Use in Cancer

Bortezomib is approved to treat adults with:

• Mantle cell lymphoma in patients who have received at least one other type of treatment.
• Multiple myeloma.

Bortezomib is also being studied in the treatment of other types of cancer.

Contraindications

• diabetes
• dehydration
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• a painful condition that affects the nerves in the legs and arms called peripheral neuropathy
• pulmonary hypertension
• chronic heart failure
• thrombotic thrombocytopenic purpura, a type of blood disorder
• orthostatic hypotension, a form of low blood pressure
• low blood pressure
• pneumonia
• a type of inflammation of the lung called interstitial pneumonitis
• acute respiratory distress syndrome, a type of lung disorder
• blocked bowels with decreased peristaltic movement
• liver problems
• abnormal liver function tests
• pregnancy
• a patient who is producing milk and breastfeeding
• a type of brain disorder called posterior reversible encephalopathy syndrome
• Child-Pugh class B liver impairment
• Child-Pugh class C liver impairment

Dosage

Strengths: 3.5 mg; 2.5 mg; 1 mg; 1 mg/mL; 2.5 mg/mL

Lymphoma

DOSAGE IN PREVIOUSLY UNTREATED MANTLE CELL LYMPHOMA:

• 1.3 mg/m2 as a bolus IV injection twice weekly in combination with IV rituximab, cyclophosphamide, doxorubicin, and oral prednisone for two weeks (days 1, 4, 8, and 11) followed by a ten-day rest period (days 12 through 21)
• The three-week period is considered a treatment cycle.
• A minimum of 72 hours should elapse between consecutive doses of bortezomib.
• For patients with a response first documented at cycle 6, two additional cycles (for a total of 8 cycles) are recommended.

FOR USE IN THE TREATMENT OF RELAPSED MANTLE CELL LYMPHOMA:

• Usual dose: 1.3 mg/m2 as a bolus IV injection or subcutaneously twice weekly for two weeks (days 1, 4, 8, and 11) followed by a ten-day rest period (days 12 through 21). Therapy extending beyond 8 cycles may be administered by the standard schedule or may be given once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest (days 23 through 35)

Multiple Myeloma

FOR USE IN THE TREATMENT OF PREVIOUSLY UNTREATED MULTIPLE MYELOMA:

• Usual dose: 1.3 mg/m2 administered as a 3 to 5-second bolus IV injection or subcutaneously in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles:
• In cycles 1 through 4, bortezomib is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5 through 9, bortezomib is administered once weekly (days 1, 8, 22, and 29).
• At least 72 hours should elapse between consecutive doses of bortezomib.

FOR USE IN THE TREATMENT OF RELAPSED MULTIPLE MYELOMA:

• Usual dose: 1.3 mg/m2 as a bolus intravenous injection or subcutaneously twice weekly for two weeks (days 1, 4, 8, and 11) followed by a ten-day rest period (days 12 through 21). Therapy extending beyond 8 cycles may be administered by the standard schedule or may be given once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest (days 23 through 35).
• Bortezomib may be administered alone or in combination with dexamethasone.
• The three-week period is considered a treatment cycle.
• A minimum of 72 hours should elapse between consecutive doses of bortezomib.
• Patients with multiple myeloma who have previously responded to treatment with bortezomib (either alone or in combination) and who have relapsed at least 6 months after their prior therapy may be started on the last tolerated dose.

Moderate to severe hepatic impairment (bilirubin levels greater than 1.5 times the upper limit of normal range [ULN]): Starting doses should be reduced to 0.7 mg/m2 in the first cycle. Dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered in subsequent cycles based on patient tolerability.

Dose Adjustments

DOSE MODIFICATION GUIDELINES FOR COMBINATION THERAPY WITH BORTEZOMIB, MELPHALAN AND PREDNISONE:

Prior to initiating any cycle of therapy with bortezomib in combination with melphalan and prednisone:

• The platelet count should be greater than or equal to 70 x 10^9/L and the ANC should be greater than or equal to 1.0 x 10^9/L.
• Non-hematological toxicities should have resolved to grade 1 or baseline.

Hematological toxicity during a cycle:

• If prolonged grade 4 neutropenia, thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle, then a reduction of the melphalan dose by 25% in the next cycle should be considered.
• If the platelet count is less than or equal to 30 x 10^9/L or ANC less than or equal to 0.75 x 10^9/L on a bortezomib dosing day (other than day 1), then the bortezomib dose should be withheld.
• If several bortezomib doses in consecutive cycles are withheld due to toxicity, the bortezomib dose should be reduced by 1 dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)
• Nonhematological toxicities greater than or equal to grade 3: Bortezomib therapy should be withheld until symptoms of the toxicity have resolved to grade 1 or baseline. Then, bortezomib may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2).

DOSE MODIFICATION GUIDELINES FOR BORTEZOMIB WHEN GIVEN IN COMBINATION WITH RITUXIMAB, CYCLOPHOSPHAMIDE, DOXORUBICIN, AND PREDNISONE:

Prior to the first day of each cycle (other than Cycle 1) of therapy with bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone:

• Platelet count should be at least 100 x 10^9/L and absolute neutrophil count (ANC) should be at least 1.5 x 10^9/L
• Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L)
• Non-hematologic toxicity should have recovered to Grade 1 or baseline

Bortezomib therapy should be interrupted at the onset of any Grade 3 hematologic or non-hematological toxicities, excluding neuropathy.

Hematological toxicity during a cycle:

• Grade 3 or higher neutropenia, or a platelet count not at or above 25 x 10^9/L:

Withhold bortezomib therapy for up to 2 weeks until the patient has an ANC at or above 0.75 x 10^9/L and a platelet count at or above 25 x 10^9/L. If, after bortezomib has been withheld, the toxicity does not resolve, discontinue bortezomib. If toxicity resolves such that the patient has an ANC at or above 0.75 x 10^9/L and a platelet count at or above 25 x 10^9/L, the bortezomib dose should be reduced by 1 dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)

• Grade 3 or higher non-hematological toxicities: Withhold bortezomib therapy until symptoms of the toxicity have resolved to Grade 2 or better. Then, bortezomib may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2).

DOSE MODIFICATION GUIDELINES FOR RELAPSED MULTIPLE MYELOMA AND MANTLE CELL LYMPHOMA:

• Bortezomib should be withheld at the onset of any grade 3 nonhematologic or grade 4 toxicities excluding neuropathy. Once the symptoms of the toxicity have been resolved, bortezomib therapy may be reinitiated at a 25% reduced dose (1.3 mg/m2 is reduced to 1 mg/m2, 1 mg/m2 is reduced to 0.7 mg/m2).
• Patients with preexisting severe neuropathy should be treated with bortezomib only after a careful risk/benefit assessment.

DOSE MODIFICATION GUIDELINES FOR ALL PATIENTS ON BORTEZOMIB:
For patients who experience bortezomib-related neuropathic pain and/or peripheral sensory neuropathy the following modifications in the dose or regimen is recommended:

• Grade 1 (paresthesias and/or loss of reflexes) without pain or loss of function – no action is required.
• Grade 1 with pain or Grade 2 (interfering with function but not with activities of daily living) – reduce the dose of bortezomib to 1 mg/m2.
• Grade 2 with pain or Grade 3 (interfering with activities of daily living) – withhold bortezomib therapy until toxicity resolves. Once the toxicity resolves, reinitiate therapy with a reduced dose of bortezomib at 0.7 mg/m2 and change the frequency to once a week.
• Grade 4 (a permanent sensory loss that interferes with function) – discontinue bortezomib.

Side Effects

The Most Common

• general weakness
• tiredness
• nausea
• vomiting
• diarrhea
• constipation
• loss of appetite
• stomach pain
• headache
• pain, redness, bruising, bleeding, or hardness at the injection site
• difficulty falling asleep or staying asleep

More Common

• weakness in the arms or legs, changes in the sense of touch, or pain, burning, numbness, or tingling in the hands, arms, legs, or feet
• sudden shooting or stabbing pain, constant aching or burning pain, or muscle weakness
• shortness of breath, fast heartbeat, headache, dizziness, pale skin, confusion, or tiredness
• swelling of the feet, ankles, or lower legs
• hives, rash, itching
• hoarseness, difficulty swallowing or breathing, or swelling of the face, throat, tongue, lips, eyes, or hands
• fever, sore throat, chills, cough or other signs of infection
• unusual bruising or bleeding
• black and tarry stools, red blood in stools, bloody vomit, or vomiting material that looks like coffee grounds
• slurred speech or inability to speak or understand speech, confusion, paralysis (loss of ability to move a part of the body), vision changes, or loss of vision, balance, coordination, memory or consciousness
• fainting, blurred vision, dizziness, nausea, or muscle cramps
• chest pressure or pain, fast heartbeat, swelling of the ankles or feet, or shortness of breath
• cough, shortness of breath, wheezing, or difficulty breathing
• headache, confusion, seizures, tiredness, or vision loss or changes
• pinpoint-sized purple dots under the skin, fever, tiredness, dizziness, shortness of breath, bruising, confusion, sleepiness, seizures, decreased urination, blood in the urine, or swelling in legs
• fever, headache, chills, nausea, pain, itching or tingling followed by a rash in the same area with skin blisters that are itchy or painful
• nausea, extreme tiredness, unusual bleeding or bruising, lack of energy, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, or flu-like symptoms.

Rare

• changes in blood pressure
• confusion
• cough
• dizziness, lightheadedness, or fainting
• inability to urinate
• low blood pressure (e.g., dizziness or fainting)
• shortness of breath
• skin rash
• chest pain
• irregular or rapid heartbeat
• seizures
• severe abdominal pain
• signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
• signs of bleeding (e.g., bloody nose, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
• signs of breathing problems (e.g., shortness of breath, troubled breathing, wheezing, or tightness in chest, fast or irregular breathing)
• signs of depression (e.g., poor concentration, changes in weight, changes in sleep, decreased interest in activities, thoughts of suicide)
• signs of heart problems (e.g., fast, irregular heartbeat or pulse, chest pain, difficulty breathing)
• signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
• symptoms of dehydration (excessive thirst, weakness, decreased urine production, dark urine)
• symptoms of liver damage (yellowing of the skin or eyes, abdominal pain, nausea, dark urine, pale stool, itching, or fluid buildup in the abdomen)
• symptoms of shingles (e.g., headache; sensitivity to light; aching joints followed by an itchy, tingling, or painful skin rash)
• signs of a severe skin reaction such as blistering, peeling, a rash covering a large area of the body, a rash that spreads quickly, or a rash combined with fever or discomfort
• symptoms of a severe allergic reaction (e.g., hives; difficulty breathing; swelling of the face, mouth, tongue, or throat)symptoms of a stroke (sudden numbness or weakness, especially on one side of the body; sudden confusion, difficulty speaking or understanding speech; sudden problems with coordination or balance; sudden vision problems in one or both eyes; sudden, severe headache with no other cause)
• symptoms of gastrointestinal (stomach or intestine) bleeding (such as blood in the stools; black, tarry stools; coughing or vomiting up of blood or material that looks like coffee grounds; abdominal pain; shortness of breath; and weakness or fatigue)

Interaction

Pregnancy and Lactation

FDA Pregnancy Category D

Pregnancy

No studies have been conducted to determine the effect of bortezomib on an unborn baby if the medication is used during pregnancy. Women should avoid becoming pregnant while taking bortezomib. Men and women should use effective contraception during bortezomib treatment and for the 3 months following treatment. If you become pregnant while using this medication, contact your doctor immediately.

Breast-feeding

It is not known if bortezomib passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Women should not breastfeed while taking bortezomib.

References