Ponatinib

Ponatinib Brand Name– Iclusig

What is Ponatinib

Ponatinib is an oral multi-kinase inhibitor.

It works by inhibiting ABL and T315I mutant ABL in addition to other tyrosine kinase proteins (e.g., VEGFR, PDGFR, FGFR, EPH, Src family kinases, KIT, RET, FLT-3, and TIE-2) that promote the growth and development of cancer cells.

Ponatinib is indicated for the treatment of T315I-positive chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) or T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), or for the treatment of patients with CP, AP, or BP CML or Ph+ALL for whom no other tyrosine kinase inhibitor is indicated.

It is not recommended for use in patients with newly diagnosed, chronic phase CML based on data from a randomized, phase III (EPIC) trial that was stopped early when serious adverse reactions were reported in this patient population.

Ponatinib was evaluated in adult patients with CP (n = 267), AP (n = 83), or BP (n = 62) CML whose disease was resistant or intolerant to prior tyrosine kinase inhibitor therapy with dasatinib or nilotinib or had a T315I-positive mutation in a multi-national, open-label, phase II trial (PACE trial).

The major cytogenic response at 12 months (primary endpoint) was 56% in CP-CML patients.

Additionally, treatment with ponatinib resulted in major hematologic response rates at 6 months (primary endpoint) of 55%, 31%, and 41% in patients with AP-CML, BP-CML, and Ph+ALL, respectively.

Ponatinib was approved by the FDA in December 2012, and subsequently withdrawn by the manufacturer in October 2013 at the request of the FDA due to the risk of life-threatening blood clots and severe narrowing of blood vessels.

In December 2013, after implementing new FDA requirements for safety measures addressing the risk of life-threatening blood clots and severe narrowing of blood vessels, the manufacturer once again began marketing ponatinib to appropriate patients.

Indications

  • acute lymphocytic leukemia (ALL)
  • chronic myelogenous leukemia (CML)

For the treatment of chronic myelogenous leukemia (CML)

for the treatment of T315I-positive CML in chronic phase, accelerated phase, or blast phase

Side Effects

  1. abdominal pain
  2. abdominal pain
  3. alopecia
  4. anemia
  5. anorexia
  6. anorexia
  7. aortic dissection
  8. arthralgia
  9. arthralgia
  10. ascites
  11. asthenia
  12. asthenia
  13. atrial fibrillation
  14. atrial flutter
  15. atrial tachycardia
  16. AV block
  17. avascular necrosis
  18. back pain
  19. back pain
  20. bleeding
  21. bleeding
  22. blurred vision
  23. bone pain
  24. bone pain
  25. bradycardia
  26. cardiac arrest
  27. cataracts
  28. cerebral edema
  29. chest pain (unspecified)
  30. chills
  31. chills
  32. conjunctivitis
  33. constipation
  34. constipation
  35. corneal erosion
  36. cough
  37. dehydration
  38. diarrhea
  39. diarrhea
  40. dizziness
  41. dysgeusia
  42. dysgeusia
  43. dyspnea
  44. dyspnea
  45. elevated hepatic enzymes
  46. elevated hepatic enzymes
  47. erythema
  48. erythema
  49. erythema multiforme
  50. fatigue
  51. fatigue
  52. fever
  53. fever
  54. fluid retention
  55. fluid retention
  56. gastrointestinal fistula
  57. GI bleeding
  58. GI perforation
  59. headache
  60. headache
  61. heart failure
  62. hematemesis
  63. hepatic failure
  64. hepatotoxicity
  65. hyperamylasemia
  66. hyperamylasemia
  67. hyperbilirubinemia
  68. hyperbilirubinemia
  69. hypercalcemia
  70. hyperemia
  71. hyperesthesia
  72. hyperglycemia
  73. hyperglycemia
  74. hyperkalemia
  75. hyperkalemia
  76. hypernatremia
  77. hypernatremia
  78. hypertension
  79. hypertensive crisis
  80. hyperthyroidism
  81. hypertriglyceridemia
  82. hypertriglyceridemia
  83. hyperuricemia
  84. hypoalbuminemia
  85. hypoalbuminemia
  86. hypocalcemia
  87. hypocalcemia
  88. hypoesthesia
  89. hypoglycemia
  90. hypokalemia
  91. hypokalemia
  92. hyponatremia
  93. hyponatremia
  94. hypophosphatemia
  95. hypophosphatemia
  96. hypothyroidism
  97. hypotonia
  98. hypotonia
  99. impaired wound healing
  100. infection
  101. infection
  102. insomnia
  103. intracranial bleeding
  104. iritis
  105. keratitis
  106. leukoencephalopathy
  107. leukopenia
  108. lymphopenia
  109. macular edema
  110. melena
  111. metabolic acidosis
  112. metabolic acidosis
  113. muscle cramps
  114. musculoskeletal pain
  115. musculoskeletal pain
  116. myalgia
  117. myalgia
  118. myocardial infarction
  119. nausea
  120. nausea
  121. nephrotoxicity
  122. nephrotoxicity
  123. neutropenia
  124. ocular irritation
  125. ocular pain
  126. oral ulceration
  127. oral ulceration
  128. pancreatitis
  129. paresthesias
  130. pericardial effusion
  131. peripheral edema
  132. peripheral edema
  133. peripheral neuropathy
  134. peripheral neuropathy
  135. pharyngitis
  136. phlebitis
  137. pleural effusion
  138. pruritus
  139. pruritus
  140. pulmonary edema
  141. pulmonary embolism
  142. QT prolongation
  143. rash
  144. rash
  145. respiratory arrest
  146. restless legs syndrome (RLS)
  147. restless legs syndrome (RLS)
  148. retinal hemorrhage
  149. retinal thrombosis
  150. sinus tachycardia
  151. Stevens-Johnson syndrome
  152. stomatitis
  153. stomatitis
  154. stroke
  155. subdural hematoma
  156. supraventricular tachycardia (SVT)
  157. syncope
  158. thrombocytopenia
  159. thromboembolism
  160. thrombosis
  161. thrombotic microangiopathy
  162. tumor lysis syndrome (TLS)
  163. ventricular tachycardia
  164. vomiting
  165. vomiting
  166. weakness
  167. weakness
  168. weight loss
  169. weight loss
  170. xerophthalmia
  171. xerosis
  172. xerosis

Monitoring Parameters

  • CBC with differential
  • LFTs
  • ophthalmologic exam
  • pregnancy testing
  • serum lipase
  • serum uric acid

Contraindications

  • alcoholism
  • anemia
  • ascites
  • atrial fibrillation
  • atrial flutter
  • AV block
  • bleeding
  • bone marrow suppression
  • bradycardia
  • breast-feeding
  • cardiac arrhythmias
  • cardiac disease
  • contraception requirements
  • diabetes mellitus
  • edema
  • geriatric
  • GI bleeding
  • heart failure
  • hepatic disease
  • hepatotoxicity
  • hyperlipidemia
  • hypertension
  • hyperuricemia
  • impaired wound healing
  • infertility
  • intracranial bleeding
  • leukopenia
  • myocardial infarction
  • neurotoxicity
  • neutropenia
  • pancreatitis
  • pericardial effusion
  • peripheral neuropathy
  • peripheral vascular disease
  • pleural effusion
  • pregnancy
  • pregnancy testing
  • QT prolongation
  • renal artery stenosis
  • reproductive risk
  • stroke
  • surgery
  • tachycardia
  • thrombocytopenia
  • thromboembolism
  • tumor lysis syndrome (TLS)
  • visual disturbance

Interactions

  • Afatinib
  • Aliskiren
  • Aliskiren; Amlodipine
  • Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ
  • Aliskiren; Hydrochlorothiazide, HCTZ
  • Aliskiren; Valsartan
  • Alpelisib
  • Aluminum Hydroxide
  • Aluminum Hydroxide; Magnesium Carbonate
  • Aluminum Hydroxide; Magnesium Hydroxide
  • Aluminum Hydroxide; Magnesium Hydroxide; Simethicone
  • Aluminum Hydroxide; Magnesium Trisilicate
  • Amoxicillin; Clarithromycin; Lansoprazole
  • Amoxicillin; Clarithromycin; Omeprazole
  • Antacids
  • Apalutamide
  • Aspirin, ASA; Citric Acid; Sodium Bicarbonate
  • Aspirin, ASA; Omeprazole
  • Atazanavir; Cobicistat
  • Atropine; Hyoscyamine; Phenobarbital; Scopolamine
  • Belladonna Alkaloids; Ergotamine; Phenobarbital
  • Betrixaban
  • Boceprevir
  • Calcium Carbonate
  • Calcium Carbonate; Magnesium Hydroxide
  • Calcium Carbonate; Risedronate
  • Calcium Carbonate; Simethicone
  • Carbamazepine
  • Ceritinib
  • Chloroquine
  • Clarithromycin
  • Clozapine
  • Cobicistat
  • Colchicine
  • Colchicine; Probenecid
  • Conivaptan
  • Dabigatran
  • Dapagliflozin; Saxagliptin
  • Darunavir; Cobicistat
  • Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide
  • Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir
  • Delavirdine
  • Dexlansoprazole
  • Dichlorphenamide
  • Digoxin
  • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide
  • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate
  • Enzalutamide
  • Esomeprazole
  • Esomeprazole; Naproxen
  • Everolimus
  • Fexofenadine
  • Fexofenadine; Pseudoephedrine
  • Fosphenytoin
  • grapefruit juice
  • H2-blockers
  • Imatinib
  • Indinavir
  • Isoniazid, INH; Pyrazinamide, PZA; Rifampin
  • Isoniazid, INH; Rifampin
  • Itraconazole
  • Ketoconazole
  • Lansoprazole
  • Lansoprazole; Naproxen
  • Lapatinib
  • Lefamulin
  • Letermovir
  • Loperamide
  • Loperamide; Simethicone
  • Lopinavir; Ritonavir
  • Magnesium Hydroxide
  • Maraviroc
  • Metformin; Saxagliptin
  • Metformin; Sitagliptin
  • Methotrexate
  • Mitoxantrone
  • Nefazodone
  • Nelfinavir
  • Ombitasvir; Paritaprevir; Ritonavir
  • Omeprazole
  • Omeprazole; Amoxicillin; Rifabutin
  • Omeprazole; Sodium Bicarbonate
  • Ozanimod
  • Pantoprazole
  • Phenobarbital
  • Phenytoin
  • Posaconazole
  • Rabeprazole
  • Ranolazine
  • Ribociclib
  • Ribociclib; Letrozole
  • Rifampin
  • Rimegepant
  • Ritonavir
  • Rosuvastatin
  • Saquinavir
  • Saxagliptin
  • Simvastatin; Sitagliptin
  • Sirolimus
  • Sitagliptin
  • Sodium Bicarbonate
  • St. John’s Wort, Hypericum perforatum
  • Sulfasalazine
  • Talazoparib
  • Telaprevir
  • Telithromycin
  • Temsirolimus
  • Tolvaptan
  • Topotecan
  • Tucatinib
  • Ubrogepant
  • Venetoclax
  • Voriconazole
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