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
    • 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
    • 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

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              Serious - Use Alternative (77)

              • abametapir

                abametapir increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.

              • afatinib

                ponatinib increases levels of afatinib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Reduce afatinib daily dose by 10 mg if not tolerated when coadministered with P-gp inhibitors.

              • alpelisib

                ponatinib will increase the level or effect of alpelisib by Other (see comment). Avoid or Use Alternate Drug. Coadministration of alpelisib (BCRP substrate) with a BCRP inhibitor may increase alpelisib concentration, which may increase the risk of toxicities. If unable to avoid or use alternant drugs, closely monitor for increased adverse reactions.

              • aluminum hydroxide

                aluminum hydroxide decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • aluminum hydroxide/magnesium carbonate

                aluminum hydroxide/magnesium carbonate decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • aluminum hydroxide/magnesium trisilicate

                aluminum hydroxide/magnesium trisilicate decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • apalutamide

                apalutamide will decrease the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.

              • atazanavir

                atazanavir increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • bosentan

                bosentan decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • calcium carbonate

                calcium carbonate decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • carbamazepine

                carbamazepine decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • chloramphenicol

                chloramphenicol will increase the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If concurrent use cannot be avoided, reduce ponatinib dose to next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg); if patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid use of chloramphenicol and consider alternative therapy; after chloramphenicol discontinued for 3 to 5 half-lives, resume dose of ponatinib tolerated prior to starting chloramphenicol

              • cimetidine

                cimetidine decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • citric acid/sodium bicarbonate

                citric acid/sodium bicarbonate decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • clarithromycin

                clarithromycin increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • cobicistat

                cobicistat will increase the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • conivaptan

                conivaptan increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • darunavir

                darunavir increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • deferiprone

                deferiprone, ponatinib. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis; if an alternative is not possible, monitor absolute neutrophil count more frequently.

              • dexamethasone

                dexamethasone decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • dexlansoprazole

                dexlansoprazole decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • edoxaban

                ponatinib will increase the level or effect of edoxaban by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Dose adjustment may be required with strong P-gp inhibitors. DVT/PE treatment: Decrease dose to 30 mg PO once daily. NVAF: No dose reduction recommended

              • elvitegravir/cobicistat/emtricitabine/tenofovir DF

                elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • enzalutamide

                enzalutamide decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • eslicarbazepine acetate

                eslicarbazepine acetate will decrease the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy

              • esomeprazole

                esomeprazole decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • etravirine

                etravirine decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • famotidine

                famotidine decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • fexinidazole

                fexinidazole will increase the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

              • fosamprenavir

                fosamprenavir increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • fosphenytoin

                fosphenytoin decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • grapefruit

                grapefruit increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • ibuprofen/famotidine

                ibuprofen/famotidine decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • idelalisib

                idelalisib will increase the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates

              • imatinib

                imatinib increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • indinavir

                indinavir increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • isoniazid

                isoniazid increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • ivosidenib

                ivosidenib will decrease the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternative therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

              • ketoconazole

                ketoconazole increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • lansoprazole

                lansoprazole decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • lopinavir

                lopinavir increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • magnesium hydroxide

                magnesium hydroxide decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • magnesium oxide

                magnesium oxide decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • mifepristone

                mifepristone will increase the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • nafcillin

                nafcillin decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • nefazodone

                nefazodone increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • nelfinavir

                nelfinavir increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • nevirapine

                nevirapine decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • nicardipine

                nicardipine increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • nizatidine

                nizatidine decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • omeprazole

                omeprazole decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • oxcarbazepine

                oxcarbazepine decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • ozanimod

                ponatinib increases toxicity of ozanimod by Other (see comment). Avoid or Use Alternate Drug. Comment: Coadministration of ozanimod (a BCRP substrate) with BCRP inhibitors increases the exposure of the minor (RP101988, RP101075) and major active metabolites (CC112273, CC1084037) of ozanimod, which may increase the risk of ozanimod adverse reactions. .

              • palifermin

                palifermin increases toxicity of ponatinib by Other (see comment). Avoid or Use Alternate Drug. Comment: Palifermin should not be administered within 24 hr before, during infusion of, or within 24 hr after administration of antineoplastic agents. Coadministration of palifermin within 24 hr of chemotherapy resulted in increased severity and duration of oral mucositis.

              • pantoprazole

                pantoprazole decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • pentobarbital

                pentobarbital decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • phenobarbital

                phenobarbital decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • phenytoin

                phenytoin decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • pomalidomide

                ponatinib increases levels of pomalidomide by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.

              • posaconazole

                posaconazole increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • primidone

                primidone decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • quinidine

                quinidine increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • rabeprazole

                rabeprazole decreases levels of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • ribociclib

                ribociclib will increase the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • rifabutin

                rifabutin decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • rifampin

                rifampin decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • rifapentine

                rifapentine decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

              • rimegepant

                ponatinib will increase the level or effect of rimegepant by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.

                ponatinib will increase the level or effect of rimegepant by Other (see comment). Avoid or Use Alternate Drug. Avoid coadministration of rimegepant (a BCRP substrate) with inhibitors of BCRP.

              • riociguat

                ponatinib will increase the level or effect of riociguat by decreasing metabolism. Avoid or Use Alternate Drug. Coadministration of riociguat (substrate of CYP isoenzymes 1A1, 2C8, 3A, 2J2) with strong CYP inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if needed

                ponatinib will increase the level or effect of riociguat by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Coadministration of riociguat (P-gp substrate) with strong P-gp inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if needed

              • ritonavir

                ritonavir increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • saquinavir

                saquinavir increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • talazoparib

                ponatinib will increase the level or effect of talazoparib by Other (see comment). Avoid or Use Alternate Drug. BCRP inhibitors may increase systemic exposure of talazoparib (a BCRP substrate). If coadministration cannot be avoided, monitor for potential adverse reactions.

              • tipranavir

                tipranavir increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • tucatinib

                tucatinib will increase the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.

              • venetoclax

                ponatinib will increase the level or effect of venetoclax by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If a P-gp inhibitor must be used, reduce the venetoclax dose by at least 50%. Monitor more closely for signs of venetoclax toxicities.

              • voriconazole

                voriconazole increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Decrease ponatinib starting dose to 30 mg qDay if coadministration with strong CYP3A4 inhibitors cannot be avoided.

              • voxelotor

                voxelotor will increase the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.

              Monitor Closely (118)

              • aliskiren

                ponatinib increases levels of aliskiren by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • alvimopan

                ponatinib increases levels of alvimopan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • ambrisentan

                ponatinib increases levels of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • amiodarone

                ponatinib increases levels of amiodarone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • amitriptyline

                ponatinib increases levels of amitriptyline by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • armodafinil

                armodafinil decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • atorvastatin

                ponatinib increases levels of atorvastatin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases toxicity of atorvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • bendamustine

                ponatinib increases levels of bendamustine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • berotralstat

                ponatinib increases levels of berotralstat by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Reduced berotralstat dose to 110 mg/day when coadministered with P-gp inhibitors.

                ponatinib increases levels of berotralstat by Other (see comment). Modify Therapy/Monitor Closely. Comment: Reduced dose of berotralstat (a BCRP substrate) to 110 mg/day when coadministered with BCRP inhibitors.

              • betrixaban

                ponatinib increases levels of betrixaban by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Decrease betrixaban dose to 80 mg PO once, then 40 mg PO qDay if coadministered with a P-gp inhibitor.

              • budesonide

                ponatinib increases levels of budesonide by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • carvedilol

                ponatinib increases levels of carvedilol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • cenobamate

                cenobamate will decrease the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.

              • ceritinib

                ponatinib increases levels of ceritinib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • cetirizine

                ponatinib increases levels of cetirizine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • chlorothiazide

                ponatinib increases levels of chlorothiazide by Other (see comment). Use Caution/Monitor.

              • cimetidine

                ponatinib increases levels of cimetidine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases levels of cimetidine by Other (see comment). Use Caution/Monitor.

              • ciprofloxacin

                ponatinib increases levels of ciprofloxacin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • clobazam

                clobazam decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • crofelemer

                crofelemer increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Crofelemer has the potential to inhibit CYP3A4 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.

              • cyclosporine

                ponatinib increases levels of cyclosporine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • dabigatran

                ponatinib will increase the level or effect of dabigatran by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Atrial fibrillation: Avoid coadministering dabigatran with P-gp inhibitors if CrCl <30 mL/min. DVT/PE treatment: Avoid coadministering dabigatran with P-gp inhibitors if CrCl <50 mL/min

              • dabrafenib

                dabrafenib will decrease the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

              • daunorubicin

                ponatinib increases levels of daunorubicin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases levels of daunorubicin by Other (see comment). Use Caution/Monitor.

              • desloratadine

                ponatinib increases levels of desloratadine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • dexamethasone

                ponatinib increases levels of dexamethasone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • dichlorphenamide

                dichlorphenamide and ponatinib both decrease serum potassium. Use Caution/Monitor.

                dichlorphenamide, ponatinib. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Both drugs can cause metabolic acidosis.

              • digoxin

                ponatinib increases levels of digoxin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • dipyridamole

                ponatinib increases levels of dipyridamole by Other (see comment). Use Caution/Monitor.

              • docetaxel

                ponatinib increases levels of docetaxel by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • doxorubicin

                ponatinib increases levels of doxorubicin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases levels of doxorubicin by Other (see comment). Use Caution/Monitor.

              • doxorubicin liposomal

                ponatinib increases levels of doxorubicin liposomal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases levels of doxorubicin liposomal by Other (see comment). Use Caution/Monitor.

              • duvelisib

                ponatinib will increase the level or effect of duvelisib by Other (see comment). Use Caution/Monitor. Coadministration of duvelisib (a BCRP substrate) with a BCRP transport inhibitor may increase levels or effects of duvelisib.

              • elagolix

                elagolix decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.

              • eletriptan

                ponatinib increases levels of eletriptan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • encorafenib

                encorafenib, ponatinib. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.

              • erythromycin base

                ponatinib increases levels of erythromycin base by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • erythromycin ethylsuccinate

                ponatinib increases levels of erythromycin ethylsuccinate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • erythromycin lactobionate

                ponatinib increases levels of erythromycin lactobionate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • erythromycin stearate

                ponatinib increases levels of erythromycin stearate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • estradiol

                ponatinib increases levels of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • etoposide

                ponatinib increases levels of etoposide by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • everolimus

                ponatinib increases levels of everolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • fexofenadine

                ponatinib increases levels of fexofenadine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • fluvastatin

                ponatinib increases toxicity of fluvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • fosamprenavir

                ponatinib increases levels of fosamprenavir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • glecaprevir/pibrentasvir

                ponatinib will increase the level or effect of glecaprevir/pibrentasvir by decreasing metabolism. Use Caution/Monitor. Caution when coadministering glecaprevir/pibrentasvir with P-gp/BCRP inhibitors.

              • glyburide

                ponatinib increases levels of glyburide by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases levels of glyburide by Other (see comment). Use Caution/Monitor.

              • hydrocortisone

                ponatinib increases levels of hydrocortisone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • iloperidone

                iloperidone increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.

              • imatinib

                ponatinib increases levels of imatinib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases levels of imatinib by Other (see comment). Use Caution/Monitor.

              • indinavir

                ponatinib increases levels of indinavir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • irinotecan

                ponatinib increases levels of irinotecan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases levels of irinotecan by Other (see comment). Use Caution/Monitor.

              • irinotecan liposomal

                ponatinib increases levels of irinotecan liposomal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases levels of irinotecan liposomal by Other (see comment). Use Caution/Monitor.

              • istradefylline

                istradefylline will increase the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.

              • itraconazole

                itraconazole increases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Decrease ponatinib starting dose to 30 mg qDay if concomitantly used with strong CYP3A4 inhibitors.

              • ivermectin

                ponatinib increases levels of ivermectin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • lapatinib

                ponatinib increases levels of lapatinib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases levels of lapatinib by Other (see comment). Use Caution/Monitor.

              • leflunomide

                ponatinib increases levels of leflunomide by Other (see comment). Use Caution/Monitor.

              • lidocaine

                ponatinib increases levels of lidocaine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • loperamide

                ponatinib increases levels of loperamide by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • loratadine

                ponatinib increases levels of loratadine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • lorlatinib

                lorlatinib will decrease the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • lovastatin

                ponatinib increases levels of lovastatin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • maraviroc

                ponatinib increases levels of maraviroc by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • mefloquine

                ponatinib increases levels of mefloquine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • methotrexate

                ponatinib increases levels of methotrexate by Other (see comment). Use Caution/Monitor.

              • methylprednisolone

                ponatinib increases levels of methylprednisolone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • mitomycin

                ponatinib increases levels of mitomycin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • mitotane

                mitotane decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.

              • mitoxantrone

                ponatinib increases levels of mitoxantrone by Other (see comment). Use Caution/Monitor.

              • morphine

                ponatinib increases levels of morphine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • naldemedine

                ponatinib increases levels of naldemedine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor naldemedine for potential adverse effects if coadministered with P-gp inhibitors.

              • nelfinavir

                ponatinib increases levels of nelfinavir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • nilotinib

                ponatinib increases levels of nilotinib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • nintedanib

                ponatinib increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .

              • nitrofurantoin

                ponatinib increases levels of nitrofurantoin by Other (see comment). Use Caution/Monitor.

              • ondansetron

                ponatinib increases levels of ondansetron by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • paclitaxel

                ponatinib increases levels of paclitaxel by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • paclitaxel protein bound

                ponatinib increases levels of paclitaxel protein bound by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • pazopanib

                ponatinib increases levels of pazopanib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • pioglitazone

                pioglitazone increases toxicity of ponatinib by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • pitavastatin

                ponatinib increases toxicity of pitavastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • ponesimod

                ponesimod and ponatinib both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

              • posaconazole

                ponatinib increases levels of posaconazole by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • pravastatin

                ponatinib increases levels of pravastatin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases toxicity of pravastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • prednisone

                ponatinib increases levels of prednisone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • quinidine

                ponatinib increases levels of quinidine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • ranolazine

                ponatinib increases levels of ranolazine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases toxicity of ranolazine by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • rifampin

                ponatinib increases levels of rifampin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • rifaximin

                ponatinib increases levels of rifaximin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • risperidone

                ponatinib increases levels of risperidone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • ritonavir

                ponatinib increases levels of ritonavir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • rosuvastatin

                ponatinib increases toxicity of rosuvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • rucaparib

                rucaparib will increase the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.

              • saquinavir

                ponatinib increases levels of saquinavir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • saxagliptin

                ponatinib increases levels of saxagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • selexipag

                ponatinib will increase the level or effect of selexipag by Other (see comment). Use Caution/Monitor. Selexipag is a ABCG2 (BCRP) substrate. Monitor selexipag for increased pharmacologic or adverse effects when coadministered with ABCG2 (BCRP) inhibitors.

              • silodosin

                ponatinib increases levels of silodosin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • simvastatin

                ponatinib increases levels of simvastatin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases levels of simvastatin by Other (see comment). Use Caution/Monitor.

              • siponimod

                siponimod and ponatinib both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

              • sirolimus

                ponatinib increases levels of sirolimus by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely.

              • sitagliptin

                ponatinib increases levels of sitagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • sodium zirconium cyclosilicate

                sodium zirconium cyclosilicate will decrease the level or effect of ponatinib by increasing gastric pH. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. Check specific recommendations for drugs that exhibit pH-dependent solubility that may affect their systemic exposure and efficacy. In general, administer drugs at least 2 hr before or after sodium zirconium cyclosilicate.

              • stiripentol

                stiripentol, ponatinib. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.

              • sulfasalazine

                ponatinib increases levels of sulfasalazine by Other (see comment). Use Caution/Monitor.

              • tacrolimus

                ponatinib increases levels of tacrolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • tazemetostat

                tazemetostat will decrease the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • tecovirimat

                tecovirimat will decrease the level or effect of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.

              • temsirolimus

                ponatinib increases levels of temsirolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • teniposide

                ponatinib increases levels of teniposide by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • testosterone

                ponatinib increases levels of testosterone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • tolvaptan

                ponatinib increases levels of tolvaptan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • topotecan

                ponatinib increases levels of topotecan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

                ponatinib increases levels of topotecan by Other (see comment). Use Caution/Monitor.

              • verapamil

                ponatinib increases levels of verapamil by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • vinblastine

                ponatinib increases levels of vinblastine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • vincristine

                ponatinib increases levels of vincristine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • vincristine liposomal

                ponatinib increases levels of vincristine liposomal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              Minor (1)

              • efavirenz

                efavirenz decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

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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

              BRAND FORM. UNIT PRICE PILL IMAGE
              Iclusig oral
              -
              15 mg tablet
              Iclusig oral
              -
              45 mg tablet

              Copyright © 2010 First DataBank, Inc.

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              Patient Handout

              Patient Education
              ponatinib oral

              PONATINIB - ORAL

              (poe-NA-ti-nib)

              COMMON BRAND NAME(S): Iclusig

              WARNING: Ponatinib has caused serious (sometimes fatal) blood clots (such as heart attack, stroke, pulmonary embolus-PE, deep vein thrombosis-DVT). Talk to your doctor about the risks and benefits of this medication. Get medical help right away if you develop symptoms of a blood clot, including chest/jaw/left arm pain, confusion, trouble speaking, weakness on one side of the body, severe headache, severe dizziness, sudden vision changes, trouble breathing, pain/swelling/redness of arms/legs.This medication can cause very serious (possibly fatal) heart failure. Tell your doctor right away if you develop symptoms of heart failure, including shortness of breath, swelling ankles/feet, unusual tiredness, unusual/sudden weight gain.Ponatinib can also rarely cause very serious (possibly fatal) liver disease. Your doctor will order blood tests to check your liver before you start and while you are taking ponatinib. Tell your doctor right away if you develop symptoms of liver disease, including nausea/vomiting that doesn't stop, stomach/abdominal pain, dark urine, yellowing eyes/skin. Your doctor may need to change your dosage or discontinue the drug.

              USES: Ponatinib is used to treat certain types of blood cancer (chronic myelogenous leukemia-CML, acute lymphoblastic leukemia-ALL). It works by slowing or stopping the growth of cancer cells. It belongs to a class of drugs known as kinase inhibitors.

              HOW TO USE: Read the Medication Guide provided by your pharmacist before you start taking ponatinib and each time you get a refill. If you have any questions, ask your doctor or pharmacist.Take this medication by mouth with or without food as directed by your doctor, usually once daily. Swallow the tablets whole. Do not crush, break, cut, chew, or dissolve the tablets. Drink plenty of fluids unless otherwise directed by your doctor. The dosage is based on your medical condition, lab results, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).Do not increase your dose or take this medication more often than directed. Your condition will not improve any faster, and your risk of side effects will increase.Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor or pharmacist says you may do so safely. Grapefruit can increase the chance of side effects with this medicine. Ask your doctor or pharmacist for more details.Acid-lowering medications for indigestion, heartburn, or ulcers (such as proton pump inhibitors/PPIs, H2 blockers, antacids) may prevent ponatinib from working. Consult your doctor or pharmacist if you are taking any of these medications.Since this drug can be absorbed through the skin and lungs and may harm an unborn baby, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the tablets.

              SIDE EFFECTS: See also Warning section.Headache, dizziness, constipation, or loss of appetite may occur. If any of these effects persist or worsen, tell your doctor or pharmacist immediately.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor right away if you have any serious side effects, including: weight gain, numb/tingling skin, pain/numbness/burning feeling in fingers/toes, fainting, fast/slow/irregular/pounding heartbeat, eye pain/swelling/irritation, slow wound healing, sudden severe headache, blurred vision/vision problems, problems thinking.Ponatinib sometimes causes side effects due to the rapid destruction of cancer cells (tumor lysis syndrome). To lower your risk, your doctor may add a medication and tell you to drink plenty of fluids. Tell your doctor right away if you have symptoms such as: signs of kidney problems (such as painful urination, pink/bloody urine, change in the amount of urine), muscle spasms/weakness.Get medical help right away if you have any very serious side effects, including: sudden/severe back pain, unusual bleeding/bruising, black/bloody stools, vomit that contains blood or looks like coffee grounds, shortness of breath, seizures.This medication may raise your blood pressure. Check your blood pressure regularly and tell your doctor if the results are high. Your doctor may control your blood pressure with medication.This medication may lower your ability to fight infections. This may make you more likely to get a serious infection or make any infection you have worse. Tell your doctor right away if have any signs of infection (such as fever, chills, persistent sore throat, cough).For women of childbearing age, ponatinib may affect your ability to have children. Ask your doctor for more details.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

              PRECAUTIONS: Before taking ponatinib, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, heart problems (such as history of heart attack, angina, high blood pressure), previous stroke or "mini-stroke" (transient ischemic attack), blood vessel problems (such as an aneurysm or a tear/break in the aorta or other blood vessels), diabetes, high cholesterol, tobacco use.This drug may make you dizzy or blur your vision. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness or clear vision until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).This medication may cause wounds to heal slowly or poorly. Your doctor or dentist may tell you to temporarily stop treatment with this medication at least 1 week before surgery or a dental procedure. Ask your doctor or dentist for specific instructions about when to stop and when to restart treatment with this medication. Tell your doctor/dentist right away if you have wounds that are not healing well.Do not have immunizations/vaccinations without the consent of your doctor. Avoid contact with people who have recently received live vaccines (such as flu vaccine inhaled through the nose).To lower the chance of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.Older adults may be more sensitive to the side effects of this drug, especially unusual bleeding/bruising, blood clots, swollen legs/ankles, muscle spasms, weakness, loss of appetite.Tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant while taking ponatinib. Ponatinib may harm an unborn baby. Your doctor will do a pregnancy test before you start taking this medication. Ask about reliable forms of birth control while taking this medication and for 3 weeks after stopping treatment. If you become pregnant, talk to your doctor right away about the risks and benefits of this medication.It is unknown if this medication passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug and for 6 days after stopping treatment is not recommended. Consult your doctor before breast-feeding.

              DRUG INTERACTIONS: See also How to Use section.Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Other medications can affect the removal of ponatinib from your body, which may affect how ponatinib works. Examples include azole antifungals (such as itraconazole), macrolide antibiotics (such as erythromycin), HIV protease inhibitors (such as lopinavir, ritonavir), rifamycins (such as rifabutin), drugs for seizures (such as phenytoin), St. John's wort, among others.

              OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

              NOTES: Do not share this medication with others.Laboratory and/or medical tests (such as blood pressure, eye exam, liver function tests, complete blood counts, lipase, uric acid) should be performed periodically to monitor your progress or check for side effects. See also Warning section.

              MISSED DOSE: If you miss a dose, skip the missed dose. Take your next dose at the regular time the next day. Do not double the dose to catch up.

              STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

              MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-888-633-4298 (US) or 1-800-668-1507 (Canada).

              Information last revised August 2021. Copyright(c) 2021 First Databank, Inc.

              IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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              Formulary

              FormularyPatient Discounts

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

              To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

              Adding plans allows you to:

              • View the formulary and any restrictions for each plan.
              • Manage and view all your plans together – even plans in different states.
              • 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.
              QL Quantity Limits
              Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
              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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              Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.