Bortezomib

Bortezomib is a proteasome inhibitor approved to treat the following cancers in adults across its available products (Velcade, Boruzu, and generic bortezomib formulations):

• Multiple myeloma — a cancer of plasma cells found in the bone marrow; approved for Velcade, Boruzu, and bortezomib injection products by intravenous or subcutaneous routes (route availability varies by specific product)
• Mantle cell lymphoma — a type of non-Hodgkin lymphoma; approved for Velcade, Boruzu, and bortezomib injection products by intravenous or subcutaneous routes (route availability varies by specific product)

Every cell has a built-in system for breaking down old or damaged proteins — called the 26S proteasome. Bortezomib reversibly blocks part of this system. When cancer cells can't clear out proteins the way they normally would, the buildup disrupts their internal signaling and ultimately causes them to die. Cancer cells are particularly sensitive to this kind of stress, which is why bortezomib can target them effectively.

Bortezomib starts inhibiting proteasome activity very quickly — peak inhibition in the blood has been measured within just five minutes of administration — and this effect is reversible, meaning the proteasome recovers between doses.

Bortezomib is given by a healthcare professional as an injection — either into a vein (intravenously) or just under the skin (subcutaneously), depending on the specific product and your care team's recommendation. It is never taken by mouth and must never be injected into the spinal fluid. Doses are given on a structured cycle, often twice weekly during active treatment weeks, followed by rest periods — your oncology team will map out the exact schedule. Patients with moderate or severe liver disease typically start at a lower dose.

• Subcutaneous injection may be preferred for patients who have or are at high risk for nerve problems (peripheral neuropathy).
• The specific product used (Velcade, Boruzu, or generic bortezomib) determines how the injection is prepared and which routes are available.
• Never adjust your dose or skip doses without talking to your care team first.

The most commonly reported side effects — occurring in at least 1 in 5 patients — include:

• Nausea, vomiting, diarrhea, and constipation
• Fatigue
• Numbness, tingling, or nerve pain in the hands and feet (peripheral neuropathy)
• Low platelet counts (thrombocytopenia), which raises the risk of bruising and bleeding
• Low white blood cell counts (neutropenia and leukopenia), which raises the risk of infection
• Anemia (low red blood cell count)
• Fever
• Rash
• Loss of appetite

Serious reactions to watch for and report immediately include signs of heart failure (shortness of breath, swelling), severe breathing difficulty, seizures or sudden vision changes, signs of serious bleeding, and worsening nerve symptoms. These may require dose changes or stopping treatment.

• Peripheral neuropathy (nerve damage): Bortezomib frequently causes numbness, tingling, burning, or weakness in the hands and feet. It can be severe. Patients with pre-existing nerve problems are at highest risk. Subcutaneous injection appears to cause less nerve-related side effects than intravenous dosing. Dose reductions often improve symptoms.
• Low blood counts: Platelet and white blood cell counts drop in a predictable cycle with each treatment. This raises the risk of bleeding and serious infections. Blood counts are monitored regularly throughout treatment.
• Heart problems: Bortezomib can worsen heart failure or cause new heart problems, including reduced heart pumping function. Patients with existing heart disease need frequent monitoring.
• Lung toxicity: Serious lung reactions — including acute respiratory distress — have occurred, some fatal. Report any new or worsening breathing symptoms right away.
• Posterior Reversible Encephalopathy Syndrome (PRES): A rare but serious brain condition causing seizures, confusion, vision changes, or high blood pressure. Brain imaging is needed if suspected, and the drug must be stopped.
• Embryo-fetal toxicity: Bortezomib can seriously harm an unborn baby. Effective contraception is required for both women and men during and after treatment.
• Liver toxicity: Liver enzymes should be monitored during treatment. Dose interruption may be needed if liver problems develop.
• Thrombotic microangiopathy: Rare damage to small blood vessels has been reported — treatment should be stopped if this is suspected.

Bortezomib is broken down in the body mainly by liver enzymes (CYP3A4, CYP2C19, and CYP1A2), so drugs that affect these enzymes can significantly change how much bortezomib is in your system:

• Strong CYP3A4 inhibitors (e.g., ketoconazole): raise bortezomib blood levels by about 35%, increasing the risk of toxicity — careful monitoring and possible dose reduction are needed if combined.
• Strong CYP3A4 inducers (e.g., rifampin): lower bortezomib blood levels by about 45%, which may make treatment less effective — avoid this combination.
• Drugs broken down by CYP2C19: Bortezomib may slow the breakdown of these drugs, raising their levels — tell your doctor all medications you take.
• Oral diabetes medications: Blood sugar levels (both high and low) may be affected in diabetic patients, requiring closer glucose monitoring and possible medication adjustments.
• No clinically significant interactions were seen with dexamethasone, omeprazole, or melphalan combined with prednisone based on available studies.

This is not a complete list of interactions. Always talk with your doctor or pharmacist before starting, stopping, or changing any medication.

• Allergy to bortezomib, boron, or mannitol: This drug is contraindicated — do not use it if you've had a serious allergic (anaphylactic) reaction to any of these.
• Pre-existing nerve problems: Tell your doctor about any numbness, tingling, or pain in your hands or feet before starting — bortezomib can make these significantly worse.
• Heart disease or risk factors for heart problems: Closer monitoring is required, as bortezomib can worsen or trigger heart failure.
• Liver disease: Moderate or severe liver impairment increases bortezomib exposure in the body — a lower starting dose is recommended.
• Pregnancy: Bortezomib can cause fetal harm and embryo-fetal death in animals. Pregnancy testing is required before starting. Women of childbearing potential must use effective contraception during treatment and for 7 months after the last dose.
• Breastfeeding: Do not breastfeed during treatment or for 2 months after the last dose, as the risk to a nursing infant is unknown.
• Men with partners who could become pregnant: Use effective contraception during treatment and for 4 months after the last dose.
• Children: Safety and effectiveness have not been established in pediatric patients.
• Diabetes: Blood glucose may fluctuate — monitoring and medication adjustments may be needed.
• Kidney disease: No dose adjustment is needed based on kidney function, including in patients on dialysis, based on available data.

There is no specific antidote for a bortezomib overdose. In humans, receiving more than twice the intended dose has been fatal, with rapid onset of dangerously low blood pressure and severely low platelet counts. If an overdose is suspected, emergency medical care is needed right away — vital signs will be monitored and supportive treatment provided.

Bortezomib begins inhibiting the proteasome very rapidly — peak inhibition of proteasome activity in the blood occurs within just 5 minutes of administration. At the doses used clinically, bortezomib inhibits proteasome activity by roughly 70–84%, which is thought to be the key driver of its anti-cancer effect. This inhibition is reversible, so proteasome activity recovers between treatment doses, which helps protect normal cells during rest periods.

After an intravenous dose, bortezomib reaches peak blood levels quickly, then distributes widely throughout the body — it binds to plasma proteins at about 83%. When given subcutaneously versus intravenously, the overall amount of drug that reaches the body (total exposure) is equivalent, though peak blood concentrations are much lower with subcutaneous dosing. Bortezomib is broken down by liver enzymes (primarily CYP3A4, CYP2C19, and CYP1A2) into inactive metabolites, and its elimination half-life — the time for blood levels to drop by half — can range widely (roughly 40 to 193 hours) depending on the dose and how many cycles have been given. Kidney function, age, and sex do not significantly affect how the body handles bortezomib, but moderate or severe liver disease increases drug exposure by about 60%, which is why a lower starting dose is used in those patients.

Unopened vials may be stored at 20° to 25ºC (68° to 77ºF); excursions permitted between 15° and 30ºC (59° and 86ºF). protect from light.