Dosing and uses of Iclusig (ponatinib)
Adult dosage forms and strengths
tablet
- 15mg
- 45mg
Chronic Myeloid Leukemia
Indicated for patients with chronic, accelerated, or blast phase T315I-positive chronic myeloid leukemia (CML) for whom no other TKI therapy is indicated
Note: Not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML (see Cautions)
45 mg PO qDay initially; continue as long as there is no evidence of disease progression or unacceptable toxicity
Acute Lymphoblastic Leukemia
Indicated for patients with T315I-positive, Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) for whom no other TKI therapy is indicated
45 mg PO qDay initially; 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
Dosing Considerations
Optimal dose not identified
In clinical trials, the starting dose was 45 mg PO qDay; however, 59% of the patients required dose reductions to 30 mg or 15 mg once daily
Consider reducing the dose in patients who have achieved a major cytogenetic response
Consider discontinuing if response has not occurred by 3 months
Gastrointestinal Stromal Tumors (Orphan)
Orphan designation for treatment of gastrointestinal stromal tumors (GIST)
Sponsor
- ARIAD Pharmaceuticals, Inc; 26 Landsdowne Street; Cambridge, MA 02339-4234
Pediatric dosage forms and strengths
Safety and efficacy not established
Iclusig (ponatinib) adverse (side) 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%)
Warnings
Black box warnings
Vascular occlusion
- Arterial and venous thrombosis and occlusions have occurred in at least 27% of 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 age 50 years or younger, experienced these events
- Monitor for evidence of thromboembolism and vascular occlusion, interrupt or stop ponatinib immediately for vascular occlusion; consider benefits and risks when deciding to restart therapy
Heart failure
- Heart failure, including fatalities, occurred in 8% of treated patients
- Monitor cardiac function; interrupt or stop ponatinib for new or worsening heart failure
Hepatotoxicity
- Hepatotoxicity, liver failure, and death reported
- Monitor hepatic function before and during treatment Interrupt and then reduce or discontinue for hepatotoxicity (see Dosage modifications)
Contraindications
None
Cautions
Monitor for thromboembolism (see Black box warnings)
Monitor for hepatotoxicity (see Black box warnings)
Monitor for signs or symptoms of heart failure and treat as clinically indicated (see Black box warnings)
Monitor for hypertension and treat as clinically indicated; treatment-emergent hypertension occurred in 67% of patients in clinical trials, including 2% who experienced symptomatic hypertension as a serious reaction, including hypertensive crisis
Pancreatitis reported; monitor serum lipase monthly; interrupt or discontinue (see Dosing modifications)
Peripheral and cranial neuropathy reported
Serious ocular toxicities leading to blindness or blurred vision reported
Interrupt dose for serious or severe hemorrhage
Monitor for fluid retention; interrupt, reduce, or discontinue
Monitor for symptoms of arrhythmias; symptomatic bradycardia and supraventricular tachycardia reported
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
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 evaluated; 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
In significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis
Not indicated for newly diagnosed CML; ponatinib-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorder in newly diagnosed chronic phase CML compared with imatinib-treated patients
Pregnancy and lactation
Pregnancy 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 categories
A: 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.
Pharmacology of Iclusig (ponatinib)
Mechanism of action
Kinase 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
Absorption
Bioavailability: 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
Distribution
Protein Bound: >99%
Vd: 1223 L (steady-state at day 28)
Metabolism
Metabolized predominantly by CYP3A4, and to a lesser extent CYP2C8, CYP2D6, and CYP3A5
Also metabolized by esterases and/or amidases P-gp substrate (weak)
Elimination
Half-life: 24 hr (range: 12-66 hr)
Excretion: 87% feces, 5% urine
Pharmacogenomics
Inhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I
Administration
Instructions
May take with or without food
Swallow tablets whole; do not chew, crush, or split
