ponatinib (Rx)

Brand and Other Names:Iclusig
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 15mg
  • 45mg
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Chronic Myeloid Leukemia

Indicated for patients with chronic, accelerated, or blast phase chronic myeloid leukemia (CML) for whom no other TKI therapy is indicated

Also indicated for T315I-postive CML (chronic, accelerated, or blast phase)

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 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other TKI therapy is indicated

Also indicated for T315I-postive Ph+ ALL

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

Safety and efficacy not established

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Interactions

Interaction Checker

and ponatinib

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            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%)

            Postmarketing Reports

            Vascular occlusion

            Venous thromboembolism

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

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            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 vascular occlusion, interrupt or stop ponatinib immediately for vascular occlusion
            • Consider benefits and risks when deciding to restart therapy

            Thromboembolism

            • Monitor for evidence of thromboembolism, interrupt or stop ponatinib
            • Consider dose modification or discontinuation in patients who develop serious venous thromboembolism
            • Thrombotic events reported include deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with vision loss

            Heart failure

            • Heart failure, including fatalities, occurred in 9% 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; conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperemias and edema or eye pain cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperemia, iritis, iridocyclitis, and ulcerative keratitis

            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

            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)

            Cases of reversible posterior leukoencephalopathy syndrome (RPLS – also known as Posterior Reversible Encephalopathy Syndrome - PRES) reported; if RPLS is diagnosed, interrupt therapy and resume treatment only once event is resolved and if benefit of continued treatment outweighs risk of RPLS

            Advise females of reproductive potential to use effective contraception during treatment with Iclusig and for 3 weeks after last dose; based on animal data, ponatinib may impair fertility in females of reproductive potential; it is not known whether these effects on fertility are reversible

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            Pregnancy & Lactation

            Pregnancy: There are no available data on 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 recommended human dose; advise pregnant women of potential risk to a fetus

            Lactation: There is no data on the presence of ponatinib in human milk, the effects on breastfed infant or on milk production; because of 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 and for 6 days following the last dose

            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.

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            Pharmacology

            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

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            Administration

            Instructions

            May take with or without food

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

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

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            • View the formulary and any restrictions for each plan.
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            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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