Composition
Each film-coated tablet contains Ponatinib Hydrochloride INN equivalent to Ponatinib 15 mg.
Each film-coated tablet contains Ponatinib Hydrochloride INN equivalent to Ponatinib 45 mg.
Therapeutic class: Anti-cancer agent.
Pharmacological action
Mechanism of action
Ponatinib is a kinase inhibitor. Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC50 concentrations of 0.4 and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC50 concentrations between 0.1 and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2 and FLT3.
Ponatinib inhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I. In mice, treatment with ponatinib reduced the size of tumors expressing native or T315I mutant BCR-ABL when compared to controls.
Pharmacodynamics
In a cell-based assay, ponatinib concentrations of 20 nM (10.65 ng/mL) were sufficient to suppress most BCR-ABL mutant clones; 40 nM (21.3 ng/mL) were required to suppress T315I mutants. Suppression of mutant clones may be achieved at once-daily doses of 15 mg or 30 mg. Grade ≥3 adverse events (hypertension, thrombocytopenia, pancreatitis, neutropenia, rash, ALT/AST and lipase increase, myelosuppression) increased significantly over the dose range of 15 to 45 mg once daily. In vitro, there was no significant inhibition of platelet aggregation at clinically relevant concentrations.
| Dose (steady state) | Median Cmax (range), nM | Median Cmin (range), nM |
|---|---|---|
| 15 mg QD (n = 8) | 49 (23 – 105) | 28 (11 – 68) |
| 30 mg QD (n = 9) | 125 (67 – 178) | 54 (41 – 89) |
| 45 mg QD (n = 21) | 161 (64 – 336) | 67 (22 – 137) |
Cardiac electrophysiology
A QT assessment in 39 patients receiving 30, 45 or 60 mg once daily detected no large changes in mean QTc (> 20 msec); a small increase (< 10 msec) cannot be excluded. In a phase 3 trial versus imatinib, the mean change to worst QTcF in ponatinib-treated patients (n = 124) was < 10 msec.
Pharmacokinetics
The geometric mean (CV%) Cmax and AUC(0-τ) of ponatinib 45 mg daily at presumed steady state in patients with advanced hematologic malignancies were 73 ng/mL (74%) and 1253 ng·hr/mL (73%). Exposure increased approximately dose-proportionally over 15 to 60 mg. A dose-intensity safety analysis showed a significant increase in grade ≥3 adverse reactions with increasing dose intensity.
- Absorption
- Absolute bioavailability is unknown. Peak concentrations are observed within 6 hours of oral administration. High-fat or low-fat meals did not change exposure (AUC and Cmax) versus fasting.
- Distribution
- Greater than 99% bound to plasma proteins in vitro, with no displacement by other highly protein-bound drugs. Apparent steady-state volume of distribution is 1223 L (102%) after 45 mg once daily for 28 days. Weak substrate of P-gp and ABCG2; not a substrate of OATP1B1, OATP1B3 or OCT1.
- Metabolism
- At least 64% of a dose undergoes phase I and phase II metabolism. CYP3A4 and, to a lesser extent, CYP2C8, CYP2D6 and CYP3A5 are involved in phase I metabolism. Also metabolized by esterases and/or amidases.
- Elimination
- Terminal half-life about 24 hours (range 12–66) after 45 mg once daily for 28 days. Exposure increased about 90% (median) between the first dose and steady state. Mainly eliminated via feces (~87%), with ~5% in urine.
Therapeutic indications
Ponatinib is a prescription kinase inhibitor indicated for the treatment of:
- Adult patients with chronic phase, accelerated phase or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
- Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
Dosage & administration
The optimal dose of ponatinib has not been identified. In clinical trials the starting dose was 45 mg once daily; in the phase 2 trial, 68% of patients required dose reductions to 30 mg or 15 mg once daily during therapy.
- Start dosing with 45 mg orally once daily.
- Consider reducing the dose for patients with chronic phase (CP) and accelerated phase (AP) CML who have achieved a major cytogenetic response.
- Consider discontinuing if a response has not occurred by 3 months (90 days).
- May be taken with or without food. Tablets should be swallowed whole.
Reduce the recommended dose to 30 mg once daily.
Recommended starting dose is 30 mg once daily (Child-Pugh A, B or C).
Dose modifications
If a serious non-hematologic adverse reaction occurs, modify the dose or interrupt treatment. Do not restart ponatinib in patients with arterial or venous occlusive reactions unless the potential benefit outweighs the risk of recurrence and the patient has no other treatment options. For other serious reactions, do not restart until the event has resolved or the benefit of resuming is judged to outweigh the risk.
Table 1 · Myelosuppression
ANC < 1 × 10⁹/L or platelets < 50 × 10⁹/L (unrelated to leukemia)
| Situation | Action |
|---|---|
| First occurrence | Interrupt and resume the initial 45 mg dose after recovery to ANC ≥ 1.5 × 10⁹/L and platelets ≥ 75 × 10⁹/L. |
| Second occurrence | Interrupt and resume at 30 mg after recovery. |
| Third occurrence | Interrupt and resume at 15 mg after recovery. |
Table 2 · Hepatotoxicity
| Situation | Action |
|---|---|
| Transaminases > 3 × ULN (grade 2+) — at 45 mg | Interrupt and monitor hepatic function; resume at 30 mg after recovery to grade 1 (< 3 × ULN). |
| — at 30 mg | Interrupt and resume at 15 mg after recovery to grade 1. |
| — at 15 mg | Discontinue. |
| AST or ALT ≥ 3 × ULN with bilirubin > 2 × ULN and alkaline phosphatase < 2 × ULN | Discontinue. |
Table 3 · Pancreatitis & lipase elevation
| Situation | Action |
|---|---|
| Asymptomatic grade 1 or 2 lipase elevation | Consider interruption or dose reduction. |
| Asymptomatic grade 3/4 lipase (> 2 × ULN) or radiologic pancreatitis (grade 2) | 45 mg: interrupt, resume at 30 mg after recovery to grade 1 (< 1.5 × ULN). 30 mg: interrupt, resume at 15 mg. 15 mg: discontinue. |
| Symptomatic grade 3 pancreatitis | 45 mg: interrupt, resume at 30 mg after complete resolution of symptoms and lipase recovery to grade 1. 30 mg: interrupt, resume at 15 mg. 15 mg: discontinue. |
| Grade 4 pancreatitis | Discontinue. |
ANC = absolute neutrophil count; ULN = upper limit of normal for the lab.
Warnings & precautions
Arterial occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain and severe peripheral vascular disease, have occurred in at least 35% of ponatinib-treated patients from the phase 1 and phase 2 trials. With a minimum of 48 months follow-up in the phase 2 trial, 33% (150/449) experienced a cardiac vascular (21%), peripheral vascular (12%) or cerebrovascular (9%) arterial occlusive event. Ponatinib can cause fatal and life-threatening arterial occlusion within 2 weeks of starting treatment and at doses as low as 15 mg per day, and can cause recurrent or multi-site vascular occlusion. Patients have required revascularization procedures.
Venous thromboembolic events occurred in 6% (25/449) of patients, including deep venous thrombosis (10), pulmonary embolism (7), superficial thrombophlebitis (3) and retinal vein thrombosis (2) with vision loss. Incidence was 9% in Ph+ ALL, 10% in BP-CML, 4% in AP-CML and 5% in CP-CML. Consider dose modification or discontinuation in patients who develop serious venous thromboembolism.
Fatal or serious heart failure or left ventricular dysfunction occurred in 6% (29/449) of patients; 9% (39) experienced any grade. The most frequent events were congestive cardiac failure and decreased ejection fraction (3% each). Monitor for signs or symptoms of heart failure and treat as clinically indicated, including interruption of ponatinib. Consider discontinuation in patients who develop serious heart failure.
Ponatinib can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred within one week of starting ponatinib; two additional fatal cases of acute liver failure occurred in patients with BP-CML or Ph+ ALL. 11% (50/449) experienced grade 3 or 4 hepatotoxicity. AST or ALT elevation occurred in 54% (all grades) and 8% (grade 3/4). Hepatotoxic events were observed in 29% of patients, with a median onset of 3 months. Monitor liver function tests at baseline, then at least monthly or as clinically indicated.
Treatment-emergent elevation of systolic or diastolic blood pressure occurred in 68% (306/449) of patients; 12% experienced symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. Patients may require urgent intervention for hypertension associated with confusion, headache, chest pain or shortness of breath. Monitor and manage blood pressure; interrupt, reduce or stop ponatinib if hypertension is not medically controlled. In significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.
Pancreatitis occurred in 7% (31/449) of patients (6% serious or grade 3/4). Treatment-emergent lipase elevation occurred in 42% (16% grade 3 or greater). Median time to onset was 14 days. Check serum lipase every 2 weeks for the first 2 months and then monthly or as clinically indicated. Do not consider restarting until symptoms have completely resolved and lipase is below 1.5 × ULN.
In a first-line trial, single-agent ponatinib 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to imatinib 400 mg once daily; arterial and venous thrombosis and occlusions occurred at least twice as frequently. The trial was halted for safety in October 2013. Ponatinib is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.
Peripheral neuropathy of any grade occurred in 20% (90/449) of patients (2% grade 3/4) and cranial neuropathy in 2%. Of patients who developed neuropathy, 26% did so during the first month. Monitor for hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain or weakness, and consider interrupting ponatinib if neuropathy is suspected.
Serious ocular toxicities leading to blindness or blurred vision have occurred. Retinal toxicities including macular edema, retinal vein occlusion and retinal hemorrhage occurred in 2% of patients; conjunctival and corneal irritation, dry eye and eye pain in 14%; visual blurring in 6%. Conduct comprehensive eye exams at baseline and periodically during treatment.
Serious hemorrhage events, including fatalities, occurred in 6% (28/449) of patients; hemorrhage of any kind occurred in 28%. Serious bleeding was more frequent in AP-CML, BP-CML and Ph+ ALL; gastrointestinal hemorrhage and subdural hematoma were most common. Most events occurred in patients with grade 4 thrombocytopenia.
Serious fluid retention occurred in 4% (18/449) of patients; one instance of brain edema was fatal. In total, fluid retention occurred in 31%, most commonly peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%) and peripheral swelling (3%). Monitor and interrupt, reduce or discontinue as clinically indicated.
Arrhythmias occurred in 19% (86/449) of patients, 7% grade 3 or greater. Atrial fibrillation was most common (7%). Symptomatic bradyarrhythmias led to pacemaker implantation in 1%. In patients with signs of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations, dizziness), interrupt ponatinib and evaluate.
Myelosuppression was reported in 59% (266/449) of patients, severe (grade 3/4) in 50%, with a median onset of 1 month. Incidence was greater in AP-CML, BP-CML and Ph+ ALL. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.
Two patients (<1%) with advanced disease developed serious tumor lysis syndrome; hyperuricemia occurred in 7%. In advanced disease (AP-CML, BP-CML or Ph+ ALL), ensure adequate hydration and treat high uric acid levels before initiating therapy.
Postmarketing cases of RPLS (also known as PRES) have been reported. Signs include seizure, headache, decreased alertness, altered mental functioning, vision loss and other visual and neurological disturbances; diagnosis is supported by brain MRI. If diagnosed, interrupt treatment and resume only once resolved and if the benefit outweighs the risk.
Based on its mechanism of action, ponatinib could compromise wound healing. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy. Interrupt ponatinib for at least 1 week before major surgery; resume based on clinical judgment of adequate wound healing.
Ponatinib can cause fetal harm. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment and for 3 weeks after the last dose.
Use in specific populations
- Pregnancy
- Based on its mechanism of action and findings in animals, ponatinib can cause fetal harm. There are no available data on use in pregnant women. In animal reproduction studies, oral administration to pregnant rats during organogenesis caused adverse developmental effects at doses lower than human exposures at the recommended dose. Advise pregnant women of the potential risk to a fetus.
- Lactation
- There are no data on the presence of ponatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential for serious adverse reactions, advise women not to breastfeed during treatment and for 6 days following the last dose.
- Females & males of reproductive potential
- Verify pregnancy status of females of reproductive potential before starting. Advise females to use effective contraception during treatment and for 3 weeks after the last dose.
- Pediatric use
- Safety and effectiveness have not been established in pediatric patients. In a juvenile rat study, 3 mg/kg/day (about 0.32 times the clinical dose on a mg/m² basis for a child) resulted in mortality related to inflammatory effects.
- Geriatric use
- 35% (155/449) of trial patients were 65 or older. In CP-CML, older patients had a lower major cytogenetic response rate (40% vs 65%). Forty percent of patients ≥65 had arterial occlusion events, and they were more likely to experience vascular occlusion, decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms and decreased appetite. Dose selection should be cautious.
- Hepatic impairment
- Administer 30 mg once daily in patients with hepatic impairment (Child-Pugh A, B or C). In a single-dose study, no major PK differences were seen, but there was an increased overall incidence of adverse reactions (including a case of severe pancreatitis). Multiple doses, or doses above 30 mg, have not been studied in hepatic impairment.
Drug interactions
Ponatinib is a substrate of CYP3A and, to a lesser extent, CYP2C8 and CYP2D6. Ketoconazole increased ponatinib AUC and Cmax by 78% and 47%. With strong CYP3A inhibitors (e.g. boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), reduce the starting dose.
Avoid carbamazepine, phenytoin, rifampin and St. John’s Wort unless the benefit outweighs the risk. Rifampin decreased ponatinib AUC and Cmax by 62% and 42%. Monitor for reduced efficacy.
May be co-administered. Lansoprazole caused a minimal (6%) decrease in ponatinib exposure.
Ponatinib inhibits P-glycoprotein, ABCG2 (BCRP) and the bile salt export pump (BSEP) in vitro.
Overdosage
Overdoses were reported in clinical trials. One patient accidentally received an estimated 540 mg via nasogastric tube; two hours later the uncorrected QT interval was 520 ms, with subsequent ECGs showing normal sinus rhythm. The patient died 9 days later from pneumonia and sepsis. Another patient self-administered 165 mg and experienced fatigue and non-cardiac chest pain. Multiple doses of 90 mg/day for 12 days resulted in pneumonia, systemic inflammatory response, atrial fibrillation and moderate pericardial effusion.
In the event of an overdose, stop ponatinib, observe the patient and provide appropriate supportive treatment.
Pharmaceutical information
- Storage condition
- Store below 30°C in a dry place, away from light and moisture. Keep out of the reach of children.
- Ponatinix 15 tablet
- Each commercial box contains 60 tablets in an HDPE pot.
- Ponatinix 45 tablet
- Each commercial box contains 30 tablets in an HDPE pot.
Manufactured by Beacon Pharmaceuticals PLC, Bhaluka, Mymensingh, Bangladesh. Marketed by Beacon Medicare Limited, Dhaka, Bangladesh. Only for export.