Carfilzomib

Registered South African indications:

• Relapsed or refractory multiple myeloma with at least one prior therapy
• Relapsed and refractory multiple myeloma with at least two prior therapies

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Breastfeeding

Cautions

South African manufacturer recommendations

• Pregnancy
• Females of childbearing potential and/or their male partners
• Males of childbearing potential
• Renal impairment
• Severe hepatic impairment
• Elderly
• Asian descent
• Risk factors for cardiac failure (See additional prescribers points) 
• Cardiac disorders, including those uncontrolled by medication 
  - New York Heart Association (NYHA) Class III and IV heart failure
  - Recent myocardial infarction
  - Cardiac conduction abnormalities
  - Angina pectoris
  - Dysrhythmias
• Hypertension
• Known risk factors for thromboembolism (See additional prescribers points)
  - Prior thrombosis
• Positive hepatitis B virus (HBV) serology
• Advanced relapsed and refractory multiple myeloma
• High tumour burden
• Transplant-ineligible patients with newly diagnosed multiple myeloma
• Prior or concurrent immunosuppressive agents
• Coadministration with P-glycoprotein (P-gp) substrates (e.g. digoxin, colchicine) 
• Coadministration with oral contraceptives
• Coadminstration with agents that may increase the risk of thrombosis (e.g. erythropoietic medicines or hormone replacement therapy)
• Controlled sodium content

International manufacturer recommendations

• Pregnancy
• Females of childbearing potential and/or their male partners
• Males of childbearing potential
• Renal impairment
• Hepatic impairment
• Elderly
• Asian descent
• Risk factors for cardiac failure (See additional prescribers points) 
• Cardiac disorders, including those uncontrolled by medication 
  - New York Heart Association (NYHA) Class III and IV heart failure
  - Recent myocardial infarction (in the last 4 months)
  - Cardiac conduction abnormalities
  - Angina or arrhythmias
• Cardiovascular risk factors
• Hypertension
• High tumour burden
• Known risk factors for thromboembolism (See additional prescribers points) 
  - Prior thrombosis 
• Positive hepatitis B virus (HBV) serology
• Previous posterior reversible encephalopathy syndrome (PRES) experience
• Prior or concurrent immunosuppressive agents
• Coadministration with P-glycoprotein (P-gp) substrates (e.g. digoxin, colchicine) 
• Coadministration of other agents that may increase the risk of thrombosis (e.g. erythropoietic agents or hormone replacement therapy)
• Coadministration with CYP1A2, 2C8, 2C9, 2C19 and 2B6 substrates (e.g. oral contraceptives)
• Controlled sodium content

---

As carfilzomib may be administered in combination with other agents, refer to their professional information for additional contraindications and cautions

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Treatment should be supervised by a healthcare professional experienced in the use of anti-cancer therapy

Used for the treatment of

• Relapsed or refractory multiple myeloma with at least one prior therapy (Additional agents required)

---

In combination with dexamethasone and daratumumab, lenalidomide and dexamethasone, or dexamethasone alone

---

Consult specialist for dosages and regimens

---

• Relapsed and refractory multiple myeloma with at least two prior therapies

---

Prior therapies that included bortezomib and an immunomodulatory therapy

---

Consult specialist for dosages and regimens

---

International manufacturer recommendations

Treatment should be supervised by a healthcare professional experienced in the use of anti-cancer therapy

Used for the treatment of

• Multiple myeloma with at least one prior therapy (Additional agents required)

---

In combination with daratumumab and dexamethasone, lenalidomide and dexamethasone, or dexamethasone alone 

---

Consult specialist for dosages and regimens

Not established for use in children

Pregnancy

South African manufacturer recommendations

• Caution; not recommended
• No data from use in pregnant women
• Embryo-foetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose
• Should only be used during pregnancy if the potential benefits to the mother outweigh the potential risks to the foetus
• Females patients of childbearing potential and/or their male partners should use effective contraception methods or abstain from sexual activity during and for 30 days after treatment
• Male patients treated and/or their female partners (if of childbearing potential) should use effective contraceptive methods or abstain from sexual activity while treated 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 carfilzomib will reduce the efficacy of oral contraceptives. Due to an increased risk of venous thrombosis associated with carfilzomib, 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
• Patients receiving carfilzomib in combination with lenalidomide should pay particular attention to the lenalidomide pregnancy testing and prevention requirements

International manufacturer recommendations

• Caution; not recommended
• No data from use in pregnant women
• Studies in animals have shown reproductive toxicity
• Should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus
• Based on its mechanism of action and findings in animals, carfilzomib can cause foetal harm when administered to a pregnant woman
• If carfilzomib 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
• Females patients of childbearing potential and/or their male 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 not using effective contraception
• 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
• 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
• 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 childbearing potential
• Patients receiving carfilzomib in combination with lenalidomide should pay particular attention to the lenalidomide pregnancy testing and prevention requirements (as lenalidomide is structurally related to thalidomide, a known human teratogen that causes severe life-threatening birth defects)

Breastfeeding

South African manufacturer recommendations

• Contraindicated 
• Mothers should not breastfeed their infants as carfilzomib is present in human breast milk

International manufacturer recommendations

• Contraindicated  
• It is unknown whether carfilzomib or its metabolites are excreted in human milk. Based on its pharmacological properties, a risk to the breastfeeding child cannot be excluded. Consequently, as a precautionary measure, breastfeeding is contraindicated during and for at least 2 days after treatment

Fertility

• No fertility studies have been performed

Renal Impairment

South African manufacturer recommendations

• Caution; no dose adjustment recommended
  No starting dose adjustment is required in patients with baseline mild, moderate, or severe renal impairment or patients on chronic dialysis. Since dialysis clearance concentrations has not been studied, the medicine should be administered after the dialysis procedure
  Incidence of acute renal failure was increased in patients with a lower baseline CrCl than among subjects with higher baseline CrCl

International manufacturer recommendations

• Caution; no dose adjustment recommended
  No starting dose adjustment is required in patients with baseline mild, moderate, or severe renal impairment or patients on chronic dialysis. Since dialysis clearance concentrations has not been studied, the medicine should be administered after the dialysis procedure. There are limited efficacy and safety data on patients with baseline CrCl<30ml/min
  Incidence of acute renal failure was higher in patients with a lower baseline CrCl than among subjects with higher baseline CrCl

Hepatic Impairment

South African manufacturer recommendations

• Mild to moderate (Child-Pugh class A and B): No dose adjustment recommended 
• Severe (Child-Pugh class C): Caution; no information available 

International manufacturer recommendations

• Mild to moderate (Child-Pugh class A and B): Caution; no dose adjustment recommended 
  Higher incidence of hepatic function abnormalities, ≥ grade 3 adverse events and serious adverse events have been reported in patients with mild or moderate baseline hepatic impairment compared with patients with normal hepatic function
• Severe (Child-Pugh class C): Caution; no information available 

Elderly

• Caution; no dose adjustment recommended 
  Incidence of certain adverse events (including cardiac failure) are higher for patients ≥75 compared to <75 years of age

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Intracranial haemorrhage
• Dizziness
• Peripheral neuropathy
• Headache
• Fatigue
• Insomnia 
• Anxiety 
• Confusional state 
• Paraesthesia
• Hypoaesthesia
• Cerebrovascular accident
• Posterior reversible encephalopathy syndrome (PRES)  

Cardiovascular Disorders

• Cardiac failure
• Myocardial infarction 
• Tachycardia
  - Ventricular tachycardia 
  - Atrial fibrillation
• Decreased ejection fraction
• Palpitations 
• Cardiac arrest
• Cardiomyopathy
• Myocardial ischaemia
• Pericarditis 
• Pericardial effusion
• Hypertension
  - Hypertensive crisis
  - Hypertensive emergency 
• Deep vein thrombosis
• Hypotension
• Flushing 
• Haemorrhage
• Chest pain
• QT interval prolongation

Respiratory Disorders

• Dyspnoea
• Cough 
• Pulmonary embolism
• Pulmonary oedema
• Pulmonary hypertension
• Oropharyngeal pain
• Dysphonia
• Wheezing
• Acute respiratory distress syndrome (ARDS) 
• Acute respiratory failure
• Pulmonary haemorrhage 
• Respiratory tract infection 
• Interstitial lung disease
• Lung infection 
  -  Pneumonia 
• Pneumonitis
• Bronchitis 
• Nasopharyngitis
• Rhinitis 
• Epistaxis

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea 
• Constipation
• Abdominal pain
• Gastrointestinal haemorrhage
• Dyspepsia
• Gastrointestinal perforation
• Acute pancreatitis 
• Gastroenteritis
• Clostridium difficile colitis 
• Toothache 

Hepatobiliary Disorders

• Increased alanine aminotransferase
• Increased aspartate aminotransferase
• Increased gamma glutamyltransferase 
• Hyperbilirubinaemia
• Hepatic failure
• Cholestasis 
• Hepatitis B virus reactivation

Genitourinary Disorders

• Increased blood creatinine
• Acute kidney injury
• Renal failure
• Renal impairment
• Decreased creatinine renal clearance
• Urinary tract infection

Endocrine and Metabolic Disorders

• Hypokalaemia
• Decreased appetite
• Dehydration
• Hyperkalaemia
• Hypomagnesaemia
• Hyponatraemia
• Hypercalcaemia
• Hypocalcaemia
• Hypophosphataemia
• Hyperuricaemia
• Hypoalbuminaemia
• Hyperglycaemia
• Tumour lysis syndrome

Musculoskeletal Disorders

• Back pain
• Bone pain
• Musculoskeletal pain
• Musculoskeletal chest pain
• Pain in extremity
• Arthralgia
• Muscle spasms
• Myalgia
• Muscular weakness

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Erythema
• Hyperhidrosis
• Angioedema 

Immune, Blood and Lymphatic System Disorders 

• Anaemia
• Thrombocytopenia
• Neutropenia
  - Febrile neutropenia 
• Lymphopenia
• Leukopenia
• Infusion related reaction
  - Infusion site reactions
• Viral infection 
  - Influenza 
  - Influenza like illness
  - Herpes zoster
  - Cytomegalovirus infection
• Sepsis 
• Opportunistic infections
  - Oral candidiasis
  - Oral herpes
  - Herpes simplex 
• Drug hypersensitivity 
• Pyrexia 
• Peripheral oedema
• Chills
• Increased c-reactive protein
• Thrombotic microangiopathy
  - Thrombotic thrombocytopenic purpura (TTP)
  - Haemolytic uraemic syndrome (HUS)

Sensory Disorders

• Cataract
• Blurred vision
• Tinnitus

Others

• Pain
• Multi-organ dysfunction syndrome
• Secondary primary malignancies

• P-glycoprotein (P-gp) substrates
• Digoxin
• Colchicine
• Oral contraceptives 

• Full blood count with differential
  - Platelets 
• Renal function
• Pulmonary function
• Hepatic function
• Electrolytes 
   - Serum potassium
• Blood pressure
• Hepatitis B virus (HBV) screening (See additional prescribers points)  
  - Hepatitis B surface antigen 
  - Hepatitis B core antibody 
  - Total Ig or IgG 
  - Antibody to hepatitis B surface antigen

Specific cases may require 

• Pregnancy status

Additional observations

• Cardiac complications and volume overload (See additional prescribers points)  
• Hydration status
• Signs/symptoms of
  - Infusion-related reactions (See additional prescribers points)  
  - Congestive heart failure
  - Haemorrhage 
  - Tumour lysis syndrome (See additional prescribers points) 
  - Peripheral neuropathy
  - Posterior reversible encephalopathy syndrome (PRES) (See additional prescribers points) 
  - Progressive multifocal leukoencephalopathy (PML), any new or worsening neurologic, cognitive or behavioural signs (See additional prescribers points)
  - Thrombocytopenic thrombotic purpura (TTP)
  - Haemolytic uraemic syndrome (HUS)
  - Venous thromboembolic events (See additional prescribers points) 

Method of administration

• Administer intravenously as 10 or 30 minute infusion, depending on dose regimen
• Should not be administered as a bolus
• Flush line with normal saline or 5% dextrose immediately before and after administration
• Do not mix or administer with other medicinal agents

Hydration, fluid and electrolyte monitoring

• Adequate hydration is required prior to dosing in cycle 1, especially those 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 needs
• Hydration is not required on days when IV daratumumab is dosed

Cardiac disorders

• New or worsening cardiac failure (e.g. congestive cardiac failure, pulmonary oedema, decreased ejection fraction), myocardial ischaemia and infarction have occurred. Death due to cardiac arrest has occurred within a day of administration and fatal outcomes have been reported with cardiac failure and myocardial infarction
• All patients should be monitored for evidence of volume overload, especially those at risk for cardiac failure. Total volume of fluids may be adjusted as clinically indicated in patients with baseline cardiac failure or who are at risk for cardiac failure
• Stop for grade 3 or 4 cardiac events until recovery and consider whether to restart at 1 dose level reduction based on a benefit/risk assessment 
• Risk of cardiac failure is increased in elderly (≥75 years) and Asian patients
• Patients with signs or symptoms of New York Heart Association (NYHA) Class III or IV cardiac failure, recent history of myocardial infarction (in the last 4 months), and in patients with uncontrolled angina or arrhythmias, should have a comprehensive cardiological assessment, prior to starting treatment

Antiviral prophylaxis 

• To reduce herpes zoster reactivation
• Positive hepatitis B virus (HBV) serology

Tumour lysis syndrome (TLS)

• Patients with a high tumour burden at greater risk for TLS
• Ensure patients are well hydrated before administration in cycle 1, and in subsequent cycles as needed
• Uric acid lowering medicines for patients at high risk for TLS
• Evidence of TLS during treatment should be monitored for, including regular measurement of serum electrolytes. Stop until TLS is resolved

Infusion reactions 

• Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial oedema, laryngeal oedema, vomiting, weakness, shortness of breath, hypotension, syncope, bradycardia, chest tightness, or angina
• Occur immediately or up to 24 hours after administration
• Dexamethasone should be administered prior to reduce incidence and severity

Venous thromboembolic events 

• 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 on an individual benefit/risk assessment
• Minimise modifiable risk factors (e.g. smoking, hypertension and hyperlipidaemia) (International manufacturer recommendations) 

Posterior reversible encephalopathy syndrome (PRES)

• Presents with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, confirmed by neuroradiological imaging
• If suspected, discontinue treatment. Safety of reinitiating therapy in patients previously experiencing PRES is not known

Progressive multifocal leukoencephalopathy (PML)

• Reported in patients receiving carfilzomib who have had prior or concurrent immunosuppressive therapy
• If suspected, suspend treatment. If confirmed, discontinue treatment

Cyclodextrin content

• Contains 3000mg of cyclodextrin (betadex sulfobutyl ether sodium) per 60mg vial which is equivalent to 88mg/kg for a 70kg adult

Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that selectively and irreversibly binds to the N terminal threonine containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome, and displays little to no activity against other protease classes. Carfilzomib had antiproliferative and proapoptotic activities in preclinical models in haematologic tumours. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumour growth in models of multiple myeloma. In vitro, carfilzomib was found to have minimal neurotoxicity and minimal reaction to non-proteasomal proteases.

Injection (per 50ml) 60mg

• Kyprolis (Amgen) originator