ponatinib

Action and Spectrum

Actions and Spectrum: 

ponatinib is a medication used to treat certain types of leukemia, including chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is a tyrosine kinase inhibitor that works by blocking the activity of certain enzymes called tyrosine kinases, which are involved in the growth and survival of cancer cells. 

ponatinib has a broad spectrum of activity against various tyrosine kinases, including BCR-ABL, the abnormal protein produced by the Philadelphia chromosome in CML and Ph+ ALL. It also inhibits other tyrosine kinases that play a role in cancer cell growth, such as FLT3, KIT, and PDGFR. By targeting these enzymes, ponatinib can help slow down or stop the growth of cancer cells, leading to improved outcomes for patients with leukemia. 

Drug Interaction

Adverse Reaction

Frequency defined:  

>10% 

Hypertension  

Neutropenia  

Leukopenia  

Anemia  

Thrombocytopenia  

Rash  

Abdominal pain  

Constipation 

Fatigue or asthenia  

Headache  

Dry skin  

Lymphopenia  

Pyrexia  

Nausea  

Arthralgia  

Decreased appetite  

Diarrhea  

Febrile neutropenia  

Vomiting  

Oral mucositis  

Peripheral edema  

Sepsis 

Dyspnea  

Pleural effusion  

Cough 

Pain in extremity  

Back pain  

Pain  

Cardiac failure  

Chills  

Peripheral neuropathy  

Muscle spasms  

Weight decreased  

Arterial ischemia  

Pneumonia  

Bone pain  

Urinary tract infection  

Insomnia  

Nasopharyngitis  

Upper respiratory tract infection  

Dizziness  

Gastro-intestinal hemorrhage  

Cellulitis   

<1% 

Change in hair color 

Increased glucose 

Nausea 

Thrombocytopenia 

Cough 

Hyperpigmentation 

Black Box Warning

Black-Box Warning: 

These are some of the important warnings associated with the use of ponatinib: 

Arterial occlusive events: 

ponatinib has been associated with arterial occlusive events (AOEs), including fatal myocardial infarction, stroke, and severe peripheral vascular disease. These events have occurred in patients both with and without cardiovascular risk factors, including young patients aged 50 years or younger. It is recommended to monitor patients for signs of AOEs and to interrupt or discontinue treatment based on severity. The decision to restart therapy should be based on an assessing the benefit-risk profile. 

Thromboembolism: 

ponatinib has also been associated with thromboembolic events such as deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with vision loss. Patients should be monitored for signs of thromboembolism, and treatment should be interrupted or stopped if serious venous thromboembolism occurs. Dose modification or discontinuation should be considered. 

Heart failure: 

Heart failure has occurred in 9% of treated patients. Cardiac function should be monitored, and treatment should be interrupted or stopped for new or worsening heart failure. 

Hepatotoxicity: 

ponatinib can cause hepatotoxicity, liver failure, and death. Hepatic function should be monitored before and during treatment, and treatment should be interrupted and then reduced or discontinued for hepatotoxicity. 

Contraindication / Caution

Contraindication/Caution: 

Contraindications: 

• Hypersensitivity to ponatinib or any of its components 
• Pregnancy or breastfeeding 

Cautions: 

• Patients with liver or kidney disease may require dose adjustments or monitoring 
• Patients with a history of pancreatitis or risk factors for pancreatitis (such as heavy alcohol use or high levels of triglycerides) may be at increased risk of developing pancreatitis while taking ponatinib 
• Patients with cardiovascular disease, including hypertension and a history of thrombosis or ischemic heart disease, may be at increased risk of cardiovascular events while taking ponatinib 
• ponatinib may interact with other medications, so it is essential to inform the doctor of all medications being taken, including prescription, over-the-counter, and herbal supplements 

Pregnancy / Lactation

Pregnancy consideration: The drug is toxic and unsafe for pregnant women and the developing fetus.  

Breastfeeding warnings: No data on the excretion of ponatinib in breast milk is available. Because of possible serious effects, women are advised to breastfeed six days after the last dose of ponatinib. 

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no affirmation of risk to the fetus found in animal reproduction studies, and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for a product in humans; Pregnant women must take care of the potential risks. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms. However, despite potential dangers may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits. The drug is not for pregnant women. 
• Category N: No data is available for the drug under this category. 

Pharmacology

Pharmacology: 

ponatinib is a tyrosine kinase inhibitor (TKI) used to treat certain types of leukemia. It works by blocking the activity of several tyrosine kinases, including BCR-ABL, associated with chronic myeloid leukemia (CML), and other mutated tyrosine kinases associated with acute lymphoblastic leukemia (ALL). 

Pharmacodynamics: 

The pharmacodynamics of ponatinib involve its inhibition of multiple kinases, which ultimately leads to the suppression of cancer cell growth and proliferation. The BCR-ABL kinase is a fusion protein formed because of the Philadelphia chromosome translocation, which is present in most CML patients and approximately 25% of Ph+ ALL patients. Ponatinib binds to the BCR-ABL kinase and prevents it from initiating downstream signaling pathways that promote cancer cell survival and growth. 

Pharmacokinetics: 

Absorption 

Bioavailability is unknown 

Peak plasma concentration is achieved in 6 hours 

The peak plasma concentration is 73 ng/mL or (45 mg/day) 

The area under the curve is 1253 mcg•h/mL (45 mg/day) 

Distribution 

The protein-bound is more than 99% 

The volume of distribution is 1223L (a steady state at day 28) 

Metabolism 

The drug is metabolized predominantly by CYP3A4, and to a lesser extent by CYP3A5, CYP2C8 and CYP2D6  

Elimination and Excretion 

The half-life is 24 hours (ranging from 12-66 hours) 

The drug is excreted 87% in feces and 5% in urine 

Adminstartion

Administration: 

ponatinib is administered orally in the form of tablets. The recommended starting dose of ponatinib for treating chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is 45 mg once daily, with or without food. 

The tablets should be swallowed whole with water and not crushed or chewed. If a dose is missed, it should be taken as soon as possible unless it is within 12 hours of the next scheduled dose, in which case the missed dose should be skipped. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: ponatinib 

Why do we use ponatinib? 

Adults with recently discovered acute lymphoblastic leukemia that is positive for the Philadelphia chromosome are treated with ponatinib. 

It can also be administered as a monotherapy in cases when a T315I-positive mutation is present or when no other kinase inhibitors are recommended. 

Ponatinib is used in the treatment of chronic myleloid leukemia (CML) with resistance or intolerance.