Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
200 mg capsules
Approved indication: chronic myeloid leukaemia
Australian Medicines Handbook section 14.2.2
Most patients who develop chronic myeloid leukaemia have an abnormal chromosome called the Philadelphia chromosome (Ph) (Aust Prescr 2006;29:76–9). This is caused by a genetic translocation of chromosomes 9 and 22. The presence of this mutation leads to the production of an abnormal tyrosine kinase which causes cells to become malignant.
The majority of patients with newly diagnosed chronic myeloid leukaemia benefit from treatment with the tyrosine kinase inhibitor imatinib. However, resistance to imatinib can arise, for example from point mutations in the tyrosine kinase which cause interference with imatinib binding.
Nilotinib is a new tyrosine kinase inhibitor which has been rationally designed to have a more selective action than imatinib. It prevents proliferation of malignant cells by binding to the abnormal tyrosine kinase. In in vitro studies, nilotinib it has been shown to inhibit the growth of 32 out of 33 imatinib-resistant cell lines. However, it is not effective against cell lines carrying the T3151 mutation.
After oral administration, peak concentrations of nilotinib are reached within three hours. Nilotinib should be taken on an empty stomach and food should not be eaten for at least two hours before and one hour after the dose. This is because the bioavailability of nilotinib is increased with food therefore the risk of toxicity is increased. The drug is metabolised mainly by cytochrome P450 3A4 and is excreted in the faeces unchanged and as metabolites.
Cytochrome P450 3A4 inhibitors (such as ketoconazole, erythromycin and grapefruit products) and inducers (such as corticosteriods, rifampicin and St John's wort) may alter serum levels of nilotinib and should be avoided. Nilotinib increases the risk of toxicity from other cytochrome P450 3A4 substrates such as simvastatin. Caution should be used with warfarin. Drugs that prolong the QT interval, such as clarithromycin and haloperidol should be avoided with nilotinib.
An initial dose-escalation trial of nilotinib showed benefits in patients with chronic myeloid leukaemia who were resistant to imatinib therapy. Nilotinib was found to be less effective in patients with blastic-phase chronic myeloid leukaemia than those in the chronic or accelerated phase of the disease.1
Two open-label phase II trials of nilotinib (400mg twice daily) have been conducted in patients with either chronic-phase2 or accelerated-phase3 chronic myeloid leukaemia who had failed to respond or were intolerant to imatinib therapy.
In the chronic-phase disease trial, around half of the patients (134 of 280) had a major cytogenetic response (0–35% Ph-positive cells in the bone marrow) to nilotinib. The median time for this response was 2.8 months. A complete haematologic response (measured by counting white blood cells, platelets, blasts, myelocytes and metamyelocytes in peripheral blood) was achieved by 74% of evaluable patients.2
In the trial of accelerated-phase disease, about a third of patients (35 of 119) had a major cytogenetic response to nilotinib and 26% (31 of 119) had a complete haematologic response after a median of seven months treatment.3 (In this trial, a third of the 119 patients had not been assessed for a haematologic response at the time of data collection.)
Nilotinib appeared to overcome imatinib resistance in many patients in these trials. However, as predicted from in vitro studies, almost all of the patients (7 of 8) carrying the T3151 mutation were resistant to nilotinib treatment.1-3
During the clinical trials, neutropenia and thrombocytopenia were seen in up to a third of patients. These were usually managed by reducing or interrupting the nilotinib dose with some patients requiring haematopoietic growth factors or platelet transfusions. As myelosuppression is common with nilotinib, complete blood counts should be performed every two weeks for the first two months and then monthly after that.
Rash, pruritus, nausea, constipation, fatigue and headache were commonly reported.1-3 Elevations in bilirubin, aspartate aminotransferase and alanine aminotransferase have been observed at daily doses of 600 mg or more. Increased concentrations of serum lipase and amylase have also been reported and caution is recommended in patients with a history of pancreatitis.
Nilotinib can potentially prolong the QT interval and sudden deaths with this drug have occurred therefore it should not be used in patients with prolonged QT interval. Electrolyte abnormalities, such as hypokalaemia and hypomagnesaemia, should be corrected before a patient starts nilotinib.
For patients who are resistant to imatinib or cannot tolerate it, nilotinib offers a second-line treatment option along with another recently approved drug, dasatinib (see New drugs, Aust Prescr 2007;30:50–5). However, like dasatinib, nilotinib is not effective for patients carrying the T3151 mutation. It is not known how nilotinib directly compares with dasatinib, but a trial of 23 patients showed that dasatinib may be effective when nilotinib therapy has failed.4
The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
- Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354:2542-551.
- Kantarjian H, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 2007;110:3540-46.
- le Coutre P, Ottmann OG, Giles F, Kim DW, Cortes J, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated phase chronic myelogenous leukemia. Blood 2008;111:1834-9.
- Quintas-Cardama A, Kantarjian H, Jones D, Nicaise C, O'Brien S, Giles F, et al. Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood 2007;109:497-9.