Carfilzomib (Kyprolis) arrests the cell cycle and causes apoptosis by inhibiting proteasomes that are responsible for protein homeostasis. It is used to treat the following conditions:

• For the treatment fo refractory or relapsed multiple myeloma as monotherapy in patients who have received one or more first-line therapies
• For the treatment fo refractory or relapsed multiple myeloma in combination with dexamethasone or lenalidomide plus dexamethasone in patients who have received 1 - 3 prior therapies.
• It is also used as Off-Label treatment in Adults:
  • For the treatment of newly diagnosed Multiple myeloma and
  • Waldenström macroglobulinemia

Carfilzomib (Kyprolis) dose in Adults

Note:

• The patient should be well hydrated with oral fluids (30 mL/kg) for at least two days prior to initiating the first cycle.
  • Intravenous hydration should be continued with 250 to 500 mL NS prior to (recommended) and after (if needed) each dose in cycle 1.
  • The infusion line should be flushed immediately before and after carfilzomib administration with 0.9% saline or 5% Dextrose water.
• Patients with a history of herpes zoster infection should be administered, prophylactic antiviral agents.
• When administering in combination with dexamethasone or with lenalidomide plus dexamethasone, antacids and thromboprophylaxis are recommended.
• Premedication with dexamethasone 4 mg orally or intravenous when infusing carfilzomib over ten minutes or with dexamethasone, 8 mg orally or intravenous when infusing carfilzomib over thirty minutes is recommended.

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Carfilzomib (Kyprolis) dose as off-label use in the treatment of newly diagnosed Multiple Myeloma:

• Adults older than 65 years or ineligible for autologous transplant:

  • Induction phase:

    • Cycle 1:
      • 20 mg/m² intravenous over 30 minutes on days 1 and 2, and 36 mg/m² intravenous over 30 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle in combination with cyclophosphamide and dexamethasone.
    • Cycles 2 - 9:
      • 36 mg/m² intravenous over 30 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle in combination with cyclophosphamide and dexamethasone

  • Maintenance phase:

    • 36 mg/m² intravenous on days 1, 2, 15, and 16 of a 28-day treatment cycle as monotherapy until disease progression or unacceptable toxicity.

Carfilzomib (Kyprolis) dose in the treatment of refractory or relapsed Multiple myeloma as a single-agent; 20/27 mg/m2 regimen [twice-weekly dosing]):

Intravenous:

• 20/27 mg/m² regimen - twice-weekly dosing

  • Cycle 1:
    • 20 mg/m² intravenous over 10 minutes on days 1 and 2
    • Increase the dose to 27 mg/m² intravenous over 10 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle.
  • Cycles 2 - 12:
    • 27 mg/m² intravenous over 10 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle
  • Cycle 13 and beyond:
    • 27 mg/m² intravenous over 10 minutes on days 1, 2, 15, and 16 of a 28-day treatment cycle until disease progression or unacceptable toxicity.

Carfilzomib (Kyprolis) dose in the treatment of refractory or relapsed Multiple myeloma as  a single-agent:

• 20/56 mg/m² regimen - twice-weekly dosing:

  • Cycle 1:
    • 20 mg/m² intravenous over 30 minutes on days 1 and 2
    • Increase the dose to 56 mg/m² intravenous over 30 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle.
  • Cycles 2 to 12:
    • 56 mg/m² intravenous over 30 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle.
  • Cycle 13 and beyond:
    • 56 mg/m² intravenous over 30 minutes on days 1, 2, 15, and 16 of a 28-day treatment cycle until disease progression or unacceptable toxicity.

Carfilzomib (Kyprolis) dose in the treatment of refractory or relapsed Multiple myeloma in combination with lenalidomide and dexamethasone:

• 20/27 mg/m² regimen - twice-weekly dosing

  • Cycle 1:
    • 20 mg/m² intravenous over 10 minutes on days 1 and 2
    • Increase the dose to 27 mg/m² intravenous over 10 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle.
  • Cycles 2 to 12:
    • 27 mg/ m² intravenous over 10 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle.
  • Cycles 13 to 18:
    • 27 mg/m² intravenous over 10 minutes on days 1, 2, 15, and 16 of a 28-day treatment cycle
    • Discontinue carfilzomib after cycle 18
    • Lenalidomide and dexamethasone may be continued until disease progression or unacceptable toxicity beginning with cycle 19.

Carfilzomib (Kyprolis) dose in the treatment of refractory or relapsed Multiple myeloma in combination with dexamethasone:

• 20/56 mg/m² regimen - twice-weekly dosing:

  • Cycle 1:
    • 20 mg/m² intravenous over 30 minutes on days 1 and 2
    • Increase the dose to 56 mg/m² intravenous over 30 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle if tolerated.
  • Cycle 2 and beyond:
    • 56 mg/m² intravenous over 30 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle until disease progression or unacceptable toxicity.

Carfilzomib (Kyprolis) dose in the treatment of refractory or relapsed Multiple myeloma in combination with dexamethasone:

• 20/70 mg/m² regimen - once-weekly dosing:

  • Cycle 1:
    • 20 mg/m² intravenous over 30 minutes on day 1
    • Increase the dose to 70 mg/m² intravenous over 30 minutes on days 8 and 15 of a 28-day treatment cycle.
  • Cycle 2 and beyond:
    • 70 mg/m² intravenous over 30 minutes on days 1, 8, and 15 of a 28-day treatment cycle until disease progression or unacceptable toxicity.

Carfilzomib (Kyprolis) dose as off label use in the treatment of Waldenström macroglobulinemia:

• Induction phase:
  • Cycle 1:
    • 20 mg/m² intravenous over 20 minutes on days 1, 2, 8, and 9 of a 21-day treatment cycle in combination with dexamethasone and rituximab.
  • Cycles 2 - 6:
    • 36 mg/m² intravenous over 30 minutes on days 1, 2, 8, and 9 of a 21-day treatment cycle in combination with dexamethasone and rituximab.

• Maintenance phase started 8 weeks after the completion of induction therapy in patients with a better response and stable disease:

  • 36 mg/m² intravenous on days 1 and 2 every 8 weeks for 8 cycles in combination with dexamethasone and rituximab.

Use in Children:

• Not applicable

Carfilzomib (Kyprolis) Pregnancy Risk Factor D

• CarfilzomibIf given to pregnant women, it can cause severe fetal harm.
• A pregnancy test should be done on all women of childbearing years before initiating therapy.
• Patients should also follow strict contraception throughout therapy and for at least six months after their last Carfilzomib dose.
• Effective contraception should be used for at least three months while on treatment, and at least three months after the last dose.
• It can also lead to impaired fertility in males as well as females.

Carfilzomib (Kyprolis) dose in renal impairment:

• Patients with Preexisting renal impairment and on hemodialysis:

  • Dosage adjustment is not necessary. Monitor the dose after dialysis.

• Renal toxicity during treatment:

  • Serum creatinine more than 2 times the baseline, CrCl less than 15 mL/minute or CrCl decreases to ≤50% of baseline, or the patient requires dialysis:
    • Withhold the dose and monitor renal function.
    • Resume the dose when the renal function has improved to within 25% of baseline.

Carfilzomib (Kyprolis) dose in hepatic impairment:

Patients with preexisting hepatic impairment:

• • Reduce carfilzomib dose by 25% in patients with mild or moderate hepatic impairment:
• Mild impairment is defined as:
  • Total bilirubin 1 - 1.5 times the ULN and any AST or
  • Total bilirubin is normal but AST is more than the ULN
• Moderate hepatic impairment is defined as:
  • Total bilirubin more than 1.5 - 3 times the ULN and any AST
• Adjustment in the dose has not been provided by the manufacturer in patients with severe hepatic impairment defined as:
  • Bilirubin level greater than 3 times the ULN.

Hepatotoxicity during treatment:

• Grade 3 or 4 elevation of bilirubin, transaminases, or other liver function abnormalities:
  • Withhold the dose until the liver functions have returned to baseline.
  • After resolution, restart at a lower dose and monitor frequently.

Common Side Effects Of Carfilzomib (Kyprolis):

• Cardiovascular:

  • Hypertension
  • Peripheral edema
  • Chest pain

• Central nervous system:

  • Fatigue
  • Chills
  • Headache
  • Insomnia
  • Dizziness
  • Hypoesthesia
  • Peripheral neuropathy

• Gastrointestinal:

  • Nausea
  • Vomiting
  • Diarrhea
  • Anorexia
  • Constipation

• Hematologic & oncologic:

  • Thrombocytopenia
  • Anemia
  • Lymphocytopenia
  • Leukopenia
  • Neutropenia

• Neuromuscular & skeletal:

  • Back pain
  • Muscle spasm

• Renal:

  • Increased serum creatinine

• Respiratory:

  • Dyspnea
  • Cough
  • Upper respiratory tract infection
  • Pneumonia

• Miscellaneous:

  • Fever

Less Common Side Effects Of Carfilzomib (Kyprolis):

• Cardiovascular:

  • Deep vein thrombosis
  • Pulmonary embolism
  • Pulmonary hypertension
  • Ischemic heart disease

• Central nervous system:

  • Paresthesia
  • Peripheral sensory neuropathy

• Endocrine & metabolic:

  • Hypercalcemia
  • Hyponatremia
  • Hypophosphatemia

• Hematologic & oncologic:

  • Febrile neutropenia

• Renal:

  • Renal insufficiency
  • Acute renal failure
  • Renal failure syndrome

• Respiratory:

  • Acute respiratory distress syndrome
  • Acute respiratory failure
  • Interstitial pulmonary disease
  • Pneumonitis

Rare Side effects of Carfilzomib (Kyprolis):

• Cardiovascular:

  • Cardiac failure
  • Hypertensive crisis
  • Hypotension
  • Thromboembolic complications

• Central nervous system:

  • Anxiety
  • Intracranial hemorrhage
  • Pain
  • Voice disorder

• Dermatologic:

  • Erythema
  • Hyperhidrosis
  • Pruritus
  • Skin rash

• Endocrine & metabolic:

  • Hyperglycemia
  • Hyperkalemia
  • Hyperuricemia
  • Hypoalbuminemia
  • Hypocalcemia
  • Hypokalemia
  • Hypomagnesemia

• Gastrointestinal:

  • Abdominal pain
  • Dyspepsia
  • Gastrointestinal hemorrhage
  • Toothache
  • Upper abdominal pain

• Genitourinary:

  • Urinary tract infection

• Hematologic & oncologic:

  • Hemorrhage
  • Pulmonary hemorrhage

• Hepatic:

  • Hepatic failure
  • Increased serum transaminases

• Infection:

  • Influenza
  • Sepsis

• Local:

  • Infusion site reaction

• Neuromuscular & skeletal:

  • Arthralgia
  • Asthenia
  • Limb pain
  • Musculoskeletal chest pain
  • Musculoskeletal pain
  • Myalgia

• Ophthalmic:

  • Blurred vision
  • Cataract

• Respiratory:

  • Bronchitis
  • Bronchopneumonia
  • Epistaxis
  • Nasopharyngitis
  • Oropharyngeal pain
  • Pulmonary edema
  • Pulmonary infection
  • Respiratory tract infection
  • Rhinitis

• Miscellaneous:

  • Multiorgan failure

Contraindications to Carfilzomib (Kyprolis):

• Allergy reactions to any component of the drug or the drug itself

Warnings and Precautions

• Suppression of bone marrow

  • Thrombocytopenia can be severe enough to require transfusion support or withholding therapy.
  • Cytopenias, especially thrombocytopenias, should be closely monitored.

• Cardiovascular effects

  • Carfilzomib has been linked to pulmonary edema.
  • This can be a new-onset, or worsening, of heart failure. It also causes decreased left ventricular Ejection fraction.
  • Restrictive cardiomyopathy. Myocardial infarction may occur.
  • Reports have indicated that a 24-hour period of drug induction has resulted in cardiac arrest.
  • Drug-induced cardiac complications can be dangerous for older patients and people with preexisting heart disease.
  • During therapy, patients should be closely observed.

• Hemorrhage

  • It is possible to have fatal or serious bleeding diathesis, with or without thrombocytopenia.
  • It is important to monitor patients and advise them to discontinue treatment or reduce their dose.

• Hypertension

  • It is important to control hypertension before you start treatment. Hypertension can lead to a hypertensive emergency or crisis.

• Infusion reactions

  • Pre-medicating patients is important before the treatment, as it could cause life-threatening reactions.
  • Infusion reactions can manifest as fever, myalgia and flushing.

• The posterior reversible syndrome of encephalopathy:

  • Therapy may be used to treat posterior irreversible encephalopathy (PRES), which can manifest as seizures, headaches, lethargy and blindness, confusion, altered awareness, hypertension and other neurological disorders.
  • It is important to stop using therapy.

• Toxicities to the lungs

  • It has been reported that pulmonary toxicity has been linked to its use.
    • Acute respiratory distress syndrome (ARDS).
    • Acute respiratory failure
    • Acute diffuse-infiltrative lung diseases such as pneumonitis or interstitial lung disease.
    • Pulmonary Hypertension
  • It is important to manage pulmonary toxicities appropriately. Treatment should be stopped until the symptoms resolve.

• Toxicity in the renal system:

  • Patients at high risk for developing renal failure, especially those with baseline renal impairment, should have their renal function monitored.

• Thrombotic microangiopathy

  • Patients receiving Carfilzomib therapy have been diagnosed with thrombotic microangiopathy (including cases of hemolytic uremic syndrome or thrombotic tuberculocytopenic purpura)
  • The treatment should not be stopped and the appropriate management should be started.

• Events that are thromboembolic:

  • Patients receiving combination therapy with dexamethasone and/or lenalidomide plus venous hemorhage are at increased risk.
  • Patients at greater risk should begin thromboprophylaxis.
  • Other contraceptives should be considered, as hormonal contraceptives can also increase the risk of venous embolism.

• Tumor lysis syndrome

  • Patients with a high tumor burden (TLS) are at greater risk.
  • Before starting therapy, patients should be properly hydrated. Patients should also be closely monitored for symptoms and signs of TLS.
  • You can add antihyperuricemic drugs to the treatment either before or during it.

• Hepatic impairment

  • Patients with mild or moderate preexisting liver impairment should be warned and adjusted to the recommended dose.

Monitoring Parameters:

• CBC with differential and platelets
• Serum potassium levels
• Renal function
• Pulmonary function
• Liver function tests
• Blood pressure
• Pregnancy test in women of reproductive potential before treatment.
• Monitor for infusion-related reactions
• Congestive heart failure
• Tumor lysis syndrome
• Peripheral neuropathy
• PRESS of posterior reversible encephalopathy syndrome
• TTP or thrombocytopenic thrombotic purpura & HUS (hemolytic uremic syndrome)
• Observe for venous thromboembolic events.

How to administer Carfilzomib (Kyprolis)?

• It should be administered intravenously for between 10 and 30 minutes, depending on the regimen.
• Avoid intravenous pushes or bolus administration.
• Before initiating the first cycle, it is important that the patient be adequately hydrated.
  • Intravenous Hydration should continue with 250-500 mL of NS before (recommended) as well as after (if necessary) each dose in Cycle 1.
  • Before and after administration of carfilzomib, flush the infusion line with 0.9% saline (or 5% Dextrose) immediately.
• You should not take it with any other medication.
• Premedication with dexamethasone 4mg orally or via intravenous when you infuse carfilzomib for more than ten minutes.
• Or with dexamethasone 8mg orally, intravenous, when you infuse carfilzomib for more than thirty minutes.

Mechanism of action of Carfilzomib (Kyprolis):

• Carfilzomib inhibits proteasomes, causing cell cycle arrest and apoptosis. (Proteasomes control intracellular protein homeostasis.
• It is specifically a powerful and irreversible inhibitor for the chymotrypsin like activity of the 20S proteasesome, which is selectively targeted by the drug.

97% of the drug's ingredients areProtein-boundIt is quickly becoming an extensively usedMetabolized. TheEliminating half-lifeWhen administered in doses of 15 mg/m2 or less within one hour. It is excreted from the urine.

Carfilzomib Available Brand Names:

• Kyprolis (Onyx pharmaceuticals)

Carfilzomib (Kyprolis) Brand Names in Pakistan:

No brands available in Pakistan