DASATINIB SANDOZ 100 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Dasatinib Sandoz 100 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 100 mg of dasatinib.

Excipient with known effect

Each film-coated tablet contains 131.1 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

White to off-white, biconvex, oval film-coated tablet with „100“ debossed on one side and plain on the other, with dimensions 14.8 mm x 7.2 mm.

4.1 Therapeutic indications

Dasatinib is indicated for the treatment of adult patients with:

newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase.

chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate.

Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with leukaemia.

Posology

The recommended starting dose for chronic phase CML is 100 mg dasatinib once daily.

The recommended starting dose for accelerated, myeloid or lymphoid blast phase (advanced phase) CML or Ph+ ALL is 140 mg once daily (see section 4.4).

Treatment duration

In clinical studies, treatment with dasatinib was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic or molecular response [including complete cytogenetic response (CCyR), major molecular response (MMR) and MR4.5] has not been investigated.

To achieve the recommended dose, Dasatinib is available as 20 mg, 50 mg, 70 mg, 80 mg, 100 mg and 140 mg film-coated tablets. Dose increase or reduction is recommended based on patient response and tolerability.

Dose escalation

In clinical studies in adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML or Ph+ ALL) was allowed in patients who did not achieve a haematologic or cytogenetic response at the recommended starting dose.

Dose adjustment for adverse reactions

Myelosuppression

In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy. Platelet transfusion and red cell transfusion were used as appropriate. Haematopoietic growth factor has been used in patients with resistant myelosuppression.

Guidelines for dose modifications are summarised in Table 1.

Table 1: Dose adjustments for neutropaenia and thrombocytopaenia

Chronic phase CML

(starting dose 100 mg once daily) ANC < 0.5 × 109/l

and/or

platelets < 50 × 109/1   1. Stop treatment until ANC > 1.0 × 109/1 and platelets > 50

x 109/l.

2. Resume treatment at the original starting dose.

3. If platelets < 25 × 109/l and/or recurrence of ANC < 0.5 × 109/l for > 7 days, repeat step 1 and resume treatment at a reduced dose of 80 mg once daily for second episode. For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue (for patients resistant or intolerant to prior therapy including imatinib).

Accelerated and blast phase CML and Ph+ ALL (starting dose 140 mg once daily) ANC < 0.5 × 109/l

and/or

platelets < 10 × 109/l   1. Check if cytopaenia is related to leukaemia (marrow

aspirate or biopsy).

2. If cytopaenia is unrelated to leukaemia, stop treatment until ANC > 1.0 × 109/1 and platelets > 20 × 109/1 and resume at the original starting dose.

3. If recurrence of cytopaenia, repeat step 1 and resume treatment at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode).

4. If cytopaenia is related to leukaemia, consider dose escalation to 180 mg once daily.

ANC: absolute neutrophil count

Non-haematological adverse reactions

If a moderate, grade 2, non-haematological adverse reaction develops with dasatinib, treatment should be interrupted until the adverse reaction has resolved or returned to baseline. The same dose should be resumed if this is the first occurrence and the dose should be reduced if this is a recurrent adverse reaction. If a severe grade 3 or 4, nonhaematological adverse reaction develops with dasatinib, treatment must be withheld until the adverse reaction has resolved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the adverse reaction. For patients with chronic phase CML who received 100 mg once daily, dose reduction to 80 mg once daily with further reduction from 80 mg once daily to 50 mg once daily, if needed, is recommended. For patients with advanced phase CML or Ph+ ALL who received 140 mg once daily, dose reduction to 100 mg once daily with further reduction from 100 mg once daily to 50 mg once daily, if needed, is recommended.

Pleural effusion

If a pleural effusion is diagnosed, dasatinib should be interrupted until patient is asymptomatic or has returned to baseline. If the episode does not improve within approximately one week, a course of diuretics or corticosteroids or both concurrently should be considered (see sections 4.4 and 4.8). Following resolution of the first episode, reintroduction of dasatinib at the same dose level should be considered. Following resolution of a subsequent episode, dasatinib at one dose level reduction should be reintroduced. Following resolution of a severe (grade 3 or 4) episode, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the adverse reaction.

Paediatric population

The safety and efficacy of dasatinib in children and adolescents below 18 years of age have not yet been established. No data are available (see section 5.1).

Elderly

No clinically relevant age-related pharmacokinetic differences have been observed in these patients. No specific dose recommendation is necessary in elderly.

Hepatic impairment

Patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose. However, dasatinib should be used with caution in patients with hepatic impairment (see sections 4.4 and 5.2).

Renal impairment

No clinical studies were conducted with dasatinib in patients with decreased renal function (the study in patients with newly diagnosed chronic phase CML excluded patients with serum creatinine concentration > 3 times the upper limit of the normal range, and studies in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy excluded patients with serum creatinine concentration > 1.5 times the upper limit of the normal range). Since the renal clearance of dasatinib and its metabolites is < 4%, a decrease in total body clearance is not expected in patients with renal insufficiency.

Method of administration

Dasatinib must be administered orally.

The film-coated tablets must not be crushed or cut in order to minimize the risk of dermal exposure, they must be swallowed whole. They can be taken with or without a meal and should be taken consistently either in the morning or in the evening.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Clinically relevant interactions

Dasatinib is a substrate and an inhibitor of cytochrome P450 (CYP) 3A4.

Therefore, there is a potential for interaction with other concomitantly administered medicinal products that are metabolized primarily by or modulate the activity of CYP3A4 (see section 4.5).

Concomitant use of dasatinib and medicinal products or substances that potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving dasatinib, coadministration of a potent CYP3A4 inhibitor is not recommended (see section 4.5).

Concomitant use of dasatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing Hypericum perforatum, also known as St. John's Wort) may substantially reduce exposure to dasatinib, potentially increasing the risk of therapeutic failure. Therefore, in patients receiving dasatinib, coadministration of alternative medicinal products with less potential for CYP3A4 induction should be selected (see section 4.5).

Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. Therefore, caution is warranted when dasatinib is coadministered with CYP3A4 substrates of narrow therapeutic index, such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine) (see section 4.5).

The concomitant use of dasatinib and a histamine-2 (H2) antagonist (e.g. famotidine), proton pump inhibitor (e.g. omeprazole), or aluminium hydroxide/magnesium hydroxide may reduce the exposure to dasatinib. Thus, H2 antagonists and proton pump inhibitors are not recommended and aluminium hydroxide/magnesium hydroxide products should be administered up to 2 hours prior to, or 2 hours following the administration of dasatinib (see section 4.5).

Special populations

Based on the findings from a single-dose pharmacokinetic study, patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose (see section 5.2). Due to the limitations of this clinical study, caution is recommended when administering dasatinib to patients with hepatic impairment.

Important adverse reactions

Myelosuppression

Treatment with dasatinib is associated with anaemia, neutropaenia and thrombocytopaenia. Their occurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. In adult patients with advanced phase CML or Ph+ ALL treated with dasatinib as monotherapy, complete blood counts (CBCs) should be performed weekly for the first 2 months, and then monthly thereafter, or as clinically indicated. In adult and paediatric patients with chronic phase CML, complete blood counts should be performed every 2 weeks for 12 weeks, then every 3 months thereafter or as clinically indicated.. In paediatric patients with Ph+ ALL treated with dasatinib in combination with chemotherapy, CBCs should be performed prior to the start of each block of chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, CBCs should be performed every 2 days until recovery (see sections 4.2 and 4.8).

Myelosuppression is generally reversible and usually managed by withholding dasatinib temporarily or by dose reduction.

Bleeding

In patients with chronic phase CML (n=548), 5 patients (1%) receiving dasatinib had grade 3 or 4 haemorrhage. In clinical studies in patients with advanced phase CML receiving the recommended dose of dasatinib (n=304), severe central nervous system (CNS) haemorrhage occurred in 1% of patients. One case was fatal and was associated with Common Toxicity Criteria (CTC) grade 4 thrombocyto­paenia. Grade 3 or 4 gastrointestinal haemorrhage occurred in 6% of patients with advanced phase CML and generally required treatment interruptions and transfusions. Other grade 3 or 4 haemorrhage occurred in 2% of patients with advanced phase CML. Most bleeding related adverse reactions in these patients were typically associated with grade 3 or 4 thrombocytopaenia (see section 4.8). Additionally, in vitro and in vivo platelet assays suggest that dasatinib treatment reversibly affects platelet activation.

Caution should be exercised if patients are required to take medicinal products that inhibit platelet function or anticoagulants.

Fluid retention

Dasatinib is associated with fluid retention. In the Phase III clinical study in patients with newly diagnosed chronic phase CML, grade 3 or 4 fluid retention was reported in 13 patients (5%) in the dasatinib-treatment group and in 2 patients (1%) in the imatinib-treatment group after a minimum of 60 months follow-up (see section 4.8). In all dasatinib treated patients with chronic phase CML, severe fluid retention occurred in 32 patients (6%) receiving dasatinib at the recommended dose (n=548). In clinical studies in patients with advanced phase CML or Ph+ ALL receiving dasatinib at the recommended dose (n=304), grade 3 or 4 fluid retention was reported in 8% of patients, including grade 3 or 4 pleural and pericardial effusion reported in 7% and 1% of patients, respectively. In these patients grade 3 or 4 pulmonary oedema and pulmonary hypertension were each reported in 1% of patients.

Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough should be evaluated by chest X-ray. Grade 3 or 4 pleural effusion may require thoracocentesis and oxygen therapy. Fluid retention adverse reactions were typically managed by supportive care measures that include diuretics and short courses of steroids (see sections 4.2 and 4.8). Patients aged 65 years and older are more likely than younger patients to experience pleural effusion, dyspnoea, cough, pericardial effusion and congestive heart failure, and should be monitored closely.

Pulmonary arterial hypertension (PAH)

PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been reported in association with dasatinib treatment (see section 4.8). In these cases, PAH was reported after initiation of dasatinib therapy, including after more than one year of treatment.

Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating dasatinib therapy. An echocardiography should be performed at treatment initiation in every patient presenting symptoms of cardiac disease and considered in patients with risk factors for cardiac or pulmonary disease. Patients who develop dyspnoea and fatigue after initiation of therapy should be evaluated for common etiologies including pleural effusion, pulmonary oedema, anaemia, or lung infiltration. In accordance with recommendations for management of non-haematologic adverse reactions (see section 4.2) the dose of dasatinib should be reduced or therapy interrupted during this evaluation. If no explanation is found, or if there is no improvement with dose reduction or interruption, the diagnosis of PAH should be considered. The diagnostic approach should follow standard practice guidelines. If PAH is confirmed, dasatinib should be permanently discontinued. Follow up should be performed according to standard practice guidelines. Improvements in haemodynamic and clinical parameters have been observed in dasatinib-treated patients with PAH following cessation of dasatinib therapy.

QT Prolongation

In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarisation (QT Interval) (see section 5.3). In 258 dasatinib-treated patients and 258 imatinib-treated patients with a minimum of 60 months follow-up in the Phase III study in newly diagnosed chronic phase CML, 1 patient (< 1%) in each group had QTc prolongation reported as an adverse reaction. The median changes in QTcF from baseline were 3.0 msec in dasatinib-treated patients compared to 8.2 msec in imatinib-treated patients. One patient (< 1%) in each group experienced a QTcF > 500 msec. In 865 patients with leukaemia treated with dasatinib in Phase II clinical studies, the mean changes from baseline in QTc interval using Fridericia's method (QTcF) were 4 – 6 msec; the upper 95% confidence intervals for all mean changes from baseline were < 7 msec (see section 4.8).

Of the 2,182 patients with resistance or intolerance to prior imatinib therapy who received dasatinib in clinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one of these patients (1%) experienced a QTcF > 500 msec.

Dasatinib should be administered with caution to 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 medicinal products or other medicinal products which lead to QT prolongation, and cumulative high dose anthracycline therapy.

Hypokalaemia or hypomagnesaemia should be corrected prior to dasatinib administration.

Cardiac adverse reactions

Dasatinib was studied in a randomised clinical study of 519 patients with newly diagnosed CML in chronic phase which included patients with prior cardiac disease. The cardiac adverse reactions of congestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmias, palpitations, QT prolongation and myocardial infarction (including fatal) were reported in patients taking dasatinib. Cardiac adverse reactions were more frequent in patients with risk factors or a history of cardiac disease. Patients with risk factors (e.g. hypertension, hyperlipidaemia, diabetes) or a history of cardiac disease (e.g. prior percutaneous coronary intervention, documented coronary artery disease) should be monitored carefully for clinical signs or symptoms consistent with cardiac dysfunction such as chest pain, shortness of breath, and diaphoresis.

If these clinical signs or symptoms develop, physicians are advised to interrupt dasatinib administration and consider the need for alternative CML-specific treatment. After resolution, a functional assessment should be performed prior to resuming treatment with dasatinib. Dasatinib may be resumed at the original dose for mild/moderate adverse reactions (< grade 2) and resumed at a dose level reduction for severe adverse reactions (> grade 3) (see section 4.2).

Patients continuing treatment should be monitored periodically.

Patients with uncontrolled or significant cardiovascular disease were not included in the clinical studies.

Thrombotic microangiopathy (TMA)

BCR-ABL tyrosine kinase inhibitors have been associated with thrombotic microangiopathy (TMA), including individual case reports for dasatinib (see section 4.8). If laboratory or clinical findings associated with TMA occur in a patient receiving dasatinib, treatment with dasatinib should be discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated in conjunction with low ADAMTS13 activity, treatment with dasatinib should not be resumed.

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 dasatinib. 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 dasatinib 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).

Effects on growth and development in, paediatric , patients

In paediatric trials of dasatinib in imatinib-resistant/into­lerant Ph+ CML-CP paediatric patients and treatment-naive Ph+ CML-CP paediatric patients after at least 2 years of treatment, treatment-related adverse events associated with bone growth and development were reported in 6 (4.6%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 6 cases included cases of epiphyses delayed fusion, osteopaenia, growth retardation, and gynecomastia (see section 5.1). These results are difficult to interpret in

the context of chronic diseases such as CML, and require long-term follow-up.

In paediatric trials of dasatinib in combination with chemotherapy in newly diagnosed Ph+ ALL paediatric patients after a maximum of 2 years of treatment, treatment-related adverse events associated with bone growth and development were reported in 1 (0.6%) patient. This case was a Grade 1 osteopenia.

Dasatinib contains lactose and sodium

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction Active substances that may increase dasatinib plasma concentrations

In vitro studies indicate that dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and medicinal products or substances which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving dasatinib, systemic administration of a potent CYP3A4 inhibitor is not recommended.

At clinically relevant concentrations, binding of dasatinib to plasma proteins is approximately 96% on the basis of in vitro experiments. No studies have been performed to evaluate dasatinib interaction with other protein-bound medicinal products. The potential for displacement and its clinical relevance are unknown.

Active substances that may decrease dasatinib plasma concentrations

When dasatinib was administered following 8 daily evening administrations of 600 mg rifampicin, a potent CYP3A4 inducer, the AUC of dasatinib was decreased by 82%. Other medicinal products that induce CYP3A4 activity (e.g. dexamethazone, phenytoin, carbamazepine, phenobarbital or herbal preparations containing Hypericum perforatum, also known as St. John's Wort) may also increase metabolism and decrease dasatinib plasma concentrations. Therefore, concomitant use of potent CYP3A4 inducers with dasatinib is not recommended. In patients in whom rifampicin or other CYP3A4 inducers are indicated, alternative medicinal products with less enzyme induction potential should be used.

Histamine-2 antagonists and proton pump inhibitors

Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (e.g. famotidine and omeprazole) is likely to reduce dasatinib exposure. In a single-dose study in healthy subjects, the administration of famotidine 10 hours prior to a single dose of dasatinib reduced dasatinib exposure by 61%. In a study of 14 healthy subjects, administration of a single 100-mg dose of dasatinib 22 hours following a 4-day, 40-mg omeprazole dose at steady state reduced the AUC of dasatinib by 43% and the Cmax of dasatinib by 42%. The use of antacids should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving dasatinib therapy (see section 4.4).

Antacids

Non-clinical data demonstrate that the solubility of dasatinib is pH-dependent. In healthy subjects, the concomitant use of aluminium hydroxide/magnesium hydroxide antacids with dasatinib reduced the AUC of a single dose of dasatinib by 55% and the Cmax by 58%. However, when antacids were administered 2 hours prior to a single dose of dasatinib no relevant changes in dasatinib concentration or exposure were observed. Thus, antacids may be administered up to 2 hours prior to or 2 hours following dasatinib (see section 4.4).

Active substances that may have their plasma concentrations altered by dasatinib

Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. In a study in healthy subjects, a single 100 mg dose of dasatinib increased AUC and Cmax exposure to simvastatin, a known CYP3A4 substrate, by 20 and 37% respectively. It cannot be excluded that the effect is larger after multiple doses of dasatinib. Therefore, CYP3A4 substrates known to have a narrow therapeutic index (e.g. astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids [ergotamine, dihydroergotamine]) should be administered with caution in patients receiving dasatinib (see section 4.4).

In vitro data indicate a potential risk for interaction with CYP2C8 substrates, such as glitazones.

4.6 Fertility, Pregnancy and lactation

Women of childbearing potential/con­traception in males and females

Both sexually active men and women of childbearing potential should use effective methods of contraception during treatment.

Pregnancy

Based on human experience, dasatinib is suspected to cause congenital malformations including neural tube defects, and harmful pharmacological effects on the foetus when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3).

Dasatinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with dasatinib. If Dasatinib is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding

There is insufficient/li­mited information on the excretion of dasatinib in human or animal breast milk. Physico-chemical and available pharmacodynamic/to­xicological data on dasatinib point to excretion in breast milk and a risk to the suckling child cannot be excluded.

Breast-feeding should be stopped during treatment with Dasatinib.

Fertility

The effect of dasatinib on sperm is unknown (see section 5.3).

4.7 Effects on ability to drive and use machines

Dasatinib has minor influence on the ability to drive and use machines. Patients should be advised that they may experience adverse reactions such as dizziness or blurred vision during treatment with dasatinib. Therefore, caution should be recommended when driving a car or operating machines.

4.8 Undesirable effects

Summary of the safety profile

The data described below reflect exposure to dasatinib in 2,712 patients in clinical studies, including 324 patients with newly diagnosed chronic phase CML and 2,388 patients with imatinib resistant or intolerant CML or Ph+ ALL. The median duration of therapy in 2,712 <dasatinib treated patients was 19.2 months (range 0–93.2 months).

In the Phase III study in patients with newly diagnosed chronic phase CML with a minimum of 5 years of follow up, the median duration of therapy was approximately 60 months for both dasatinib (range 0.03–72.7 months) and for imatinib (range 0.374.6 months). The median duration of therapy in 1,618 patients with all chronic phase CML was 29 months (range 0–92.9 months). In 1,094 patients with advanced phase CML or Ph+ ALL, the median duration of treatment for patients was 6.2 months (range 0–9.32 months).

Of the 2,712 patients treated, 18% were > 65 years of age, while 5% were > 75 years of age.

The majority of dasatinib – treated patients experienced adverse reactions at some time. In the overall population of 2,712 dasatinib treated patients, 520 (19%) experienced adverse reactions leading to treatment discontinuation. Most reactions were of mild-to-moderate grade.

In the Phase III study in patients with newly diagnosed chronic phase CML, treatment was discontinued for adverse reactions in 5% of dasatinib – treated patients and 4% of imatinib-treated patients with a minimum of 12 months follow-up. After a minimum of 60 months follow-up, the cumulative discontinuation rates were 14% and 7%, respectively. Among the 1,618 dasatinib-treated patients with chronic phase CML, adverse reactions leading to discontinuation were reported in 329 (20.3%) patients, and among the 1,094 dasatinib-treated patients with advanced phase disease, adverse reactions leading to discontinuation were reported in 191 (17.5%) patients.

The majority of imatinib-intolerant patients with chronic phase CML were able to tolerate treatment with dasatinib. In clinical studies with 24 months follow-up in chronic phase CML, 10 of the 215 imatinib-intolerant patients had the same grade 3 or 4 non-haematologic toxicity with dasatinib as they did with prior imatinib; 8 of these 10 patients were managed with dose reduction and were able to continue dasatinib treatment.

Based on a minimum of 12 months follow-up the most frequently reported adverse reactions in dasatinib – treated patients with newly diagnosed chronic phase CML were fluid retention (including pleural effusion) (19%), diarrhoea (17%), headache (12%), rash (11%), musculoskeletal pain (11%), nausea (8%), fatigue (8%), myalgia (6%), vomiting (5%), and muscle inflammation (4%). After a minimum of 60 months follow-up the cumulative rates for rash (14%), musculoskeletal pain (14%), headache (13%), fatigue (11%), nausea (10%), myalgia (7%), vomiting (5%), and muscle inflammation or spasms (5%) increased by < 3%. Cumulative rates of fluid retention and diarrhoea were 39% and 22%, respectively. The most frequently reported adverse reactions in dasatinib – treated patients with resistance or intolerance to prior imatinib therapy were fluid retention (including pleural effusion), diarrhoea, headache, nausea, skin rash, dyspnoea, haemorrhage, fatigue, musculoskeletal pain, infection, vomiting, cough, abdominal pain and pyrexia. Drug-related febrile neutropaenia was reported in 5% of dasatinib – treated patients with resistance or intolerance to prior imatinib therapy.

In clinical studies with patients with resistance or intolerance to prior imatinib therapy, it was recommended that treatment with imatinib be discontinued at least 7 days before starting treatment with dasatinib.

Tabulated list of adverse reactions

The following adverse reactions, excluding laboratory abnormalities, were reported in patients in dasatinib clinical studies and post-marketing experience (Table 2). These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); not known (cannot be estimated from available post-marketing data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Tabulated summary of adverse reactions

Infections and infestations

Very common infection (including bacterial, viral, fungal, non-specified)

Common pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflam­mation, herpes virus infection (including cytomegalovirus-CMV), enterocolitis infection, sepsis (including uncommon cases with fatal outcomes)

Not known hepatitis B reactivation

Blood and lymphatic system disorders

Very Common myelosuppression (including anaemia, neutropaenia, thrombocytopaenia)

Common      febrile neutropaenia

Uncommon   lymphadenopathy, lymphopaenia

Rare aplasia pure red cell

Immune system disorders

Uncommon hypersensitivity (including erythema nodosum)

Endocrine disorders

Uncommon hypothyroidism

Rare hyperthyroidism, thyroiditis

Metabolism and nutrition disorders

Common      appetite disturbancesa, hyperuricaemia

Uncommon   tumour lysis syndrome, dehydration, hypoalbuminemia,

hypercholeste­rolemia

Rare diabetes mellitus

Psychiatric disorders

Common     depression, insomnia

Uncommon    anxiety, confusional state, affect lability, libido decreased

Nervous system disorders

Very common headache

Common neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence

Uncommon CNS bleeding*b, syncope, tremor, amnesia, balance disorder

Rare cerebrovascular accident, transient ischaemic attack, convulsion, optic neuritis, VIIth nerve paralysis, dementia, ataxia

Eye disorders

Common visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye

Uncommon visual impairment, conjunctivitis, photophobia, lacrimation increased

Ear and labyrinth disorders

Common     tinnitus

Uncommon   hearing loss, vertigo

Cardiac disorders

Common      congestive heart failure/cardiac dysfunction*c, pericardial effusion*,

arrhythmia (including tachycardia), palpitations

Uncommon    myocardial infarction (including fatal outcome), electrocardiogram

QT prolonged, pericarditis, ventricular arrhythmia (including ventricular tachycardia), angina pectoris, cardiomegaly, electrocardiogram T wave abnormal, troponin increased

Rare cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest, electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis

Not known atrial fibrillation/atrial flutter

Vascular disorders

Very common Haemorrhage*d

Common      hypertension, flushing

Uncommon   hypotension, thrombophlebitis

Rare deep vein thrombosis, embolism, livedo reticularis

Respiratory, thoracic and mediastinal disorders

Very common pleural effusion*, dyspnoea

Common pulmonary oedema*, pulmonary hypertension*, lung infiltration, pneumonitis, cough

Uncommon   pulmonary arterial hypertension, bronchospasm, as­thma

Rare pulmonary embolism, acute respiratory distress syndrome

Not known     interstitial lung disease

Gastrointestinal disorders

Very common diarrhoea, vomiting, nausea, abdominal pain

Common gastrointestinal bleeding*, colitis (including neutropaenic colitis), gastritis, mucosal inflammation (including mucositis/sto­matitis), dyspepsia, abdominal distension, constipation, oral soft tissue disorder

Uncommon pancreatitis (including acute pancreatitis), upper gastrointestinal ulcer, oesophagitis, ascites*, anal fissure, dysphagia, gastroesophageal reflux disease

Rare protein-losing gastroenteropathy, ileus, anal fistula

Not known    fatal gastrointestinal haemorrhage*

Hepatobiliary disorders

Uncommon    hepatitis, cholecystitis, cholestasis

Skin and subcutaneous tissue disorders

Very common skin rashe

Common alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, hyperhidrosis

Uncommon neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesia syndrome, hair disorder

Rare leukocytoclastic vasculitis, skin fibrosis

Not known Stevens-Johnson Syndromef

Musculoskeletal and connective tissue disorders

Very common musculoskeletal pain

Common arthralgia, myalgia, muscular weakness, musculoskeletal stiffness, muscle spasm

Uncommon rhabdomyolysis, osteonecrosis, muscle inflammation, tendonitis, arthritis

Renal and urinary disorders

Uncommon renal impairment (including renal failure), urinary frequency, proteinuria

Not known nephrotic syndrome

Pregnancy, puerperium and perinatal conditions

Rare abortion

Reproductive system and breast disorders

Uncommon gynecomastia, menstrual disorder

General disorders and administration site conditions

Very common peripheral oedemag, fatigue, pyrexia, face oedemah

Common asthenia, pain, chest pain, generalised oedema*i, chills

Uncommon malaise, other superficial oedemaj

Rare gait disturbance

Investigations

Common      weight decreased, weight increased

Uncommon   blood creatine phosphokinase increased, gamma-glutamyltransferase

increased

Injury, poisoning, and procedural complications

Common contusion

a Includes decreased appetite, early satiety, increased appetite.

b Includes central nervous system haemorrhage, cerebral haematoma, cerebral haemorrhage, extradural haematoma, haemorrhage intracranial, haemorrhagic stroke, subarachnoid haemorrhage, subdural haematoma, and subdural haemorrhage.

c Includes brain natriuretic peptide increased, ventricular dysfunction, left ventricular dysfunction, right ventricular dysfunction, cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased and ventricular failure, left ventricular failure, right ventricular failure, and ventricular hypokinesia.

d Excludes gastrointestinal bleeding and CNS bleeding; these adverse reactions are reported under the gastrointestinal disorders system organ class and the nervous system disorders system organ class, respectively.

e Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalised erythema, genital rash, heat rash, milia, miliaria, pustular psoriaisis, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation, toxic skin eruption, urticaria vesiculosa, and vasculitic rash.

f In the post-marketing setting, individual cases of Stevens-Johnson syndrome have been reported. It could not be determined whether these mucocutaneous adverse reactions were directly related to Dasatinib or to concomitant medicinal product.

g Gravitational oedema, localised oedema, oedema peripheral.

h Conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, lip oedema, macular oedema, oedema mouth, orbital oedema, periorbitalo oedema, swelling face.

i Fluid overload, fluid retention, gastrointestinal oedema, generalised oedema, oedema, oedema due to cardiac disease, perinephric effusion, post procedural oedema, visceral oedema.

j Genital swelling, incision site oedema, oedema genital, penile oedema, penile swelling, scrotal oedema, skin swelling, testicular swelling, vulvovaginal swelling.

* For additional details, see section „Description of selected adverse reactions“

Description of selected adverse reactions

Myelosuppression

Treatment with dasatinib is associated with anaemia, neutropaenia and thrombocytopaenia. Their occurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML (see section 4.4).

Bleeding

Bleeding drug-related adverse reactions, ranging from petechiae and epistaxis to grade 3 or 4 gastrointestinal haemorrhage and CNS bleeding, were reported in patients taking dasatinib (see section 4.4).

Fluid retention

Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and pericardial effusion with or without superficial oedema may be collectively described as “fluid retention”. In the newly diagnosed chronic phase CML study after a minimum of 60 months follow-up, dasatinib-related fluid retention adverse reactions included pleural effusion (28%), superficial oedema (14%), pulmonary hypertension (5%), generalised oedema (4%), and pericardial effusion (4%).

Congestive heart failure/cardiac dysfunction and pulmonary oedema were reported in < 2% of patients.

The cumulative rate of dasatinib-related pleural effusion (all grades) over time was 10% at 12 months, 14% at 24 months, 19% at 36 months, 24% at 48 months and 28% at 60 months. A total of 46 dasatinib-treated patients had recurrent pleural effusions. Seventeen patients had 2 separate adverse reactions, 6 had 3 adverse reactions, 18 had 4 to 8 adverse reactions and 5 had > 8 episodes of pleural effusions.

The median time to first dasatinib-related grade 1 or 2 pleural effusion was 114 weeks (range: 4 to 299 weeks). Less than 10% of patients with pleural effusion had severe (grade 3 or 4) dasatinib-related pleural effusions. The median time to first occurrence of grade > 3 dasatinib-related pleural effusion was 175 weeks (range: 114 to 274 weeks). The median duration of dasatinib-related pleural effusion (all grades) was 283 days (~40 weeks).

Pleural effusion was usually reversible and managed by interrupting dasatinib treatment and using diuretics or other appropriate supportive care measures (see sections 4.2 and 4.4). Among dasatinib-treated patients with drug-related pleural effusion (n=73), 45 (62%) had dose interruptions and 30 (41%) had dose reductions. Additionally, 34 (47%) received diuretics, 23 (32%) received corticosteroids, and 20 (27%) received both corticosteroids and diuretics. Nine (12%) patients underwent therapeutic thoracentesis.

Six percent of dasatinib-treated patients discontinued treatment due to drug-related pleural effusion. Pleural effusion did not impair the ability of patients to obtain a response. Among the dasatinib-treated patients with pleural effusion, 96% achieved a cCCyR, 82% achieved a MMR, and 50% achieved a MR4.5 despite dose interruptions or dose adjustment.

See section 4.4 for further information on patients with chronic phase CML and advanced phase CML or Ph+ ALL.

Pulmonary arterial hypertension (PAH)

PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been reported in association with dasatinib exposure. In these cases, PAH was reported after initiation of dasatinib therapy, including after more than one year of treatment. Patients with PAH reported during dasatinib treatment were often taking concomitant medicinal products or had co-morbidities in addition to the underlying malignancy. Improvements in haemodynamic and clinical parameters have been observed in patients with PAH following discontinuation of dasatinib.

QT Prolongation

In the Phase III study in patients with newly diagnosed chronic phase CML, one patient (< 1%) of the dasatinib – treated patients had a QTcF > 500 msec after a minimum of 12 months follow-up (see section 4.4). No additional patients were reported to have QTcF > 500 msec after a minimum of 60 months follow-up.

In 5 Phase II clinical studies in patients with resistance or intolerance to prior imatinib therapy, repeated baseline and on-treatment ECGs were obtained at pre-specified time points and read centrally for 865 patients receiving dasatinib 70 mg twice daily. QT interval was corrected for heart rate by Fridericia's met­hod. At all post-dose time points on day 8, the mean changes from baseline in QTcF interval were 4 – 6 msec, with associated upper 95% confidence intervals < 7 msec. Of the 2,182 patients with resistance or intolerance to prior imatinib therapy who received dasatinib in clinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one patients (1%) experienced a QTcF > 500 msec (see section 4.4).

Cardiac adverse reactions

Patients with risk factors or a history of cardiac disease should be monitored carefully for signs or symptoms consistent with cardiac dysfunction and should be evaluated and treated appropriately (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).

In the Phase III dose-optimisation study in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy (median duration of treatment of 30 months), the incidence of pleural effusion and congestive heart failure/cardiac dysfunction was lower in patients treated with dasatinib 100 mg once daily than in those treated with dasatinib 70 mg twice daily. Myelosuppression was also reported less frequently in the 100 mg once daily treatment group (see Laboratory test abnormalities below). The median duration of therapy in the 100 mg once daily group was 37 months (range 1–91 months). Cumulative rates of selected adverse reactions that were reported in the 100 mg once daily recommended starting dose are shown in Table 3a.

Table 3a:      Selected adverse reactions reported in a phase 3 dose optimisation

study (imatinib intolerant or resistant chronic phase CML)a

Minimum of 2 years follow up Minimum of 5 years follow up Minimum of 7 years follow up

a Phase 3 dose optimisation study results reported in recommended starting dose of 100 mg once daily (n=165) population

In the Phase III dose-optimisation study in patients with advanced phase CML and Ph+ ALL, the median duration of treatment was 14 months for accelerated phase CML, 3 months for myeloid blast CML, 4 months for lymphoid blast CML and 3 months for Ph+ ALL. Selected adverse reactions that were reported in the recommended starting dose of 140 mg once daily are shown in Table 3b. A 70 mg twice daily regimen was also studied. The 140 mg once daily regimen showed a comparable efficacy profile to the 70 mg twice daily regimen but a more favourable safety profile.

Table 3b:      Selected adverse reactions reported in phase III dose-optimisation

study: Advanced phase CML and Ph+ ALLa

140 mg once daily

n = 304

All grades     Grade 3/4

Preferred term Percent (%) of patients

Diarrhoea     28     3

Fluid retention 33     7

Superficial oedema    15

Pleural effusion 20

Generalised oedema 2

Congestive heart failure / cardiac dysfunctionb 1

Pericardial effusion    2

Pulmonary oedema    1

Haemorrhage 23

Gastrointestinal bleeding 8

a Phase 3 dose optimisation study results reported at the recommended starting dose of 140 mg once daily (n=304) population at 2 year final study follow up.

b Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure.

Laboratory test abnormalities

Haematology

In the Phase III newly diagnosed chronic phase CML study, the following grade 3 or 4 laboratory abnormalities were reported after a minimum of 12 months follow-up in patients taking dasatinib:

neutropaenia (21%), thrombocytopaenia (19%), and anaemia (10%). After a minimum of 60 months follow-up, the cumulative rates of neutropaenia, thrombocytopaenia, and anaemia were 29%, 22% and 13%, respectively.

In dasatinib – treated patients with newly diagnosed chronic phase CML who experienced grade 3 or 4 myelosuppression, recovery generally occurred following brief dose interruptions and/or reductions and permanent discontinuation of treatment occurred in 1.6% of patients after a minimum of 12 months follow-up. After a minimum of 60 months follow-up the cumulative rate of permanent discontinuation due to grade 3 or 4 myelosuppression was 2.3%.

In patients with CML with resistance or intolerance to prior imatinib therapy, cytopaenias (thrombocytopaenia, neutropaenia, and anaemia) were a consistent finding. However, the occurrence of cytopaenias was also clearly dependent on the stage of the disease. The frequency of grade 3 and 4 haematological abnormalities is presented in Table 4.

Table 4:       CTC grades 3/4 haematological laboratory abnormalities in clinical

studies in patients with resistance or intolerance to prior imatinib therapya

Chronic phase

(n= 165)b     Accelerated phase

(n= 157)c     Myeloid Blast

phase

(n= 74)c Lymphoid

blast phase

and

Ph+ ALL

(n= 168)c

Percent (%) of patients

Haematology parameters

a Phase 3 dose optimisation study results reported at 2 year study follow up.

b CA180–034 study results in recommended starting dose of 100 mg once daily.

c CA180–035 study results in recommended starting dose of 140 mg once daily.

CTC grades: neutropaenia (Grade 3 > 0.5– < 1.0 × 109/1, Grade 4 < 0.5 × 109/1); thrombocytopaenia (Grade 3 > 25 – < 50 × 109/1, Grade 4 < 25 × 109/1); anaemia (haemoglobin Grade 3 > 65 – < 80 g/1, Grade 4 < 65 g/1).

Cumu1ative grade 3 or 4 cytopaenias among patients treated with 100 mg once dai1y were simi1ar at2 and 5 years inc1uding: neutropaenia (35% vs. 36%), thrombocytopaenia (23% vs.24%) and anaemia (13% vs. 13%).

In patients who experienced grade 3 or 4 mye1osuppression, recovery genera11y occurred fo11owing brief dose interruptions and/or reductions and permanent discontinuation of treatment occurred in 5% of patients. Most patients continued treatment without further evidence of mye1osuppression.

Biochemistry

In the new1y diagnosed chronic phase CML study, grade 3 or 4 hypophosphataemia was reported in 4% of dasatinib – treated patients, and grade 3 or 4 e1evations of transaminases, creatinine, and bi1irubin were reported in < 1% of patients after a minimum of 12 months fo11ow-up. After a minimum of 60 months fo11ow-up the cumu1ative rate of grade 3 or 4 hypophosphataemia was 7%, grade 3 or 4 e1evations of creatinine and bi1irubin was 1% and grade 3 or 4 e1evations of transaminases remained 1%. There were no discontinuations of dasatinib therapy due to these biochemica1 1aboratory parameters.

year fo11ow-up

Grade 3 or 4 e1evations of transaminases or bi1irubin were reported in 1% of patients with chronic phase CML (resistant or into1erant to imatinib), but e1evations were reported with an increased frequency of 1 to 7% of patients with advanced phase CML and Ph+ ALL. It was usua11y managed with dose reduction or interruption. In the Phase III dose-optimisation study in chronic phase CML, grade 3 or 4 e1evations of transaminases or bi1irubin were reported in < 1% of patients with simi1ar 1ow incidence in the four treatment groups. In the Phase III dose-optimisation study in advanced phase CML and Ph+ALL, grade 3 or 4 elevations of transaminases or bilirubin were reported in 1% to 5% of patients across treatment groups.

Approximately 5% of the dasatinib – treated patients who had normal baseline levels experienced grade 3 or 4 transient hypocalcaemia at some time during the course of the study. In general, there was no association of decreased calcium with clinical symptoms. Patients developing grade 3 or 4 hypocalcaemia often had recovery with oral calcium supplementation.

Grade 3 or 4 hypocalcaemia, hypokalaemia, and hypophosphataemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML and Ph+ ALL. Grade 3 or 4 elevations in creatinine were reported in < 1% of patients with chronic phase CML and were reported with an increased frequency of 1 to 4% of patients with advanced phase CML.

Special population

While the safety profile of dasatinib in elderly was similar to that in the younger population, patients aged 65 years and older are more likely to experience the commonly reported adverse reactions such as fatigue, pleural effusion, dyspnoea, cough, lower gastrointestinal haemorrhage, and appetite disturbance and more likely to experience less frequently reported adverse reactions such as abdominal distention, dizziness, pericardial effusion, congestive heart failure, and weight decrease and should be monitored closely (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in Google play or Apple App store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

5.3 Preclinical safety data

The non-clinical safety profile of dasatinib was assessed in a battery of in vitro and in vivo studies in mice, rats, monkeys, and rabbits.

The primary toxicities occurred in the gastrointestinal, haematopoietic, and lymphoid systems. Gastrointestinal toxicity was dose-limiting in rats and monkeys, as the intestine was a consistent target organ. In rats, minimal to mild decreases in erythrocyte parameters were accompanied by bone

marrow changes; similar changes occurred in monkeys at a lower incidence. Lymphoid toxicity in rats consisted of lymphoid depletion of the lymph nodes, spleen, and thymus, and decreased lymphoid organ weights. Changes in the gastrointestinal, haematopoietic and lymphoid systems were reversible following cessation of treatment.

Renal changes in monkeys treated for up to 9 months were limited to an increase in background kidney mineralisation. Cutaneous haemorrhage was observed in an acute, single-dose oral study in monkeys but was not observed in repeat-dose studies in either monkeys or rats. In rats, dasatinib inhibited platelet aggregation in vitro and prolonged cuticle bleeding time in vivo, but did not invoke spontaneous haemorrhage.

Dasatinib activity in vitro in hERG and Purkinje fiber assays suggested a potential for prolongation of cardiac ventricular repolarisation (QT interval). However, in an in vivo single-dose study in conscious telemetered monkeys, there were no changes in QT interval or ECG wave form.

Dasatinib was not mutagenic in in vitro bacterial cell assays (Ames test) and was not genotoxic in an in vivo rat micronucleus study. Dasatinib was clastogenic in vitro to dividing Chinese Hamster Ovary (CHO) cells.

Dasatinib did not affect male or female fertility in a conventional rat fertility and early embryonic development study, but induced embryolethality at dose levels approximating human clinical exposures. In embryofoetal development studies, dasatinib likewise induced embryolethality with associated decreases in litter size in rats, as well as foetal skeletal alterations in both rats and rabbits. These effects occurred at doses that did not produce maternal toxicity, indicating that dasatinib is a selective reproductive toxicant from implantation through the completion of organogenesis.

In mice, dasatinib induced immunosuppression, which was dose-related and effectively managed by dose reduction and/or changes in dosing schedule. Dasatinib had phototoxic potential in an in vitro neutral red uptake phototoxicity assay in mouse fibroblasts. Dasatinib was considered to be non-phototoxic in vivo after a single oral administration to female hairless mice at exposures up to 3-fold the human exposure following administration of the recommended therapeutic dose (based on AUC).

In a two-year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma exposure (AUC) level generally equivalent to the human exposure at the recommended range of starting doses from 100 mg to 140 mg daily. A statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose females and of prostate adenoma in low-dose males was noted. The relevance of the findings from the rat carcinogenicity study for humans is not known.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Cellulose, Microcrystalline (E460)

Lactose Monohydrate Croscarmellose Sodium

Hydroxypropyl­cellulose (E463)

Magnesium Stearate (E470b)

Film-coating

Poly(Vinyl Alcohol) (E1203)

Titanium Dioxide (E171)

Talc (E553b)

Glyceryl Monostearate (E471)

Sodium Laurilsulfate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

The film-coated tablets are packed in aluminium-OPA/aluminium/PVC blisters (calendar blisters or perforated unit dose blisters) or are packed in a HDPE bottle with a polypropylene child-resistant closure and a plastic (HDPE) canister containing silica gel and inserted in a carton.

Pack sizes:

Carton containing 10 film-coated tablets in 1 calendar blister.

Carton containing 10 × 1 and 30 × 1 film-coated tablets in perforated unit dose blisters.

Carton containing one bottle with 30 film-coated tablets.

Not all pack sizes may be marketed

6.6 Special precautions for disposal

The film-coated tablets consist of a core tablet, surrounded by a film coating to prevent exposure of health care professionals to the active substance. However, if the film-coated tablets are unintentionally crushed or broken, health care professionals should wear disposable chemotherapy gloves for appropriate disposal in order to minimise the risk of dermal exposure.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Sandoz Limited

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 04416/1508

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

24/08/2018