Wirkstoffe & Arzneimittelsicherheit

Gegenanzeigen · Fotivda

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HOS-224252 · Präparat HOS-217292

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

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Gegenanzeigen · Fotivda

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HOS-224253 · Präparat HOS-217292

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

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Wechselwirkungen · Fotivda

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HOS-224254 · Präparat HOS-217292

Contraindication of concomitant use Herbal preparations containing St. John's wort (Hypericum perforatum) are contraindicated. If a patient is already taking St John’s wort, this should be stopped before starting tivozanib treatment. The inducing 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).

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Wechselwirkungen · Fotivda

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HOS-224255 · Präparat HOS-217292

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

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): rifampin (HOS-088791)

Wechselwirkungen · Fotivda

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HOS-224257 · Präparat HOS-217292

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

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): ketoconazole (HOS-084513)

Wechselwirkungen · Fotivda

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HOS-224258 · Präparat HOS-217292

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 is unknown (see section 5.2). Caution should be exercised if tivozanib is co-administered with rosuvastatin. Alternatively, a statin not subject to restriction of intestinal absorption by BCRP should be considered. Patients taking an oral BCRP substrate with a clinically-relevant efflux interaction in the gut should ensure that a suitable time window (e.g. 2 hours) is applied between administration of tivozanib and the BCRP substrate.

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): rosuvastatin (HOS-086307)

Wechselwirkungen · Fotivda

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HOS-224259 · Präparat HOS-217292

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).

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Nebenwirkungen · Fotivda

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HOS-224260 · Präparat HOS-217292

Summary of the safety profile

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Nebenwirkungen · Fotivda

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HOS-224261 · Präparat HOS-217292

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

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Nebenwirkungen · Fotivda

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HOS-224262 · Präparat HOS-217292

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%).

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Nebenwirkungen · Fotivda

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HOS-224263 · Präparat HOS-217292

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 severe hypertension (0.3%), or acute myocardial infarction (0.3%). The most frequent adverse reactions leading 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 outcome death; one was uncontrolled hypertension in the setting of a suspected overdose (see section 4.9) and two were reported simply as death.

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Nebenwirkungen · Fotivda

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HOS-224264 · Präparat HOS-217292

Tabulated summary of adverse reactions

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Nebenwirkungen · Fotivda

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HOS-224265 · Präparat HOS-217292

Adverse reactions occurring in patients who continued to receive tivozanib as their initial on trial therapy in the five RCC monotherapy studies were pooled and are listed below by MedDRA body system 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 not known (cannot be estimated from available data). Within each SOC, adverse reactions are presented in order of decreasing seriousness.

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Nebenwirkungen · Fotivda

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HOS-224266 · Präparat HOS-217292

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

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Nebenwirkungen · Fotivda

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HOS-224267 · Präparat HOS-217292

System Very common Common Uncommon Rare Not known Organ Class Infections and Fungal infection infestations Pustular rash Blood and Anaemia Thrombocytopenia lymphatic Haemoglobin system disorders increased Endocrine Hypothyroidism Hyperthyroidism disorders Goitre1 Metabolism and Decreased appetite Anorexia nutrition disorders Psychiatric Insomnia disorders Nervous system Headache Peripheral Transient Posterior disorders neuropathy2 ischaemic attack reversible encephalopathy Dizziness Memory syndrome (PRES)5 3 impairment4 Dysgeusia Eye disorders Vision impairment6 Increased lacrimation Ear and Vertigo Ear congestion labyrinth Tinnitus disorders Cardiac Myocardial Pulmonary oedema disorders infarction (acute) / Coronary artery ischaemia7 insufficiency Angina pectoris Electrocardiogram Tachycardia8 QT prolonged Vascular Hypertension Haemorrhage9 Aneurysms and disorders artery Arterial dissections thromboembolism10 Venous thromboembolism11 Persistent severe hypertension12 Flushing13 Respiratory, Dyspnoea14 Epistaxis thoracic and Dysphonia Rhinorrhoea mediastinal Cough Nasal congestion disorders

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Nebenwirkungen · Fotivda

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HOS-224268 · Präparat HOS-217292

8  System Very common Common Uncommon Rare Not known Organ Class Gastrointestinal Abdominal pain15 Pancreatitis17 Duodenal ulcer 18 disorders Nausea Dysphagia Diarrhoea Vomiting 16 Stomatitis Gastrooesophageal reflux disease Abdominal distension Glossitis19 Gingivitis20 Dyspepsia Constipation Dry mouth Flatulence Hepatobiliary ALT increased / disorders AST increased21 Gamma- glutamyltransferase increased Blood alkaline phosphatase increased Skin and Palmar-plantar Skin exfoliation Urticaria subcutaneous erythrodysaesthesia Erythema22 Dermatitis26 tissue disorders syndrome / Hand foot skin reaction Pruritus23 Hyperhidrosis (PPE/HFS) Alopecia Xeroderma Rash24 Acne25 Dry skin Musculoskeletal Back pain Arthralgia Muscular and weakness Myalgia connective Musculoskeletal tissue chest pain disorders Renal and Proteinuria urinary Blood creatinine disorders increased General Pain27 Chest pain28 Mucosal disorders and 29 inflammation Asthenia Chills administration Fatigue Pyrexia site Peripheral oedema conditions

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Nebenwirkungen · Fotivda

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HOS-224269 · Präparat HOS-217292

9  System Very common Common Uncommon Rare Not known Organ Class Investigations Weight decreased Amylase increased Lipase increased Blood thyroid stimulating hormone 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 goitre 2 Peripheral neuropathy including hyperaesthesia, hypoaesthesia, mononeuropathy, neuropathy peripheral, peripheral sensory neuropathy and paraesthesia 3 Dysgeusia including ageusia, dysgeusia and hypogeusia 4 Memory impairment including amnesia and memory impairment 5 PRES was not observed in patients treated with tivozanib in the five RCC monotherapy studies. One patient experienced Grade 4 PRES and hypertension in Study AV-951-09-901. 6 Vision impairment including reduced visual acuity, vision blurred and visual impairment 7 Myocardial infarction (acute) / ischaemia including acute myocardial infarction, ischaemia and myocardial infarction 8 Tachycardia including sinus tachycardia, supraventricular tachycardia, tachycardia and tachycardia paroxysmal 9 Haemorrhage including adrenal haemorrhage, anal haemorrhage, cervix haemorrhage uterine, duodenal ulcer haemorrhage, gingival bleeding, haematemesis, haemoptysis, haemorrhagic anaemia, haemorrhagic erosive gastritis, haemorrhagic stroke, mouth haemorrhage, pulmonary haemorrhage and respiratory tract haemorrhage 10 Arterial thromboembolism including acute myocardial infarction, arterial thrombosis, iliac artery thrombosis, ischaemic stroke, myocardial infarction and transient ischaemic attack 11 Venous thromboembolism including deep vein thrombosis, embolism venous and pulmonary embolism 12 Persistent severe hypertension including hypertensive crisis 13 Flushing including flushing and hot flush 14 Dyspnoea including dyspnoea and exertional dyspnoea 15 Abdominal pain including abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper and abdominal rigidity 16 Stomatitis including oral discomfort, oral disorder and stomatitis 17 Pancreatitis including pancreatitis and pancreatitis acute 18 Dysphagia including dysphagia, odynophagia and oropharyngeal pain 19 Glossitis including glossitis and glossodynia 20 Gingivitis including gingival bleeding, gingival disorder, gingival pain and gingivitis 21 Alanine aminotransferase (ALT) increased / Aspartate aminotransferase (AST) increased including ALT increased and AST increased 22 Erythema including erythema, generalised erythema and palmar erythema 23 Pruritus including generalised pruritus and pruritus 24 Rash including rash, rash erythematous, rash generalised, rash maculo-papular, rash papular and rash pruritic 25 Acne including acne and dermatitis acneiform 26 Dermatitis including dermatitis and dermatitis bullous 27 Pain including bone pain, cancer pain, flank pain, groin pain, oral pain, pain, pain in extremity and tumour pain 28 Chest pain including chest pain and non-cardiac chest pain 29 Chills including chills and hypothermia

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Nebenwirkungen · Fotivda

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HOS-224270 · Präparat HOS-217292

Description of selected adverse reactions

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Nebenwirkungen · Fotivda

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HOS-224271 · Präparat HOS-217292

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

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Nebenwirkungen · Fotivda

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HOS-224272 · Präparat HOS-217292

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

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