Zanubrutinib - Indications, Side Effects, Dosage, and Precautions

Overview:

Zanubrutinib is a tyrosine kinase inhibitor that is used to treat mantle cell lymphoma (a fast-growing tumor that initiates from immune cells) and other types of malignancies like Waldenstrom's macroglobulinemia (a slow-growing tumor that initiates from white cells of the bone marrow), marginal zone lymphoma (slow growing tumor initiates from the white cells of infection-fighting cells), chronic lymphocytic leukemia (cancer that begins from white cells) or small lymphocytic leukemia (cancer that develops from lymph nodes). Zanubrutinib is available in capsules with 80 mg (milligrams) of Zanubrutinib. It inhibits malignant cell proliferation and decreases further tumor growth. The FDA (Food and Drug Administration) approved Zanubrutinib on November 14, 2019 for treating mantle cell lymphoma.

Indications:

• Zanubrutinib is used to treat mantle cell lymphoma (MCL) in adult patients and patients who have received one previous therapy.

• Waldenstrom's macroglobulinemia.

• Marginal zone lymphoma.

• Chronic lymphocytic leukemia.

• Small lymphocytic leukemia.

How Is the Dosage and Administration?

• Dosage form: Capsule.

• Dosage strength: 80 milligrams.

• Recommended dose: 160 milligrams twice daily or 320 milligrams taken orally daily.

• Dosage modification for hepatic impairment: 80-milligram dosage twice a day.

• Dosage modification for drug interaction: Strong CYP3A for 80 milligrams once daily. For moderate CYP3A, 80 milligrams twice daily.

Warning and Precautions:

• Hemorrhage: The patients treated with Zanubrutinib while suffering from hematological malignancies have been seen with serious hemorrhagic events. Events like intracranial hemorrhage, gastrointestinal hemorrhage, hematuria, hemothorax, petechiae, and purpura. It is also seen that co-administration of Zanubrutinib with an antiplatelet or anticoagulant can increase the risk of hemorrhage.

• Infections: Infections like opportunistic infections or bacterial or viral infections are also seen prevailing in the cases of monotherapy of Zanubrutinib used to treat hematological malignancy. Hepatitis B virus activation and pneumonia also seem to occur.

• Cytopenias: Neutropenia, thrombocytopenia, and anemia are seen after Zanubrutinib treatment. Monitoring the patient with a complete blood count is important.

• Secondary Primary Malignancy: It involves non-skin carcinoma and skin cancers after Zanubrutinib dosage, so skin protection is required.

• Embryo-Fetal Toxicity: As using Zanubrutinib can cause fetal harm, it is not justified to use it in pregnancy.

• Cardiac Arrhythmias: If the patient is seen with atrial fibrillation and atrial flutter, the patient should be managed according to the situation.

Adverse Reactions:

• Neutrophil counts decrease.

• Platelet counts decrease.

• Upper respiratory tract infections.

• White blood cell counts decrease.

• Rashes.

• Bruises.

• Diarrhea.

• Cough.

• Hemoglobin decreases.

Specific Considerations:

• Pregnancy: The patient should avoid taking Zanubrutinib if pregnant. Zanubrutinib can cause fetal harm if taken while pregnant. Although no relevant data is present to determine the particular effects of Zanubrutinib on pregnant women, it can also cause miscarriage or other fetal defects.

• Lactation: Zanubrutinib is not recommended to be taken when the woman is breastfeeding, as it can be excreted in breast milk. So, Zanubrutinib-treated patients cannot breastfeed for at least two weeks after the treatment.

• Reproductive Potentials in Males and Females: Zanubrutinib can cause embryonic or fetal harm if administered during pregnancy or while getting pregnant. Both males and females should avoid getting pregnant while having Zanubrutinib for at least one week after the treatment.

• Pediatric Use: The safety and effectiveness of Zanubrutinib in pediatric patients have not been established, so Zanubrutinib is not recommended for children.

• Geriatric Use: No differences are seen in older or child patients after Zanubrutinib administration in the safety and effectiveness of the drug.

• Hepatic Impairments: Although dosage modification is required in patients with hepatic impairment, the safety has not been justified in severely impaired patients. No dosage adjustment is required in moderately to mildly impaired patients.

• Renal Impairment: No dosage adjustment is required in mildly to moderately impaired patients who are renally impaired, but in severe cases, a dosage adjustment is required.

For Patients:

Why Is Zanubrutinib Prescribed?

Zanubrutinib is mainly used to treat mantle cell lymphoma patients who have already tried treatment with other therapies like chemotherapy. It is even used to treat other slow-growing cancers like Waldenstrom's macroglobulinemia, marginal zone lymphoma, and other types of cancer like chronic lymphocytic leukemia and small lymphocytic lymphoma. It is a kinase inhibitor that works by stopping the proteins that help to signal the cancer cells to multiply, which further helps by blocking the action of the abnormal protein that signals cancer cells to multiply and further stops the spread of cancer cells.

What Is Mantle Cell Lymphoma?

Mantle cell lymphoma (MCL) is one of the uncommon subclasses of non-Hodgkin lymphoma (B-cell type). It is a cancer originating in the lymphatic system. This lymphoma develops because of genetic changes like translocation leading to CCND1 gene (cyclin D1) overexpression. The diagnosis of mantle cell lymphoma is challenging and it often shows aggressive clinical progression.

How Is Zanubrutinib Used?

Zanubrutinib is available in the form of capsules, which are easily taken through the mouth. It is taken once, twice, or without food. Take the medicine as recommended by the doctor, and do not try to take less or more medication than the prescribed dosage. And do not chew, crush, or open the capsule; instead, swallow the whole capsule with a glass of water. Withdraw the Zanubrutinib dose or lessen it after consulting the doctor.

What Are the Precautions Taken While Taking Zanubrutinib?

• The patient should inform the doctor about the allergic reactions due to Zanubrutinib capsules.

• The patient should inform the doctor about any other medications the patient is taking, like vitamins or supplements.

• Inform the doctor if the patient is starting other medications with Zanubrutinib and discuss their effects.

• Informing the doctor about the infection, like hepatitis B or surgery, or other issues like liver damage, irregular heartbeat, high blood pressure, or bleeding problems.

• Informing the doctor about the pregnancy or planning a pregnancy while taking Zanubrutinib needs to be informed to the doctor. The patient must take precautions or take birth control pills if pregnancy occurs and continue for one week after the last dose of Zanubrutinib, as Zanubrutinib can cause fetal harm.

• Inform the doctor if the patient is breastfeeding while taking Zanubrutinib. It is recommended not to breastfeed while taking Zanubrutinib capsules for a minimum of two weeks after the last dose.

• If, in any case, the patient goes for the surgery, then the patient should stop taking the Zanubrutinib dose.

• The patient must be protected from sunlight, as Zanubrutinib can cause skin sensitivity and lead to skin cancer.

What if Someone Forgets the Regularly Scheduled Dose?

If the patient forgets to take the regularly scheduled dose, then have the dose as soon as the patient remembers it, or if the timing for the next dose is near, then go for the next dose and skip the missed dose but do not take the double dose.

What Are the Side Effects of Zanubrutinib?

The side effects of Zanubrutinib are:

• Constipation.

• Diarrhea.

• Nausea.

• Vomiting.

• Cough.

• Muscle or joint pain.

• Rashes.

• Headache.

• Tiredness.

There are a few side effects that need immediate medical attention.

These side effects are:

• Fever.

• Sore throat.

• Cough.

• Chills.

• Signs of infections.

• Frequent urination can be painful.

• Unusual bruising.

• Abnormal bleeding.

• Blood in stools.

• Pink or brown urine.

• Blood vomit.

• Coughing blood.

• Dizziness.

• Weakness.

• Confusion.

• Irregular heartbeat.

• Faintness.

• Shortness of breath.

• Chest pain.

• Palpitation.

• Chances of developing cancer.

How to Store and Dispose of Zanubrutinib?

The storage of Zanubrutinib is done at room temperature, away from areas of excess heat and moisture. It is kept away from the children in a tightly closed container. All medicine is kept out of reach of children with tightly closed caps. And any unneeded medications are disposed of, especially so that no pet, child, or person takes the medicine unknowingly. Instead of flushing the medicine down the toilet, a special take-back program is provided. To learn more about the take-back program, the Food and Drug Administration has provided safe disposal of medicine information on its website.

What to Do if Overdose Occurs?

If the patient suffers from symptoms like troublesome breathing, collapsing, or seizures (uncontrolled muscular contractions), then the patient should be taken under complete medical attention.

For Doctors:

Description:

Zanubrutinib is a tyrosine kinase inhibitor. The chemical name of Zanubrutinib is (S)-7-(1-acryloyl piperidine-4-yl)-2-(4­ phenoxy phenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carboxamide. The empirical formula for Zanubrutinib is C27H29N5O3. It is an off-white powder with a 7.8 pH solution that is saturated in nature. It contains Zanubrutinib and other inactive ingredients such as colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. It has a molecular weight of 471.55 Daltons.

What Are the Clinical Pharmacological Aspects?

Zanubrutinib is Bruton's tyrosine kinase inhibitor. It forms a covalent bond with the active site of BTK and inhibits BTK. BTK works as the signaling molecule for the B-cell antigen receptor and cytokine receptor. BTK activates B-cell proliferation, chemotaxis, and adhesion.

Pharmacodynamics:

• Peripheral Blood Mononuclear Cells and Lymph Nodes: The steady state of peripheral blood mononuclear cells is 100 percent in 24 hours at the dose of 320 mg in B-cell malignancies. And the lymph nodes occupy nearly 94 percent of the area to approve the recommended dose.

• Cardiac Electrophysiology: There is no relevant evaluation of Zanubrutinib on the QT interval, seen above the therapeutic exposure.

Pharmacokinetics:

Zanubrutinib plasma concentration and area under plasma drug concentration can easily increase proportionally with the dosage increase from 40 mg to 320 mg.

• Absorption: The median maximum dose of Zanubrutinib is 2 hours. The studies have suggested no significant effects of foods on the plasma concentration of Zanubrutinib.

• Distribution: The volume of distribution of Zanubrutinib is 537 liters, or 73 (percent). The plasma protein binding of Zanubrutinib is 94 percent, with a blood plasma ratio of 0.7 to 0.8.

• Elimination: The half-life of Zanubrutinib is two to four hours in an oral Zanubrutinib dose of 160 mg or 320 mg. The oral clearance of Zanubrutinib is 128 L/hr or 58 percent.

• Metabolism: Zanubrutininb is metabolized by cytochrome P450 (CYP)34 enzymes.

• Excretion: 87 percent of the dosage is excreted in feces (38 percent), and eight percent in urine.

Drug Interaction:

• CYP3A Inhibitors: When co-administration of CYP3A inhibitors with Zanubrutinib is seen, it increases Zanubrutinib plasma drug concentration.

• CYP3A Inducers: When the co-administration of CYP3A inducers like Rifampicin with Zanubrutinib is done, it decreases the plasma concentration of Zanubrutinib by 92 percent. And if a moderate CYP3A inducer like Efavirenz is co-administered, then the total plasma concentration of Zanubrutinib decreases by 58 percent, and the AUC seems to be 60 percent.

• CYP3A Substrates: When the co-administration of Zanubrutinib with Midazolam, a CYP3A substrate, occurs, the total plasma concentration of Zanubrutinib decreases by 30 percent.

• CYP2C19 Substrates: When co-administration of Zanubrutinib with Omeprazole occurs, plasma concentration decreases by 20 percent, and AUC seems to be 36 percent.

• Other CYP Substrates: No significant differences were seen when Zanubrutinib is co-administered with CYP2C9 substrate like Warfarin.

• Transporter Systems: When the co-administration of Zanubrutinib is seen with Digoxin, then plasma concentration decreases by 34 percent, and AUC decreases by 11 percent. And no changes were observed in plasma concentration when co-administration of the Rosuvastatin with Zanubrutinib occurred.

• Gastric Acid-Reducing Agents: No clinical changes were observed after the administration of gastric acid-reducing agents, like proton pump inhibitors.

• In Vitro Studies: Zanubrutinib can form an inducer of CYP2B6 and CYP2C8 along with a substrate of P-gp.

Nonclinical Toxicology:

• Carcinogenesis: There are no studies related to the carcinogenic effects of Zanubrutinib.

• Mutagenesis: The studies performed on the Ames essay or the chromosomal aberration assay in mammalian cells were not clastogenic or had no mutagenic effects on the mammalian cell or rats.

• Impairment of Fertility: When the male and female combined studies related to fertility were performed in the early embryonic stages of the fetus development on rats with Zanubrutinib 30 to 300 mg/kg/day. Then no effects were seen, but its highest-dosed males (300 mg/kg/day) have shown sperm abnormalities and post-implantation loss.

Clinical Studies:

Mantle Cell Lymphoma:

• BGB-3111-206 was performed as a phase 2, open-labeled, multicenter, single-arm clinical trial with 86 patients already undergoing chemotherapy. Zanubrutinib is given orally at 160 mg twice a day until the patient develops any toxicity. The patients were around 34 to 75 years old, and the maximum was male. The time was nearly 30 months from diagnosis to study. Commonly, regimens were CHOP based (91 %), followed by Rituximab-based (74 %), And patients with extranodal involvement and refractory diseases or blastoid variants of mantle cell lymphoma were also included. The MIPI scores were as low as 58 %, as high as 13%, or as intermediate as 29%.

• BGB-3111-AU-003 was the study for Zanubrutinb, and it was ½ phase, multicenter, open-label, global study with single-arm B-cell malignancies that had 32 patients who were treated with Zanubrutinb and had mantle cell lymphoma. In this study, Zanubrutininb was given at 160 mg twice a day or 320 mg twice a day. The median age of the patients was 70 years, and the majority were males (69 percent)

• The MIPI score was as low as 28 percent, intermediate at 41 percent, and high at 31 percent.

• Results: The overall efficacy results were 84% (74, 91) for BGB-3111-206 and BGB-3111-AU-003 84 percent (67, 95).

• The CR was 59 percent for BGB-3111-206 and 22 percent for BGB-3111-AU-003. The PR for BGB-3111-206 is 24 percent, and for BGB-3111-AU-003 is 62 percent.

Storage and Handling:

Zanubrutinib is supplied in the form of capsules. It comes in a bottle with 120 capsules. It is stored at 20 to 25 degrees Celsius, or 68 to 77 degrees Fahrenheit. But if an excursion occurs, it is permitted to be at 15 to 30 degrees Celsius, or 59 to 86 degrees Fahrenheit.

Patient Counseling Information:

• Hemorrhage: The patient should be acknowledged for the signs and symptoms of severe bleeding after using Zanubrutinib. And also, if the patient is going for any surgery, Zanubrutinib must be stopped as it interrupts the surgery.

• Infections: The patient should be aware of the signs of infection and report to the doctor if it occurs after Zanubrutinib use.

• Cytopenias: The patient's blood tests should be observed, as Zanubrutinib can decrease blood cell counts.

• Secondary Primary Malignancies: The patient should be informed about the other reported malignancies that can occur after Zanubrutinib usage. The use of sun protection is important as it can cause skin sensitivity upon exposure.

• Cardiac Arrhythmias: The patient should be informed about the other symptoms of cardiac irregularities, like shortness of breath, dizziness, fainting, and palpitation. If such symptoms appear, the patient should report to the doctor soon.

• Embryo-Fetal Toxicity: Women patients should avoid pregnancy during the treatment, as Zanubrutinib can cause fetal harm. And avoid pregnancy for at least one week after the last dose.

• Breastfeeding: The patients are also not allowed to breastfeed during the Zanubrutinib treatment for at least two weeks from the last dose.

• Administration: The patient is advised not to chew or crush the capsule but instead to swallow as such with a glass of water. It can be taken with food or without food.

• Missed Dose: Advise the patients to take the missed dose as instructed and never double the dose; if the timing for the next dose is near, then go for the next scheduled dose and miss the skipped dose.

• Drug Interactions: The patient should inform the doctor about all the medication the patient is taking, maybe herbal, vitamins, or all over-the-counter medication.