Idelalisib - Uses, Dosage, Side Effects, Interation - Rxharun

Idelalisib – Uses, Dosage, Side Effects, Interation

Mechanism of Action

Idelalisib specifically inhibits P110δ, the delta isoform of the enzyme phosphatidylinositol-4,5-bisphosphate 3-kinase, also known as PI-3K. The PI-3Ks are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In contrast to the other class IA PI3Ks p110α and p110β, p110δ is principally expressed in leukocytes (white blood cells) and is important for the function of T cells, B cell, mast cells and neutrophils. By inhibiting this enzyme, idelalisib induces apoptosis of malignant cells and inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and C-X-C chemokine receptors type 5 and type 4 signalling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib has been shown to result in inhibition of chemotaxis and adhesion, and reduced cell viability.

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Idelalisib is an inhibitor of PI3Kdelta kinase, which is expressed in normal and malignant B-cells. Idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B-cells and in primary tumor cells. Idelalisib inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion, and reduced cell viability.

Indications

  • Idelalisib is indicated in the treatment of chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL). For the treatment of relapsed CLL, it is currently indicated as a second-line agent in combination with rituximab in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities, while in the treatment of FL and SLL it is intended to be used in patients who have received at least two prior systemic therapies.
  • Zydelig is indicated in combination with an anti‑CD20 monoclonal antibody (rituximab or ofatumumab) for the treatment of adult patients with chronic lymphocytic leukaemia (CLL): who have received at least one prior therapy, or as first line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies.
  • Zydelig is indicated as monotherapy for the treatment of adult patients with follicular lymphoma (FL) that is refractory to two prior lines of treatment.
  • Idelalisib is an oral kinase inhibitor that is approved for use in combination with rituximab in relapsed or refractory chronic lymphocytic leukemia (CLL) and as monotherapy for relapsed follicular B cell, small lymphocytic lymphoma and indolent non-Hodgkin lymphoma.
  • Idelalisib is an antineoplastic kinase inhibitor used to treat chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL).
  • Idelalisib is a second-line drug for patients whose chronic lymphocytic leukemia (CLL) has relapsed. Used in combination with rituximab,[rx] idelalisib is to be used in patients for whom rituximab alone would be considered appropriate therapy due to other existing medical conditions.[rx] It appears to be effective and leads to improvement of lymphadenopathy and splenomegaly. However, the lymphocyte counts take longer to decrease to normal levels with idelalisib. It is not recommended as a first-line treatment.[rx]
  • It is also approved for the treatment of follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL), both in patients who have received at least two prior systemic therapies.[rx]
  • In combination with rituximab, for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other co-morbidities. The treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL) who have received at least 2 prior systemic therapies. The treatment of patients with relapsed small lymphocytic lymphoma (SLL) who have received at least 2 prior systemic therapies.
  • Relapsed Chronic Lymphocytic Leukemia
  • Relapsed Small Lymphocytic Lymphoma
  • Relapsed follicular B-cell non-Hodgkin’s lymphoma

Use in Cancer

Idelalisib is approved to treat:

Idelalisib is also being studied in the treatment of other types of cancer.

Contraindications

  • a bad infection
  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • a type of inflammation of the lung called interstitial pneumonitis
  • a hole in the intestine
  • liver problems
  • high amount of bilirubin in the blood
  • diarrhea
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • progressive multifocal leukoencephalopathy, a type of brain infection

Dosage

Strengths: 100 mg; 150 mg

Non-Hodgkin’s Lymphoma

  • 150 mg orally 2 times a day until disease progression or unacceptable toxicity
  • This drug can be taken with or without food.
  • Tablets should be swallowed whole.
  • If the patient misses a dose within 6 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal dosing schedule.
  • If a patient misses a dose by more than 6 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

Chronic Lymphocytic Leukemia

  • 150 mg orally 2 times a day until disease progression or unacceptable toxicity
  • This drug can be taken with or without food.
  • Tablets should be swallowed whole.
  • If the patient misses a dose within 6 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal dosing schedule.
  • If a patient misses a dose by more than 6 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

Lymphoma

  • 150 mg orally 2 times a day until disease progression or unacceptable toxicity
  • This drug can be taken with or without food.
  • Tablets should be swallowed whole.
  • If the patient misses a dose within 6 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal dosing schedule.
  • If a patient misses a dose by more than 6 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.
  • In combination with rituximab, for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.
  • The treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL) who have received at least 2 prior systemic therapies.
  • The treatment of patients with relapsed small lymphocytic lymphoma (SLL) who have received at least 2 prior systemic therapies.

Liver Dose Adjustments

  • AST and/or ALT greater than 3 to 5 times the upper limit of normal (3 to 5 x ULN): Maintain dose, monitor at least weekly until less than or equal to ULN.
  • AST and/or ALT greater than 5 to 20 x ULN: Withhold therapy, monitor at least weekly until less than or equal to ULN, may resume at 100 mg twice a day.
  • AST and/or ALT greater than 20 x ULN: Permanently discontinue therapy.
  • Bilirubin greater than 1.5 to 3 x ULN: Maintain dose, monitor at least weekly until less than or equal to ULN.
  • Bilirubin greater than 3 to 10 x ULN: Withhold therapy, monitor at least weekly until less than or equal to ULN, may resume at 100 mg twice a day.
  • Bilirubin greater than 10 x ULN: Permanently discontinue therapy.

Dose Adjustments

Pneumonitis:

  • Discontinue therapy in patients with any severity of symptomatic pneumonitis.

Diarrhea:

  • If moderate diarrhea develops during therapy (increase of 4 to 6 stools per day over baseline), maintain dose and monitor at least weekly until resolved.
  • If severe diarrhea develops during therapy (increase of 7 or more stools per day over baseline), withhold therapy and monitor at least weekly until resolved, then resume therapy at 100 mg twice a day.
  • If life-threatening diarrhea develops during treatment, discontinue therapy permanently.

Neutropenia:

  • ANC 1 to less than 1.5 Gi/L: Maintain dose.
  • ANC 0.5 to less than 1 Gi/L: Maintain dose and monitor ANC at least weeky.
  • ANC less than 0.5: interrupt therapy and monitor at least weekly until ANC is 0.5 Gi/L or greater, then resume therapy at 100 mg twice a day.

Thrombocytopenia:

  • Platelets 50 to less than 75 Gi/L: Maintain dose.
  • Platelets 25 to less than 50 Gi/L: Maintain dose and monitor platelet counts at least weekly.
  • Platelets less than 25 Gi/L: Withhold therapy and monitor at least weekly; resume therapy at 100 mg twice a day when platelets are 25 Gi/L or greater.

Infections:

  • Grade 3 or higher sepsis or pneumonia: Interrupt therapy until infection has resolved.
  • Evidence of CMV infection or viremia: Interrupt therapy in patients with evidence of active CMV infection of any grade or viremia (positive PCR or antigen test) until the viremia has resolved. If therapy is resumed, monitor patients by PCR or antigen test for CMV reactivation at least monthly.
  • Evidence of PJP infection: Interrupt therapy in patients with suspected PJP infection of any grade. Permanently discontinue therapy if PJP infection is confirmed.

Lymphocytosis:

  • No dose modification is required for lymphocytosis, which has been observed in some patients taking this drug. This lymphocytosis is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings.

FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, and INTESTINAL PERFORATION:

  • Fatal and/or serious hepatotoxicity occurred in 16% to 18% of patients. Monitor hepatic function prior to and during therapy. Interrupt therapy and then reduce or discontinue the drug as recommended.
  • Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of patients. Monitor for development of severe diarrhea or colitis. Interrupt therapy and then reduce or discontinue the drug as recommended.
  • Fatal and/or serious pneumonitis occurred in 4% of patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt therapy and then reduce or discontinue the drug as recommended.
  • Fatal and/or serious infections occurred in 21% to 48% of patients. Monitor for infection. Interrupt therapy if infection is suspected.
  • Fatal and serious intestinal perforation can occur. Discontinue therapy for intestinal perforation.

Administration advice:

  • Take with or without food.
  • Tablets should be swallowed whole.

Side Effects

The Most Common

  • headache
  • difficulty falling asleep or staying asleep
  • decreased appetite
  • increased thirst
  • heartburn
  • joint pain
  • night sweats
  • lack of energy
  • swelling of the hands, feet, ankles, or lower legs
  • red, itching, peeling, or blistering skin
  • painful sores or ulcers on your skin, lips, or in your mouth
  • difficulty swallowing or breathing; swelling of the face, lips, or throat; hives; itching
  • Bloating or swelling of the face, arms, hands, lower legs, or feet
  • decreased appetite
  • difficulty with moving
  • muscle pain or stiffness
  • night sweats
  • pain in the joints
  • rapid weight gain
  • tingling of the hands or feet
  • trouble sleeping
  • unusual weight gain or loss

More common

  • Black, tarry stools
  • body aches or pain
  • chest tightness
  • chills
  • clay colored stools
  • confusion
  • cough
  • cough producing mucus
  • dark urine
  • decreased appetite
  • difficulty with breathing
  • dizziness
  • ear congestion
  • fainting
  • fast heartbeat
  • fever
  • headache
  • itching or skin rash
  • lightheadedness
  • loss of appetite
  • loss of voice
  • lower back or side pain
  • nausea and vomiting
  • pain
  • pain or tenderness around the eyes and cheekbones
  • painful or difficult urination
  • pale skin
  • rapid, shallow breathing
  • sneezing
  • sore throat
  • stomach cramps, pain, or tenderness
  • stuffy or runny nose
  • swelling of the feet or lower legs
  • trouble breathing
  • ulcers, sores, or white spots in the mouth
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • watery or bloody diarrhea
  • yellow eyes or skin

Rare

  • Bladder pain
  • bloody or cloudy urine
  • difficult, burning, or painful urination
  • frequent urge to urinate
  • lower back or side pain
  • Blistering, peeling, or loosening of the skin
  • chest pain
  • cracks in the skin
  • difficulty with swallowing
  • general feeling of discomfort or illness
  • heartburn
  • hives
  • indigestion
  • joint or muscle pain
  • loss of heat from the body
  • 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
  • red, swollen skin
  • scaly skin
  • severe abdominal or stomach pain, cramping, or burning
  • thickening of bronchial secretions
  • vomiting of material that looks like coffee grounds, severe and continuing

Drug Interactions

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Pregnancy and Lactation

FDA Pregnancy Category D

Pregnancy

Based on findings in animals, Zydelig may cause fetal harm when administered to a pregnant woman. Idelalisib was teratogenic in animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Lactation

No information is available on the clinical use of idelalisib during breastfeeding. Because idelalisib is more than 84% bound to plasma proteins, the amount in milk is likely to be low. It is sometimes given in combination with rituximab, which may increase the risk to the infant. The manufacturer recommends that breastfeeding be discontinued during idelalisib therapy and for at least 1 month after the last dose.

How should this medicine be used?

Idelalisib comes as a tablet to take by mouth. It is usually taken with or without food twice a day. Take idelalisib at around the same times 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 idelalisib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not split, chew, or crush them.

Your doctor may decrease your dose of idelalisib or tell you to stop taking the medication for a time or permanently if you experience serious side effects during 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 idelalisib even if you feel well. Do not stop taking idelalisib without talking to your doctor. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

What special precautions should I follow?

Before taking idelalisib,

  • tell your doctor and pharmacist if you are allergic to idelalisib, any other medications, or any of the ingredients in idelalisib tablets. If you have ever had a severe allergic reaction in the past, such as swelling of your face, lips or throat; difficulty swallowing or breathing; or peeling, blistering skin, your doctor will probably tell you not to take idelalisib.Ask your pharmacist or check the Medication Guide 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: carbamazepine (Carbatrol, Epitol, Equetro, others); clarithromycin (Biaxin, in PrevPac); itraconazole (Onmel, Sporanox); ketoconazole (Nizoral); medications used to treat human immunodeficiency virus (HIV) such as efavirenz (Sustiva, in Atripla), indinavir (Crixivan), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir, in Kaletra, in Technivie); midazolam; nefazodone; phenobarbital; phenytoin (Dilantin, Phenytek); pioglitazone (Actos, in Actoplus Met, in Duetact, in Oseni); rifabutin (Mycobutin); and rifampin (Rifadin, Rimactane, in Rifamate, in Rifater). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with idelalisib, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • tell your doctor and pharmacist what herbal products you are taking, especially St. John’s wort. You should not take St. John’s wort during your treatment with idelalisib.
  • tell your doctor if you are pregnant, plan to become pregnant, or plan to father a child. You should not become pregnant during your treatment with idelalisib. You should use birth control to prevent pregnancy during your treatment with idelalisib and at least 1 month after your final dose. If you are a male and your partner can become pregnant, you should use effective birth control during your treatment and for 3 months after your final dose. If you or your partner become pregnant while taking idelalisib, call your doctor immediately. Idelalisib may harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed while you are taking idelalisib and for at least one month after your final dose.
References
Consumer Information – TrustArc The Leader in Privacy Management SoftwareLooking online for info on your child's health? Here are some tipsJanja Kristan - Chief Administrative Officer - AACI | LinkedIn
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