Nilonib

• Leukemia

Nilotinib is indicated in advanced renal cell carcinoma (RCC), advanced soft tissue sarcoma (STS) who have received prior chemotherapy. The efficacy of Nilotinib 200 for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.

N/A

It is contraindicated in patients with known hypersensitivity to Pazopanib or any other components of this product.

Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (Kit), interleukin-2 receptor-inducible T- cell kinase (Itk), lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). In vitro, Pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR receptors.Absorption: Pazopanib is absorbed orally with the median time to achieve peak concentrations of 2 to 4 hours after the dose. Daily dosing at 800 mg results in geometric mean AUC and Cmax of 1,037 mcg/mL and 58.1 mcg/mL (equivalent to 132 μM), respectively. There was no consistent increase in AUC or Cmax at Pazopanib doses above 800 mg.Distribution: Binding of Pazopanib to human plasma protein in vivo was greater than 99% with no concentration dependence over the range of 10 to 100 mcg/mL. In vitro, studies suggest that Pazopanib is a substrate for P-gp and BCRP.Metabolism: In vitro studies demonstrated that Pazopanib is metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C8.Elimination: Pazopanib has a mean half-life of 30.9 hours after administration of the recommended dose of 800 mg. Elimination is primarily via feces with renal elimination accounting for less than 4% of the administered dose.

Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of Pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of Pazopanib.CYP3A4 Inhibitors: Co-administration of Pazopanib with strong inhibitors of CYP3A4 (e.g., Ketoconazole, Ritonavir, Clarithromycin) increases Pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If co-administration of a strong CYP3A4 inhibitor is warranted, reduce the dose of Pazopanib to 400 mg. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of Pazopanib.CYP3A4 Inducers: CYP3A4 inducers, such as Rifampin, may decrease plasma Pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. Pazopanib should not be used if chronic use of strong CYP3A4 inducers cannot be avoided.Drugs that Inhibit Transporters: In vitro studies suggested that Pazopanib is a substrate of P- glycoprotein (P gp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of Pazopanib may be influenced by products that affect P-gp and BCRP. Concomitant treatment with strong inhibitors of P-gp or BCRP should be avoided due to the risk of increased exposure to Pazopanib. The selection of alternative concomitant medicinal products with no or minimal potential to inhibit P-gp or BCRP should be considered.Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that Pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19. Concomitant use of Pazopanib with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Co-administration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.Effect of Concomitant Use of Pazopanib and Simvastatin: Concomitant use of Pazopanib and Simvastatin increases the incidence of ALT elevations. Across monotherapy trials with Pazopanib, ALT greater than 3 x ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of Simvastatin. If a patient receiving concomitant Simvastatin develops ALT elevations, follow dosing guidelines for Pazopanib or consider alternatives to Pazopanib. Alternatively, consider discontinuing Simvastatin. Insufficient data are available to assess the risk of concomitant administration of alternative statins and Pazopanib.

Rash, pruritus, hepatotoxicity, headache, fever, fatigue, GI disturbances (nausea, constipation, diarrhoea), alopecia, asthenia, muscle spasms, arthralgia, myalgia, pain (e.g. musculoskeletal or chest pain), oedema, folliculitis, papilloma, insomnia, dizziness, vertigo, anxiety, paraesthesia, hyperhidrosis, dry skin, urticaria, acne, conjunctivitis, dry eye, flushing, dyspnoea, cough, myelosuppression (e.g. thrombocytopenia, neutropenia, and anaemia), thrombotic disorders or haemorrhage, arrhythmias, heart failure, pericarditis, palpitations, HTN, angina, MI; elevated AST/ALT, serum lipase; electrolyte imbalances.

Pazopanib doses up to 2000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2000 mg daily and 1000 mg daily, respectively. Treatment of overdose with Nilotinib should consist of general supportive measures. There is no specific antidote for overdosage of Nilotinib. Hemodialysis is not expected to enhance the elimination of Nilotinib because Pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

Pazopanib can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform a drug-associated risk. Pregnant women or women should be advised of the childbearing potential of the risk to a fetus. There is no information regarding the presence of Pazopanib or its metabolites in human milk, or their effects on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions in breastfed infants from Pazopanib, a lactating woman should be advised not to breastfeed during treatment with Pazopanib and for 2 weeks after the final dose.Females contraception: Females of reproductive potential should be advised to use effective contraception during treatment and for at least 2 weeks after the last dose of Pazopanib.Males contraception: To avoid potential drug exposure to pregnant partners and female partners of reproductive potential, male patients (including those who have had vasectomies) with female partners of reproductive potential should be advised to use condoms during treatment with Pazopanib and for at least 2 weeks after the last dose.

Hepatic Toxicity and Hepatic Impairment: In clinical trials with Pazopanib, hepatotoxicity, manifested as increases in serum transaminases (alanine transferase [ALT], aspartate aminotransferase [AST]) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Patients older than 65 years are at greater risk for hepatotoxicity. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks).QT Prolongation and Torsades De Pointes: In the RCC trials of Pazopanib, QT prolongation (greater than or equal to 500 msec) was identified on routine electrocardiogram (ECG) monitoring in 2% (11/558) of patients. Torsades de pointes occurred in less than 1% (2/977) of patients who received Pazopanib in the monotherapy trials. Pazopanib should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using Pazopanib, baseline and periodic monitoring of ECGs and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed.Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials; there were no reports of fatal hemorrhage in the STS trials. In the randomized RCC trial, 13% (37/290) of patients treated with Pazopanib and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with Pazopanib were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with Pazopanib, who had hemorrhagic events, experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with Pazopanib died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in less than 1% (2/586) of patients treated with Pazopanib.Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials and in no patients in the STS trials. In the randomized RCC trial, 2% (5/290) of patients receiving Pazopanib experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. In the randomized STS trial, 2% (4/240) of patients receiving Pazopanib experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident, and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo in either trial. Pazopanib should be used with caution in patients who are at increased risk for these events or who have had a history of these events. Pazopanib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. Venous Thromboembolic Events: In RCC and STS trials of Pazopanib, venous thromboembolic events (VTEs), including venous thrombosis and fatal pulmonary embolus (PE), have occurred. In the randomized STS trial, VTEs were reported in 5% of patients treated with Pazopanib compared with 2% with placebo. In the randomized RCC trial, the rate was 1% in both arms. Fatal PE occurred in 1% (2/240) of STS patients receiving Pazopanib and in no patients receiving placebo. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), has been reported in clinical trials of Pazopanib as monotherapy, in combination with Bevacizumab, and in combination with Topotecan. Pazopanib is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of Pazonib-200. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue Pazopanib in patients developing TMA. Manage as clinically indicated. Gastrointestinal Perforation and Fistula: In the RCC and STS trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients and 1% (4/382) of patients receiving Pazopanib, respectively. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials and in 0.3% (1/382) of these patients in the STS trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula.Interstitial Lung Disease/Pneumonitis: Interstitial lung disease (ILD)/pneumonitis, which can be fatal, has been reported in association with Pazopanib. In clinical trials, ILD/pneumonitis occurred in 0.1% of patients treated with Pazopanib.. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and discontinue Pazopanib in patients developing ILD or pneumonitis.Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving Pazopanib and may be fatal. RPLS is a neurological disorder that can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue Pazopanib in patients developing RPLS.Wound Healing: No formal trials on the effect of Pazopanib on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as Pazopanib may impair wound healing, treatment with Pazopanib should be stopped at least 7 days prior to scheduled surgery. The decision to resume Pazopanib after surgery should be based on clinical judgment of adequate wound healing. Pazopanib should be discontinued in patients with wound dehiscence.Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with Pazopanib in the randomized RCC trial and in 5% (11/240) of patients treated with Pazopanib in the randomized STS trial. No patients on the placebo arm of either trial had hypothyroidism. In RCC and STS trials of Pazopanib, hypothyroidism was reported as an adverse reaction in 4% (26/586) and 5% (20/382) of patients, respectively. Proactive monitoring of thyroid function tests is recommended.Tumor Lysis Syndrome: Cases of tumor lysis syndrome (TLS), including fatal cases, have been reported in RCC and STS patients treated with Pazopanib. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis, and treat as clinically indicated.Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of Pazopanib for serious infections. Increased Toxicity with other Cancer Therapy: Pazopanib is not indicated for use in combination with other agents. Clinical trials of Pazopanib in combination with Pemetrexed and Lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.