Vativio 10 mg/400 mg FC tablets

VATIVIO is indicated for:

• treatment of adult and paediatric patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (CML).
• treatment of adult and paediatric patients with CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
• treatment of adult patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy.
• treatment of adult patients with relapsed or refractory Ph+ ALL as monotherapy.
• treatment of adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
• treatment of adult patients with systemic mastocytosis (SM) without the D816V c-Kit mutation and eosinophilia.
• treatment of adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFRu03b1 rearrangement.
• treatment of adult patients with unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST).
• adjuvant treatment of adult patients following resection of Kit-positive GIST.
• treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).

The effectiveness of VATIVIO is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in SM, HES/CEL, on objective response rates and progression-free survival in unresectable and/or metastatic GIST, on recurrence free survival in adjuvant GIST, and on objective response rates in DFSP (see section 5 - Pharmacological Properties). Increased survival in controlled trials has been demonstrated only in newly diagnosed chronic phase CML.

Therapy should be initiated by a medical practitioner experienced in the treatment of patients with malignancies.

The prescribed dose should be administered orally with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening.

For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 ml for a 100 mg tablet, and 200 ml for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s).

Dosage in CML in Adults: The recommended dosage of VATIVIO is 400 mg/day for patients in chronic phase CML and 600 mg/day for patients in accelerated phase or blast crisis. Treatment should be continued as long as the patient continues to benefit. Dose increase from 400 mg to 600 mg, or to 800 mg in patients with chronic phase disease, or from 600 mg to a maximum of 800 mg daily in patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenic response.

Dosage in CML in Children: Dosing in children should be on the basis of body surface area (mg/mu00b2). The dose of 340 mg/mu00b2 daily is recommended for children with chronic phase and advanced phase CML (not to exceed the total dose of 600 mg daily). Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations u2013 one in the morning and one in the evening. The dose recommendation is currently based on a small number of paediatric patients (see Pharmacological action and Pharmacokinetics). There is no experience with the use of VATIVIO in children below 2 years of age.

Dosage in Ph+ ALL in Adults: The recommended dose of VATIVIO is 600 mg/day for patients with Ph+ ALL.

Dosage in MDS/MPD: The recommended dose of VATIVIO is 400 mg/day for patients with MDS/MPD.

Dosage in SM: The recommended dose of VATIVIO is 400 mg/day for adult patients with SM without the D816V KIT mutation or mutational status unknown or not responding satisfactorily to other therapies. For patients with SM associated with eosinophilia, a clonal haematological disease related to the fusion kinase FIP1L1-PDGFRu03b1, a starting dose of 100 mg/day is recommended. A dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

Dosage in HES/CEL: The recommended dose of VATIVIO is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRu03b1 fusion kinase, a starting dose of 100 mg/day is recommended. A dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

Dosage in GIST: The recommended dose of VATIVIO is 400 mg/day for patients with unresectable and/or metastatic, malignant GIST. A dose increase from 400 mg to 600 mg or to 800 mg for patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

The recommended dose of VATIVIO is 400 mg/day for the adjuvant treatment of adult patients following resection of GIST. The recommended minimum treatment duration is 36 months. In the adjuvant setting the optimal treatment duration with VATIVIO is not known.

Dosage in DFSP: The recommended dose of VATIVIO is 800 mg/day for patients with DFSP.

Dose adjustments for adverse reactions: Non-haematological adverse reactions: If a severe non-haematological adverse reaction develops with VATIVIO use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event. If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, VATIVIO should be withheld until bilirubin levels have returned to a < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with VATIVIO may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from 800 mg to 600 mg and in children from 340 to 260 mg/mu00b2/day.

Haematological adverse reactions: Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the table below.

Hypersensitivity to imatinib or to any of the excipients of VATIVIO. Pregnancy and lactation (see section 4.6).

Hepatitis B reactivation: Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving a BCR-ABL tyrosine kinase inhibitor (TKI), such as VATIVIO. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section 4.8). Patients currently on VATIVIO should have baseline testing for hepatitis B infection in order to identify chronic carriers of the virus. 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 hepatitis B infection during treatment. Carriers of hepatitis B virus who require treatment with VATIVIO should be closely monitored for signs and symptoms of active hepatitis B infection throughout therapy and for several months following termination of therapy.

When VATIVIO is co-administered with other medicines, there is a potential for interactions (see section 4.5). Caution should be used when taking VATIVIO with rifampicin or other strong CYP3A4 inducers, ketoconazole, or other strong CYP3A4 inhibitors, CYP3A4 substrates with a narrow therapeutic window (e.g. ciclosporin or pimozide) or CYP2C9 substrates with a narrow therapeutic window (e.g. warfarin). One patient, who was taking paracetamol regularly for fever, died of acute liver failure. Although the aetiology is currently unknown, special caution should be exercised when using paracetamol (see section 4.5).

Hypothyroidism: Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with VATIVIO. TSH levels should be closely monitored in such patients (see section 4.5).

Hepatotoxicity: In patients with hepatic dysfunction, peripheral blood counts and liver enzymes should be carefully monitored (see section 4.2, 4.8 and 5.2). When VATIVIO is combined with high dose chemotherapy regimens, liver toxicity in the form of transaminase elevation and hyperbilirubinaemia have been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended in circumstances where VATIVIO is combined with chemotherapy regimens also known to be associated with hepatic dysfunction (see section 4.5 and 4.8).

Fluid retention: Severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, superficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients taking VATIVIO. Therefore, it is recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these events in elderly patients and those with a prior history of cardiac disease.

Patients with cardiac disease or renal failure: Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated. In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib. Myelodysplastic/myeloproliferative diseases and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or SM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with VATIVIO should be considered at the initiation of therapy.

Gastrointestinal haemorrhage: In the Phase III GIST studies in patients with unresectable or metastatic malignant GIST, 211 patients (12.9%) reported Grade 3/4 haemorrhage at any site. In the Phase II GIST study in patients with unresectable or metastatic malignant GIST, eight patients (5.4%) were reported to have had gastrointestinal (GI) haemorrhage and four patients (2.7%) were reported to have had haemorrhages at the site of tumour deposits. The tumour haemorrhages have been either intra-abdominal or intra-hepatic, depending on the anatomical location of tumour lesions. GI sites of tumour may have contributed to reports of GI bleeding in this patient population (see section 4.8). Patients should therefore be monitored for gastrointestinal symptoms at the start of and during VATIVIO therapy. When needed, VATIVIO discontinuation may be considered (see section 4.8).

Tumour Lysis Syndrome: Cases of Tumour Lysis Syndrome (TLS) have been reported in patients treated with VATIVIO. Due to possible occurrence of TLS, correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of VATIVIO (see section 4.8).

Class effects: Class effects of Tyrosine Kinase Inhibitors (TKIs) such as contained in VATIVIO. Although TKIs may have different kinase inhibition profiles and/or off target binding profiles, there is some evidence that the TKIs share to a variable degree, class related cerebrovascular adverse events (e.g. cerebrovascular accident, transient ischaemic attack, ischaemic stroke, and cerebral infarction). These cerebrovascular adverse events may occur in patients on treatment with TKIs with or without risk factors for these events and may occur at any time during treatment with TKIs. Patients on treatment with VATIVIO should be carefully monitored, and relevant risk factors managed to reduce the risk for these class related cerebrovascular adverse events. Treatment with VATIVIO should be discontinued, and alternative treatment options be considered in patients who developed these class related cerebrovascular adverse events.

Patients with cardiac disease or renal failure: Patients with cardiac disease or risk factors for cardiac failure or history of renal failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure or renal failure should be evaluated and treated.

Laboratory tests: Full blood counts must be performed regularly during therapy with VATIVIO. Treatment of CML patients with VATIVIO has been associated with neutropenia and/or thrombocytopenia. However, the occurrence of these cytopenias is also related to the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with chronic phase CML. Treatment with VATIVIO may be interrupted or the dose be reduced, as recommended in section 4.2. Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving VATIVIO (see section 4.2). As recommended in section 4.2, non-haematological adverse reactions, these laboratory abnormalities should be managed with interruption and/or dose reduction of the treatment with VATIVIO. VATIVIO and its metabolites are not excreted via the kidney to a significant extent. Creatinine clearance (CrCL) is known to decrease with age, and age did not significantly affect VATIVIO kinetics (see section 5). In patients with impaired renal function, imatinib plasma exposure seems to be higher than that in patients with normal renal function, probably due to an elevated plasma level of alpha-acid glycoprotein (AGP), an imatinib-binding protein, in these patients. There is no correlation between imatinib exposure and the degree of renal impairment, as classified by the measurement of creatinine clearance (CrCL), between patients with mild (CrCL: 40 to 59 mL/min) and severe (CrCL: < 20 mL/min) renal impairment. However, as recommended in section 4.2, the starting dose of VATIVIO can be reduced if not tolerated.

Observed interactions resulting in a concomitant use not recommended: Medicines that may decrease VATIVIO plasma concentrations: Medicines that are inducers of CYP3A4 activity could increase metabolism and decrease VATIVIO plasma concentrations. Co-medications which induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbitone and hypericum perforatum (also known as St. Johnu2019s Wort) may significantly reduce exposure to VATIVIO. Pre-treatment of 14 healthy volunteers with multiple doses of rifampicin, 600 mg daily for 8 days, followed by a single 400 mg dose of VATIVIO, increased VATIVIO oral-dose clearance by 3.8-fold (90% confidence interval = 3.5 to 4.3-fold), which represents mean decreases Cmax, AUC (0-24) and AUC (0-u221e) by 54%, 68% and 74%, of the respective values without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with VATIVIO while taking enzyme-inducing anti-epileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbitone, and primidone. The plasma AUC for imatinib decreased by 73% compared to patients not on EIAEDs. In two published studies, concomitant administration of imatinib and a product containing St. Johnu2019s wort led to a 30-32% reduction in the AUC of VATIVIO. In patients where rifampicin or other CYP3A4 inducers are indicated, alternative medicines with less enzyme induction potential should be considered.

Other interactions that may affect exposure to VATIVIO or other drugs: Medicines that may increase VATIVIO plasma concentrations: Medicines that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin) could decrease metabolism and increase VATIVIO concentrations. There was a significant increase in exposure to VATIVIO (the mean Cmax and AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be exercised when administering VATIVIO with inhibitors of the CYP3A4 family. Medicines that may have their plasma concentration altered by VATIVIO: VATIVIO increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by VATIVIO. Therefore, caution is recommended when administering VATIVIO with CYP3A4 substrates with a narrow therapeutic window (e.g. ciclosporin or pimozide). VATIVIO may increase plasma concentration of other CYP3A4 metabolised medicines (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors i.e. statins, etc.). VATIVIO also inhibits CYP2C9 and CYP2C19 activity in vitro. PT prolongation was observed following co-administration with warfarin. When giving warfarin, short-term PT monitoring is therefore necessary at the start and end of VATIVIO therapy and when altering the dosage. Alternatively, the use of low-molecular weight heparin should be considered. In vitro, VATIVIO inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. VATIVIO at 400 mg twice daily had a weak inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol Cmax and AUC being increased by approximately 23%. Co-administration of imatinib with CYP2D6 substrates, such as metoprolol, does not seem to be a risk factor for interactions and dose adjustment may not be necessary. In vitro, VATIVIO inhibits paracetamol O-glucuronidation (Ki value of 58.5 MicroM at therapeutic levels) (see section 4.4). Co-administration of VATIVIO (400 mg/day for eight days) with paracetamol (1000 mg single dose on day eight) in patients with CML did not result in any changes in the pharmacokinetics of paracetamol. VATIVIO pharmacokinetics was not altered in the presence of single-dose paracetamol.

Pregnancy: VATIVIO is contraindicated in Pregnancy and Lactation (see section 4.3). VATIVIO can cause foetal harm when administered to a pregnant woman based on findings from animal reproduction studies. Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity (increased incidence of congenital abnormalities) following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on body surface area. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken VATIVIO during pregnancy. VATIVIO should therefore not be used during pregnancy.

Lactation: Both imatinib and its active metabolite are transferred into human milk. The effects of low-dose exposure of the infant to imatinib are unknown. Because of the potential for serious adverse drug reactions in the breastfed child, breastfeeding is not recommended during treatment and for at least 15 days after stopping treatment with VATIVIO.

Fertility: Women of child-bearing potential must be advised to use highly effective contraception (methods that result in less than 1% pregnancy rates) such as use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) during treatment with VATIVIO and for at least 15 days after stopping treatment with VATIVIO. Human studies on male patients receiving VATIVIO and its effect on male fertility and spermatogenesis have not been performed. Males using VATIVIO should use barrier contraceptives (condoms) for at least 15 days after stopping treatment with VATIVIO. Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights as well as a reduced number of motile sperm were observed in the high dose males rats. In pre- and postnatal study in rats, fertility in the first generation offspring was also not affected by VATIVIO.

Patients should be advised that they may experience undesirable effects such as dizziness, syncope, somnolence or blurred vision or other eye disorders during treatment with VATIVIO (see section 4.8). Therefore, caution is recommended when driving a car or operating machinery.

Summary of the safety profile: During clinical development, the majority of patients experienced adverse events at some point in time. The most frequently reported ADRs (>10%) were neutropenia, thrombocytopenia, anaemia, headache, dyspepsia, oedema, weight increased, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhoea, rash, fatigue, and abdominal pain. Events were of mild to moderate grade; 2% to 5% of patients permanently discontinued therapy due to medicine-related events. The safety profile of VATIVIO in adult and paediatric patients with Ph+ leukaemias is similar. The differences in the safety profile between Ph+ leukaemias and solid tumours are a higher incidence and severity of myelosuppression in Ph+ leukaemias, and GI and intra-tumoural haemorrhages in GIST patients and are probably due to disease-related factors. Myelosuppression, GI adverse events, oedema, and rashes are common in these two patient populations. Other GI conditions, such as gastrointestinal obstruction, perforation and ulceration, appear to be more indication-specific. Other prominent adverse events that have been observed after exposure to VATIVIO, and which may be causally related, include hepatotoxicity, acute renal failure, hypophosphataemia, severe respiratory adverse reactions, and tumour lysis syndrome and growth retardation in children. Depending on severity of events, dose adjustment may be required. Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (u22651/10); common (u22651/100, <1/10); uncommon (u22651/1,000, <1/100); rare (u22651/10,000, <1/1,000); very rare (<1/10,000), including isolated reports.

Adverse reactions and their frequencies reported in Table 2 are based on the registration studies for CML and GIST:

• Infections and infestations: Uncommon: Sepsis, pneumonia, herpes simplex, herpes zoster, nasopharyngitis upper respiratory tract infection, gastroenteritis, sinusitis, cellulitis, influenza, urinary tract infection. Rare: Fungal infection.
• Blood and lymphatic system disorders: Very common: Neutropenia, thrombocytopenia, anaemia. Common: Febrile neutropenia, pancytopenia. Uncommon: Thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy. Rare: Haemolytic anaemia.
• Metabolism and nutrition disorders: Common: Anorexia. Uncommon: Dehydration, hyperuricaemia, hypokalaemia, increased appetite, decreased appetite, gout, hypophosphataemia, hypercalcaemia, hyperglycaemia, hyponatraemia. Rare: Hyperkalaemia, hypomagnesaemia.
• Psychiatric disorders: Common: Insomnia. Uncommon: Depression, anxiety, decreased libido. Rare: Confusion.
• Nervous system disorders: Very common: Headache. Common: Dizziness, taste disturbance, paraesthesia, hypoaesthesia. Uncommon: Cerebral haemorrhage, syncope, peripheral neuropathy, somnolence, migraine, memory impairment, sciatica, restless leg syndrome, tremor. Rare: Optic neuritis, increased intracranial pressure, convulsions.
• Eye disorders: Common: Conjunctivitis, increased lacrimation, blurred vision, eyelid oedema, conjunctival haemorrhage, dry eye. Uncommon: Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedema. Rare: Cataract, papilloedema, glaucoma.
• Ear and labyrinth disorders: Uncommon: Vertigo, tinnitus, hearing loss.
• Cardiac disorders: Uncommon: Cardiac failure congestive, pulmonary oedema, palpitations, tachycardia. Rare: Pericardial effusion, arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris.
• Vascular disorders: Common: Flushing, haemorrhage. Uncommon: Haematoma, hypertension, hypotension, peripheral coldness, Raynaud's phenomenon.
• Respiratory, thoracic and mediastinal disorders: Common: Epistaxis, dyspnoea, cough. Uncommon: Pleural effusion, pharyngolaryngeal pain, pharyngitis. Rare: Pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary haemorrhage.
• Gastrointestinal disorders: Very common: Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain. Common: Abdominal distension, flatulence, constipation, gastro-oesophageal reflux, dry mouth, gastritis. Uncommon: Gastrointestinal haemorrhage, eructation, melaena, oesophagitis, ascites, gastric ulcer, mouth ulceration, stomatitis, haematemesis, cheilitis, dysphagia, pancreatitis. Rare: Colitis, ileus/inflammatory bowel disease.
• Hepato-biliary disorders: Common: Increased hepatic enzymes. Uncommon: Jaundice, hepatitis, hyperbilirubinaemia. Rare: Hepatic failure, hepatic necrosis.
• Skin and subcutaneous tissue disorders: Very common: Periorbital oedema, dermatitis/eczema/rash. Common: Facial oedema, pruritus, erythema, dry skin, alopecia, night sweats, photosensitivity reaction. Uncommon: Pustular rash, petechiae, contusion, increased sweating, urticaria, ecchymosis, increased tendency to bruise, onychoclasis, folliculitis, purpura, hypotrichosis, skin hyperpigmentation, psoriasis, exfoliative dermatitis and bullous eruptions, skin hypopigmentation. Rare: Nail discolouration, vesicular rash, Stevens-Johnson syndrome, acute febrile neutrophilic dermatosis (Sweetu2019s syndrome), erythema multiforme, leucocytoclastic vasculitis, angioneurotic oedema, acute generalised exanthematous pustulosis (AGEP).
• Musculoskeletal, connective tissue and bone disorders: Very common: Muscle spasm and cramps, musculoskeletal pain, including myalgia, arthralgia, bone pain. Common: Joint swelling. Uncommon: Joint and muscle stiffness. Rare: Muscular weakness, arthritis.
• Renal and urinary disorders: Uncommon: Renal failure, renal pain, increased urinary frequency, haematuria.
• Reproductive system and breast disorders: Uncommon: Gynaecomastia, erectile dysfunction, breast enlargement, scrotal oedema, menorrhagia, irregular menstruation, nipple pain, sexual dysfunction.
• General disorders and administration site conditions: Very common: Fluid retention and oedema, fatigue. Common: Pyrexia, weakness, rigors, anasarca, chills. Uncommon: Malaise, chest pain.
• Investigations: Very common: Increased weight. Common: Decreased weight. Uncommon: Increased blood alkaline phosphatase, increased blood creatinine, increased blood creatine phosphokinase, increased blood lactate dehydrogenase. Rare: Increased blood amylase.

1 Pneumonia was reported most commonly in patients with transformed CML and in patients with GIST. 2 Headache was the most common in GIST patients. 3 On a patient-year basis, cardiac events including congestive heart failure were more commonly observed in patients with transformed CML than in patients with chronic CML. 4 Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was most common in patients with GIST and with transformed CML (CML-AP and CML-BC). 5 Pleural effusion was reported more commonly in patients with GIST and in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML. 6/7 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST patients. 8 Musculoskeletal pain and related events were more commonly observed in patients with CML than in GIST patients. 9 Some fatal cases of hepatic failure and hepatic necrosis have been reported.

In overdose, side effects will be elicited and exacerbated (see section 4.8). Experience with doses greater than 800 mg is limited. Isolated cases of VATIVIO overdose have been reported. In such an event of overdosage, the patient should be observed and appropriate supportive treatment given.

Adult overdose: 1,200 mg to 1,600 mg (duration varying between 1 to 10 days) resulted in: Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 mg to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain. 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increased transaminases. 8 g to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric overdose: One 3 year old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3 year old male exposed to a single dose of 980 mg dose experienced decreased white blood cell count and diarrhoea.