Ibrutinib – Uses, Dosage, Side Effects, Interaction

Ibrutinib is an orally bioavailable, small-molecule inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon oral administration, ibrutinib binds to and irreversibly inhibits BTK activity, thereby preventing both B-cell activation and B-cell-mediated signaling. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is required for B-cell receptor signaling, plays a key role in B-cell maturation, and is overexpressed in a number of B-cell malignancies. The expression of BTK in tumor cells is also associated with increased proliferation and survival.

Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase that is used in the therapy of refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. Ibrutinib has not been associated with serum enzyme elevations during therapy but has been linked to rare cases of clinically apparent acute liver injury and to the reactivation of hepatitis B.

Ibrutinib is a member of the class of acrylamides that is (3R)-3-[4-amino-3-(4-phenoxy phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine in which the piperidine nitrogen is replaced by an acryloyl group. A selective and covalent inhibitor of the enzyme Bruton’s tyrosine kinase, it is used for the treatment of B-cell malignancies. It has a role as an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor and an antineoplastic agent. It is a pyrazolopyrimidine, an aromatic amine, an aromatic ether, a member of acrylamides, an N-acylpiperidine, and a tertiary carboxamide.

Mechanism of Action

Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). It forms a covalent bond with a cysteine residue in the active site of BTK (Cys481), leading to its inhibition. The inhibition of BTK plays a role in the B-cell receptor signaling and thus, the presence of ibrutinib prevents the phosphorylation of downstream substrates such as PLC-γ.

or

Ibrutinib is a novel oral tyrosine kinase inhibitor that irreversibly binds and inhibits tyrosine-protein kinase BTK (Bruton tyrosine kinase). BTK has been found to be important in the function of B-cell receptor signaling and therefore in the maintenance and expansion of various B-cell malignancies including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Targeting BTK with ibrutinib has been found to be an effective strategy in treating these malignancies. Phase I clinical testing in non-Hodgkin’s lymphomas and CLL showed that the drug was extremely well tolerated with no major dose-limiting toxicities and a 54% overall response rate. Subsequently, two-phase Ib/II studies were performed on patients with CLL, one in relapsed/refractory CLL and one in previously untreated elderly patients with CLL. Both of these studies continued to show good tolerability of the drug and an overall response rate of about 71% with an extended duration of response. Another phase II study using ibrutinib in relapsed/refractory MCL was conducted and also showed that it was well tolerated with an overall response rate of 68% and an extended duration of response. Due to these results, the U.S. Food and Drug Administration granted accelerated approval for ibrutinib in November 2013 for patients with MCL who had received at least one prior therapy and in February 2014 for patients with CLL who had received at least one prior therapy. This review will discuss the preclinical pharmacology, pharmacokinetics, and clinical efficacy to date of ibrutinib in the treatment of CLL and MCL

In vitro studies have shown induction of CLL cell apoptosis even in presence of prosurvival factors. It has also been reported inhibition of CLL cell survival and proliferation as well as an impairment in cell migration and a reduction in the secretion of chemokines such as CCL3 and CCL4. The latter effect has been shown to produce regression in xenograft mouse models. Clinical studies for relapsed/refractory CLL in phases I and II showed an approximate 71% of overall response rate.. In the case of relapsed/refractory mantle cell lymphoma, approximately 70% of the tested patients presented a partial or complete response.. In clinical trials for relapsed/refractory diffuse large B-cell lymphoma, a partial response was found in between 15-20% of the patients studied; while for patients with relapsed/refractory Waldenstrom’s macroglobulinemia, a partial response was observed in over 75% of the patients tested. Finally, for patients with relapsed/refractory follicular lymphoma, a partial to complete response was obtained in approximately 54% of the patients.

Indications

  • Ibrutinib acquired accelerated approval for the treatment of mantle cell lymphoma who have received at least one prior therapy. Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma that develops in the outer edge of a lymph node. MCL is usually diagnosed at late stages and it is easily spread into bone marrow, spleen, liver, and gastrointestinal tract. Ibrutinib is indicated for the treatment of chronic lymphocytic leukemia (CLL) who have at least one prior therapy. CLL is a type of cancer caused by an overproduction of lymphocytes in the bone marrow. Some of the symptoms include swollen lymph nodes and tiredness. Ibrutinib is indicated for the treatment of chronic lymphocytic leukemia (CLL) with 17p deletion. CLL with 17p is a type of leukemia in which a deletion in 17p disrupts the tumor suppressor p53 by deleting one allele of the TP53 gene. The remaining allele is mainly inactivated and thus, this type of leukemia is unresponsive to p53-dependent treatments. Ibrutinib is indicated for the treatment of patients with Waldenstrom’s Macroglobulinemia (WM). WM, also called lymphoplasmacytic lymphoma, is a type of non-Hodgkin lymphoma in which the cancer cells make large amounts of macroglobulin. Macroglobulin is a monoclonal protein that corresponds to the type of IgM antibodies and the unrestricted formation of this protein causes typical symptoms such as excessive bleeding and affects vision and the nervous system.
  • Ibrutinib is an antineoplastic agent used to treat chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom’s Macroglobulinemia.
  • IMBRUVICA as a single agent is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).
  • IMBRUVICA as a single agent or in combination with rituximab or obinutuzumab or venetoclax is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukemia (CLL) (see section 5. 1).
  • IMBRUVICA as a single agent or in combination with bendamustine and rituximab (BR) is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.
  • IMBRUVICA as a single agent is indicated for the treatment of adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemoimmunotherapy. IMBRUVICA in combination with rituximab is indicated for the treatment of adult patients with WM.
  • Treatment of chronic Graft versus Host Disease (cGvHD)
  • Treatment of lymphoplasmacytic lymphoma
  • Treatment of mantle cell lymphoma
  • Treatment of mature B-cell neoplasms
  • Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase that is used in the therapy of refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma.
  • Ibrutinib is indicated for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic graft versus host disease (cGVHD)

Contraindications

  • Severe myelosuppression including neutropenia, thrombocytopenia, and anemia has been reported in patients who received ibrutinib. Monitor complete blood counts monthly. A dosage adjustment or therapy discontinuation may be necessary for patients who develop hematologic toxicity.
  • a bad infection
  • anemia
  • an increased risk of bleeding
  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • high blood pressure
  • rapid ventricular heartbeat
  • atrial fibrillation
  • atrial flutter
  • chronic heart failure
  • a stroke
  • bleeding
  • liver problems
  • recent operation
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • lung tissue problem
  • progressive multifocal leukoencephalopathy, a type of brain infection
  • Child-Pugh class A liver impairment
  • Child-Pugh class B liver impairment
    Child-Pugh class C liver impairment

Dosage

Strengths: 70 mg/mL; 140 mg; 70 mg; 280 mg; 420 mg; 560 mg

Lymphoma

  • 560 mg orally once a day
  • Therapy should be continued until the disease progresses or unacceptable toxicity.
  • For the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy
  • For the treatment of adult patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy

Chronic Lymphocytic Leukemia

  • 420 mg orally once a day
  • Therapy should be continued until disease progresses or unacceptable toxicity.
  • This drug can be administered as a single agent, in combination with rituximab or obinutuzumab, or in combination with bendamustine and rituximab.
  • When administering in combination with rituximab or obinutuzumab, consider administering this drug prior to rituximab or obinutuzumab when given on the same day.
  • For the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
  • For the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with 17p deletion

Non-Hodgkin’s Lymphoma

  • 420 mg orally once a day
  • Therapy for Waldenstrom’s Macroglobulinemia (WM) should be continued until disease progression or unacceptable toxicity.
  • When used for WM, this drug can be administered as a single agent or in combination with rituximab.
  • Therapy for cGVHD should be continued until disease progression, recurrence of an underlying malignancy, or unacceptable toxicity
  • For the treatment of adult patients with Waldenstrom’s macroglobulinemia (WM)
  • For the treatment of adult patients with chronic graft-versus-host disease (cGVHD) after the failure of one or more lines of systemic therapy

Graft Versus Host Disease

  • 420 mg orally once a day
  • Therapy for Waldenstrom’s Macroglobulinemia (WM) should be continued until disease progression or unacceptable toxicity.
  • When used for WM, this drug can be administered as a single agent or in combination with rituximab.
  • Therapy for cGVHD should be continued until disease progression, recurrence of an underlying malignancy, or unacceptable toxicity
  • For the treatment of adult patients with Waldenstrom’s macroglobulinemia (WM)
  • For the treatment of adult patients with chronic graft-versus-host disease (cGVHD) after the failure of one or more lines of systemic therapy

Renal Dose Adjustments

  • Mild or moderate renal impairment (CrCl 25 mL/min or greater): No adjustment is recommended.
  • Severe renal impairment (CrCl less than 25 mL/min): Data not available

Liver Dose Adjustments

  • Mild hepatic impairment (Child-Pugh A): 140 mg orally daily
  • Moderate hepatic impairment (Child-Pugh B): 70 mg orally daily
  • Severe hepatic impairment (Child-Pugh C): Not recommended.

Dose Adjustments

ADVERSE REACTIONS:

  • Interrupt therapy for any Grade 3 or greater nonhematologic toxicity, Grade 3 or greater neutropenia with infection or fever, or Grade 4 hematological toxicity. -When toxicity has resolved to Grade 1 or baseline, therapy may be reinitiated at the starting dose.
  • If toxicity reoccurs, reduce the dose by 140 mg per day.
  • A second reduction of the dose by 140 mg may be considered if needed.
  • If toxicity persists or recurs following 2 dose reductions, discontinue therapy.

DOSE MODIFICATION FOR MCL AND MZL AFTER RECOVERY (Starting Dose = 560 mg):

  • The first occurrence of toxicity: Restart at 560 mg daily
  • The second occurrence of toxicity: Restart at 420 mg daily
  • The third occurrence of toxicity: Restart at 280 mg daily
  • The fourth occurrence of toxicity: Discontinue therapy

DOSE MODIFICATION FOR CLL/SLL, WM, AND CGVHD AFTER RECOVERY (Starting Dose = 420 mg):

  • The first occurrence of toxicity: Restart at 420 mg daily
  • The second occurrence of toxicity: Restart at 280 mg daily
  • The third occurrence of toxicity: Restart at 140 mg daily
  • The fourth occurrence of toxicity: Discontinue therapy

CONCOMITANT USE WITH CYP450 3A4 INHIBITORS:
PATIENTS WITH B-CELL MALIGNANCIES:

  • Concomitant administration of moderate CYP450 3A inhibitor: Administer 280 mg orally once daily; modify dose as recommended
  • Voriconazole 200 mg orally twice daily or posaconazole suspension 100 mg orally once daily, 100 mg orally twice daily, or 200 mg orally twice daily: Administer 140 mg orally once daily; modify dose as recommended
  • Posaconazole suspension 200 mg orally 3 times daily or 400 mg orally 2 times daily or posaconazole 300 mg IV once daily or posaconazole delayed-release tablets 300 mg orally once daily: Administer 70 mg orally once daily
  • Other strong CYP450 3A inhibitors: Avoid concomitant use; if these inhibitors will be used short-term (such as anti-infectives for 7 days or less): Interrupt therapy

PATIENTS WITH CHRONIC GRAFT VERSUS HOST DISEASE:

  • Concomitant administration of moderate CYP450 3A Inhibitor: Administer usual dose (420 mg orally once a day); modify dose as recommended.
  • Concomitant administration of voriconazole 200 mg orally 2 times a day or posaconazole suspension 100 mg orally once daily, 100 mg orally twice daily, or 200 mg orally twice daily: Administer 280 mg orally once daily; modify dose as recommended.
  • Concomitant administration of posaconazole suspension 200 mg orally 3 times daily or 400 mg orally 2 times daily or posaconazole 300 mg IV once daily or posaconazole delayed-release tablets 300 mg orally once daily: Administer 140 mg orally once daily; interrupt dose as recommended
  • Other strong CYP450 3A inhibitors: Avoid concomitant use; if these inhibitors will be used short-term (such as anti-infectives for 7 days or less): Interrupt therapy
  • After discontinuation of a CYP450 3A inhibitor, resume the previous dose of this drug.
  • Administer this drug at approximately the same time each day.
  • Instruct patients to swallow capsules or tablets whole with water, and not to open, break, or chew the capsules. Do not cut, crush, or chew the tablets.
  • Instruct the patient that this drug must not be taken with grapefruit juice or Seville oranges.
  • Administer a missed dose as soon as possible on the same day with a return to the normal dosing schedule the following day; do not administer extra doses to make up for the missed dose.

Side Effects

The Most Common

  • diarrhea
  • nausea
  • constipation
  • vomiting
  • stomach pain
  • heartburn or indigestion
  • decreased appetite
  • excessive tiredness or weakness
  • muscle, bone, and joint pain
  • muscle spasms
  • swelling of the hands, feet, ankles, or lower legs
  • rash
  • itching
  • sores in the mouth and throat
  • anxiety
  • difficulty falling asleep or staying asleep
  • cough, runny or stuffed nose
  • blurred vision
  • dry or watery eyes
  • pink eye
  • swelling of the face, throat, tongue, lips, and eyes
  • difficulty swallowing or breathing
  • hives
  • unusual bruising or bleeding
  • pink, red, or dark brown urine
  • bloody or black, tarry stools
  • nose bleeding
  • bloody vomit; or vomiting blood or brown material that resembles coffee grounds
  • seizures
  • fast or irregular heartbeat
  • shortness of breath
  • chest discomfort
  • dizziness, lightheadedness or feeling faint
  • vision changes
  • headache (that lasts a long time)
  • fever, chills, cough, red, warm skin, or other signs of infection
  • confusion
  • changes in your speech
  • decreased urination
  • painful, frequent, or urgent urination

More common

  • Back pain
  • bladder pain
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • bloody or black, tarry stools
  • bloody or cloudy urine
  • blurred vision
  • body aches or pain
  • chest pain or tightness
  • chills
  • confusion
  • cough
  • decreased frequency or amount of urine
  • difficult, burning, or painful urination
  • dizziness or lightheadedness
  • drowsiness
  • dry mouth
  • fainting
  • fast or irregular heartbeat
  • fever
  • frequent urge to urinate
  • headache
  • hoarseness
  • increased thirst
  • irregular heartbeat
  • itching
  • loss of appetite
  • lower back or side pain
  • nausea
  • rapid weight gain
  • seizures
  • severe headache
  • severe stomach pain
  • sore throat
  • tingling of the hands or feet
  • trouble breathing
  • ulcers, sores, or white spots in the mouth
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • unusual weight gain or loss
  • vomiting
  • vomiting of blood or material that looks like coffee grounds
  • wrinkled skin

Rare

  • Persistent non-healing sore
  • pink skin growth
  • reddish skin patch or irritated area
  • shiny skin bump
  • white, yellow or waxy scar-like area on the skin
  • Blistering, peeling, or loosening of the skin
  • dark urine
  • diarrhea
  • dilated neck veins
  • difficulty swallowing
  • a general feeling of tiredness or weakness
  • hives, skin rash
  • joint pain, stiffness, or swelling
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals
  • light-colored stools
  • muscle pain
  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
  • red skin lesions, often with a purple center
  • red, irritated eyes
  • yellow eyes or skin

Drug Interaction

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Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: Not Assigned

Pregnancy

This drug is a kinase inhibitor and can cause fetal harm based on findings from animal studies. Administration to pregnant animals during organogenesis at exposures up to 2 to 20 times the recommended human dose caused embryofetal toxicity including structural abnormalities. This drug should not be used during pregnancy unless the benefit outweighs the risk to the fetus. Advise females of reproductive potential and male patients to use effective contraceptive measures during therapy and for 1 to 3 months after. Females taking hormonal contraception should add a barrier contraceptive method as it is currently unknown whether this drug reduces the effectiveness of hormonal contraceptives. Male patients should not donate sperm during therapy and for 1 to 3 months after. Verify the pregnancy status of females of reproductive potential prior to initiating therapy. The time following treatment with this drug when it is safe to become pregnant is unknown.

Lactation

No information is available on the clinical use of ibrutinib during breastfeeding. Because ibrutinib is more than 97% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during ibrutinib therapy and for 1 week after the last dose.

How should this medicine be used?

Ibrutinib comes as a capsule and a tablet to take by mouth. It is usually taken once daily. Take ibrutinib 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 ibrutinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsules whole with a glass of water; do not open, break, or chew them. Swallow the tablets whole with a glass of water; do not cut, crush or chew them.

If you are receiving an obinutuzumab (Gazyva) injection or rituximab (Rituxan) injection, your doctor may tell you to take your dose of ibrutinib before you receive your injection.

Your doctor may decrease your dose, or interrupt or discontinue your treatment. This depends on how well the medication works for you and the side effects you experience. Talk to your doctor about how you are feeling during your treatment. Continue to take ibrutinib even if you feel well. Do not stop taking ibrutinib without talking to your doctor. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

How should I take ibrutinib tablets and capsules

  • Swallow ibrutinib capsules or tablets whole with a glass of water.
  • Do not open, break, or chew the capsules.
  • Do not cut, crush, or chew the tablets.

How should I take ibrutinib oral suspension

  • Follow the Instructions for Use that comes with your oral suspension for information about the correct way to give a dose to your child. If you have questions about how to give this medication, talk to your healthcare provider or call 1-877-877-3536.
    • Each oral suspension carton contains:
      • 1 bottle of the medication with pre-inserted bottle adapter. Do not remove the bottle adapter
      • 2 reusable 3 mL oral dosing syringes (called ‘syringe’ in this Instructions for Use) measuring in 0.1 mL increments.
      • Only use the syringes that come with your medication. Do not use the syringes for other patients or with other medicines.
      • If you cannot read the markings on the syringes, throw them away and call 1-877-877-3536 to get new ones.
    • Preparing and giving a dose of ibrutinib oral suspension
      • Step 1: Gather and check supplies
        • Check your child’s prescribed dose in milliliters (mLs). Find this mL marking on the syringe.
        • If the dose is more than the marking on the syringe, split the dose between syringes as prescribed.
        • Gather bottle and syringe(s).
        • Check the bottle and make sure that it is the correct medication and the printed on it and the expiration date (“EXP”) has not passed.
        • Do not use if the expiration date has passed or the carton seal has been tampered with
      • Step 2: Record or check discard date
        • When opening the bottle for the first time, record the date that is 60 days from the day the bottle is opened underneath the words “Discard Date. Use within 60 days of opening.
      • Step 3: Shake bottle before each use
      • Step 4: Remove cap from bottle
        • Press down and twist the cap counterclockwise to remove it from the bottle.
        • If there is fluid on top of the adapter you may wipe it with clean disposable tissue.
        • Do not remove the bottle adapter.
      • Step 5: Attach syringe to bottle
        • Make sure the syringe is clean and dry before use.
        • Push the plunger down all the way.
        • Gently insert tip of the syringe into the adapter.
        • Turn the assembled bottle and syringe upside down.
      • Step 6: Fill syringe
        • Slowly pull the syringe plunger down, past the number of mLs for your prescribed dose.
        • Check for air bubbles and proceed to Step 7 for instructions on how to remove air bubbles.
      • Step 7: Remove air bubbles and adjust to the prescribed dose (mL)
        • Hold the syringe and tap the sides to send bubbles to the tip.
        • With the syringe attached to the bottle, push the plunger up to remove the air bubbles from the top.
        • After the bubbles are removed, push the plunger up until the top of the colored plunger is even with the markings on the syringe for the dose.
        • Air bubbles must be removed to ensure the correct dose. Repeat steps 6 and 7 if any air bubbles remain.
      • Step 8: Remove syringe from bottle
        • Turn the assembled bottle upright.
        • Hold the middle of the syringe and carefully remove it from the bottle.
        • Place the bottle aside.
        • Do not touch the plunger of the syringe to avoid accidentally spilling the medicine before you are ready.
        • Note: If more than 1 syringe is needed to give the full dose, repeat steps 5 to 8 with the second syringe to complete the prescribed dose.
      • Step 9: Give ibrutinib oral suspension
        • Place the tip of the syringe along the inside of your child’s cheek.
        • Slowly push the plunger all the way in to give the entire dose.
        • Repeat with second syringe if needed to complete the prescribed dose.
        • Note: this medication must be given as soon as possible after being drawn from the bottle.
        • Note: Make sure your child drinks water after swallowing the dose of medicine.
      • Step 10: Recap bottle
        • Place the cap back on the bottle.
        • Make sure the bottle is tightly closed between each use.
      • Step 11: Rinse syringe
        • Remove plunger from the syringe, rinse only with water and air dry.
        • Store the syringe in a clean, dry place.
        • Do not clean the syringe with soap or in the dishwasher.

What special precautions should I follow?

Before taking ibrutinib,

  • tell your doctor and pharmacist if you are allergic to ibrutinib, any other medications, or any of the ingredients in ibrutinib capsules or tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin, Jantoven); antifungals such as fluconazole (Diflucan), itraconazole (Onmel, Sporanox), ketoconazole (Nizoral), posaconazole (Noxafil), and voriconazole (Vfend); antiplatelet medications such as clopidogrel (Plavix), prasugrel (Effient), ticagrelor (Brilinta), and ticlopidine; aprepitant (Emend); carbamazepine (Carbatrol, Epitol, Tegretol, Teril); clarithromycin (Biaxin, Prevpac), digoxin (Lanoxin); diltiazem (Cardizem, Cartia, Tiazac, others); erythromycin (E.E.S., Erythrocin, others), certain medications to treat human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) such as efavirenz (Sustiva, in Atripla), indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), and saquinavir (Invirase); methotrexate (Otrexup, Rasuvo, Trexall, Xatmep); nefazodone; phenytoin (Dilantin, Phenytek); rifampin (Rifadin, Rifamate, Rimactane, others); verapamil (Calan, Covera, in Tarka, others); and telithromycin (no longer available in the U.S.; Ketek). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor what herbal products you are taking, especially St. John’s Wort.
  • tell your doctor if you have an infection or recently had surgery. Also tell your doctor if you smoke or if you have or have ever had diabetes, an irregular heartbeat, hypertension (high blood pressure), high cholesterol, bleeding problems, or heart, kidney, or liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, are breast-feeding, or if you plan on fathering a child. You should not become pregnant while you are taking ibrutinib. If you are female, you will need to take a pregnancy test before you start treatment and should use birth control to prevent pregnancy during your treatment with ibrutinib and for 1 month after you stop taking the medication. If you are male, you and your female partner should use birth control during your treatment with ibrutinib and continue for 1 month after your final dose. If you or your partner become pregnant while taking ibrutinib, call your doctor immediately. Ibrutinib can cause fetal harm.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking ibrutinib. Your doctor may tell you to stop taking ibrutinib 3 to 7 days before the surgery or procedure.

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    Ibrutinib
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    Ibrutinib
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    Ibrutinib
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  22. https://www.cancer.gov/policies/copyright-reuse
    https://ncithesaurus.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C81934
    https://ncit.nci.nih.gov
  23. http://www.ebi.ac.uk/Information/termsofuse.html
    https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL1873475/
    ChEMBL Protein Target Tree
    https://www.ebi.ac.uk/chembl/g/#browse/targets
  24. https://www.chemicalprobes.org/ibrutinib
  25. http://ctdbase.org/about/legal.jsp
    ibrutinib
    https://ctdbase.org/detail.go?type=chem&acc=C551803
  26. http://www.dgidb.org/downloads
    IBRUTINIB
    https://www.dgidb.org/drugs/IBRUTINIB
  27. https://www.guidetopharmacology.org/about.jsp#license
    ibrutinib
    https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6912
    https://www.guidetopharmacology.org/targets.jsp
  28. Therapeutic Target Database (TTD)
    Ibrutinib
    http://idrblab.net/ttd/data/drug/details/D09KTS
  29. https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
    https://clinicaltrials.gov/
  30. DailyMed
    LICENSE
    https://www.nlm.nih.gov/copyright.html
    IBRUTINIB
    https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=IBRUTINIB
  31. Nature Chemical Biology
    https://pubchem.ncbi.nlm.nih.gov/substance/184611713
    https://pubchem.ncbi.nlm.nih.gov/substance/376241258
  32. https://www.ema.europa.eu/en/about-us/legal-notice
    Imbruvica (EMEA/H/C/003791)
    https://www.ema.europa.eu/en/medicines/human/EPAR/imbruvica
    Ibrutinib (P/0421/2019)
    https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-001397-pip04-17-m01
    Ibrutinib (P/0297/2017)
    https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-001397-pip06-17
    Ibrutinib (P/0298/2017)
    https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-001397-pip05-17
    Ibrutinib (P/0271/2014)
    https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-001397-pip02-13
    Ibrutinib (P/0149/2013)
    https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-001397-pip01-12
    Ibrutinib (P/0337/2021)
    https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-001397-pip03-14-m06
  33. Drugs and Lactation Database (LactMed)
    LICENSE
    https://www.nlm.nih.gov/copyright.html
    Ibrutinib
    https://www.ncbi.nlm.nih.gov/books/NBK500851/
  34. EU Clinical Trials Register
    https://www.clinicaltrialsregister.eu/
  35. https://www.fda.gov/about-fda/about-website/website-policies#linking
    https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
  36. https://creativecommons.org/licenses/by/4.0/
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  37. https://www.whocc.no/copyright_disclaimer/
    https://www.whocc.no/atc/
    ATC Code
    https://www.whocc.no/atc_ddd_index/
  38. https://www.fda.gov/about-fda/about-website/website-policies#linking
    IBRUTINIB
    https://www.fda.gov/drugs/drug-approvals-and-databases/national-drug-code-directory
  39. NCI Cancer Drugs
    LICENSE
    https://www.cancer.gov/policies/copyright-reuse
    Ibrutinib
    https://www.cancer.gov/about-cancer/treatment/drugs/ibrutinib
  40. NIPH Clinical Trials Search of Japan
    https://rctportal.niph.go.jp/en/
  41. https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
    ibrutinib
    https://rxnav.nlm.nih.gov/id/rxnorm/1442981
  42. Protein Data Bank in Europe (PDBe)
    http://www.ebi.ac.uk/pdbe-srv/pdbechem/chemicalCompound/show/1E8
  43. PubChem
    https://pubchem.ncbi.nlm.nih.gov
  44. https://www.rcsb.org/pages/policies
    https://www.rcsb.org/
  45. Springer Nature
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=15745&sourceid=33055840-867692601
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=15745&sourceid=33055840-867676031
  46. https://creativecommons.org/licenses/by-nc-nd/4.0/
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=22163&sourceid=33055840-867677981
  47. https://www.who.int/about/who-we-are/publishing-policies/copyright
    https://list.essentialmeds.org/medicines/618
  48. Wikidata
    LICENSE
    CCZero
    https://creativecommons.org/publicdomain/zero/1.0/
    Ibrutinib
    https://www.wikidata.org/wiki/Q5984881
  49. https://www.nlm.nih.gov/copyright.html
    ibrutinib
    https://www.ncbi.nlm.nih.gov/mesh/67551803
    MeSH Tree
    http://www.nlm.nih.gov/mesh/meshhome.html
  50. https://www.kegg.jp/kegg/legal.html
    Therapeutic category of drugs in Japan
    http://www.genome.jp/kegg-bin/get_htext?br08301.keg
    USP drug classification
    http://www.genome.jp/kegg-bin/get_htext?br08302.keg
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
    Drug Groups
    http://www.genome.jp/kegg-bin/get_htext?br08330.keg
    Drug Classes
    http://www.genome.jp/kegg-bin/get_htext?br08332.keg
  51. UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
    GHS Classification Tree
    http://www.unece.org/trans/danger/publi/ghs/ghs_welcome_e.html
  52. PATENTSCOPE (WIPO)
    SID 391370447
    https://pubchem.ncbi.nlm.nih.gov/substance/391370447
  53. NCBI
    https://www.ncbi.nlm.nih.gov/projects/linkout

References