Ponatinib is an oral multi-kinase inhibitor. It is indicated for the treatment of adult patients with previously treated chronic phase (CP) chronic myeloid leukemia (CML), T315I-positive CML, and accelerated or blast phase CML for whom no other tyrosine kinase inhibitor is indicated. Use is not recommended in patients with newly diagnosed CP CML. Ponatinib is also indicated in adults with newly diagnosed Philadelphia chromosome-positive (Ph+) ALL in combination with chemotherapy, T315I-positive Ph+ ALL, and Ph+ ALL for whom no other kinase inhibitors are indicated. Ponatinib has a black box warning for arterial occlusive events, venous thromboembolic events, heart failure, and hepatotoxicity.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Emetic Risk
-Minimal/Low
-Administer prn antiemetics as necessary.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Ponatinib may be taken with or without food.
-Swallow tablets whole; do not break, crush, cut, chew, or dissolve tablets.
-Do not take 2 doses at the same time if a dose is missed.
-A ponatinib dose adjustment is necessary in patients who ingest grapefruit juice.
Heart failure was reported in 6% to 13% (grade 3 or higher, 1.1% to 7%) of patients with chronic myelogenous leukemia or acute lymphoblastic leukemia who received ponatinib in clinical trials. Monitor patients for signs and symptoms of heart failure and manage as clinically indicated. Therapy interruption, a dosage reduction, or discontinuation may be necessary in patients who develop new or worsening heart failure. Heart failure events reported in clinical trials included left ventricular hypertrophy (3.2% or less), increased brain natriuretic peptide level (3.2% or less), congestive heart failure (3.1% or less), and decreased ejection fraction (2.9% or less).
Myelosuppression occurred in patients who received ponatinib in clinical trials. Obtain complete blood counts (CBCs) every 2 weeks for the first 3 months of ponatinib therapy, then monitor CBCs monthly or as clinically indicated. Therapy interruption and a dose reduction may be necessary in patients who develop severe myelosuppression. Neutropenia (55% to 66%; grade 3 or 4, 22% to 63%), thrombocytopenia (63% to 65%; grade 3 or 4, 31% to 62%), anemia (35% to 53%; grade 3 or 4, 14% to 38%), decreased white blood cell count/leukopenia (79% or less; grade 3 or 4, 12% to 71%), and decreased lymphocyte count/lymphopenia (77% or less; grade 3 or 4, 7% to 61%) were reported in patients with chronic myelogenous leukemia or acute lymphoblastic leukemia (ALL) who received ponatinib in clinical trials. The incidence of myelosuppression was highest in patients with ALL. The median time to onset of severe myelosuppression ranged from 1 day to 4.1 years). Additionally, febrile neutropenia was reported in 1.1% to 28% (grade 3 or 4, 1.1% to 25%) of patients who received ponatinib in clinical trials.
Cardiac arrhythmias were reported in 16% to 22% (grade 3 or higher, 2.5% to 7%) of patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL) who received ponatinib in clinical trials. Monitor patients for signs and symptoms of slow or fast heart rate and manage as clinically indicated. Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on recurrence or the severity of the cardiac arrhythmia. Grade 3 or 4 cardiac arrhythmias including tachycardia, syncope, atrial fibrillation, and supraventricular tachycardia (SVT) each occurred in 0.6% of patients with newly diagnosed ALL who received ponatinib in combination with chemotherapy (n = 163) in a randomized trial. In patients with CML or ALL who received ponatinib (n = 449), cardiac arrhythmias included ventricular arrhythmia (3.4%), symptomatic bradyarrhythmia/bradycardia leading to pacemaker implantation (1%), atrial fibrillation (8%; grade 3 or 4, 3.3%), grade 3 or 4 syncope (2%), sinus tachycardia (0.4%), bradycardia (0.4% or less), QT prolongation (0.2%), atrial flutter (0.2%), SVT (0.2%), ventricular tachycardia (0.2%), atrial tachycardia (0.2%), complete AV block (0.2%), cardiac arrest/respiratory arrest (0.2%), loss of consciousness (0.2%), and sinus node dysfunction (0.2%). Grade 3 or 4 patients atrial fibrillation, cardiac arrest/respiratory arrest, supraventricular extrasystoles, and syncope were reported in patients with chronic phase CML who received the recommended starting dose of ponatinib 45 mg (n = 94).
Hepatotoxicity was reported in 28% (grade 3 or 4, 6%) of patients with chronic phase (CP)-chronic myelogenous leukemia (CML) and 32% (grade 3 or 4, 13%) of patients with CML or acute lymphoblastic leukemia (ALL) who received single-agent ponatinib in 2 clinical trials. Additionally, hepatotoxicity occurred in 66% (grade 3 or 4, 30%) of patients with newly diagnosed ALL who received ponatinib in combination with chemotherapy in a clinical trial. Increased gamma-glutamyl transferase level and decreased fibrinogen level/hypofibrinogenemia were reported also. Monitor liver function tests at baseline and then at least monthly or as clinically indicated during therapy. Therapy interruption, a dosage reduction, or discontinuation may be necessary based on recurrence or the severity of hepatotoxicity. Elevated hepatic enzymes including increased ALT (69%; grade 3 or 4, 21%), AST (53%; grade 3 or 4, 7%), and alkaline phosphatase (44%; grade 3 or 4, 1.2%) levels and hyperbilirubinemia including increased total bilirubin (25%; grade 3 or 4, 0.6%) and direct bilirubin (24%; grade 3 or 4, 4.3%) levels that worsened from baseline were reported in patients with newly diagnosed ALL who received ponatinib in combination with chemotherapy (n = 163) in a randomized trial. The median time to onset of hepatotoxicity was 15 days (range, 1 day to 10 months). Increased ALT (49%; grade 3 or 4, 1.1%), AST (40%), and alkaline phosphatase (23%; grade 3 or 4, 1.1%) levels that worsened from baseline were reported in patients with CP-CML who received the recommended starting dose of ponatinib 45 mg (n = 94) in a clinical trial. The median time to onset of hepatotoxicity was 1.9 months (range, 3 days to 4.1 years). Increased ALT (41%; grade 3 or 4, 6%), AST (35%; grade 3 or 4, 3.6%), and alkaline phosphatase (40%; grade 3 or 4, 2%) levels and hyperbilirubinemia (13%; grade 3 or 4, 0.9%) occurred in patients with CML or ALL who received ponatinib (n = 449) in another clinical trial. Fulminant hepatic failure leading to death occurred in 3 patients in this trial; hepatic failure occurred within 1 week of starting ponatinib in 1 of these patients. The median time to onset of hepatotoxicity was 3.1 months (range, 1 day to 4.9 years).
Pancreatitis was reported in 23% to 34% (grade 3 or 4, 15% to 17%) of patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL) who received ponatinib in clinical trials. Monitor serum lipase levels every 2 weeks for the first 2 months of ponatinib therapy, then monitor serum lipase levels monthly or as clinically indicated; consider additional monitoring in patients with a history of alcoholism or pancreatitis. Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on the severity of serum lipase level elevations. Evaluate patients for pancreatitis when lipase level elevation is accompanied by abdominal symptoms. Increased lipase (60%; grade 3 or 4, 24%) and amylase (25%; grade 3 or 4, 6%) levels that worsened from baseline were reported in patients with newly diagnosed ALL who received ponatinib in combination with chemotherapy (n = 163) in a randomized trial. The median time to onset of pancreatitis was 8 days (range, 1 day to 2 years). Increased lipase levels that worsened from baseline occurred in 34% (grade 3 or 4, 12%) of patients with chronic phase CML who received the recommended starting dose of ponatinib 45 mg (n = 94) in a clinical trial. The median time to onset of pancreatitis was 23 days (range, 3 days to 5.6 months). Increased lipase level (40%; grade 3 or 4, 14%) and increased amylase level/hyperamylasemia (18%; grade 3 or 4, 3.6%) were reported in patients with CML or ALL who received ponatinib (n = 449) in another clinical trial. The median time to onset of pancreatitis was 29 days (range, 1 day to 4 years).
Bleeding was reported in 12% to 31% (grade 3 or 4, 2.1% to 6%) of patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL) who received ponatinib in clinical trials. Monitor patients for signs and symptoms of bleeding and manage as clinically indicated. Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on recurrence or the severity of the bleeding. Intracranial bleeding occurred in 1.2% of patients with newly diagnosed ALL who received ponatinib in combination with chemotherapy (n = 163) in a randomized trial. Subdural hematoma was reported in 1 patient (1%) with chronic phase CML who received the recommended starting dose of ponatinib 45 mg (n = 94) in a clinical trial. GI bleeding and subdural hematoma were each reported in 0.9% of patients with CML or ALL who received ponatinib (n = 449) in another clinical trial. Most serious bleeding events occurred in patients who had grade 4 thrombocytopenia.
Fluid retention was reported in 5% to 33% (grade 3 or 4, 4.5% or less) of patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL) who received ponatinib in clinical trials. Fluid retention included peripheral edema (2.1% to 17%), pleural effusion (2.1% to 9% grade 3 or 4, 1.6% or less), and pericardial effusion (4.2% or less; grade 3 or 4, 1.6% or less). Monitor patients for signs and symptoms of fluid retention and manage as clinically indicated. Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on recurrence or the severity of fluid retention. Peripheral swelling (3.8%) and angioedema (grade 3 or 4, 0.4%) were reported in patients with CML or ALL who received ponatinib (n = 449) in a clinical trial. Fatal cerebral edema occurred in 1 patient in this trial.
Tumor lysis syndrome (TLS) (0.4% to 1.1%) and hyperuricemia (2.1% to 10%) occurred in patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL) who received ponatinib in clinical trials. Monitor uric acid levels. Provide adequate hydration and treat high uric acid levels prior to starting ponatinib therapy.
Gastrointestinal (GI) toxicity has been reported with ponatinib use. GI perforation and gastrointestinal fistula have been reported in postmarketing surveillance of ponatinib. Permanently discontinue ponatinib in patients who develop a GI perforation. GI adverse reactions including abdominal pain (25% to 54%; grade 3 or 4, 3.2% to 13%), anorexia/decreased appetite (8% to 31%; grade 3 or 4, 1.2% or less), constipation (11% to 53%; grade 3 or 4, 3.1% or less), nausea (22% to 37%; grade 3 or 4, 3.1% or less), diarrhea (13% to 29%; grade 3 or 4, 3.2% or less), vomiting (19% to 27%; grade 3 or 4, 1.6% or less), and oral ulceration/mucositis (9% to 24%; grade 3 or 4, 3.1% or less) were reported in patients with chronic myelogenous leukemia or acute lymphoblastic leukemia who received ponatinib in clinical trials. The term abdominal pain included colitis, enteritis, enterocolitis, gastric ulcer, gastritis, gastroenteritis, and gastroesophageal reflux disease. The term mucositis included aphthous ulcer, lip blister, mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, and stomatitis.
Infection including upper respiratory tract infection (3.1% to 14%; grade 3 or 4, 1.6% or less), urinary tract infection (1.6% to 14%; grade 3 or 4, 3.5% or less), naso-pharyngitis (3.1% to 18%), pneumonia (8% to 22%; grade 3 or 4, 4.8% to 16%), cellulitis (13% or less; grade 3 or 4, 4.8% or less), and sepsis (2.6% to 28%; grade 3 or 4, 25% or less) occurred in patients with chronic myelogenous leukemia or acute lymphoblastic leukemia who received ponatinib in clinical trials. Fatal sepsis was reported in 3.7% or less of patients.
Neuropathy was reported in 9% of patients with chronic phase chronic myelogenous leukemia (CML) and 22% (grade 3 or 4, 2.4%) of patients with CML or acute lymphoblastic leukemia (ALL) who received single-agent ponatinib in 2 clinical trials. Additionally, neuropathy occurred in 68% (grade 3 or 4, 3.1%) of patients with newly diagnosed ALL who received ponatinib in combination with chemotherapy in a clinical trial. Monitor patients for symptoms of neuropathy. Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on recurrence or the severity of the neuropathy. In clinical trials, neuropathy included peripheral neuropathy (6% to 33%; grade 3 or 4, 1.8% or less), peripheral sensory neuropathy (12% or less), hypoesthesia (3.6% or less), muscular weakness (2.1% or less), paresthesias (2.1% to 22%), and cranial neuropathy (0.6% to 3%; grade 3 or 4, 0.7% or less). The median times to onset of peripheral neuropathy ranged from 1 day to 4.6 years. The median time to onset of cranial neuropathy ranged from 1 day to 4.2 years.
Cough (6% to 24%) and dyspnea (13% to 23%; grade 3 or 4, 6% or less) were reported in patients with chronic myelogenous leukemia or acute lymphoblastic leukemia who received ponatinib in clinical trials. Additionally, fatal pneumonitis and respiratory failure each occurred in 0.6% of patients with newly diagnosed ALL who received ponatinib in combination with chemotherapy (n = 163) in a randomized trial.
Hypertensive events/hypertension occurred in 32% to 34% (grade 3 or 4, 12% to 14%) of patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL) who received ponatinib in clinical trials. Monitor patient blood pressure prior to and as clinically indicated during treatment. Treat hypertension as appropriate; patients may require urgent clinical intervention if hypertension is associated with confusion, headache, chest pain, or shortness of breath. Therapy interruption, a dosage adjustment, or discontinuation may be necessary if hypertension is not medically controlled. In patients with significant worsening, labile, or treatment-resistant hypertension, interrupt therapy and evaluate for renal artery stenosis. In 2 clinical trials, hypertensive crisis occurred in 3.2% of patients with chronic phase CML who received the recommended starting dose of ponatinib 45 mg (n = 94) and less than 1% of patients with CML or ALL who received ponatinib (n = 449).
Arterial occlusive events (AOEs) were reported in 6% to 26% (grade 3 or 4, 3.7% to 14%) of patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL) who received ponatinib in clinical trials. Monitor patients for evidence of AOEs. Therapy interruption, a dosage reduction, or discontinuation may be necessary based on recurrence or severity. Consider the benefits and risks prior to restarting ponatinib therapy. Cardiovascular (3.1%), cerebrovascular (1.8%), and peripheral vascular (1.2%) AOEs occurred in patients with newly diagnosed ALL who received ponatinib in combination with chemotherapy (n = 163) in a randomized trial. The median time to onset of the first AOE was 11.3 months (range, 8 days to 2.8 years). Grade 3 or 4 AOEs included myocardial infarction (MI) (1.2%), peripheral arterial occlusive disease (1.2%), angina pectoris (0.6%), and cerebrovascular accident/stoke (0.6%). Cardiovascular (7%), cerebrovascular (3%), and peripheral vascular (2.1%) AOEs were reported in patients with chronic phase CML who received the recommended starting dose of ponatinib 45 mg (n = 94) in a clinical trial. The median times to onset of the first cardiovascular, cerebrovascular, or peripheral vascular event were 4.7 months (range, 12 days to 2.1 years), 11.7 months (range, 15 days to 1.6 years), and 3.6 months (range, 23 days to 6.3 months), respectively. Grade 3 or 4 AOEs including MI, acute coronary syndrome, arterial thrombosis, ischemic stroke, ischemic cerebral infarction, and unstable angina each occurred in 1.1% of patients in this trial; AOEs resulted in sudden death were reported in 2.1% of patients. Cardiovascular (15%), cerebrovascular (7%), and peripheral vascular (11%) AOEs occurred in patients with CML or ALL who received ponatinib (n = 449) in another clinical trial. Some patients had recurrent or multi-site vascular occlusions. The median times to onset of the first cardiovascular, cerebrovascular, and peripheral vascular event were 1 year (range, 1 day to 4.1 years), 1.4 years (range, 2 days to 4.5 years), and 2 years (range, 10 days to 4.9 years), respectively. Grade 3 or 4 AOEs including peripheral arterial occlusive disease (3.1%), MI (2%), coronary artery disease (1.6%), and cerebral infarction/stroke (1.6%) occurred in this trial; fatal AOEs including cardiac arrest (0.9%) were reported in 2% of patients. Additionally, some patients developed heart failure during or following a myocardial ischemic event, stenosis over multiple segments in major arterial vessels that supply the brain, digital or distal extremity necrosis (avascular necrosis) requiring amputation, or required revascularization procedures.
Rash and related conditions were reported in 47% (grade 3 or 4, 1.2%) of patients with newly diagnosed acute lymphoblastic leukemia (ALL) who received ponatinib in combination with chemotherapy (n = 163) in a randomized trial. Rash (51%; grade 3 or 4, 3.2%) and xerosis (12%) occurred in patients with chronic phase (CP)-chronic myelogenous leukemia (CML) who received the recommended starting dose of ponatinib 45 mg (n = 94) in a clinical trial. Rash (50% to 75%; grade 3 or 4, 3.1% to 12%), xerosis (% to %; grade 3 or 4, 3.3% or less), and alopecia (6% to 11%) were reported in patients with CP (n = 270), accelerated phase (n = 85), and blast phase (n = 62) CML and ALL (n = 32) who received ponatinib in another clinical trial. Severe cutaneous reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, panniculitis, erythema nodosum) have been reported in postmarketing surveillance of ponatinib.
Arthralgia (30% to 61%; grade 3 or 4, 9% or less), myalgia (6% to 24%; grade 3 or 4, 1.2% or less), muscle cramps/spasms (4.8% to 14%), bone pain (9% to 14%; grade 3 or 4, 0.4% to 3%), and musculoskeletal pain (6% to 11%; grade 3 or 4, 3% or less) were reported in patients with chronic myelogenous leukemia or acute lymphoblastic leukemia who received ponatinib in clinical trials. The term arthralgia included arthritis, back pain, intervertebral disc degeneration, osteoarthritis, pain, neck pain, extremity pain, skin pain, sciatica, spinal pain, tendonitis, and tenosynovitis.
Fatigue or asthenia occurred in 10% to 47% (grade 3 or 4, 1.1% to 8%) of patients with chronic myelogenous leukemia or acute lymphoblastic leukemia who received ponatinib in clinical trials.
Weight loss/decreased weight was reported in 4.8% to 13% (grade 3 or 4, 0.4% or less) of patients with chronic phase (n = 270), accelerated phase (n = 85), and blast phase (n = 62) chronic myelogenous leukemia and acute lymphoblastic leukemia (n = 32) who received ponatinib in a clinical trial.
Insomnia (11% to 13%) and anxiety (4.8% to 18%) were reported in patients with chronic phase (n = 270), accelerated phase (n = 85), and blast phase (n = 62) chronic myelogenous leukemia and acute lymphoblastic leukemia (n = 32) who received ponatinib in a clinical trial.
Fever occurred in 16% to 44% (grade 3 or 4, 1.1% to 7%) of patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL) who received ponatinib in clinical trials. Additionally, chills were reported in 8% to 13% (grade 3 or 4, 1.6% or less) of patients with chronic phase (n = 270), accelerated phase (n = 85), and blast phase (n = 62) CML and ALL (n = 32) who received ponatinib in a clinical trial.
Metabolic and electrolyte abnormalities have been reported in patients with chronic myelogenous leukemia or acute lymphoblastic leukemia who received ponatinib in clinical trials including hypokalemia (44% or less; grade 3 or 4, 10% or less), hyperglycemia (34% to 54%; grade 3 or 4, 1.1% to 7%), hypophosphatemia (27% to 58%; grade 3 or 4, 3.2% to 16%), hypocalcemia (67% or less; grade 3 or 4, 3.1% or less), hyponatremia (32% or less; grade 3 or 4, 4.9% or less), hyperkalemia (31% or less; grade 3 or 4, 3.7% or less), decreased bicarbonate level/metabolic acidosis (27% or less; grade 3 or 4, 0.2% or less), impaired glucose tolerance (20% or less; grade 3 or 4, 4.9% or less), and hypomagnesemia (15% or less; grade 3 or 4, 0.6% or less).
Ocular toxicity occurred in 11% to 33% (grade 3 or 4, 1.1% to 3.6%) of patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL) who received ponatinib in clinical trials. Vision loss/blindness has been reported. The most common ocular toxicities were ocular pain, blurred vision, and xerophthalmia. Perform comprehensive eye exams prior to starting therapy and periodically during treatment. Retinal toxicities (4.3%) including grade 3 retinal vein occlusion (0.6%) and retinal hemorrhage (1.8%) were reported in patients with newly diagnosed ALL who received ponatinib in combination with chemotherapy (n = 163) in a randomized trial. Retinal toxicities including age-related macular degeneration and retinal vein occlusion occurred in 2.1% of patients with chronic phase CML who received the recommended starting dose of ponatinib 45 mg (n = 94) in a clinical trial. Retinal toxicities (3.6%) including macular edema (0.7%), retinal vein occlusion (0.7%), retinal thrombosis with vision loss (0.4%), retinal hemorrhage (0.7%), and vitreous floaters (0.7%) were reported in patients with CML or ALL who received ponatinib (n = 449) in another clinical trial.
Nephrotoxicity, specifically increased serum creatinine level (34% or less; grade 3 or 4, 3.7% or less), was reported in patients with chronic myelogenous leukemia or acute lymphoblastic leukemia (ALL) who received ponatinib in clinical trials. Additionally, acute kidney injury occurred in 4.3% of patients with newly diagnosed ALL who received ponatinib in combination with chemotherapy (n = 163) in a randomized trial.
Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in postmarketing surveillance of ponatinib. Interrupt ponatinib therapy if RPLS is diagnosed; the safety of resuming treatment following symptom resolution is unknown. RPLS may present with signs and symptoms of hypertension, seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances.
Venous thromboembolism/thromboembolic events (VTEs) occurred in 3.5% to 12% (grade 3 or 4, 5.8% or less) of patients with chronic myelogenous leukemia or acute lymphoblastic leukemia who received ponatinib in clinical trials. Therapy interruption, a dosage reduction, or discontinuation may be necessary based on recurrence or severity. VTEs included deep venous thrombosis (6% or less), superficial vein thrombosis (2.5% or less), embolism (1.8% or less), pulmonary embolism (1.8% or less), thrombosis (1.2% or less), superficial thrombo-phlebitis (0.7% or less), and jugular vein thrombosis (0.6% or less).
Dehydration has been reported in postmarketing surveillance of ponatinib.
Thrombotic microangiopathy has been reported in postmarketing surveillance of ponatinib.
Impaired wound healing has been reported in postmarketing surveillance of ponatinib. Hold ponatinib for at least 1 week prior to elective surgery. Do not start or resume ponatinib until at least 2 weeks after major surgery and until adequate wound healing has occurred. The safety of resuming ponatinib therapy after wound healing complications have resolved has not been established.
Endocrine disorders were reported with ponatinib therapy. In 2 clinical trials, hypothyroidism was reported in 3.2% of patients with chronic phase-chronic myelogenous leukemia (CML) who received the recommended starting dose of ponatinib 45 mg (n = 94) and 3% of patients with CML or acute lymphoblastic leukemia who received ponatinib (n = 449). Hyperthyroidism was reported in postmarketing surveillance of ponatinib.
Arterial (including aortic) aneurysms, dissections (aortic dissection), and rupture have been reported in postmarketing surveillance of ponatinib.
Headache occurred in 17% to 45% (grade 3 or 4, 3.3% or less) of patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (CML) who received ponatinib in clinical trials. Additionally, dizziness was reported in 3.1% to 17% (grade 3 or 4, 0.4% or less) of patients with chronic phase (n = 270), accelerated phase (n = 85), and blast phase (n = 62) CML and acute lymphoblastic leukemia (n = 32) who received ponatinib in a clinical trial.
Hyperlipidemia occurred in 3.1% to 28% (grade 3 or 4, 2.1% or less) of patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia who received ponatinib in clinical trials. Additionally, increased triglyceride levels/hypertriglyceridemia (44%; grade 3 or 4, 3.2%) was reported in patients with chronic phase CML who received the recommended starting dose of ponatinib 45 mg (n = 94) in a clinical trial. The term hyperlipidemia included increased blood cholesterol level, increased blood triglycerides level, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, and increased low density lipoprotein level.
Decreased albumin level/hypoalbuminemia occurred in 42% or less (grade 3 or 4, 1.8% or less) of patients with chronic myelogenous leukemia or acute lymphoblastic leukemia who received ponatinib in clinical trials.
Arterial occlusive vascular disease/arterial occlusive events (AOEs) including myocardial infarction, stroke, stenosis of large arterial vessels of the brain, and severe peripheral vascular disease have been reported with ponatinib therapy; some cases required urgent revascularization procedures or were fatal. Monitor patients for evidence of AOEs. Therapy interruption, a dosage reduction, or discontinuation may be necessary based on recurrence or severity. Consider the benefits and risks prior to restarting ponatinib therapy. AOEs have occurred in patients without cardiac risk factors and in patients aged 50 years and younger. However, patients with advanced age, cardiac disease or ischemia, diabetes mellitus, hypercholesterolemia, and high blood pressure may be at increased risk for developing arterial AOEs.
Venous thromboembolism/venous thromboembolic events (VTEs) including deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis have been reported with ponatinib therapy. Monitor patients for evidence of VTEs. Therapy interruption, a dosage reduction, or discontinuation may be necessary based on recurrence or severity.
Hepatotoxicity has been reported with ponatinib therapy; some cases were fatal. Monitor liver function tests at baseline and then at least monthly or as clinically indicated during therapy. An initial dosage reduction is recommended in patients with chronic phase, acute phase, or blast phase CML or Philadelphia chromosome-positive (Ph+) ALL who have baseline hepatic disease (Childs-Pugh class A, B, or C) and receive ponatinib monotherapy. Patients with newly diagnosed Ph+ ALL do not require an initial ponatinib dosage adjustment. Therapy interruption, a dosage reduction, or discontinuation may be necessary based on recurrence or the severity of hepatotoxicity.
Heart failure events including congestive heart failure, decreased ejection fraction, and left ventricular hypertrophy have been reported with ponatinib therapy; some cases were fatal. Monitor patients for signs and symptoms of heart failure and manage as clinically indicated. Therapy interruption, a dosage reduction, or discontinuation may be necessary in patients who develop new or worsening heart failure.
Pancreatitis has been reported with ponatinib therapy. Monitor serum lipase levels every 2 weeks for the first 2 months of ponatinib therapy, then monitor serum lipase levels monthly or as clinically indicated; consider additional monitoring in patients with a history of alcoholism or pancreatitis. Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on the severity of serum lipase level elevations. Evaluate patients for pancreatitis when lipase level elevation is accompanied by abdominal symptoms.
Myelosuppression including neutropenia and thrombocytopenia has been reported with ponatinib therapy. Obtain complete blood counts (CBCs) every 2 weeks for the first 3 months of ponatinib therapy, then monitor CBCs monthly or as clinically indicated. Therapy interruption and a dosage reduction may be necessary in patients who experience severe myelosuppression. Severe myelosuppression occurred more often in patients with accelerated phase or blast phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.
Serious bleeding has been reported with ponatinib therapy, including GI bleeding and subdural hematoma; some cases were fatal. Monitor patients for signs and symptoms of bleeding and mange as clinically indicated. Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on recurrence or the severity of the bleeding event. Serious bleeding events occurred more frequently in patients with accelerated phase or blast phase chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. The majority of serious bleeding events occurred in patients who had grade 4 thrombocytopenia.
Fluid retention events including pleural effusion, pericardial effusion, and cerebral edema have been reported with ponatinib therapy; some cases were fatal. Monitor patients for signs and symptoms of fluid retention and manage as clinically indicated. Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on recurrence or the severity of fluid retention.
Cardiac arrhythmias including atrial fibrillation or flutter, AV block, and QT prolongation have been reported with ponatinib therapy. Monitor patients for signs and symptoms of bradycardia (e.g., fainting, dizziness) or tachycardia (e.g., palpitations, dizziness, and chest pain) and manage as clinically indicated. Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on recurrence or the severity of the cardiac arrhythmia.
Tumor lysis syndrome (TLS) and hyperuricemia have been reported with ponatinib use, particularly in patients with chronic myelogenous leukemia. Monitor uric acid levels. Provide adequate hydration and treat high uric acid levels prior to starting ponatinib therapy.
Impaired wound healing has been reported with ponatinib therapy. Hold ponatinib for at least 1 week prior to elective surgery. Do not start or resume ponatinib until at least 2 weeks after major surgery and until adequate wound healing has occurred. The safety of resuming ponatinib therapy after wound healing complications have resolved has not been established. Gastrointestinal (GI) perforation or fistula has also occurred with ponatinib therapy; permanently discontinue ponatinib in patients who develop GI perforation.
Geriatric patients aged 65 years or older may have a higher incidence of treatment-related adverse events with ponatinib therapy including asthenia, decreased appetite, decreased platelet count, dyspnea, increased lipase levels, muscle spasm, peripheral edema, and vascular occlusion compared with younger patients.
Ocular disease/toxicity including age-related macular degeneration, retinal vein occlusion, and retinal bleeding has been reported with ponatinib therapy. Perform an ophthalmologic exam prior to and periodically during treatment.
Hypertension including hypertensive crisis has been reported with ponatinib therapy. Monitor patient blood pressure prior to and as clinically indicated during treatment. Treat hypertension as appropriate; patients may require urgent clinical intervention. Therapy interruption, a dosage adjustment, or discontinuation may be necessary if hypertension is not medically controlled. In patients with significant worsening, labile, or treatment-resistant hypertension, interrupt therapy and evaluate for renal artery stenosis.
Neurotoxicity including peripheral neuropathy has been reported with ponatinib therapy. Monitor patients for symptoms of neuropathy such as hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, and neuropathic pain or weakness; consider interrupting therapy if neuropathy is suspected.Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on recurrence or the severity of the neuropathy.
Ponatinib may cause fetal harm if used during pregnancy, based on its mechanism of action and data from animal studies. Advise patients of reproductive potential to avoid pregnancy while taking ponatinib. Patients who become pregnant while receiving ponatinib should be apprised of the potential hazard to the fetus. Embryo-fetal toxicity (e.g., increased resorptions, reduced body weight, external alterations, multiple fetal soft tissue and skeletal alterations, and reduced ossification) occurred in rats when ponatinib was administered during organogenesis at doses that were 0.32 times or less the maximum recommended human dose of 45 mg/day.
Counsel patients about the reproductive risk and contraception requirements during ponatinib treatment. Pregnancy testing should be performed prior to starting ponatinib in female patients of reproductive potential. These patients should avoid pregnancy and use effective contraception during and for 3 weeks after the last ponatinib dose. Women who become pregnant while receiving ponatinib should be apprised of the potential hazard to the fetus. Infertility may occur with ponatinib use in females based on animal data. It is not known whether fertility effects are reversible.
It is not known if ponatinib is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in breast-fed infants including arterial occlusion, venous thromboembolism, heart failure, and hepatotoxicity, women should discontinue breast-feeding during ponatinib therapy and for 1 week after the last dose.
For the treatment of chronic myelogenous leukemia (CML):
-for the treatment of T315I-positive CML in chronic phase, accelerated phase, or blast phase:
Oral dosage:
Adults: 45 mg orally once daily until loss of response or unacceptable toxicity; consider discontinuing ponatinib therapy if a response has not occurred by 3 months. The optimal dose of ponatinib has not been established. Consider a dosage reduction for patients with CML in accelerated phase who have achieved a major cytogenetic response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with ponatinib was evaluated in adult patients with chronic phase (CP, n = 267), accelerated phase (AP, n = 83), or blast phase (BP, n = 62) CML whose disease was resistant or intolerant to prior tyrosine kinase inhibitor therapy (dasatinib or nilotinib) or had a T315I-positive mutation in a randomized, open-label, phase 2 trial (PACE trial). After a median follow-up of 40.5 months, major cytogenetic response (MCyR) occurred in 55% of the overall population of patients with CP-CML and in 70% of the cohort of patients with a T315I mutation. A complete cytogenetic response (CCyR) occurred in 46% and 66% of patients, respectively. The median time to MCyR was 3 months; with a minimum follow-up of 60 months, the median duration had not been reached. Treatment with ponatinib resulted in a major hematologic response (MaHR) in 57% of patients with AP-CML (complete hematologic response [CHR], 51%) and in 31% of patients with BP-CML (CHR, 21%). The median time to MaHR was 0.8 months in patients with AP-CML and 1 month in those with BP-CML; the median duration of response was 14 months and 6.4 months, respectively.
-for the treatment of accelerated phase or blast phase CML for whom no other tyrosine kinase inhibitor therapy is indicated:
Oral dosage:
Adults: 45 mg orally once daily until loss of response or unacceptable toxicity; consider discontinuing ponatinib therapy if a response has not occurred by 3 months. The optimal dose of ponatinib has not been established. Consider a dosage reduction for patients with CML in accelerated phase who have achieved a major cytogenetic response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with ponatinib was evaluated in adult patients with chronic phase (CP, n = 267), accelerated phase (AP, n = 83), or blast phase (BP, n = 62) CML whose disease was resistant or intolerant to prior tyrosine kinase inhibitor therapy (dasatinib or nilotinib) or had a T315I-positive mutation in a multinational, open-label, phase 2 trial (PACE trial). After a median follow-up of 40.5 months, major cytogenetic response (MCyR) occurred in 55% of the overall population of patients with CP-CML; and 51% in the cohort of patients with resistance or intolerance to prior TKI therapy. A complete cytogenetic response (CCyR) occurred in 46% and 40% of patients, respectively. The median time to MCyR was 3 months; with a minimum follow-up of 60 months, the median duration had not been reached. Treatment with ponatinib resulted in a major hematologic response (MaHR) in 57% of patients with AP-CML (complete hematologic response [CHR], 51%) and in 31% of patients with BP-CML (CHR, 21%). The median time to MaHR was 0.8 months in patients with AP-CML and 1 month in those with BP-CML; the median duration of response was 14 months and 6.4 months, respectively.
-for the treatment of chronic phase CML in patients with resistance or intolerance to at least 2 prior tyrosine kinase inhibitors:
Oral dosage:
Adults: 45 mg orally once daily; reduce the dose to 15 mg PO once daily upon achievement of 1% or less BCR-ABL1. If loss of response occurs, the dose may be re-escalated to a previously tolerated dose of 30 mg or 45 mg PO once daily; in this case, continue ponatinib until loss of response at the re-escalated dose or unacceptable toxicity. Consider discontinuing ponatinib therapy if a response has not occurred by 3 months. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a dose-optimization trial (the OPTIC trial), patients with chronic phase (CP) CML that was resistant or intolerant to at least 2 prior kinase inhibitors or who have the T315I mutation were treated with ponatinib at starting doses of 15 mg, 30 mg, or 45 mg once daily. After a median follow-up of 27 months, the major efficacy outcome of 1% or less BCR-ABL at 12 months occurred in 48% of patients in the cohort of patients receiving a starting dose of 45 mg per day (n = 93); this rate was unchanged in patients with a T315I mutation. A major cytogenetic response (MCyR) was achieved by 12 months in 49% of patients in the intention-to-treat analysis (n = 91) who received a starting dose of 45 mg once daily. A response was maintained at the reduced dose for at least 90 days in 28 patients and at least 1 year in 18 patients; the median duration of response was not reached.
-for the treatment of newly diagnosed, chronic phase CML*:
Oral dosage:
Adults: Two clinical trials were stopped early due to a concern over an increased risk of ponatinib-related toxicity, particularly vascular thrombotic events and arterial occlusive events in patients with newly diagnosed, chronic phase CML. Ponatinib is not recommended for use in these patients.
For the treatment of acute lymphocytic leukemia (ALL):
-for the treatment of T315I-positive, Philadelphia chromosome-positive ALL (Ph+ ALL):
Oral dosage:
Adults: 45 mg orally once daily until loss of response or unacceptable toxicity; consider discontinuing ponatinib therapy if a response has not occurred by 3 months. The optimal dose of ponatinib has not been established. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with ponatinib was evaluated in adult patients with chronic phase (CP, n = 267), accelerated phase (AP, n = 83), blast phase (BP, n = 62) CML, or Philadelphia chromosome positive (Ph+) ALL (n = 32) whose disease was resistant or intolerant to prior tyrosine kinase inhibitor therapy (dasatinib or nilotinib) or had a T315I-positive mutation in a multinational, open-label, phase 2 trial (PACE trial). Treatment with ponatinib resulted in a major hematologic response (MaHR) in 41% of patients with Ph+ ALL; the rate of complete hematologic response (CHR) was 34%. The median time to MaHR was 0.7 months in patients with Ph+ ALL; the median duration of response was 3.5 months.
-for the treatment of Philadelphia chromosome-positive ALL (Ph+ ALL) for whom no other tyrosine kinase inhibitor therapy is indicated:
Oral dosage:
Adults: 45 mg orally once daily until loss of response or unacceptable toxicity; consider discontinuing ponatinib therapy if a response has not occurred by 3 months. The optimal dose of ponatinib has not been established. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with ponatinib was evaluated in adult patients with chronic phase (CP, n = 267), accelerated phase (AP, n = 83), blast phase (BP, n = 62) CML, or Philadelphia chromosome positive (Ph+) ALL (n = 32) whose disease was resistant or intolerant to prior tyrosine kinase inhibitor therapy (dasatinib or nilotinib) or had a T315I-positive mutation in a multinational, open-label, phase 2 trial (PACE trial). Treatment with ponatinib resulted in a major hematologic response (MaHR) in 41% of patients with Ph+ ALL; the rate of complete hematologic response (CHR) was 34%. The median time to MaHR was 0.7 months in patients with Ph+ ALL; the median duration of response was 3.5 months.
-for the treatment of newly diagnosed Philadelphia chromosome-positive ALL (Ph+ ALL), in combination with chemotherapy:
Oral dosage:
Adults: 30 mg orally once daily in combination with chemotherapy; reduce the dose to 15 mg PO once daily upon achievement of MRD-negative complete response (0.01% BCR-ABL1/ABL1 or less). Continue ponatinib in combination with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Chemotherapy cycles were repeated every 28 days and consisted of the following: Induction (cycles 1, 2, and 3): vincristine 1.4 mg/m2 (Max of 2 mg) IV on days 1 and 14 plus dexamethasone 40 mg/day (or 20 mg/day in patients aged 60 years and older) PO on days 1, 2, 3, and 4 and days 11, 12, 13, and 14; Consolidation with methotrexate (cycles 4, 6, and 8): methotrexate 1,000 mg/m2 (or 250 mg/m2 in patients aged 60 years and older) IV on day 1; Consolidation with cytarabine (cycles 5, 7, and 9): cytarabine 1,000 mg/m2 (or 250 mg/m2 in patients aged 60 years and older) IV every 12 hours on days 1, 3, and 5; Maintenance (cycles 10 to 20): vincristine 1.4 mg/m2 (Max of 2 mg) IV on day 1 plus prednisone 200 mg/day (or 100 mg/day in patients aged 60 to 69 years; or 50 mg/day in patients aged 70 years and older) PO on days 1, 2, 3, 4, and 5. The minimal residual disease (MRD)-negative complete response (CR) rate at the end of induction therapy was significantly higher in 232 patients with newly diagnosed Ph+ALL and a baseline BCR-ABL1/ABL1 dominant variant of p190 or p210 who received ponatinib plus chemotherapy compared with imatinib plus chemotherapy (30% vs. 12%; p-value = 0.0004) in a randomized (2:1), open-label, phase 3 (PhALLCON) trial. Additionally, 79% of patients in the ponatinib arm and 63% of patients in the imatinib arm (n = 39/81) achieved a CR; the overall rate of hematopoietic stem-cell transplant was 34% (n = 56/164) and 48% (n = 39/81), respectively. In this study, 37% of patients were aged 60 years or older.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities
Interrupt ponatinib therapy per specific instructions below. Restart ponatinib as appropriate at the following reduced doses:
Chronic Phase CML:
-First dose reduction: 30 mg PO once daily.
-Second dose reduction: 15 mg PO once daily.
-Third dose reduction: 10 mg PO once daily.
-Subsequent dose reduction: Permanently discontinue ponatinib therapy in patients unable to tolerate a dose of 10 mg once daily.
Acute Phase or Blast Phase CML, or Philadelphia Chromosome-positive ALL (monotherapy):
-First dose reduction: 30 mg PO once daily.
-Second dose reduction: 15 mg PO once daily.
-Subsequent dose reduction: Permanently discontinue ponatinib therapy in patients unable to tolerate a dose of 15 mg once daily.
Newly Diagnosed Ph+ ALL (with chemotherapy):
-First dose reduction: 15 mg PO once daily.
-Second dose reduction: 10 mg PO once daily.
-Subsequent dose reduction: Permanently discontinue ponatinib therapy in patients unable to tolerate a dose of 10 mg once daily.
Arterial Occlusive Event (AOE)
-Grade 1: Hold ponatinib therapy. Upon resolution of the AOE, resume treatment with ponatinib at the same dose.
-Grade 2: Hold ponatinib therapy for a first occurrence of grade 2 AOE. Upon resolution to grade 1 or less, resume treatment at the next lower dose for the first occurrence of cardiovascular or cerebrovascular AOEs; discontinue ponatinib for a recurrence. For the first occurrence of a peripheral vascular or other AOE, resume treatment at the same dose upon resolution to grade 1 or less; decrease the ponatinib dose to the next lower dose level for a recurrence.
-Grade 3: Discontinue ponatinib therapy for grade 3 cardiovascular or cerebrovascular AOEs. Hold ponatinib therapy for a first occurrence of grade 2 peripheral vascular or other AOE. Upon resolution to grade 1 or less, resume treatment at the next lower dose; discontinue ponatinib for a recurrence.
-Grade 4: Discontinue ponatinib therapy.
Heart Failure
-Grade 2 or 3: Hold ponatinib therapy. For the first occurrence, resume treatment at the next lower dose upon resolution to grade 1 or less; discontinue ponatinib for a recurrence.
-Grade 4: Discontinue ponatinib therapy.
Myelosuppression
-ANC less than 1,000 cells/mm3 or platelets less than 50,000 cells/mm3: Hold ponatinib therapy. For the first occurrence, resume treatment with ponatinib at the same dose when the ANC is at least 1,500 cells/mm3 and the platelet count is at least 75,000 cells/mm3; decrease the ponatinib dose to the next lower dose level for a recurrence.
Pancreatitis or Elevated Serum Lipase
-Serum lipase 1.1 to 1.5 times ULN: Consider interrupting ponatinib therapy. Upon resolution, resume treatment at the same dose.
-Serum lipase 1.6 to 2 times ULN; serum lipase 2.1 to 5 times ULN and asymptomatic; or asymptomatic radiologic pancreatitis: Hold ponatinib therapy. Upon resolution to grade 1 or less (lipase concentration less than 1.5 times ULN), resume treatment with ponatinib at the next lower dose.
-Serum lipase 2.1 to 5 times ULN and symptomatic; or serum lipase greater than 5 times ULN and asymptomatic: Hold ponatinib therapy. Upon complete resolution of symptoms and after recovery of lipase concentrations to grade 1 or less, resume treatment with ponatinib at the next lower dose.
-Serum lipase greater than 5 times ULN and symptomatic pancreatitis: Discontinue ponatinib therapy.
-Grade 2 pancreatitis: Hold ponatinib therapy. For the first occurrence, resume treatment at the next lower dose upon resolution to grade 1 or less; discontinue ponatinib for a recurrence.
-Grade 3 pancreatitis: Hold ponatinib therapy. For the first occurrence, resume treatment at the next lower dose upon resolution to grade 1 or less and complete resolution of symptoms; discontinue ponatinib for a recurrence.
-Grade 4 pancreatitis: Discontinue ponatinib for a recurrence.
Venous Thromboembolic Event
-Grade 1: Hold ponatinib therapy. Upon resolution, resume treatment with ponatinib at the same dose.
-Grade 2: Hold ponatinib therapy. For the first occurrence, resume treatment at the same dose upon resolution to grade 1 or less; decrease the ponatinib dose to the next lower dose level for a recurrence.
-Grade 3: Hold ponatinib therapy. For the first occurrence, resume treatment at the next lower dose upon resolution to grade 1 or less; discontinue ponatinib for a recurrence.
-Grade 4: Discontinue ponatinib therapy.
Other Nonhematologic Adverse Reactions
-Grade 1: Hold ponatinib therapy. Upon resolution, resume treatment with ponatinib at the same dose.
-Grade 2: Hold ponatinib therapy. For the first occurrence, resume treatment at the same dose upon resolution to grade 1 or less; decrease the ponatinib dose to the next lower dose level for a recurrence.
-Grade 3 or 4: Hold ponatinib therapy. For the first occurrence, resume treatment at the next lower dose upon resolution to grade 1 or less; discontinue ponatinib for a recurrence.
Maximum Dosage Limits:
-Adults
45 mg/day PO.
-Geriatric
45 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
Chronic Phase CML, Acute Phase or Blast Phase CML, or Philadelphia Chromosome-positive ALL (monotherapy):
Mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C): Reduce the starting dose to 30 mg PO once daily.
Newly Diagnosed Ph+ ALL (with chemotherapy):
Mild hepatic impairment (Child-Pugh A): No initial dosage adjustment necessary.
Moderate or severe hepatic impairment (Child-Pugh B or C): No initial dosage adjustment necessary. Monitor patients for adverse drug reactions (ADR) and dose adjust as recommended if ADRs occur.
Treatment-Related Hepatotoxicity
-AST or ALT levels more than 3 times the ULN: Hold ponatinib therapy. Upon resolution to grade 1 or less, resume treatment at the next lower dose.
-AST or ALT levels at least 3 times the ULN concurrent with bilirubin level greater than 2 times the ULN and alkaline phosphatase level less than 2 times ULN: Discontinue ponatinib therapy.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no initial dosage adjustments are needed.
*non-FDA-approved indication
Adagrasib: (Major) Avoid coadministration of ponatinib and adagrasib due to the potential for increased ponatinib exposure. If concurrent use is necessary, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of adagrasib and consider alternative therapy. After adagrasib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting adagrasib. Ponatinib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the ponatinib AUC by 78%.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of ponatinib and clarithromycin due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of clarithromycin and consider alternative therapy. After clarithromycin has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting clarithromycin. Ponatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Apalutamide: (Major) Avoid coadministration of ponatinib with apalutamide if possible due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Atazanavir: (Major) Avoid coadministration of ponatinib and atazanavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of atazanavir and consider alternative therapy. After atazanavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting atazanavir. Ponatinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Atazanavir; Cobicistat: (Major) Avoid coadministration of ponatinib and atazanavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of atazanavir and consider alternative therapy. After atazanavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting atazanavir. Ponatinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%. (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Carbamazepine: (Major) Avoid coadministration of ponatinib with carbamazepine due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Ceritinib: (Major) Avoid coadministration of ponatinib and ceritinib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ceritinib and consider alternative therapy. After ceritinib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ceritinib. Ponatinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Chloramphenicol: (Major) Avoid coadministration of ponatinib and chloramphenicol due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of chloramphenicol and consider alternative therapy. After chloramphenicol has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting chloramphenicol. Ponatinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Chloroquine: (Moderate) Concurrent use of chloroquine and ponatinib is not recommended as there is an increased risk of retinal toxicity.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clarithromycin: (Major) Avoid coadministration of ponatinib and clarithromycin due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of clarithromycin and consider alternative therapy. After clarithromycin has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting clarithromycin. Ponatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Cobicistat: (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Darunavir: (Major) Avoid coadministration of ponatinib and darunavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of darunavir and consider alternative therapy. After darunavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting darunavir. Ponatinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Darunavir; Cobicistat: (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%. (Major) Avoid coadministration of ponatinib and darunavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of darunavir and consider alternative therapy. After darunavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting darunavir. Ponatinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%. (Major) Avoid coadministration of ponatinib and darunavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of darunavir and consider alternative therapy. After darunavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting darunavir. Ponatinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Delavirdine: (Major) Avoid coadministration of ponatinib and delavirdine due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of delavirdine and consider alternative therapy. After delavirdine has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting delavirdine. Ponatinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Encorafenib: (Major) Avoid coadministration of ponatinib with encorafenib due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ponatinib exposure by 62%.
Enzalutamide: (Major) Avoid coadministration of ponatinib with enzalutamide if possible due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Fosamprenavir: (Major) Avoid coadministration of ponatinib and fosamprenavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of fosamprenavir and consider alternative therapy. After fosamprenavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting fosamprenavir. Ponatinib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Fosphenytoin: (Major) Avoid coadministration of ponatinib with fosphenytoin due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Grapefruit juice: (Major) Instruct patients to avoid grapefruit or grapefruit juice with ponatinib due to the potential for increased ponatinib exposure and subsequent toxicity. Ponatinib is a CYP3A4 substrate; grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Idelalisib: (Major) Avoid coadministration of ponatinib and idelalisib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of idelalisib and consider alternative therapy. After idelalisib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting idelalisib. Ponatinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Indinavir: (Major) Avoid coadministration of ponatinib and indinavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of indinavir and consider alternative therapy. After indinavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting indinavir. Ponatinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of ponatinib with rifampin due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased ponatinib exposure by 62%.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of ponatinib with rifampin due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased ponatinib exposure by 62%.
Itraconazole: (Major) Avoid coadministration of ponatinib and itraconazole due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of itraconazole and consider alternative therapy. After itraconazole has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting itraconazole. Ponatinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Ketoconazole: (Major) Avoid coadministration of ponatinib and ketoconazole due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ketoconazole and consider alternative therapy. After ketoconazole has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ketoconazole. Ponatinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the ponatinib AUC by 78%.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of ponatinib and clarithromycin due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of clarithromycin and consider alternative therapy. After clarithromycin has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting clarithromycin. Ponatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Letermovir: (Moderate) Avoid coadministration of ponatinib and letermovir in patients who are also taking cyclosporine due to the potential for increased ponatinib exposure; ponatinib may be taken with letermovir in patients who are not taking cyclosporine. If concurrent use of ponatinib and letermovir in combination with cyclosporine cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of letermovir with cyclosporine and consider alternative therapy. After cyclosporine has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting letermovir with cyclosporine. Ponatinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Levoketoconazole: (Major) Avoid coadministration of ponatinib and ketoconazole due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ketoconazole and consider alternative therapy. After ketoconazole has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ketoconazole. Ponatinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the ponatinib AUC by 78%.
Lonafarnib: (Major) Avoid coadministration of ponatinib and lonafarnib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of lonafarnib and consider alternative therapy. After lonafarnib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting lonafarnib. Ponatinib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Lopinavir; Ritonavir: (Major) Avoid coadministration of ponatinib and ritonavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ritonavir and consider alternative therapy. After ritonavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ritonavir. Ponatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of ponatinib with lumacaftor due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of ponatinib with lumacaftor due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Mifepristone: (Major) Avoid coadministration of ponatinib and mifepristone due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of mifepristone and consider alternative therapy. After mifepristone has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting mifepristone. Ponatinib is a CYP3A4 substrate; mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
Mitotane: (Major) Avoid coadministration of ponatinib with mitotane due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Nefazodone: (Major) Avoid coadministration of ponatinib and nefazodone due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of nefazodone and consider alternative therapy. After nefazodone has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting nefazodone. Ponatinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Nelfinavir: (Major) Avoid coadministration of ponatinib and nelfinavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of nelfinavir and consider alternative therapy. After nelfinavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting nelfinavir. Ponatinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of ponatinib and ritonavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ritonavir and consider alternative therapy. After ritonavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ritonavir. Ponatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Phenobarbital: (Major) Avoid coadministration of ponatinib with phenobarbital due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of ponatinib with phenobarbital due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Phenytoin: (Major) Avoid coadministration of ponatinib with phenytoin due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Posaconazole: (Major) Avoid coadministration of ponatinib and posaconazole due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of posaconazole and consider alternative therapy. After posaconazole has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting posaconazole. Ponatinib is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Primidone: (Major) Avoid coadministration of ponatinib with primidone due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Ribociclib: (Major) Avoid coadministration of ponatinib and ribociclib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ribociclib and consider alternative therapy. After ribociclib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ribociclib. Ponatinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Ribociclib; Letrozole: (Major) Avoid coadministration of ponatinib and ribociclib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ribociclib and consider alternative therapy. After ribociclib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ribociclib. Ponatinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Rifampin: (Major) Avoid coadministration of ponatinib with rifampin due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased ponatinib exposure by 62%.
Rifapentine: (Major) Avoid coadministration of ponatinib with rifapentine due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Ritonavir: (Major) Avoid coadministration of ponatinib and ritonavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ritonavir and consider alternative therapy. After ritonavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ritonavir. Ponatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Saquinavir: (Major) Avoid coadministration of ponatinib and saquinavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of saquinavir and consider alternative therapy. After saquinavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting saquinavir. Ponatinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of ponatinib with St. Johns Wort due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Tipranavir: (Major) Avoid coadministration of ponatinib and tipranavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of tipranavir and consider alternative therapy. After tipranavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting tipranavir. Ponatinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Tucatinib: (Major) Avoid coadministration of ponatinib and tucatinib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of tucatinib and consider alternative therapy. After tucatinib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting tucatinib. Ponatinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of ponatinib and clarithromycin due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of clarithromycin and consider alternative therapy. After clarithromycin has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting clarithromycin. Ponatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Voriconazole: (Major) Avoid coadministration of ponatinib and voriconazole due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of voriconazole and consider alternative therapy. After voriconazole has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting voriconazole. Ponatinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Ponatinib is an oral multi-tyrosine kinase inhibitor (TKI). In vitro, ponatinib inhibits BCR-ABL (IC50 concentration, 0.4 nanomolar) and T315I-mutant BCR-ABL (IC50 concentration, 2 nanomolar) in addition to other tyrosine kinase proteins such as VEGFR, PDGFR, FGFR, EPH, Src family kinases, KIT, RET, FLT-3, and TIE-2 (IC50 concentration range, 0.1 to 20 nanomolar) that promote the growth and development of cancer cells. In tumor cells with native or mutant BCR-ABL, including T315I mutant ABL, ponatinib inhibited growth in vitro and resulted in reduced tumor size in mice models. The Philadelphia chromosome encodes for the BCR-ABL oncogene and is found in most chronic myelogenous leukemia cells. A common mutation occurs in the kinase domain caused by a substitution of a threonine residue with isoleucine at amino acid position 315 (T315I mutation). This mutation causes drug resistance to imatinib and some second generation TKI agents such as nilotinib and dasatinib. The T315I mutation prevents the formation of an important hydrogen bond between TKI agents and T315 of the BCR-ABL molecule. Ponatinib was designed to bind while allowing for the accommodation of the bulky isoleucine side chain. It also has activity against several other BCR-ABL mutations including the E255K, Y253H, and G250E mutations.
Ponatinib is administered orally. It is greater than 99% bound to plasma proteins in vitro. The mean apparent steady-state volume of distribution was 1,223 liters (CV, 102%) and the mean terminal elimination half-life was approximately 24 hours (range, 12 to 66 hours) in patients with cancer. At least 64% of each ponatinib dose undergoes Phase I and Phase II metabolism. Following a single oral dose of radiolabeled ponatinib, about 87% of the total radioactivity was recovered in the feces and about 5% was recovered in the urine.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP3A5, CYP2C8, CYP2D6, P-gp, BCRP
Ponatinib is a CYP3A substrate. It is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and CYP3A5; it is also metabolized by esterases and/or amidases. In vitro, ponatinib is a weak P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate and inhibits P-gp, BCRP, and bile salt export pump (BSEP).
-Route-Specific Pharmacokinetics
Oral Route
The absolute bioavailability of ponatinib is not known. Ponatinib exhibited dose-proportional increases in steady-state Cmax and AUC over a dose range of 2 to 60 mg in patients with cancer. Following a single oral dose of ponatinib, the time to peak plasma concentration (Tmax) was 6 hours. In patients with advanced hematologic malignancies who received oral ponatinib 45 mg/day, the steady-state mean Cmax and AUC values were 73 nanograms (ng)/mL and 1,253 ng x hour/mL, respectively; median exposure increased by about 90% (range, 20% to 440%) between the first dose and steady-state. In patients with advanced hematologic malignancies who received oral ponatinib 30 mg/day, the steady-state mean Cmax and AUC values were 65 ng/mL and 1,080 ng x hour/mL, respectively.
Effect of Food: The Cmax and AUC of ponatinib were not different when ponatinib was administered with a high-fat (900 to 1,000 calories; approximately 60% to 67% fat) or low-fat meal (547 calories; approximately 11% to 12% fat) compared with fasting conditions in 22 healthy subjects. Administration with multiple doses of a proton pump inhibitor decreased the AUC of ponatinib by 6% and decreased the Cmax by 25%.
-Special Populations
Hepatic Impairment
There was no trend of increased ponatinib exposure in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C) compared to subjects with normal hepatic function after a single 30 mg dose. However, subjects with hepatic impairment had an increased incidence of adverse reactions (e.g., gastrointestinal disorders including a case of severe pancreatitis).
Renal Impairment
Mild to moderate renal impairment (CrCl 30 to 89 mL/min) does not have a clinically significant effect on the pharmacokinetics of ponatinib. Although renal excretion is not a major route of ponatinib elimination, the potential for severe renal impairment to affect hepatic elimination has not been determined; ponatinib has not been studied in patients with severe renal impairment.
Geriatric
Age (19 to 85 years) does not have a clinically significant effect on the pharmacokinetics of ponatinib.
Obesity
Body weight (41 kg to 152 kg) does not have a clinically significant effect on the pharmacokinetics of ponatinib.