LuciPona Ponatinib tablets 15mg/45mg

Product Name: LuciPona

Chinese Name: Ponatinib

English Name: Ponatinib

Dosage Form and Strength: 15 mg/tablet, 30 tablets/bottle; 45 mg/tablet, 30 tablets/bottle

[Summary]

Ponatinib is indicated for the treatment of the following adult patients: 1. Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). 2. Chronic myeloid leukemia (CML).

[Indications]

Ponatinib is a kinase inhibitor indicated for the treatment of adult patients with the following conditions:

1. Chronic Phase (CP) Chronic Myeloid Leukemia (CML) that is resistant to or intolerant of at least two prior kinase inhibitors.

2. Accelerated Phase (AP) or Blast Phase (BP) CML, or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), for whom no other kinase inhibitors are indicated.

3. T315I-positive CML (Chronic Phase, Accelerated Phase, or Blast Phase) or T315I-positive Ph+ ALL.

[Storage]

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

[Dosage and Administration]

1. Recommended Dosage for CP-CML: The starting dose is 45 mg orally once daily; reduce the dose to 15 mg orally once daily when BCR-ABL1 IS ≤ 1%.

2. Recommended Dosage for AP-CML, BP-CML, and Ph+ ALL: The starting dose is 45 mg orally once daily.

3. Patients with Hepatic Impairment: Reduce the starting dose to 30 mg orally once daily.

4. May be taken with or without food. 【 Adverse Reactions 】

1. Arterial Occlusive Events

2. Venous Thromboembolic Events

3. Heart Failure

4. Hepatotoxicity

5. Hypertension

6. Pancreatitis

7. Neuropathy

8. Ocular Toxicity

9. Hemorrhage

10. Fluid Retention

11. Arrhythmias

12. Myelosuppression

13. Tumor Lysis Syndrome

14. Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

15. Impaired Wound Healing and Gastrointestinal Perforation

【 Precautions 】

1. Arterial Occlusive Events

Arterial occlusive events (AOEs), including fatalities, have occurred in patients treated with Ponatinib.

In the PhALLCON study, AOEs occurred in 6% of the 163 patients; specifically, cardiovascular, cerebrovascular, and peripheral vascular AOEs occurred in 3.1%, 1.8%, and 1.2% of patients, respectively. The median time to the first onset of an AOE was 11.3 months (range: 8 days to 2.8 years). Grade 3 or 4 AOEs occurred in 3.7% of patients; the most common Grade 3 or 4 AOEs were myocardial infarction (1.2%), peripheral arterial occlusive disease (1.2%), angina pectoris, and cerebrovascular accident (0.6% each). One patient (0.6%) experienced a fatal AOE (sudden death). The incidence of AOEs increases with age.

2. Venous Thromboembolic Events

Serious or severe venous thromboembolic events (VTEs) have occurred in patients treated with Ponatinib.

In the PhALLCON study, VTEs occurred in 12% of the 163 patients, with serious or severe (Grade 3 or 4) events accounting for 3.1%. VTEs included deep vein thrombosis (6%), superficial vein thrombosis (2.5%), embolism (1.8%), pulmonary embolism and thrombosis (1.2% each), and jugular vein thrombosis and retinal vein occlusion (0.6% each). The median time to onset of the first VTE event was 2.5 months (range: 6 days to 1.8 years).

In the OPTIC study, among 94 patients receiving a starting dose of 45 mg, 1 patient experienced a VTE event (Grade 1 retinal vein occlusion).

In the PACE study, VTE occurred in 6% of the 449 patients; of these, 5.8% were severe or Grade 3 or 4 events. VTE events included deep vein thrombosis with vision loss (2.2%), pulmonary embolism (1.8%), thrombophlebitis superficial (0.7%), retinal vein occlusion (0.7%), and retinal vein thrombosis (0.4%). VTE occurred in 10% of 62 patients with BP-CML, 9% of 32 patients with Ph+ ALL, 6% of 270 patients with CP-CML, and 3.5% of 85 patients with AP-CML.

Monitor for signs of ventricular tachycardia. Interrupt treatment, then resume at the same or a reduced dose—or discontinue Ponatinib—based on the recurrence/severity of the event.

3. Heart Failure

Fatal, severe, or Grade 3 or 4 heart failure events have occurred in patients treated with Ponatinib.

In the PhALLCON study, heart failure occurred in 6% of the 163 patients; 1.2% experienced severe or Grade 3 or 4 heart failure. The most frequently reported heart failure event (>1 patient) was elevated B-type natriuretic peptide (BNP) levels (2.5%).

In the OPTIC study, among 94 patients receiving a starting dose of 45 mg, heart failure occurred in 13% of patients; 1.1% experienced severe or Grade 3 or 4 heart failure. The most frequently reported heart failure events (>1 patient each) were left ventricular hypertrophy (3.2%) and elevated BNP levels (3.2%). In the PACE trial, fatal or serious heart failure occurred. The incidence of heart failure was 9% (449 patients); 7% experienced serious or severe (Grade 3 or higher) heart failure. The most frequently reported heart failure events (≥2%) were congestive heart failure (3.1%), decreased ejection fraction (2.9%), and heart failure (2%).

Monitor patients for signs or symptoms consistent with heart failure, and manage heart failure as clinically indicated. Interrupt dosing, then resume at a reduced dose, or discontinue Ponatinib permanently in cases of new or worsening heart failure.

4. Hepatotoxicity

Ponatinib can cause hepatotoxicity, including hepatic failure and death. Fatal hepatic failure occurred in 3 patients; in one of these cases, hepatic failure occurred within 1 week of initiating Ponatinib treatment. These fatal cases occurred in patients with BP-CML or Ph+ ALL receiving monotherapy.

In the PhALLCON trial, hepatotoxicity occurred in 66% of the 163 patients; 30% experienced Grade 3 or 4 hepatotoxicity. The median time to onset of hepatotoxicity was 15 days (range: 1 day to 10 months). The most common hepatotoxicity events were elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), bilirubin, and alkaline phosphatase, as well as decreases in albumin and fibrinogen. Among the 73 patients who reported elevated ALT or AST, the events remained unresolved in 6% of patients at the time of their last follow-up.

In the OPTIC trial, hepatotoxicity occurred in 28% of the 94 patients who initiated treatment at a dose of 45 mg; 6% experienced Grade 3 or 4 hepatotoxicity. The median time to onset of hepatotoxicity was 1.9 months (range: 3 days to 4.1 years). The most common hepatotoxicity events were elevations in ALT, AST, alkaline phosphatase, and GGT. Among the 21 patients reporting elevated ALT or AST levels, the event remained unresolved in 29% of patients at the time of their last follow-up.

In the PACE study, hepatotoxicity occurred in 32% of the 449 patients; 13% experienced Grade 3 or 4 hepatotoxicity. The median time to onset of hepatotoxicity was 3.1 months, ranging from 1 day to 4.9 years. The most common hepatotoxicity events were elevations in ALT, AST, GGT, bilirubin, and alkaline phosphatase. Among the 88 patients reporting elevated ALT or AST levels, the event remained unresolved in 9% of patients at the time of their last follow-up.

Monitor liver function tests at baseline, and subsequently at least monthly or as clinically indicated. Interrupt dosing, then resume at a reduced dose or discontinue Ponatinib based on recurrence or severity.

5. Hypertension

Severe or serious hypertension, including hypertensive crisis, has occurred in patients treated with Ponatinib.

In the PhALLCON study, hypertension occurred in 34% of the 163 patients; 14% experienced severe or serious hypertension. Based on vital sign data, 15 of the 60 patients (25%) with normal baseline blood pressure experienced a Grade 1 increase; 67 of the 134 patients (50%) with baseline blood pressure below Grade 2 experienced a Grade 2 increase; and 63 of the 160 patients (39%) with baseline blood pressure below Grade 3 experienced a Grade 3 increase.

In the OPTIC study, among the 94 patients initiated on a 45 mg dose, 32% reported hypertension events; 12% experienced severe or serious hypertension. Based on vital sign data, 8 of the 18 patients (44%) with normal baseline blood pressure experienced a Grade 1 increase; 28 of the 81 patients (35%) with baseline blood pressure below Grade 2 experienced a Grade 2 increase; and 18 of the 92 patients (20%) with baseline blood pressure below Grade 3 experienced a Grade 3 increase. Three patients (3.2%) experienced a hypertensive crisis. In the PACE study, 32% of the 449 patients reported hypertensive events; 13% experienced severe or Grade 3/4 hypertension. Among patients with normal baseline blood pressure, 44% of the 449 patients experienced a post-baseline increase in systolic or diastolic blood pressure of Grade 2 or higher. The incidence of Grade 1 BP elevation was 26%, Grade 2 was 45%, and Grade 3 was 26%. Two patients (< 1%) experienced Grade 4 hypertension (hypertensive crisis).

Patients may require urgent clinical intervention for hypertension accompanied by confusion, headache, chest pain, or shortness of breath. Monitor blood pressure based on baseline values and clinical indications, and manage hypertension as clinically indicated. If hypertension is not medically controlled, interrupt, reduce the dose of, or discontinue Ponatinib. For hypertension that significantly worsens, becomes unstable, or is refractory to treatment, interrupt Ponatinib and consider an evaluation for renal artery stenosis.

6. Pancreatitis

Severe or Grade 3/4 pancreatitis has occurred in patients treated with Ponatinib.

In the PhALLCON study, 34% of the 163 patients experienced pancreatitis; 15% experienced severe or Grade 3/4 pancreatitis. The median time to onset of pancreatitis was 8 days (range: 1 day to 2 years). In the 7 patients with clinical pancreatitis that led to dose adjustment, the pancreatitis resolved within 3 weeks. Laboratory abnormalities included elevated amylase in 25% of patients and elevated lipase in 60% of patients.

In the OPTIC study, among the 94 patients initially treated with a 45 mg dose, 23% experienced pancreatitis; 15% experienced severe or Grade 3/4 pancreatitis. Pancreatitis led to permanent discontinuation of the drug in 1.1% of patients, and to interruption and/or dose reduction in 20% of patients. The median time to onset of pancreatitis was 23 days (range: 3 days to 5.6 months). In the 2 patients with clinical pancreatitis that led to dose adjustment or treatment discontinuation, the pancreatitis resolved within 2 weeks. 11% of patients experienced laboratory abnormalities involving elevated amylase levels, while 34% experienced elevated lipase levels.

In the PACE trial, pancreatitis occurred in 26% of the 449 patients; 17% experienced severe or Grade 3 or 4 pancreatitis. Pancreatitis led to treatment discontinuation in 0.4% of patients, and to treatment interruption and/or dose reduction in 17% of patients. The median time to onset of pancreatitis was 29 days (range: 1 day to 4 years). Of the 28 cases of clinical pancreatitis that resulted in dose adjustment or treatment discontinuation, 19 resolved within 2 weeks. 18% of patients experienced laboratory abnormalities involving elevated amylase levels, while 39% experienced elevated lipase levels.

Monitor serum lipase levels every 2 weeks during the first 2 months of treatment, and thereafter monthly or as clinically indicated. Consider additional serum lipase monitoring for patients with a history of pancreatitis or alcohol abuse. Interrupt dosing, then resume at the same or a reduced dose—or permanently discontinue Ponatinib—depending on the severity of the event. Evaluate for pancreatitis when elevated lipase levels are accompanied by abdominal symptoms.

7. Increased Toxicity in Newly Diagnosed Chronic Phase CML

In a prospective, randomized clinical trial evaluating first-line treatment in patients with newly diagnosed chronic phase CML (CP-CML), Ponatinib monotherapy at a dose of 45 mg once daily was associated with an increased risk of severe adverse reactions. This risk was approximately twofold higher compared to Imatinib monotherapy at a dose of 400 mg once daily. The median duration of treatment exposure was less than 6 months. For safety reasons, the trial was halted. Compared to the Imatinib arm, the incidence of arterial and venous thrombotic and occlusive events was at least twice as high in the Ponatinib arm. Furthermore, compared to patients treated with Imatinib, patients treated with Ponatinib experienced higher rates of myelosuppression, pancreatitis, hepatotoxicity, heart failure, hypertension, and skin and subcutaneous tissue disorders. Conclusion: The use of Ponatinib—either alone or in combination with Imatinib—is not recommended for the treatment of newly diagnosed CP-CML patients. 8. Neuropathy

In PhALLCON, peripheral neuropathy occurred in 68% of 163 patients; 3.1% experienced Grade 3 or 4 peripheral neuropathy. The most common peripheral neuropathies were peripheral neuropathy (33%), paresthesia (22%), and peripheral sensory neuropathy (12%). The median time to onset of peripheral neuropathy was 1.1 months (range: 1 day to 17.2 months). Cranial neuropathy was reported in 0.6% of the 163 patients.

In OPTIC, among 94 patients who initiated treatment at a dose of 45 mg, neuropathy occurred in 9%. Peripheral neuropathy occurred in 6% of patients. The most commonly reported peripheral neuropathies were hypoesthesia (2.1%), muscle weakness (2.1%), and paresthesia (2.1%). Two patients experienced cranial neuropathy. The median time to onset for peripheral neuropathy and cranial neuropathy was 7.7 months (range: 1.5 months to 1.4 years) and 2.1 years (range: Day 1 to 4.2 years), respectively.

In PACE, neuropathy occurred in 22% of patients; 2.4% experienced Grade 3 or 4 neuropathy. Peripheral neuropathy occurred in 20% of 449 patients; 1.8% experienced Grade 3 or 4 peripheral neuropathy. The most common peripheral neuropathies were paresthesia (5%), peripheral neuropathy (4.5%), and hypoesthesia (3.6%). Cranial neuropathy occurred in 3% of patients; 0.7% were Grade 3 or 4. The median time to onset for peripheral neuropathy and cranial neuropathy was 5.3 months (range: 1 day to 4.6 years) and 1.2 years (range: 18 days to 4 years), respectively.

Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, or weakness. Interrupt dosing, then resume at the same or a reduced dose—or discontinue Ponatinib—based on recurrence or severity.

9. Ocular Toxicity

Serious ocular toxicity, including blindness and blurred vision, has occurred in patients treated with Ponatinib.

In PhALLCON, ocular toxicity occurred in 33% of 163 patients; 1.8% experienced severe or Grade 3 ocular toxicity. The most common ocular toxicities were blurred vision and dry eye. Retinal toxicity occurred in 4.3% of patients; 0.6% experienced Grade 3 retinal vein occlusion. The most common retinal toxicity event (> 1 patient) was retinal hemorrhage (1.8%).

In OPTIC, among 94 patients who received a starting dose of 45 mg, ocular toxicity occurred in 11%; 1.1% experienced severe or Grade 3 ocular toxicity. The most common ocular toxicities were blurred vision and eye pain. Retinal toxicity occurred in 2.1% of patients, including age-related macular degeneration and retinal vein occlusion.

In PACE, ocular toxicity occurred in 30% of 449 patients; 3.6% experienced severe or Grade 3 ocular toxicity. The most common ocular toxicities were dry eye, blurred vision, and eye pain. Retinal toxicity occurred in 3.6% of patients. The most common retinal toxicities were macular edema, retinal vein occlusion, retinal hemorrhage, and vitreous floaters (0.7% each).

Perform comprehensive ophthalmologic examinations at baseline and periodically during treatment.

10. Hemorrhage

Fatal and serious hemorrhage events have occurred in patients treated with Ponatinib.

In PhALLCON, hemorrhage occurred in 31% of 163 patients; 2.5% experienced serious hemorrhage. Intracranial hemorrhage was the most frequently reported serious hemorrhage, occurring in 1.2% of patients.

In OPTIC, among 94 patients who initiated treatment at a dose of 45 mg, hemorrhage occurred in 12%; one patient experienced a serious subdural hematoma. In the PACE study, bleeding occurred in 28% of 449 patients; 6% experienced serious bleeding, and 1.3% experienced fatal bleeding. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most frequently reported serious bleeding events, each occurring in 0.9% of patients. Most bleeding events occurred in patients with Grade 4 thrombocytopenia.

Monitor for bleeding and manage patients as clinically indicated. Interrupt dosing, then resume at the same or a reduced dose, or discontinue Ponatinib, based on recurrence or severity.

11. Fluid Retention

Fatal and serious fluid retention events have occurred in patients treated with Ponatinib.

In the PhALLCON study, fluid retention occurred in 24% of 163 patients; 1.2% experienced serious fluid accumulation, including pericardial effusion (1.2%). The most common fluid accumulations were peripheral edema (11%) and pleural effusion (6%).

In the OPTIC study, fluid retention occurred in 5% of the 94 patients who initiated treatment at a dose of 45 mg. The most common fluid retention events were peripheral edema (2.1%) and pleural effusion (2.1%).

In the PACE study, fluid retention events occurred in 33% of 449 patients; 4.5% experienced serious fluid accumulation. One case of cerebral edema was fatal. Serious fluid accumulations included pleural effusion (1.6%), pericardial effusion (1.6%), and angioedema (0.4%). The most common fluid retention events were peripheral edema (17%), pleural effusion (9%), pericardial effusion (4.2%), and peripheral swelling (3.8%).

Monitor for fluid retention and manage patients as clinically indicated. Interrupt dosing, then resume at the same or a reduced dose, or discontinue Ponatinib, based on recurrence or severity. 12. Arrhythmias

In PhALLCON, arrhythmias occurred in 22% of the 163 patients; 2.5% experienced Grade 3 or 4 arrhythmias, including tachycardia, syncope, atrial fibrillation, and supraventricular tachycardia (0.6% each).

In OPTIC, among the 94 patients initially treated with the 45 mg dose, arrhythmias occurred in 16%; 4.3% experienced Grade 3 or 4 arrhythmias. Grade 3 or 4 arrhythmias included atrial fibrillation, cardiopulmonary arrest, supraventricular premature beats, and syncope.

In PACE, arrhythmias occurred in 20% of the 449 patients; 7% experienced Grade 3 or 4 arrhythmias. Among the 89 patients reporting arrhythmias, 3.4% experienced ventricular arrhythmias, one of which was a Grade 3 or 4 event. 1% of patients experienced symptomatic bradyarrhythmias requiring pacemaker implantation. Atrial fibrillation was the most common arrhythmia (8%), with 3.3% being Grade 3 or 4. Other Grade 3 or 4 arrhythmia events included syncope (2%); tachycardia and bradycardia (0.4% each); QT interval prolongation, atrial flutter, sinus bradycardia, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, complete atrioventricular block, cardiopulmonary arrest, loss of consciousness, and sinoatrial node dysfunction (0.2% each). 31 patients were hospitalized due to arrhythmias.

Monitor for signs and symptoms suggestive of slowed heart rate (syncope, dizziness) or rapid heart rate (chest pain, palpitations, or dizziness), and manage patients as clinically indicated. Interrupt dosing, then resume at the same or a reduced dose, or discontinue Ponatinib, based on recurrence/severity. 13. Myelosuppression

In PhALLCON, among 163 patients, neutropenia occurred in 66 patients (63 [39%] Grade 3 or 4), thrombocytopenia occurred in 65 patients (62 [38%] Grade 3 or 4), and anemia occurred in 53 patients (38 [23%] Grade 3 or 4). The median time to onset of Grade 3 or 4 myelosuppression was 27 days (range: 1 day to 9.2 months).

In OPTIC, among 94 patients treated with a starting dose of 45 mg, neutropenia occurred in 55% (22 [23%] Grade 3 or 4), thrombocytopenia occurred in 65% (31 [33%] Grade 3 or 4), and anemia occurred in 35% (14 [15%] Grade 3 or 4). The median time to onset of Grade 3 or 4 myelosuppression was 1.4 months (range: 1 day to 1.2 years).

In PACE, the incidence of neutropenia was 56% (34% Grade 3 or 4), thrombocytopenia was 63% (40% Grade 3 or 4), and anemia was 52% (20% Grade 3 or 4). The incidence of myelosuppression was higher in patients with AP-CML, BP-CML, and Ph+ ALL compared to those with CP-CML. Severe myelosuppression (Grade 3 or 4) was observed early in treatment, with a median time to onset of 29 days (range: 1 day to 4.1 years).

Obtain complete blood counts every 2 weeks for the first 3 months, and then monthly or as clinically indicated. If the ANC is less than 1 x 10⁹/L or platelets are less than 50 x 10⁹/L, interrupt ICLUSIG until the ANC is at least 1.5 x 10⁹/L and platelets are at least 75 x 10⁹/L, then resume at the same or a reduced dose.

14. Tumor Lysis Syndrome

In PhALLCON, severe tumor lysis syndrome (TLS) occurred in 0.6% of the 163 patients. Hyperuricemia occurred in 10% of patients.

In the OPTIC study, among the 94 patients initially treated with a 45 mg dose, severe TLS occurred in 1.1% of patients. Hyperuricemia occurred in 2.1% of patients.

In the PACE study, severe TLS occurred in 0.4% of the 449 patients. One case occurred in a patient with advanced AP-CML, and one case occurred in a patient with BP-CML. Hyperuricemia occurred in 7% of patients.

Ensure adequate hydration and treat hyperuricemia prior to initiating Ponatinib therapy.

15. Reversible Posterior Leukoencephalopathy Syndrome

Reversible Posterior Leukoencephalopathy Syndrome (RPLS; also known as Reversible Posterior Encephalopathy Syndrome) has been reported. Patients may present with hypertension, seizures, headaches, decreased alertness, altered mental status, vision loss, and other visual and neurological disturbances. Magnetic Resonance Imaging (MRI) must be performed to confirm the diagnosis. Discontinue Ponatinib until the condition resolves. The safety of resuming Ponatinib after the resolution of RPLS is unknown.

16. Impaired Wound Healing and Gastrointestinal Perforation

Impaired wound healing has been observed in patients receiving Ponatinib therapy. Discontinue Ponatinib at least 1 week prior to elective surgery. Do not administer Ponatinib for at least 2 weeks following major surgery, or until the wound has adequately healed. The safety of resuming Ponatinib after the resolution of wound healing complications has not been established.

17. Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, Ponatinib may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of Ponatinib to pregnant animals during organogenesis resulted in adverse developmental effects at exposures lower than those associated with the maximum recommended human dose of 45 mg/day. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with Ponatinib and for 3 weeks after the last dose.

【Use in Specific Populations】

1. Pregnancy

Based on findings in animals and its mechanism of action, Ponatinib can cause fetal harm when administered to a pregnant woman. There are no available data on Ponatinib use in pregnant women. In animal reproduction studies, oral administration of Ponatinib to pregnant animals during organogenesis resulted in adverse developmental effects at doses lower than the maximum recommended human dose of 45 mg/day. Advise pregnant women of the potential risk to the fetus.

2. Lactation

There are no data on the presence of Ponatinib in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Ponatinib and for 1 week after the last dose.

3. Females and Males of Reproductive Potential

Ponatinib can cause fetal harm when administered to a pregnant woman.

Verify the pregnancy status of females of reproductive potential prior to initiating treatment with Ponatinib.

Advise females of reproductive potential to use effective contraception during treatment with Ponatinib and for 3 weeks after the last dose.

Based on animal data, Ponatinib may impair the fertility of males and females of reproductive potential. It is not known whether these effects on fertility are reversible.

4. Pediatric Use

The safety and effectiveness of Ponatinib in pediatric patients have not been established.

5. Geriatric Use

Of the 163 patients with Ph+ ALL treated with Ponatinib in the PhALLCON study, 21% were 65 years of age and older, and 7% were 75 years of age and older. Overall, no differences in the efficacy of Ponatinib were observed between patients aged 65 years and older compared to younger patients. AOEs occurred in 21% (7/34) of patients aged 65 years and older, and in 2.3% (3/129) of patients younger than 65 years.

Among 94 patients with CP-CML who initiated treatment with 45 mg of Ponatinib, 17% were aged 65 years and older, and 2.1% were aged 75 years and older. Compared to patients younger than 65 years (47%), patients aged 65 years and older had a lower BCR::ABL1 IS rate at 12 months (27%). AOEs occurred in 38% (6/16) of patients aged 65 years and older, and in 9% (7/78) of patients younger than 65 years.

Among 449 patients treated with Ponatinib in the PACE trial, 35% were aged 65 years and older, and 8% were aged 75 years and older. In patients with CP-CML, the major cytogenetic response rate in patients aged 65 years and older (40%) was lower than that in patients younger than 65 years (65%).

Patients aged 65 years and older were more likely to experience adverse reactions, including vascular occlusion, decreased platelet count, peripheral edema, increased lipase, dyspnea, fatigue, muscle spasms, and decreased appetite. In general, dose selection for elderly patients should be cautious, reflecting the higher frequency of decreased hepatic, renal, or cardiac function, as well as concomitant disease or other drug therapies.

6. Hepatic Impairment

Compared to patients with normal hepatic function, patients with hepatic impairment were more likely to experience adverse reactions. For patients with CP-CML, AP-CML, BP-CML, and Ph+ ALL receiving monotherapy, the starting dose of Ponatinib should be reduced for patients with pre-existing hepatic impairment (Child-Pugh A, B, or C). For patients with newly diagnosed Ph+ ALL, dose adjustment is not recommended when administering Ponatinib to patients with mild hepatic impairment (Child-Pugh A). As there are no clinical data available for patients with newly diagnosed Ph+ ALL and pre-existing moderate or severe hepatic impairment (Child-Pugh B or C), patients should be closely monitored for a potential increase in the incidence of adverse reactions. Adjust the Ponatinib dose in the event of adverse reactions. The safety of multiple doses or doses exceeding 30 mg has not been studied in patients with hepatic impairment.

[Drug Interactions]

Effects of Other Drugs on Ponatinib

1. Strong CYP3A Inhibitors

Co-administration of Ponatinib with a strong CYP3A inhibitor increases Ponatinib plasma concentrations, which may increase the risk of adverse reactions associated with Ponatinib. Avoid the concomitant use of Ponatinib with strong CYP3A inhibitors. If co-administration of Ponatinib with a strong CYP3A inhibitor cannot be avoided, the dose of Ponatinib should be reduced.

2. Strong CYP3A Inducers

Co-administration of Ponatinib with a strong CYP3A inducer decreases Ponatinib plasma concentrations. Avoid the concomitant use of Ponatinib with strong CYP3A inducers unless the benefits outweigh the risks associated with reduced Ponatinib exposure. Monitor patients for reduced efficacy. It is recommended to select concomitant medications that have no or minimal potential for CYP3A induction.

Overdosage

Overdosage with Ponatinib has been reported in clinical trials. One patient was estimated to have ingested 540 mg via a nasogastric tube. Two hours after the overdose, the patient's uncorrected QT interval was 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 ms and 400 ms. The patient died 9 days after the overdose due to pneumonia and sepsis. Another patient self-administered 165 mg on Day 2 of Cycle 1. The patient developed fatigue and non-cardiac chest pain on Day 3. In this patient, multiple daily doses of 90 mg administered over 12 days resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and moderate pericardial effusion.

In the event of an overdose, discontinue Ponatinib, observe the patient, and provide appropriate supportive care.