Venetoclax - Uses, Dosage, Side Effects, Drug Warnings, and Precautions

Overview

Venetoclax is a medication used in combination with other drugs like Rituximab and Obinutuzumab to treat chronic lymphocytic leukemia (CLL). It is a BCL-2 inhibitor and works by inhibiting the restoring apoptosis of chronic lymphocytic leukemia cells. It is available as a 10 mg, 50 mg, and 100 mg film-coated tablet. The U.S Food and Administration (FDA) approved Venetoclax with Rituximab and Obinutuzumab on May 15, 2019, to treat chronic lymphocytic leukemia. The safety of Venetoclax in children is not yet established.

How Does Venetoclax Work?

Venetoclax belongs to a group of drugs known as B-cell lymphoma-2 (BCL-2) inhibitors. It functions by preventing the body from using a certain protein that aids in the survival of cancer cells. As a result, cancer cells are killed.

What Is Venetoclax Used For?

• To treat adult patients with small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL).

• In patients newly diagnosed with acute myeloid leukemia, in combination with drugs Azacitidine, Decitabine, or low-dose Cytarabine, in adults 75 years or older or with comorbidities that hinder the use of intensive induction chemotherapy.

Dosage:

Venetoclax is available as 10 mg, 50 mg, and 100 mg tablets. Venetoclax is initiated at 20 mg for the treatment of CLL. Over the course of five weeks, the dosage must be gradually increased until it reaches the daily amount of 400 mg.

Follow the instructions given by the doctor or pharmacist for administering the drug.

• Venetoclax should be taken orally.

• Administer the drug with a meal and water at about the same time each day.

• Swallow the tablets as a whole.

• Avoid chewing, crushing, or breaking the tablet.

• Missed dose: If a dose of the medication is missed within eight hours of the usual time, take the dose at the earliest and resume the usual daily dosing schedule. If a dose is missed by more than 8 hours, do not take the missed dose and resume the usual dosing schedule the next day.

• Vomited Dose: Do not administer a replacement dose; wait until the next scheduled dose is due.

Warnings:

• Tumor Lysis Syndrome (TLS): A condition where a large number of malignant (cancerous) cells are destroyed within a short span resulting in the release of the contents of the destroyed cells into the blood. Symptoms include diarrhea, nausea, vomiting, increased urine output, blood in urine, seizures, etc. These symptoms have to be reported immediately for necessary medical intervention. Anti-hyperuricemic medication and enough hydration should be taken in advance. As the overall risk rises, implement more extensive measures (intravenous hydration, frequent monitoring, hospitalization).

• Neutropenia: Keep track of blood counts and look for infection symptoms; treat as a doctor prescribes.

• Infections: Keep an eye out for early warning signs and symptoms of infection and treat immediately. Refrain from treating infections of Grade 3 or above until they have cleared up.

• Immunization: Live attenuated vaccines should not be taken before, during, or after treatment with Venetoclax.

• Embryo-Fetal Toxicity: This may be harmful to developing embryos. Mention the potential danger to a fetus to women who may become pregnant and encourage them to utilize reliable contraception while receiving therapy.

For Patients:

What Is Chronic Lymphocytic Leukemia (CLL)?

Chronic Lymphocytic Leukemia is a type of cancer where white blood cells called B-cells multiply out of control. The B-cells are responsible for making antibodies and fighting infections. In some cases, they may become malignant (cancerous). The exact cause of CLL is not known. However, researchers believe that genetics play a role.

Chronic lymphocytic leukemia occurs when the body produces abnormal B-cells. The symptoms of CLL vary depending on how advanced the disease is. Early symptoms include fatigue, fever, weight loss, night sweats, swollen glands, and shortness of breath. Other symptoms include coughing, chest pain, and difficulty swallowing. CLL can lead to complications, including infection, bleeding, organ failure, and others if left untreated.

To diagnose CLL, doctors use tests to check the number of B-cells in the blood and bone marrow. Doctors also look at the size of the spleen and lymph nodes. A CT scan or MRI may also help determine if the disease has spread outside the lymph nodes. The treatment options for CLL depend on the stage of the disease and include chemotherapy, radiation therapy, stem cell transplantation, and targeted therapies.

Learn More About Venetoclax:

What Are the Drug Warnings and Precautions?

Inform the doctor if any of the following conditions are present,

• History of allergy to drugs.

• Have liver diseases, as this may increase the risk for side effects.

• Have any kidney diseases, as this may increase the risk for a side effect known as tumor lysis syndrome.

• If currently on therapy with drugs Itraconazole, Posaconazole, Ketoconazole, or Voriconazole for fungal infections, antibiotic Clarithromycin for bacterial infections, or Ritonavir for HIV infection, as they may interact with the drug leading to adverse effects.

• If an infection is suspected, or the patient has experienced a persistent infection or has experienced recurring infections, the doctor may need to lower the drug dose.

• If a vaccine is due shortly.

Starting Venetoclax:

How Is Venetoclax Given?

The first week of Venetoclax medication will be at a low dose. Over the next four weeks, the doctor will progressively raise the dosage to the full recommended level.

• Initially, 20 mg (two 10 mg pills) once daily for seven days.

• Week 1: The dosage will be increased to 50 mg (one 50 mg tablet).

• Week 2: The dosage will be increased to 100 mg (one 100 mg tablet).

• Week 3: The dosage will be increased to 200 mg (two 100 mg pills) once daily.

• Week 4: The dosage will be increased to 400 mg (four 100 mg pills).

• While undergoing Venetoclax treatment alone, continue taking the recommended amount of 400 mg daily for as long as required.

• Take 400 mg of Venetoclax every day for 24 months if Rituximab is also used as part of the treatment.

• Take 400 mg daily for roughly ten months while receiving Obinutuzumab and Venetoclax therapy.

• Due to possible side effects, the dose may need to be changed. The doctor will suggest the required dose.

How to Take Venetoclax?

• Take the tablets with a meal at around the same time each day.

• Administer with a glass of water, whole.

• Never chew, crack, or crush the tablets.

• Taking the tablets in the morning is preferred to make it easier to follow up with blood tests, if necessary, throughout the first few days or weeks of treatment.

• Do not take an additional drug dose on the same day if the previous dose is vomited. Instead, take the next dose at the regular time the following day. Speak with the doctor regarding any queries regarding drug use.

• Take in a lot of water. At least 1.5 to 2 liters of water should be consumed daily to help the body eliminate cancer cell breakdown components through urine and lower the risk of TLS.

Things to Do After Starting Venetoclax:

Following the initiation of Venetoclax medication, the doctor will keep track of the blood count. A decrease in the white blood cell count can raise the risk of infection. A few symptoms include coughing, pain or a burning sensation when passing urine, fever, chills, weakness or confusion, and feeling weak. There is a chance that some infections could be fatal. Report to the doctor if these symptoms arise.

What Are the Side Effects of Venetoclax?

Adverse effects are quite common with chemotherapy. Report to the doctor if these symptoms are experienced.

Very common :

• Pneumonia

• Fatigue.

• Upper respiratory tract infection.

• Diarrhea.

• Nausea.

• Vomiting.

• Constipation.

• Low blood counts.

• High potassium levels.

• High calcium levels.

• High phosphate levels.

Common :

• Sepsis (severe infection in the blood).

• Febrile neutropenia (low number of white blood cells with fever).

• Urinary tract infection

• High creatinine levels.

• High urea levels.

Dietary Alterations:

Avoid taking grapefruit, starfruit, or their juices while taking Venetoclax, as it may alter the drug's efficacy. The drug should be taken at around the same time each day as instructed by the physician.

What Should Be Done if a Dose Is Missed?

If a dose of the medication is missed within eight hours of the usual time, take the dose as soon as possible and resume the regular daily dosing schedule. If a dose is missed by more than 8 hours, do not take the missed dose and resume the usual dosing schedule the next day.

What Should Be Done to Treat Venetoclax Overdose?

If Venetoclax is taken more than the recommended dosage, immediately report it to the doctor or nurse or contact the emergency department.

How to Store the Venetoclax Tablet?

• There are no unique storage requirements for this medication.

• Keep the drug away from the reach of children and pets.

• Avoid using the medication after the expiration date, noted on the carton and blister.

• Never dispose of medications in wastewater or household garbage. Find out from the pharmacist how to dispose of expired medications. These actions will aid in environmental protection.

Avoid Self-Medication:

Venetoclax is a highly potent medication that impacts cell growth and proliferation and is only available on a doctor's prescription. Consequently, using this drug without a prescription can result in a number of severe side effects. It is not advisable to take this drug on the advice of another patient or with a prescription written for a different patient.

For Doctors:

Indication:

Venetoclax is indicated for treating chronic lymphocytic leukemia (CLL) in adult patients who have 17p deletion and has received at least one prior therapy.

Dosing:

Premedication:

In all patients, initiate with Allopurinol or a xanthine oxidase inhibitor two to three days before taking Venetoclax. If a patient has a significant tumor burden, rasburicase should also be considered if their baseline uric acid level is elevated.

Ramp-Up Dosage:

The ramp-up schedule is as follows:

20 mg orally once daily for the first week, 50 mg once daily for the second week, 100 mg once daily for the third, 200 mg once daily for the fourth, and 400 mg once daily for the fifth week and above.

Adult Dosing:

Monotherapy: 400 mg orally once a day following the conclusion of the 5-week ramp-up regimen or until disease progression or intolerable toxicity.

Other Dosing Considerations:

• Mild, Moderate to Severe Renal Impairment: No specific dosage adjustment is required.

• Mild to Moderate Hepatic Impairment (Child-Pugh A or B): No specific dosage considerations are required.

• Severe Hepatic impairment (Child-Pugh C): Reduce the once-daily dosage by 50 % and monitor for adverse effects.

• Geriatric: No specific recommendations are available.

• Hemodialysis: Dosing information has not been determined.

Hematologic Toxicity in Patients With CLL:

• In patients with Grade 3 neutropenia with infection or fever or Grade 4 toxicities, excluding lymphopenia- resume therapy at the same dosage after a break until resolution to Grade 1 or baseline.

• The risk of tumor lysis syndrome is to be reassessed to see if dosing should be restarted with a lower dosage if it is halted for longer than a week during the ramp-up phase or for longer than two weeks after the ramp-up phase has ended. If a patient requires a dosage reduction to less than 100 mg once daily for more than two weeks, consider stopping the medication.

Non-Hematologic Toxicity:

• Grade 3 or 4: Interrupt therapy until the first episode resolves to Grade 1 or baseline in patients with CLL, then restart at the same dosage.

• With Second And Subsequent Occurrences: Resuming therapy at a lower dosage after a break in treatment till resolution. If the dosage at the time of interruption was 400 mg, start over with 300 mg; if it's 200 mg, start over with 100 mg; if it's 100 mg, start over with 50 mg; if it's 50 mg, start over with 20 mg; and if it's 20 mg, start over with 10 mg. The dose may be required to be reduced further. Continue the reduced dosage during the ramp-up period for a week before raising it.

• Reassess the risk of tumor lysis syndrome to see if dosing should be restarted with a lower dosage if it is halted for longer than a week during the ramp-up phase or for longer than two weeks after the ramp-up phase has ended. If a patient requires a dosage reduction to less than 100 mg once daily for more than two weeks, consider stopping the medication.

Tumor Lysis Syndrome in Patients With CLL:

• If the blood chemistry changes or symptoms point to TLS (tumor lysis syndrome ), then delay the dose for the following day; if symptoms go away in 24 to 48 hours, resume at the same dose. Continue at a lower dose if blood chemistries do not improve after 48 hours or the symptoms stop. If the dosage at the time of interruption was 400 mg, start over with 300 mg; if it's 200 mg, start over with 100 mg; if it's 100 mg, start over with 50 mg; if it's 50 mg, start over with 20 mg; and if it's 20 mg, start over with 10 mg. Continue the reduced dosage during the ramp-up period for a week before raising it.

• Reassess the risk of tumor lysis syndrome to see if dosing should be restarted with a lower dosage if it is halted for longer than a week during the ramp-up phase or for longer than two weeks after the ramp-up phase has ended. If a patient requires a dosage reduction to less than 100 mg once daily for more than two weeks, consider stopping the medication.

Mechanism of Action:

Venetoclax is a BCL-2 inhibitor. Studies indicate that the overexpression of BCL-2 in CLL cells mediates malignant cell survival and has been linked to chemotherapy resistance.

By directly binding to the BCL-2 protein and displacing pro-apoptotic proteins like BIM, causing mitochondrial outer membrane permeabilization, and activating caspases, Venetoclax aids in the restoration of the apoptotic process. Venetoclax has also exhibited cytotoxic effects in tumor cells that overexpress BCL-2 in nonclinical investigations.

Pharmacodynamics:

Cardiac Electrophysiology: In an open-label, single-arm trial involving 176 patients, the impact of several doses of Venetoclax up to 1200 mg once daily on the QTc interval was assessed. The QTc interval was unaffected by Venetoclax, and there was no correlation between exposure to Venetoclax and changes in the QTc interval.

Active Ingredients:

The active ingredient in all the film-coated tablets is Venetoclax.

Inactive Ingredients:

The inactive ingredients in each tablet include,

• Tablet Core: Copovidone, colloidal anhydrous silica, polysorbate 80, anhydrous calcium hydrogen phosphate, sodium stearyl fumarate.

• Film-Coating: Iron oxide yellow, titanium dioxide, polyvinyl alcohol, macrogol 3350, and talc.

Pharmacokinetics:

Absorption:

Maximum plasma concentration of Venetoclax was attained 5 to 8 hours after dosing after several oral administrations under fed conditions. Over the 150 to 800 mg dosing range, the Venetoclax steady-state AUC increased proportionately. Compared to the fasting state, treatment with a low-fat meal raised Venetoclax exposure by around 3.4 times, and administration with a high-fat meal increased Venetoclax exposure by 5.1 to 5.3 times.

Distribution:

The drug is highly bound to human plasma protein, and the mean blood-to-plasma ratio was

estimated to be 0.57.

Metabolism:

Studies conducted in vitro showed that CYP3A4/5 is the primary metabolizer of Venetoclax. M27 was a significant plasma metabolite with a BCL-2 inhibitory activity at least 58-fold lower than Venetoclax in vitro.

Excretion:

Venetoclax is removed from the systemic circulation through hepatic elimination. Twenty-eight percent of the radioactive dose delivered was eliminated in feces as unchanged Venetoclax.

Toxicity:

• Carcinogenicity: No investigations on Venetoclax's carcinogenicity have been reported.

• Mutagenicity: In an in vitro chromosome aberration assay employing human peripheral blood lymphocytes, Venetoclax did not cause any structural or numerical mutations, and at doses up to 835 mg/kg in a mouse bone marrow micronucleus assay, it did not have any clastogenic effects.

• Impairment of Fertility: Based on tests in male and female mice, Venetoclax did not affect estrus cycles, mating, fertility, uterine implants, or live embryos per litter at doses up to 600 mg/kg/day. However, testicular toxicity (loss of germ cells) shown in dogs at doses as low as 0.5 times the human AUC exposure at the advised dose suggests a potential risk to male fertility in humans.

• Animal Toxicology: Venetoclax produced single-cell necrosis in various tissues, including the exocrine pancreas, the stomach, and the gallbladder, in dogs, although there was no sign of any damage to organ function or disruption of tissue integrity. Minimal single-cell necrosis was still visible in some tissues after a 4-week and 4-week recovery period, and longer dosing or recovery times were not tested for reversibility. Additionally, Venetoclax produced increasing white discoloration of the hair coat in dogs after around three months of daily treatment due to loss of melanin pigment.

Warning and Precaution:

• Tumor Lysis Syndrome (TLS): TLS has been reported, including fatal events and renal failure requiring dialysis; it may happen as soon as 6 hours after the first dose and is most likely to occur during the initiation and dose ramp-up phase in all patients as well as during the reinitiation after dosage interruptions in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma; risk is based on tumor burden and type of malignancy and increases with reduced renal function. Evaluate the risk for TLS; prophylactic TLS treatment is advised, as is monitoring; treatment, dosage change, or interruption may be required.

• Hematologic: Monitoring is advised, and treatment, dosage adjustment, or discontinuation may be required. Neutropenia has been recorded and may return with consecutive cycles of medication.

• Immunologic: Serious and fatal infections, including sepsis and pneumonia, have been recorded; monitoring is advised; treatment, therapy cessation, and dose adjustment may be required.

• Reproductive: The drug may cause heam to the fetus. Sexually active women should use effective contraception for treatment at least 30 days after the last dose.

• Concomitant Use: Before, during, or after therapy, avoid giving live attenuated vaccinations until B-cell recovery occurs. Use with grapefruit products, Seville oranges, strong or moderate CYP3A inducers, P-gp substrates, and starfruit should be avoided.

Contraindications:

Venetoclax is contraindicated with potent CYP3A inhibitors simultaneously in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma throughout the first phase of the dosage regimen and during the ramp-up phase.

Dosage Form:

Venetoclax is a round, biconvex, light yellow film-coated tablet debossed with "V" on one side and "dose" on the other.

Clinical Studies:

A study was conducted with 432 individuals with previously untreated CLL and associated medical problems randomized (1:1), open-label, multicenter, actively controlled trial of Venetoclax combined with Obinutuzumab (VEN+G) versus Obinutuzumab combined with Chlorambucil (GClb).

Results:

Progression-free survival (PFS), as determined by an independent review committee, was the primary efficacy endpoint. The experiment showed that patients who received VEN+G compared to those who received GClb had significantly longer PFS. In the trial, rates of minimal residual disease negative (less than one CLL cell per 104 leukocytes) in the bone marrow and peripheral blood showed statistically significant improvements.

Other Specifications:

Venetoclax in Pregnant Women:

No information regarding Venetoclax safety in expectant mothers is available. For at least thirty days following treatment with the drug, women of reproductive age must take a highly effective form of contraception to prevent pregnancy.

Venetoclax in Lactating Women:

It is unknown if the active ingredient in the drug enters breast milk. Hence, advise the patient to avoid breastfeeding while using this medication.

Venetoclax in Pediatric Patients:

The efficacy and safety of the drug are not established in pediatric patients.

Venetoclax in Geriatric Patients:

There were no overall differences between older and younger patients regarding safety and efficacy.

What Are the Drug Interactions of Venetoclax?

The drug interactions of Venetoclax are as listed below:

1. With Other Drugs:

• Aliskiren.

• Amiodarone.

• Aprepitant.

• Atazanavir.

• Belzutifan.

• Betrixaban.

• Bosentan.

• Capmatinib.

• Carbamazepine.

• Carvedilol.

• Ciprofloxacin.

• Colchicine.

• Crizotinib.

• Cyclosporine.

• Dabigatran Etexilate.

• Digoxin.

• Diltiazem.

• Doxorubicin.

• Dronedarone.

• Duvelisib.

• Efavirenz.

• Elagolix.

• Enzalutamide.

• Erythromycin.

• Everolimus.

• Fedratinib.

• Fexinidazole.

• Fexofenadine.

• Flibanserin.

• Fluconazole.

• Fluvoxamine.

• Fosnetupitant.

• Fosphenytoin.

• Glecaprevir.

• Imatinib.

• Ivosidenib.

• Lapatinib.

• Larotrectinib.

• Lasmiditan.

• Lefamulin.

• Letermovir.

• Loperamide.

• Lorlatinib.

• Maraviroc.

• Mitotane.

• Modafinil.

• Nafcillin.

• Naldemedine.

• Netupitant.

• Nilotinib.

• Pacritinib.

• Phenobarbital.

• Phenytoin.

• Pibrentasvir.

• Primidone.

• Quinidine.

• Ranolazine.

• Rifampin.

• Sirolimus.

• St John's Wort.

• Talazoparib.

• Tolvaptan.

• Topotecan.

• Vemurafenib.

• Verapamil.

• Voxilaprevir.

2. With Alcohol: Venetoclax has no serious interaction with alcohol. Only moderate drinking is preferred.

3. With Food: Avoid grapefruit, starfruit, Seville oranges, or their juices due to serious interactions with the drug.