Chronic Myeloid Leukemia
Indicated for chronic, accelerated, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior TKI therapy, including those with the T315I mutation of BCR-ABL

45 mg PO qDay; continue as long as there is no evidence of disease progression or unacceptable toxicity

Acute Lymphoblastic Leukemia
Indicated for Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior TKI therapy, including those with the T315I mutation of BCR-ABL

45 mg PO qDay; continue as long as there is no evidence of disease progression or unacceptable toxicity

Dosage Modifications
Coadministration with strong CYP3A inhibitors

Reduce dose to 30 mg qDay
Renal & hepatic impairment

Hepatic: Major route of excretion; avoid with moderate-to-severe hepatic impairment (Child-Pugh B or C) unless benefit outweighs risks
Renal: Has not been studied; renal excretion is not a major route of elimination; unknown if moderate or severe renal impairment would affect hepatic elimination
Myelosuppression

ANC <1.0 x 10^9/L and platelets <50 x 10^9/L
First occurrence: Interrupt therapy and resume initial 45 mg/day after recovery to ANC ≥1.5 x 10^9/L and platelets ≥75 x 10^9/L
Second occurrence: Interrupt therapy and resume at 30 mg/day after recovery to ANC ≥1.5 x 10^9/L and platelets ≥75 x 10^9/L
Third occurrence: Interrupt therapy and resume at 15 mg/day after recovery to ANC ≥1.5 x 10^9/L and platelets ≥75 x 10^9/L
Liver transaminases >3 x ULN (≥Grade 2)

Occurrence at 45 mg/day: Interrupt therapy and monitor hepatic function; resume at 30 mg after recovery to ≤Grade 1 (<3 x ULN)
Occurrence at 30 mg/day: Interrupt therapy and resume at 15 mg after recover to ≤Grade 1
Occurrence at 15 mg: Discontinue
Elevated AST/ALT, bilirubin, and decreased alkaline phosphatase

Elevation of AST or ALT ≥3 x ULN concurrent with an elevation of bilirubin >2 x ULN and alkaline phosphatase
<2 x ULN: Discontinue therapy
Asymptomatic Grade 1 or 2 lipase elevation

Consider dose interruption or reduction
Asymptomatic Grade 3 or 4 lipase elevation

Lipase >2 x ULN or asymptomatic radiologic pancreatitis (Grade 2 pancreatitis)
Occurrence at 45 mg/day: Interrupt therapy and resume at 30 mg after recover to ≤Grade 1 (<1.5 x ULN)
Occurrence at 30 mg/day: Interrupt Iclusig and resume at 15 mg after recovery to ≤Grade 1
Occurrence at 15 mg/day: Discontinue
Symptomatic Grade 3 pancreatitis

Occurrence at 45 mg: Interrupt therapy and resume at 30 mg after complete resolution of symptoms and recovery of lipase elevation to ≤Grade 1
Occurrence at 30 mg: Interrupt therapy and resume at 15 mg after complete resolution of symptoms and recovery of lipase elevation to <Grade 1
Occurrence at 15 mg/day: Discontinue
Grade 4 pancreatitis

Discontinue therapy
Dosage Considerations
Decrease dose when coadministered with strong CYP3A inhibitors (see Dosage modifications)

Avoid coadministration with strong CYP3A inducers; these drugs are likely to reduce ponatinib exposure

Although coadministration with drugs that increase gastric pH (eg, PPIs, H2 antagonists, antacids) was not eva luated; elevated gastric pH may reduce ponatinib bioavailability and systemic exposure

Inhibits P-gp and ABCG2 (BCRP) transporter systems; may affect substrates of these transport systems

Administration
May take with or without food

Swallow tablets whole; do not chew, crush, or split

Safety and efficacy not established

 Interactions Drug InteractionsInteraction Checkerponatinib and No Results
   No Interactions FoundInteractions FoundContraindicatedSerious - Use AlternativeSignificant - Monitor CloselyMinorSort by :    PreviousNext Section: Interactions
Adverse Effects>10%Hypertension (53-71%)
Neutropenia (24-63%)
Leukopenia (14-63%)
Anemia (9-55%)
Thrombocytopenia (36-57%)
Rash (34-54%)
Abdominal pain (34-49%)
Constipation (24-47%)
Fatigue or asthenia (31-39%)
Headache (25-39%)
Dry skin (24-39%)
Lymphopenia (10-37%)
Pyrexia (23-32%)
Nausea (22-32%)
Arthralgia (13-31%)
Decreased appetite (8-31%)
Diarrhea (13-26%)
Febrile neutropenia (1-25%)
Vomiting (13-24%)
Oral mucositis (9-23%)
Edema, peripheral (13-22%)
Myalgia (6-22%)
Sepsis (1-22%)
Dyspnea (7-21%)
Pleural effusion (3-19%)
Cough (6-18%)
Pain in extremity (9-17%)
Back pain (11-16%)
Pain (6-16%)
Cardiac failure (6-15%)
Chills (7-13%)
Peripheral neuropathy (6-13%)
Muscle spasms (5-13%)
Weight decreased (5-13%)
Arterial ischemia (3-13%)
Pneumonia (3-13%)
Bone pain (9-12%)
Urinary tract infection (7-12%)
Insomnia (7-12%)
Nasopharyngitis (3-12%)
Upper respiratory tract infection (8-11%)
Dizziness (3-11%)
GI hemorrhage (2-11%)
Cellulitis (2-11%)
1-10%Arterial ischemic event (8%)
MI (5%)
Pancreatitis (5%)
Abdominal pain (4%)
Hemorrhage (4%)
Cardiac failure (4%)
Pneumonia, severe (4%)
Effusions (3%)
Febrile neutropenia (3%)
Thrombocytopenia, severe (3%)
Pyrexia, severe (3%)
Sepsis, severe (2%)
Anemia, severe (2%)
Atrial fibrillation (2%)
Venous thromboembolism (2%)
Hypertension (2%)
Stroke or TIA (2%)
Peripheral arterial disease (2%)
CNS hemorrhage (2%)
GI hemorrhage (2%)
 Interactions
Contraindications & Cautions Black Box WarningsArterial thrombosis
Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal MI and stroke reportedIn clinical trials, serious arterial thrombosis occurred in 8% of patientsInterrupt therapy and consider discontinuation if arterial thrombotic events developHepatotoxicity
Hepatotoxicity, liver failure, and death reportedMonitor hepatic function before and during treatment Interrupt and then reduce or discontinue for hepatotoxicity (see Dosage Modifications) ContraindicationsNone
CautionsMonitor for signs or symptoms of CHF and treat as clinically indicated
Monitor for hypertension and treat as clinically indicated
Monitor serum lipase monthly; interrupt or discontinue (see Dosing modifications)
Interrupt dose for serious or severe hemorrhage
Monitor for fluid retention; interrupt, reduce, or discontinue
Monitor for symptoms of arrhythmias
Thrombocytopenia, neutropenia, and anemia may require dose interruption, or reduction; monitor CBC q2weeks x 3 months and then monthly and as clinically indicated; interrupt for ANC < 1000/mm³ or thrombocytopenia < 50,000/mm³ (see Dosage modifications)
Ensure adequate hydration and correct high uric acid levels prior to initiating therapy to decrease risk for tumor lysis syndrome
May compromise wound healing or increase risk for GI perforation; temporarily interrupt therapy in patients undergoing major surgical procedures
Can cause fetal harm; advise women of potential risk to a fetus
PreviousNext Section: Interactions
Pregnancy & LactationPregnancy Category: D; can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals
Lactation: Unknown whether distributed in human breast milk; a decision should be made whether to discontinue breastfeeding or to discontinue ponatinib, taking into account the importance of the drug to the mother
Pregnancy CategoriesA:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
PreviousNext Section: Interactions
PharmacologyMechanism of ActionKinase inhibitor; inhibits activity of ABL and T315I mutant ABL; inhibits additional kinases including BEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3
AbsorptionBioavailability: Unknown
Peak Plasma Time: 6 hr Peak
Plasma Concentration: 73 ng/mL(45 mg/day)
AUC: 1253 mcg•h/mL (45 mg/day)
Aqueous solubility is pH dependent, with higher pH resulting in lower solubility
DistributionProtein Bound: >99%
Vd: 1223 L (steady-state at day 28)
MetabolismMetabolized predominantly by CYP3A4, and to a lesser extent CYP2C8, CYP2D6, and CYP3A5
Also metabolized by esterases and/or amidases P-gp substrate (weak)
EliminationHalf-life: 24 hr (range: 12-66 hr)
Excretion: 87% feces, 5% urine
PharmacogenomicsInhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I
PreviousNext Section: Interactions
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