Nilotinib

L01X - Other antineoplastic agents ATC L01XE08 Small molecule approved 2007 Oral First-in-class Black-box warning

JFDA label: Tasigna

⚠ Black-Box Warning

QT Prolongation and Sudden Deaths:

Mechanism of Action

Nilotinib is a selective tyrosine kinase inhibitor that targets BCR-ABL kinase, c-KIT and platelet derived growth factor receptor (PDGFR); it does not have activity against the SRC family. Nilotinib inhibits BCR-ABL mediated proliferation of leukemic cell lines by binding to the ATP-binding site of BCR-ABL and inhibiting tyrosine kinase activity. Nilotinib has activity in imatinib-resistant BCR-ABL kinase mutations.

Indications

Approved

Chronic myelogenous leukemia

Off-label

Acute lymphoblastic leukemia (ALL), Philadelphia chromosome-positive (Ph+)
Gastrointestinal stromal tumor (GIST) (refractory)

Class profile

mechanismClass	Tyrosine kinase inhibitor (TKI)
targetMolecule	BCR-ABL,KIT,PDGFR
targetPathway	BCR-ABL signaling
generation	2nd generation ABL TKI
primaryTumors	CML
resistanceMechanisms	T315I and E255K/V (primary resistance),Y253H,F359C/V
source	NCCN/OncoKB/Goodman&Gilman13ed

Contraindications

Source: Lexicomp

Additional contraindications (not in the US labeling): Hypersensitivity to nilotinib or any component of the formulation Absolute
Hypokalemia, hypomagnesemia, or long QT syndrome Absolute
persistent QTc >480 msec Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (20)

Very Common hypertension · Peripheral edema

Common angina pectoris · cardiac arrhythmia (including AV block, atrial fibrillation, bradycardia, cardiac flutter, extrasystoles, and tachycardia) · cerebral ischemia · chest discomfort · chest pain (including noncardiac) · flushing · Ischemic heart disease · palpitations · pericardial effusion · peripheral arterial disease · prolonged Q-T interval on ECG

Not Known Hypotension · occlusive arterial disease (basilar, peripheral) · pericarditis · reduced ejection fraction · shock (hemorrhagic) · thrombosis · ventricular dysfunction

Nervous system disorders (24)

Very Common dizziness · fatigue · Headache · insomnia

Common Anxiety · depression · flank pain · hypoesthesia · malaise · myasthenia · pain · paresthesia · peripheral neuropathy · vertigo · voice disorder

Not Known Amnesia · breast induration · cerebral edema · confusion · disorientation · dysesthesia · dysphoria · lethargy · restless leg syndrome

Hepatobiliary disorders (7)

Very Common Hepatic: Increased serum ALT · hyperbilirubinemia · increased serum AST

Common Ascites · hepatic insufficiency · increased serum alkaline phosphatase

Not Known Hepatomegaly

Renal and urinary disorders (5)

Common Pollakiuria

Not Known Hematuria · Renal failure · urinary incontinence · urine discoloration

Blood and lymphatic system disorders (19)

Very Common anemia · Neutropenia · thrombocytopenia

Common Bruise · cutaneous papilloma · decreased hemoglobin · eosinophilia · febrile neutropenia · hemophthalmos · hemorrhage · leukopenia · lymphocytopenia · pancytopenia

Not Known Increased parathyroid hormone · leukocytosis · paraproteinemia · petechiae · retroperitoneal hemorrhage · thrombocythemia

Immune system disorders (2)

Common Change in serum protein (decreased globulins)

Not Known Hypersensitivity

Metabolism and nutrition disorders (29)

Very Common hyperglycemia · hypophosphatemia · increased serum cholesterol · Increased serum glucose · increased serum triglycerides

Common Decreased serum albumin · diabetes mellitus · fluid retention · hypercalcemia · hypercholesterolemia · hyperkalemia · hyperlipidemia · hyperphosphatemia · hypertriglyceridemia · hypocalcemia · hypokalemia · hypomagnesemia · hyponatremia · increased gamma-glutamyl transferase · increased HDL cholesterol · increased VLDL · weight gain · weight loss

Not Known Altered hormone level (insulin C-peptide decreased) · hypermenorrhea · hyperparathyroidism (secondary) · hyperuricemia · hypoglycemia · thyroiditis

Gastrointestinal disorders (28)

Very Common abdominal pain · constipation · decreased appetite · diarrhea · increased serum lipase · Nausea · upper abdominal pain · vomiting

Common abdominal distension · abdominal distress · dysgeusia · Dyspepsia · flatulence · gastroenteritis · gastrointestinal hemorrhage · increased serum amylase · pancreatitis

Not Known Cholestasis · enterocolitis · gastric ulcer (perforation possible) · gingivitis · hematemesis · hemorrhoids · hiatal hernia · intestinal obstruction · oral lesion (papilloma) · rectal hemorrhage · ulcerative esophagitis

Skin and subcutaneous tissue disorders (27)

Very Common alopecia · night sweats · pruritus · Skin rash · xeroderma

Common Acne vulgaris · dermatitis (including allergic and acneiform) · eczema · erythema · folliculitis · hyperhidrosis · urticaria

Not Known Dermal ulcer · erythema multiforme · erythema nodosum · exfoliative dermatitis · furuncle · hyperkeratosis · palmar-plantar erythrodysesthesia · psoriasis · skin atrophy · skin blister · skin discoloration · skin hyperpigmentation · skin hypertrophy · skin photosensitivity · tinea pedis

Musculoskeletal and connective tissue disorders (11)

Very Common Arthralgia · back pain · limb pain · muscle spasm · musculoskeletal pain · myalgia · ostealgia · weakness

Common Increased creatine phosphokinase · neck pain

Not Known Arthritis

Eye disorders (13)

Common conjunctivitis · eye pruritus · Eyelid edema · periorbital edema · xerophthalmia

Not Known Blepharitis · diplopia · eye pain · optic neuritis · papilledema · photophobia · retinopathy (central serous chorioretinopathy) · swelling of eye

Ear and labyrinth disorders (3)

Not Known Auditory impairment · otalgia · tinnitus

Infections and infestations (5)

Very Common Influenza

Not Known Abscess · anal abscess · reactivation of HBV · sepsis

General disorders and administration site conditions (6)

Very Common Fever

Not Known Benign nodule (sebaceous hyperplasia) · cyst (dermal) · Local swelling (nipple) · localized edema · troponin increased

Respiratory, thoracic and mediastinal disorders (12)

Very Common Cough · dyspnea · flu-like symptoms · nasopharyngitis · oropharyngeal pain · upper respiratory tract infection

Common epistaxis · hoarseness · Pleural effusion · pulmonary edema

Not Known Pulmonary hypertension · wheezing

Dosing

Source: Lexicomp

Note: If clinically indicated, may be administered in combination with hematopoietic growth factors (eg, erythropoietin, filgrastim) and with hydroxyurea or anagrelide. Acute lymphoblastic leukemia (ALL), Philadelphia chromosome-positive (Ph+), newly diagnosed (off-label use): Oral: 400 mg twice daily starting on day 8 of induction chemotherapy (in combination with daunorubicin, vincristine, and prednisolone); continue up to the start of stem cell transplant conditioning or until the end of consolidation therapy. Patients who completed 5 cycles of consolidation treatment received 2 years of nilotinib maintenance. Patients who underwent allogeneic stem cell transplant did not receive nilotinib after transplant (Kim 2015). ALL, Ph+, relapsed/refractory (off-label use): Oral: 400 mg twice daily (Ottmann 2013) Chronic myeloid leukemia (CML), Ph+, newly-diagnosed in chronic phase: Oral: 300 mg twice daily (Kantarjian 2011b; Saglio 2010) Discontinuation of therapy (following a sustained molecular response [MR4.5]): May consider nilotinib discontinuation in patients who have been treated with nilotinib for at least 3 years, maintained a molecular response of at least MR4.0 (corresponding to BCR-ABL/ABL ≤0.01% IS) for 1 year (prior to discontinuation), achieved an MR4.5 (corresponding to BCR-ABL/ABL ≤0.0032% IS) for the last assessment taken immediately prior to discontinuation, been confirmed to express the typical BCR-ABL transcripts (e13A2/b2a2 or e14a2/b3a2), no history of accelerated phase or blast crisis, and no history of prior attempts of treatment-free remission discontinuation that resulted in relapse. Reinitiation of therapy: Patients who lose major molecular response after nilotinib discontinuation must reinitiate treatment within 4 weeks at the dose used prior to discontinuation. Monitor BCR-ABL transcript levels monthly until major molecular response is re-established and every 12 weeks thereafter. BCR-ABL kinase domain mutation testing should be performed if major molecular response is not achieved after 3 months of therapy reinitiation. CML, Ph+, resistant or intolerant in accelerated phase: Oral: 400 mg twice daily (le Coutre 2012) CML, Ph+, resistant or intolerant in chronic phase: Oral: 400 mg twice daily (Kantarjian 2007; Kantarjian 2011a) Discontinuation of therapy (following a sustained molecular response [MR4.5]): May consider nilotinib discontinuation in patients with CML in chronic phase (resistant or intolerant to prior imatinib therapy) who have been treated with nilotinib for at least 3 years, been treated with imatinib (only) prior to nilotinib treatment, achieved an MR4.5 (corresponding to BCR-ABL/ABL ≤0.0032% IS), achieved a sustained MR4.5 for a minimum of 1 year immediately prior to discontinuation, been confirmed to express the typical BCR-ABL transcripts (e13A2/b2a2 or e14a2/b3a2), no history of accelerated phase or blast crisis, and no history of prior attempts of treatment-free remission discontinuation that resulted

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied in patients with serum creatinine >1.5 times ULN); however, nilotinib and its metabolites have minimal renal excretion; dosage adjustments for renal dysfunction may not be necessary.

Hepatic impairment at treatment initiation: Note: Consider alternative therapies first if possible; recommendations vary by indication Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase: Mild to severe impairment (Child-Pugh class A, B, or C): Initial: 200 mg twice daily; may increase to 300 mg twice daily based on patient tolerability Resistant or intolerant Ph+ CML in chronic or accelerated phase: Mild to moderate impairment (Child-Pugh class A or B): Initial: 300 mg twice daily; may increase to 400 mg twice daily based on patient tolerability Severe impairment (Child-Pugh class C): Initial: 200 mg twice daily; may increase to 300 mg twice daily and then further increase to 400 mg twice daily based on patient tolerability Hepatotoxicity during treatment: If bilirubin ≥ grade 3: Withhold treatment, monitor bilirubin, resume treatment at 400 mg once daily when bilirubin returns to ≤ grade 1 If ALT or AST ≥ grade 3: Withhold treatment, monitor transaminases, resume treatment at 400 mg once daily when ALT or AST returns to ≤ grade 1

Warnings & Precautions

Source: Lexicomp

Bone marrow suppression

Reversible myelosuppression, including grades 3 and 4 thrombocytopenia, neutropenia, and anemia may occur; may require dose reductions and/or treatment delay. Monitor blood counts every 2 weeks for the first 2 months, then monthly.

Cardiovascular

Cardiovascular events such as ischemic heart disease-related events, arterial vascular occlusive events, peripheral arterial occlusive disease, and ischemic cerebrovascular accident have been reported. Use caution in patients with preexisting risk factors, and monitor for new or worsening symptoms suggestive of cardiovascular events.

Electrolyte imbalance

Electrolyte abnormalities may occur during treatment, including hypophosphatemia, hyper-/hypokalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to treatment initiation; monitor periodically.

Fluid retention

Fluid retention, including pleural and pericardial effusions, ascites, and pulmonary edema were reported; may be severe. Monitor closely for signs/symptoms of fluid retention (eg, rapid weight gain or swelling) and for symptoms of respiratory or cardiac distress (eg, shortness of breath). Evaluate promptly and manage as appropriate.

Hemorrhage

Serious hemorrhagic events (including fatal events) have occurred in chronic myelogenous leukemia (CML) patients treated with nilotinib. In a clinical study comparing nilotinib and imatinib in the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase CML, hemorrhagic events (eg, GI hemorrhage, including grade 3 or 4 events) occurred more frequently in the nilotinib arm. Monitor for signs/symptoms of bleeding and manage as clinically appropriate.

Hepatotoxicity

Nilotinib may cause hepatotoxicity, including dose-limiting elevations in bilirubin, transaminases, and alkaline phosphatase; monitor liver function monthly or as clinically indicated.

QT prolongation/sudden death

May prolong the QT interval; sudden deaths have been reported. Use in patients with hypokalemia, hypomagnesemia, or long QT syndrome is contraindicated. Correct hypomagnesemia and hypokalemia prior to initiating therapy; monitor electrolytes periodically. Monitor ECG and QTc (baseline, at 7 days, with dose change, and periodically). Avoid the use of QT-prolonging agents and strong CYP3A4 inhibitors; also avoid concurrent use with antiarrhythmics; may increase the risk of potentially-fatal arrhythmias. The sudden deaths reported appear to be related to dose-dependent ventricular repolarization abnormalities. Prolonged QT interval may result in torsade de pointes, which may cause syncope, seizure, and/or death. Patients with uncontrolled or significant cardiovascular disease were excluded from studies.

Tumor lysis syndrome

Tumor lysis syndrome (TLS) has been reported in patients with resistant or intolerant CML; the majority of cases had malignant disease progression, high WBC counts, and/or dehydration. Maintain adequate hydration and treat high uric acid levels prior to nilotinib initiation. Disease-related concerns:

Gastrectomy

Consider alternative therapy or a dosage increase (with more frequent monitoring) in patients with total gastrectomy (nilotinib exposure is reduced).

Hepatic impairment

Dosage reduction is recommended in patients with hepatic impairment, along with close monitoring of QT interval. Nilotinib metabolism is primarily hepatic; exposure is increased in patients with hepatic impairment.

Pancreatitis

Use with caution in patients with a history of pancreatitis, may cause dose-limiting elevations of serum lipase and amylase; monitor. In patients with abdominal symptoms in conjunction with lipase increases, withhold treatment and consider diagnostics to exclude pancreatitis. Monitor serum lipase levels monthly or as clinically necessary. Concurrent drug therapy issues:

Drug-drug/drug-food interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. [US Boxed Warning]: Avoid concurrent use with medications known to prolong the QT interval and with strong CYP3A4 inhibitors. Special populations:

Polymorphisms

UGT1A1 polymorphisms may be a risk factor for increased toxicity (eg, hyperbilirubinemia) (Shibata 2013). Dosage form specific issues:

Lactose

Capsules contain lactose; do not use with galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption syndromes. Other warnings/precautions:

Appropriate administration

Administer on an empty stomach, at least 1 hour before and 2 hours after food. Food increased the bioavailability/serum levels which may then prolong QTc. Nilotinib solubility is decreased at higher pH; concurrent use with proton pump inhibitors is not recommended. If necessary, H2-receptor blockers may be administered ~10 hours before and 2 hours after a nilotinib dose. Antacids (eg, aluminum hydroxide, magnesium hydroxide, simethicone) may be administered ~2 hours before or 2 hours after nilotinib.

BCR-ABL transcript monitoring

Monitor BCR-ABL transcript levels in patients eligible for treatment discontinuation using an authorized test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤0.0032% IS). Information on authorized tests for detection and quantitation of BCR-ABL transcripts is available at http://www.fda.gov/CompanionDiagnostics.

Pregnancy & Lactation

Pregnancy

Based on data from animal reproduction studies and the mechanism of action, nilotinib may cause fetal harm if administered during pregnancy. Verify pregnancy status in females of reproductive potential prior to initiating therapy. Women of reproductive potential should be advised to use effective contraception during treatment and for at least 14 days after the last dose.

Lactation

Avoid

It is not known if nilotinib is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for at least 14 days after the last dose.

Monitoring

Efficacy	Tumour response (RECIST criteria, tumour markers, imaging); progression-free survival; performance status (ECOG/Karnofsky)
Toxicity	CBC with differential (nadir timing depends on agent); LFTs; renal function; ECG (QT for relevant agents); echocardiogram for cardiotoxic agents (anthracyclines, trastuzumab); cumulative dose tracking for dose-limited toxicities
Clinical pearl	Treatment response is assessed after 2–3 cycles. Grade 3–4 toxicities typically require dose reduction or interruption per protocol-defined criteria.
Counseling	Attend all scheduled blood tests and imaging appointments. Report fever > 38°C (risk of neutropaenic sepsis — medical emergency), unusual bleeding, or new pain immediately.

Chemistry & Properties

Formula	C28H22F3N7O
Molecular weight	529.53 g/mol
IUPAC name	4-methyl-N-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide
CAS	641571-10-0
PubChem CID	644241
InChIKey	`HHZIURLSWUIHRB-UHFFFAOYSA-N`
logP	6.36 (XLogP 4.9)
Polar surface area	97.62 Å²
H-bond acceptors / donors	7 / 2
Drug-likeness (QED)	0.27
Lipinski violations	2

SMILES

Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	—
CYP2C8	Inhibitor	—
CYP2C9	Substrate	—
CYP2D6	Substrate	—
CYP3A4	Inhibitor	IC₅₀ 0.5800000000000001 µM
CYP3A4	Substrate	—

Receptor binding (top 28)

Target	Action	Affinity
discoidin domain receptor tyrosine kinase 2 (DDR2)	Inhibitor	pIC50 9.3
V-abl Abelson murine leukemia viral oncogene homolog	Binding	pKi 9.0
Platelet-derived growth factor receptor, alpha polypeptid	Binding	pKi 8.7
Platelet-derived growth factor receptor, beta polypeptide (PDGFRB)	Binding	pKi 8.7
V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (avian) (KIT)	Binding	pKi 8.7
EPH receptor B2	Binding	pKi 8.4
EPH receptor B1 (EPHB1)	Binding	pKi 7.8
ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1)	Inhibitor	pIC50 7.8
EPH receptor B4 (EPHB4)	Binding	pKi 7.4
discoidin domain receptor tyrosine kinase 1 (DDR1)	Inhibitor	pIC50 7.4
Lymphocyte-specific protein tyrosine kinase (LCK)	Binding	pKi 5.7
Protein-tyrosine kinase Tie2	Binding	pKi 5.4
Fms-related tyrosine kinase 3 (FLT3)	Binding	pKi 5.4
V-yes-1 Yamaguchi sarcoma viral related oncogene homolog (LYN)	Binding	pKi 5.4
Insulin receptor (INSR)	Binding	pKi 5.4

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)CNT1 (Inhibitor)CNT3 (Inhibitor)ENT1 (Inhibitor)ENT2 (Inhibitor)MATE1 (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP1 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)OCT3 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)OATP1B1 (Substrate)OATP1B3 (Substrate)OCT1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Abarelix	major
Abiraterone	major
Adalimumab	major
Adenosine	major
Alfuzosin	major
Alimemazine	major
Amiodarone	major
Amisulpride	major
Amitriptyline	major
Amoxapine	major
Amprenavir	major
Anagrelide	major
Apalutamide	major
Apomorphine	major
Arsenic trioxide	major
Asenapine	major
Astemizole	major
Atazanavir	major
Atomoxetine	major
Azithromycin	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Bedaquiline	major
Bepridil	major
Bexarotene	major
Bicalutamide	major
Boceprevir	major
Brexpiprazole	major
Buprenorphine	major
Cabozantinib	major
Carbamazepine	major
Ceritinib	major
Certolizumab pegol	major
Chloroquine	major
Chlorpromazine	major
Ciprofloxacin	major
Cisapride	major
Citalopram	major
Cladribine	major
Clarithromycin	major

Showing 40 of 100+.

Registered Products (5)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
NILONIB 150	Capsule 150 mg	28 cap	Omicron Pharma	—
NILONIB 200	Capsule 227.38 mg	28 cap	Omicron Pharma	—
Tasigna	Capsule 200 mg	28 cap pack varies	The Jordan Drugstore Co	—
Tasigna	Capsule 200 mg	112 cap pack varies	The Jordan Drugstore Co	—
Tasigna	Tablet 150 mg	112 tab	The Jordan Drugstore Co	—