Venetoclax

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 (Cordarone, Nexterone, Pacerone), azithromycin (Zithromax, Zmax), bosentan (Tracleer), captopril, carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Teril), carvedilol (Coreg), ciprofloxacin (Cipro), 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), modafinil (Nuvigil, Provigil), nafcillin (Nallpen), phenytoin (Dilantin, Phenytek), quinidine (in Nuedexta), ranolazine (Ranexa), rifampin (Rifadin, Rimactane, in Rifamate, Rifater), sirolimus (Repamune), ticagrelor (Brilinta), verapamil (Calan, Covera-HS, 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 Saint 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, plan to become pregnant, or are breast-feeding. 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 last 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.
• 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 6-8 glasses (48-64 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.

Dosage Forms & Strengths

tablet

• 10mg
• 50mg
• 100mg

Chronic Lymphocytic Leukemia (CLL)

Indicated for patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least 1 prior therapy

Dose ramp-up phase

• Administer dose according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg
• Week 1: 20 mg PO qDay
• Week 2: 50 mg PO qDay
• Week 3: 100 mg PO qDay
• Week 4: 200 mg PO qDay
• Week 5 and beyond: 400 mg PO qDay
• Continue daily dose until disease progression or unacceptable toxicity
• See Dosing Considerations and Dosage Modifications for tumor lysis syndrome (TLS) prophylaxis regimens

Dosage Modifications

Dose reduction schedule

• Dose at interruption is 400 mg: Restart at 300 mg
• Dose at interruption 300 mg: Restart at 200 mg
• Dose at interruption 200 mg: Restart at 100 mg
• Dose at interruption 100 mg: Restart at 50 mg
• Dose at interruption 50 mg: Restart at 20 mg
• Dose at interruption 20 mg: Restart at 10 mg
• During the ramp-up phase, continue the reduced dose for 1 week before increasing the dose

Tumor lysis syndrome

• Modify for any occurrence of blood chemistry changes or symptoms suggestive of TLS
• Withhold the next day’s dose; if resolved within 24-48 hr of last dose, resume at the same dose
• For any blood chemistry changes requiring >48 hr to resolve, resume at a reduced dose
• For any events of clinical TLS, resume at a reduced dose following resolution

Nonhematologic toxicities (grades 3 or 4)

• First occurrence: Interrupt dose; once the toxicity has resolved to grade 1 or baseline level, may resume at the same dose; no dose modification is required
• Second and subsequent occurrences: Interrupt dose; once the toxicity has resolved to grade 1 or baseline level, decrease dose according instructions listed above; a larger dose reduction may occur at the discretion of the physician

Hematologic toxicities

• The following applies to grades 3 or 4 neutropenia with infection or fever, or grade 4 hematologic toxicities (except lymphopenia)
• First occurrence: Interrupt dose; to reduce the infection risks with neutropenia, G-CSF may be administered with venetoclax if clinically indicated; once the toxicity has resolved to grade 1 or baseline level, may resume at the same dose
• Second and subsequent occurrences: Interrupt dose; consider using G-CSF as clinically indicated; follow dose reduction listed above when resuming after resolution; a larger dose reduction may occur at the discretion of the physician

Coadministration with CYP3A and/or P-gp inhibitors

• Strong CYP3A inhibitor
  • Contraindicated during initiation and ramp-up phase
  • At steady daily dose (ie, after ramp-up phase): Avoid strong inhibitor or reduce venetoclax dose by at least 75%
• Moderate CYP3A inhibitor or P-gp inhibitor
  • Avoid strong inhibitor or reduce venetoclax dose by at least 50%

Dosing Considerations

Patients without 17p deletion at diagnosis should be retested at relapse because acquisition of 17p deletion can occur

TLS risk

• Assess patient-specific factors for level of risk of TLS and provide prophylactic hydration and antihyperuricemics to patients prior to first dose to reduce risk of TLS
• Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5­week ramp-up phase
• Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6-8 hr after the first dose and at each dose increase
• The risk of TLS is a continuum based on multiple factors, including tumor burden and comorbidities
• Perform tumor burden assessments, including radiographic evaluation (eg, CT scan); assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all patients and correct preexisting abnormalities prior to initiating
• Reduced renal function (CrCl <80 mL/min) further increases the risk
• Risk may decrease as tumor burden decreases

TSL prophylaxis

• Low tumor burden
  • All lymph nodes (LNs) <5 cm AND absolute neutrophil count (ALC) <25 x10^9/L
  • Give oral hydration of 1.5-2 L and allopurinol 2-3 days before initiating venetoclax
  • Outpatient: Monitor blood chemistry predose, at 6-8 hr, and 24 hr after first dose and predose for subsequent ramp-up doses
• Medium tumor burden
  • Any LN 5 cm to <10 cm OR ALC ≥25 x10^9/L
  • Give oral hydration of 1.5-2 L (also consider additional IV hydration) and allopurinol 2-3 days before initiating venetoclax
  • Outpatient: Monitor blood chemistry predose, at 6-8 hr, and 24 hr after first dose and predose for subsequent ramp-up doses
  • Consider hospitalization for patients with CrCl <80 mL/min at first dose of 20 mg and 50 mg
• High tumor burden
  • Any LN >10 cm OR, ALC ≥25 x10^9/L AND any LN ≥5 cm
  • Hydration: Oral (1.5-2 L) and IV (150-200 mL/hr as tolerated)
  • Give allopurinol 2-3 days before initiating venetoclax; consider rasburicase if baseline uric acid is elevated
  • In hospital: Monitor blood chemistry at first dose of 20 mg and 50 mg; predose, 4, 8, 12, and 24 hr
  • Outpatient: Monitor blood chemistry at subsequent ramp-up doses; predose, at 6-8 hr, and 24 hr after dose

Orphan Designations

Acute myeloid leukemia

Multiple myeloma

Mantle cell lymphoma

Sponsor

• AbbVie Inc; 1 Waukegan Road, Dept PA77, Bldg. AP30; North Chicago, Illinois 60044

Safety and efficacy not established

Venetoclax inhibits a certain protein in cancer cells (abnormal lymphocytes produced in chronic lymphocytic leukemia) that helps keep those cells alive and makes them resistant to chemotherapy. Venetoclax binds to this protein, which helps kill the cancerous lymphocytes in blood and bone marrow.

Venetoclax is used to treat chronic lymphocytic leukemia (CLL) in adults with 17p deletion. Venetoclax is used only if you have a specific genetic marker, for which your doctor will test.

Venetoclax is usually given after at least one other cancer medicine has been tried without success.

Venetoclax may also be used for purposes not listed in this medication guide.

Many drugs can interact with venetoclax, and some drugs should not be used together. Tell your doctor about all medicines you use. Do not start or stop using any medicine without asking your doctor.

You should not use venetoclax if you are allergic to it.

Some medicines can interact with venetoclax and should not be used at the same time. Your doctor may need to change your treatment plan if you use any of the following drugs:

• imatinib;
• isoniazid;
• nefazodone;
• an antibiotic--clarithromycin, telithromycin;
• antifungal medicine--itraconazole, ketoconazole, posaconazole, voriconazole;
• heart medication--nicardipine, quinidine; or
• antiviral medicine to treat hepatitis C or HIV/AIDS--atazanavir, boceprevir, cobicistat, delavirdine, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, telaprevir.

Tell your doctor about all medicines you use. Do not start or stop using any medicine without asking your doctor.

To make sure venetoclax is safe for you, tell your doctor if you have:

• liver or kidney disease;
• an electrolyte imbalance (such as low levels of potassium or calcium in your blood);
• gout, or high levels of uric acid in your blood; or
• if you are scheduled to receive any vaccinations.

Do not use venetoclax if you are pregnant. It could harm the unborn baby or cause birth defects. You may need to have a negative pregnancy test before starting this treatment. Tell your doctor right away if you become pregnant while taking venetoclax. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 30 days after your last dose.

This medicine may affect fertility (ability to have children) in men. Talk to your doctor if you are concerned about this risk.

It is not known whether venetoclax passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• signs of pneumonia--cough with yellow or green mucus, stabbing chest pain, wheezing, trouble breathing;
• low blood cell counts--fever, chills, flu-like symptoms, swollen gums, mouth sores, skin sores, pale or yellowed skin, dark colored urine, confusion or weakness; or
• signs of tumor cell breakdown--fever, chills, joint or muscle pain, feeling tired or short of breath, fast or slow heartbeats, confusion, nausea, vomiting, dark or cloudy urine, or seizure (convulsions).

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects may include:

• nausea, diarrhea;
• feeling tired;
• easy bruising, unusual bleeding; or
• cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• signs of pneumonia--cough with yellow or green mucus, stabbing chest pain, wheezing, trouble breathing;

• low blood cell counts--fever, chills, flu-like symptoms, swollen gums, mouth sores, skin sores, pale or yellowed skin, dark colored urine, confusion or weakness; or

• signs of tumor cell breakdown--fever, chills, joint or muscle pain, feeling tired or short of breath, fast or slow heartbeats, confusion, nausea, vomiting, dark or cloudy urine, or seizure (convulsions).

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects may include:

• nausea, diarrhea;

• feeling tired;

• easy bruising, unusual bleeding; or

• cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Many drugs can interact with venetoclax. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• aprepitant;

• cimetidine;

• cyclosporine;

• haloperidol;

• imatinib;

• St. John's wort;

• warfarin (Coumadin, Jantoven);

• an antibiotic--azithromycin, ciprofloxacin, clarithromycin, doxycycline, erythromycin, metronidazole, norfloxacin, rifampin, tetracycline;

• antifungal medicine--clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole;

• an antidepressant--desipramine, sertraline;

• heart or blood pressure medicine--amiodarone, captopril, carvedilol, diltiazem, dronedarone, felodipine, lidocaine, quinidine, ranolazine, verapamil; or

• HIV/AIDS medicine--lopinavir with ritonavir.

This list is not complete and many other drugs can interact with venetoclax. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Absorption

Bioavailability

Exhibits linear pharmacokinetics over the dose range of 150–800 mg.1 7

Following oral administration under fed conditions, peak plasma concentrations are attained in 5–8 hours.1 7

Food

Oral administration with a low-fat or high-fat meal increases AUC by 3.4- and 5.2-fold, respectively.1 6

Special Populations

In patients with mild or moderate hepatic impairment, systemic exposure similar to that in patients with normal hepatic function.1 Pharmacokinetics not studied in patients with severe hepatic impairment.1

In patients with mild or moderate renal impairment, systemic exposure similar to that in patients with normal renal function.1 Pharmacokinetics not studied in patients with severe renal impairment or those requiring dialysis.1

Distribution

Extent

Not known whether distributed into milk.1

Plasma Protein Binding

>99%.1

Elimination

Metabolism

Metabolized principally by CYP3A4/5 to the major metabolite, M27.1

Elimination Route

Eliminated in feces (99.9%) and urine (<0.1%) within 9 days.1

Half-life

Mean terminal half-life approximately 26 hours.1 8

Special Populations

Age (range: 25–88 years), gender, race, and body weight do not substantially affect clearance of venetoclax.1 8

Venetoclax is used to treat chronic lymphocytic leukemia (CLL) in patients who have received at least one prior treatment. It interferes with the growth of cancer cells, which are eventually destroyed by the body. Venetoclax is an antineoplastic agent (cancer medicine).

venetoclax is available only with your doctor's prescription.

Take venetoclax exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Do not change your dose or stop taking venetoclax, unless you are told to do so by your doctor.

venetoclax comes with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Take venetoclax with food and water at the same time each day. Swallow the tablet whole. Do not break, crush, or chew it.

Drink plenty of water each day to help prevent an unwanted effect called tumor lysis syndrome.

Do not eat grapefruit products, starfruit, or Seville oranges with venetoclax.

Dosing

The dose of venetoclax will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of venetoclax. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For chronic lymphocytic leukemia:
    • Adults—At first, 20 milligrams (mg) once a day. Your doctor will gradually increase your dose each week. However, the dose is usually not more than 400 mg per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of venetoclax, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose and it is less than 8 hours after your normal time, take it as soon as you can and continue with your normal schedule. If it is more than 8 hours after your normal time, skip the missed dose and continue with a normal dosing schedule.

If you vomit after taking a dose, do not take an extra dose. Take the next dose at the usual time the following day.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep the Starting Pack tablets in the original package. Do not transfer the medicine to a pillbox or another container.

It is very important that your doctor check your progress at regular visits while you are using venetoclax. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it. Blood and urine tests may be needed to check for unwanted effects.

Using venetoclax while you are pregnant can harm your unborn baby. Women must have a negative pregnancy test before starting venetoclax. Use an effective form of birth control during treatment and for at least 30 days after the last dose to prevent pregnancy. If you think you have become pregnant while taking venetoclax, tell your doctor right away.

Do not use venetoclax together with clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, posaconazole, ritonavir, telaprevir, and voriconazole. Using these medicines together may cause serious unwanted effects.

venetoclax may cause a serious type of reaction called tumor lysis syndrome. Your doctor may give you a medicine to help prevent this. Call your doctor right away if you have a decrease or change in urine amount, joint pain, stiffness, or swelling, lower back, side, or stomach pain, a rapid weight gain, swelling of the feet or lower legs, or unusual tiredness or weakness.

Check with your doctor if you have symptoms of an infection such as a fever, chills, or sore throat. venetoclax may decrease the amount of white blood cells in the blood. White blood cells help your immune system fight infections.

While you are being treated with venetoclax, and after you stop treatment with it, do not have any immunizations (vaccines) without your doctor's approval. Venetoclax may lower your body's resistance and the vaccine may not work as well or you might get the infection the vaccine is meant to prevent. In addition, you should not be around other persons living in your household who receive live virus vaccines because there is a chance they could pass the virus on to you. Some examples of live vaccines include measles, mumps, influenza (nasal flu vaccine), poliovirus (oral form), rotavirus, and rubella. Do not get close to them and do not stay in the same room with them for very long. If you have questions about this, talk to your doctor.

Talk with your doctor before using venetoclax if you plan to have children. Some men who use venetoclax may become infertile (unable to have children).

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

• Tell all of your health care providers that you take venetoclax. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Other drugs will be given with this medicine to help avoid side effects.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• If you have upset stomach, throwing up, loose stools (diarrhea), or are not hungry, talk with your doctor. There may be ways to lower these side effects.
• Talk with your doctor before getting any vaccines. Use with venetoclax may either raise the chance of an infection or make the vaccine not work as well.
• Avoid grapefruit and grapefruit juice, Seville oranges, and starfruit.
• If you are taking warfarin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with this medicine.
• Some drugs may need to be taken at a different time than venetoclax. If you also take digoxin, everolimus, or sirolimus, take it at least 6 hours before you take this medicine. There may also be other drugs as well. Talk with your doctor or pharmacist to find out if your other drugs need to be taken at a different time than venetoclax.
• This medicine may affect being able to father a child. Talk with the doctor.
• If you are able to get pregnant, a pregnancy test will be done to show that you are NOT pregnant before starting this medicine. Talk with your doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust to prevent pregnancy while taking venetoclax and for 1 month after stopping this medicine.
• If you get pregnant while taking venetoclax or within 1 month after your last dose, call your doctor right away.

• 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.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time venetoclax is refilled. If you have any questions about this medicine, please talk with the doctor, 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 venetoclax 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 this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to venetoclax. 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 this medicine.

Review Date: October 4, 2017

(ven ET oh klax)

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Venclexta: 10 mg, 50 mg, 100 mg

Tablet Therapy Pack, Oral:

Venclexta Starting Pack: Week 1: 10 mg (14); Week 2: 50 mg (7); Week 3: 100 mg (7); Week 4: 100 mg (14) (42 ea)

Oral: Administer with a meal and water at approximately the same time each day. Swallow whole; do not crush, chew, or break.

Missed or vomited doses: If a dose is missed and it is within 8 hours of the missed usual dosing time, administer the missed dose as soon as possible and resume the normal daily dosing schedule. If it is more than 8 hours, do not administer the missed dose and resume the usual dosing schedule the next day. If the patient vomits following administration of a dose, no additional doses should be administered that day; the next prescribed dose should be taken at the usual time.

Administration with a low-fat meal increased exposure by ~3.4 fold and administration with a high-fat meal increased exposure by ~5.1 to 5.3 fold, compared to fasting. Avoid grapefruit products, Seville oranges, and Star Fruit.

Based on the mechanism of action and data from animal reproduction studies, venetoclax is expected to cause fetal harm if administered during pregnancy. Females of reproductive potential should have a pregnancy test prior to therapy, and use effective contraception during treatment and for at least 30 days after the final dose. Based on animal data, venetoclax may compromise fertility in males.

-Mild (total bilirubin and AST greater than upper limit of normal [ULN] OR total bilirubin greater than 1.0 to 1.5 x ULN) to Moderate (total bilirubin greater than 1.5 to 3.0 x ULN) Hepatic Impairment: No adjustment recommended.
-Severe Hepatic Impairment (total bilirubin greater than 3.0 x ULN): Data not available; a recommended dose has not been determined.

Safety and efficacy have not been established in pediatric patients.

Consult WARNINGS section for additional precautions.