FOTIVDA 890mcg capsules medication leaflet

Fotivda 890 microgram hard capsules

Fotivda 1340 microgram hard capsules

Fotivda 890 microgram hard capsules

Each hard capsule contains tivozanib hydrochloride monohydrate equivalent to 890 microgramtivozanib.

Each hard capsule contains trace amounts of tartrazine (E102) (8-12% of the yellow printing inkcomposition) (see section 4.4).

Fotivda 1340 microgram hard capsules

Each hard capsule contains tivozanib hydrochloride monohydrate equivalent to 1340 microgramtivozanib.

For the full list of excipients, see section 6.1.

Hard capsule.

Fotivda 890 microgram hard capsules

Hard capsule with dark blue opaque cap and bright yellow opaque body, printed with yellow ink“TIVZ” on the cap and with dark blue ink “LD” on the body.

Fotivda 1340 microgram hard capsules

Hard capsule with bright yellow opaque cap and bright yellow opaque body, printed with dark blueink “TIVZ” on the cap and with dark blue ink “SD” on the body.

Fotivda is indicated for the first line treatment of adult patients with advanced renal cell carcinoma(RCC) and for adult patients who are VEGFR and mTOR pathway inhibitor-naïve following diseaseprogression after one prior treatment with cytokine therapy for advanced RCC.

Fotivda should be supervised by a physician experienced in the use of anticancer therapies.

The recommended dose of tivozanib is 1340 microgram once daily for 21 days, followed by a 7-dayrest period to comprise one complete treatment cycle of 4 weeks.

This treatment schedule should be continued until disease progression or unacceptable toxicity.

No more than one dose of Fotivda must be taken per day.

The occurrence of undesirable effects may require temporary interruption and/or dose reduction oftivozanib therapy (see section 4.4). In the pivotal study, the dose was reduced for grade 3 events andinterrupted for grade 4 events.

When dose reduction is necessary, the tivozanib dose can be reduced to 890 microgram once dailywith the normal treatment schedule of 21 days of dosing, followed by a 7-day rest period.

In the case of a missed dose a replacement dose must not be taken to make up for a forgotten dose.

The next dose should be taken at the next scheduled time.

In the case of vomiting a replacement dose should not be taken; the next dose should be taken at thenext scheduled time.

The safety and efficacy of tivozanib in children and adolescents aged below 18 years have not beenestablished. No data are available. There is no relevant use of tivozanib in the paediatric population inthe indication advanced renal cell carcinoma.

No dose adjustment is required in patients 65 years of age or older (see sections 4.4 and 5.1).

No dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2).

Caution is advised in patients with severe renal impairment due to limited experience and in patientsundergoing dialysis as there is no experience of tivozanib in this patient population.

All patients should have liver function tests evaluated, including alanine aminotransferase (ALT),aspartate aminotransferase (AST), bilirubin, and alkaline phosphatase (AP), to determine hepaticfunction before starting and during treatment with tivozanib.

Tivozanib is not recommended in patients with severe hepatic impairment. Patients with moderatehepatic impairment should only be treated with one tivozanib 1340 microgram capsule every other dayas they may be at an increased risk of adverse reactions due to increased exposure with the dose of1340 microgram every day (see section 4.4 and section 5.2). No dose adjustment is required whenadministering tivozanib to patients with mild hepatic impairment. Tivozanib should be used withcaution in patients with mild and moderate hepatic impairment with close monitoring of tolerability.

Fotivda is for oral use.

Fotivda may be taken with or without food (see section 5.2). The capsules must be swallowed wholewith a glass of water and must not be opened.

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

Co-administration with herbal preparations containing St. John’s wort (Hypericum perforatum)(see section 4.5).

In clinical studies with tivozanib, hypertension (including persistent severe hypertension) has occurred(see section 4.8). In approximately one-third of the patients, hypertension developed within the first2 months of treatment. Blood pressure should be well controlled prior to initiating tivozanib. Duringtreatment, patients should be monitored for hypertension and treated as needed with anti-hypertensivetherapy according to standard medical practice. In the case of persistent hypertension despite use ofanti-hypertensive therapy, the tivozanib dose should be reduced, or the treatment interrupted andre-initiated at a lower dose once the blood pressure is controlled, according to clinical judgment (seesection 4.2). Discontinuation of treatment should be considered in cases of persistent severehypertension, posterior reversible encephalopathy syndrome (see below), or other complications ofhypertension. Patients receiving anti-hypertensive medicinal product should still be monitored forhypotension when tivozanib is either interrupted or discontinued.

In clinical studies with tivozanib, arterial thromboembolic events (ATEs) have occurred (see section4.8). Risk factors for ATE include malignant disease, age > 65 years, hypertension, diabetes mellitus,smoking, hypercholesterolaemia, and prior thromboembolic disease. Tivozanib has not been studied inpatients who had an ATE within the preceding 6 months of clinical study initiation. Tivozanib must beused with caution in patients who are at risk for, or who have a history of these events (such asmyocardial infarction, stroke).

In clinical studies with tivozanib, venous thromboembolic events (VTEs) have been reported includingpulmonary embolism and deep vein thrombosis (see section 4.8). Risk factors for VTEs include majorsurgery, multiple trauma, prior VTEs, advanced age, obesity, cardiac or respiratory failure, andprolonged immobility. Tivozanib has not been studied in patients who had a VTE within the preceding6 months of clinical study initiation. Treatment decision, especially in patients who are at risk for

VTEs, should be based on individual patient benefit/risk assessment.

Cardiac failure

In clinical studies with tivozanib as monotherapy for the treatment of patients with RCC, cardiacfailure has been reported (see section 4.8). Signs or symptoms of cardiac failure should be periodicallymonitored throughout treatment with tivozanib. Management of cardiac failure events may requiretemporary interruption or permanent discontinuation and/or dose reduction of tivozanib therapy, plustreatment of potential underlying causes of cardiac failure, e.g. hypertension.

In clinical studies with tivozanib, haemorrhagic events have been reported (see section 4.8). Tivozanibmust be used with caution in patients who are at risk for, or who have a history of bleeding. If anybleeding requires medical intervention, tivozanib should be temporarily interrupted.

Proteinuria

Proteinuria has been reported in clinical studies with tivozanib (see section 4.8). Monitoring forproteinuria before initiation of, and periodically throughout treatment is recommended. For patientswho develop Grade 2 (> 1.0-3.4 g/24 hours) or Grade 3 (≥ 3.5 g/24 hours) proteinuria (National

Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]), the dose oftivozanib has to be reduced or the treatment temporarily interrupted. If the patient develops Grade 4proteinuria (nephrotic syndrome) tivozanib has to be discontinued. Risk factors for proteinuria includehigh blood pressure.

In clinical studies with tivozanib, elevations of ALT, AST, and bilirubin have been reported (seesection 4.8). The majority of AST and ALT elevations were not accompanied with concomitantelevations of bilirubin. AST, ALT, bilirubin, and AP should be monitored before initiation of andperiodically throughout treatment with tivozanib because of the potential risk of hepatotoxicity (seesection 4.2).

Tivozanib is not recommended in patients with severe hepatic impairment.

Posterior reversible encephalopathy syndrome (PRES)

In clinical studies, one case of PRES was confirmed after treatment with tivozanib (see section 4.8).

PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion,blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present.

Magnetic Resonance Imaging is necessary to confirm the diagnosis of PRES. Tivozanib must bediscontinued in patients developing signs or symptoms of PRES. The safety of re-initiating tivozanibtherapy in patients previously experiencing PRES is not known and tivozanib should only be usedwith caution in these patients.

Hand foot skin reaction (HFSR)

In clinical studies with tivozanib, hand foot skin reaction (palmar-plantar erythrodysaesthesia) hasbeen reported. Most events in the five renal cell carcinoma monotherapy studies were CTC

Grade 1 or 2 (≥ CTC Grade 3 was observed in < 2% of patients treated with tivozanib) and there wereno serious events (see section 4.8). Management of patients experiencing HFSR may include topicaltherapies for symptomatic relief with consideration of temporary interruption and/or reduction intreatment dose or, in severe or persistent cases, permanent discontinuation of treatment.

QT interval prolongation

In clinical studies with tivozanib, QT/QTc interval prolongation has been reported (see section 4.8 andsection 5.1). QT/QTc interval prolongation may lead to an increased risk for ventricular arrhythmias.

It is recommended that tivozanib be used with caution in patients with a history of QT intervalprolongation or other relevant pre-existing cardiac disease and those receiving other medicationsknown to increase the QT interval. Baseline and periodic monitoring of electrocardiograms andmaintenance of electrolytes (e.g. calcium, magnesium, potassium) within the normal range isrecommended.

Gastrointestinal (GI) perforation/fistula

It is recommended that symptoms of GI perforation or fistula should be periodically monitoredthroughout treatment with tivozanib and that tivozanib should be used with caution in patients at riskfor GI perforation or fistula.

For precautionary reasons, temporary interruption of tivozanib therapy is recommended in patientsundergoing major surgical procedures. The decision to resume tivozanib therapy after surgery shouldbe based on clinical judgment of adequate wound healing.

In clinical studies with tivozanib, hypothyroidism has been reported (see section 4.8). Hypothyroidismhas been observed to occur at any time during treatment with tivozanib, developing as early as withintwo months of treatment initiation. Risk factors for hypothyroidism include prior history ofhypothyroidism and use of anti-thyroid medications. Thyroid function should be monitored beforeinitiation of, and periodically throughout treatment with tivozanib. Hypothyroidism should be treatedaccording to standard medical practice.

Dysphonia, diarrhoea, fatigue, weight decreased, appetite decreased and hypothyroidism occurredmore commonly in patients ≥ 65 years of age. Healthcare professions should be aware that elderlypatients may be at increased risk of adverse reactions.

Tartrazine

Fotivda 890 microgram hard capsules contain tartrazine (E102) which may cause allergic reactions.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote theformation of aneurysms and/or artery dissections. Before initiating Fotivda, this risk should becarefully considered in patients with risk factors such as hypertension or history of aneurysm.

Contraindication of concomitant use

Herbal preparations containing St. John's wort (Hypericum perforatum) are contraindicated. If apatient is already taking St John’s wort, this should be stopped before starting tivozanib treatment. Theinducing effect of St John’s wort may persist for at least 2 weeks after cessation of treatment with St

John’s wort (see section 4.3).

In a clinical study in healthy volunteers, co-administration of a single 1340 microgram dose oftivozanib with a strong CYP3A4 inducer at steady-state (rifampin 600 mg once daily) decreased theaverage half-life of tivozanib from 121 to 54 hours which was associated with a decrease in the singledose AUC0-∞ of 48% compared with AUC0-∞ in the absence of rifampin. Average Cmax and AUC0-24hrwere not significantly affected (8% increase and 6% decrease respectively). The clinical effects ofstrong CYP3A4 inducers on repeated daily dosing of tivozanib has not been studied but potentially theaverage time to reach steady-state and the average steady-state serum concentration of tivozanib maybe reduced, due to the reduction in half-life. It is recommended that concomitant administration oftivozanib with strong CYP3A4 inducers, if used, should be undertaken with caution.

Moderate CYP3A4 inducers are not expected to have a clinically relevant effect on tivozanibexposure.

In a clinical study in healthy volunteers, co-administration of tivozanib with a potent CYP3A4inhibitor, ketoconazole (400 mg once daily), had no influence on tivozanib serum concentrations (Cmaxor AUC); therefore, tivozanib exposure is unlikely to be altered by CYP3A4 inhibitors.

Medicinal products for which intestinal absorption is restricted by BCRP

Tivozanib inhibits the transporter protein BCRP in vitro, but the clinical relevance of this finding isunknown (see section 5.2). Caution should be exercised if tivozanib is co-administered withrosuvastatin. Alternatively, a statin not subject to restriction of intestinal absorption by BCRP shouldbe considered. Patients taking an oral BCRP substrate with a clinically-relevant efflux interaction inthe gut should ensure that a suitable time window (e.g. 2 hours) is applied between administration oftivozanib and the BCRP substrate.

Contraceptives

It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives,and therefore women using hormonal contraceptives should add a barrier method (see section 4.6).

Women of childbearing potential should avoid becoming pregnant while on tivozanib. Female partnersof male patients taking tivozanib should also avoid pregnancy. Effective methods of contraceptionshould be used by male and female patients and their partners during therapy, and for at least onemonth after completing therapy. It is currently unknown whether tivozanib may reduce theeffectiveness of hormonal contraceptives and therefore women using hormonal contraceptives shouldadd a barrier method.

There are no data from the use of tivozanib in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

Tivozanib should not be used during pregnancy. If tivozanib is used during pregnancy, or if the patientbecomes pregnant while receiving tivozanib, the potential hazard to the foetus must be explained tothe patient.

It is unknown whether tivozanib is excreted in human milk, but the potential exists. Because of thepotential for tivozanib-mediated adverse reactions in breastfed infants, women should not breast-feedwhile taking tivozanib.

Animal studies indicate that male and female fertility may be affected by treatment with tivozanib (seesection 5.3).

Tivozanib may have a minor influence on the ability to drive and use machines. Patients should beadvised to be cautious when driving or using machines if they experience asthenia, fatigue, and/ordizziness during treatment with tivozanib (see section 4.8).

Pooled data of 674 patients with advanced RCC who continued to receive tivozanib as their initial ontrial therapy in the five core RCC monotherapy studies have been evaluated in the overall assessmentof safety and tolerability of tivozanib.

The most important serious adverse reaction is hypertension.

The most common adverse reactions of any grade include hypertension (47.6%), dysphonia(26.9%), fatigue (25.8%) and diarrhoea (25.5%).

In the five core RCC monotherapy studies tivozanib was discontinued in a total of 20 patients (3%)owing to adverse reactions, most commonly due to hypertension (0.4%), persistent severehypertension (0.3%), or acute myocardial infarction (0.3%). The most frequent adverse reactionsleading to tivozanib dose reduction/ interruption were hypertension (4.7%), diarrhoea (3.1%), fatigue(1.8%).

In patients receiving tivozanib as initial therapy, there were three adverse reactions with outcomedeath; one was uncontrolled hypertension in the setting of a suspected overdose (see section 4.9) andtwo were reported simply as death.

Adverse reactions occurring in patients who continued to receive tivozanib as their initial on trialtherapy in the five RCC monotherapy studies were pooled and are listed below by MedDRA bodysystem organ class (SOC) and frequency. Frequencies are defined as follows: 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) and notknown (cannot be estimated from available data). Within each SOC, adverse reactions are presented inorder of decreasing seriousness.

Table 1: Tabulated list of adverse reactions (presented using frequencies for all-causalityadverse events)

System Very common Common Uncommon Rare Not known

Organ

Class

Infections and Fungal infectioninfestations

Pustular rash

Blood and Anaemia Thrombocytopenialymphatic

Haemoglobinsystem disorders increased

Endocrine Hypothyroidism Hyperthyroidismdisorders

Goitre1

Metabolism and Decreased appetite Anorexianutritiondisorders

Psychiatric Insomniadisorders

Nervous system Headache Peripheral Transient Posteriordisorders neuropathy2 ischaemic attack reversibleencephalopathy

Dizziness Memory4 syndrome (PRES)5impairment

Dysgeusia3

Eye disorders Vision impairment6 Increasedlacrimation

Ear and Vertigo Ear congestionlabyrinth Tinnitusdisorders

Cardiac Myocardial Pulmonary oedemadisorders infarction (acute) /7 Coronary arteryischaemiainsufficiency

Angina pectoris

Electrocardiogram

Tachycardia8 QT prolonged

Vascular Hypertension Haemorrhage9 Aneurysms anddisorders artery

Arterialdissectionsthromboembolism10

Venousthromboembolism11

Persistent severehypertension12

Flushing13

Respiratory, Dyspnoea14 Epistaxisthoracic and

Dysphonia Rhinorrhoeamediastinal

Cough Nasal congestiondisorders

System Very common Common Uncommon Rare Not known

Organ

Class

Gastrointestinal Abdominal pain15 Pancreatitis17 Duodenal ulcerdisorders Nausea Dysphagia18

Diarrhoea Vomiting

Stomatitis16 Gastrooesophagealreflux disease

Abdominaldistension

Glossitis19

Gingivitis20

Dyspepsia

Dry mouth

Flatulence

Hepatobiliary ALT increased /disorders AST increased21

Gamma-glutamyltransferaseincreased

Blood alkalinephosphataseincreased

Skin and Palmar-plantar Skin exfoliation Urticariasubcutaneous erythrodysaesthesia

Erythema22 Dermatitis26tissue disorders syndrome/Handfoot skin reaction Pruritus23 Hyperhidrosis(PPE/HFS)

Alopecia Xeroderma

Rash24

Acne25

Dry skin

Musculoskeletal Back pain Arthralgia Muscularand weakness

Myalgiaconnective

Musculoskeletaltissuechest paindisorders

Renal and Proteinuriaurinary

Blood creatininedisorders increased

General Pain27 Chest pain28 Mucosaldisorders and inflammation

Asthenia Chills29administration

Fatigue Pyrexiasite

Peripheral oedemaconditions

System Very common Common Uncommon Rare Not known

Organ

Class

Investigations Weight decreased Amylase increased

Lipase increased

Blood thyroidstimulatinghormone increased

Adverse reactions from clinical studies are presented using frequencies for all-causality adverse events.

The following terms have been combined:

1 Goitre including goitre and toxic nodular goitre2 Peripheral neuropathy including hyperaesthesia, hypoaesthesia, mononeuropathy, neuropathy peripheral, peripheralsensory neuropathy and paraesthesia3 Dysgeusia including ageusia, dysgeusia and hypogeusia4 Memory impairment including amnesia and memory impairment5 PRES was not observed in patients treated with tivozanib in the five RCC monotherapy studies. One patientexperienced Grade 4 PRES and hypertension in Study AV-951-09-901.

6 Vision impairment including reduced visual acuity, vision blurred and visual impairment7 Myocardial infarction (acute)/ischaemia including acute myocardial infarction, ischaemia and myocardial infarction8 Tachycardia including sinus tachycardia, supraventricular tachycardia, tachycardia and tachycardia paroxysmal9 Haemorrhage including adrenal haemorrhage, anal haemorrhage, cervix haemorrhage uterine, duodenal ulcerhaemorrhage, gingival bleeding, haematemesis, haemoptysis, haemorrhagic anaemia, haemorrhagic erosive gastritis,haemorrhagic stroke, mouth haemorrhage, pulmonary haemorrhage and respiratory tract haemorrhage10 Arterial thromboembolism including acute myocardial infarction, arterial thrombosis, iliac artery thrombosis,ischaemic stroke, myocardial infarction and transient ischaemic attack11 Venous thromboembolism including deep vein thrombosis, embolism venous and pulmonary embolism12 Persistent severe hypertension including hypertensive crisis13 Flushing including flushing and hot flush14 Dyspnoea including dyspnoea and exertional dyspnoea15 Abdominal pain including abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper andabdominal rigidity16 Stomatitis including oral discomfort, oral disorder and stomatitis17 Pancreatitis including pancreatitis and pancreatitis acute18 Dysphagia including dysphagia, odynophagia and oropharyngeal pain19 Glossitis including glossitis and glossodynia20 Gingivitis including gingival bleeding, gingival disorder, gingival pain and gingivitis21 Alanine aminotransferase (ALT) increased/Aspartate aminotransferase (AST) increased including ALT increasedand AST increased22 Erythema including erythema, generalised erythema and palmar erythema23 Pruritus including generalised pruritus and pruritus24 Rash including rash, rash erythematous, rash generalised, rash maculo-papular, rash papular and rash pruritic25 Acne including acne and dermatitis acneiform26 Dermatitis including dermatitis and dermatitis bullous27 Pain including bone pain, cancer pain, flank pain, groin pain, oral pain, pain, pain in extremity and tumour pain28 Chest pain including chest pain and non-cardiac chest pain29 Chills including chills and hypothermia

Hypertension was reported as an adverse reaction in 47.6% of patients receiving tivozanib as initialtherapy; in 23.0% the hypertension was CTC ≥Grade 3. Persistent severe hypertension (‘hypertensivecrisis’) was an adverse reaction in 1.0%, CTC Grade 3 or higher in 0.9%. One patient died as a resultof uncontrolled hypertension in the setting of a suspected overdose.

Posterior Reversible Encephalopathy Syndrome (PRES)

PRES (also known as reversible posterior leukoencephalopathy syndrome (RPLS)) was confirmed inone non-RCC patient after approximately 8 weeks on tivozanib. PRES is a neurological disorder thatmay present with headache, seizure, lethargy, confusion, blindness and other visual and neurologicdisturbances. Mild to severe hypertension may be present (see section 4.4).

Pulmonary embolism was reported in patients (0.7%) receiving tivozanib as initial therapy in the fivecore RCC monotherapy studies, with the majority CTC Grade ≥ 3 (see section 4.4). Deep veinthrombosis was also reported in two patients (0.3%) and was CTC Grade ≥ 3 in one patient (0.1%)receiving initial tivozanib therapy.

Arterial thromboembolic adverse reactions in the patients receiving tivozanib as initial therapy wereischaemic stroke (1.0%), myocardial infarction (0.7%), transient ischaemic attack (0.7%) and acutemyocardial infarction (0.4%), the majority of which were at least CTC Grade 3, plus iliac arterythrombosis (0.1%). There were no deaths due to arterial thromboembolic adverse reactions in thosereceiving tivozanib as initial therapy but a myocardial infarction in a patient receiving second-linetivozanib had a fatal outcome.

Cardiac failure

Pulmonary oedema was reported in two patients (0.3%) receiving tivozanib as initial therapy in thefive core RCC monotherapy studies. Both events were CTC Grade 3 (see section 4.4).

QT/QTc prolongation

QT prolongation was reported in two patients (CTC Grade 2 and Grade 3) in the tivozanib cardiacsafety study, neither reaction was considered serious (see section 4.4 and section 5.1).

Hypothyroidism was reported as an adverse reaction for 5.6% of patients during initial therapy andwas CTC Grade 2 or lower in all cases. It was reported as serious in one patient.

Haemorrhage adverse reactions were reported in the core monotherapy studies during initial treatment(see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Two patients received excessive doses of tivozanib during the monotherapy studies. A patient with ahistory of hypertension experienced aggravated uncontrolled hypertension that was fatal after taking3 doses of 1340 microgram tivozanib in one day (total 4020 microgram). No adverse reaction wasexperienced by the second patient who took 2 doses of 1340 microgram tivozanib in one day (total2680 microgram).

Blood pressure should be well controlled prior to initiating tivozanib and patients should be monitoredfor hypertension during treatment (see section 4.4).

In cases of suspected overdose, tivozanib should be discontinued and the patient monitored forhypertension and treated as needed with standard anti-hypertensive therapy.

There is no specific treatment or antidote for tivozanib overdose.

Pharmacotherapeutic group: antineoplastic agents, protein-kinase inhibitors, ATC code: L01EK03

Tivozanib potently and selectively blocks all 3 vascular endothelial growth factor receptors (VEGFR)and has been shown to block various VEGF-induced biochemical and biologic responses in vitro,including VEGF-ligand-induced phosphorylation of all three VEGFR 1, 2 and 3, and proliferation ofhuman endothelial cells. The next most potently inhibited kinase is c-kit which is 8-fold less sensitiveto inhibition by tivozanib compared to VEGFR 1, 2 and 3. VEGF is a potent mitogenic factor thatplays a central role in angiogenesis and vascular permeability of tumour tissues. By blocking

VEGF-induced VEGFR activation, tivozanib inhibits angiogenesis and vascular permeability intumour tissues, leading to inhibition of tumour growth in vivo.

The efficacy of tivozanib in the treatment of advanced RCC was studied in the following randomisedclinical study.

Study AV-951-09-301

This controlled clinical study was a Phase 3 multi-centre, open-label, international, randomised studycomparing tivozanib with sorafenib in patients with advanced RCC. Five hundred and seventeen (517)patients with recurrent or metastatic RCC with a clear cell component were randomised (1:1) toreceive either tivozanib 1340 microgram once daily on a schedule of 3 weeks on treatment followedby 1 week off (schedule 3/1) or sorafenib 400 mg twice a day. The study included patients who had allundergone prior nephrectomy, and who had received either no prior therapy or no more than one priorsystemic therapy in the metastatic setting (immunotherapy/chemotherapy); prior treatment with VEGFor mechanistic Target of Rapamycin (mTOR) targeted therapy was not allowed. Cross-over to thetivozanib arm was permitted upon Response Evaluation Criteria In Solid Tumours (RECIST)-definedprogression on sorafenib according to the protocol of a separate extension study.

The primary endpoint of the study was progression-free survival (PFS) by blinded independentradiology review; key secondary endpoints included overall survival (OS) and objective response rate(ORR) by independent radiology review.

The intent-to-treat (ITT) population included 517 patients, 260 randomised to tivozanib and257 randomised to sorafenib. The baseline demographic and disease characteristics were generallywell balanced across the tivozanib and sorafenib arms with regard to age (mean age 58.2 vs 58.4 yearsrespectively), gender (71.2% vs 73.5% male respectively), race (95.8% vs 96.9% white respectively),geographic region (88.1% vs 88.7% from Central/Eastern Europe respectively) and prior treatment formetastatic RCC (69.6% vs 70.8% treatment naïve respectively). For the 30% of patients receivingprior treatment, the predominant therapy was interferon alpha as monotherapy which was received by75 patients in the tivozanib arm and 62 patients in the sorafenib arm.

Tivozanib showed a statistically significant improvement in PFS and ORR over sorafenib byindependent radiology review (Table 2 and Figure 1).

Figure 1: Kaplan-Meier plot of progression free survival, independent radiological review(ITT Population)

Table 2: Efficacy analysis by independent radiology review (ITT population)

Tivozanib Sorafenib Hazard Ratio P-value(95% CI) (Log ranktest)

Progression-free survival N=260 11.9 N=257 9.1 0.797 0.042b[median, months (9.3, 14.7) (7.3, 9.5) (0.639, 0.993)a(95% CI)], ITTpopulation

Objective response rate N=260 33.1% N=257 23.3% 0.014c(95% CI), ITT population (27.4, 39.2) (18.3, 29.0)

Progression-free survival, N=181 12.7 N=181 9.1 0.756 0.037eno prior treatment for (9.1, 15.0) (7.3, 10.8) (0.580, 0.985)dmetastatic RCC subgroup[median, months(95% CI)]

Progression-free survival, N=78 11.9 N=76 9.1 0.877 0.520eone prior therapy for (8.0, 16.6) (7.2, 11.1) (0.587, 1.309)dmetastatic diseasesubgroup [median,months (95% CI)]a Hazard ratio for tivozanib arm vs. sorafenib arm, based on stratified Cox proportional hazards model.

Stratification factors are number of prior treatments (0 or 1) and number of metastatic sites/organs involved(1 or ≥2). Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate infavour of tivozanib;b p-value based on stratified log-rank test. Stratification factors are number of prior treatments (0 or 1) andnumber of metastatic sites/organs involved (1 or ≥2);c p-value based on stratified Cochran-Mantel-Haenszel (CMH) statistic. Stratification factors are number of priortreatments (0 or 1) and number of metastatic sites/organs involved (1 or ≥2);d Hazard ratio for tivozanib arm vs. sorafenib arm subgroup analyses, based on unstratified Cox proportionalhazards model. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate infavour of tivozanib;e p-value for subgroup analyses based on unstratified log-rank test.

OS was a key secondary endpoint in the pivotal study and the analysis included data from allrandomized patients, including those who progressed on sorafenib and crossed over to receivetivozanib as part of the extension study. In the ITT population there was a small numerical differencebetween the two arms in terms of overall survival. median OS was 28.2 months (95% CI 22.5, 33.0)in the tivozanib arm compared to 30.8 months (95% CI 28.4, 33.3) in the sorafenib arm (HR=1.147,p=0.276).

In a controlled clinical study (AV-951-09-301), in which 25% of patients receiving tivozanib were≥ 65 years of age, no overall differences was observed in efficacy between elderly and youngerpatients (see section 4.2).

In the core RCC studies some adverse reaction occurred more commonly in the elderly (see section4.4).

In a cardiac safety study of 50 patients with advanced solid tumours treated with tivozanib at1340 microgram daily for 21 days, the mean change from baseline in QTcF was 6.8 ms on day 21 ofdosing. The maximum change in QTcF from baseline was 9.3 ms (90% CI: 5, 13.6), which occurred2.5 hours after dosing on Day 21. The central tendency change for all measured days and across alltime points was 2.2 ms. No subjects had a new > 500 ms change in QTcF; 2 patients (4%) had QTcFvalues > 480 ms. One subject (2%) had a > 60 ms change from baseline in QTcF and 6 subjects (12%)had a 30 ms to 60 ms change from baseline (see section 4.4 and section 4.8).

The European Medicines Agency has waived the obligation to submit the results of studies withtivozanib in all subsets of the paediatric population in advanced renal cell carcinoma (see section 4.2for information on paediatric use).

Following oral administration of tivozanib, peak serum levels are achieved after approximately 2 to24 hours. After a single 1340 microgram dose, mean Cmax was 10.2 to 25.2 ng/mL across healthysubject and patient studies. Single dose AUC0-inf for healthy volunteers dosed with 1340 microgramtivozanib was 1,950 to 2,491 ng.hr/mL. After once daily dosing of 1340 microgram tivozanib for 21 or28 days in RCC patients, Cmax was 67.5 to 94.3 ng/mL and AUC0-24 was 1,180 to 1,641 ng.hr/mL.

Exposure is dose proportional between 890 and 1340 microgram and dose related over the wider rangeof 450 mg and 1790 microgram. Accumulation at steady-state is approximately 6- to 7- fold theexposure observed at single-dose levels. Clearance is similar between acute and chronic dosingindicating no time dependent changes in PK.

When tivozanib was evaluated in a food effect study in healthy subjects, a high fat meal decreased thepeak serum concentrations (Cmax) by 23.4% compared to the fasted state. There was no effect of foodon the overall exposure (AUC). Based on these data, tivozanib can be dosed with or without food (seesection 4.2).

In vitro protein binding studies have shown that tivozanib is > 99% bound to plasma proteins. Noconcentration dependence of plasma protein binding was observed over the range of 0.1 to 5 µmol/Ltivozanib. Albumin is the major tivozanib binding component in human plasma. In vitro studies haveshown that tivozanib is neither a substrate nor an inhibitor of the multidrug efflux pump,

P-glycoprotein. In vitro studies suggest that tivozanib is an inhibitor of intestinal BCRP.

In vitro metabolism studies have shown that CYP3A4 and CYP1A1 are capable of metabolisingtivozanib. Unchanged tivozanib is the major circulating form of the molecule, and there were no majormetabolites detected in serum at exposure equal to or greater than 10% of the total radioactivityexposure. As CYP1A1 is primarily expressed in extrahepatic tissues such as the lung and intestine, itwas considered unlikely that this isoform would be extensively involved in hepatic metabolism.

In vitro studies have shown that metabolites of tivozanib can undergo UGT mediatedbiotransformation via the UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT1A10pathways. Direct N-glucoronidation of tivozanib was a minor pathway of metabolism in vitro.

After chronic dosing of tivozanib in RCC patients for 21 days followed by 7 days withoutadministration of tivozanib, tivozanib Cmin is approximately 16.0 to 30.9 ng/mL.

In studies that evaluated the terminal elimination phase, tivozanib had a mean t½ of 4.5 - 5.1 days.

After a single dose oral dose of [14C] tivozanib, approximately 79% of the radioactivity was recoveredin the faeces and approximately 12% was found in the urine as metabolites. There was no unchangedtivozanib recovered in the urine indicating that tivozanib does not undergo renal excretion. [14C]

Tivozanib was the predominant drug-related material in faeces. There were no [14C]-containingmetabolites present in faeces at greater than 10% of the dose.

Based on the population pharmacokinetic analysis, there is no clinically relevant effect of age, genderor race on the pharmacokinetics of tivozanib.

Results from a single dose study to evaluate the pharmacokinetics, safety and tolerability of tivozanibin subjects with hepatic impairment show that across the entire measurement period, tivozanib waseliminated more slowly in subjects with moderate (Child-Pugh Class B) or severe (Child-Pugh Class

C) hepatic impairment. Tivozanib exposure was increased in patients with severe hepatic impairment(mean AUC0-∞ by 4.0-fold) and in patients with moderate hepatic impairment (mean

AUC0-∞ by 2.6-fold). No significant increase in exposure was observed in patients with mild(Child-Pugh Class A) hepatic impairment (mean AUC0-∞ by 1.2-fold). Tivozanib should be used withcaution in patients with moderate hepatic impairment and the dose reduced to one 1340 microgramcapsule every other day. Tivozanib should not be used in patients with severe hepatic impairment (seesection 4.2 and section 4.4).

Clinical studies with tivozanib were conducted in RCC patients with serum creatinine concentration≤ 2 times the upper limit of normal, including those who may have had a prior nephrectomy. Althoughthe impact of further impairment of renal function on the overall disposition of tivozanib is unknown,a clinical study has shown that no unchanged tivozanib is excreted in the urine indicating thattivozanib does not undergo renal excretion. According to the population pharmacokinetic analysis oftivozanib exposure, no dose adjustment is required in patients with mild or moderate renal impairment.

Experience of tivozanib use in patients with severe renal impairment is limited and caution is advised.

CYP and UGT in vitro studies

In vitro studies with tivozanib indicate that it is not a CYP enzyme inducer. In vitro studies conductedin human liver microsomes and hepatocytes evaluating the activity of CYP1A2, CYP2B6, CYP2A6,

CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 suggested that tivozanib is a weak inhibitor of

CYP2B6 and CYP2C8. Based on the in vitro IC50 and in vivo unbound Cmax, tivozanib was unlikely tointeract in a clinically relevant manner with active substances that are metabolised by these enzymepathways.

Studies conducted in vitro have shown that tivozanib is not a potent inhibitor of UGT(UDP-glucuronosyltransferase) metabolic activities and clinically relevant drug-drug interactions areunlikely with medicinal products metabolised by these pathways.

Transporter in vitro studies

In vitro studies have shown that tivozanib is neither a substrate nor inhibitor of the transporter proteins

MDR1 (P-gp), OCT1, OATP1B1, OATP1B3 and BSEP. Furthermore, tivozanib was not an in vitroinhibitor of OAT1, OAT3, OCT2, MATE1 and MATE2-K or substrate of MRP2 and BCRP.

Tivozanib inhibits the transporter protein BCRP in vitro, at concentrations that are likely to restrict theeffect to intestinal BCRP activity in vivo.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar toclinical exposure levels and with possible relevance to clinical use were as follows.

In repeat-dose toxicity studies in rats, abnormalities were noted in growing incisors (thin brittle teeth,tooth loss, malocclusions) at doses approximately 2-fold greater than the calculated human equivalentdose and growth plate hypertrophy was observed at doses approximately 0.7- to 7-fold greater than thecalculated human equivalent dose. Tivozanib was shown to cause growth plate hypertrophy, absenceof active corpora lutea and no maturing follicles in cynomolgus monkeys at dose levels that producedexposures equivalent to those seen at the recommended clinical dose.

Reproduction, mutagenesis, impairment of fertility

Tivozanib may impair human fertility. In nonclinical studies assessing mating and fertility parametersin male rats, doses > 2-fold higher than the recommended clinical dose, produced increasedepididymis and testis weights associated with infertility. Increased testis weights were observed at adose 7-fold higher than the recommended clinical dose. In female rats, an increase in non-viablefoetuses was noted at a dose 0.7-fold the recommended clinical dose, while dose levels ≥ 2 fold therecommended clinical dose produced infertility.

Tivozanib was shown to be teratogenic, embryotoxic and foetotoxic in pregnant rats at dose levels5 times lower than the recommended clinical dose (based on a 60 kg human). Studies in pregnantrabbits showed no effect on maternal health or embryo foetal development at doses approximately0.6 times the human exposure at the recommended dose.

Carcinogenicity studies have not been performed with tivozanib.

Fotivda 890 microgram hard capsules

Mannitol

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Indigo carmine (E132)

Yellow iron oxide (E172)

Printing ink (yellow)

Shellac

Strong ammonia solution

Titanium dioxide (E171)

Tartrazine aluminium lake (E102)

Printing ink (blue)

Shellac

Strong ammonia solution

Indigo carmine aluminium lake (E132)

Fotivda 1340 microgram hard capsules

Mannitol

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172)

Printing ink (blue)

Shellac

Strong ammonia solution

Indigo carmine aluminium lake (E132)

Not applicable.

5 years.

Keep the bottle tightly closed in order to protect from moisture.

White HDPE bottle with a child resistant closure containing 21 hard capsules.

Each pack contains 1 bottle.

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

Recordati Netherlands B.V.

Beechavenue 54,1119PW Schiphol-Rijk

Netherlands

Fotivda 890 microgram hard capsules

EU/1/17/1215/001

Fotivda 1340 microgram hard capsules

EU/1/17/1215/002

Date of first authorisation: 24/08/2017

Date of latest renewal: 15/07/2022

{MM/YYYY}

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.