Imbruvica

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

Ibrutinib is used to treat mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and Waldenström macroglobulinemia (WM). It interferes with the growth of cancer cells, which are eventually destroyed by the body. Ibrutinib is an antineoplastic agent (cancer medicine).

This medicine is available only with your doctor's prescription.

This product is available in the following dosage forms:

• Capsule

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aprepitant
• Atazanavir
• Boceprevir
• Carbamazepine
• Clarithromycin
• Cobicistat
• Conivaptan
• Diltiazem
• Dronedarone
• Enzalutamide
• Erythromycin
• Fluconazole
• Fosaprepitant
• Fosphenytoin
• Idelalisib
• Imatinib
• Indinavir
• Itraconazole
• Ketoconazole
• Lopinavir
• Mitotane
• Nefazodone
• Nelfinavir
• Phenytoin
• Posaconazole
• Rifampin
• Ritonavir
• Saquinavir
• St John's Wort
• Telaprevir
• Telithromycin
• Verapamil
• Voriconazole

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take this medicine with a full glass of water. Drink plenty of liquids while you are taking ibrutinib.

Ibrutinib is usually taken once per day until your body no longer responds to the medication. Take the medicine at the same time each day.

Do not crush, chew, break, or open an ibrutinib capsule. Swallow it whole.

If you need surgery or dental work, tell the surgeon or dentist ahead of time that you are using ibrutinib. You may need to stop using the medicine for a short time.

Call your doctor if you have severe or ongoing diarrhea. You can easily become dehydrated while taking ibrutinib.

You may need frequent medical tests to be sure this medicine is not causing harmful effects. Your cancer treatments may be delayed based on the results of these tests.

Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.

Grapefruit and grapefruit juice may interact with ibrutinib and lead to unwanted side effects. Avoid the use of grapefruit products while taking ibrutinib. Also avoid eating Seville oranges and marmalades made with these.

• Selectively and irreversibly inhibits BTK, resulting in inhibition of downstream effector activity within the B-cell antigen receptor (BCR) signaling pathway.1 4 5 6 7

• Inhibits other receptor kinases (e.g., Bmx/Etk, EGFR, Hck, Yes) in vitro.8

• Inhibits proliferation and survival of malignant B-cells in vivo.1

• Demonstrates cell migration and substrate adhesion of CLL cells and mantle cell lymphoma cells in vitro;1 2 mobilization of cells from tissues to peripheral blood results in a transient increase in absolute lymphocyte count in peripheral blood.2 12 13

• Demonstrates substantial activity in activated B-cell-like diffuse B-cell non-Hodgkin's lymphoma (ABC-DLBCL) cells expressing wild-type caspase recruitment domain-containing protein-11 (wild-type CARD-11) in vitro and in vivo.5 6

• Importance of advising patients to take ibrutinib as directed by their clinician and at approximately the same time each day.1 If a dose is missed, importance of administering the missed dose on the same day as soon as it is remembered.1 Patients should be advised not to take 2 doses on the same day to make up for a missed dose.1

• Importance of advising patients to swallow ibrutinib capsules whole with a glass of water and not to open, break, or chew the capsules.1

• Risk of bleeding.1 Importance of promptly informing clinician of any episodes of unusual bleeding (e.g., blood in stool or urine, prolonged or uncontrolled bleeding).1 Importance of notifying clinician before any planned surgeries, including dental procedures.1

• Risk of serious infection.1 Importance of reporting signs or symptoms of possible infection (e.g., chills, fever).1

• Risk of atrial fibrillation.1 Importance of informing clinician if palpitations, lightheadedness, dizziness, fainting, shortness of breath, or chest discomfort occurs.1

• Risk of nephrotoxicity.1

• Possible risk of developing a second primary malignancy (e.g., skin cancer).1

• Risk of tumor lysis syndrome.1 Importance of reporting signs or symptoms of tumor lysis syndrome (e.g., arrhythmia, seizure).1

• Risk of fetal harm.1 Apprise patient of potential hazard to the fetus if used during pregnancy; women of childbearing potential should avoid becoming pregnant.1

• Risk of diarrhea.1 Importance of advising patients to maintain adequate hydration during ibrutinib therapy.1 Importance of informing clinician if diarrhea persists.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.1 Importance of advising patients not to consume grapefruit or Seville oranges.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
• Signs of fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or very bad upset stomach or throwing up.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Dizziness or passing out.
• Chest pain or pressure or a fast heartbeat.
• A heartbeat that does not feel normal.
• Very loose stools (diarrhea).
• Loose stools (diarrhea) that will not go away.
• Feeling very tired or weak.
• Change in color or size of a mole.
• A skin lump or growth.

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.

Dosing Guidelines

Administer Imbruvica orally once daily at approximately the same time each day. Swallow the capsules whole with water. Do not open, break, or chew the capsules.

Dosage

Mantle Cell Lymphoma and Marginal Zone Lymphoma

The recommended dose of Imbruvica for MCL and MZL is 560 mg (four 140 mg capsules) orally once daily until disease progression or unacceptable toxicity.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström's Macroglobulinemia

The recommended dose of Imbruvica for CLL/SLL and WM is 420 mg (three 140 mg capsules) orally once daily until disease progression or unacceptable toxicity.

The recommended dose of Imbruvica for CLL/SLL when used in combination with bendamustine and rituximab (administered every 28 days for up to 6 cycles) is 420 mg (three 140 mg capsules) orally once daily until disease progression or unacceptable toxicity.

Chronic Graft versus Host Disease

The recommended dose of Imbruvica for cGVHD is 420 mg (three 140 mg capsules) orally once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for the treatment of cGVHD, Imbruvica should be discontinued considering the medical assessment of the individual patient.

Dose Modifications for Adverse Reactions

Interrupt Imbruvica therapy for any Grade 3 or greater non-hematological toxicities, Grade 3 or greater neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), Imbruvica therapy may be reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by one capsule (140 mg per day). A second reduction of dose by 140 mg may be considered as needed. If these toxicities persist or recur following two dose reductions, discontinue Imbruvica.

Recommended dose modifications are described below:

Dose Modifications for Use with CYP3A Inhibitors

Recommended dose modifications are described below [see Drug Interactions (7.1)]:

Dose Modifications for Use in Hepatic Impairment

The recommended dose is 140 mg daily for patients with mild hepatic impairment (Child-Pugh class A). Avoid the use of Imbruvica in patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Missed Dose

If a dose of Imbruvica is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. Extra capsules of Imbruvica should not be taken to make up for the missed dose.

There is no specific experience in the management of ibrutinib overdose in patients. One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 1680 mg. Closely monitor patients who ingest more than the recommended dosage and provide appropriate supportive treatment.

Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK). It is a white to off-white solid with the empirical formula C25H24N6O2 and a molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water.

The chemical name for ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the following structure:

Imbruvica (ibrutinib) capsules for oral administration are supplied as white opaque capsules that contain 140 mg ibrutinib as the active ingredient. Each capsule also contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide and black ink. Each white opaque capsule is marked with "ibr 140 mg" in black ink.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with ibrutinib.

Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.

Rats were administered oral daily doses of ibrutinib for 4 weeks prior to pairing and during pairing in males and 2 weeks prior to pairing and during pairing in females. Treatment of female rats continued following pregnancy up to gestation day (GD) 7, and treatment of male rats continued until end of study. No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose [HED] 16 mg/kg).

Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Hemorrhage:
  Inform patients of the possibility of bleeding, and to report any signs or symptoms (severe headache, blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that Imbruvica may need to be interrupted for medical or dental procedures [see Warnings and Precautions (5.1)].
• Infections:
  Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills, weakness, confusion) suggestive of infection [see Warnings and Precautions (5.2)].
• Atrial fibrillation:
  Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions (5.4)].
• Hypertension:
  Inform patients that high blood pressure has occurred in patients taking Imbruvica, which may require treatment with anti-hypertensive therapy [see Warnings and Precautions (5.5].
• Second primary malignancies:
  Inform patients that other malignancies have occurred in patients who have been treated with Imbruvica, including skin cancers and other carcinomas [see Warnings and Precautions (5.6)].
• Tumor lysis syndrome:
  Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.7)].
• Embryo-fetal toxicity:
  Advise women of the potential hazard to a fetus and to avoid becoming pregnant during treatment and for 1 month after the last dose of Imbruvica [see Warnings and Precautions (5.8)].
• Inform patients to take Imbruvica orally once daily according to their physician's instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1)].
• Advise patients that in the event of a missed daily dose of Imbruvica, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.6)].
• Advise patients of the common side effects associated with Imbruvica [see Adverse Reactions (6)]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.
• Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].
• Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration [see Adverse Reactions (6.1)].

Active ingredient made in China.

Distributed and Marketed by:
Pharmacyclics LLC
Sunnyvale, CA USA 94085
and
Marketed by:
Janssen Biotech, Inc.
Horsham, PA USA 19044

Patent http://www.Imbruvica.com
Imbruvica® is a registered trademark owned by Pharmacyclics LLC

© Pharmacyclics LLC 2017
© Janssen Biotech, Inc. 2017