Ponatinib

Ponatinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia in patients resistant or intolerant to prior TKIs. In vitro studies suggested that metabolism of ponatinib is partially mediated by CYP3A4. The effects of CYP3A4 inhibition on the pharmacokinetics of ponatinib and its CYP3A4-mediated metabolite, AP24567, were evaluated in a single-center, randomized, two-period, two-sequence crossover study in healthy volunteers. Subjects (N = 22) received two single doses (orally) of ponatinib 15 mg, once given alone and once coadministered with daily (5 days) ketoconazole 400 mg, a CYP3A4 inhibitor. Ponatinib plus ketoconazole increased ponatinib maximum plasma concentration (C(max)) and area under the concentration-time curve (AUC) compared with ponatinib alone. The estimated mean ratios for AUC0-8, AUC0-t, and C(max) indicated increased exposures to ponatinib of 78%, 70%, and 47%, respectively; exposure to AP24567 decreased by 71%. Exposure to AP24567 was marginal after ponatinib alone (no more than 4% of the exposure to ponatinib). These results suggest that caution should be exercised with the concurrent use of ponatinib and strong CYP3A4 inhibitors and that a ponatinib dose decrease to 30 mg daily, from the 45 mg daily starting dose, could be considered.

... Ponatinib at pharmacologically relevant concentrations produced synergistic cytotoxicity with ABCB1 and ABCG2 substrate chemotherapy drugs and enhanced apoptosis induced by these drugs, including daunorubicin, mitoxantrone, topotecan, and flavopiridol, in cells overexpressing these transport proteins. ...

In large clinical trials, elevations in serum aminotransferase levels during ponatinib therapy occurred in up to 56% of patients and were above 5 times upper limit of normal (ULN) in 8% of patients. While these abnormalities were reversible in most patients, they were prolonged or severe in some. Instances of clinically apparent liver disease and progressive hepatic failure and death were reported in clinical trials of ponatinib, although the clinical features of the liver injury have not been well described. The latency until onset can be rapid and most cases have had a hepatocellular pattern of serum enzyme elevations. Because of the potential for serious hepatotoxicity, routine monitoring of liver tests is recommended during ponatinib therapy and dose modification or discontinuation recommended for ALT or AST elevations above 3 times ULN. Thus, ponatinib therapy is associated with a high rate of transient serum aminotransferase elevations and is reported to cause rare instances of severe hepatic injury, but there have been no cases described in the literature.

/SIGNS AND SYMPTOMS/ Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit-risk consideration should guide a decision to restart Iclusig therapy. Heart failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure. Hepatotoxicity: Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.

/SIGNS AND SYMPTOMS/ Hepatotoxicity and acute hepatic failure with fatal outcome have been reported in patients receiving ponatinib; liver biopsies predominantly showed hepatocellular necrosis.6 Fulminant hepatic failure resulting in death following 1 week of therapy was reported in one ponatinib-treated patient in the premarketing clinical trial. Elevations in serum aminotransferase (ALT or AST) concentrations were reported in 56% of patients receiving ponatinib in the premarketing clinical trial; median time to onset of these elevations was 46 days.6 Severe hepatotoxicity has been reported in all the disease cohorts; however, fatal cases have only been reported in patients with blast phase chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphocytic (lymphoblastic) leukemia (ALL).

/CASE REPORTS/ Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis.

/CASE REPORTS/ Ponatinib is a bcr-abl tyrosine-kinase inhibitor used to treat resistant and refractory chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia that express bcr-abl. Neutrophilic panniculitis has been described in rare cases of patients on other tyrosine-kinase inhibitors in the same class as ponatinib.

/LABORATORY ANIMALS: Acute Exposure/ In a phototoxicity study, there was no evidence of cutaneous phototoxicity. Low level phototoxic reactions were observed in the form of lenticular epithelial hyperplasia at 5 mg/kg, and in the form of corneal oedema and inflammatory changes, and lenticular epithelial hyperplasia at 10 mg/kg.

/LABORATORY ANIMALS: Acute Exposure/ Under the experimental conditions, ponatinib had no clinically relevant effects on the CNS or pulmonary function. Ponatinib at 3, 10, and 30 mg/kg produced increases in urine output and electrolyte excretions without affecting pH or electrolyte concentrations. Ponatinib at 3, 10, and 30 mg/kg did not affect gastrointestinal motility in rats but did cause a non-dose dependent decrease in gastric emptying.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ /Cynomolgus monkeys received oral doses of 0, 1, 2.5 or 5 mg/kg/day with a 28 day recovery./ Mortality: 5 mg/kg: Three animals (2M, 1F) euthanized in moribound condition during study (days 19, 21 and 22). 5 mg/kg: Dry flaky skin, mild to marked skin erythema at a large number of anatomical sites. Ocular discharge. Decreased thyroid hormone T3 levels and increased T4 levels. Pancreas diffusely thickened due to either diffuse fibrosis or insterstitial oedema. Acinar cell necrosis or atrophy in pancreas. All early descendants had lymphoid depletion in thymus. Degeneration of germ cell epithelium of testes, decrease numbers of spermatids. Increased follicular atresia in ovaries and atrophy of the uterine endometrium follicles. > o r= 2.5 mg/kg: Pancreas: Acinar cell necrosis, atrophy or regeneration. Lymphoid depletion in thymus, spleen , lymph nodes and gut associated lymphoid tissue. Granulamotous inflammation of the lung. > or = mg/kg: Dose-dependent decrease in body weight and/or body weight gain. Lower food consumption. Systolic heart murmurs in all dose groups (LD 1M, MD 1F, HD 1M+1F). Increase excretion of urinary protein, no microscopic correlates. At the end of recovery period, atrophy of thyroid gland in one male at 5 mg/kg, increased urinary protein at all doses. No microorganisms or evidence for infectious agents were apparent microscopically. /From table/

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ /Rats received oral doses of 0, 1.5, 3 or 6 mg/kg/day for 28 days with 28 days of recovery./ Seven (2 males, 5 females) of the 30 animals at 6 mg/kg/day in the toxicology portion of the study were found dead/sacrificed in moribund condition between dose Days 5 and 9. Because of poor health, dosing of animals in this high dose group was stopped. Three (1 male, 2 females) of 30 animals at 3 mg/kg/day in the toxicology portion of the study were found dead/sacrificed in moribund condition between Days 9 and 13. One animal (a male) of 30 animals at 1.5 mg/kg/day in the toxicology portion of the study was found dead on Day 28. 6 mg/kg: Hyperplasia of bone marrow. Minimal to marked necrosis of thymus. Sporadic necrosis of the glandular and non-glandular mucosa of the stomach. > or = 3 mg/kg: rough hair coats; inappetance; thinness; lethargy; hunched posture; cold skin; dry, red material (porphyrin staining) on the eyes, nose, face, and forepaws; scant feces; urine staining; dark yellow urine; eye squint; and labored breathing. Dry, flaky skin of forepaws. Reduced body weight gain and food consumption. Hyperplasia of epiphyseal plate of the femur. > or = 1.5 mg/kg: Slight increases in neutrophils, monocytes and eosinophils and decreases in lymphocytes; most pronounced in 3 and 6 mg/kg groups. Transient and minor increases in ALT, AST, BUN, glucose and triglycerides. Slight decrease in thyroid hormone T3. With the exception on lower body weight gain in males at 3 mg/kg, all findings were reversible. /From table/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ponatinib hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Ponatinib hydrochloride/

Drug Name: Iclusig; FDA Application No.: (NDA) 203469; Active Ingredient: Ponatinib hydrochloride; Company: Arid; Original Approval or Tentative Approval Date: December 14, 2012; Chemical Type: 1 New molecular entity (NME); Review Classification: Priority review drug, orphan drug. /Ponatinib hydrochloride/

MEDICATION

Antineoplastic Agents; Protein Kinase Inhibitors