Ibrutinib (eye-broo-ti-nib), which is marketed under the tradename of Imbruvica® in the U.S. and Canada, is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK). Upon oral administration, ibrutinib binds to and irreversibly inhibits the activity of BTK which prevents both B-cell activation and B-cell-mediated signaling. This action leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK is required for B-cell signaling, plays a key role in B-cell maturation, and is overexpressed in a number of B-cell malignancies, including CLL/SLL. The expression of BTK in tumor cells is associated with increased proliferation and survival.
Imbruvica® is supplied as a 140mg capsule with the standard starting dose of 3 capsules (420mg) by mouth once a day. Your medical team may adjust the dose downward depending upon such factors as adverse side effects or if you have known liver failure. At present, there is no recommended dosage adjustment for renal failure patients however the use of ibrutinib in End Stage Renal Disease and dialysis has not been studied.
Ibrutinib can be used as a sole agent or in combination with other drugs depending on the the type of CLL/SLL or whether you have relapsed on some prior treatment.
Many patients become alarmed when first starting ibrutinib because the first lab tests after starting this medication often show a dramatic rise in the White Blood Cell (WBC) count. This is, in fact, a sign that the medication is working as lymphocytes in the bone marrow and lymph nodes are driven into the circulating blood where they can be affected by the drug. Your provider will likely start you on the anti-gout medication Allopurinol when you start Ibrutinib because there is a possibility that the drug may cause a phenomenon known as Tumor Lysis Syndrome (TLS). In TLS the malignant cells rupture and in doing so release large quantities of uric acid. Gout is the manifestation of increased uric acid levels and the allopurinol enhances the excretion of uric acid both in gout and TLS.
When taking ibrutinib it is important to take it at approximately the same time each day with a full glass of water and you should maintain good hydration throughout the day. It is important to swallow the capsules whole and not open, break or chew the capsules. Some providers caution that this medication should be taken on an empty stomach either one-hour before eating or two hours after eating however, an analysis of 3 pharmacokinetic studies suggest that ibrutinib can be taken without regard to food. (Cancer Chemotherapeutic Pharmacology 2015;75(5):907-916.) I suggest you not make a change from your prescriber’s instructions without first talking to them about this study as they may have more up to date information or a different rationale.
Ibrutinib has a mild anti-coagulant effect essentially equivalent to 325mg of Aspirin. It is important that you provide a complete list of medications that includes any nutritional supplements or over-the-counter medications to your provider. Your provider or the clinical pharmacist assigned to your clinic will review your medication history and make recommendations on items to reduce or eliminate. Some common medications to avoid without provider approval are, aspirin or Non-Steroidal Anti-Inflammatory agents such as ibuprofen, naproxen, or diclofenac; and anti-platelet agents. In addition several herbal products can enhance the anti-coagulant properties of ibrutinib including Omega-3 Fatty Acids (Fish-Oil), Flaxseed Oil, Vitamin E, and Curcumin/Tumeric. Of course if you are on any anticoagulant or antiplatelet therapy your medical team may need to adjust or eliminate your current therapy. Be sure to discuss any pending surgery with your CLL team and the surgeon to determine how you should take ibrutinib both before and after surgery. I recently had hip replacement surgery and we titrated my dose down to 2 caps for 2 days, 1 cap for 2 days and then off 2 days prior to surgery. Because they would normally give anticoagulant therapy after this surgery I started back the next day. Just remember every surgery is different, I just offer this to show an option. This strategy was developed in collaboration between my hematologist and surgeon.
In addition there are numerous drug to drug interactions to consider as well, I will only discuss the most significant.
- Many HIV and antifungal drugs inhibit the enzyme that metabolizes ibrutinib and result in increased blood levels and side effects. The HIV drugs can be recognized because they end in “Vir” and the antifungals end in “Zole”. In addition, the antibiotics clarithromycin and telithromycin and the antidepressant nefazodone have the same effect.
- On the opposite side are drugs that induce the enzyme that metabolizes ibrutinib and reduces the blood levels and may render the drug sub-therapeutic. These include the anti-seizure medications phenytoin, carbamazepine and phenobarbital, the anti-tubercular agents rifampin, rifabuten and rifapentin, the steroid dexamethasone and the herbal product St. John’s Wort.
Your provider will evaluate the risks of these interactions and decide to either adjust therapy or potentially switch to similar agents for the same purpose that do not interact with ibrutinib. I must caution that the listing I have provided is only a small group of more significance. This is why you must discuss all current and contemplated new medications with all your medical team including your primary care provider.
There are some serious food interactions to consider as well. Grapefruit, Grapefruit Juice and Seville Oranges inhibit the enzyme that metabolizes ibrutinib and the drug levels increase risking worsening of potential side effects. Seville oranges are often used to make orange marmalade and should be avoided.
The list of POTENTIAL side-effects is long. Some are merely a nuisance and tend to be transient and others are more severe and require medical intervention. Seek immediate medical attention for:
- Any signs of an allergic reaction such as rash, hives, tightness in the chest or throat, trouble breathing or talking, swelling of the mouth tongue or throat.
- Signs of bleeding internally such as throwing up what looks like coffee grounds, blood in the urine or black, red or tarry stools.
- Signs of high blood pressure such as a very bad headache, dizziness, passing out or change in eyesight.
- Shortness of breath, sudden weight gain of more than 5 pounds or swelling in the arms or legs
- Chest pain or rapid heartbeat
Ibrutinib is a breakthrough in the treatment of CLL. It is generally a safe medication but all medications have risks. By educating yourself and listening to your body you will likely benefit from this drug and be able to identify potential problems and risks in your treatment.
I would like to share one hint that I received from a non-healthcare professional. I, like many ibrutinib users, suffer from dry fingernails that crack, break and peel. A nail technician friend suggested keeping a small bowl filled with olive oil and soak fingernails daily for 5 minutes then dry excess oil with a paper towel. The results have been remarkable!
Thomas Henry is a Registered Pharmacist and CLL Patient. He is President and Senior Consultant for Burlington Consulting Associates, a company that provides consulting services to health systems nationwide. Tom is a CLL Society Medical Advisory Board member and strives to educate other CLL patients through his blog https//www.cllpharmacist.com. He has a forty-two-year career in pharmacy and has served as Chief Pharmacy Officer at two Top-15 Comprehensive Cancer Centers, Moffitt (Tampa, FL) and Roswell Park (Buffalo, NY).
Originally published in The CLL Tribune Q3 2017.