ICLUSIG

Ponatinib is a novel

Bcr-Abl tyrosine kinase inhibitor that is especially effective against the T315I mutation for the treatment of chronic myeloid leukemia.

FDA approved on

December 14, 2012.

Ponatinib is indicated to treat adults with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia, in combination with chemotherapy.

It can also be used as a monotherapy where no other kinase inhibitors are indicated or where there is a T315I-positive mutation.

Ponatinib is indicated in the treatment of chronic myleloid leukemia (CML) with resistance or intolerance to at least 2 kinase inhibitors.

It can also be used for accelerated or blast phase CML where no other kinase inhibitors are indicated.

Finally, it is also indicated for T315I-positive CML in the chronic, accelerated, or blast phase.

Ponatinib is a kinase inhibitor.

Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC 50 concentrations of 0.4 nM and 2.0 nM, respectively.

Ponatinib inhibited the in vitro activity of additional kinases with IC 50 concentrations between 0.1 nM 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. 12.2 Pharmacodynamics In PACE, the dose intensity-safety relationship indicated that there are significant increases in Grade ≥3 adverse reactions (hypertension, thrombocytopenia, pancreatitis, neutropenia, rash, ALT increase, AST increase, lipase increase, myelosuppression) over the dose range of 15 mg to 45 mg. In addition to dose, increased age and history of ischemia, hypertension, diabetes, or hypercholesterolemia were also contributory factors to a higher incidence of AOEs.

In OPTIC, an exposure-response relationship between ponatinib exposure and molecular response rate at 12 months was observed.

A relationship between higher ponatinib exposures and higher incidence of adverse reactions, including thrombocytopenia (Grade ≥3) and AOEs, was observed.

In vitro, there was no significant inhibition of platelet aggregation with ponatinib at concentrations seen clinically and up to 0.7 mcg/mL (1.23 μM).

Cardiac Electrophysiology The QT interval prolongation potential of ICLUSIG was assessed in 39 patients with cancer who received ICLUSIG 30 mg, 45 mg, or 60 mg (0.67 to 1.33 times the approved maximum recommended starting dose) orally once daily.

No large mean increase (i.e., >20 msec) in QTc interval was detected. 12.3 Pharmacokinetics Ponatinib administered to patients with cancer exhibited approximately dose proportional increases in both steady-state C max and AUC over the dose range of 2 mg to 60 mg (0.04 to 1.33 times the approved maximum recommended starting dose).

The mean (CV%) C max and AUC of ICLUSIG 45 mg orally once daily at presumed steady-state in patients with advanced hematologic malignancies were 73 ng/mL (74%) and 1253 ng∙hr/mL (73%), respectively.

The mean (CV%) C max and AUC of ICLUSIG 30 mg orally once daily at presumed steady-state in patients with advanced hematologic malignancies were 65 ng/mL (28%) and 1080 ng∙hr/mL (29%), respectively.

Exposure increased by approximately 90% (median) [range: 20% to 440%] between the first dose and presumed steady-state.

The absolute bioavailability of ponatinib is unknown.

Peak concentrations of ponatinib are observed within 6 hours after ICLUSIG oral administration.

Following ingestion of either a high-fat (approximately to 1000 calories with approximately 150, 250, and to 600 calories derived from protein, carbohydrate, and fat, respectively) or low-fat meal (approximately 547 calories with approximately and 63 calories derived from protein, carbohydrate, and fat, respectively) by 22 healthy volunteers, plasma ponatinib exposures (AUC and C max ) were not different when compared to fasting conditions.

Ponatinib is greater than 99% bound to plasma proteins in vitro.

There was no plasma protein binding displacement of ponatinib (145 nM) in vitro by other highly protein bound medications (ibuprofen, nifedipine, propranolol, salicylic acid, and warfarin).

The mean (CV%) apparent steady-state volume of distribution is 1,223 liters (102%) following oral administration of ICLUSIG 45 mg orally once daily for 28 days in patients with cancer.

The mean (range) terminal elimination half-life of ponatinib was approximately 24 (12 to 66) hours following ICLUSIG 45 mg orally once daily for 28 days in patients with cancer.

At least 64% of a dose undergoes Phase I and Phase II metabolism.

CYP3A4 and to a lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in the Phase I metabolism of ponatinib in vitro.

Ponatinib is also metabolized by esterases and/or amidases.

Following a single oral dose of radiolabeled ponatinib, approximately 87% of the radioactive dose was recovered in the feces and approximately 5% in the urine.

No clinically significant differences in the pharmacokinetics of ponatinib were observed based on age (19 to 85 years), body weight (41 to 152 kg), and mild to moderate renal impairment (creatinine clearance to 89 mL/min, estimated by the Cockcroft-Gault equation).

ICLUSIG has not been studied in patients with severe renal impairment.

Although renal excretion is not a major route of ponatinib elimination, the potential for severe renal impairment to affect hepatic elimination has not been determined.

A single 30 mg oral dose of ICLUSIG was administered to subjects with normal hepatic function and to subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment.

Compared to subjects with normal hepatic function, there was no trend of increased ponatinib exposure in subjects with hepatic impairment.

There was an increased incidence of adverse reactions (e.g., gastrointestinal disorders, including a case of severe pancreatitis) in subjects with hepatic impairment compared to subjects with normal hepatic function.

Drug Interaction Studies Clinical Studies Strong

CYP3A Inhibitors: Coadministration of ponatinib with multiple doses of ketoconazole (strong CYP3A inhibitor) increased the ponatinib AUC 0-INF by 78% and C max by 47%.

CYP3A Inducers: Coadministration of ponatinib with multiple doses of rifampin (strong CYP3A inducer) decreased the ponatinib AUC 0-INF by 62% and C max by 42%.

Coadministration of ponatinib with multiple doses of lansoprazole (proton pump inhibitor) decreased the ponatinib AUC 0-INF by 6% and C max by 25%.

Ponatinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, or CYP2D6 and does not induce CYP1A2, CYP2B6, or CYP3A.

Ponatinib is a weak substrate for both P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Ponatinib is not a substrate for organic anion transporting polypeptides (OATP1B1, OATP1B3) and organic cation transporter 1 (OCT1).

Ponatinib inhibits

P-gp, BCRP, and bile salt export pump (BSEP).

Ponatinib does not inhibit

OATP1B1, OATP1B3, OCT1, OCT2, or the organic anion transporters OAT1 and OAT3.

Tyrosine-protein kinase

ABL1 Inhibitor Breakpoint cluster region protein Inhibitor.

The absolute bioavailability of ponatinib is unknown.

Peak concentrations of ponatinib are observed within 6 hours after Iclusig oral administration.

Food does not affect absorption of food.

The aqueous solubility of ponatinib is pH dependent, with higher pH resulting in lower solubility.

When 45 mg of ponatinib is given to cancer patients, the pharmacokinetic parameters are as follows: Cmax = 73 ng/mL AUC = 1253 ng•hr/mL.

After oral administration of 45 mg ponatinib once daily for 28 days in cancer patients, the steady state volume of distribution is 1223 L.

Ponatinib is a weak substrate for P-gp and ABCG2.

At least 64% of a ponatinib dose undergoes phase I and phase II metabolism.

CYP3A4 and to a lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in the phase I metabolism of ponatinib in vitro.

Ponatinib is also metabolized by esterases and/or amidases.

Ponatinib is mainly eliminated via feces.

Following a single oral dose of -labeled ponatinib, approximately 87% of the radioactive dose is recovered in the feces and approximately 5% in the urine.

After oral administration of 45 mg ponatinib once daily for 28 days in cancer patients, the terminal elimination half-life is 24 hours (range of 12-66 hours).

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The most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia.

Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Ph+ ALL: Starting dose is 30 mg orally once daily in combination with chemotherapy, with a reduction to 15 mg once daily upon achievement of MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at the end of induction.

Recommended Dosage in Monotherapy for

Ph+ ALL for Whom No Other Kinase Inhibitors are Indicated or T315I-positive Ph+ ALL: Starting dose is 45 mg orally once daily.

Starting dose is 45 mg orally once daily with a reduction to 15 mg once daily upon achievement of ≤1% BCR::ABL1 IS.

Starting dose is 45 mg orally once daily.

See the Full Prescribing Information for dosage modifications for hepatic impairment.

ICLUSIG may be taken with or without food. 2.1 Recommended Dosage Newly Diagnosed Ph+ ALL The recommended starting dosage of ICLUSIG in combination with chemotherapy is 30 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at the end of induction.

ICLUSIG in combination with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity.

For a description of dosing of agents administered in combination with ICLUSIG, .

Monotherapy for

Ph+ ALL for Whom No Other Kinase Inhibitors Are Indicated or T315I-positive Ph+ ALL The optimal dose of ICLUSIG has not been identified.

The recommended starting dosage of

ICLUSIG is 45 mg orally once daily.

ICLUSIG until loss of response or unacceptable toxicity.

Consider discontinuing

ICLUSIG if response has not occurred by 3 months.

CP-CML The recommended starting dosage of

ICLUSIG is 45 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of ≤1% BCR::ABL1 IS.

Patients with loss of response can re-escalate the dose of ICLUSIG to a previously tolerated dosage of 30 mg or 45 mg orally once daily.

ICLUSIG until loss of response at the re-escalated dose or unacceptable toxicity.

ICLUSIG if hematologic response has not occurred by 3 months.

AP-CML and BP-CML The optimal dose of ICLUSIG has not been identified.

Consider reducing the dose of

ICLUSIG for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response.

Administration Advise patients of the following

ICLUSIG may be taken with or without food.

Swallow tablets whole.

Do not crush, break, cut or chew tablets.

If a dose is missed, take the next dose at the regularly scheduled time the next day. 2.2 Dosage Modifications for Adverse Reactions Recommended dosage modifications of ICLUSIG for adverse reactions are provided in Table and recommended dose reductions of ICLUSIG for adverse reactions are presented in Table 2.

Table 1: Recommended Dosage Modifications for ICLUSIG for Adverse Reactions Adverse Reaction Severity ICLUSIG Dosage Modifications Based on CTCAE v5.0: Grade 1 mild, Grade 2 moderate, Grade 3 severe, Grade 4 life-threatening ULN = Upper Limit of Normal for the lab; AOE = Arterial Occlusive Event; VTE = Venous Thromboembolic Event; ANC = absolute neutrophil count AOE: cardiovascular or cerebrovascular Grade 1 Interrupt ICLUSIG until resolved, then resume at same dose.

Grade 2 Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.

ICLUSIG if recurrence.

Grade 3 or 4 Discontinue ICLUSIG.

AOE: peripheral vascular and other or VTE Grade 1 Interrupt ICLUSIG until resolved, then resume at same dose.

Grade 2 Interrupt ICLUSIG until Grade 0 or 1, then resume at same dose.

If recurrence, interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.

Grade 3 Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.

Grade 4 Discontinue ICLUSIG.

Grade 2 or 3 Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.

Hepatotoxicity AST or

ALT greater than 3 times ULN Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.

AST or

ALT at least 3 times ULN concurrent with bilirubin greater than 2 times ULN and alkaline phosphatase less than 2 times ULN Discontinue ICLUSIG.

Serum lipase greater than to 1.5 times ULN Consider interrupting ICLUSIG until resolution, then resume at same dose.

Serum lipase greater than 1.5 to 2 times ULN, 2 to 5 times ULN and asymptomatic, or asymptomatic radiologic pancreatitis Interrupt ICLUSIG until Grade 0 or 1 (less than 1.5 times ULN), then resume at next lower dose.

Serum lipase greater than to 5 times ULN and symptomatic, symptomatic Grade 3 pancreatitis, or serum lipase greater than 5 times ULN and asymptomatic Interrupt ICLUSIG until complete resolution of symptoms and after recovery of lipase elevation Grade 0 or 1, then resume at next lower dose.

Symptomatic pancreatitis and serum lipase greater than 5 times ULN Discontinue ICLUSIG.

ANC less than 1 × 10 9 /L or Platelets less than 50 × 10 9 /L Interrupt ICLUSIG until ANC at least 1.5 × 10 9 /L and platelet at least 75 × 10 9 /L, then resume at same dose.

If recurrence, interrupt ICLUSIG until resolution, then resume at next lower dose.

Grade 1 Interrupt ICLUSIG until resolved, then resume at same dose.

Grade 3 or 4 Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.

Table 2: Recommended Dose Reductions for ICLUSIG for Adverse Reactions Dose Reduction Dosage for Patients with CP-CML Dosage for Patients with AP-CML, BP-CML, and Ph+ ALL Monotherapy Dosage for Patients with Newly Diagnosed Ph+ ALL First 30 mg orally once daily 30 mg orally once daily 15 mg orally once daily Second 15 mg orally once daily 15 mg orally once daily 10 mg orally once daily Third 10 mg orally once daily Permanently discontinue ICLUSIG in patients unable to tolerate 15 mg orally once daily.

Permanently discontinue

ICLUSIG in patients unable to tolerate 10 mg orally once daily.

Subsequent Reduction Permanently discontinue

ICLUSIG in patients unable to tolerate 10 mg orally once daily. 2.3 Dosage Modification for Coadministration of Strong CYP3A Inhibitors Avoid coadministration of ICLUSIG with strong CYP3A inhibitors.

If coadministration of a strong

CYP3A inhibitor cannot be avoided, reduce the dosage of ICLUSIG as recommended in Table 3.

After the strong

CYP3A inhibitor has been discontinued for to 5 elimination half-lives, resume the ICLUSIG dosage that was tolerated prior to initiating the strong CYP3A inhibitor.

Table 3: Recommended ICLUSIG Dosage for Coadministration of Strong CYP3A Inhibitors Current ICLUSIG Dosage Recommended ICLUSIG Dosage with a Strong CYP3A Inhibitor 45 mg orally once daily 30 mg orally once daily 30 mg orally once daily 15 mg orally once daily 15 mg orally once daily 10 mg orally once daily 10 mg orally once daily Avoid coadministration of ICLUSIG with a strong CYP3A inhibitor 2.4 Dosage for Patients with Hepatic Impairment For patients with CP-CML, AP-CML, BP-CML, and Ph+ ALL receiving monotherapy, reduce the starting dose of ICLUSIG from 45 mg orally once daily to 30 mg orally once daily in patients with pre-existing hepatic impairment (Child-Pugh A, B, or C).

For patients with newly diagnosed

Ph+ ALL, no dosage adjustment is recommended when administering ICLUSIG to patients with mild hepatic impairment (Child-Pugh A).

Closely monitor patients with moderate or severe hepatic impairment (Child-Pugh B or C) and modify the ICLUSIG dosage in the event of adverse reactions.

tablets are available in the following configurations.

Presentation 10 mg 63020-536-30 oval, white to off-white, biconvex film-coated tablets with debossed "NZ" on one side and plain on the other side 30 tablets in a wide-mouth white high density polyethylene (HDPE) bottle with a desiccant canister and induction sealed child resistant closure. 15 mg 63020-535-30 round, white, biconvex film-coated tablets with debossed "A5" on one side and plain on the other side 30 tablets in a wide-mouth white high density polyethylene (HDPE) bottle with a desiccant canister and induction sealed child resistant closure. 63020-535-60 60 tablets in a wide-mouth white high density polyethylene (HDPE) bottle with a desiccant canister and induction sealed child resistant closure. 30 mg 63020-533-30 round, white, biconvex film-coated tablets with debossed "C7" on one side and plain on the other side 30 tablets in a wide-mouth white high density polyethylene (HDPE) bottle with a desiccant canister and induction sealed child resistant closure. 45 mg 63020-534-30 round, white, biconvex film-coated tablets with debossed "AP4" on one side and plain on the other side 30 tablets in a wide-mouth white high density polyethylene (HDPE) bottle with a desiccant canister and induction sealed child resistant closure.

ICLUSIG tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

ICLUSIG tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Based on findings in animals and its mechanism of action, ICLUSIG can cause fetal harm when administered to a pregnant woman.

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 maximum recommended human dose of 45 mg/day.

Advise pregnant women of the potential risk to a fetus.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

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

At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the maximum recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification.

Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the maximum recommended dose of 45 mg/day) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

Safety and effectiveness of

ICLUSIG have not been established in pediatric patients.

A juvenile toxicity study in 15 day old rats was conducted with daily oral gavage administration of ponatinib at 0.75 mg/kg/day, 1.5 mg/kg/day, 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 to 7 days following initiation of treatment.

The dose of 3 mg/kg/day is approximately 0.32 times the maximum recommended human dose of 45 mg/day on a mg/m 2 basis for a child.

Of the 163 patients with Ph+ALL who received ICLUSIG in PhALLCON, 21% were 65 years and older and 7% were 75 years and older.

Overall, no differences in efficacy of ICLUSIG were observed between patients 65 years of age or older compared to younger patients.

AOEs occurred in 21% (7/34) of patients 65 years and older and 2.3% (3/129) of patients less than 65 years of age.

Of the 94 patients with CP-CML who received ICLUSIG at a starting dose of 45 mg in OPTIC, 17% were 65 years and older and 2.1% were 75 years and older.

Patients aged 65 years and older had a lower ≤1% BCR::ABL1 IS rate at 12 months (27%) than patients less than 65 years of age (47%).

By 60 months, patients aged 65 years and older had a ≤1% BCR::ABL1 IS rate of 40% and patients less than 65 years of age had a rate of 64%.

AOEs occurred in 38% (6/16) of patients 65 years and older and 14% (11/78) of patients less than 65 years of age.

Of the 449 patients who received ICLUSIG in PACE, 35% were 65 years and older and 8% were 75 years and older.

In patients with

CP-CML, patients aged 65 years and older had a lower major cytogenetic response rate (40%) as compared with patients less than 65 years of age (65%).

AP-CML, BP-CML, and Ph+ ALL, patients aged 65 years and older had a similar hematologic response rate (45%) as compared with patients less than 65 years of age (44%).

AOEs occurred in 35% (54/155) of patients 65 years and older and in 21% (61/294) of patients less than 65 years of age.

Patients aged 65 years or older are more likely to experience adverse reactions including vascular occlusion, 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.