 6 days following the last dose.

8.4 Pediatric Use

(additions and/or revisions are underlined)

Safety and effectiveness have not been established in pediatric patients.

Juvenile Animal Toxicity Data

A juvenile toxicity study in 15-day-old rats was conducted with daily oral gavage administration of ponatinib at 0.75, 1.5, or 3 mg/kg/day for 21 days. There were no adverse effects of ponatinib on juvenile rat developmental parameters (vaginal opening, preputial separation or bone measurements) observed in this study. Once daily oral administration of 3 mg/kg/day ponatinib to juvenile rats beginning on Day 15 postpartum (pp) resulted in mortality related to inflammatory effects after 6 to 7 days following initiation of treatment. The dose of 3 mg/kg/day is approximately 0.32 times the clinical dose on a mg/m2 basis for a child.

8.5 Geriatric Use

(additions and/or revisions are underlined)

In patients with CP-CML, patients of age greater than or equal to 65 years had a lower major cytogenetic response rate (40%) as compared with patients less than 65 years of age (65%).  In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age greater than or equal to 65 years had a similar hematologic response rate (45%) as compared with patients less than 65 years of age (44%).  Forty percent of patients greater than or equal to 65 years had arterial occlusion events...

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(additions and/or revisions are underlined)

Arterial Occlusions and Venous Thromboembolism

Inform patients that serious arterial thromboses…

Hypertension

...Advise patients to contact their health care provider for elevated blood pressure or if symptoms of hypertension occur including confusion, headache...

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Inform patients of the possibility of developing Reversible Posterior Leukoencephalopathy Syndrome while being treated with Iclusig. Advise patients to report symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances.

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Iclusig and for 3 weeks after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy.

Lactation

Advise women not to breastfeed during treatment with Iclusig and for 6 days after the last dose.

Infertility

Advise females of reproductive potential of the potential for reduced fertility from Iclusig.

MEDICATION GUIDE

(additions and/or revisions are underlined)

What is the most important information I should know about Iclusig? Iclusig can cause serious side effects, including:

Liver problems

Get medical help right away if you get any of these symptoms of liver problems during treatment:

  • yellowing of your skin or the white part of your eyes (jaundice)

  • dark “tea-colored” urine

  • sleepiness

  • loss of appetite

  • bleeding or bruising

What should I tell my healthcare provider before taking Iclusig? Before you take Iclusig, tell your healthcare provider if you:

  • have high blood pressure

  • are pregnant or plan to become pregnant. Iclusig can harm your unborn baby.

    • Your healthcare provider will do a pregnancy test before you start taking Iclusig.

    • You should not become pregnant during treatment with Iclusig.

    • For females who can become pregnant :

      • Use an effective form of birth control during treatment and for 3 weeks after your last dose of Iclusig.

      • Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with Iclusig.

      • Iclusig may affect your ability to have children. Tell your healthcare provider if this is a concern for you.

  • are breastfeeding or plan to breastfeed. It is not known if Iclusig passes into your breast milk. Do not breastfeed during treatment and for 6 days after your last dose of Iclusig.

What are the possible side effects of Iclusig? Iclusig may cause serious side effects, including:

  • Neuropathy.

    • double vision and other problems with eyesight, trouble moving the eye, drooping of part of the face, sagging or drooping eyelids, change in taste

  • Effects on the eye. Serious eye problems that can lead to blindness or blurred vision may happen with Iclusig. Tell your healthcare provider if you get any of the following symptoms: bleeding in the eye, perceived flashes of light, light sensitivity, floaters, dry inflamed, swollen, or itchy eyes, and eye pain.

The most common side effects of Iclusig include:

  • high blood pressure

  • diarrhea

  • increase of a serum protein known as lipase

  • vomiting

  • muscle pain

  • pain in arms, hands, legs, and feet

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with Iclusig if you have certain side effects.

06/02/2016 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

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.

6 Adverse Reactions

(addition of subheadings)

  • Clinical Trial Experience
  • Previously Treated CML or Ph+ ALL
  • The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation…
(addition to bulleted list)

  • Increased Toxicity in Newly Diagnosed Chronic Phase CML

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MG - What is Iclusig?

  • Iclusig is not for use to treat people with newly diagnosed chronic phase CML

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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