Dasamia 20, 50, 70 & 100 20 mg, 50 mg, 70 mg & 100 mg Tablet

DASAMIA is indicated for the treatment of adults with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML) in chronic phase.

• DASAMIA is indicated for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib.
• DASAMIA is also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) with resistance or intolerance to prior therapy.

The recommended starting dosage of DASAMIA for chronic phase CML is 100 mg once daily, administered orally. DASAMIA can be taken with or without a meal and should be taken consistently either in the morning or in the evening.

The recommended starting dosage of DASAMIA for accelerated, myeloid or lymphoid blast phase (advanced phase) CML or Ph+ ALL is 70 mg twice daily, administered orally. DASAMIA can be taken with or without a meal and should be taken consistently in the morning and in the evening.

Dose increase or reduction is recommended based on individual patient response and tolerability.

Dose escalation

In clinical trials of CML and Ph+ ALL, dose escalation to a total maximum of 70 mg twice daily (chronic phase CML) or 90 mg twice daily (advanced phase CML or Ph+ ALL) was allowed in patients who did not achieve a haematologic or cytogenetic response at the recommended starting dosage.

Dose adjustment for undesirable effects

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 in adults are summarised in table below.

Table 1: Dose adjustments for neutropenia and thrombocytopenia.

Chronic phase CML (starting dose 100 mg once daily) ANC* < 0,5 x 10 9 /L or platelets < 50 x 10 9 /L

1. Stop DASAMIA until ANC u2265 1,0 x 10 9 /L and platelets u2265 50 x 10 9 /L.
2. Resume treatment with DASAMIA at the original starting dose.
3. If platelets < 25 x 10 9 /L or recurrence of ANC 7 days, repeat Step 1 and resume DASAMIA 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 DASAMIA (for patients resistant or intolerant to prior including imatinib).

Accelerated phase CML, Blast phase CML and Ph+ ALL (starting dose 70 mg twice daily ANC < 0,5 x 10 9 /L or platelets < 10 x 10 9 /L

1. Check if cytopenia is related to leukaemia (marrow aspirate or biopsy).
2. If cytopenia is unrelated to leukaemia, stop DASAMIA until ANC u2265 1,0 x 10 9 /L and platelets u2265 20 x 10 9 /L and resume at the original starting dose.
3. If recurrence of cytopenia, repeat Step 1 and resume DASAMIA at a reduced dose of 50 mg twice daily (second episode) or 40 mg twice daily (third episode).
4. If cytopenia is related to leukaemia, consider dose escalation to 100 mg twice daily.

* ANC: absolute neutrophil count

Non-haematological adverse reactions

If a severe non-haematological adverse reaction develops with DASAMIA use, treatment must be withheld until the event has resolved or improved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence of the event (see section 4.4).

Renal Impairment: See section 5.2

Hepatic Impairment: See section 5.2

Geriatric: No clinically relevant age-related pharmacokinetic differences have been reported. No specific dose recommendation is necessary.

Paediatric Patients: The safety and efficacy of dasatinib in patients < 18 years of age have not been established.

Method of administration

DASAMIA is administered orally. Tablets should not be crushed or cut; they should be swallowed whole.

• DASAMIA is contra-indicated in patients with hypersensitivity to dasatinib or to any other component of DASAMIA.
• The concomitant use of H2 antagonists or proton pump inhibitors with DASAMIA is not recommended.

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 medicines that are metabolised primarily by or modulate the activity of CYP3A4 (see section 4.5).

Concomitant use of dasatinib and medicines 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 medicines 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 medicines 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 co-administered 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 reported single-dose pharmacokinetic study, patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose. Due to the limitations of this reported clinical study, caution is recommended when administering dasatinib to patients with hepatic impairment.

Effect of other medicines on DASAMIA.

Medicines that may increase dasatinib plasma concentrations

CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and medicines that inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, telithromycin, grapefruit juice) may increase exposure to DASAMIA and should be avoided. Selection of an alternate concomitant medication with no or minimal CYP3A4 inhibition potential is recommended. If systemic administration of a potent CYP3A4 inhibitor cannot be avoided, the patient should be closely monitored for toxicity.

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

Medicines that may decrease dasatinib plasma concentrations

CYP3A4 Inducers: Medicines that induce CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St. Johnu2019s Wort (Hypericum perforatum) may reduce exposure to dasatinib. Concomitant use of potent CYP3A4 inducers with dasatinib is not recommended. In patients for whom CYP3A4 inducers are indicated, alternative medicines with no or minimal CYP3A4 induction potential should be selected. Concomitant use of dexamethasone, a weak CYP3A4 inducer, with dasatinib is allowed; dasatinib AUC is reported to decrease approximately 25 % with concomitant use of dexamethasone, which is not likely to be clinically meaningful.

Rifampicin: Data from a reported study of healthy subjects indicate that when a single morning dose of dasatinib was administered following 8 days of continuous evening administration of 600 mg of rifampicin, a potent CYP3A4 inducer, the mean Cmax, and AUC of dasatinib were decreased by 81 % and 82 %, respectively.

Antacids (aluminium hydroxide/magnesium hydroxide products): Reported non-clinical data demonstrate that the solubility of dasatinib is pH dependent. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of DASAMIA. Simultaneous administration of DASAMIA with antacids should be avoided.

H2 antagonists/proton pump inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors reduces dasatinib exposure by >60 %. The concomitant use of H2 antagonists or proton pump inhibitors with DASAMIA is not recommended. The use of antacids should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving DASAMIA therapy.

Effect of dasatinib on other medicines

CYP3A4 substrates: Dasatinib is an inhibitor of CYP3A4. Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, ciclosporin, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, bepridil or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving DASAMIA. Reported in vitro data indicate a potential risk for interaction with CYP2C8 substrates, such as glitazones.

Simvastatin: Single dose data from a reported study of healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37 % and 20 %, respectively, when simvastatin was administered in combination with a single 100 mg dose of dasatinib.

Women of childbearing potential/contraception in males and females

Sexually active male or female patients taking DASAMIA should use adequate contraception.

Pregnancy

Based on reported human experience, dasatinib is suspected to cause congenital malformations including neural tube defects, and harmful pharmacological effects on the foetus when administered during pregnancy. Reported studies in animals have shown reproductive toxicity.

Dasatinib may cause foetal harm when administered to a pregnant woman. There have been post-marketing reports of spontaneous abortion and foetal and infant anomalies from women who have taken dasatinib during pregnancy. Dasatinib is not recommended for use in women who are pregnant or contemplating pregnancy. If dasatinib is used during pregnancy, or if the patient becomes pregnant while taking dasatinib, the patient should be apprised of the potential hazard to the foetus.

Breastfeeding

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. Women who are taking DASAMIA should not breastfeed.

Fertility

Medical practitioners and other healthcare providers should counsel male patients of appropriate age about possible effects of DASAMIA on fertility, and this counselling may include consideration of semen deposition.

DASAMIA 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 DASAMIA. Therefore, cautions should be recommended when driving a car or operating machines. No studies on the effects on the ability to drive and use machines have been performed.

Table 2: Tabulated summary of adverse reactions

System Organ Class Frequent Less frequent Frequency not known

Infections and infestations Infection (including bacterial, viral, fungal, non-specified), 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).

• Hepatitis B reactivation

Blood and lymphatic system disorders Myelosuppression (including anaemia, neutropenia, lymphopenia, pure red cell aplasia, thrombocytopenia), febrile neutropenia

• Lymphadenopathy

Immune system disorders - Hypersensitivity (including erythema nodosum), anaphylactic shock

• -

Endocrine disorders - Hypothyroidism, hyperthyroidism, thyroiditis

• -

Metabolism and nutrition disorders Appetite disturbances, hyperuricaemia

• Tumour lysis syndrome, dehydration, hypoalbuminemia, hypercholesterolemia, diabetes mellitus

Psychiatric disorders Depression, insomnia

• Anxiety, confusional state, affect lability, decrease of libido

Nervous System disorders Headache, neuropathy (including, peripheral neuropathy), dizziness, dysgeusia, somnolence, CNS bleeding, syncope, tremor, amnesia, balance disorder, cerebrovascular accident, transient ischaemic attack, convulsion, optic neuritis, VIIth nerve paralysis

• -

Eye disorders Visual disorder (including visual disturbance, vision, blurred, and visual acuity reduced), dry eye

• Visual impairment, conjunctivitis, photophobia, lacrimation increased

Ear and labyrinth disorders Tinnitus

• Hearing loss, vertigo

Cardiac disorders Congestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmia (including tachycardia), palpitations

• Myocardial infarction (including fatal outcome), electrocardiogram QT prolonged, pericarditis, ventricular dysrhythmia (including ventricular tachycardia), angina pectoris, cardiomegaly, electrocardiogram T wave abnormal, Troponin increased, Cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest, electrocardiogram PR prolongation, coronary artery disease, pleuro-pericarditis

Vascular disorders Haemorrhage, hypertension, flushing

• Hypotension, thrombophlebitis, thrombosis, deep vein thrombosis, embolism, livedo reticularis. Thrombotic micro-angiopathy

Respiratory, Thoracic and mediastinal disorders Pleural effusion, dyspnoea, pulmonary oedema, pulmonary hypertension, lung infiltration, pneumonitis, cough

• Pulmonary arterial hypertension, bronchospasm, asthma, dysphonia, acute respiratory distress syndrome, chylothorax, interstitial lung disease

Gastrointestinal disorders Diarrhoea, nausea, vomiting, abdominal pain, gastrointestinal bleeding, colitis (including neutropaenic colitis), gastritis, mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, oral soft tissue disorder

• Pancreatitis (including Acute pancreatitis), upper gastrointestinal ulcer, oesophagitis, ascites, anal fissure, dysphagia, gastroesophageal reflux disease, Protein-losing gastroenteropathy, ileus, anal fistula, Fatal gastro-intestinal haemorrhage

Hepatobiliary disorders - Hepatitis, cholecystitis, cholestasis

• -

Skin and Subcutaneous tissue disorders Skin rash, alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, hyperhidrosis

• Neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesiasyndrome, hair disorder, leukocytoclastic vasculitis, skin fibrosis

Musculoskeletal and connective tissue disorders Musculoskeletal pain, arthralgia, myalgia

• Muscular weakness, musculoskeletal stiffness, muscle spasm, Rhabdomyolysis, osteonecrosis, muscle inflammation, tendonitis, arthritis, epiphyses delayed fusion, growth retardation.

Renal and urinary disorders - Renal failure, urinary frequency, proteinuria, renal impairment.

• Nephrotic syndrome

Reproductive system and breast disorders - Gynecomastia, menstrual disorder.

• -

General disorders and administration site conditions Peripheral oedema, fatigue, pyrexia, face oedema, malaise, other superficial oedema, gait disturbance

• -

Investigations Decreased weight, increased weight

• Increased blood creatinine phosphokinase, increased Gamma-glutamyl-transferase

-

Reported post-marketing experience

The following additional adverse reactions have been identified during post approval use of dasatinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Special populations

While the safety profile of dasatinib in elderly was reported to be 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 medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Experience with overdose of dasatinib in reported clinical studies is limited to isolated cases. Overdose of 280 mg per day for one week was reported in two patients and both developed a significant decrease in platelet counts. Since dasatinib is associated with severe myelosuppression (see section 4.4), patients who ingest more than the recommended dosage should be closely monitored for myelosuppression and appropriate supportive treatment given.