The U.S. Food and Drug Administration is alerting health care professionals, oncology clinical investigators and patients about the risks associated with the investigational use of venetoclax (Venclexta) for the treatment of patients with multiple myeloma based on data from a clinical trial. Venetoclax is not approved for the treatment of multiple myeloma.
FDA reviewed data from the BELLINI clinical trial (NCT02755597, Study M14-031) evaluating the use of venetoclax combined with bortezomib, a proteasome inhibitor, and dexamethasone in patients with multiple myeloma. The interim trial results demonstrated an increased risk of death for patients receiving venetoclax as compared to the control group. On March 6, 2019, the FDA required no new patients be enrolled on the Bellini trial. Patients who are receiving clinical benefit can continue treatment in the trial after they reconsent. More information about the BELLINI clinical trial findings can be found below (see statistical analysis section below).
This statement does not apply to patients taking venetoclax for an approved indication. For approved indications, see the product labelling available at: http://bit.ly/2Ttjo8h. Patients taking venetoclax for an approved indication should continue to take their medication as directed by their health care professional. Venetoclax is safe and effective for its approved uses.
The FDA suspended enrollment in other ongoing multiple myeloma clinical trials of venetoclax. Patients who are receiving clinical benefit can continue treatment in these trials after they reconsent. FDA will be working directly with sponsors of venetoclax, as well as other investigators conducting clinical trials in patients with multiple myeloma, to determine the extent of the safety issue. The agency will communicate any new information as appropriate.
Statistical Analysis and Findings: Following is a summary of findings from the BELLINI clinical trial. The FDA conducted a safety and effectiveness analysis based on a November 26, 2018 data cutoff date for the BELLINI Study.
Bellini is a phase 3, double-blind, randomized, controlled trial of bortezomib and low-dose dexamethasone with or without venetoclax in patients with relapsed and refractory multiple myeloma who have received 1 to 3 prior lines of therapy.
Using a data cutoff date of November 26, 2018, an evaluation of safety and efficacy was performed. There were 291 randomized patients included in the analysis. The median follow-up was approximately 17.9 months. At the interim analysis for overall survival, there were 41/194 (21.1%) deaths on the venetoclax-containing investigational arm and 11/97 (11.3%) deaths on the placebo arm. The hazard ratio (HR) of the venetoclax-containing investigational arm compared to the placebo arm was 2.03 (95% CI: 1.04,3.94), increasing the relative risk of death by approximately two-fold compared to the placebo arm.
The median progression-free survival (PFS) time (95% CI) was 22.4 months (15.3, -) for the venetoclax arm and 11.5 months (9.6, 15.0) for the placebo arm. The estimated HR was 0.63 (0.44, 0.90). The objective response rate (ORR) was 82.0% (75.8, 87.1) in the investigational arm compared to 68.0% (57.8, 77.1) in the placebo arm. MRD negativity rate (10-5) was 13.4% (8.9, 19.0) compared to 1.0% (0.0, 5.6) in the placebo arm.
The incidence of severe, grade 3-5 toxicity (86.5% vs. 87.5%, venetoclax vs. placebo arm) and serious adverse events (48.2% vs.50.0%) was similar between the two arms. The incidence of infections (by System Organ Class) was 79.8% in the venetoclax arm and 77.1% in the placebo arm. The incidence of pneumonia was 20.7% in the venetoclax arm and 15.6% in the placebo arm. Serious infection related adverse events were reported in 28.0% of patients in the venetoclax arm and 27.1% in the placebo arm. Serious adverse events of pneumonia were reported in 14.0% of patients in the venetoclax arm and 12.5% of patients in the placebo arm. Common non-disease progression causes of death identified in the venetoclax arm were: sepsis, pneumonia, and cardiac arrest.
For more information visit the FDA website at: http://www.fda.gov/Safety/MedWatch/SafetyInformation and http://www.fda.gov/Drugs/DrugSafety.
Why is this medication prescribed?
Venetoclax is used alone or in combination with rituximab (Rituxan) to treat certain types of chronic lymphocytic leukemia (CLL; a type of cancer that begins in the white blood cells) or certain types of small lymphocytic lymphoma (SLL; a type of cancer that begins mostly in the lymph nodes) in people who have already been treated with at least one other chemotherapy medication. It is also used in combination with either azacitidine (Vidaza), decitabine (Dacogen), or cytarabine as a first treatment for acute myeloid leukemia (AML; a type of cancer that begins in the white blood cells) in people 75 years of age or older, or in adults who have medical conditions that prevents them from being treated with other chemotherapy medications. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It works by blocking the action of a certain protein in the body that helps cancer cells survive. This helps to kill cancer cells.
How should this medicine be used?
Venetoclax comes as a tablet to take by mouth. It is usually taken with a meal and water once a day. Take venetoclax at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take venetoclax exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.
Swallow the tablets whole; do not split, chew, or crush them.
If you vomit after taking venetoclax, do not repeat the dose. Continue your regular dosing schedule.
Your doctor will probably start you on a low dose of venetoclax and gradually increase your dose, not more than once every week for the first 5 weeks if you are being treated for CLL or SLL, and once a day for the first 3 or 4 days if you are being treated for AML.
Your doctor may need to interrupt or stop your treatment if you experience certain side effects. Be sure to tell your doctor how you are feeling during your treatment with venetoclax. For certain side effects, your doctor may tell you to start taking venetoclax at a lower dose.
Your doctor or pharmacist will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with venetoclax and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer's website to obtain the Medication Guide.
Other uses for this medicine
This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.
What special precautions should I follow?
Before taking venetoclax,
- tell your doctor and pharmacist if you are allergic to venetoclax, any other medications, or any of the ingredients in venetoclax tablets. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
- tell your doctor if you are taking clarithromycin (Biaxin, in Prevpac), conivaptan (Vaprisol), indinavir (Crixivan), itraconazole (Onmel, Sporanox), ketoconazole, lopinavir (in Kaletra), posaconazole (Noxafil), ritonavir (Norvir, in Kaletra, Technivie, Viekira Pak), or voriconazole (Vfend). Your doctor may tell you not to take venetoclax if you are taking one or more of these medications.
- tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: amiodarone (Nexterone, Pacerone), azithromycin (Zithromax, Zmax), bosentan (Tracleer), buprenorphine with naloxone (Suboxone), captopril, carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Teril), carvedilol (Coreg), ciprofloxacin (Cipro), clarithromycin, cyclosporine (Gengraf, Neoral, Sandimmune), digoxin (Digitek, Lanoxin), diltiazem (Cardizem, Cartia XT, Diltzac, Taztia, Tiazac), dronedarone (Multaq), efavirenz (Sustiva, in Atripla), erythromycin (E.E.S., Eryc, Eryped, Ery-tab, Erythrocin), etravirine (Intelence), everolimus (Afinitor, Zortress), felodipine, fluconazole (Diflucan), indinavir (Crixivan), itraconazole (Onmel, Sporanox), ketoconazole, modafinil (Nuvigil, Provigil), nafcillin (Nallpen), nefazodone, nelfinavir (Viracept), phenytoin (Dilantin, Phenytek), posaconazole (Noxafil), quinidine (in Nuedexta), ranolazine (Ranexa), rifampin (Rifadin, Rimactane, in Rifamate, Rifater), ritonavir (Norvir, in Kaletra, Technivie, Viekira Pak), sirolimus (Repamune), ticagrelor (Brilinta), verapamil (Calan, Verelan, in Tarka), or warfarin (Coumadin, Jantoven). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with venetoclax, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
- tell your doctor what herbal products you are taking, especially quercetin or St. John's wort.
- tell your doctor if you have or have ever had problems with your levels of potassium, phosphorus, or calcium in your blood; high levels of uric acid in your blood; gout (a type of arthritis caused by crystals deposited in the joints); or kidney or liver disease.
- tell your doctor if you are pregnant or plan to become pregnant. If you can become pregnant, you will need to have a pregnancy test before beginning treatment with venetoclax. You should not become pregnant during your treatment and for 30 days after your final dose. Talk to your doctor about birth control methods that you can use during your treatment. If you become pregnant while taking venetoclax, call your doctor.
- tell your doctor if you are breastfeeding. Do not breastfeed while taking venetoclax.
- you should know that this medication may decrease fertility in men. Talk to your doctor about the risks of taking venetoclax.
- do not have any vaccinations before, during, or after treatment with venetoclax without talking to your doctor.
- you should know that you may experience tumor lysis syndrome (TLS; a condition caused by the fast breakdown of cancer cells that can cause kidney failure and other complications) during your treatment with venetoclax. This is more likely to happen when you are first starting treatment, and each time your dose is increased. To help reduce your risk of experiencing TLS you should drink at least 6 to 8 glasses (48 to 64 ounces) of water a day for 2 days before and on the day of your first dose, and each time your dose is increased. In addition your doctor will give you a medication to take before starting and during your treatment to help prevent this side effect. If you experience any of the following symptoms of TLS call your doctor immediately: fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.
What special dietary instructions should I follow?
Do not eat grapefruit, starfruit, or Seville oranges (sometimes used in marmalades), or drink grapefruit juice while taking this medication.
What should I do if I forget a dose?
If you remember the missed dose within 8 hours of the time you were scheduled to take it, take the missed dose right away. However, if more than 8 hours have passed since the time you usually take venetoclax, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.
What side effects can this medication cause?
Venetoclax may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:
- swelling of your arms or hands
- back pain
- runny or stuffy nose
- pale skin
Some side effects can be serious. If you experience any of these symptoms or those listed in the SPECIAL PRECAUTIONS section, call your doctor immediately:
- fever alone or along with sore throat, cough, chills, and other signs of infection
- decreased urination
- swelling of your legs, ankles, or feet
- unusual bleeding or bruising
Venetoclax may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.
If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).
What should I know about storage and disposal of this medication?
Keep this medication in the container it came in, tightly closed, and out of reach of children. Do not transfer the medication to a different container. Store it at room temperature and away from excess heat and moisture (not in the bathroom).
It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org
Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.
In case of emergency/overdose
In case of overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services at 911.
What other information should I know?
Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests before and during your treatment to check your body's response to venetoclax.
Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.
It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.