Filokyp 60 mg Injection

FILOKYP, as a single medicine is indicated for the treatment of patients with relapsed and refractory multiple myeloma who have received at least 2 prior therapies that included bortezomib and an immunomodulatory therapy (see section 5.1).

FILOKYP treatment should be supervised by a healthcare professional experienced in the use of anti-cancer therapy. Posology: FILOKYP is an intravenous (IV) infusion that can be administered once or twice weekly based on the selected regimen. (see Table 1). Treatment may be continued until disease progression or until unacceptable toxicity occurs.

Table 1: FILOKYP Dosing Information

Regimen Starting Dose If Tolerated, Increase FILOKYP Dose on Day 8 of Cycle 1 FILOKYP Infusion Time a FILOKYP Monotherapy 20 mg/m2 27 mg/m2 twice weekly 10 minutes a Infusion time remains consistent throughout each regimen. The dose is calculated using the patientu2019s baseline body surface area (BSA). Patients with a BSA greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%. FILOKYP Monotherapy Twice weekly (27 mg/m2) FILOKYP is administered at a starting dose of 20 mg/m2 in Cycle 1 on Days 1 and 2. If tolerated, the dose should be increased to 27 mg/m2 on Day 8 of Cycle 1. FILOKYP is omitted on Days 8 and 9 of Cycles 13 and higher. FILOKYP 20/27 mg/m2 is administered IV on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle.

Table 2: FILOKYP Monotherapy 20/27 mg/m2 Twice Weekly (10-Minute Infusion)

Cycle 1 Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3 u2013 7 Day 8 Day 9 Days 10 u2013 14 Day 15 Day 16 Days 17 u2013 21 Days 22 u2013 28 FILOKYP (mg/m2) a 20 20 - 27 27 - 27 27 - - Cycles 2 to 12 Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3 u2013 7 Day 8 Day 9 Days 10 u2013 14 Day 15 Day 16 Days 17 u2013 21 Days 22 u2013 28 FILOKYP (mg/m2) 27 27 - 27 27 - 27 27 - - Cycles 13 and later Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3 u2013 7 Day 8 Day 9 Days 10 u2013 14 Day 15 Day 16 Days 17 u2013 21 Days 22 u2013 28 FILOKYP (mg/m2) 27 27 - - - - 27 27 - - a Dexamethasone premedication is required for each FILOKYP dose in Cycle 1, (See Section 4.2 Dexamethasone Premedication for FILOKYP Monotherapy).

Concomitant medicine Consider antiviral prophylaxis in patients being treated with FILOKYP to decrease the risk of herpes zoster reactivation (see section 4.8). Hydration, fluid and electrolyte monitoring Adequate hydration is required prior to dosing in Cycle 1, especially in patients at high risk of tumour lysis syndrome or renal toxicity. All patients should be monitored for evidence of volume overload and fluid requirements should be tailored to individual patient needs. The total volume of fluids may be adjusted as clinically indicated in patients with baseline cardiac failure or who are at risk for cardiac failure (see section 4.4). Recommended hydration includes both oral fluids (30 ml/kg/day for 48 hours before Cycle 1, Day 1) and intravenous fluids (250 ml to 500 ml of appropriate intravenous fluid prior to each dose in Cycle 1). Give an additional 250 ml to 500 ml of intravenous fluids as needed following FILOKYP administration. Continue oral and/or intravenous hydration, as needed, in subsequent cycles. Monitor serum potassium levels regularly during treatment with FILOKYP. Recommended dose modifications Modify dosing based on toxicity. Recommended actions and dose modifications are presented in Table 3. Dose level reductions are presented in Table 4.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Women who are breast feeding (see section 4.6).

Cardiac disorders New or worsening cardiac failure (e.g., congestive cardiac failure, pulmonary oedema) decreased ejection fraction) myocardial ischaemia and infarction have occurred following administration of carfilzomib. Death due to cardiac arrest has occurred within a day of carfilzomib administration and fatal outcomes have been reported with cardiac failure and myocardial infarction. While adequate hydration is required prior to dosing in Cycle 1, all patients should be monitored for evidence of volume overload, especially patients at risk for cardiac failure. The total volume of fluids may be adjusted as clinically indicated in patients with baseline cardiac failure or who are at risk for cardiac failure (see section 4.2). Stop FILOKYP for Grade 3 or 4 cardiac events until recovery and consider whether to restart FILOKYP at 1 dose level reduction based on a benefit/risk assessment (see section 4.2). The risk of cardiac failure is increased in elderly patients (u2265 75 years). The risk of cardiac failure is also increased in Asian patients. It should be noted that patients with New York Heart Association (NYHA) Class III and IV heart failure, recent myocardial infarction, cardiac conduction abnormalities, angina pectoris or dysrhythmias uncontrolled by medications were excluded from the clinical trials. These patients may be at greater risk for cardiac complications and should have a comprehensive cardiological assessment (particularly, blood pressure control and volume of fluids management) prior to starting treatment with FILOKYP. Subsequently these patients should be treated with caution and remain under close follow up.

Electrocardiographic changes There have been cases of QT interval prolongation reported in clinical studies and post-marketing. Cases of ventricular tachycardia have been reported in patients receiving carfilzomib.

Pulmonary toxicity Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving carfilzomib. Some of these events have been fatal. FILOKYP should be discontinued in these cases (see section 4.2).

Pulmonary hypertension Pulmonary hypertension has been reported commonly in patients treated with carfilzomib. Some of these events have been fatal. Evaluate as appropriate. Stop FILOKYP for pulmonary hypertension until resolved or returned to baseline and consider whether to restart FILOKYP based on a benefit/risk assessment (see Section 4.2).

Dyspnoea Dyspnoea was reported very commonly in patients treated with carfilzomib. Evaluate dyspnoea to exclude cardiopulmonary conditions including cardiac failure and Pulmonary syndromes. Stop FILOKYP for Grade 3 and 4 dyspnoea until resolved or returned to baseline and consider whether to restart FILOKYP based on a benefit/risk assessment (see sections 4.2 and 4.8)

Hypertension Hypertension occurred very commonly and included cases of hypertensive crisis and hypertensive emergency. Some of these events have been fatal. It is recommended to control hypertension prior to starting FILOKYP. All patients should be routinely evaluated for hypertension while on FILOKYP and treated as needed. If the hypertension cannot be controlled, FILOKYP dose should be discontinued until resolved. In case of hypertensive crisis, FILOKYP should be discontinued (see section 4.2).

Acute renal failure Cases of acute renal failure have been reported in patients who received carfilzomib. Some of these events have been fatal. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received carfilzomib monotherapy. This incidence was increased in patients with a lower baseline creatinine clearance, than among subjects with higher baseline creatinine clearance. Renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance should be monitored. Reduce or stop FILOKYP as appropriate (see section 4.2).

Tumour lysis syndrome Cases of tumour lysis syndrome (TLS), including fatal outcome, have been reported in patients who received carfilzomib. Patients with a high tumour burden should be considered to be at greater risk for TLS. Ensure that patients are well hydrated before administration of FILOKYP in Cycle 1, and in subsequent cycles as needed. Uric acid lowering medicines should be considered in patients at high risk for TLS. Monitor for evidence of TLS during treatment including regular measurement of serum electrolytes, and manage promptly. Interrupt FILOKYP until TLS is resolved (see section 4.2).

Infusion reactions Infusion reactions, including life-threatening reactions, have been reported in patients who received carfilzomib. Signs and symptoms may include fever, chills, arthralgia, myalgia, facial flushing, facial oedema, laryngeal oedema, vomiting, weakness, shortness of breath, hypotension, syncope, bradycardia, chest tightness, or angina pectoris. These reactions can occur immediately following or up to 24 hours after administration of carfilzomib.

Haemorrhage and Thrombocytopenia Cases of haemorrhage (e.g. gastrointestinal, pulmonary and intracranial haemorrhage) have been reported in patients treated with carfilzomib, often associated with thrombocytopenia. Some of these events have been fatal (see section 4.8). FILOKYP causes thrombocytopenia with platelet nadirs observed on Day 8 or Day 15 of each 28 day cycle usually with recovery to baseline platelet count by the start of the next cycle (see section 4.8). Monitor platelet counts frequently during treatment with FILOKYP. Reduce or stop dose as appropriate (see section 4.2).

Venous thromboembolic events Cases of venous thromboembolic events, including deep vein thrombosis and pulmonary embolism with fatal outcomes, have been reported in patients who received carfilzomib. Patients with known risk factors for thromboembolism u2013 including prior thrombosis u2013 should be closely monitored. Thromboprophylaxis should be considered based on an individual benefit/risk assessment. Caution should be used in the concomitant administration of other products that may increase the risk of thrombosis (e.g. erythropoietic medicines or hormone replacement therapy). Patients and physicians are advised to observe for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, haemoptysis, arm or leg swelling or pain.

Hepatic toxicity Cases of hepatic failure, including fatal cases, have been reported. FILOKYP can cause elevations of serum transaminases (see section 4.8). Monitor liver enzymes regularly, regardless of baseline values. Reduce or stop dose as appropriate (see section 4.2).

Thrombotic microangiopathy Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and haemolytic uremic syndrome (TTP/HUS) have been reported in patients who received carfilzomib. Some of these events have been fatal. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop FILOKYP and evaluate patients for possible TTP/HUS. If the diagnosis of TTP/HUS is excluded, FILOKYP can be restarted. The safety of reinitiating FILOKYP therapy in patients previously experiencing TTP/HUS is not known.

Posterior reversible encephalopathy syndrome Posterior reversible encephalopathy syndrome (PRES), formerly termed reversible Posterior leukoencephalopathy syndrome (RPLS), is a neurological disorder, which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis is confirmed by neuro radiological imaging. Cases of PRES have been reported in patients receiving carfilzomib. Discontinue FILOKYP if PRES is suspected. The safety of reinitiating FILOKYP therapy in patients previously experiencing PRES is not known.

Hepatitis B Virus (HBV) Reactivation Cases of Hepatitis B Virus (HBV) reactivation have been reported in patients receiving carfilzomib. Patients should be tested for HBV infection before initiating treatment. For patients who are carriers of HBV, prophylaxis with antivirals should be considered. Carriers of HBV who require treatment with FILOKYP should be closely monitored for signs and symptoms of active HBV infection throughout and following the end of treatment. Consider consulting a specialist for patients who test positive for HBV infection prior to or during treatment.

Progressive Multifocal Leukoencephalopathy Cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in patients treated with carfilzomib who have had prior or concurrent immunosuppressive therapy. The causal relationship with FILOKYP is unknown. Patients should be monitored for any new or worsening neurologic, cognitive or behavioural signs or symptoms that may be suggestive of PML as part of the differential diagnosis of CNS disorders. If PML is suspected, further FILOKYP administration must be suspended and the patients should be promptly referred to a specialist and appropriate diagnostic testing should be initiated. Discontinue FILOKYP if PML diagnosis is confirmed.

Increased Incidence of Fatal and Serious Adverse Events in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Multiple Myeloma Patients In a clinical trial of 955 transplant ineligible patients with newly diagnosed multiple myeloma randomized to carfilzomib (20/36 mg/m2 by 30 minute infusion twice weekly for four weeks of each six week cycle), melphalan and prednisone (KMP) or bortezomib, melphalan and prednisone (VMP), a higher incidence of fatal adverse events (6.5 % versus 4.3 %), a higher incidence of serious adverse events (49.6 % versus 42.1 %) and a higher incidence of any grade adverse events involving cardiac failure (10.8 % versus 4.3 %), hypertension (24.7 % versus 8.1 %), acute renal failure (13.9 % versus 6.2 %), and dyspnoea (18.1 % versus were observed in patients in the KMP arm compared to patients in the VMP arm. This study did not meet its primary outcome measure of superiority in progression free survival (PFS) for the KMP arm. FILOKYP in combination with melphalan and prednisone is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.

Carfilzomib, as found in FILOKYP, is primarily metabolised via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other medicines (see section 5.2). Based on in vitro and in vivo data, carfilzomib is not expected to inhibit CYP3A4/5 activities and/or affect the exposure to CYP3A4/5 substrates. A clinical trial using oral midazolam as a CYP3A probe demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant carfilzomib administration. Carfilzomib is a P glycoprotein (P-gp) substrate but not a BCRP substrate. However, given that carfilzomib is administrated intravenously and is extensively metabolised, the pharmacokinetic profile of carfilzomib is unlikely to be affected by P-gp or BCRP inhibitors or inducers. In vitro, at concentrations (3 u03bcM) lower than those expected at therapeutic doses, carfilzomib inhibits the efflux transport of digoxin, a P-gp substrate, by 25%. Caution should be observed when carfilzomib is combined with substrates of P-gp (e.g. digoxin, colchicine).

Women of childbearing potential / Contraception in males and females Females and males of reproductive potential should be advised to avoid conceiving/fathering a child while being treated with FILOKYP. Females patients of child bearing potential treated with FILOKYP and/or their male partners should use effective contraception methods or abstain from sexual activity during and for 30 days after treatment with FILOKYP (see section 5). Male patients treated with FILOKYP and/or their female partners (if of childbearing potential) should use effective contraceptive methods or abstain from sexual activity while treated with FILOKYP and for 90 days after treatment.

If pregnancy occurs during this time, patients should be apprised of the potential hazard to the foetus. It is not known if FILOKYP will reduce the efficacy of oral contraceptives. Due to an increased risk of venous thrombosis associated with FILOKYP, patients currently using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception (see sections 4.4 and 4.8).

Pregnancy: There are no data on the use of FILOKYP in pregnant women. FILOKYP caused embryo-foetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. FILOKYP should only be used during pregnancy if the potential benefits to the mother outweigh the potential risks to the foetus.

Breastfeeding: Mothers should not breastfeed their infants as FILOKYP is present in human breast milk.

Fertility: No fertility studies have been performed.

No studies on the effects of FILOKYP on the ability to drive or use machines have been performed. Fatigue, dizziness, fainting and/or a drop in blood pressure have been observed in clinical trials. Patients being treated with FILOKYP should, therefore, be advised not to drive or operate machinery if they experience any of these symptoms.

a. Summary of the safety profile Serious adverse reactions that may occur during FILOKYP treatment include: cardiac failure, myocardial infarction, cardiac arrest, myocardial ischemia, interstitial lung disease, pneumonitis, acute respiratory distress syndrome, acute respiratory failure, pulmonary hypertension, dyspnoea, hypertension including hypertensive crisis, acute kidney injury, tumour lysis syndrome, infusion related reaction, gastrointestinal haemorrhage, intracranial haemorrhage, pulmonary haemorrhage, thrombocytopenia, hepatic failure, hepatitis B virus reactivation, PRES and thrombotic microangiopathy. The most frequent adverse reactions were: anaemia, thrombocytopenia, neutropenia, nausea, diarrhoea, fatigue, pyrexia, respiratory tract infection, dyspnoea, and cough.

b. Tabulated summary of adverse reactions System Organ Class Adverse Reaction Preferred Term Frequency Blood and Lymphatic System Disorders Anaemia, Thrombocytopenia, Neutropenia, Lymphopenia, Leukopenia, Febrile neutropenia Frequent Thrombotic microangiopathy, Thrombotic thrombocytopenic purpura Less frequent Cardiac Disorders Cardiac failure, Tachycardia Palpitations, Atrial fibrillation, Myocardial infarction Frequent Cardiac arrest, Cardiomyopathy, Myocardial ischaemia, Pericardial effusion Less frequent Ear and labyrinth disorders Tinnitus Frequent Eye Disorders Blurred vision, Cataract Frequent Gastrointestinal Disorders Nausea, Diarrhoea, Vomiting, Constipation, Abdominal pain, Dyspepsia, Toothache Frequent Gastrointestinal haemorrhage, Pancreatitis acute, Intestinal obstruction Less frequent General Disorders and Administration Site Conditions Fatigue, Pyrexia, Oedema peripheral, Asthenia, Chills, Pain Chest pain, Infusion site reactions, Malaise, Influenza like illness Frequent Multi-organ dysfunction syndrome Less frequent Hepatobiliary Disorders Hyperbilirubinemia Frequent Hepatic failure, Cholestasis Less frequent Immune System Disorders Drug hypersensitivity Less frequent Infections and Infestations Respiratory tract infection, Pneumonia, Nasopharyngitis, Bronchitis, Urinary tract infection, Influenza, Rhinitis Viral infection, Sepsis, Gastroenteritis, Lung infection Frequent Septic shock, Clostridium difficile colitis, Hepatitis B Virus Reactivation, Cytomegalovirus infection Less frequent Injury, Poisoning and Procedural Complications Infusion related reaction Frequent Investigations Serum creatinine increased, Alanine aminotransferase increased, Aspartate aminotransferase increased, Creatinine clearance decreased, Serum uric acid increased, Gamma-glutamyltransferase increased C-reactive protein increased Frequent Cardiac ejection fraction decreased Less frequent Metabolism and Nutrition Disorders Decreased appetite, Hypokalaemia, Hyperglycaemia Hypocalcaemia, Hypophosphatemia, Hypomagnesemia, Hyponatremia, Hyperuricemia Hyperkalaemia, Hypercalcemia Dehydration, Hypoalbuminemia Frequent Tumour lysis syndrome Less frequent Musculoskeletal and Connective Tissue Disorders Back pain, Muscle spasms, Arthralgia, Pain in extremity, Musculoskeletal chest pain, Musculoskeletal pain, Bone pain, Muscular weakness, Myalgia Frequent Nervous System Disorders Headache, Dizziness, Peripheral neuropathy, Paraesthesia, Hypoesthesia Frequent Cerebrovascular accident, Intracranial haemorrhage, PRES Less frequent Psychiatric Disorders Insomnia, Anxiety Frequent Renal and Urinary Disorders Acute kidney injury, Renal failure, Renal impairment Frequent Respiratory, Thoracic, and Mediastinal Disorders Dyspnoea, Cough, Epistaxis Oropharyngeal pain, Wheezing Dysphonia, Pulmonary embolism, Pulmonary oedema, Pulmonary hypertension Frequent Pulmonary haemorrhage, Pneumonitis, Acute respiratory distress syndrome, Acute respiratory failure, Interstitial lung disease Less frequent Skin and Subcutaneous Tissue Disorders Rash, Pruritus, Erythema, Hyperhidrosis Frequent Vascular Disorders Hypertension, Hypotension, Deep vein thrombosis, Flushing Frequent Hypertensive crisis, Haemorrhage, Hypertensive emergency Less frequent

Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia, and lymphopenia have been reported following a dose of 200 mg of carfilzomib administered in error. There is no known specific antidote for carfilzomib overdose. In the event of an overdose, the patient should be monitored, specifically for the side effects and/or adverse medicine reactions (see section 4.8).