TASIGNA (nilotinib) Prescribing Information

2008 ‫פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר על ידו במרץ‬
TASIGNA®
(nilotinib)
200 mg hard capsules
Prescribing Information
1
Name of the medicinal product
TASIGNA® 200 mg hard capsules.
2
Qualitative and quantitative composition
Each capsule contains 200 mg nilotinib base (as hydrochloride, monohydrate)
For a full list of excipients, see section 6.1 List of excipients.
3
Pharmaceutical form
Hard capsules.
White to slightly yellowish powder in light yellow opaque hard gelatin capsules, size 0 with
red axial imprint “NVR/TKI”
TAS API MAR08 CL V1
1
REF 110407
4
Clinical particulars
4.1
Therapeutic indications
Treatment of Philadelphia chromosome positive chronic myeloid leukaemia (Ph+ CML) in
chronic or accelerated phase in patients resistant to or experiencing significant toxicity during
treatment with imatinib.
4.2
Posology and method of administration
Therapy should be initiated by a physician experienced in the treatment of patients with CML.
The recommended dose of TASIGNA is 400 mg twice daily (see section 5.2 Pharmacokinetic
properties). Treatment should be continued as long as the patient continues to benefit.
TASIGNA should be taken twice daily approximately 12 hours apart and should not be taken
with food. The capsules should be swallowed whole with water. No food should be consumed
for at least 2 hours before the dose is taken and no additional food should be consumed for at
least one hour after the dose is taken (see section 4.4 Special warnings and precautions for
use, 4.5 Interaction with other medicinal products and other forms of interaction and 5.2
Pharmacokinetic properties).
TASIGNA may be given in combination with haematopoietic growth factors such as
erythropoietin or G-CSF if clinically indicated. TASIGNA may be given with hydroxyurea or
anagrelide if clinically indicated.
Dose Adjustments or Modifications
TASIGNA may need to be temporarily withheld and/or dose reduced for haematological
toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukaemia (see
Table 1).
Table 1
Chronic Phase
or Accelerated
Phase CML at
400 mg bid
Dose Adjustments for Neutropenia and Thrombocytopenia
(ANC) < 0.5 x 109/L
1. Stop TASIGNA, and monitor blood counts
or
platelet counts
109/L
2. Resume within 2 weeks at prior dose if ANC >0.5 x
109/L and/or platelets > 50 x 109/L
<50 x
3. If blood counts remain low a drug reduction may be
required to 400 mg qd
If clinically significant moderate or severe non-haematologic toxicity develops, dosing should
be interrupted, and may be resumed at 400 mg once daily once the toxicity has resolved. If
clinically appropriate, re-escalation of the dose to 400 mg twice daily should be considered.
Asymptomatic serum lipase elevations were observed. Few of these elevations were
associated with clinical symptoms such as abdominal pain or a diagnosis of pancreatitis.
Elevations in serum lipase did not lead to treatment discontinuation in any patient. Overall,
this finding was clinically manageable in the majority of patients without requirement for
TAS API MAR08 CL V1
2
REF 110407
dose reduction or interruption. For Grade 3 to 4 lipase elevations, doses were reduced to 400
mg qd (see section 4.8 Undesirable effects).
In clinical studies, the majority of bilirubin and hepatic transaminase laboratory abnormalities
in patients were of low grade toxicity which did not require dose interruption or reduction.
Treatment discontinuation due to elevated serum bilirubin occurred in only 1 patient (0.3%).
For Grade 3 to 4 bilirubin elevations, doses were reduced to 400 mg qd (see section 4.8
Undesirable effects).
If a dose is missed the patient should not take an additional dose, but take the usual prescribed
next dose.
Children and adolescents
Clinical studies have not been conducted in children and adolescents.
Elderly patients
Approximately 30% of subjects in clinical studies were 65 or over. No major differences were
observed for safety and efficacy in patients ≥65 years of age as compared to adults 18 to 65
years of age.
Patients with renal impairment
Clinical studies have not been performed in patients with impaired renal function. Clinical
studies have excluded patients with serum creatinine concentration >1.5 times the upper limit
of the normal range.
Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance
is not anticipated in patients with renal impairment.
Patients with hepatic impairment
TASIGNA has not been investigated in patients with hepatic impairment. Clinical studies
have excluded patients with ALT and/ or AST >2.5 (or >5, if related to disease) times the
upper limit of the normal range and/or total bilirubin >1.5 times the upper limit of the normal
range. Metabolism of nilotinib is mainly hepatic.
Cardiac disorders
In clinical studies, patients were excluded with clinically significant cardiac syndromes (e.g.,
complete left bundle branch block, unstable angina, uncontrolled congestive heart failure, or
recent myocardial infarction).
4.3
Contraindications
Known hypersensitivity to nilotinib or to any of the excipients.
TAS API MAR08 CL V1
3
REF 110407
4.4
Special warnings and precautions for use
Myelosuppression
Treatment with TASIGNA is associated with thrombocytopenia, neutropenia and anaemia
(NCI CTC Grade 3/4). Occurrence is more frequent in patients with CML AP. Complete
blood counts should be performed every two weeks for the first 2 months and then monthly
thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually
managed by withholding TASIGNA temporarily or reducing the dose (see section 4.2
Posology and method of administration).
QT Prolongation
In vitro data suggest that nilotinib has the potential to prolong cardiac ventricular
repolarization (QT interval). In the Phase II study in imatinib-resistant and intolerant CML
patients in chronic and accelerated phase, the change from baseline in mean time-averaged
QTcF interval at steady state was 6 and 8 msec, respectively. QTcF of >500 msec was
observed in <1% of these patients.
In a healthy volunteer study with exposures that were comparable to the exposures observed
in patients, the time-averaged mean placebo-subtracted QTcF change from baseline was 7
msec (CI ± 4 msec). No subject had a QTcF >450 msec. Additionally, no clinically relevant
arrhythmias were observed during the conduct of the trial. In particular, no episodes of
torsade de pointes (transient or sustained) were observed.
TASIGNA should be used with caution in patients who have or may develop prolongation of
QTc. These include patients with hypokalaemia or hypomagnesaemia, patients with
congenital long QT syndrome, patients taking anti-arrhythmic medicines or other drugs that
may lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalaemia
or hypomagnesaemia must be corrected prior to TASIGNA administration.
Drug Interactions
The administration of TASIGNA with agents that are strong CYP3A4 inhibitors (including
but not limited to, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin,
ritonavir) should be avoided. Should treatment with any of these agents be required, it is
recommended that therapy with TASIGNA be interrupted if possible (see section 4.5
Interaction with other medicinal products and other forms of interaction). If transient
interruption of treatment with TASIGNA is not possible, close monitoring of the individual
for prolongation of the QT interval is indicated (see section 4.2 Posology and method of
administration, 4.5 Interaction with other medicinal products and other forms of interaction
and 5.2 Pharmacokinetic properties).
Food Effect
The bioavailability of nilotinib is increased by food. TASIGNA should not be taken in
conjunction with food (see section 4.2 Posology and method of administration and 4.5
Interaction with other medicinal products and other forms of interaction) and should be taken
2 hours after a meal. No food should be consumed for at least one hour after the dose is taken.
Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided.
TAS API MAR08 CL V1
4
REF 110407
Hepatic Impairment
Tasigna has not been investigated in patients with hepatic impairment. Clinical studies have
excluded patients with ALT and/ or AST >2.5 (or >5, if related to disease) times the upper
limit of the normal range and/or total bilirubin >1.5 times the upper limit of the normal range.
Metabolism of nilotinib is mainly hepatic. Caution is recommended in patients with hepatic
impairment (see section 4.2 Posology and method of administration).
Serum Lipase
Elevation in serum lipase has been observed. Caution is recommended in patients with
previous history of pancreatitis.
Lactose
Since the capsules contain lactose, TASIGNA is not recommended for patients with rare
hereditary problems of galactose intolerance, severe lactase deficiency or of glucose-galactose
malabsorption.
4.5
Interaction with other medicinal products and other forms of
interaction
Drugs that may increase nilotinib serum concentrations
Nilotinib is mainly metabolized in the liver, and is also a substrate for the multi-drug efflux
pump, P-glycoprotein (Pgp). Therefore, absorption and subsequent elimination of
systemically absorbed nilotinib may be influenced by drugs that affect CYP3A4 and/or Pgp.
The bioavailability of nilotinib in healthy subjects was increased by 3-fold when coadministered with the strong CYP3A4 inhibitor ketoconazole. Concurrent treatment with
strong CYP3A4 inhibitors should therefore be avoided (including but not limited to
ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin) (see
section 4.2 Posology and method of administration and 4.4 Special warnings and precautions
for use regarding QT prolongation). Alternative concomitant medications with no or minimal
CYP3A4 inhibition should be considered.
Drugs that may decrease nilotinib serum concentrations
Inducers of CYP3A4 activity could increase the metabolism of nilotinib and thereby decrease
plasma concentrations of nilotinib. The concomitant administration of medications that induce
CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John’s Wort)
may reduce exposure to nilotinib. In patients for whom CYP3A4 inducers are indicated,
alternative agents with less enzyme induction potential should be considered.
Drugs that may have their systemic concentration altered by nilotinib
Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, and CYP2D6 in vitro,
potentially increasing the concentrations of drugs eliminated by these enzymes. In addition,
single-dose administration of TASIGNA with midazolam to healthy subjects increased
midazolam exposure by 30%. Caution should be exercised when co-administering TASIGNA
with substrates of these enzymes that have a narrow therapeutic index. Since warfarin is
TAS API MAR08 CL V1
5
REF 110407
metabolized by CYP2C9 and CYP3A4 it should be given with caution. Other medications for
anticoagulation should be considered.
Anti-arrhythmic medicines and other drugs that may prolong QT
Nilotinib should be used with caution in patients who have or may develop prolongation of
QT including those patients taking anti-arrhythmic medicines such as amiodarone,
disopyramide, procainamide, quinidine and sotalol or other drugs that may lead to QT
prolongation such as chloroquine, halofantrine, clarithromycin, haloperidol and methadone
(see section 4.4 Special warnings and precautions for use).
Other interactions that may affect serum concentrations
The absorption of TASIGNA is increased if it is taken with food, resulting in higher serum
concentration (see section 4.2 Posology and method of administration, 4.4 Special warnings
and precautions for use and 5.2 Pharmacokinetic properties).
TASIGNA should not be taken in conjunction with food and should be taken 2 hours after a
meal. No food should be consumed for at least one hour after the dose is taken. Grapefruit
juice and other foods that are known to inhibit CYP3A4 should be avoided.
4.6
Pregnancy and lactation
Pregnancy
There are no data on the use of TASIGNA in pregnant women. Studies in animals showed no
teratogenicity, but embryo- and foetotoxicity was seen at doses which also showed maternal
toxicity (see section 5.3 Preclinical safety data). TASIGNA should not be used during
pregnancy unless necessary. If the drug is used during pregnancy, the patient must be
informed of the potential risk to the foetus.
Women of childbearing potential
Women of childbearing potential must be advised to use effective contraception during
treatment with TASIGNA.
Lactation
It is not known whether nilotinib is excreted in human milk. Studies in animals demonstrate
that it is excreted into breast milk. Women should not breast-feed while taking TASIGNA.
Fertility
No effects on sperm count/motility, and on fertility were noted in male and female rats up to
the highest tested dose approximately 5 times the recommended dosage for human. Sexually
active male or female patients taking TASIGNA should use adequate contraception (see
section 5.3 Preclinical safety data).
TAS API MAR08 CL V1
6
REF 110407
4.7
Effects on ability to drive and use machines
No studies on the effects of nilotinib on the ability to drive and operate machines have been
performed. Patients experiencing dizziness, visual impairment or other undesirable effects
with a potential impact on the ability to safely drive or use machines should refrain from these
activities as long as these undesirable effects persist (see section 4.8 Undesirable effects).
4.8
Undesirable effects
The data described below reflect exposure to TASIGNA in 438 patients in an open-label
multicenter study. At cut-off, 46% of patients in CML-CP had durations of exposure of 6 to
12 months and 18% of patients had durations of exposure more than 12 months; 62% of
patients in CML-AP had durations of exposure of 3 to 12 months and 10% of patients had
durations of exposure more than 12 months. The dose was 400 mg twice-daily. The median
duration of exposure in days for these CML-CP and CML-AP patients were 245 (1 to 502)
and 138 (2 to 503), respectively.
The most frequent non-haematologic drug-related adverse events were rash, pruritus, nausea,
fatigue, headache, constipation and diarrhoea. Most of these adverse events were mild to
moderate in severity. Bone pain, arthralgia, muscle spasms and peripheral oedema were
observed less commonly and have been of mild to moderate severity. Discontinuation for
adverse events regardless of causality was observed in 16% of CP and 14% of AP patients.
Treatment emergent haematologic toxicities included thrombocytopenia (27%), neutropenia
(15%), and anaemia (13%). Pleural and pericardial effusions as well as complications of fluid
retention occurred in 1% of patients receiving TASIGNA. Congestive heart failure was
observed in 1% of patients. Gastrointestinal and CNS haemorrhage was reported in 3% and
1% of patients, respectively.
QTcF exceeding 500 msec was observed in < 1% of patients. No episodes of Torsade de
Pointes (transient or sustained) were observed.
Non-haematologic adverse reactions (excluding laboratory abnormalities) that are reported in
at least 5% of the patients in TASIGNA clinical studies are shown in Table 2. These are
ranked under heading of frequency, the most frequent first, using the following convention:
very common (≥ 1/10) or common (≥ 1/100, ≤ 1/10).
Table 2
System Organ
Class
Adverse Reactions (> 5% of all patients, N=438)
Frequency
Adverse
Reaction
All grades
Grade
3/4
Chronic
Phase
Grade
3/4
Accelerated
Phase
Grade 3/4
%
%
%
%
Metabolism and
nutrition
disorders
Common
Anorexia
5
0
0
0
Nervous system
disorders
Very common
Headache
15
1
2
<1
Gastrointestinal
disorders
Very common
Very common
Nausea
Constipation
19
11
<1
0
<1
0
<1
0
TAS API MAR08 CL V1
7
REF 110407
System Organ
Class
Skin and
subcutaneous
tissue disorders
Musculoskeletal
and connective
tissue disorders
General
disorders and
administration
site conditions
Frequency
Adverse
Reaction
All grades
Grade
3/4
Chronic
Phase
Grade
3/4
Accelerated
Phase
Grade 3/4
%
%
%
%
Very common
Common
Common
Very common
Very common
Common
Diarrhoea
Vomiting
Abdominal pain
Rash
Pruritus
Alopecia
10
9
5
26
22
7
2
<1
<1
1
<1
0
2
<1
<1
<1
<1
<1
0
<1
0
0
0
0
Common
Common
Common
Common
Very common
Common
Common
Myalgia
Arthralgia
Muscle spasms
Bone pain
Fatigue
Asthenia
Oedema
peripheral
8
6
6
6
16
6
5
<1
<1
0
<1
<1
0
0
<1
<1
0
<1
<1
0
0
<1
0
0
0
<1
0
0
Additional Data from Clinical Trials
The following adverse reactions were reported in patients in the TASIGNA clinical studies at
a frequency of less than 5% (common is ≥ 1/100 and < 1/10; uncommon is >1/1,000 and
<1/100; single events are captured as unknown in frequency). For laboratory abnormalities,
very common events (≥1/10) not included in Table 2 are also reported. These adverse
reactions are included based on clinical relevance and ranked in decreasing order of frequency
within each category.
Infections and Infestations: Uncommon: pneumonia, urinary tract infection,
gastroenteritis, pharyngitits. Unknown frequency: sepsis, bronchitis, herpes simplex,
candidiasis.
Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia.
Unknown frequency: thrombocythaemia, leukocytosis.
Endocrine
Disorders:
hypothyroidism, thyroiditis.
Uncommon:
hyperthyroidism.
Unknown
frequency:
Metabolism and Nutrition Disorders: Common: hypomagnesaemia, hyperkalaemia,
hyperglycaemia.
Uncommon:
hypokalaemia,
hyponatraemia,
hypocalcaemia,
hypophosphataemia, dehydration, decreased appetite, increased appetite. Unknown frequency:
diabetes mellitus, hypercalcaemia, hyperphosphataemia.
Psychiatric Disorders: Common: insomnia. Uncommon: depression, anxiety. Unknown
frequency: disorientation, confusional state.
Nervous System Disorders: Common: dizziness, paraesthesia. Uncommon: intracranial
haemorrhage, migraine, tremor, hypoaesthesia, hyperaesthesia. Unknown frequency: brain
TAS API MAR08 CL V1
8
REF 110407
oedema, loss of consciousness, optic neuritis, peripheral neuropathy.
Eye Disorders: Uncommon: eye haemorrhage, visual acuity reduced, periorbital oedema,
conjunctivitis, eye irritation, dry eye. Unknown frequency: papilloedema, diplopia, vision
blurred, photophobia, eye swelling, blepharitis, eye pain.
Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired,
ear pain.
Cardiac Disorders: Common: palpitations, electrocardiogram QT prolonged. Uncommon:
cardiac failure, angina pectoris, atrial fibrillation, pericardial effusion, coronary artery disease,
cardiomegaly, cardiac murmur, bradycardia. Unknown frequency: myocardial infarction,
ventricular dysfunction, pericarditis, cardiac flutter, extrasystoles.
Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis,
haematoma. Unknown frequency: shock haemorrhagic, hypotension, thrombosis.
Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnoea, dyspnoea
exertional, cough, dysphonia. Uncommon: pulmonary oedema, pleural effusion, interstitial
lung disease, pleuric pain, pleurisy, epistaxis, pharyngolaryngeal pain, throat irritation.
Unknown frequency: pulmonary hypertension.
Gastrointestinal Disorders: Common: abdominal discomfort, dyspepsia, flatulence.
Uncommon: pancreatitis, gastrointestinal haemorrhage, melaena, abdominal distension,
mouth ulceration, gastroesophageal reflux, stomatitis, dry mouth. Unknown frequency:
gastrointestinal ulcer perforation, retroperitoneal haemorrhage, haematemesis, gastric ulcer,
oesophagitis ulcerative, subileus.
Hepatobiliary Disorders: Uncommon: hepatitis. Unknown frequency: hepatotoxicity,
hepatomegaly, jaundice.
Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria,
erythema, hyperhidrosis, dry skin. Uncommon: exfoliative rash, ecchymosis, swelling face.
Unknown frequency: erythema nodosum, skin ulcer, petechiae, photosensitivity.
Musculoskeletal and Connective Tissue Disorders: Common: musculoskeletal chest
pain, musculoskeletal pain. Uncommon: muscular weakness. Unknown frequency: arthritis,
joint swelling.
Renal and Urinary Disorders: Uncommon: dysuria, micturition urgency, nocturia
pollakiuria. Unknown frequency: renal failure, haematuria, urinary incontinence.
Reproductive System and Breast Disorders: Uncommon: breast pain, gynaecomastia,
erectile dysfunction.
General Disorders and Administration Site Conditions: Common: pyrexia.
Uncommon: chest pain, face oedema, gravitational oedema, influenza-like illness, chills,
malaise.
Investigations: Very common: lipase increased. Common: blood amylase increased,
alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin
increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood
creatinine phosphokinase increased, blood glucose increased, weight decreased, weight
increased. Uncommon: blood lactate dehydrogenase increased, blood glucose decreased,
TAS API MAR08 CL V1
9
REF 110407
blood creatinine increased, blood urea increased. Unknown frequency: troponin increased,
blood potassium decreased, blood bilirubin unconjugated increased.
Clinically relevant or severe abnormalities of routine haematologic or biochemistry laboratory
values are presented in Table 3.
Table 3
Grade 3/4 Laboratory Abnormalities
Haematologic Parameters
-Neutropenia
-Thrombocytopenia
-Anaemia
Biochemistry Parameters
-Elevated creatinine
-Elevated lipase
-Elevated SGOT (AST)
-Elevated SGPT (ALT)
-Hypophosphataemia
-Elevated Bilirubin (total)
4.9
CML-CP
N=318
%
Grades 3/4
CML-AP
N=120
%
Grades 3/4
28%
28%
8%
37%
37%
23%
<1%
15%
1%
4%
10%
9%
0
17%
<1%
2%
10%
10%
Overdose
No case of overdose has been reported. In the event of overdose, the patient should be
observed and appropriate supportive treatment given.
5
Pharmacological properties
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents - Protein-tyrosine kinase inhibitor. ATC
code: under assessment.
TASIGNA is a potent inhibitor of the Abl tyrosine kinase activity of the Bcr-Abl oncoprotein
both in cell lines and in primary Philadelphia-chromosome positive leukaemia cells. The drug
binds with high affinity to the ATP-binding site in such a manner that it is a potent inhibitor
of wild-type Bcr-Abl and maintains activity against 32/33 imatinib-resistant mutant forms of
Bcr-Abl. As a consequence of this biochemical activity, nilotinib selectively inhibits the
proliferation and induces apoptosis in cell lines and in primary Philadelphia-chromosome
positive leukaemia cells from CML patients. In murine models of CML, as a single agent
nilotinib reduces tumour burden and prolongs survival following oral administration.
TASIGNA has little or no effect against the majority of other protein kinases examined,
including Src, except for the PDGF, Kit and Ephrin receptor kinases which it inhibits at
concentrations within the range achieved following oral administration at therapeutic doses
recommended for the treatment of CML (see Table 4).
TAS API MAR08 CL V1
10
REF 110407
Table 4
Kinase Profile of Nilotinib (Phosphorylation IC50 nM)
Bcr-Abl
20
PDGFR
69
KIT
210
CLINICAL STUDIES
An open label multicenter Phase II study was conducted to determine the efficacy of
TASIGNA in patients with imatinib resistant or intolerant CML with separate treatment arms
for chronic and accelerated phase disease. The study is ongoing. Efficacy was based on 280
CP patients and 96 AP patients enrolled. Median duration of treatment was 261 days and 191
days, respectively (see Table 5). TASIGNA was administered on a continuous basis, (twice
daily 2 hours after a meal and no additional food for at least one hour) unless there was
evidence of inadequate response or disease progression. Dose escalation to 600 mg BID was
allowed.
Table 5
Duration of Exposure with TASIGNA
Chronic Phase
Accelerated Phase
N = 280
N = 96
261
191
(164-346)
(89-278)
Median duration of therapy in days (25th –
75th percentiles)
Resistance to imatinib included failure to achieve a complete haematologic response (by 3
months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or
progression of disease after a previous cytogenetic or haematologic response. Imatinib
intolerance included patients who discontinued imatinib because of toxicity and were not in
major cytogenetic response at time of study entry.
Overall, 73% of patients were imatinib-resistant while 27% were imatinib-intolerant. The
majority of patients had a long history of CML that included extensive prior treatment with
other antineoplastic agents such as imatinib, hydroxyurea, interferon, and some that had even
failed stem cell transplant (Table 6). The median highest prior imatinib dose had been 600
mg/day for CP patients and 800 mg/day for AP patients, and the highest prior imatinib dose
was >600 mg/day in 76% of all patients with 45% of patients receiving imatinib doses >800
mg/day.
TAS API MAR08 CL V1
11
REF 110407
Table 6
CML Disease History Characteristics
Chronic Phase
Accelerated Phase
(n = 280)
(n = 96)
57
73
(5-275)
(2-298)
Resistant
194 (69%)
79 (82%)
Intolerant without MCyR
86 (31%)
17 (18%)
Median time of imatinib treatment in days
(25th – 75th percentiles)
973
939
(503-1,470)
(468-1,497)
Prior Hydroxyurea
83%
90%
Prior Interferon
66%
60%
Prior organ transplant
8%
7%
Median time since diagnosis in months
(range)
Imatinib
The primary endpoint in the CP patients was major cytogenetic response (MCyR), defined as
elimination (CCyR, complete cytogenetic response) or significant reduction to <35% Ph+
metaphases (partial cytogenetic response) of Ph+ haematopoietic cells. Complete
haematologic response (CHR) in CP patients was evaluated as a secondary endpoint. The
primary endpoint in the AP patients was overall confirmed haematologic response (HR),
defined as either a complete haematologic response, no evidence of leukaemia or return to
chronic phase.
The MCyR rate in 280 CP patients was 52%. Most responders achieved their MCyR rapidly
within 3 months (median 2.8 months) of starting TASIGNA treatment and these were
sustained (median duration has not been reached). Patients with a CHR at baseline achieved a
MCyR faster (1 vs. 2.8 months). Of CP patients without a baseline CHR, 74% achieved a
CHR and median time to CHR was 1 month and median duration of CHR has not been
reached.
The overall confirmed HR rate in 96 AP patients was 45%. Most responders achieved a HR
early with TASIGNA treatment (median 1.0 months) and these have been durable (median
duration has not been reached). No patients have had a loss of CHR. The MCyR rate was 30%
with a median time to response of 2.0 months.The rates of response for the 2 treatment arms
are reported in Table 7.
TAS API MAR08 CL V1
12
REF 110407
Table 7
Response in CML
(Best Response Rate)
Haematologic Response (%)
Overall (95%CI)
Complete
NEL
Return to CP
Cytogenetic Response (%)
Major (95%CI)
Complete
Partial
Chronic Phase
Accelerated
Intolerant
(n = 86)
Resistant
(n = 194)
Total
(n = 280
Total
(n=96)
90 (78-97)
-
68 (60-76)
-
741 (67-80)
-
45 (35-55)
19
9
17
55 (44-65)
41
14
51 (43-58)
31
19
52 (46-58)
34
18
30 (21-40)
16
15
NEL = no evidence of leukaemia/marrow response
1
- 185 CP patients had a CHR at baseline and were therefore not assessable for complete haematologic
Separate treatment arms were also included in the Phase II study to study TASIGNA in a
group of CP and AP patients who had been extensively pre-treated with multiple therapies
including a tyrosine kinase inhibitor agent in addition to imatinib. Of these patients 30/36
(83%) were treatment-resistant not intolerant. In 22 CP patients evaluated for efficacy
TASIGNA induced a 32% MCyR rate and a 50% CHR rate. In 11 AP patients evaluated for
efficacy, treatment induced a 36% overall HR rate.
After imatinib failure, 24 different BCR-ABL mutations were noted in 45% of chronic phase
and 57% of accelerated phase CML patients who were evaluated for mutations. TASIGNA
demonstrated efficacy in patients harboring a variety of BCR-ABL mutations associated with
imatinib resistance, except T315I.
5.2
Pharmacokinetic properties
Absorption
Peak concentrations of nilotinib are reached 3 hours after oral administration. Nilotinib
absorption following oral administration was approximately 30%. In healthy volunteers, Cmax
and area under the serum concentration-time curve (AUC) of nilotinib are increased by 112%
and 82%, respectively compared to fasting conditions when TASIGNA is given with food.
Administration of TASIGNA 30 minutes or 2 hours after food increased bioavailability of
nilotinib by 29% or 15%, respectively (see section 4.2, Posology and method of
administration, 4.4 Special warnings and precautions for use and 4.5 Interaction with other
medicinal products and other forms of interaction).
TAS API MAR08 CL V1
13
REF 110407
Distribution
Blood-to-plasma ratio of nilotinib is 0.68. Plasma protein binding is approximately 98% on
the basis of in vitro experiments.
Biotransformation
Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation.
Nilotinib is the main circulating component in the serum. None of the metabolites contribute
significantly to the pharmacological activity of nilotinib.
Elimination
After a single dose of radiolabelled nilotinib in healthy subjects, greater than 90% of the dose
was eliminated within 7 days mainly in faeces. Parent drug accounted for 69% of the dose.
Linearity / non-linearity
Steady-state nilotinib exposure was dose-dependent with less than dose-proportional increases
in systemic exposure at dose levels higher than 400 mg given as once daily dosing. Daily
serum exposure to nilotinib of 400 mg twice-daily dosing at steady state was 35% higher than
with 800 mg once-daily dosing. There was no relevant increase in exposure to nilotinib when
the dose was increased from 400 mg twice-daily to 600 mg twice-daily.
Characteristics in patients
Steady state conditions were essentially achieved by day 8. An increase in serum exposure to
nilotinib between the first dose and steady state was approximately 2-fold for daily dosing and
3.8-fold for twice-daily dosing. The apparent elimination half-life estimated from the multiple
dose PK with daily dosing was approximately 17 hours. Inter-patient variability in nilotinib
PK was moderate to high.
5.3
Preclinical safety data
Nilotinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity,
reproductive toxicity studies and phototoxicity studies.
Nilotinib did not have effects on CNS or respiratory functions. In vitro cardiac safety studies
demonstrated a preclinical signal for QT prolongation. No effects were seen in ECG
measurements in dogs or monkeys treated up to 39 weeks or in a special telemetry study in
dogs.
Repeated dose toxicity studies in dogs up to 4 weeks duration and in cynomolgus monkeys up
to 9 months duration, revealed the liver as the primary target organ of toxicity of nilotinib.
Alterations included increased alanine aminotransferase and alkaline phosphatase activity,
and histopathology findings (mainly sinusoidal cell or Kupffer cell hyperplasia/hypertrophy,
bile duct hyperplasia and periportal fibrosis). In general the changes in clinical chemistry
were fully reversible after a four week recovery period, the histological alterations only
showed partial reversibility. Exposures at the lowest dose levels where the liver effects were
seen were lower than the exposure in humans at a dose of 800 mg/day. Only minor liver
alterations were seen in mice or rats treated up to 26 weeks. Mainly reversible increases in
cholesterol levels were seen in rats, dogs and monkeys.
TAS API MAR08 CL V1
14
REF 110407
Genotoxicity studies in bacterial in vitro systems and in mammalian in vitro and in vivo
systems with and without metabolic activation did not reveal any evidence for a mutagenic
potential of nilotinib.
Nilotinib did not induce teratogenicity, but did show embryo- and foetotoxicity at doses
which also showed maternal toxicity. Increased postimplantation loss was observed in both
the fertility study, with treatment of both males and females, and in the embryotoxicity study
with the treatment of females. Embryo-lethality and foetal effects (mainly decreased foetal
weights, visceral and skeletal variations) in rats and increased resorption of foetuses and
skeletal variations in rabbits were present in the embryotoxicity studies. Exposure to nilotinib
in females at No-Observed-Adverse-Effect-Levels was generally less or equal to that in
humans at 800 mg/day.
Nilotinib was shown to absorb light in the UV-B and UV-A range, and to be distributed into
the skin showing a phototoxic potential in vitro. However, no such effects have been
observed in vivo. Therefore the risk that nilotinib causes photosensitization in patients is
considered very low.
Carcinogenicity studies with nilotinib have not been performed.
6
Pharmaceutical particulars
6.1
List of excipients
Capsule content: Lactose monohydrate; Crospovidone; Poloxamer 188; Silica colloidal,
anhydrous/Colloidal silicon dioxide; Magnesium stearate
Capsule shell: Gelatin; Titanium dioxide (E 171); Iron oxide, yellow (E 172)
Printing ink: Iron oxide, red (E 172)
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
24 months
6.4
Special precautions for storage and other handling
Do not store above 30°C.
Store in the original package.
TASIGNA must be kept out of reach and sight of children.
6.5
Nature and contents of container
PVC/PVDC and PA/AL/PVC blisters.
TAS API MAR08 CL V1
15
REF 110407
6.6
Special precautions for disposal
No special requirements.
7. Manufacturer:
Novartis Pharma Stein AG, Stein, Switzerland
for Novartis Pharma AG, Basel, Switzerland
8. License Holder:
PharmaExcel Ltd, 23 Hasivim St., Petach Tikva
TAS API MAR08 CL V1
16
REF 110407