Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: TASICAP 150 and 200  
Dosage form and strength: Capsules and 150 mg & 200 mg  
SCHEDULING STATUS  
S4i  
1.  
NAME OF THE MEDICINE  
TASICAP 150 capsules  
TASICAP 200 capsules  
2.  
QUALITATIVE AND QUANTITATIVE COMPOSITION  
TASICAP 150: Each capsule contains nilotinib hydrochloride dihydrate equivalent to nilotinib  
150 mg.  
TASICAP 200: Each capsule contains nilotinib hydrochloride dihydrate equivalent to  
nilotinib 200 mg.  
Sugar free.  
For the full list of excipients, see section 6.1.  
3.  
PHARMACEUTICAL FORM  
Capsules.  
TASICAP 150: Opaque red cap and opaque red body size '1' hard gelatine capsules  
imprinted with 'H' on cap and '23' on body, filled with slightly yellow to yellowish granular  
powder.  
TASICAP 200: Opaque yellow cap and yellow body size '0' hard gelatine capsules imprinted  
with 'H' on cap and '24' on body, filled with slightly yellow to yellowish granular powder.  
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Product proprietary name: TASICAP 150 and 200  
Dosage form and strength: Capsules and 150 mg & 200 mg  
4.  
CLINICAL PARTICULARS  
Therapeutic indications  
4.1  
•
Treatment of adult patients with newly diagnosed Philadelphia chromosome positive  
chronic myelogenous leukaemia (Ph+ CML) in chronic phase.  
•
Treatment of chronic phase and accelerated phase Philadelphia chromosome positive  
chronic myelogenous leukaemia (Ph+ CML) in adult patients resistant to or intolerant to  
at least one prior therapy including imatinib.  
4.2  
Posology and method of administration  
Therapy should be initiated by a medical practitioner experienced in the treatment of patients  
with CML.  
TASICAP may be given in combination with haematopoietic growth factors such as  
erythropoietin or granulocyte- colony stimulating factor (G-CSF) if clinically indicated.  
TASICAP may be given with hydroxyurea or anagrelide if clinically indicated.  
Posology  
Dosing in patients with newly diagnosed Ph+ CML-chronic phase:  
The recommended dose of TASICAP is 300 mg twice daily. Treatment should be continued  
as long as the patient continues to benefit.  
Dosing in patients with Ph+ CML-chronic phase and CML-accelerated phase resistant to or  
intolerant to at least one prior therapy including] imatinib:  
The recommended dose of TASICAP is 400 mg twice daily. Treatment should be continued  
as long as the patient continues to benefit.  
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Product proprietary name: TASICAP 150 and 200  
Dosage form and strength: Capsules and 150 mg & 200 mg  
Dose adjustments or modifications:  
TASICAP 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 below).  
Table 1: Dose adjustments for neutropenia and thrombocytopenia  
• Newly diagnosed  
CML in chronic  
phase at 300 mg  
twice daily.  
(ANC) < 0,5 x  
109/L or platelet  
counts < 50 x  
109/L  
1. Stop [PRODUCT  
NAME], and monitor  
blood counts.  
2. Resume within 2 weeks at  
prior dose if ANC > 0,5 x  
109/L and/or platelets > 50  
x 109/L.  
• Chronic phase or  
accelerated  
phase CML at  
400 mg twice  
daily.  
3. If blood counts remain low  
a medicine reduction may  
be required to 400 mg  
once daily.  
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 300 mg (newly-diagnosed Ph+ CML-CP)  
or 400 mg (resistant or intolerant Ph+ CML-chronic  
phase and CML-accelerated phase) twice daily should be attempted.  
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 dose  
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Product proprietary name: TASICAP 150 and 200  
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reduction or interruption. For Grade 3 to 4 lipase elevations, doses were reduced to 400 mg  
once daily (see section 4.8).  
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 or hepatic transaminase elevations, doses were reduced to 400  
mg once daily (see section 4.8).  
If a dose is missed, the patient should not take an additional dose, but take the usual  
prescribed next dose.  
Special populations  
Children and adolescents:  
Clinical studies have not been conducted in children and adolescents. TASICAP should not  
be used in these categories of patients.  
Elderly patients:  
Approximately 12 % and 30 % of subjects in clinical studies (newly diagnosed Ph+ CML-CP  
and resistant or intolerant Ph+ CML-chronic phase and CML-accelerated phase) were 65  
years 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:  
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Product proprietary name: TASICAP 150 and 200  
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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 normalrange. 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:  
TASICAP 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).  
Method of administration  
TASICAP 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 sections 4.4, 4.5 and 5.2).  
For patients who are unable to swallow capsules, the content of each capsule may be  
dispersed in one teaspoon of applesauce (pureed apple) and should be taken immediately.  
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Product proprietary name: TASICAP 150 and 200  
Dosage form and strength: Capsules and 150 mg & 200 mg  
Not more than oneteaspoon of applesauce and no food other than applesauce must be used  
(see sections 4.4 and 5.2).  
4.3  
Contraindications  
Known hypersensitivity to nilotinib or to any of the excipients (see  
section 6.1).  
4.4  
Special warnings and precautions for use  
QT Prolongation: TASICAP prolongs the QT interval. Correct hypokalaemia or  
hypomagnesaemia prior to administration and monitor periodically. Avoid medicines  
known to prolong the QT interval and strong CYP3A4 inhibitors. Use caution in  
patients with hepatic impairment. Obtain ECGs at baseline, seven days after  
initiation, and periodically thereafter, as well as following any dose adjustments.  
Ventricular repolarization abnormalities may have contributed to their occurrence.  
Myelosuppression  
Treatment with nilotinib is associated with thrombocytopenia, neutropenia and anaemia,  
(National Cancer Institute Common Toxicity Criteria grade 3 – 4). Occurrence is more  
frequent in patients with imatinib-resistant or intolerant CML, particularly in patients with  
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accelerated-phase CML. 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 TASICAP  
temporarily or dose reduction (see section 4.2).  
QT prolongation  
Nilotinib, as in TASICAP, has been shown to prolong cardiac ventricular repolarisation, as  
measured by the QT interval on the surface ECG in a concentration-dependent manner, in  
adult and paediatric patients.  
Significant prolongation of the QT interval may occur when  
TASICAP is inappropriately taken with strong CYP3A4 inhibitors and/or medicines with a  
known potential to prolong the QT interval, and/or food (see section 4.5). The presence of  
hypokalaemia and hypomagnesaemia may further enhance this effect. Prolongation of the  
QT interval may expose patients to the risk of fatal outcome.  
TASICAP should be used with caution in patients who have or who are at significant risk of  
developing prolongation of QTc, such as those:  
•
•
with congenital long QT prolongation  
with uncontrolled or significant cardiac disease, including: recent myocardial infarction,  
congestive heart failure, unstable  
angina or clinically significant bradycardia  
•
taking anti-dysrhythmic medicines or other substances that lead to QT prolongation.  
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Product proprietary name: TASICAP 150 and 200  
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Close monitoring for an effect on the QTc interval is advisable and a baseline ECG is  
recommended prior to initiating nilotinib therapy and as clinically indicated. Hypokalaemia or  
hypomagnesaemia must be corrected prior to TASICAP administration and should be  
monitored periodically during therapy.  
Sudden death  
Uncommon cases (0,1 to 1 %) of sudden deaths have been reported in patients with  
imatinib-resistant or intolerant CML in chronic phase or accelerated phase with a past  
medical history of cardiac disease or significant cardiac risk factors.  
Co-morbidities in addition to the underlying malignancy were also frequently present as were  
concomitant medicines. Ventricular repolarisation abnormalities may have been contributory  
factors. No cases of sudden death were reported in the Phase III study in newly diagnosed  
patients with CML in chronic phase.  
Fluid retention and oedema  
Severe forms of drug-related fluid retention such as pleural effusion, pulmonary oedema and  
pericardial effusion were uncommonly (0,1 to 1 %) observed in a Phase III study of newly  
diagnosed CML patients. Similar events were observed in post-marketing reports.  
Unexpected, rapid increase in body mass should be carefully investigated. If signs of severe  
fluid retention appear during treatment with TASICAP, the aetiology should be evaluated,  
and patients treated accordingly (see section 4.2 for instructions on managing non-  
haematological toxicities).  
Cardiovascular events  
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Cardiovascular events were reported in a randomised Phase III study in newly diagnosed  
CML patients and observed in post-marketing reports. In this clinical study with a median on-  
therapy time of 60,5 months, Grade 3 – 4 cardiovascular events included peripheral arterial  
occlusive disease (1,4 % and 1,1 % at 300 mg and 400 mg nilotinib twice daily,  
respectively),ischaemic heart disease(2,2 % and 6,1 % at 300 mg and 400 mg nilotinib twice  
daily, respectively) and ischaemic cerebrovascular events  
(1,1 % and 2,2 % at 300 mg and 400 mg nilotinib twice daily, respectively). Patients should  
be advised to seek immediate medical attention if they experience acute signs or symptoms  
of cardiovascular events. The cardiovascular status of patients should be evaluated, and  
cardiovascular risk factors monitored and actively managed during nilotinib therapy  
according to standard guidelines.  
Appropriate therapy should be prescribed to manage cardiovascular risk factors (see section  
4.2 for instructions on managing non-haematological toxicities).  
Hepatitis B reactivation  
Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after  
these patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute  
hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.  
Patients should be tested for HBV infection before initiating treatment with nilotinib. Experts  
in liver disease and in the treatment of hepatitis B should be consulted before treatment is  
initiated in patients with positive hepatitis B serology (including those with active disease)  
and for patients who test positive for HBV infection during treatment. Carriers of HBV who  
require treatment with nilotinib should be closely monitored for signs and symptoms of active  
HBV infection throughout therapy and for several months following termination of therapy  
(see section 4.8).  
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Product proprietary name: TASICAP 150 and 200  
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Special monitoring of adult Ph+ CML patients in chronic phase who have achieved a  
sustained deep molecular response  
Eligibility for discontinuation of treatment  
Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2  
or e14a2/b3a2, can be considered for treatment discontinuation. Patients must have  
typical BCR-ABL transcripts to allow quantitation of BCRABL, evaluation of the depth of  
molecular response, and determination of a possible loss of molecular remission after  
discontinuation of treatment with nilotinib.  
Monitoring of patients who have discontinued therapy  
Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment  
discontinuation must be performed with a quantitative diagnostic test validated to measure  
molecular response levels with a sensitivity of at least MR4,5 (BCR-ABL/ABL ≤ 0,0032 %  
IS). BCR-ABL transcript levels must be assessed prior to and during treatment  
discontinuation (see sections 4.2 and 5.1).  
Loss of major molecular response (MMR = BCR-ABL/ABL ≤ 0,1 % IS) in CML patients who  
received nilotinib as first- or second-line therapy, or confirmed loss of MR4 (two consecutive  
measures separated by at least 4 weeks showing loss of MR4 (MR4 = BCR-ABL/ABL ≤ 0,01  
% IS)) in CML patients who received nilotinib as second-line therapy will trigger treatment re-  
initiation within 4 weeks of when loss of remission is known to have occurred. Molecular  
relapse can occur during the treatment-free phase, and long-term outcome data are not yet  
available. It is therefore crucial to perform frequent monitoring of BCR-ABL transcript levels  
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and complete blood count with differential in order to detect possible loss of remission (see  
section 4.2). For patients who fail to achieve MMR after three  
months of treatment re-initiation, BCR-ABL kinase domain mutation testing should be  
performed.  
Laboratory tests and monitoring  
Blood lipids  
In a Phase III study in newly diagnosed CML patients, 1,1 % of the patients treated with 400  
mg nilotinib twice daily showed a Grade 3 – 4 elevation in total cholesterol; no Grade 3 – 4  
elevations were however observed in the 300 mg twice daily dose group (see section 4.8). It  
is recommended that the lipid profiles be determined before initiating treatment with nilotinib,  
assessed at month 3 and 6 after initiating therapy and at least yearly during chronic therapy  
(see section 4.2). If an HMG-CoA reductase inhibitor (a lipid-lowering agent) is required,  
please refer to section 4.5 before initiating treatment since certain HMG-CoA reductase  
inhibitors are also metabolised by the CYP3A4 pathway.  
Blood glucose  
In a Phase III study in newly diagnosed CML patients, 6,9 % and 7,2 % of the patients  
treated with 400 mg nilotinib and 300 mg nilotinib twice daily, respectively, showed a Grade  
3 – 4 elevation in blood glucose. It is recommended that the glucose levels be assessed  
before initiating treatment with TASICAP and monitored during treatment, as clinically  
indicated (see section 4.2). If test results warrant therapy, medical practitioners should follow  
their local standards of practice and treatment guidelines.  
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Product proprietary name: TASICAP 150 and 200  
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Interactions with other medicines  
The administration of TASICAP with medicines 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 medicines be required, it is  
recommended that TASICAP therapy be interrupted if possible. If transient interruption of  
treatment is not possible, close monitoring of the individual for prolongation of the QT  
interval is indicated (see sections 4.2, 4.5 and 5.2).  
Concomitant use of TASICAP with medicines that are potent inducers of CYP3A4 (e.g.  
phenytoin, rifampicin, carbamazepine, phenobarbital and St John's wort) is likely to reduce  
exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving TASICAP,  
co-administration of alternative therapeutic medicines with less potential for CYP3A4  
induction should be selected (see section 4.5).  
Food effect  
The bioavailability of nilotinib, as in TASICAP, is increased by food. TASICAP must not be  
taken in conjunction with food (see sections 4.2 and 4.5) 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. For patients who  
are unable to swallow hard capsules, the content of each hard capsule may be dispersed in  
one teaspoon of apple sauce and should be taken immediately. Not more than one teaspoon  
of apple sauce and no food other than apple sauce must be used (see section 5.2).  
Hepatic impairment  
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Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Single dose  
administration of 200 mg of nilotinib resulted in increases in AUC of 35 %, 35 % and 19 % in  
subjects with mild, moderate and severe hepatic impairment, respectively, compared to a  
control group of subjects with normal hepatic function. The predicted steady state Cmax of  
nilotinib showed an increase of 29 %, 18 % and 22 %, respectively. Clinical studies have  
excluded patients with alanine transaminase (ALT) and/or aspartate transaminase (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. Patients with hepatic impairment might therefore have increased exposure to  
nilotinib and should be treated with caution (see section 4.2).  
Serum lipase  
Elevation in serum lipase has been observed. Caution is recommended in patients with  
previous history of pancreatitis.  
In case lipase elevations are accompanied by abdominal symptoms,  
TASICAP therapy should be interrupted and appropriate diagnostic measures considered to  
exclude pancreatitis.  
Total gastrectomy  
The bioavailability of nilotinib might be reduced in patients with total gastrectomy (see  
section 5.2). More frequent follow-up of these patients should be considered.  
Tumour lysis syndrome  
Due to possible occurrence of tumour lysis syndrome (TLS) correction of clinically significant  
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dehydration and treatment of high uric acid levels are recommended prior to initiating  
TASICAP therapy (see section 4.8).  
Paediatric population  
Laboratory abnormalities of mild to moderate transient elevations of aminotransferases and  
total bilirubin have been observed in children at a higher frequency than in adults, indicating  
a higher risk of hepatotoxicity in the paediatric population (see section 4.8). Liver function  
(bilirubin and hepatic transaminases levels) should be monitored monthly or as clinically  
indicated. Elevations of bilirubin and hepatic transaminases should be managed by  
withholding nilotinib temporarily, dose reduction and/or discontinuation of nilotinib (see  
section 4.2). The long-term effects of prolonged treatment with nilotinib in children and  
adolescents are unknown.  
4.5  
Interaction with other medicines and other forms of interaction  
TASICAP may be given in combination with haematopoietic growth factors, such as  
erythropoietin or granulocyte colony stimulating factor (G-CSF), if clinically indicated. It may  
be given with hydroxyurea or anagrelide if clinically indicated.  
Nilotinib is mainly metabolised in the liver with CYP3A4 expected to be the main contributor  
to the oxidative metabolism. Nilotinib is also a substrate for the multi-drug efflux pump, P-  
glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically  
absorbed nilotinib may be influenced by substances that affect CYP3A4 and/or P-gp.  
Substances that may increase nilotinib serum concentrations  
Concomitant administration of nilotinib with imatinib (a substrate and moderator of P-gp and  
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CYP3A4), had a slight inhibitory effect on CYP3A4 and/or P-gp. The AUC of imatinib was  
increased by 18 % to 39 %, and the AUC of nilotinib was increased by 18 % to 40 %. These  
changes are unlikely to be clinically important.  
The exposure to nilotinib in healthy subjects was increased 3-fold when co-administered with  
the strong CYP3A4 inhibitor ketoconazole. Concomitant treatment with strong CYP3A4  
inhibitors, including ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and  
telithromycin, should therefore be avoided (see section 4.4). Increased exposure to nilotinib  
might also be expected with moderate CYP3A4 inhibitors. Alternative concomitant medicines  
with no or minimal CYP3A4 inhibition should be considered.  
Substances that may decrease nilotinib serum concentrations  
Rifampicin, a potent CYP3A4 inducer, decreases nilotinib Cmax by 64 % and reduces nilotinib  
AUC by 80 %. Rifampicin and nilotinib should not be used concomitantly.  
The concomitant administration of other medicines that induce CYP3A4 (e.g. phenytoin,  
carbamazepine, phenobarbital and St John's wort) is likewise likely to reduce exposure to  
nilotinib to a clinically relevant extent. In patients for whom CYP3A4 inducers are indicated,  
alternative medicines with less enzyme induction potential should be selected.  
Nilotinib has pH dependent solubility, with lower solubility at higher pH. In healthy subjects  
receiving esomeprazole at 40 mg once daily for 5 days, gastric pH was markedly increased,  
but nilotinib absorption was only decreased modestly (27 % decrease in Cmax and 34 %  
decrease in AUC0-∞). Nilotinib may be used concurrently with esomeprazole or other proton  
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pump inhibitors as needed.  
Substances that may have their systemic concentration altered by nilotinib  
In vitro, nilotinib is a relatively strong inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and  
UGT1A1, with Ki value being lowest for CYP2C9 (Ki = 0,13 microM).  
Anti-dysrhythmic medicines and other substances that may prolong the QT interval  
Nilotinib should be used with caution in patients who have or may develop prolongation of  
the QT interval, including those patients taking antidysrhythmic medicines such as  
amiodarone, disopyramide, procainamide, quinidine and sotalol or other medicines that may  
lead to QT prolongation such as chloroquine, halofantrine, clarithromycin, haloperidol,  
methadone and moxifloxacin (see section 4.4).  
Food interactions  
The absorption and bioavailability of nilotinib are increased if it is taken with food, resulting in  
a higher serum concentration (see sections 4.2, 4.4 and 5.2).  
Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided.  
Paediatric population  
Interaction studies have only been performed in adults.  
4.6  
Fertility, pregnancy and lactation  
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Women of childbearing potential / Contraception  
Women of childbearing potential have to use highly effective contraception during treatment  
with nilotinib and for up to two weeks after ending treatment.  
Pregnancy  
There are no or limited amount of data from the use of nilotinib in pregnant women. Animal  
studies have shown reproductive toxicity. TASICAP should not be used during pregnancy,  
unless the clinical condition of the woman requires treatment with nilotinib. If it is used during  
pregnancy, the patient must be informed of the potential risk to the fetus.  
If a woman who is being treated with TASICAP is considering pregnancy, treatment  
discontinuation may be considered based on the eligibility criteria for discontinuing treatment  
as described in sections 4.2 and 4.4. There is a limited amount of data on pregnancies in  
patients while attempting treatment-free remission (TFR). If pregnancy is planned during the  
TFR phase, the patient must be informed of a potential need to re-initiate nilotinib treatment  
during pregnancy (see sections 4.2 and 4.4).  
Breastfeeding  
It is unknown whether nilotinib is excreted in human milk. Available toxicological data in  
animals have shown excretion of nilotinib in milk (see section 5.3). Since a risk to the  
newborns/infants cannot be excluded, women should not breastfeed during TASICAP  
treatment and for 2 weeks after the last dose.  
Fertility  
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Animal studies did not show an effect on fertility in male and female  
rats (see section 5.3).  
Sexually active male or female patients taking TASICAP  
should use adequate contraception.  
4.7  
Effects on ability to drive and use machines  
TASICAP has no or negligible influence on the ability to drive a vehicle and use machines.  
However, it is recommended that patients experiencing dizziness, fatigue, visual impairment  
or other undesirable effects with a potential impact on the ability to drive a vehicle or use  
machines safely should refrain from these activities as long as the undesirable effects persist  
(see section 4.8).  
4.8  
Undesirable effects  
In adult patients with newly diagnosed CML in chronic phase  
The median duration of exposure was 60,5 months (range 0,1 – 70,8 months).  
The most frequent (≥ 10 %) non-haematological adverse reactions were rash, pruritus,  
headache, nausea, fatigue, alopecia, myalgia and upper abdominal pain. Most of these  
adverse reactions were mild to moderate in severity.  
Constipation, dry skin, asthenia, muscle spasms, diarrhoea, arthralgia, abdominal pain,  
vomiting and peripheral oedema were observed less frequently (< 10 % and ≥ 5 %) were of  
mild to moderate severity, manageable and generally did not require dose reduction.  
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Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia  
(18 %), neutropenia (15 %) and anaemia (8 %). Biochemical adverse drug reactions include  
increased alanine aminotransferase (24 %), hyperbilirubinaemia (16 %), increased aspartate  
aminotransferase (12 %), increased lipase (11 %), increased blood bilirubin (10 %),  
hyperglycaemia (4 %), hypercholesterolaemia (3 %) and hypertriglyceridaemia (< 1 %).  
Pleural and pericardial effusions, regardless of causality, occurred in 2 % and < 1% of  
patients, respectively, receiving nilotinib 300 mg twice daily.  
Gastrointestinal haemorrhage, regardless of causality, was reported in 3 % of these patients.  
The change from baseline in mean time-averaged QTcF interval at steady state was 6 msec.  
No patient had an absolute QTcF > 500 msec while on the study medicine. QTcF increase  
from baseline exceeding 60 msec was observed in < 1 % of patients while on the study  
medicine.  
No sudden deaths or episodes of torsades de pointes (transient or sustained) were  
observed. No decrease from baseline in mean left ventricular ejection fraction (LVEF) was  
observed at any time during treatment.  
No patient had a LVEF of < 45 % during treatment nor an absolute reduction in LVEF of  
more than 15 %.  
Discontinuation due to adverse drug reactions was observed in 10 % of patients.  
Initial: ………………………  
April 2021  
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Product proprietary name: TASICAP 150 and 200  
Dosage form and strength: Capsules and 150 mg & 200 mg  
In adult patients with imatinib-resistant or intolerant CML in chronic phase and accelerated  
phase  
The most frequent (≥ 10 %) non-haematological drug-related adverse events were rash,  
pruritus, nausea, fatigue, headache, vomiting, myalgia, constipation and diarrhoea. Most of  
these adverse events were mild to moderate in severity.  
Alopecia, muscle spasms, decreased appetite, arthralgia, abdominal pain, bone pain,  
peripheral oedema, asthenia, upper abdominal pain, dry skin, erythema and pain in  
extremity were observed less frequently (< 10 % and ≥ 5 %) and have been of mild to  
moderate severity (Grade 1 or 2).  
Discontinuation due to adverse drug reactions was observed in 16 % of chronic phase and  
10 % of accelerated phase patients.  
Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia  
(31 %), neutropenia (17 %) and anaemia (14 %). Pleural and pericardial effusions as well as  
complications of fluid retention occurred in < 1 % of patients receiving TASICAP.  
Cardiac failure was observed in < 1 % of patients. Gastrointestinal and CNS haemorrhage  
were reported in 1 % and < 1 % of patients, respectively.QTcF exceeding 500 msec was  
observed in < 1 % of patients. No episodes of torsades de pointes (transient or sustained)  
were observed.  
Table 2: Non-haematological adverse reactions (≥ 5 % of all patients)*  
Initial: ………………………  
April 2021  
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Product proprietary name: TASICAP 150 and 200  
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Newly diagnosed  
CML-CP  
300 mg twice daily  
n = 279  
Imatinib-resistant or intolerant CML-CP  
and CML-AP  
400 mg twice daily  
n = 458  
60-month analysis  
24-month analysis  
System organ  
class/  
All  
grades  
Grade  
3 – 4  
All  
grades  
Grade  
3 – 4  
CML-CP  
n = 321  
CML-AP  
n = 137  
Adverse  
Grade 3 – 4 Grade 3 – 4  
reaction  
%
%
%
%
%
%
Metabolism and nutrition disorders  
Frequent:  
Decreased  
appetite **  
4
0
2
8
< 1  
< 1  
0
Nervous system disorders  
Frequent:  
Headache  
16  
15  
1
2
< 1  
Gastrointestinal disorders  
Frequent:  
Nausea  
14  
10  
9
< 1  
0
20  
12  
11  
10  
5
< 1  
< 1  
2
< 1  
< 1  
2
< 1  
0
Constipation  
Diarrhoea  
Vomiting  
< 1  
0
< 1  
0
6
< 1  
< 1  
< 1  
< 1  
Upper  
10  
1
0
abdominal pain  
Abdominal pain  
Dyspepsia  
6
5
0
0
6
3
< 1  
0
< 1  
0
< 1  
0
Skin and subcutaneous tissue disorders  
Frequent:  
Rash  
33  
18  
10  
10  
3
< 1  
< 1  
0
28  
24  
9
1
< 1  
0
2
< 1  
0
0
0
0
0
0
Pruritus  
Alopecia  
Dry skin  
Erythema  
0
5
0
0
0
5
< 1  
< 1  
Musculoskeletal and connective tissue disorders  
Frequent:  
Myalgia  
10  
9
< 1  
0
10  
8
< 1  
< 1  
< 1  
< 1  
< 1  
< 1  
< 1  
1
< 1  
0
Muscle spasms  
Arthralgia  
8
< 1  
0
7
0
Bone pain  
4
6
< 1  
< 1  
0
Pain in  
5
< 1  
5
< 1  
extremity  
General disorders and administration site conditions  
Frequent:  
Fatigue  
12  
9
0
17  
6
1
0
0
1
0
0
< 1  
0
Asthenia  
< 1  
< 1  
Oedema  
5
6
0
peripheral  
* Percentages are rounded to integer for presentation in this table. However, percentages with one decimal  
precision are used to identify terms with a frequency of at least 5 % and to classify terms according to frequency  
Initial: ………………………  
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categories.  
**Also includes preferred term anorexia.  
Table 3: Adverse reactions in adult patients  
Infections and infestations  
Frequent:  
folliculitis, upper respiratory tract infection  
(including pharyngitis, nasopharyngitis, rhinitis)  
Less frequent:  
pneumonia, urinary tract infection, gastroenteritis,  
bronchitis, herpes virus infection, candidiasis  
(including oral candidiasis)  
Frequency unknown:  
sepsis, subcutaneous abscess, anal abscess,  
furuncle, tinea pedis, hepatitis B reactivation  
Neoplasms benign, malignant and unspecified (including cysts and  
polyps)  
Frequent:  
skin papilloma  
Frequency unknown:  
oral papilloma, paraproteinaemia  
Blood and lymphatic system disorders  
Frequent:  
leukopenia, eosinophilia, febrile neutropenia,  
pancytopenia, lymphopenia  
Less frequent:  
thrombocythaemia, leukocytosis  
Immune system disorders  
Frequency unknown:  
Endocrine disorders  
Less frequent:  
hypersensitivity  
hyperthyroidism, hypothyroidism  
Frequency unknown:  
hyperparathyroidism secondary, thyroiditis  
Metabolism and nutrition disorders  
Frequent: hypophosphataemia (including blood phosphorus  
decreased), electrolyte imbalance (including  
hypomagnesaemia, hyperkalaemia,  
hypokalaemia, hyponatraemia, hypocalcaemia,  
hypercalcaemia, hyperphosphataemia), diabetes  
mellitus, hyperglycaemia, hypercholesterolaemia,  
hyperlipidaemia, hypertriglyceridaemia  
Initial: ………………………  
April 2021  
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Less frequent:  
dehydration, increased appetite, gout,  
dyslipidaemia  
Frequency unknown:  
Psychiatric disorders  
Frequent:  
hyperuricaemia, hypoglycaemia  
depression, insomnia, anxiety  
Frequency unknown:  
disorientation, confusional state, amnesia,  
dysphoria  
Nervous system disorders  
Frequent:  
dizziness, peripheral neuropathy, hypoaesthesia,  
paraesthesia  
Less frequent:  
intracranial haemorrhage, ischaemic stroke,  
transient ischaemic attack, cerebral infarction,  
migraine, loss of consciousness (including  
syncope), tremor, disturbance in attention,  
hyperaesthesia  
Frequency unknown:  
cerebrovascular incident, brain oedema, optic  
neuritis, lethargy, dysaesthesia, restless legs  
syndrome  
Eye disorders  
Frequent:  
eye haemorrhage, periorbital oedema, eye  
pruritus, conjunctivitis, dry eye (including  
xerophthalmia)  
Less frequent:  
visual impairment, blurred vision, conjunctival  
haemorrhage, reduced visual acuity, eyelid  
oedema, photopsia, hyperaemia (scleral,  
conjunctival, ocular), eye irritation  
Frequency unknown:  
papilloedema, chorioretinopathy, diplopia,  
photophobia, eye swelling, blepharitis, eye pain,  
allergic conjunctivitis, ocular surface disease  
Ear and labyrinth disorders  
Frequent:  
vertigo  
Frequency unknown:  
Cardiac disorders  
Frequent:  
impaired hearing, ear pain, tinnitus  
angina pectoris, dysrhythmia (including  
atroventricular block, cardiac flutter,  
Initial: ………………………  
April 2021  
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Product proprietary name: TASICAP 150 and 200  
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extrasystoles, tachycardia, atrial fibrillation,  
bradycardia), palpitations, prolonged  
electrocardiogram QT  
Less frequent:  
cardiac failure, myocardial infarction, coronary  
artery disease, cardiac murmur, pericardial  
effusion, cyanosis  
Frequency unknown:  
ventricular dysfunction, pericarditis, decreased  
ejection fraction  
Vascular disorders  
Frequent:  
hypertension, flushing, peripheral artery stenosis  
Less frequent:  
hypertensive crisis, peripheral arterial occlusive  
disease, intermittent claudication, arterial stenosis  
limb, haematoma, arteriosclerosis  
Frequency unknown:  
haemorrhagic shock, hypotension, thrombosis  
Respiratory, thoracic and mediastinal disorders  
Frequent:  
dyspnoea, dyspnoea exertional, epistaxis, cough,  
dysphonia  
Less frequent:  
pulmonary oedema, pleural effusion, interstitial  
lung disease, pleuritic pain, pleurisy,  
pharyngolaryngeal pain, throat irritation  
Frequency unknown:  
pulmonary hypertension, wheezing,  
oropharyngeal pain  
Gastrointestinal disorders  
Frequent:  
pancreatitis, abdominal discomfort, abdominal  
distension, dysgeusia, flatulence  
Less frequent:  
gastrointestinal haemorrhage, melaena, mouth  
ulceration, gastroesophageal reflux, stomatitis,  
oesophageal pain, dry mouth, gastritis, sensitivity  
of teeth  
Frequency unknown:  
gastrointestinal ulcer perforation, retroperitoneal  
haemorrhage, haematemesis, gastric ulcer,  
oesophagitis ulcerative, subileus, enterocolitis,  
haemorrhoids, hiatus hernia, rectal haemorrhage,  
gingivitis  
Hepatobiliary disorders  
Initial: ………………………  
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Frequent:  
hyperbilirubinaemia (including blood bilirubin  
increased), hepatic function abnormal  
hepatotoxicity, toxic hepatitis, jaundice  
cholestasis, hepatomegaly  
Less frequent:  
Frequency unknown:  
Skin and subcutaneous tissue disorders  
Frequent:  
night sweats, eczema, urticaria, hyperhidrosis,  
contusion, acne, dermatitis (including allergic,  
exfoliative and acneiform)  
Less frequent:  
exfoliative rash, drug eruption, skin pain,  
ecchymosis, swelling of the face  
Frequency unknown:  
erythema multiforme, erythema nodosum, skin  
ulcer, palmar-plantar erythrodysaesthesia  
syndrome, petechiae, photosensitivity, blister,  
dermal cysts, sebaceous hyperplasia, skin  
atrophy, skin discolouration, skin exfoliation, skin  
hyperpigmentation, skin hypertrophy,  
hyperkeratosis, psoriasis  
Musculoskeletal and connective tissue disorders  
Frequent:  
musculoskeletal chest pain, musculoskeletal pain,  
back pain, flank pain, neck pain, muscular  
weakness  
Less frequent:  
musculoskeletal stiffness, joint swelling  
arthritis  
Frequency unknown:  
Renal and urinary disorders  
Frequent:  
pollakiuria  
Less frequent:  
Frequency unknown:  
dysuria, micturition urgency, nocturia  
renal failure, haematuria, urinary incontinence,  
chromaturia  
Reproductive system and breast disorders  
Less frequent:  
breast pain, gynaecomastia, erectile dysfunction  
breast induration, menorrhagia, nipple swelling  
Frequency unknown:  
General disorders and administration site conditions  
Frequent:  
chest pain (including non-cardiac chest pain),  
pain, pyrexia, chest discomfort, malaise  
Initial: ………………………  
April 2021  
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Less frequent:  
face oedema, gravitational oedema, influenza-like  
illness, chills, feeling body temperature change  
(including feeling hot, feeling cold)  
Frequency unknown:  
Investigations  
Frequent:  
localised oedema  
increased alanine aminotransferase, increased  
aspartate aminotransferase, increased lipase,  
increased lipoprotein cholesterol (including low  
density and high density), increased total  
cholesterol, increased blood triglycerides,  
decreased haemoglobin, increased blood  
amylase, increased blood alkaline phosphatase,  
increased gamma-glutamyltransferase, increased  
blood creatinine phosphokinase, decreased or  
increased body mass, increased blood insulin,  
decreased globulins  
Less frequent:  
increased blood lactate dehydrogenase,  
decreased blood glucose, increased blood urea  
Frequency unknown:  
increased troponin, increased blood bilirubin  
unconjugated, decreased blood insulin,  
decreased insulin C-peptide, increased blood  
parathyroid hormone  
Clinically relevant or severe abnormalities of routine haematological or biochemistry laboratory values  
in adult patients are presented in Table 4.  
Table 4 Grade 3 – 4 laboratory abnormalities*  
Newly  
diagnosed  
CML-CP  
Imatinib-resistant or  
intolerant CML-CP and  
CML-AP  
300 mg twice  
daily  
400 mg twice daily  
CML-CP  
n = 321  
(%)  
CML-AP  
n = 137  
(%)  
n = 279  
(%)  
Haematological parameters  
Myelosuppression  
- Neutropenia  
12  
10  
4
31  
30  
11  
42  
42  
27  
- Thrombocytopenia  
- Anaemia  
Initial: ………………………  
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Biochemistry parameters  
- Elevated creatinine  
- Elevated lipase  
0
9
1
4
8
4
7
0
0
1
18  
3
< 1  
18  
2
- Elevated SGOT (AST)  
- Elevated SGPT (ALT)  
- Hypophosphataemia  
- Elevated bilirubin (total)  
- Elevated glucose  
4
4
17  
7
15  
9
12  
**  
**  
6
- Elevated cholesterol (total)  
- Elevated triglycerides  
**  
**  
* Percentages with one decimal precision are used and rounded to integer for presentation in this table  
**Parameters not collected  
Treatment discontinuation in adult Ph+ CML patients in chronic phase who have  
achieved a sustained deep molecular response  
After discontinuation of nilotinib therapy within the framework of attempting TFR, patients  
may experience musculoskeletal symptoms more frequently than before treatment  
discontinuation, e.g. myalgia, pain in extremity, arthralgia, bone pain, spinal pain or  
musculoskeletal pain.  
Description of selected adverse reactions  
Sudden death  
Less frequently occurring cases (0,1 to 1 %) of sudden deaths have been reported in clinical  
trials and/or compassionate use programs in patients with imatinib-resistant or intolerant  
CML in chronic phase or accelerated phase with a past medical history of cardiac disease or  
significant cardiac risk factors (see section 4.4).  
Hepatitis B reactivation  
Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases  
resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a  
fatal outcome (see section 4.4).  
Initial: ………………………  
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Post-marketing experience  
The following adverse reactions have been derived from post-marketing experience with  
nilotinib via spontaneous case reports, literature cases, expanded access programmes and  
clinical studies other than the global registration trials.  
Since these reactions are reported voluntarily from a population of uncertain size, it is not  
always possible to reliably estimate their frequency or establish a causal relationship to  
nilotinib exposure.  
Less frequent: Cases of tumour lysis syndrome have been reported in patients treated with  
nilotinib.  
Paediatric population  
The safety of nilotinib in paediatric patients (from 2 to < 18 years of age) with Philadelphia  
chromosome positive CML in chronic phase (n = 69) has been investigated in two studies  
(see section 5.1). In paediatric patients, the frequency, type and severity of adverse  
reactions observed have been generally consistent with those observed in adults, with the  
exception of the laboratory abnormalities hyperbilirubinaemia (Grade 3/4: 13,0 %) and  
transaminase elevation (AST Grade 3/4: 1,4 %, ALT Grade 3/4: 8,7 %) which were reported  
at a higher frequency than in adult patients. Bilirubin and hepatic transaminase levels should  
be monitored during treatment (see sections 4.2 and 4.4).  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of TASICAP is important. It allows  
continued monitoring of the benefit/risk balance of TASICAP. Health care providers are  
asked to report any suspected adverse reactions via the “6.04 Adverse Drug Reaction  
Initial: ………………………  
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Reporting Form”, found online under SAHPRA’s publications:  
https://www.sahpra.org.za/Publications/Index/8.  
4.9  
Overdose  
Isolated reports on intentional overdose with nilotinib were reported, where an unspecified  
number of TASICAP capsules were ingested in combination with alcohol and other  
medicines. Events included neutropenia, vomiting and drowsiness. No ECG changes or  
hepatotoxicity were reported.  
Outcomes were reported as recovered. In the event of overdose, the patient should be  
observed and appropriate supportive treatment given.  
5.  
PHARMACOLOGICAL PROPERTIES  
Category and class: A.26 Cytostatic agents  
Pharmacotherapeutic group: Antineoplastic agents, protein kinase  
inhibitors, ATC code: L01XE08  
5.1  
Pharmacodynamic properties  
Nilotinib is a potent and selective inhibitor of the Abl tyrosine kinase activity of the Bcr-Abl  
oncoprotein both in cell lines and in primary Philadelphia-chromosome positive leukaemia  
cells.  
Nilotinib binds with high affinity to the ATP-binding site in such a manner that it is a potent  
inhibitor of wild-type 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.  
Initial: ………………………  
April 2021  
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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 nilotinib is given with food.  
Administration of nilotinib 30 minutes or 2 hours after food increased bioavailability of  
nilotinib by 29 % or 15 %, respectively (see sections 4.2, 4.4 and 4.5).  
Nilotinib absorption (relative bioavailability) might be reduced by approximately 48 % and 22  
% in patients with total gastrectomy and partial gastrectomy, respectively.  
Single dose administration of 400 mg nilotinib, using two capsules of  
200 mg whereby the content of each capsule was dispersed in one teaspoon of applesauce,  
was shown to be bioequivalent with  
a single dose administration of 2 intact capsules of 200 mg.  
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  
Initial: ………………………  
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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 compound 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 systemic exposure to nilotinib with 400 mg twice-daily dosing at steady state  
was 35 % higher than with 800 mg once-daily dosing. Systemic exposure (AUC) of nilotinib  
at steady state at a dose level of 400 mg twice daily was approximately 13,4 % higher than  
at a dose level of 300 mg twice daily. The average nilotinib trough and peak concentrations  
over 12 months were approximately 15,7 % and 14,8 % higher following 400 mg twice-daily  
dosing compared to 300 mg twice daily. 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.  
Initial: ………………………  
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5.3  
Preclinical safety data  
No further information of relevance available.  
6.  
PHARMACEUTICAL PARTICULARS  
List of excipients  
6.1  
Capsule content  
Dibasic calcium phosphate dihydrate  
Povidone  
Colloidal silicon dioxide  
Magnesium stearate  
Capsule shell  
Iron oxide red (E172) (only for TASICAP 150)  
Iron oxide yellow (E172)  
Sodium laurilsulfate  
Titanium dioxide (E171)  
Gelatine  
6.2  
Incompatibilities  
Not applicable.  
6.3  
Shelf life  
2 years.  
6.4  
Special precautions for storage  
•
•
Store at or below 25 °C. Protect from light and moisture.  
Keep capsules in original container until required for use.  
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6.5  
Nature and contents of container  
Round, white opaque HDPE 60 mL container, closed with a child resistant plastic cap with a  
pulp liner, containing a 2 gram silica gel desiccant.  
Pack size: 28 capsules.  
Aluminium/aluminium blister strips of cold PVC/aluminium/OPA forming foil and plain  
aluminium lidding foil, containing 6 or 10 capsules per blister strip.  
Pack sizes: 36 (6 blister strips containg 6 capsules) or 60 (6 blister strips containg 10  
capsules).  
6.6  
Special precautions for disposal and other handling  
Any unused medicine should be disposed of in accordance with local requirements.  
7.  
HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Jean Park Chambers, 252 Jean Avenue  
Building 6, Unit 17 & 18.  
Centurion  
8.  
REGISTRATION NUMBER(S)  
TASICAP 150: 54/26/0276.274  
TASICAP 200:. 54/26/0277.275  
9.  
DATE OF FIRST AUTHORISATION  
28 April 2021  
Initial: ………………………  
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10.  
--  
DATE OF REVISION OF THE TEXT  
Initial: ………………………  
April 2021  
Page 34 of 34