Tasigna

Nilotinib (Nilotinib) instructions
Common name: Nilotinib
Trade name: Tasigna
Full names: Nilotinib, Tasina, Nilotinib, Tasigna

Indications:
For adult patients with Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+CML) in the chronic phase or accelerated phase who are resistant or intolerant to previous treatments (including imatinib).

Usage and Dosage:
1. The initial treatment of this product should be carried out under the guidance of a physician with experience in treating CML patients.
2. The definition of imatinib resistance is: failure to achieve complete hematological remission after 3 months of imatinib treatment, failure to achieve cytogenetic remission after 6 months of treatment, or failure to achieve major cytogenetic remission after 12 months of treatment, loss of complete hematological remission or cytogenetic remission, disease progression, or the emergence of drug-resistant Bcr-Abl kinase mutations.
3. Imatinib intolerance is defined as: a patient discontinues imatinib treatment due to the persistence of grade 3 or 4 adverse events at any dose and/or treatment period despite best supportive care; or, despite best supportive care, a grade 2 adverse event related to imatinib treatment persists for ≥1 month or recurs more than 3 times, regardless of dose reduction or discontinuation of treatment.
4. The recommended dose is 400mg twice a day, about 12 hours apart, and should not be taken with food. Do not eat for at least 2 hours before taking the medicine and for at least 1 hour after taking the medicine.
5. As long as the patient continues to benefit, treatment with this product should continue.
6. The capsule should be swallowed completely with water. The capsule should not be chewed or sucked, and the capsule should not be opened. Hands should be washed immediately after contact with capsules. Be careful not to inhale any powder in the capsule (e.g. if the capsule is damaged) or allow the powder to come into contact with the skin or mucous membranes. If skin contact occurs, wash area with soap and water. If powder comes into contact with eyes, flush with water. If the powder from the capsule is spilled, it should be wiped up with gloves and a disposable wet towel, placed in a sealed container and discarded properly.
7. For patients who cannot swallow capsules, the contents of the capsule can be mixed with a teaspoon of applesauce, and should be taken immediately after mixing. No more than one teaspoon of applesauce, and no other foods other than applesauce.
8. Treatment should be followed as prescribed by the doctor. However, if a dose is missed, the patient must not take an additional dose and must take the next dose as prescribed.
9. If clinically necessary, this product can be used in combination with hematopoietic growth factors such as EPO or G-CSF, or with hydroxyurea or anagrelide.
10. Monitoring recommendations and dosage adjustments.
11. Special dosage recommendations:
(1) Children and adolescents: There have been no clinical studies conducted in children or adolescents. Therefore, it is not recommended for the treatment of patients younger than 18 years of age.
(2) Elderly patients: For patients over 65 years old, no special dose adjustment is required.
(3) Patients with renal impairment: Clinical studies have not been conducted in patients with renal impairment.
(4) Only a small part of this product and its metabolites are excreted by the kidneys. Therefore, patients with renal impairment are not expected to experience a decrease in overall clearance. In patients with renal impairment, no dose adjustment is required.
(5) Patients with liver damage: This product is not recommended for patients with liver damage whose transaminase exceeds 2.5 times the normal value or whose bilirubin rises more than 1.5 times the normal value.

Adverse reactions:
> 10%
Skin rash (33%)
Headache (31%)
Nausea (31%)
Pruritus (29%)
Fatigue (28%)
Irritability (24%)
Diarrhea (22 %)
Constipation (21%)
Vomiting (21%)
Joint pain (18%)
Cough (17%)
Extremity pain (16%)
Weakness (14%)
Muscle spasms (14%)
Myalgia (14%)
Abdominal pain (13%)
Bone pain (13%)
Back pain (12%)
Dyspnea (11%)
Nasopharyngitis (11%)
weeks Periedema (11%)

1-10%
Dizziness
Insomnia
Paresthesia
QT prolongation

HTN
Palpitations
QT prolongation
Hyperglycemia
Hyperkalemia
Hypomagnesemia
Neutropenia
Pancytopenia

<1%
Peripheral arterial occlusive disease
Tumor lysis syndrome
Aortic valve sclerosis
Abscess
Amnesia
Dehydration

Post-marketing reports
Infection: hepatitis B virus reactivation
Sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis
Thrombotic microangiopathy

Contraindications:
1. Those who are allergic to the active substance of this product or any excipient ingredients.
2. It is contraindicated in patients with hypokalemia, hypomagnesemia or long QT syndrome.

Notes:
1. Bone marrow suppression: This product can cause grade 3/4 thrombocytopenia, neutropenia and anemia. It occurs more frequently in CML patients who are resistant or intolerant to imatinib, especially those in the accelerated phase of CML. A complete blood count should be performed every 2 weeks for the first 2 months and then monthly or as clinically indicated. Myelosuppression is generally reversible and can be controlled by temporarily discontinuing this product or reducing the dose.
2. QT interval prolongation: This product has been shown to prolong ventricular repolarization, which can be detected by the QT interval on the electrocardiogram in a dose-dependent manner. QT prolongation can cause torsade de pointes, which may cause syncope, convulsions, and/or death. ECGs should be performed regularly at baseline, 7 days after starting medication, when clinically indicated, and after dose adjustment.
3. This product is contraindicated in patients with hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia and hypomagnesemia should be corrected before using this product, and electrolytes should be monitored regularly during treatment. Clinically significant prolongation of the QT interval may occur if this product is taken with food (an inappropriate method of administration) and/or with strong CYP3A4 inhibitors and/or other drugs known to potentially prolong QT. Therefore, coadministration with food must be avoided, and drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. The presence of hypokalemia and hypomagnesemia may increase the patient's risk for QT prolongation.
4. In a phase III study of newly diagnosed Ph+CML chronic phase patients, in the 300 mg twice daily dose group of this product, it was observed that the mean time-averaged QTcF interval at steady state changed by 6 milliseconds compared with baseline. At the recommended 300 mg twice daily dose group, no patient had an absolute QTcF greater than 480 msec and no torsade de pointes events were observed.
5. In a phase II clinical study targeting patients with imatinib-resistant or intolerant chronic-phase and accelerated-phase CML, subjects received 400 mg of nilotinib twice daily. It was observed that the mean time-averaged QTcF interval at steady state changed by 5 and 8 milliseconds from baseline, respectively. In 4 patients (500 ms of total patients).
6. In exposure studies with healthy volunteers, exposures were comparable to those observed in patients, and the mean time-averaged QTcF interval net of placebo changed from baseline by 7 ms (CI ± 4 ms). No patient had a QTcF >450 ms. In addition, no clinically relevant arrhythmias were observed during the trial. In particular, no torsades de pointes (either transient or sustained) were observed. 7. Use this product with caution in patients with QTc prolongation or risk for significant QTc prolongation, such as patients with uncontrolled or clinically significant cardiac disease. Includes recent myocardial infarction, congestive heart failure, unstable angina, or clinically significant bradycardia.
8. Sudden death: In clinical trials, sudden death events were rare (0.1 to 1%) in imatinib-resistant or intolerant CML patients in the chronic phase or accelerated phase who had a history of heart disease or significant risk of heart disease and were treated with this product. When combined with other drugs, complications other than underlying malignancy occur more frequently, and ventricular repolarization abnormalities may be a major factor. Based on postmarketing exposure (patient-years), the estimated spontaneous reporting rate of sudden death was 0.02% per patient-year. No sudden deaths were reported in the Phase III study of patients with newly diagnosed Ph+CML chronic phase.
9. Cardiovascular events: Cardiovascular events have been reported in a randomized, phase III study of nilotinib in patients with newly diagnosed Ph+CML chronic phase, and in post-marketing reports. Over a median treatment period of 48 months in clinical trials, grade 3/4 cardiovascular events included peripheral arterial occlusive disease (1.1% and 0.4% in the 300 mg and 400 mg twice daily doses, respectively), ischemic heart disease (the incidence rates in the 300 mg and 400 mg twice daily dose groups were 2.2% and 3.2%, respectively), and ischemic cerebrovascular events (the incidence rates in the 300 mg and 400 mg twice daily dose groups were 0.7% and 1.4%, respectively). If acute signs or symptoms of a cardiovascular event occur, patients are advised to seek immediate treatment. Patients' cardiovascular status should be assessed, and cardiovascular risk factors should be monitored and treated aggressively according to standard treatment guidelines during treatment with this product.
10. Increased serum lipase: Using this product will cause increased serum lipase. It is recommended to use with caution in patients with a history of pancreatitis. Serum lipase levels should be monitored regularly. If elevated lipase is associated with abdominal symptoms, administration of this product should be interrupted and appropriate diagnosis should be made to rule out pancreatitis.
11. Abnormal liver function: Use of this product may cause increases in bilirubin, ALT/AST and alkaline phosphatase, and liver function tests should be performed regularly.
12. Electrolyte abnormalities: Use of this product may cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcium and hyponatremia. Electrolyte abnormalities must be corrected before starting use of this product, and electrolytes should be monitored regularly during treatment.
13. Drug interactions: Avoid using strong CYP3A4 inducers or drugs that prolong the QT interval. If the patient must take such drug treatment, he should consider stopping taking this product; if the treatment of this product cannot be stopped and the above drugs need to be taken at the same time, the QT interval should be closely monitored.
14. The combined use of this product with potential CYP3A4 inducers may reduce the exposure of nilotinib to a clinically relevant level. Therefore, in patients receiving this product, alternative therapies with lower CYP3A4 induction potential should be selected for concomitant use.
15. The role of food: Eating will increase the bioavailability of this product. This product should not be taken with food. Avoid eating within 2 hours before taking the medicine and within 1 hour after taking the medicine. Grapefruit juice and other foods known to inhibit CYP3A4 should be avoided at all times.
16. For patients who cannot swallow capsules, the contents of the capsule can be mixed with a teaspoon of applesauce. The mixture should be taken immediately. No more than one teaspoon of applesauce, and no other foods other than applesauce.
17. Liver damage: Liver damage has a slight impact on the pharmacokinetics of this product. Compared with subjects with normal hepatic function in the control group, administration of a single dose of this product in patients with mild, moderate, or severe hepatic impairment resulted in an increase in AUC of 35%, 35%, and 19%, respectively. The predicted Cmax of this product at steady state increased by 29%, 18% and 22% respectively. Patients with ALT and/or AST >2 and 5 (or >5, if disease-related) times the upper limit of normal and/or total bilirubin >1 and 5 times the upper limit of normal have been excluded from clinical studies. This product is mainly metabolized by the liver. Therefore, the exposure of patients with hepatic impairment may be increased. Caution is recommended in patients with hepatic impairment, and these patients should be closely monitored for QT interval prolongation.
18. Total gastrectomy: In patients with total gastrectomy, the bioavailability of this product may be reduced. More frequent follow-up should be considered in such patients.
19. Oncolytic syndrome: There are cases of oncolytic syndrome in patients treated with this product. Most cases demonstrate disease progression, high white blood cell counts, and/or dehydration. Due to the potential for oncolytic syndrome (TLS), it is recommended that clinically apparent dehydration be corrected and hyperuricemia treated before initiating treatment with AZA.
20. Lactose: This product contains lactose, so it is not recommended for patients with hereditary galactose intolerance, severe lactose deficiency or glucose-galactose malabsorption.
21. Laboratory tests: Patients receiving this product should undergo laboratory tests at a certain frequency based on the doctor's judgment.
(1) Blood lipids: In a phase III study in newly diagnosed CML patients, grade 3 or 4 cholesterol elevations were seen in 1.1% of patients receiving nilotinib 400 mg twice daily; however, no grade 3 or 4 cholesterol elevations were seen in the 300 mg twice daily dose group. It is recommended that serum lipids be assessed before initiating treatment with this product and if any clinical indication occurs during treatment.
(2) Blood glucose: In a phase III study in newly diagnosed CML patients, 5.8% of patients receiving nilotinib 400 mg twice daily experienced grade 3 or 4 blood glucose elevations; 6.5% of patients receiving 300 mg twice daily developed grade 3 or 4 blood glucose elevations. It is recommended to assess blood glucose levels before initiating treatment with this product and to monitor if any clinical indication occurs during treatment. If the examination suggests the need for treatment, your doctor should treat it according to local practice and treatment guidelines.
22. Effect on driving ability and ability to operate machines: No research has been conducted on the effect of this product on driving ability and ability to operate machines. Adverse reactions such as dizziness, nausea and vomiting may occur during treatment with this product, so caution should be used when driving or operating machinery.
23. Medication for pregnant and lactating women:
(1) Women of childbearing age: Women of childbearing age must take effective contraceptive measures while receiving this product and for at least 2 weeks after the end of treatment.
(2) Pregnancy: There are no data on the use of this product in pregnant women. There is no evidence of teratogenicity in animal studies, but embryotoxicity and fetal toxicity have been observed at doses that cause maternal toxicity. This product should not be taken during pregnancy and if use during pregnancy is necessary, the patient must be informed of the potential toxicity to the fetus. While taking this product, male patients and female patients who may become pregnant must use effective contraceptive measures.
(3) Breastfeeding: It is unclear whether this product is excreted through human milk. Animal studies have shown that this product passes into breast milk. Women taking this product should not breastfeed.
(4) Fertility: The impact of nilotinib on male and female fertility is unknown. In animal experiments, no effects on sperm count/motility or fertility were observed in female and male rats at the highest doses tested (approximately 5 times higher than the recommended human dose).
24. Medication in children: There are no clinical studies conducted in children or adolescents. Therefore, it is not recommended for the treatment of patients younger than 18 years of age.
25. Medication for the elderly: For patients over 65 years old, no special dose adjustment is required.
26. Drug overdose: Cases of drug overdose have been reported. Some people swallowed unknown doses of nilotinib capsules with alcohol and other drugs, resulting in neutropenia, vomiting, and drowsiness. When overdose occurs, the patient should be closely observed and given appropriate supportive care.

Storage:
Save below 30℃.

Mechanism of action:
1. Nilotinib is a BCR-ABL kinase inhibitor. Nilotinib binds to and stabilizes the inactive conformation of the ABL protein kinase site. In vitro, nilotinib inhibits BCR-ABL kinase-mediated proliferation of murine leukemia cell lines and cell lines derived from Ph+ CML patients. Among the 33 mutations tested, nilotinib was able to overcome imatinib resistance caused by 32 BCR-ABL kinase mutations. Due to this biochemical activity, nilotinib selectively inhibits proliferation and induces apoptosis in BCR-ABL cell lines and Philadelphia chromosome-positive primary leukemia cells in all CML patients. Nilotinib inhibits autophosphorylation of the following kinases: Bcr-Abl (20-60nM), PDGFR (69nM), and c-Kit (210nM). In vivo, nilotinib reduced tumor volume in a murine BCR-ABL xenograft model. In murine models of CML, nilotinib as monotherapy reduced tumor burden and prolonged survival after oral administration.
2. Nilotinib has an inhibitory effect on PDGF, Kit, CSF-1R, DDR and Ephrin receptor kinase within the concentration range achieved after oral administration under the recommended CML treatment dose conditions. Furthermore, nilotinib had little or no effect on most other protein kinases tested, including Src.

Efficacy and safety:
In vitro studies have shown that it can selectively inhibit bcr-aLl autophosphorylation and reduce the proliferation and development ability of wild-type bcr-aLl and Gleevec-resistant mutant cells. Effects of Dashina (nilotinib) u2003 Treatment with Dashina (nilotinib) is effective for most patients with advanced CML. For patients in the accelerated phase, the overall hematologic response rate (normalization of white blood cell count) was 72%, while the cytogenetic response rate (reduction or disappearance of the Ph chromosome) was 48%. In blast crisis patients, these two response rates were 39% and 27%, respectively.
Phase II clinical studies have shown that Daxina (nilotinib) is effective in 46% of patients with Gleevec resistance and has fewer side effects. Common toxic reactions (such as fluid retention, body surface edema, and weight gain) that are common in Gleevec treatment are not usually seen. Adverse effects of Nilotinib: Researchers believe that Nilotinib is generally well tolerated. Common adverse events include bone marrow suppression, transient elevated blood bilirubinemia, and rash. In addition, the researchers observed that toxicities commonly seen with Gleevec (imatinib) treatment (e.g., fluid retention, surface edema, weight gain) or, very rarely, pleural and pericardial effusions were not generally seen with Dashina.