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Iclusig

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Iclusig

Side Effects
Interactions

SIDE EFFECTS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The following adverse reactions are discussed in greater detail in other sections of the prescribing information:

The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation. All patients received a starting dose of 45 mg Iclusig once daily. At the time of analysis, the median duration of treatment with Iclusig was 337 days in patients with CPCML, 362 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg or 83% of the expected 45 mg dose. The events of arterial ischemia, cardiac failure, and peripheral neuropathy reported in Tables 5 and 6 below include data from an additional 13 months of follow-up (median duration of treatment CP-CML: 672 days, AP-CML: 590 days, BP-CML: 89 days, Ph+ ALL: 81 days).

Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 5. Overall, the most common non-hematologic adverse reactions ( ≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia.

The rates of treatment-emergent adverse events resulting in discontinuation were 13% in CP-CML, 11% in AP-CML, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse events that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%).

Dose modifications (dose delays or dose reductions) due to adverse reactions occurred in 74% of the patients. The most common adverse reactions ( ≥ 5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), lipase increased (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and ALT, AST, or GGT increased (6%).

Table 5: Adverse Reactions Occurring in > 10% of Patients, Any Group

System Organ Class CP-CML
(N=270)
AP-CML
(N=85)
BP-CML
(N=62)
Ph+ ALL
(N=32)
Any Grade (%) CTCAE Grade 3 / 4 (%) Any Grade (%) CTCAE Grade 3 / 4 (%) Any Grade (%) CTCAE Grade 3 / 4 (%) Any Grade (%) CTCAE Grade 3 / 4 (%)
Cardiac or Vascular disorders
  Hypertensiona 68 39 71 36 65 26 53 31
  Arterial ischemiab* 20 11 19 9 10 5 3 0
  Cardiac Failurec* 7 4 6 4 15 8 6 3
Gastrointestinal disorders
  Abdominal paind 49 10 40 8 34 6 44 6
  Constipation 37 2 24 2 26 0 47 3
  Nausea 23 1 27 0 32 2 22 0
  Diarrhea 16 1 26 0 18 3 13 3
  Vomiting 13 2 24 0 23 2 22 0
  Oral mucositise 10 1 15 1 23 0 9 3
  GI hemorrhagef 2 < 1 8 1 11 5 9 6
Blood and lymphatic system disorders
  Febrile neutropenia 1 < 1 4 4 11 11 25 25
Infections and infestations
  Sepsis 1 1 5 5 8 8 22 22
  Pneumonia 3 2 11 9 13 11 9 3
  Urinary tract infection 7 1 12 1 0 0 9 0
  Upper respiratory tract infection 11 1 8 0 11 2 0 0
  Nasopharyngitis 9 0 12 0 3 0 3 0
  Cellulitis 2 1 4 2 11 3 0 0
Nervous system disorders
  Headache 39 3 28 0 31 3 25 0
  Peripheral neuropathyg* 16 2 11 1 8 0 6 0
  Dizziness 11 0 5 0 5 0 3 0
Respiratory, thoracic, and mediastinal disorders
  Pleural effusion 3 1 11 2 13 0 19 3
  Cough 12 0 17 0 18 0 6 0
  Dyspnea 11 2 15 2 21 7 6 0
Skin and subcutaneous tissue disorders
  Rash and related conditions 54 5 48 8 39 5 34 6
  Dry skin 39 2 27 1 24 2 25 0
Musculoskeletal and connective tissue disorders
  Arthralgia 26 2 31 1 19 0 13 0
  Myalgia 22 1 20 0 16 0 6 0
  Pain in extremity 17 2 17 0 13 0 9 0
  Back pain 15 1 11 2 16 2 13 0
  Muscle spasms 12 0 5 0 5 0 13 0
  Bone pain 12 < 1 12 1 11 3 9 3
General disorders and administration site conditions
  Fatigue or asthenia 39 3 36 6 35 5 31 3
  Pyrexia 23 1 31 5 32 3 25 0
  Edema, peripheral 13 < 1 19 0 13 0 22 0
  Pain 8 < 1 7 0 16 3 6 3
  Chills 7 0 11 0 13 2 9 0
Metabolism and nutrition disorders
  Decreased appetite 8 < 1 12 1 8 0 31 0
Investigations
  Weight decreased 6 < 1 7 0 5 0 13 0
Psychiatric disorders
  Insomnia 7 0 12 0 8 0 9 0
Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI Common Terminology Criteria for Adverse Events) for assessment of toxicity. Treatment-emergent, all causality events
a derived from blood pressure (BP) measurement recorded monthly while on trial
b includes cardiovascular, cerebrovascular, and peripheral vascular ischemia
c includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, right ventricular failure
d includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort
e includes aphthous stomatitis, lip blister, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, stomatitis, tongue ulceration
f includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal hemorrhage, and upper gastrointestinal hemorrhage
g includes burning sensation, skin burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, polyneuropathy
* represents an additional 13 months of follow-up

Table 6: Serious Adverse Reactions (SAR)

  N (%)
Cardiovascular disorders
  Arterial ischemic event* 53 (11.8%)
     Cardiovascular 28 (6.2%)
     Cerebrovascular 18 (4.0%)
     Peripheral vascular 16 (3.6%)
  Hemorrhage 22 (4.9%)
     CNS hemorrhage 10 (2.2%)
     Gastrointestinal hemorrhage 10 (2.2%)
  Cardiac failure* 22 (4.9%)
  Effusions(a) 13 (2.9%)
  Atrial fibrillation 11 (2.4%)
  Venous thromboembolism 10 (2.2%)
  Hypertension 8 (1.8%)
Gastrointestinal disorders
  Pancreatitis 23 (5.1%)
  Abdominal pain 17 (3.8%)
Blood and lymphatic system disorders
  Febrile neutropenia 13 (2.9%)
  Thrombocytopenia 13 (2.9%)
  Anemia 12 (2.7%)
Infections
  Pneumonia 24 (5.3%)
  Sepsis 11 (2.4%)
General
  Pyrexia 14 (3.1%)
a includes pericardial effusion, pleural effusion, and ascites
* represents an additional 13 months of follow-up

Laboratory Abnormalities

Myelosuppression was commonly reported in all patient populations. The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 7).

Table 7: Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities

Laboratory Test CP-CML
(N=270) (%)
AP-CML
(N=85) (%)
BP-CML
(N=62) (%)
Ph+ ALL
(N=32) (%)
Hematology
  Thrombocytopenia (platelet count decreased) 36 47 57 47
  Neutropenia (ANC decreased) 24 51 55 63
  Leukopenia (WBC decreased) 14 35 53 63
  Anemia (Hgb decreased) 9 26 55 34
  Lymphopenia 10 26 37 22
ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count
*Reported using NCI-CTC-AE v 4.0

Table 8: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities

Laboratory Test Safety Population
N=449
Any Grade* (%) CTCAE Grade 3/4 (%)
Liver function tests
  ALT increased 53 8
  AST increased 41 4
  Alkaline phosphatase increased 37 2
  Albumin decreased 28 1
  Bilirubin increased 19 1
Pancreatic enzymes
  Lipase increased 41 15
  Amylase increased 3 < 1
Chemistry
  Glucose increased 58 6
  Phosphorus decreased 57 8
  Calcium decreased 52 1
  Sodium decreased 29 5
  Glucose decreased 24 0
  Potassium decreased 16 2
  Potassium increased 15 2
  Sodium increased 10 < 1
  Bicarbonate decreased 11 < 1
  Creatinine increased 7 < 1
  Calcium increased 5 0
  Triglycerides increased 3 < 1
ALT=alanine aminotransferase, AST=aspartate aminotransferase.
*Graded using NCI-CTC-AE v 4.0

Read the Iclusig (ponatinib tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Based on in vitro studies, ponatinib is a substrate of CYP3A and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see CLINICAL PHARMACOLOGY].

Drugs That Are Strong Inhibitors Of CYP3A Enzymes

In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see CLINICAL PHARMACOLOGY]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced [see DOSAGE AND ADMINISTRATION]. Patients taking concomitant strong CYP3A inhibitors may be at increased risk for adverse reactions [see CLINICAL PHARMACOLOGY].

Drugs That Are Strong Inducers Of CYP3A Enzymes

Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John's Wort) with Iclusig should be avoided unless the benefit outweighs the risk of decreased ponatinib exposure. Monitor patients for reduced efficacy. Selection of concomitant medication with no or minimal CYP3A induction potential is recommended. In a drug interaction study in healthy volunteers, co-administration of Iclusig following multiple doses of rifampin resulted in decreased ponatinib AUC0-inf and Cmax values by 62% and 42%, respectively [see CLINICAL PHARMACOLOGY].

Drugs That Elevate Gastric pH

Iclusig may be co-administered with gastric pH-elevating medications. In a drug interaction study in healthy volunteers, coadministration of Iclusig following multiple doses of lansoprazole resulted in a minimal (6%) decrease in ponatinib exposure. [see CLINICAL PHARMACOLOGY].

Drugs That Are Substrates Of The P-gp Or ABCG2 Transporter Systems

In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

Last reviewed on RxList: 8/7/2014
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
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