Inlyta 1 mg, 3 mg, 5 mg, 7 mg Film-coated tablets.

INLYTA is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) with a clear cell component or advanced papillary cell renal carcinoma, after failure of previous systemic therapy and total nephrectomy of the involved kidney.

Treatment with INLYTA should be conducted by a medical practitioner experienced in the use of anticancer therapies.

Posology

The recommended starting oral dose of INLYTA is 5 mg twice daily. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.

Dose adjustments

Dose increase or reduction is recommended based on individual safety and tolerability. Patients who tolerate the INLYTA starting dose of 5 mg twice daily with no adverse reactions > Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]) for two consecutive weeks, are normotensive, and are not receiving anti-hypertensive medication, may have their dose increased to 7 mg twice daily. Subsequently, using the same criteria, patients who tolerate the INLYTA dose of 7 mg twice daily, may have their dose increased to a maximum of 10 mg twice daily.

Management of some adverse drug reactions may require temporary or permanent discontinuation and/or dose reduction of INLYTA therapy. When dose reduction is necessary, the INLYTA dose may be reduced to 3 mg twice daily and further to 2 mg twice daily. Dose adjustment is not required on the basis of patient age, race, gender, or body weight.

Special populations

Use in the elderly
No dose adjustment is required.

Hepatic impairment
No dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B) (e.g. the starting dose should be reduced from 5 mg twice daily to 2 mg twice daily). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Renal impairment
No dose adjustment is required (see section 5.2).

Paediatric population
The safety and efficacy of INLYTA in children (< 18 years) have not been established. No data are available.

Method of administration
INLYTA is for oral use. INLYTA may be taken with or without food. The film-coated tablets should be swallowed whole with a glass of water.

• Hypersensitivity to axitinib or any of the ingredients contained in INLYTA (listed in section 6.1).
• Pregnancy and lactation, and women of childbearing potential (see section 4.6).
• Children < 18 years of age (see section 4.2).
• Patients with evidence of untreated brain metastasis or recent gastrointestinal bleeding (see section 4.4).
• Severe hepatic impairment.
• History of recent (within the previous 12 months) arterial thromboembolism (myocardial infarction, stroke, transient ischaemic attack) when other appropriate treatment options are available (see section 4.4).
• History of recent (within the previous 6 months) venous thromboembolism (deep vein thrombosis, pulmonary embolism) when other appropriate treatment options are available (see section 4.4).
• Uncontrolled hypertension
• Uncontrolled cardiac failure
• Uncontrolled hypothyroidism
• A history of previous posterior reversible encephalopathy syndrome (PRES)
• A tendency to bleeding
• A recent history of a gastrointestinal perforation and/or fistula when other treatment options are available
• Unhealed surgery of trauma wounds

Cardiac failure events
In clinical studies with INLYTA for the treatment of patients with RCC, cardiac failure events (including cardiac failure, cardiac failure congestive, cardiopulmonary failure, left ventricular dysfunction, ejection fraction decreased, and right ventricular failure) were reported in 12/672 patients (1,8 %) receiving INLYTA. Grade 3/4 cardiac failure events were reported in 7/672 patients (1,0 %) and fatal cardiac failure events were reported in 2/672 patients (0,3 %) receiving INLYTA. Monitor for signs or symptoms of cardiac failure periodically throughout treatment with INLYTA. Management of cardiac failure events may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy.

Hypertension
In pooled clinical studies with INLYTA for the treatment of patients with RCC, hypertension was reported in 344/672 patients (51 %) receiving INLYTA. Grade 3 hypertension was reported in 148/672 patients (22 %) receiving INLYTA. Grade 4 hypertension was reported in 7/672 patients (1 %) receiving INLYTA. In the pivotal study hypertensive crisis was reported in 2/359 patients ( 150 mmHg or diastolic blood pressure > 100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Discontinuation of INLYTA treatment due to hypertension may be necessary. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, INLYTA should be stopped. If INLYTA is stopped, patients receiving anti-hypertensive medications should be monitored for hypotension.

Thyroid dysfunction
In pooled clinical studies with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 165/672 patients (25 %) receiving INLYTA. Hyperthyroidism was reported in 11/672 patients (2 %) receiving INLYTA. In the pivotal study hyperthyroidism was reported in 4/359 patients (1 %) receiving INLYTA. In patients who had thyroid stimulating hormone (TSH) < 5 u03bcU/mL before treatment, elevations of TSH to u2265 10 u03bcU/mL occurred in 79/245 patients (32 %) receiving INLYTA. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Hypothyroidism and hyperthyroidism should be treated according to standard medical practice to maintain euthyroid state.

Arterial thromboembolic events
In pooled clinical studies with INLYTA for the treatment of patients with RCC, arterial thromboembolic events were reported in 19/672 patients (3 %) receiving INLYTA. Grade 3 arterial thromboembolic events were reported in 8/672 patients (1 %). Grade 4 arterial thromboembolic events were reported in 9/672 patients (1 %). Fatal arterial thromboembolic events were reported in 2 patients (< 1 %) receiving INLYTA. In the pivotal study the most frequent arterial thromboembolic event was transient ischaemic attack (1 %). Fatal cerebrovascular accident was reported in < 1 % of patients receiving INLYTA. INLYTA should be used with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months (see section 4.3).

Venous thromboembolic events
In pooled clinical studies with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 19/672 patients (3 %) receiving INLYTA. Grade 3 venous thromboembolic events were reported in 6/672 patients (1 %). Grade 4 venous thromboembolic events were reported in 8/672 patients (1 %). Grade 3/4 venous thromboembolic events included pulmonary embolism, deep vein thrombosis and retinal vein occlusion/thrombosis. Fatal venous thromboembolic events were reported in 1/672 patients (< 1 %) receiving INLYTA. INLYTA should be used with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months (see section 4.3).

Elevation of haemoglobin or haematocrit
Increases in haemoglobin or haematocrit, reflective of increases in red blood cell mass, may occur during treatment with INLYTA. An increase in red blood cell mass may increase the risk of thromboembolic events. Elevated haemoglobin above the upper limit of normal (ULN) was observed in 31/320 patients (10 %) receiving INLYTA. Monitor haemoglobin or haematocrit before initiation of, and periodically throughout, treatment with INLYTA. If haemoglobin or haematocrit becomes elevated above the normal level, patients should be treated according to standard medical practice to decrease haemoglobin or haematocrit to an acceptable level.

Haemorrhage
In pooled clinical studies with INLYTA for the treatment of patients with RCC, haemorrhagic events were reported in 173/672 patients (26 %) receiving INLYTA. Grade 3 haemorrhagic events were reported in 20/672 patients (3 %). Grade 4 haemorrhagic events were reported in 7/672 patients (1 %) and fatal haemorrhagic events were reported in 3/672 patients (< 1 %) receiving INLYTA. In the pivotal study the most common haemorrhagic events in patients treated with INLYTA were epistaxis (6 %), haematuria (3 %), haemoptysis (2 %), and rectal haemorrhage (2 %). Grade 3/4 haemorrhagic events were reported in 5/359 patients (1 %) receiving INLYTA (including cerebral haemorrhage, haematuria, haemoptysis, lower gastrointestinal haemorrhage, and melaena). Fatal haemorrhage was reported in 1/359 patients (< 1 %) receiving INLYTA (gastric haemorrhage). INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Gastrointestinal perforation and fistula formation
In pooled clinical studies with INLYTA for the treatment of patients with RCC, gastrointestinal perforation and fistula were reported in 13/672 patients (2 %) receiving INLYTA. A case of fatal gastrointestinal perforation has been reported in a monotherapy study. Monitor for symptoms of gastrointestinal perforation periodically throughout treatment with INLYTA.

Wound healing complications
Treatment with INLYTA should be stopped at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing.

Reversible posterior leukoencephalopathy syndrome
In pooled clinical studies with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 2/672 patients (< 1 %) receiving INLYTA. RPLS 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 RPLS. In patients with signs/symptoms of RPLS, temporarily interrupt or permanently discontinue INLYTA. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known.

Proteinuria
In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11 %) receiving INLYTA. Grade 3 proteinuria was reported in 11/359 patients (3 %) receiving INLYTA. In pooled clinical studies with INLYTA for the treatment of patients with RCC, proteinuria was reported in 142/672 patients (21 %) receiving INLYTA. Grade 3 proteinuria was reported in 32/672 patients (5 %) receiving INLYTA. Grade 4 proteinuria was reported in 1/672 patients (< 1 %) receiving INLYTA. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

Elevation of liver enzymes
In a clinical dose-finding study, concurrent elevations of alanine aminotransferase [ALT] (12 times the ULN) and bilirubin (2,3 times the ULN), considered to be drug-related hepatotoxicity, were observed in 1 patient who received INLYTA at a starting dose of 20 mg twice daily (4 times the recommended starting dose). In a controlled clinical study with INLYTA for the treatment of patients with RCC, no concurrent elevations of ALT (> 3 times the ULN) and bilirubin (> 2 times the ULN) were observed for INLYTA (n=359). Monitor liver function tests before initiation of, and periodically throughout, treatment with INLYTA.

In vitro data indicate that INLYTA is metabolised primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1.

CYP3A4/5 inhibitors
Ketoconazole, a strong inhibitor of CYP3A4/5, administered at a dose of 400 mg once daily for 7 days, increased the mean area under the curve (AUC) 2-fold and C max 1,5-fold of a single 5-mg oral dose of INLYTA in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) may increase INLYTA plasma concentrations. Grapefruit may also increase INLYTA plasma concentrations. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be co-administered, a dose adjustment of INLYTA is recommended.

CYP3A4/5 inducers
Rifampicin, a strong inducer of CYP3A4/5, administered at a dose of 600 mg once daily for 9 days, reduced the mean AUC by 79 % and C max by 71 % of a single 5 mg dose of INLYTA in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g. rifampicin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbitone, and Hypericum perforatum (also known as St. Johnu2019s wort)) may decrease INLYTA plasma concentrations. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended. If a strong CYP3A4/5 inducer must be co-administered, a dose adjustment of INLYTA is recommended.

In vitro studies of CYP and UGT inhibition and induction
In vitro studies indicated that INLYTA does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1 at therapeutic plasma concentrations. In vitro studies indicated that INLYTA has a potential to inhibit CYP1A2. Therefore, co-administration of INLYTA with CYP1A2 substrates may result in increased plasma concentrations of CYP1A2 substrates (e.g. theophylline). In vitro studies also indicated that INLYTA has the potential to inhibit CYP2C8. However, co-administration of INLYTA with paclitaxel, a known CYP2C8 substrate, did not result in increased plasma concentrations of paclitaxel in patients with advanced cancer, indicating lack of clinical CYP2C8 inhibition. In vitro studies in human hepatocytes also indicated that INLYTA does not induce CYP1A1, CYP1A2, or CYP3A4/5, therefore co-administration of INLYTA is not expected to reduce the plasma concentration of co-administered CYP1A1, CYP1A2, or CYP3A4/5 substrates in vivo. In vitro studies with P-glycoprotein.

Women of childbearing potential
Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. They should use adequate contraception. Women of childbearing potential must use effective contraception during and up to 1 week after treatment.

Pregnancy
INLYTA is contraindicated during pregnancy (see section 4.3).

Breastfeeding
Women taking INLYTA should not breastfeed their infants (see section 4.3).

Fertility
Based on non-clinical findings, INLYTA has the potential to impair reproductive function and fertility in men and women. Conservation of sperm or ova should be considered before initiation of treatment with INLYTA.

Patients should be advised that they may experience events such as dizziness and/or fatigue during treatment with INLYTA. Such symptoms may impair their ability to drive or to use machines.

Summary of the safety profile
The most common (u2265 20 %) adverse reactions observed following treatment with INLYTA were diarrhoea, hypertension, fatigue, decreased appetite, nausea, weight decreased, dysphonia, palmar-plantar erythrodysaesthesia (hand-foot) syndrome, haemorrhage, hypothyroidism, vomiting, proteinuria, cough, and constipation.

Tabulated list of adverse reactions
The data described below reflect exposure to INLYTA in 672 patients with advanced RCC who participated in the pivotal randomised clinical study or 4 additional studies with INLYTA in patients with RCC. Frequency categories are defined as very common (u2265 1/10), common (u2265 1/100 to < 1/10), uncommon (u2265 1/1 000 to < 1/100), rare (u2265 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data).

Table 1. Adverse reactions reported in patients with advanced RCC who received INLYTA

System organ class Frequency category Adverse reaction INLYTA (N=672) frequency All Grades % Grade 3 % Grade 4 % Blood and lymphatic system disorders Common Anaemia Polycythaemia 6,3 1,5 1,2 0,1 0,4 0 Endocrine disorders Very common Hypothyroidism 24,6 0,3 0 Common Hyperthyroidism 1,6 0,1 0,1 Metabolism and nutrition disorders Very common Decreased appetite 39,0 3,6 0,3 Common Dehydration Hyperkalaemia Hypercalcaemia 6,7 2,7 2,2 3,1 1,2 0,1 0,3 0,1 0,3

The symptoms of an overdose may include hypertension, seizures associated with hypertension, and fatal haemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted. There is no specific treatment for INLYTA overdose.