Carfilzomib

Name: Carfilzomib

Carfilzomib Dosage

Carfilzomib is injected into a vein through an IV. A healthcare provider will give you this injection.

Carfilzomib is given in a 28-day treatment cycle. You will receive an injection only on certain days of this cycle.

Your doctor will determine how many treatment cycles you should receive.

Drink plenty of liquids before and after your carfilzomib injections.

You may be given medication to prevent certain side effects while you are receiving carfilzomib.

Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while receiving this medication.

You may need frequent medical tests to be sure carfilzomib is not causing harmful effects. Your cancer treatments may be delayed based on the results of these tests.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Call your doctor for instructions if you miss an appointment for your carfilzomib injection.

How supplied

Dosage Forms And Strengths

Kyprolis is supplied as follows:

  • For injection: 30 mg lyophilized cake or powder in single-dose vial for reconstitution
  • For injection: 60 mg lyophilized cake or powder in single-dose vial for reconstitution

Kyprolis (carfilzomib) is supplied as:

  • An individually packaged single-dose vial containing 30 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-102-01.
  • An individually packaged single-dose vial containing 60 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-101-01.

Storage And Handling

Unopened vials should be stored refrigerated (2°C to 8°C; 36°F to 46°F). Retain in original package to protect from light.

Manufactured for: Onyx Pharmaceuticals, Inc. Thousand Oaks, CA 91320-1799 U.S.A. Revised: May 2017

Pregnancy & Lactation

Pregnancy Category: D; Based on mechanism of action and findings in animals, can cause fetal harm

Lactation: Unknown whether distributed in human milk; avoid use in nursing mothers

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Pharmacology

Mechanism of Action

Tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome; has antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells

Absorption

Peak Plasma Concentration: 4232 ng/mL

AUC: 379 ng⋅hr/mL

Distribution

Protein Bound: 97%

Vd: 28 L

Metabolism

Rapidly and extensively metabolized

Principal pathways of metabolism: peptidase cleavage and epoxide hydrolysis

The metabolites have no known biologic activity

Elimination

Half-life: <20 hr

Clearance: 151 to 263 L/hr

Carfilzomib Overdose

Since this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.
 

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
  • Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
  • Signs of electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, seizures, not hungry, or very bad upset stomach or throwing up.
  • Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
  • Chest pain or pressure.
  • Dizziness or passing out.
  • Very bad headache.
  • A burning, numbness, or tingling feeling that is not normal.
  • Feeling very tired or weak.
  • Muscle or joint pain.
  • Flushing.
  • Very bad and sometimes deadly lung problems have happened with this medicine. Call your doctor right away if you have lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.
  • Very bad and sometimes deadly liver problems have happened with carfilzomib. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about carfilzomib, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about carfilzomib. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using carfilzomib.

Review Date: October 4, 2017

Special Populations Renal Function Impairment

Patients with relapsed or progressive advanced malignancies with end-stage renal disease (ESRD) requiring hemodialysis had a 33% higher AUC compared to patients with normal renal function.

Special Populations Hepatic Function Impairment

Patients with relapsed or progressive advanced malignancies with mild (bilirubin >1 to 1.5 x ULN or AST > ULN) or moderate (bilirubin >1.5 to 3 x ULN) hepatic impairment had an approximately 50% greater AUC compared to patients with normal hepatic function.

Contraindications

There are no contraindications listed in the manufacturer's US labeling

Canadian labeling: Hypersensitivity to carfilzomib or any component of the formulation

Dosing Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: In general, utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012). Note: According to the manufacturer, patients with a body surface area (BSA) >2.2 m2 should be dosed based upon a maximum BSA of 2.2 m2; dose adjustments for weight changes of ≤20% are not necessary.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Store in original carton until use to protect from light. Reconstituted drug (in the vial or in a syringe) and preparations diluted for infusion in D5W are stable for 4 hours at room temperature or for 24 hours refrigerated at 2°C to 8°C (36°F to 46°F).

For Healthcare Professionals

Applies to carfilzomib: intravenous powder for injection

Hematologic

Very common (10% or more): Anemia (47%), thrombocytopenia (36%), lymphopenia (24%), neutropenia (21%), leukopenia (14%)
Common (1% to 10%): Deep vein thrombosis
Uncommon (0.1% to 1%): Hemolytic uremic syndrome (HUS)
Rare (less than 0.1%): Thrombotic thrombocytopenic purpura (TTP), thrombotic microangiopathy, hemorrhage[Ref]

Cardiovascular

Very common (10% or more): Hypertension (14%)
Common (1% to 10%): Cardiac failure (i.e., pulmonary edema, decreased ejection fraction), atrial fibrillation, tachycardia, palpitations, flushing
Uncommon (0.1% to 1%): Cardiac arrest, myocardial infarction, myocardial ischemia, pericarditis, pericardial effusion
Rare (less than 0.1%): Hypertensive crisis[Ref]

Hepatic

Very common (10% or more): Increased aspartate aminotransferase (13%)
Common (1% to 10%): Increased alanine aminotransferase, increased gamma-glutamyltransferase, hyperbilirubinemia
Uncommon (0.1% to 1%): Hepatic failure, cholestasis[Ref]

Nervous system

Very common (10% or more): Headache (28%), peripheral neuropathy (14%), dizziness (13%), hypoesthesia (12%), dizziness
Postmarketing reports: Posterior reversible encephalopathy syndrome, paresthesia, hypoesthesia
Uncommon (0.1% to 1%): Intracranial hemorrhage, cerebrovascular accident
Rare (less than 0.1%): Posterior reversible encephalopathy syndrome (PRES)[Ref]

Other

Very common (10% or more): Fatigue (56%), pyrexia (30%), peripheral edema (24%), chills (16%), arthralgia (16%), asthenia (14%), pain (12%), infusion reaction
Common (1% to 10%): Dysphonia
Uncommon (0.1% to 1%): Multi-organ failure[Ref]

Respiratory

Very common (10% or more): Dyspnea (35%), upper respiratory tract infection (28%), cough (26%), pneumonia (13%), nasopharyngitis
Common (1% to 10%): Pulmonary hypertension, bronchitis, pulmonary embolism, pulmonary edema, epistaxis, rhinitis, wheezing
Uncommon (0.1% to 1%): Lung infection
Rare (less than 0.1%): Acute respiratory distress syndrome (ARDS), acute respiratory failure, pulmonary hemorrhage, interstitial lung disease, pneumonitis[Ref]

Gastrointestinal

Very common (10% or more): Nausea (45%), diarrhea (33%), vomiting (22%), constipation (21%), abdominal pain
Common (1% to 10%): Oropharyngeal pain, dyspepsia, toothache
Rare (less than 0.1%): GI hemorrhage, GI perforation[Ref]

Renal

Very common (10% or more): Increased blood creatinine (24%)
Common (1% to 10%): Acute renal failure, renal failure, renal impairment, decreased creatinine renal clearance[Ref]

Metabolic

Very common (10% or more): Hypokalemia (14%), hypomagnesemia (14%), anorexia (12%), hyperglycemia (12%), hypercalcemia (11%), hypophosphatemia (11%), hyponatremia (10%)
Common (1% to 10%): Dehydration, hyperkalemia, hypocalcemia, hyperuricemia, hypoalbuminemia
Uncommon (0.1% to 1%): Tumor lysis syndrome[Ref]

Musculoskeletal

Very common (10% or more): Back pain (20%), extremity pain (13%), chest wall pain (11%), arthralgia, muscle spasms
Common (1% to 10%): Musculoskeletal pain, musculoskeletal chest pain, bone pain, myalgia, muscular weakness[Ref]

Psychiatric

Very common (10% or more): Insomnia (17.9%)
Common (1% to 10%): Anxiety[Ref]

Immunologic

Common (1% to 10%): Herpes zoster reactivation, sepsis, influenza, viral infection[Ref]

Dermatologic

Common (1% to 10%): Rash, pruritus, erythema, hyperhidrosis[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Drug hypersensitivity[Ref]

Ocular

Common (1% to 10%): Cataract, blurred vision[Ref]

Some side effects of carfilzomib may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Usual Adult Dose for Multiple Myeloma

BEFORE INITIATING DOSING:
-Hydrate patients with both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and IV fluids (250 to 500 mL of IV fluids prior to each dose in Cycle 1). If needed, give an additional 250 to 500 mL of IV fluids following administration. Continue oral and/or IV hydration, as needed, in subsequent cycles. Monitor for volume overload and adjust hydration to individual needs (especially in patients with or at risk for cardiac failure).
-Monitor serum potassium levels regularly during therapy.
-The dose is calculated using the patient's actual BSA at baseline. Patients with a BSA greater than 2.2 m2 should receive a dose based upon a BSA of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.

DOSE IN COMBINATION WITH LENALIDOMIDE AND DEXAMETHASONE:
-Cycle 1: 20 mg/m2 IV over 10 minutes on Days 1 and 2; if tolerated, increase to 27 mg/m2 IV over 10 minutes on Days 8, 9, 15, and 16 of a 28-day treatment cycle
-Cycles 2 through 12: 27 mg/m2 IV over 10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle
-Cycle 13 and later: Omit the Day 8 and 9 doses
-Discontinue this drug after Cycle 18
-Lenalidomide 25 mg is taken orally on Days 1 through 21 and dexamethasone 40 mg orally or IV on Days 1, 8, 15, and 22 of the 28-day cycles
-Each 28-day period is considered one treatment cycle
-Continue therapy until disease progression or unacceptable toxicity occurs
-Refer to the lenalidomide and dexamethasone prescribing information for other concomitant medications.

DOSE IN COMBINATION WITH DEXAMETHASONE:
-Cycle 1: 20 mg/m2 IV over 30 minutes on Days 1 and 2; if tolerated, increase to 56 mg/m2 IV over 30 minutes on Days 8, 9, 15, and 16 of a 28-day treatment cycle
-Cycles 2 and later: 56 mg/m2 IV over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle
-Dexamethasone 20 mg is taken orally or IV Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle; administer dexamethasone 30 minutes to 4 hours before this drug
-Continue therapy until disease progression or unacceptable toxicity occurs
-Refer to the dexamethasone prescribing information for other concomitant medications.

MONOTHERAPY BY THE 10-MINUTE INFUSION:
-Cycle 1: 20 mg/m2 IV over 10 minutes on Days 1 and 2; if tolerated, increase to 27 mg/m2 IV over 10 minutes on Days 8, 9, 15, and 16 of a 28-day treatment cycle
-Cycles 2 through 12: 27 mg/m2 IV over 10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle
-Cycle 13 and later: Omit the Day 8 and 9 doses
-Premedicate with dexamethasone 4 mg orally or IV 30 minutes to 4 hours before each dose of this drug in Cycle 1, then as needed to help prevent infusion reactions.
-Continue therapy until disease progression or unacceptable toxicity occurs

MONOTHERAPY BY THE 30-MINUTE INFUSION:
-Cycle 1: 20 mg/m2 IV over 30 minutes on Days 1 and 2; if tolerated, increase to 56 mg/m2 IV over 30 minutes on Days 8, 9, 15, and 16 of a 28-day treatment cycle
-Cycles 2 through 12: 56 mg/m2 IV over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle
-Cycle 13 and later: Omit the Day 8 and 9 doses
-Premedicate with dexamethasone 8 mg orally or IV 30 minutes to 4 hours before each dose of this drug in Cycle 1, then as needed to help prevent infusion reactions.
-Continue therapy until disease progression or unacceptable toxicity occurs

Comments:
-Monitor serum potassium levels regularly during therapy.
-Thromboprophylaxis is recommended for patients being treated with the combination of this drug with dexamethasone or with lenalidomide plus dexamethasone.
-Antiviral prophylaxis should be considered to decrease the risk of herpes zoster reactivation.
-For patients on hemodialysis, administer this drug after the hemodialysis procedure.

Uses:
-In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received 1 to 3 lines of therapy
-As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received 1 or more lines of therapy

Renal Dose Adjustments

-Serum creatinine 2 x baseline or greater, OR CrCl less than 15 mL/min, OR CrCl decreased to 50% or less of baseline, OR need for hemodialysis: Withhold dose and monitor renal function (serum creatinine or CrCl)
-If attributable to this drug, resume when renal function has recovered to within 25% of baseline; start at 1 dose level reduction
-If not attributable to this drug, dosing may be resumed at the discretion of the physician

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