2.1 Recommended Dosing

The recommended dose and schedule for Iclusig is 45 mg administered orally once daily. Continue treatment as long as the patient does not show evidence of disease progression or unacceptable toxicity.

Iclusig may be taken with or without food. Tablets should be swallowed whole.

2.2 Dose Modifications for Myelosuppression

Suggested dose modifications for neutropenia (ANC* less than 1.0 × 109/L) and thrombocytopenia (platelet less than 50 × 109/L) that are unrelated to leukemia are summarized in Table 1.

2.3 Dose Modifications for Non-Hematologic Adverse Reactions

If a serious non-hematologic adverse reaction occurs, modify the dose or interrupt treatment. Do not restart Iclusig in patients with serious ischemic reactions unless the potential benefit outweighs the risk of recurrent ischemia and the patient has no other treatment options. For serious reactions other than ischemia, do not restart Iclusig until the serious event has resolved or the potential benefit of resuming therapy is judged to outweigh the risk.

2.4 Dose Modification for Use With Strong CYP3A Inhibitors

The recommended dose should be reduced to 30 mg once daily when administering Iclusig with strong CYP3A inhibitors [see Drug Interactions (7.1)].

5.1 Thrombosis and Thromboembolism

5.2 Hepatotoxicity

Hepatotoxicity that has resulted in liver failure and death occurred in Iclusig-treated patients. Fulminant hepatic failure leading to death occurred in an Iclusig-treated 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.

The incidence of aspartate aminotransferase (ALT) or alanine aminotransferase (AST) elevation was 56% (all grades) and 8% (grade 3 or 4). Iclusig-treatment may result in elevation in ALT, AST, or both. ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.

Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

5.3 Congestive Heart Failure

Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure or left ventricular dysfunction, with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of congestive heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with congestive heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious congestive heart failure [see Dosage and Administration (2.3)].

5.4 Hypertension

Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. These patients required urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath.

Treatment-emergent hypertension occurred in 67% of patients (300/449) [see Adverse Reactions (6)]. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg) while 29% developed Stage 2 hypertension (defined as systolic BP≥160 mm Hg or diastolic BP≥100 mm Hg. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations.

5.5 Pancreatitis

Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). Twenty-two of the 28 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. The incidence of treatment-emergent lipase elevation was 41%.

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 [see Dosage and Administration (2.3)]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 × ULN.

5.6 Hemorrhage

Serious bleeding events, occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ALL. Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia [see Warnings and Precautions (5.9)]. Interrupt Iclusig for serious or severe hemorrhage [see Dosage and Administration (2.3)].

5.7 Fluid Retention

Fluid retention events judged as serious occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. Serious fluid retention events in more than 1 patient included: pericardial effusion (6/449, 1%), pleural effusion (5/449, 1%), and ascites (2/449, <1%).

In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%).

Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

5.8 Cardiac Arrhythmias

Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. The cardiac rhythms (1 case each) identified were complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain).

Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. The other supraventricular tachyarrhythmias were atrial flutter (4 patients), supraventricular tachycardia (4 patients), and atrial tachycardia (1 patient). For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).

5.9 Myelosuppression

Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with accelerated phase CML (AP-CML), blast phase CML (BP-CML) and Ph+ALL than in patients with chronic phase CML (CP-CML). 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 [see Dosage and Administration (2.2)].

5.10 Tumor Lysis Syndrome

Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. Both cases occurred in patients with advanced CML. Hyperuricemia occurred in 7% (30/449) of patients, the majority had chronic phase CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease (AP-CML, BP-CML, or Ph+ ALL), ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

5.11 Compromised Wound Healing and Gastrointestinal Perforation

No formal studies of the effect of Iclusig on wound healing have been conducted. Based on the mechanism of action [see Clinical Pharmacology (12.1)], Iclusig could compromise wound healing. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Interrupt Iclusig for at least 1 week prior to major surgery. The decision when to resume Iclusig after surgery should be based on clinical judgment of adequate wound healing.

5.12 Embryo-Fetal Toxicity

Iclusig can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Ponatinib caused embryo-fetal toxicity in rats at exposures lower than human exposures at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig [see Use in Specific Populations (8.1)].

Laboratory Abnormalities

Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ALL than in patients with CP-CML (see Table 6).

7.1 Drugs That Are Strong Inhibitors of CYP3A Enzymes

In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced to 30 mg once daily [see Dosage and Administration (2.1)]. Patients taking concomitant strong inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

7.2 Drugs That Are Strong Inducers of CYP3A Enzymes

Coadministration of Iclusig with strong CYP3A inducers was not evaluated in vitro or in a clinical trial; however, a reduction in ponatinib exposure is likely [see Clinical Pharmacology (12.3)]. Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John's Wort) with Iclusig should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.3 Drugs That Elevate Gastric pH

Coadministration of Iclusig with drugs that elevate the gastric pH was not evaluated in a clinical trial. Based on the chemical properties of ponatinib, elevated gastric pH may reduce bioavailability and exposure [see Clinical Pharmacology (12.3)]. Coadministration of Iclusig with drugs that elevate the gastric pH (e.g., proton pump inhibitors, H2 blockers, or antacids) should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.4 Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems

In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 [also known as BCRP] transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 [also known as BCRP] (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

8.1 Pregnancy

8.3 Nursing Mothers

It is unknown whether ponatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ponatinib, a decision should be made whether to discontinue nursing or to discontinue Iclusig, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

8.5 Geriatric Use

One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (38%) as compared with patients < 65 years of age (64%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a higher major hematologic response rate (47%) as compared with patients < 65 years of age (40%). Patients of age ≥ 65 years may be more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

Iclusig has not been studied in patients with hepatic impairment.

As hepatic elimination is a major route of excretion for Iclusig, hepatic impairment may result in increased ponatinib exposure. Avoid Iclusig in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure [see Clinical Pharmacology (12.3)]. Patients with moderate to severe hepatic impairment may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Ponatinib is a kinase inhibitor. Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC50 concentrations of 0.4 and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC50 concentrations between 0.1 and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3. Ponatinib inhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I. In mice, treatment with ponatinib reduced the size of tumors expressing native or T315I mutant BCR-ABL when compared to controls.

12.3 Pharmacokinetics

The geometric mean (CV%) Cmax and AUC(0-τ) of Iclusig 45 mg daily at presumed steady state in patients with advanced hematologic malignancies were 73 ng/mL (74%) and 1253 ng•hr/mL (73%), respectively. Ponatinib administered as an investigational capsule formulation to patients with cancer exhibited approximately dose proportional increases in both Cmax and AUC over the dose range of 15 to 60 mg. A dose intensity safety analysis showed a significant increase in grade 3 or higher adverse reactions (i.e., thrombocytopenia, neutropenia, rash, ALT elevation, AST elevation, pancreatitis, and lipase elevation) with an increase in dose intensity.

12.6 QT/QTc Prolongation

A QT assessment was performed in 39 patients with cancer who received 30 mg, 45 mg, or 60 mg Iclusig once daily. No large changes in the mean QTc interval (i.e., > 20 ms) from baseline were detected in the study. However, a small increase in the mean QTc interval (i.e., < 10 ms) cannot be excluded because of study design limitations.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with ponatinib.

Ponatinib was not mutagenic in a bacterial mutagenesis (Ames) assay, was not clastogenic in a chromosome aberration assay in human lymphocytes, nor was it clastogenic in an in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg.

Ponatinib may impair male and female fertility. Fertility studies using ponatinib were not conducted. However, ponatinib effects on male and female reproductive organs observed during general toxicology studies included degeneration of epithelium of the testes in rats and monkeys and follicular atresia in the monkey ovary with associated endometrial atrophy. Effects seen in rats were at exposures approximating the AUC in patients receiving the recommended dose of 45 mg/day and in monkeys were approximately 4 times the AUC in patients.

Iclusig tablets should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15°to30° C (59° to 86° F) [see USP Controlled Room Temperature]. Keep away from children.

Thrombosis and Thromboembolism

Inform patients that serious arterial thromboses (including arterial stenosis sometimes requiring revascularization) and venous thromboembolism events have occurred. Advise patients to immediately contact their health care provider with any symptoms suggestive of a blood clot such as chest pain, shortness of breath, weakness on one side of the body, speech problems, leg pain, or leg swelling [see Warnings and Precautions (5.1)].

Hepatotoxicity

Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their health care provider if signs of liver failure occur, including yellowing of the eyes or skin, "tea"-colored urine, or drowsiness [see Warnings and Precautions (5.2)].

Congestive Heart Failure and Cardiac Arrhythmias

Inform patients of the possibility of congestive heart failure, and abnormally slow or fast heart rates. Advise patients to contact their health care provide if they experience symptoms such as shortness of breath, chest pain, palpitations, dizziness, or fainting [see Warnings and Precautions (5.3, 5.8)].

Hypertension

Inform patients of the possibility of new or worsening of existing hypertension. Advise patients to contact their health care provider for elevated blood pressure or if symptoms of hypertension occur including headache, dizziness, chest pain, or shortness of breath [see Warnings and Precautions (5.4)].

Pancreatitis

Inform patients of the possibility of developing pancreatitis that may be accompanied by nausea, vomiting, abdominal pain, or abdominal discomfort, and to promptly report these symptoms [see Warnings and Precautions (5.5)].

Hemorrhage

Inform patients of the possibility of serious bleeding and to immediately contact their health care provider with any signs or symptoms suggestive of hemorrhage such as unusual bleeding or easy bruising [see Warnings and Precautions (5.6)].

Fluid Retention

Inform patients of the possibility of developing fluid retention and to contact their health care provider for symptoms such as leg swelling, abdominal swelling, weight gain, or shortness of breath [see Warnings and Precautions (5.7)].

Myelosuppression

Inform patients of the possibility of developing low blood cell counts; inform patients to report immediately should fever develop, particularly in association with any suggestion of infection [see Warnings and Precautions (5.9)].

Compromised Wound Healing and Gastrointestinal Perforation

Advise patients to inform their health care provider if they plan to undergo a surgical procedure or had recent surgery [see Warnings and Precautions (5.11)].

Inform patients that cases of gastrointestinal perforation have been reported [see Warnings and Precautions (5.12)].

Embryo-Fetal Toxicity

Inform patients that Iclusig can cause fetal harm when administered to a pregnant woman. Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions (5.12) and Use in Specific Populations (8.1)].

Instructions for Taking Iclusig

Advise patients to take Iclusig exactly as prescribed and not to change their dose or to stop taking Iclusig unless they are told to do so by their health care provider. Iclusig may be taken with or without food. Iclusig tablets should be swallowed whole. Patients should not crush or dissolve the tablets.

Patients should not take two doses at the same time to make up for a missed dose.

Lactose

Inform patients that Iclusig contains 121 mg of lactose monohydrate in a 45 mg daily dose.