Ponatinib is a medication that belongs to a class of drugs called tyrosine kinase inhibitors (TKIs). It is primarily used for the treatment of certain types of leukemia, specifically chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL).

Ponatinib is specifically designed to target and inhibit an abnormal protein called BCR-ABL, which is created by a genetic mutation in some leukemia cells. This mutation causes the overproduction of abnormal white blood cells, leading to the progression of leukemia. By inhibiting the BCR-ABL protein, ponatinib helps to slow down or stop the growth and division of these cancer cells.

Ponatinib (Iclusig) Uses:

• Acute lymphoblastic leukemia:
  • Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in patients for whom no other tyrosine kinase inhibitor therapy is indicated or who are T315I-positive.
• Chronic myeloid leukemia:
  • Treatment of chronic myeloid leukemia (CML) in chronic, accelerated, or blast phase in patients for whom no other tyrosine kinase inhibitor therapy is indicated or who are T315I-positive.
• Limitations of use: 
  • Ponatinib is not indicated for the treatment of newly diagnosed chronic phase of CML.

Ponatinib (Iclusig) Dose in Adults

Note:

• Ponatinib is a medicine used to treat certain types of leukemia.
•  It works by targeting and blocking an abnormal protein in cancer cells.
•  The dosage of ponatinib is not yet determined, and if there is no improvement after 3 months of treatment, it may be stopped.

Ponatinib (Iclusig) Dose in the treatment of Acute lymphoblastic leukemia (ALL):

• In the treatment of Acute lymphoblastic leukemia (ALL), Philadelphia chromosome-positive (Ph+), T315I-positive, or in patients who are not eligible for other tyrosine kinase inhibitor therapy, the initial recommended dose of Ponatinib is 45 mg taken orally once daily.

Ponatinib (Iclusig) Dose in the treatment of Chronic myeloid leukemia (CML; chronic, accelerated, or blast phase):

• In the treatment of Chronic myeloid leukemia (CML) in chronic, accelerated, or blast phase, specifically for patients who are T315I-positive or for whom no other tyrosine kinase inhibitor therapy is indicated, the initial recommended dose of Ponatinib is 45 mg taken orally once daily.
• However, for patients in the chronic or accelerated phase of CML who have achieved a major cytogenetic response, the dose may be reduced.

Note: This drug is not recommended for treatment of newly diagnosed chronic phase CML.

Dosage adjustment for strong CYP3A inhibitors:

• If Ponatinib is administered concurrently with strong CYP3A inhibitors (such as boceprevir, clarithromycin, grapefruit juice, itraconazole, ketoconazole, ritonavir, etc.), the dose of Ponatinib should be reduced to 30 mg once daily.

Use in Children:

Not indicated.   

Pregnancy Risk Category: D

• Ponatinib can be harmful to unborn babies, based on studies with animals and how it works in the body.
•  So, it's important to confirm if a woman is pregnant before starting ponatinib treatment.
• Women who can have children should use reliable birth control methods while taking ponatinib and for three weeks after stopping the medication to avoid pregnancy.
• This is to ensure the safety of both the woman and potential unborn child.

Use Ponatinib while breastfeeding

• The presence of ponatinib in breast milk is currently unknown.
• However, as there is a risk of serious adverse reactions in nursing infants, the manufacturer advises that breastfeeding should be stopped while undergoing ponatinib treatment and for six days after the last dose.
• This recommendation is made to protect the well-being of the nursing infant.

Ponatinib (Iclusig) Dose in Kidney Disease:

• The manufacturer's labeling for ponatinib does not provide specific dosage adjustments based on renal function.
• This is because renal excretion is not a significant route of elimination for ponatinib.
• The medication is primarily metabolized and eliminated through other pathways in the body.

Ponatinib (Iclusig) Dose in Liver disease:

Hepatic impairment prior to treatment initiation:

• If a person has mild-to-severe liver impairment (Child-Pugh class A, B, or C) before starting ponatinib, the initial recommended dose is 30 mg once daily.
• It's important to closely monitor for any signs of toxicity in these individuals.

Hepatotoxicity during treatment:

• If the liver enzyme levels (AST or ALT) increase to more than three times the upper limit of normal (≥ Grade 2) during treatment with a dose of 45 mg daily, the therapy should be temporarily stopped. Once the enzyme levels recover to grade 1 or lower (<3 times ULN), the treatment can be resumed with a reduced dose of 30 mg daily.
• If the liver enzyme levels increase to grade 2 or higher at a dose of 30 mg daily, the therapy should be interrupted. After the enzyme levels recover to grade 1 or lower, the treatment can be resumed with a further reduced dose of 15 mg daily.
• If the liver enzyme levels increase to grade 2 or higher at a dose of 15 mg daily, the therapy should be discontinued.
• In cases where the ALT or AST levels are three times the upper limit of normal or higher, along with bilirubin levels more than two times the upper limit of normal, and alkaline phosphatase levels less than two times the upper limit of normal, the therapy should be discontinued.

Common Side Effects of Ponatinib (Iclusig):

• Cardiovascular:
  • Hypertension
  • Arterial Ischemia
  • Peripheral Vascular Disease
  • Arterial Embolism
  • Cerebral Ischemia
  • Cerebrovascular Accident
  • Myocardial Infarction
  • Peripheral Edema
  • Coronary Occlusion
  • Occlusive Arterial Disease
  • Cardiac Arrhythmia
  • Cardiac Failure
  • Hypertensive Crisis
  • Mesenteric Artery Occlusion
  • Peripheral Arterial Disease
• Central Nervous System:
  • Fatigue
  • Headache
  • Peripheral Neuropathy
  • Pain
  • Dizziness
  • Insomnia
  • Chills
• Dermatologic:
  • Skin Rash
  • Xeroderma
  • Pruritus
  • Cellulitis
  • Alopecia
• Endocrine & Metabolic:
  • Increased Serum Glucose
  • Decreased Serum Phosphate
  • Fluid Retention
  • Decreased Serum Calcium
  • Decreased Serum Albumin
  • Decreased Serum Sodium
  • Decreased Serum Bicarbonate
  • Increased Serum Potassium
  • Decreased Serum Potassium
  • Decreased Serum Glucose
  • Weight Loss
  • Increased Serum Calcium
• Gastrointestinal:
  • Constipation
  • Abdominal Pain
  • Increased Serum Lipase
  • Nausea
  • Decreased Appetite
  • Vomiting
  • Diarrhea
  • Stomatitis
  • Increased Serum Amylase
• Genitourinary:
  • Urinary Tract Infection
• Hematologic & Oncologic:
  • Leukopenia
  • Bone Marrow Depression
  • Neutropenia
  • Anemia
  • Thrombocytopenia
  • Lymphocytopenia
  • Hemorrhage
  • Febrile Neutropenia
• Hepatic:
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Alkaline Phosphatase
  • Increased Serum Aspartate Aminotransferase
  • Hepatotoxicity
  • Increased Serum Bilirubin
• Infection:
  • Sepsis
• Neuromuscular & Skeletal:
  • Arthralgia
  • Myalgia
  • Limb Pain
  • Back Pain
  • Ostealgia
  • Muscle Spasm
  • Musculoskeletal Pain
• Ophthalmic:
  • Conjunctival Edema
  • Conjunctival Hemorrhage
  • Conjunctival Hyperemia
  • Conjunctival Irritation
  • Conjunctivitis
  • Corneal Abrasion
  • Corneal Erosion
  • Dry Eye Syndrome
  • Eye Pain
• Renal:
  • Increased Serum Creatinine
• Respiratory:
  • Cough
  • Dyspnea
  • Pleural Effusion
  • Nasopharyngitis
  • Pneumonia
  • Upper Respiratory Tract Infection
• Miscellaneous:
  • Fever

Less Common Side Effects of Ponatinib (Iclusig):

• Cardiovascular:
  • Left Ventricular Dysfunction
  • Atrial Fibrillation
  • Venous Thromboembolism
  • Pericardial Effusion
  • Reduced Ejection Fraction
  • Deep Vein Thrombosis
  • Pulmonary Embolism
  • Syncope
  • Retinal Vein Occlusion
  • Subdural Hematoma
• Central Nervous System:
  • Paresthesia
  • Hypoesthesia
  • Cranial Nerve Palsy
  • Myasthenia
  • Cerebral Hemorrhage
  • Hyperesthesia
• Dermatologic:
  • Erythema
• Endocrine & Metabolic:
  • Increased Serum Sodium
  • Hyperuricemia
  • Increased Serum Triglycerides
• Gastrointestinal:
  • Gastrointestinal Hemorrhage
  • Pancreatitis
  • Dysgeusia
• Hematologic & Oncologic:
  • Major Hemorrhage
• Hepatic:
  • Ascites
• Ophthalmic:
  • Blurred Vision
  • Macular Edema
  • Retinal Hemorrhage

Rare Side effects of Ponatinib (Iclusig):

• Genitourinary:
  • Decreased Renal Blood Flow
• Hepatic:
  • Hepatic Failure
• Ophthalmic:
  • Blepharitis
  • Cataract
  • Corneal Ulcer
  • Eyelid Edema
  • Glaucoma
  • Iridocyclitis
  • Iritis
  • Ocular Hyperemia
  • Periorbital Edema

Contraindications to Ponatinib (Iclusig):

Manufacturer's US labeling: The manufacturer's labeling for ponatinib does not list any specific contraindications.

Canadian labeling: Ponatinib should not be used in individuals who have:

• Hypersensitivity or allergic reactions to ponatinib or any component of the formulation.
• Unmanaged cardiovascular risk factors, including uncontrolled hypertension (high blood pressure).
• Patients who are not adequately hydrated and have uncorrected hyperuricemia (high levels of uric acid in the blood).

Warnings and precautions

Arrhythmias

• Arrhythmias, which are irregular heart rhythms, have been reported in patients taking ponatinib.
• The most commonly reported arrhythmia is atrial fibrillation, with about half of the cases being severe (grade 3 or 4).
• Other severe rhythm disorders have also been observed in individual case reports.
• Some of these events were serious enough to require hospitalization, and in a few cases, patients needed a pacemaker implanted due to symptomatic bradyarrhythmia (slow heart rate).
• It's important to monitor for signs and symptoms of bradycardia (fainting, dizziness, chest pain) and tachycardia (palpitations, dizziness).
• If such symptoms occur, therapy with ponatinib may need to be temporarily stopped, and further evaluation may be necessary.

Arterial occlusion [US Boxed Warn]

• Arterial occlusion is a severe and potentially life-threatening risk associated with the use of ponatinib, as stated in the US Boxed Warning.
• Studies have shown that at least 35% of patients treated with ponatinib experienced arterial occlusion.
• These events include fatal heart attacks (myocardial infarction), strokes, narrowing of large brain arteries, severe peripheral vascular disease, and the need for urgent procedures to restore blood flow.
• Arterial occlusions can occur in patients both with and without pre-existing cardiovascular risk factors, including those who are younger than 50 years old.
• Close monitoring for signs of arterial occlusion is essential, and if it occurs, the treatment should be immediately interrupted or discontinued.
• The decision to restart the therapy should carefully consider the risk-to-benefit ratio.
• Arterial occlusion can be fatal or life-threatening and may occur within two weeks of starting the treatment, regardless of the dose (even as low as 15 mg daily).
• It can also lead to recurrent or multiple occlusions at different sites.
• The most common risk factors for developing arterial occlusive events include hypertension, high cholesterol levels (hyperlipidemia), and a history of cardiac disease.
• Increasing age and a prior history of ischemia, hypertension, diabetes, or hyperlipidemia also increase the risk.
• Some patients have required procedures to restore blood flow in the brain (cerebrovascular), heart (coronary), and peripheral arteries due to serious arterial thrombosis/occlusion.
• Arterial occlusion in the coronary arteries can result in heart failure due to insufficient blood supply to the heart muscle.
• Cerebrovascular occlusion, including fatal strokes, can cause narrowing across multiple segments of major arteries that supply the brain.
• Peripheral arterial occlusion events, including fatal occlusion of the mesenteric artery and life-threatening peripheral arterial disease, have been reported.
• In some cases, patients have required amputation due to tissue death (necrosis) in the fingers or extremities.
• Renal artery stenosis, associated with worsening or treatment-resistant hypertension, has also been observed.
• Given the serious and potentially fatal nature of arterial occlusion, it is crucial to closely monitor patients receiving ponatinib and promptly address any signs or symptoms suggestive of arterial occlusion.

Suppression of bone marrow

• Bone marrow suppression, characterized by a significant decrease in blood cell production, is a common side effect of ponatinib treatment.
• Severe myelosuppression, classified as grade 3 or 4, is frequently observed in patients taking ponatinib, particularly in those with accelerated or blast phase chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
• The onset of severe myelosuppression typically occurs around one month after starting ponatinib, but it can occur earlier or later, with the range being up to 40 months.
•  Close monitoring of blood cell counts is essential during treatment.
• If severe myelosuppression occurs, therapy may need to be temporarily stopped or the dosage reduced.

Fluid retention/edema

• Fluid retention and edema, the buildup of excess fluid in the body, can occur as a serious side effect of ponatinib treatment.
•  In some cases, these events have been severe and even resulted in fatalities, such as brain edema (swelling of the brain).
•  Commonly observed fluid retention events include peripheral edema (swelling in the limbs), pleural effusions (fluid around the lungs), pericardial effusions (fluid around the heart), and peripheral swelling.
•  It is important to closely monitor patients for signs of fluid retention while they are receiving ponatinib.
•  If fluid retention occurs, the treatment may need to be temporarily stopped, the dosage reduced, or in some cases, the medication may need to be discontinued.

Perforation of the gastrointestinal tract:

• Gastrointestinal perforation, a rare but serious complication, can occur in patients treated with ponatinib.
• This condition involves the formation of a hole or abnormal connection in the gastrointestinal tract.
• It is important to monitor for any signs or symptoms of gastrointestinal perforation or fistula while receiving ponatinib treatment.
• Such signs may include severe abdominal pain, fever, chills, nausea, vomiting, or the presence of blood in the stool.
• If any of these symptoms occur, it is crucial to seek immediate medical attention.
• Regular monitoring and prompt reporting of any potential gastrointestinal complications are essential for early detection and appropriate management.

Heart Failure: [US Boxed Warning]

• Heart failure is a significant and potentially life-threatening risk associated with the use of ponatinib, as highlighted in the US Boxed Warning.
• Clinical trials have reported serious cases of heart failure or left ventricular dysfunction, including fatalities.
• It is important to monitor for signs and symptoms of heart failure while on ponatinib treatment.
• If new or worsening heart failure is detected, the therapy should be promptly interrupted or discontinued.
• The most commonly reported heart failure events are congestive heart failure (when the heart is unable to pump blood effectively) and decreased ejection fraction (a measure of the heart's pumping efficiency).
• If heart failure develops, it should be treated according to standard clinical practices.
• In severe cases of heart failure, it may be necessary to discontinue ponatinib treatment.

Hemorrhage

• Hemorrhage, which refers to abnormal bleeding, is a potential risk associated with the use of ponatinib.
• Patients treated with ponatinib have experienced hemorrhagic events, including serious cases such as cerebral (subdural hematoma) and gastrointestinal bleeding, some of which have resulted in fatalities.
• Serious bleeding episodes are more commonly observed in patients with accelerated or blast phase chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), with most patients also experiencing grade 4 thrombocytopenia (very low platelet levels).
• Close monitoring of platelet levels is crucial, along with monitoring for signs and symptoms of bleeding.
• If necessary, therapy may need to be interrupted to manage the bleeding.

Hepatotoxicity: [US Boxed Warning]

• Hepatotoxicity, a severe and potentially life-threatening liver-related adverse event, has been observed in patients treated with ponatinib, as emphasized in the US Boxed Warning.
• Liver failure and even death can result from ponatinib-induced hepatotoxicity.
• To mitigate this risk, liver function should be evaluated before starting treatment and monitored regularly, at least monthly or as determined by the healthcare provider, throughout the course of treatment.
• The onset of hepatotoxicity typically occurs around 3 months after initiating ponatinib, but it can happen earlier or later, with a range of less than 1 month to 47 months.
• If hepatotoxicity is detected, treatment interruption (followed by dose reduction) or discontinuation may be necessary.
• It is essential to note that in some cases, severe liver damage, such as fulminant hepatic failure, has occurred within just one week of starting therapy.
• Elevations in liver enzymes such as ALT, AST, bilirubin, and alkaline phosphatase are common with ponatinib treatment.
• t is possible for ALT and/or AST elevations to be irreversible.
• Close monitoring of liver function and prompt reporting of any signs or symptoms of liver damage are crucial for early detection and appropriate management of hepatotoxicity.

Hypertension

• Hypertension, or high blood pressure, is a common treatment-related side effect of ponatinib.
• More than two-thirds of patients treated with ponatinib experience an increase in blood pressure, either systolic or diastolic.
• In some cases, symptomatic hypertension or hypertensive crisis, requiring urgent medical intervention, have been reported.
• It is important to note that blood pressure can worsen in patients with preexisting hypertension.
• Close monitoring of blood pressure is necessary during ponatinib treatment, and elevated blood pressures should be managed according to clinical judgment.
• If hypertension persists despite medical management, therapy may need to be temporarily interrupted, the dosage reduced, or in some cases, the medication may need to be discontinued.
• Renal artery stenosis, a condition characterized by narrowing of the renal arteries, has been observed in some patients receiving ponatinib.
• If there is a significant worsening, instability, or treatment resistance of hypertension, evaluation for renal artery stenosis should be considered.
• Regular blood pressure monitoring and timely management of hypertension are crucial to minimize potential risks and optimize patient care during ponatinib treatment.

Neuropathy

• Neuropathy, which involves damage to the peripheral nerves or cranial nerves, has been observed in patients treated with ponatinib.
• The most commonly reported neuropathic symptoms include peripheral neuropathy (affecting the nerves in the arms and legs), paresthesia (abnormal sensations like tingling or numbness), hypoesthesia (reduced sensation), hyperesthesia (heightened sensitivity), dysgeusia (distorted sense of taste), and muscular weakness.
• Cranial neuropathy, although rare, has also been reported.
• It is noteworthy that one-quarter of patients who experienced neuropathic symptoms developed them within the first month of starting ponatinib therapy.
• Monitoring for signs and symptoms of neuropathy is important during treatment.
• If neuropathy develops, it may be necessary to interrupt the treatment.

Ocular toxicities:

• Ocular toxicity is a potential concern associated with the use of ponatinib.
•  Some patients treated with ponatinib have experienced serious ocular events, including blindness and blurred vision.
• Other ocular complications reported include macular edema (swelling in the central part of the retina), retinal vein occlusion (blockage of a vein in the retina), and retinal hemorrhage (bleeding in the retina).
• Conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperemia and edema (redness and swelling), and eye pain have also been observed more frequently.
• Additionally, other ocular toxicities such as cataracts, periorbital edema (swelling around the eyes), blepharitis (inflammation of the eyelids), glaucoma, eyelid edema, ocular hyperemia, iritis (inflammation of the iris), iridocyclitis (inflammation of the iris and ciliary body), and ulcerative keratitis (corneal ulcer) have been reported.
• It is recommended to perform comprehensive ophthalmic exams before initiating ponatinib therapy and periodically throughout treatment to monitor for any ocular changes or complications.
• Regular monitoring and timely intervention can help detect and manage ocular toxicity, ensuring the best possible eye health and visual outcomes for patients receiving ponatinib treatment.

Pancreatitis

• Pancreatitis, an inflammation of the pancreas, has been observed in clinical studies of patients treated with ponatinib.
• Elevations in lipase (an enzyme produced by the pancreas) and clinical cases of pancreatitis, including severe cases (grade 3 and 4), have been reported.
• The onset of pancreatitis symptoms typically occurred within a median time of 14 days, but it can range from 3 days to approximately 48 months.
• In most cases, pancreatitis resolved within two weeks of interrupting the therapy or reducing the dose.
• To monitor for potential pancreatitis, it is recommended to regularly measure serum lipase levels every two weeks during the first two months of treatment and monthly thereafter or as clinically indicated.
• Patients with a history of pancreatitis or alcohol abuse may require more frequent monitoring.
• Clinical signs of pancreatitis, such as abdominal symptoms, should also be monitored.
• If pancreatitis is suspected, it may be necessary to interrupt the therapy.
• Treatment should not be reinitiated until symptoms have completely resolved, and the lipase level is less than 1.5 times the upper limit of normal (ULN).
• Close monitoring and appropriate management are essential to promptly identify and address pancreatitis in patients receiving ponatinib, ensuring their safety and well-being.

Reversible posterior Leukoencephalopathy Syndrome:

• Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare condition that has been reported in postmarketing surveillance of patients using ponatinib.
• RPLS can cause various signs and symptoms, including seizures, headaches, decreased awareness, altered mental status, vision loss, and other visual and/or neurological disturbances.
• Hypertension (high blood pressure) is often present in individuals with RPLS.
• Diagnosis of RPLS is typically confirmed through magnetic resonance imaging (MRI) of the brain.
• If RPLS is diagnosed, ponatinib should be discontinued.
• Treatment with ponatinib may only be resumed if the RPLS condition resolves and the potential benefits of continuing the medication outweigh the associated risks.
• Prompt recognition, appropriate diagnosis, and management of RPLS are crucial to ensure the well-being and safety of patients receiving ponatinib.

Tumor lysis syndrome

• Tumor lysis syndrome is a rare but serious condition that can occur in patients treated with ponatinib.
• It is characterized by high levels of uric acid in the blood and can lead to various complications.
• To minimize the risk of tumor lysis syndrome, patients should receive sufficient hydration and be closely monitored for elevated uric acid levels and the development of this syndrome.
• Before starting ponatinib treatment, it is important to manage any pre-existing elevated uric acid levels.
• Adequate monitoring and appropriate management of uric acid levels and tumor lysis syndrome are necessary to ensure the safety and well-being of patients receiving ponatinib.

Venous thromboembolism: [US-Bound Warning]

• Venous thromboembolism is a potential risk associated with the use of ponatinib.
• It is characterized by the formation of blood clots in the veins, which can lead to serious complications.
• Approximately 6% of patients treated with ponatinib have experienced venous occlusive events.
• It is important to monitor patients closely for signs of venous thromboembolism and consider adjusting the dose or discontinuing ponatinib in patients who develop this condition.
• Venous thromboembolism can manifest as deep vein thrombosis (clots in the deep veins), pulmonary embolism (clots in the lungs), superficial thrombophlebitis (inflammation of superficial veins), and retinal vein thrombosis (clots in the retinal veins).
• Prompt recognition and appropriate management of venous thromboembolism are essential to ensure the well-being and safety of patients receiving ponatinib.

Inability to heal wounds

• Ponatinib can potentially impair the healing process of wounds due to its inhibitory effect on VEGF (vascular endothelial growth factor) activity.
• Therefore, it is recommended to temporarily discontinue ponatinib treatment for at least 1 week before undergoing major surgery.
• The decision to resume therapy after the surgical procedure should be based on the clinical judgment of healthcare professionals, taking into consideration the appropriate healing of the wound.
• This precaution helps ensure optimal wound healing and reduces the potential risks associated with impaired healing while on ponatinib therapy.

Cardiovascular disease

• Cardiovascular disease is a concern in patients treated with ponatinib, regardless of their cardiovascular risk factors or medical history.
• Individuals with a prior history of conditions such as ischemia, hypertension, diabetes, or hyperlipidemia may be at higher risk for vascular occlusion while taking ponatinib.
• It is important to closely monitor patients for any signs or symptoms of occlusion, such as blood clot formation.
• If thrombosis or occlusion occurs, therapy should be interrupted and discontinuation of ponatinib may be considered.
• This proactive approach helps identify and address potential cardiovascular complications in order to ensure the well-being and safety of patients during treatment.

CML in chronic phase (newly diagnosed).

• In a study comparing the first-line treatment of newly diagnosed chronic phase chronic myeloid leukemia (CML), ponatinib showed a two-fold increased risk of serious adverse reactions compared to imatinib.
• Due to safety concerns, the study was halted.
• The incidence of arterial and venous thrombosis and occlusion events was more than twice as frequent in the ponatinib group compared to the imatinib group.
• Patients receiving ponatinib also had a higher occurrence of hematologic toxicity, pancreatitis, hepatotoxicity, heart failure, hypertension, and dermatologic/subcutaneous tissue disorders.
• Therefore, ponatinib is not recommended for and not indicated in the treatment of newly diagnosed chronic phase CML.
• Other treatment options should be considered for these patients.

Hepatic impairment

• A study examining the effects of hepatic impairment on ponatinib exposure found that there was no significant increase in drug levels in patients with impaired liver function compared to those with normal liver function.
• However, patients with hepatic impairment did experience a higher overall incidence of adverse reactions, particularly related to gastrointestinal disorders and pancreatitis.
• Therefore, it is important to closely monitor patients with impaired liver function when administering ponatinib.
• Additionally, a lower starting dose should be considered for patients with hepatic impairment to minimize the risk of adverse effects.

Ponatinib: Drug Interaction

Risk Factor C (Monitor therapy)
Chloramphenicol (Ophthalmic)	May enhance the adverse/toxic effect of Myelosuppressive Agents.
CloZAPine	Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.
Mesalamine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Promazine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Risk Factor D (Consider therapy modification)
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of PONATinib. Management: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor.
Deferiprone	Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely.
Grapefruit Juice	May increase the serum concentration of PONATinib. Management: Reduce ponatinib starting dose to 30 mg daily when patients consume grapefruit consistently or in large amounts. Since grapefruit effects on CYP3A mediated metabolism are variable and poorly predictable, consider advising patients to avoid.
Risk Factor X (Avoid combination)
BCG (Intravesical)	Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).
Cladribine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
CYP3A4 Inducers (Strong)	May decrease the serum concentration of PONATinib.
Dipyrone	May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
St John's Wort	May decrease the serum concentration of PONATinib.

Monitoring parameters:

• Complete Blood Count (CBC) with differential and platelet counts:
  • Every 2 weeks for the first 3 months
  • Monthly thereafter or as clinically needed
• Liver function tests:
  • Baseline measurement
  • At least monthly thereafter
  • More frequent monitoring if clinically warranted
• Serum lipase:
  • Every 2 weeks for the first 2 months
  • Monthly thereafter
  • More frequent monitoring for patients with a history of pancreatitis or alcohol abuse
• Serum electrolytes and uric acid levels
• Cardiac function and blood pressure monitoring
• Signs and symptoms of the following should be monitored:
  • Arterial/venous occlusion or thromboembolism
  • Hemorrhage
  • Fluid retention
  • Pancreatitis (clinical signs)
  • Gastrointestinal perforation/fistula
  • Hepatotoxicity (jaundice, anorexia, bleeding, bruising)
  • Reversible posterior leukoencephalopathy syndrome
• Comprehensive ocular examination at baseline and periodically
• Signs and symptoms of neuropathy

How to administer Ponatinib?

Food:

• Ponatinib can be taken with or without food.

Tablet

• Consumption: Swallow the tablets whole; do not crush or dissolve them.   

Mechanism of action of Ponatinib (Iclusig):

• Ponatinib is a pan-BCR-ABL tyrosine kinase inhibitor.
• It inhibits the activity of both native and mutant forms of BCR-ABL, including the T315I mutation.
• In addition to BCR-ABL, ponatinib also targets other kinases such as VEGFR, FGFR, PDGFR, EPH, and SRC.
• It exhibits inhibitory effects on KIT, RET, TIE2, and FLT3 kinases.

Absorption:

• Ponatinib is absorbed well and its plasma concentrations are not affected by food.

Distribution:

• The volume of distribution (V) of ponatinib is approximately 1223 liters.
• It binds to plasma proteins with more than 99% affinity.

Metabolism:

• The primary pathway of metabolism for ponatinib is through the liver, primarily by the enzyme CYP3A4.
• Other enzymes such as CYP2C8, CYP2D6, and CYP3A5 also contribute to its metabolism.
• Phase II metabolism occurs via esterases and/or amidases.

Half-life elimination:

• The half-life of elimination for ponatinib is approximately 24 hours, but it can range from 12 to 66 hours.

Time to peak:

• Ponatinib reaches its peak plasma concentration within 6 hours after administration.

Excretion:

• The majority of ponatinib is excreted in the feces (approximately 87%).
• A smaller portion is excreted in the urine (approximately 5%).

International Brand Names of Ponatinib:

• Iclusig

Ponatinib Brand Names in Pakistan:

No Brands Available in Pakistan.