ponatinib (Rx)

Brand and Other Names:Iclusig
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 15mg
  • 45mg

Chronic Myeloid Leukemia

Indicated for patients with chronic phase (CP) chronic myeloid leukemia (CML) with resistance or intolerance to at least 2 prior kinase inhibitors

Also indicated for accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated, and for T315I-postive CML (CP, AP, BP)

CP-CML

  • 45 mg PO qDay initially
  • Reduce to 15 mg PO qDay upon achievement of ≤1% BCR-ABL1IS
  • Re-escalate dose to previously tolerated dosage of 30 mg or 45 mg PO qDay in patients with loss of response
  • Continue until loss of response at the re-escalated dose or unacceptable toxicity

AP-CML or BP-CML

  • Optimal dose not identified
  • 45 mg PO qDay
  • AP CML
    • Consider reducing dose for AP CML in patients who have achieved a major cytogenetic response
    • Continue until loss of response or unacceptable toxicity
    • Consider discontinuing treatment if response has not occurred by 3 months

Acute Lymphoblastic Leukemia

Indicated for patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other kinase inhibitors are indicated

Also indicated for T315I-postive Ph+ ALL Optimal dose not identified

45 mg PO qDay initially

Continue until loss of response or unacceptable toxicity

Consider discontinuing treatment if response has not occurred by 3 months

Dosage Modifications

Dose reductions for adverse reactions

  • CP-CML H5
  • First reduction: 30 mg PO qDay
  • Second reduction: 15 mg PO qDay
  • Third reduction: 10 mg PO qDay
  • Unable to tolerate 10 mg/day: Permanently discontinue
  • AP-CML, BP-CML, and Ph+ ALL H5
  • First reduction: 30 mg PO qDay
  • Second reduction: 15 mg PO qDay
  • Unable to tolerate 15 mg/day: Permanently discontinue

Arterial occlusive events (cardiovascular or cerebrovascular)

  • Grade 1: Interrupt therapy until resolved, then resume at same dose
  • Grade 2: Interrupt therapy until Grade ≤1, then resume at next lower dose
  • Grade 2 recurs or Grade 3 or 4: Discontinue treatment

Arterial occlusive events (peripheral vascular and other or venous thromboembolism [VTE])

  • Grade 1 or 2: Interrupt therapy until resolved, then resume at same dose
  • Grade 2 recurs or Grade 3: Interrupt therapy until Grade ≤1, then resume at next lower dose
  • Grade 3 recurs or 4: Discontinue treatment

Heart failure

  • Grade 2 or 3: Interrupt therapy until Grade ≤1, then resume at next lower dose
  • Grade 2 or 3 recurs or Grade 4: Discontinue treatment

Hepatotoxicity

  • AST or ALT >3x ULN: Interrupt therapy until Grade ≤1, then resume at next lower dose
  • AST or ALT ≥3x ULN with bilirubin >2x ULN and alkaline phosphatase <2x ULN: Discontinue treatment

Pancreatitis and elevated lipase

  • Serum lipase >1 to 1.5x ULN: Consider interrupting therapy until resolution then resume at same dose
  • Serum lipase >1.5 to 2x ULN, 2 to 5x ULN and asymptomatic, or asymptomatic radiologic pancreatitis: Interrupt therapy until Grade ≤1 (defined as <1.5x ULN) then resume at next lower dose
  • Serum lipase >2 to 5x ULN and symptomatic, symptomatic Grade 3 pancreatitis, or serum lipase >5x ULN and asymptomatic: Interrupt therapy until complete resolution of symptoms and after recovery of lipase elevation Grade ≤1, then resume at next lower dose
  • Symptomatic pancreatitis and serum lipase >5x ULN: Discontinue therapy

Myelosuppression

  • ANC <1 x 109/L or platelets <50 x 109/L: Interrupt therapy until ANC at least 1.5 x 109/L and platelet at least 75 x 109/L, then resume at same dose
  • If recurrence, interrupt therapy until resolution, then resume at next lower dose

Other nonhematologic adverse reactions

  • Grade 1: Interrupt therapy until resolved, then resume at same dose
  • Grade 2: Interrupt therapy until Grade ≤1, then resume at same dose
  • Grade 2 recurs or Grade 3 or 4: Interrupt therapy until Grade ≤1, then resume at next lower dose
  • Grade 3 or 4 recurs: Discontinue therapy

Strong CYP3A4 inhibitors H4

  • Avoid coadministration with strong CYP3A inhibitors
  • If unavoidable, reduce dosage as recommended
  • After strong CYP3A inhibitor has been discontinued for 3-5 elimination half-lives, resume dosage that was tolerated before initiating the strong CYP3A
  • Recommended dose for coadministration of strong CYP3A inhibitors
    • Current ponatinib dose is 45 mg qDay: Reduce ponatinib to 30 mg qDay
    • Current ponatinib dose is 30 mg qDay: Reduce ponatinib to 15 mg qDay
    • Current ponatinib dose is 15 mg qDay: Reduce ponatinib to 10 mg qDay
    • Current ponatinib dose is 10 mg qDay: Avoid coadministration

Renal impairment

  • Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment required
  • Severe (CrCl <30 mL/min): Not studied

Hepatic impairment

  • Pre-existing hepatic impairment (Child-Pugh A, B, or C): Reduce starting dose from 45 mg qDay to 30 mg qDay

Dosing Considerations

Verify pregnancy status of females of reproductive potential before initiation

Limitation of use

  • Not indicated and is not recommended for patients with newly diagnosed CP-CML

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

            All Interactions Sort By:
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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

            Arterial occlusion

            Venous thromboembolism

            Thrombotic microangiopathy

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

            Metabolism and nutrition disorders: Dehydration

            Skin and subcutaneous tissue disorders: Severe cutaneous reaction (e.g. Erythema multiforme, Stevens-Johnson syndrome)

            Gastrointestinal perforation, fistula

            Endocrine disorders: Hyperthyroidism

            Vascular disorders: Arterial (including aortic) aneurysms, dissections, and rupture

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            Warnings

            Black Box Warnings

            Arterial occlusive events

            • Arterial occlusive events (AOEs), including fatalities, have occurred
            • AOEs included 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, experienced these events
            • Monitor for evidence of AOEs
            • Interrupt or discontinue treatment based on severity
            • Consider benefit-risk to guide a decision 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

            Arterial occlusive events, including fatalities, have occurred

            Serious or severe VTEs have occurred

            Fatal, serious or severe heart failure events reported

            May cause hepatotoxicity, including liver failure and death

            Serious or severe pancreatitis has occurred

            Peripheral and cranial neuropathy reported; monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness; interrupt, then resume at same or reduced dose or discontinue drug based on recurrence/severity

            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; conduct comprehensive eye exams at baseline and periodically during treatment

            Fatal and serious hemorrhage events have occurred; interrupt dose for serious or severe hemorrhage

            Severe myelosuppression (Grade 3 or 4) was observed early, with a median onset time of 1 month (range less than 1-40 months)

            Monitor for fluid retention; interrupt, reduce, or discontinue

            Monitor for symptoms of arrhythmias; monitor for signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations, or dizziness) and manage patients as clinically indicated; interrupt, then resume at same or reduced dose or discontinue drug based on recurrence/severity; 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

            Serious tumor lysis syndrome developed and hyperuricemia occurred; ensure adequate hydration and correct high uric acid levels before 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

            Monitor serum lipase every 2 weeks for 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; interrupt, then resume at same or reduced dose or discontinue drug based on severity; evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms

            Can cause fetal harm; advise women of potential risk to a fetus

            Revere posterior leukoencephalopathy syndrome

            • Reversible posterior leukoencephalopathy syndrome (RPLS; also known as posterior reversible encephalopathy syndrome) has been reported; symptoms include hypertension, seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances
            • Confirm diagnosis with a MRI
            • Interrupt therapy until resolution; safety of resumption in patients upon resolution of RPLS is unknown

            Hypertension

            • Serious or severe hypertension, including hypertensive crisis, has occurred
            • Urgent clinical intervention may be required for hypertension associated with confusion, headache, chest pain, or shortness of breath
            • Monitor blood pressure at baseline and as clinically indicated and manage hypertension as clinically indicated
            • Interrupt, dose reduce, or stop therapy if hypertension is not medically controlled
            • For significant worsening, labile or treatment-resistant hypertension, interrupt therapy and consider evaluating for renal artery stenosis

            Increased toxicity in newly diagnosed CP-CML

            • Study showed ponatinib-treated patients with CP-CML had 2-fold increased risk of serious adverse reaction compared with imatinib
            • Median exposure to treatment was <6 months
            • Arterial and venous thrombosis and occlusions occurred at least twice as frequently with ponatinib compared with imatinib; ponatinib-treated patients also exhibited greater incidence of myelosuppression, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders
            • Ponatinib is not indicated nor recommended for newly diagnosed CP-CML

            Drug interaction overview

            • CYP3A4 substrate
            • Inhibits P-gp, BCRP, and bile salt export pump
            • Strong CYP3A inhibitors
              • Avoid coadministration
              • Strong CYP3A inhibitors increase ponatinib plasma concentrations and toxicities; if unable to avoid, reduce ponatinib dose
            • Strong CYP3A4 inducers
              • Avoid coadministration unless benefits outweighs risks; monitor for reduced efficacy of ponatinib
              • Strong CYP3A inducers decrease ponatinib plasma concentrations
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            Pregnancy & Lactation

            Pregnancy

            Based on findings in animals and its mechanism of action, fetal harm when administered to pregnant females

            No data available on use in pregnant females

            Verify pregnancy status of females of reproductive potential before initiation

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for 3 weeks after final dose

            Infertility

            • Based on animal data, impair fertility in females of reproductive potential may occur
            • Unknown whether these effects on fertility are reversible

            Animal data

            • Oral administration to pregnant rats during organogenesis caused adverse developmental effects at doses lower than human exposures at the recommended human dose
            • Advise pregnant females of potential risk to a fetus

            Lactation

            There is no data on drug presence in human milk or the effects on breastfed children, or on milk production

            Advise females not to breastfeed during treatment and for 6 days following 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

            Oral Administration

            May take with or without food

            Swallow tablets whole; do not crush, break, cut, or chew tablets

            Missed dose: Take next dose at regularly scheduled time the next day

            Storage

            Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

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            Images

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            Formulary

            FormularyPatient Discounts

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            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.
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            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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