Idelalisib - Uses, Dosage, Side Effects, and Drug Warnings

Overview

Idelalisib is a kinase inhibitor used to treat patients with relapsed chronic lymphocytic leukemia along with Rituximab, relapsed follicular B-cell non-Hodgin lymphoma, and relapsed small lymphocytic lymphoma. The United States Food and Drug Administration (USFDA) approved the drug on July 23, 2014; accelerated approval was granted for the treatment of relapsed follicular B- cell non-Hodgin lymphoma and relapsed small lymphocytic lymphoma based on the overall response rate and continued approval for these indications may depend on the verification of the clinical benefits in the confirmatory trials.

How Does Idelalisib Work?

The enzyme PI3K - delta plays an important role in white blood cells growth, multiplication, and survival (WBC). It is overactive in conditions of blood cancer and helps in the survival of WBCs. Idelalisib targets this enzyme PI3K - delta and blocks these functions, leading to the cancer cells' death, thereby stopping or delaying the cancer progression.

Indications:

• In combination with Rituximab, Idelalisib is used to treat patients with relapsed conditions of chronic lymphocytic leukemia (CLL).

• Idelalisib is used in patients who have received prior systemic therapies at least twice for relapsed follicular B-cell non-Hodgkin lymphoma (FL).

• In treating relapsed small lymphocytic lymphoma (SLL), Idelalisib is used in patients who have received prior systemic therapies at least twice.

Contraindications:

• Idelalisib is contraindicated in patients with a history of serious allergic reactions, which include anaphylaxis and toxic epidermal necrolysis.

Dosage, Administration, and Modifications:

• Idelalisib tablets are 100 mg and 150 mg film-coated tablets.

• Idelalisib is recommended at a maximum starting dose of 150 mg, to be taken orally (swallowed whole) twice a day, with or without food. The treatment must be continued until the progression of the disease, or it causes unacceptable toxicity.

• If severe or life-threatening toxicities are reported, Idelalisib must be withheld until the toxicity is resolved; if resuming Idelalisib after an interruption for other severe toxicities, the dose must be reduced to 100 mg twice a day. The drug must be permanently discontinued if severe or life-threatening toxicities related to Idelalisib reoccur after the rechallenge.

Warnings and Precautions:

• Liver Toxicity: Hepatotoxicity reactions that were either serious or fatal occurred in patients treated with Idelalisib. Within the first 12 weeks of treatment, a rise in the alanine aminotransferase (ALT), or aspartate aminotransferase (AST), greater than five times the normal upper limit was observed, which was reversible with dose interruption. At lower doses also, some patients experienced elevated ALT and AST enzymes. Hence, Idelalisib must be discontinued for recurrent hepatotoxicity, concurrent use of Idelalisib with other drugs that may cause liver toxicity must be avoided, and frequent monitoring of the enzymes is required during the treatment with Idelalisib.

• Severe Diarrhea: It was observed during the clinical trials that patients treated with Idelalisib experienced severe diarrhea or colitis; hence, concurrent use of Idelalisib with other drugs that cause diarrhea must be avoided.

• Embryo-Fetal Toxicity: Idelalisib may cause harm to the fetus when administered to pregnant women, as it is teratogenic in rats at systemic exposure levels of 12 times at the recommended dose. Thus, female patients of reproductive potential are advised not to become pregnant and follow effective contraception methods during the treatment and for at least one month after the last dose of Idelalisib.

• Pneumonitis: Idelalisib may be associated with pneumonitis, and patients who experience symptoms such as cough, dyspnea, and hypoxia must contact the doctor and be evaluated for pneumonitis.

• Interstitial Perforation: Interstitial perforation that may be fatal and serious is observed in patients treated with idelalisib, and hence the patients must report promptly in case of symptoms such as abdominal pain, chills, fever, nausea, and vomiting are observed.

• Hypersensitivity Reactions: Idelalisib may be associated with serious allergic reactions, including anaphylaxis, and patients developing such allergic reactions must contact the doctor and discontinue the drug, and supportive measures must be taken.

• Skin Reactions: Idelalisib can cause skin reactions such as generalized or erythematous rashes, macular, papular, or maculopapular rashes, and dermatitis; hence, patients must be monitored frequently.

• Neutropenia: Grade 3 or 4 neutropenia occurred in patients treated with Idelalisib during clinical trials. Hence, blood counts must be monitored every two weeks and weekly in patients with reduced neutrophil counts.

Adverse Reactions:

Severe adverse reactions associated with Idelalisib during the clinical trials include:

• Hepatotoxicity.

• Severe diarrhea or colitis.

• Intestinal perforation.

• Pneumonitis.

• Anaphylaxis.

• Neutropenia.

• Severe cutaneous reactions.

For Patients:

What Is Chronic Lymphocytic Leukemia?

Chronic lymphocytic leukemia is a type of cancer of the blood and bone marrow associated with symptoms such as painful and enlarged lymph nodes, pain in the upper left area of the abdomen, fever, fatigue, weight loss, and increased susceptibility to infections. The exact cause is unknown, but studies suggest that CLL may be due to mutations in the DNA of the blood cells. A family history of CLL may be a risk factor in the development of the disease.

What Is Idelalisib?

Idelalisib is a medicine prescribed to treat patients with;

• Chronic Lymphocytic Lymphoma (CLL): When CLL relapses after receiving other cancer treatments, Idelalisib is used in combination with Rituximab.

• Follicular B-cell Non-Hodgkin Lymphoma (FL): When the disease relapses after treatment with at least two prior medications.

• Small Lymphocytic Lymphoma (SLL): When the disease relapses after treatment with at least two prior medications.

What Is the Most Important Information About Idelalisib?

Idelalisib may cause serious adverse effects and can be fatal. Suppose any serious side effects are observed during the treatment with Idelalisib. In that case, the doctor may withhold the treatment or change the dose of Idelalisib or completely stop the treatment with the drug. Some of the serious side effects include;

• Severe Diarrhea: Diarrhea is one of the common side effects of Idelalisib and can be severe, and patients must inform the doctor and get treated if the bowel movements are more than six times or more per day.

• Liver Problems: Before starting and during the treatment with Idelalisib, the doctor will advise certain blood tests to check the liver problems. Patients must report if they experience the following symptoms: abdominal pain in the upper right side, bleeding more easily, yellowish skin or the white part of the eyes (jaundice), and dark or brown urine.

• Breathing Problems: The doctor may perform tests to check the lungs in case of breathing problems during the treatment with Idelalisib, and the patients must also tell the doctor in case of cough, shortness of breath, wheezing, etc.

• Tear in the Intestinal Wall: Medical help is required if the patients experience new or worsening stomach pain, fever, chills, nausea, or vomiting.

• Neutropenia: The doctor may frequently advise blood tests to monitor the white blood cell count, and the patient is advised to inform the doctor in the presence of a fever or other signs of infection.

What Are the Instructions for Taking Idelalisib?

• Patients must take Idelalisib exactly as prescribed by the doctor and must not change the doses or stop taking the drug unless instructed by the doctor.

• Idelalisib can be taken with or without food and should be swallowed whole.

• If a dose of Idelalisib is missed by less than six hours, it must be taken immediately, and the next dose must be taken as usual.

• If a dose of Idelalisib is missed by more than six hours, patients must take the next dose at the usual time.

What Must the Patients Inform the Doctor?

• The patients must inform the doctor if they suffer from liver or lung problems.

• Female patients must inform if they are pregnant or plan to become pregnant or if they become pregnant during the treatment with Idelalisib.

• Idelalisib may pass into breast milk, and female patients must inform if they are breastfeeding or planning to breastfeed.

• The doctor must be informed if the patients take other medicines, over-the-counter (OTC) medications, vitamins, or herbal supplements.

What Are the Side Effects of Idelalisib?

Idelalisib may cause serious side effects, and the patients must inform the doctor if they experience any of the following symptoms:

• Liver problems.

• Severe skin reactions include rashes, painful ulcers, blisters, peeling skin, etc.

• Anaphylaxis or allergic reactions.

• Fever and chills, feeling tired.

• Nausea and vomiting.

• Stomach pain.

• Cough.

How Should Idelalisib Be Stored?

Idelalisib must be stored between 20 to 30 degrees, kept in its original container, and not used if the seal is broken or missing.

For Doctors:

Idelalisib is a phosphatidylinositol 3- kinase inhibitor, and each tablet contains either 100 mg or 150 mg of Idelalisib, with inactive ingredients such as;

• Microcrystalline cellulose.

• Hydroxypropyl cellulose.

• Croscarmellose sodium.

• Sodium starch glycolate.

• Magnesium stearate.

The table coat consists of the following:

• Polyethylene glycol.

• Talc.

• Polyvinyl alcohol.

• Titanium dioxide.

Mechanism of Action:

Phosphatidylinositol 3-kinase is expressed in healthy and malignant B-cells. However, it is hyperactive in malignant cells and consists of multiple signaling pathways, which result in the proliferation, multiplication, and retention of malignant cells in lymphoid and bone marrow. Idelalisib inhibits phosphatidylinositol 3-kinase by binding to adenosine-5-triphosphate (ATP), thereby preventing its phosphorylation; inducing apoptosis and proliferation of cell lines that are derived from malignant cells. Through signaling induced by chemokines, Idelalisib inhibits chemokine receptors and prevents the retention of malignant cells in lymphoid tissues and bone marrow.

Pharmacodynamics:

• The electrocardiographic effect of Idelalisib was evaluated in 40 patients, and at a dose of 2.7 times the maximum recommended dose, there was no prolongation in the QT/QTc interval.

• On initiation of treatment with Idelalisib, a temporary lymphocytosis was observed in two-thirds of the patients with CLL treated with Idelalisib alone and one-fourth of patients with CLL treated with combination therapy.

Pharmacokinetics:

• Absorption: After administering a single dose of Idelalisib orally, in a fasting state, the time taken to reach the maximum concentration in systemic circulation was observed to be 1.5 hours. Following a high-fat meal, the oral administration of Idelalisib showed an increase in the area under the curve by 1.4-fold, suggesting that Idelalisib can be taken without regard to food.

• Distribution: Approximately 84 percent of Idelalisib binds to plasma proteins without concentration dependence and a mean blood-to-plasma ratio of 0.7. The volume of distribution at steady state is 23 L.

• Metabolism: Idelalisib gets metabolized by aldehyde oxidase and CYP3A to GS- 563117, which is inactive against phosphatidylinositol 3-kinase in vitro, and also undergoes minor metabolism by UGT1A4.

• Elimination: About 78 percent of an orally administered single dose of 150 mg Idelalisib was excreted in feces and 15 percent in urine, unchanged 23 percent of total radioactivity in urine over 48 hours and 12 percent in feces over 144 hours. The total clearance of Idelalisib was 14.9 L/h, and the terminal elimination half-life was 8.2 hours, following the oral administration of Idelalisib 150 mg twice daily.

Drug Interactions:

• Administration of Idelalisib with strong CYP3A and P-gp inducers such as Rifampin must be avoided as Rifampin may reduce the concentration of Idelalisib in the systemic circulation.

• Administration of strong CYP3A and P-gp inhibitors, such as Ketoconazole, increases the Idelalisib mean concentration by 1.8 folds; hence, frequent monitoring for the signs of toxicity of Idelalisib is required.

• On administration of Midazolam 5mg orally alone or after Idelalisib, the mean concentration of Midazolam in systemic circulation was increased; hence, the administration of Idelalisib with strong CYP3A inhibitors must be avoided.

• On administration of a single dose of Rosuvastatin 10 mg orally alone or after Idelalisib 150 mg, no changes were observed.

• No changes were observed on administering a single dose of Digoxin 0.5 mg orally alone or after Idelalisib 150 mg.

Results of Clinical Trials:

• Clinical trials were performed under varying conditions. Study I involved 218 patients with relapsed chronic lymphoid leukemia who were given up to eight doses of Rituximab with or without Idelalisib twice daily. The median duration of exposure to Idelalisib was five months. Serious adverse reactions were noted in 54 patients treated with Idelalisib and Rituximab combination. It includes; pneumonia, pyrexia, sepsis, febrile neutropenia, and diarrhea. Common adverse reactions such as hepatotoxicity and diarrhea led to the discontinuation of Idelalisib in 11 patients. Dose interruptions were made in 39 patients and dose reductions in 16 patients with elevated levels of transaminases, diarrhea, and rashes.

• Clinical trial safety data reflect exposure to Idelalisib in 146 patients with indolent non-Hodgkin lymphoma, treated with Idelalisib 150 mg twice daily for around 6.1 months. Serious adverse reactions such as pneumonia, diarrhea, and pyrexia were reported in 73 patients. Dose interruptions and discontinuation were due to diarrhea, pneumonia, and elevated levels of transaminases in 78 patients.

Carcinogenicity, Mutagenicity, Impairment of Fertility, and Toxicity:

• Idelalisib did not cause mutations but was found to be genotoxic in males based on animal studies. Based on a fertility study in male and female rats treated with Idelalisib, reduced sperm concentrations at medium and high doses and decreased epididymal and testicular weights at all dose levels were observed. Still, there were no adverse effects on fertility. Carcinogenicity studies have not been conducted about Idelalisib.

• Toxicity may occur with Idelalisib, based on animal studies. Idelalisib may cause depletion of lymphoid tissues in the thymus, spleen, lymph nodes, etc. Inflammatory changes and hepatic necrosis were observed in animals at higher exposure rates than humans.

Uses of Idelalisib in Specific Populations:

• Pregnant Women: Idelalisib may cause fetal harm when administered to pregnant women; it was based on the findings in animal studies, which reported teratogenicity in animals. Decreased fetal weights, urogenital blood loss, increased post-implantation loss, complete resorption, and developmental malformations were observed when Idelalisib was administered to pregnant rats.

• Females of Reproductive Potential: Idelalisib may harm the fetus when administered during pregnancy, so females of reproductive potential are advised to avoid becoming pregnant and use effective contraception during the treatment and at least one month after the last dose of Idelalisib. Patients are also advised to contact the doctor if they become pregnant or if pregnancy is suspected.

• Lactating Women: Many medications are excreted in human milk, and since it may result in major adverse reactions in nursing infants, it must be decided whether Idelalisib must be discontinued or nursing, considering the importance of the drug to the mother.

• Children: The safety and effectiveness of Idelalisib are not established in children under the age of 18 years.

• Geriatric Use: During the clinical trials, no significant differences were observed in patients above 65 years. However, a higher incidence of discontinuation was seen due to adverse reactions compared to younger patients.

• Renal Impairment: For patients with a creatinine clearance of more than 15mL/min, no adjustment in doses of Idelalisib is required.

• Hepatic Impairment: In Inpatients with moderate or severe liver impairment (increased levels of ALT and AST), the area under the curve (AUC) of Idelalisib was 1.7 times higher compared to patients with normal ALT and AST enzyme levels.