Venclexta

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.

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.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Do not eat grapefruit, starfruit, or Seville oranges (sometimes used in marmalades), or drink grapefruit juice while taking this medication.

Serious side effects have been reported with Venclexta. See the "Drug Precautions" section.

Common side effects of Venclexta include:

• a decrease in blood cell counts
• diarrhea
• nausea
• upper respiratory tract infection
• fatigue

This is not a complete list of Venclexta side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor if you are pregnant or plan to become pregnant.

There are no well-controlled studies that have been done in pregnant women. Based on toxicity observed in mice, Venclexta may harm your unborn baby when administered to pregnant women. If Venclexta is used during pregnancy or if the patient becomes pregnant while taking Venclexta, know there is a potential risk to a fetus.

If you are able to become pregnant, your doctor should do a pregnancy test before you start treatment with Venclexta. It is recommended females who are able to become pregnant use effective birth control during treatment and for 30 days after the last dose of Venclexta. If you become pregnant or think you are pregnant, tell your doctor right away.

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.

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

Take this medicine 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 this medicine, unless you are told to do so by your doctor.

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

Take this medicine 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 this medicine.

Dosing

The dose of this medicine 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 this medicine. 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 this medicine, 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.

• If you have an allergy to Venclexta (venetoclax) or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you take any drugs (prescription or OTC, natural products, vitamins) that must not be taken with Venclexta, like certain drugs that are used for HIV, infections, or seizures. There are many drugs that must not be taken with this medicine.
• If you are taking St. John's wort. Do not take St. John's wort with Venclexta. This medicine may not work as well.
• If you are breast-feeding. Do not breast-feed while you take this medicine.

This is not a list of all drugs or health problems that interact with Venclexta.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Pregnancy

Risk Summary

There are no available human data on the use of Venclexta in pregnant women. Based on toxicity observed in mice, Venclexta may cause fetal harm when administered to pregnant women. In mice, venetoclax was fetotoxic at exposures 1.2 times the human clinical exposure based on AUC at the recommended human dose of 400 mg daily. If Venclexta is used during pregnancy or if the patient becomes pregnant while taking Venclexta, the patient should be apprised of the potential risk to a fetus.

The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal data

In embryo-fetal development studies, venetoclax was administered to pregnant mice and rabbits during the period of organogenesis. In mice, venetoclax was associated with increased post-implantation loss and decreased fetal body weight at 150 mg/kg/day (maternal exposures approximately 1.2 times the human AUC exposure at the recommended dose of 400 mg daily). No teratogenicity was observed in either the mouse or the rabbit.

Lactation

Risk Summary

There are no data on the presence of Venclexta in human milk, the effects of Venclexta on the breastfed child, or the effects of Venclexta on milk production. Because many drugs are excreted in human milk and because the potential for serious adverse reactions in breastfed infants from Venclexta is unknown, advise nursing women to discontinue breastfeeding during treatment with Venclexta.

Females and Males of Reproductive Potential

Venclexta may cause fetal harm [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].

Pregnancy Testing

Females of reproductive potential should undergo pregnancy testing before initiation of Venclexta [see Use in Specific Populations (8.1)].

Contraception

Advise females of reproductive potential to use effective contraception during treatment with Venclexta and for at least 30 days after the last dose [see Use in Specific Populations (8.1)].

Infertility

Based on findings in animals, male fertility may be compromised by treatment with Venclexta [see Nonclinical Toxicology (13.1)].

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

Geriatric Use

Of the 106 patients with previously treated CLL with 17p deletion who were evaluated for efficacy, 57% were ≥65 years of age and 17% were ≥75 years of age.

Of the 240 patients with previously treated CLL evaluated for safety from 3 open-label trials, 58% were ≥65 years of age and 17% were ≥75 years of age.

No overall differences in safety and effectiveness were observed between older and younger patients.

Renal Impairment

Patients with reduced renal function (CrCl <80 mL/min) are at increased risk of TLS. These patients may require more intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with Venclexta [see Dosage and Administration (2.3, 2.4)].

No specific clinical trials have been conducted in subjects with renal impairment. Less than 0.1% of radioactive Venclexta dose was detected in urine. No dose adjustment is needed for patients with mild or moderate renal impairment (CrCl ≥30 mL/min) based on results of the population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. A recommended dose has not been determined for patients with severe renal impairment (CrCl <30 mL/min) or patients on dialysis.

Hepatic Impairment

No specific clinical trials have been conducted in subjects with hepatic impairment, however human mass balance study showed that venetoclax undergoes hepatic elimination. Although no dose adjustment is recommended in patients with mild or moderate hepatic impairment based on results of the population pharmacokinetic analysis [see Clinical Pharmacology (12.3)], a trend for increased adverse events was observed in patients with moderate hepatic impairment; monitor these patients more closely for signs of toxicity during the initiation and dose ramp-up phase. A recommended dose has not been determined for patients with severe hepatic impairment.

Venclexta (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.

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

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

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

Some medicines can interact with Venclexta 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 Venclexta 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 Venclexta 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 Venclexta. 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.