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Carfilnat special warnings and precautions

Special warnings and precautions for use

As Carfilnat is administered in combination with other medicinal products, the summary of product characteristics of these other medicinal products must be consulted prior to initiation of treatment with Carfilnat. As lenalidomide may be used in combination with Carfilnat, particular attention to the lenalidomide pregnancy testing and prevention requirements is needed.

Cardiac disorders: New or worsening cardiac failure (e.g. congestive cardiac failure, pulmonary oedema, and decreased ejection fraction), myocardial ischaemia and infarction have occurred following administration of Carfilnat. Death due to cardiac arrest has occurred within a day of Carfilnat 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.

Electrocardiographic changes: There have been cases of QT interval prolongation reported in clinical studies. An effect of Carfilnat on QT interval cannot be excluded.

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 Carfilnat. Some of these events have been fatal. Evaluate and stop Carfilnat until resolved and consider whether to restart Carfilnat based on a benefit/risk assessment.

Pulmonary hypertension: Pulmonary hypertension has been reported in patients treated with Carfilnat. Some of these events have been fatal. Evaluate as appropriate. Stop Carfilnat for pulmonary hypertension until resolved or returned to baseline and consider whether to restart Carfilnat based on a benefit/risk assessment.

Dyspnea: Dyspnea was commonly reported in patients treated with Carfilnat. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Carfilnat for grade 3 and 4 dyspnea until resolved or returned to baseline and consider whether to restart Carfilnat based on a benefit/risk assessment.

Hypertension: Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Carfilnat. Some of these events have been fatal. It is recommended to control hypertension prior to starting treatment. All patients should be routinely evaluated for hypertension while on Carfilnat and treated as needed. If the hypertension cannot be controlled, the Carfilnat dose should be reduced. In case of hypertensive crises, stop Carfilnat until resolved or returned to baseline and consider whether to restart Carfilnat based on a benefit/risk assessment.

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Acute renal failure: Cases of acute renal failure have been reported in patients who received Carfilnat. 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 Carfilnat monotherapy. In phase 3 clinical studies the incidence of adverse events of acute renal failure was higher in subjects with lower baseline creatinine clearance than that among subjects with higher baseline creatinine clearance.

Creatinine clearance was stable over time for the majority of patients. Renal function should be monitored at least monthly or in accordance with accepted clinical practice guidelines, particularly in patients with lower baseline creatinine clearance. Reduce or stop dose as appropriate.

Tumour lysis syndrome: Cases of tumour lysis syndrome (TLS), including with fatal outcome, have been reported in patients who received Carfilnat. 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 Carfilnat in cycle 1, and in subsequent cycles as needed. Uric acid lowering medicinal products should be considered in patients at high risk for TLS. Evidence of TLS during treatment should be monitored for, including regular measurement of serum electrolytes, and managed promptly. Stop Carfilnat until TLS is resolved.

Infusion reactions: Infusion reactions, including life-threatening reactions, have been reported in patients who received Carfilnat. Symptoms may include fever, chills, arthralgia, myalgia, facial flushing, facial oedema, vomiting, and weakness, shortness of breath, hypotension, syncope, chest tightness, or angina.

These reactions can occur immediately following or up to 24 hours after administration of Carfilnat. Dexamethasone should be administered prior to Carfilnat to reduce the incidence and severity of reactions.

Haemorrhage and thrombocytopenia: Cases of haemorrhage (e.g. gastrointestinal, pulmonary and intracranial haemorrhage) have been reported in patients treated with Carfilnat, often associated with thrombocytopenia. Some of these events have been fatal.

Carfilnat causes thrombocytopenia with platelet nadirs observed on day 8 or day 15 of each 28-day cycle with recovery to baseline platelet count by the start of the next cycle.

Platelet counts should be monitored frequently during treatment with Carfilnat. Reduce or stop dose as appropriate.

Venous thrombosis: Cases of venous thromboembolic events, including deep vein thrombosis and pulmonary embolism with fatal outcomes, have been reported in patients who received Carfilnat.

Patients with known risk factors for thromboembolism – including prior thrombosis – should be closely monitored. Action should be taken to try to minimise all modifiable risk factors (e.g. smoking, hypertension and hyperlipidaemia). Caution should be used in the concomitant administration of other agents that may increase the risk of thrombosis (e.g. erythropoietic agents or hormone replacement therapy). Patients and physicians are advised to be observant 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.

Thromboprophylaxis should be considered based on an individual benefit/risk assessment.

Hepatic toxicity: Cases of hepatic failure, including fatal cases, have been reported. Carfilnat can cause elevations of serum transaminases. Reduce or stop dose as appropriate. Liver enzymes and bilirubin should be monitored at treatment initiation and monthly during treatment with carfilzomib, regardless of baseline values.

Thrombotic microangiopathy: Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome (TTP/HUS) have been reported in patients who received Carfilnat.

Some of these events have been fatal. Signs and symptoms of TTP/HUS should be monitored for.

If the diagnosis is suspected, stop Carfilnat and evaluate patients for possible TTP/HUS. If the diagnosis of TTP/HUS is excluded, Carfilnat can be restarted. The safety of reinitiating Carfilnat therapy in patients previously experiencing TTP/HUS is not known.

Posterior reversible encephalopathy syndrome: Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving Carfilnat. PRES, formerly termed reversible posterior leukoencephalopathy syndrome (RPLS), is a rare, 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. Carfilnat should be discontinued if PRES is suspected. The safety of reinitiating Carfilnat therapy in patients previously experiencing PRES is not known.

Contraception: Female patients of child bearing potential (and/or their partners) must use effective contraception measures during and for one month following treatment. Male patients must use effective contraception measures during and for 3 months following treatment if their partner is pregnant or of childbearing potential and not using effective contraception. Carfilzomib may decrease the efficacy of oral contraceptives.

Sodium content: This medicinal product contains 0.3 mmols (7 mg) of sodium per mL of reconstituted solution.

This should be taken into consideration for patients on a controlled sodium diet.

Interaction with other medicinal products and other forms of interaction

Carfilzomib 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.

Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Female patients of child bearing potential treated with Carfilnat (and/or their partners) must use effective contraception measures during and for one month following treatment.

It cannot be excluded that the efficacy of oral contraceptives may be reduced during carfilzomib treatment. In addition, due to an increased risk of venous thromboembolic events associated with carfilzomib, females should avoid the use of hormonal contraceptives that are associated with a risk of thrombosis during treatment with carfilzomib. If a patient is currently using oral contraceptives or a hormonal method of contraception that is associated with a risk of thrombosis, the patient should switch to an alternative method of effective contraception.

Male patients must use effective contraception measures during and for 3 months following treatment if their partner is pregnant or of child bearing potential not using effective contraception.

Pregnancy: There are no data from the use of carfilzomib in pregnant women.

Studies in animals have shown reproductive toxicity.

Based on its mechanism of action and findings in animals, Carfilnat can cause foetal harm when administered to a pregnant woman. Carfilnat should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus. If Carfilnat is used during pregnancy, or if the patient becomes pregnant while taking this medicinal product, the patient should be apprised of the potential hazard to the foetus.

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected. The conditions of the

Pregnancy Prevention Programme for lenalidomide must be fulfilled for all patients unless there is reliable evidence that the patient does not have child bearing potential. Please refer to the current lenalidomide summary of product characteristics.

Breast-feeding: It is unknown whether carfilzomib or its metabolites are excreted in human milk. Based on its pharmacological properties, a risk to the suckling child cannot be excluded. Consequently, as a precautionary measure, breast-feeding is contra-indicated during and for at least 2 days after treatment with Carfilnat.

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Fertility: No fertility studies have been performed in animals.

Effects on ability to drive and use machines

Carfilnat has minor influence on the ability to drive and use machines. Fatigue, dizziness, fainting, blurred vision, somnolence and/or a drop in blood pressure have been observed in clinical trials. Patients being treated with Carfilnat should be advised not to drive or operate machines in the event that they experience any of these symptoms.

Undesirable effects

Serious adverse reactions that may occur during Carfilnat treatment include: cardiac failure,

myocardial infarction, cardiac arrest, myocardial ischaemia, interstitial lung disease, pneumonitis, acute respiratory distress syndrome, acute respiratory failure, pulmonary hypertension, dyspnea, hypertension including hypertensive crises, acute kidney injury, tumour lysis syndrome, infusion related reaction, gastrointestinal haemorrhage, intracranial haemorrhage, pulmonary haemorrhage, thrombocytopenia, hepatic failure, PRES, thrombotic microangiopathy and TTP/HUS. In clinical studies with Carfilnat, cardiac toxicity and dyspnea typically occurred early in the course of Carfilnat therapy.

 The most common adverse reactions (occurring in > 20% of subjects) were: anaemia, fatigue, thrombocytopenia, nausea, diarrhoea, pyrexia, dyspnea, respiratory tract infection, cough and neutropenia.

Overdose

There is currently insufficient information to draw conclusions about the safety of doses higher than those evaluated in clinical studies. Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia and lymphopenia has been reported following a dose of 200 mg of Carfilnat 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 adverse reactions to Carfilnat

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