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Idelalisib

Pronunciation

(eye del a LIS ib)

Index Terms

  • CAL-101
  • GS-1101
  • PI3K Delta Inhibitor CAL-101

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Zydelig: 100 mg, 150 mg

Brand Names: U.S.

  • Zydelig

Pharmacologic Category

  • Antineoplastic Agent, Phosphatidylinositol 3-Kinase Inhibitor

Pharmacology

Potent small molecule inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ), which is highly expressed in malignant lymphoid B-cells. PI3Kδ inhibition results in apoptosis of malignant tumor cells. In addition, idelalisib inhibits several signaling pathways, including B-cell receptor, CXCR4 and CXCR5 signaling which may play important roles in CLL pathophysiology (Furman, 2014).

Distribution

23 L

Metabolism

Hepatic; primarily via aldehyde oxidase and CYP3A (to major metabolite GS-563117); minor metabolism via UGT1A4

Excretion

Feces (78%; 44% as GS-563117); urine (14%; 49% as GS-563117)

Time to Peak

Median: 1.5 hours

Half-Life Elimination

~8 hours

Protein Binding

>84%

Special Populations: Hepatic Function Impairment

Exposure increased 1.7-fold in patients with ALT/AST/bilirubin >ULN as compared to patients with normal liver function tests.

Use: Labeled Indications

Chronic lymphocytic leukemia: Treatment of relapsed chronic lymphocytic leukemia (CLL) (in combination with rituximab) when rituximab alone is appropriate therapy due to other comorbidities

Follicular B-cell non-Hodgkin lymphoma: Treatment of relapsed follicular B-cell non-Hodgkin lymphoma after at least 2 prior systemic therapies

Small lymphocytic lymphoma: Treatment of relapsed small lymphocytic lymphoma (SLL) after at least 2 prior systemic therapies

Contraindications

Serious hypersensitivity reactions (including anaphylaxis and toxic epidermal necrolysis) to idelalisib or any component of the formulation

Dosing: Adult

Note: The maximum recommended starting dose is 150 mg twice daily. Optimal duration and safety of therapy beyond several months is currently unknown.

Chronic lymphocytic leukemia, relapsed: Oral: 150 mg twice daily (in combination with rituximab); continue until disease progression or unacceptable toxicity (Furman, 2014)

Follicular B-cell non-Hodgkin lymphoma, relapsed: Oral: 150 mg twice daily; continue until disease progression or unacceptable toxicity (Gopal, 2014)

Small lymphocytic lymphoma, relapsed: Oral: 150 mg twice daily; continue until disease progression or unacceptable toxicity (Gopal, 2014)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥15 mL/minute: No dosage adjustment necessary (Jin 2015b).

CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Preexisting hepatic impairment: Exposure is increased in patients with ALT/AST or bilirubin >ULN as compared to patients with normal hepatic function; patients with ALT/AST >2.5 times ULN or bilirubin >1.5 times ULN were excluded from some studies. Based on a pharmacokinetic study in patients with moderate and severe hepatic impairment (Child Pugh classes B and C) compared to healthy subjects, single oral doses of 150 mg were well tolerated; idelalisib and GS-563117 exposure differences were observed but not considered clinically relevant (Jin 2015a). Monitor closely for toxicity.

Hepatotoxicity during treatment:

ALT/AST >3 to 5 times ULN or bilirubin >1.5 to 3 times ULN: Continue current dose; monitor LFTs at least weekly until ALT/AST and/or bilirubin ≤1 times ULN.

ALT/AST >5 to 20 times ULN or bilirubin >3 to 10 times ULN: Temporarily interrupt therapy. Monitor LFTs at least weekly until ALT/AST and/or bilirubin ≤1 times ULN, then may reinitiate therapy at 100 mg twice daily.

ALT/AST >20 times ULN or bilirubin >10 times ULN: Discontinue permanently.

Recurrent hepatotoxicity: Discontinue.

Dosing: Adjustment for Toxicity

Anaphylaxis: Permanently discontinue.

Dermatologic toxicity: Severe cutaneous reactions: Discontinue.

Hematologic toxicity:

Neutropenia:

ANC 1,000 to <1,500 cells/mm3: Continue current dose.

ANC 500 to <1,000 cells/mm3: Continue current dose; monitor blood counts at least weekly.

ANC <500 cells/mm3: Temporarily interrupt therapy; monitor blood counts at least weekly until ANC ≥500 cells/mm3, then may reinitiate therapy at 100 mg twice daily.

Thrombocytopenia:

Platelets 50,000 to <75,000 cells/mm3: Continue current dose.

Platelets 25,000 to <50,000 cells/mm3: Continue current dose; monitor platelet counts at least weekly.

Platelets <25,000 cells/mm3: Temporarily interrupt therapy; monitor platelet counts at least weekly, may reinitiate therapy at 100 mg twice daily when platelets recover to ≥25,000 cells/mm3.

Gastrointestinal toxicity:

Moderate diarrhea (increase of 4 to 6 stools/day over baseline): Continue current dose; monitor at least weekly until resolved.

Severe diarrhea (increase of ≥7 stools/day over baseline) or hospitalization: Temporarily interrupt therapy; monitor at least weekly until resolved, then may reinitiate therapy at 100 mg twice daily.

Life-threatening diarrhea: Discontinue permanently.

Pulmonary toxicity: If pneumonitis is suspected, interrupt therapy and evaluate; discontinue for symptomatic pneumonitis of any severity thought to be associated with therapy (may also require corticosteroids).

Other toxicity (not listed above): If severe or life-threatening toxicities occur, interrupt therapy until toxicity is resolved. If the decision is made to resume therapy, reduce the dose to 100 mg twice daily. Discontinue permanently if severe or life-threatening toxicities recur upon rechallenge.

Administration

Administer orally twice daily with or without food. Swallow tablets whole.

Missed doses: May administer a missed dose if within 6 hours of usual dosing time. If >6 hours, skip the missed dose and resume therapy with the next scheduled dose.

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single gloving for administration of intact tablets (NIOSH 2014).

Storage

Store at 20°C to 30°C (68°F to 86°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Dispense in the original container.

Drug Interactions

Ado-Trastuzumab Emtansine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component. Avoid combination

Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Avoid combination

Almotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan adult dose to 6.25 mg and maximum adult dose to 12.5 mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Consider therapy modification

Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Apixaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant. Avoid combination

Astemizole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Astemizole. Avoid combination

Asunaprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir. Avoid combination

Avanafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil. Avoid combination

Axitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended. Avoid combination

Barnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine. Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bedaquiline: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bedaquiline. Management: Limit the duration of concomitant administration of bedaquiline with CYP3A4 inhibitors to no more than 14 days, unless the benefit of continued administration is judged to outweigh the possible risks. Monitor for toxic effects of bedaquiline. Consider therapy modification

Blonanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin. Avoid combination

Bortezomib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Brinzolamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine. Avoid combination

Budesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal). Monitor therapy

Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation). Monitor therapy

Budesonide (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Calcifediol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcifediol. Monitor therapy

Cannabis: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

Ceritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ceritinib. Management: If such combinations cannot be avoided, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Avoid combination

CloZAPine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Monitor therapy

Cobimetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan. Avoid combination

Corticosteroids (Orally Inhaled): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Orally inhaled fluticasone propionate with a strong CYP3A4 inhibitor is not recommended. Exceptions: Beclomethasone (Oral Inhalation); Triamcinolone (Systemic). Monitor therapy

Corticosteroids (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Systemic). Exceptions: MethylPREDNISolone; PrednisoLONE (Systemic); PredniSONE. Monitor therapy

Crizotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Crizotinib. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Idelalisib. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Idelalisib. Monitor therapy

CYP3A4 Substrates: Idelalisib may increase the serum concentration of CYP3A4 Substrates. Avoid combination

Dabrafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination

Dapoxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Avoid combination

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dienogest: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dienogest. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dofetilide. Monitor therapy

Domperidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Domperidone. Avoid combination

Doxercalciferol: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Doxercalciferol. Monitor therapy

Dronabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronabinol. Monitor therapy

Dronedarone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Avoid combination

Drospirenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Drospirenone. Monitor therapy

Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Eletriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan. Avoid combination

Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Avoid combination

Estazolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estazolam. Monitor therapy

Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Avoid combination

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Avoid combination

Fluticasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal). Monitor therapy

Halofantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Avoid combination

Ibrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: If a strong CYP3A inhibitor must be used short-term (e.g. antifungals and antibiotics for 7 days or less), consider stopping ibrutinib until the CYP3A inhibitor is no longer needed. Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Iloperidone: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor. Consider therapy modification

Imatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib. Monitor therapy

Imidafenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin. Monitor therapy

Isavuconazonium Sulfate: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Management: Combined use is considered contraindicated per US labeling. Lopinavir/ritonavir (and possibly other uses of ritonavir doses less than 400 mg every 12 hours) is treated as a possible exception to this contraindication despite strongly inhibiting CYP3A4. Avoid combination

Ivabradine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine. Avoid combination

Lacosamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy

Lapatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor. Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lercanidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine. Avoid combination

Levobupivacaine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide. Avoid combination

Lovastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lovastatin. Avoid combination

Lumefantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine. Monitor therapy

Lurasidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone. Avoid combination

Macitentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan. Avoid combination

MedroxyPROGESTERone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MedroxyPROGESTERone. Monitor therapy

MethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose reduction in patients receiving strong CYP3A4 inhibitors and monitor for increased steroid related adverse effects. Consider therapy modification

Naloxegol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol. Avoid combination

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nilotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Avoid combination

NiMODipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine. Avoid combination

Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Olaparib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Avoid combination

Ospemifene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy

Oxybutynin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin. Monitor therapy

Palbociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib. Avoid combination

Parecoxib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pimozide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimozide. Avoid combination

PONATinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib. Management: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor. Consider therapy modification

Pranlukast: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast. Monitor therapy

Prasugrel: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel. Monitor therapy

PrednisoLONE (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of PrednisoLONE (Systemic). Monitor therapy

PredniSONE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PredniSONE. Monitor therapy

Propafenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Propafenone. Monitor therapy

Ramelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Avoid combination

Red Yeast Rice: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased. Avoid combination

Regorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib. Avoid combination

Repaglinide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure. Monitor therapy

Retapamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin. Management: Avoid this combination in patients less than 2 years old. No action is required in other populations. Monitor therapy

Rilpivirine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rilpivirine. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

RomiDEPsin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin. Monitor therapy

Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Avoid combination

Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir. Avoid combination

Simvastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin. Avoid combination

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Sonidegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib. Avoid combination

SORAfenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SORAfenib. Monitor therapy

St John's Wort: May decrease the serum concentration of Idelalisib. Avoid combination

Suvorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant. Avoid combination

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Avoid combination

Tasimelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Monitor therapy

Terfenadine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Terfenadine. Avoid combination

Tetrahydrocannabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Avoid combination

Toremifene: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of Toremifene. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin. Avoid combination

TraMADol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Udenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Udenafil. Avoid combination

Ulipristal: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combo should be monitored for ulipristal toxicity. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Vemurafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vemurafenib. Avoid combination

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg/day in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor. Consider therapy modification

VinCRIStine (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vindesine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine. Monitor therapy

Vinflunine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine. Avoid combination

Vorapaxar: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar. Avoid combination

Zolpidem: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zolpidem. Monitor therapy

Zuclopenthixol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Management: Consider zuclopenthixol dosage reduction with concomitant use of a strong CYP3A4 inhibitor (eg, ketoconazole) in poor CYP2D6 metabolizers or with strong CYP2D6 inhibitors (eg, paroxetine). Monitor for increased zuclopenthixol levels/toxicity. Consider therapy modification

Adverse Reactions

As reported with monotherapy.

>10%:

Central nervous system: Fatigue (30%), insomnia (12%), headache (11%)

Dermatologic: Skin rash (21%; grade ≥3: 3%), night sweats (12%)

Gastrointestinal: Diarrhea (47%; grade ≥3: 14%), nausea (29%), abdominal pain (26%), decreased appetite (16%), vomiting (15%)

Hematologic & oncologic: Decreased neutrophils (53%; grade 3: 14%; grade 4: 11%), decreased hemoglobin (28%; grade 3: 2%), decreased platelet count (26%; grade 3: 3%; grade 4: 3%)

Hepatic: Increased serum ALT (50%; grade 3: 14%; grade 4: 5%), increased serum AST (41%; grade 3: 8%; grade 4: 4%), severe hepatotoxicity (14%)

Neuromuscular & skeletal: Weakness (12%)

Respiratory: Cough (29%), pneumonia (25%; grade ≥3: 16%), dyspnea (17%), upper respiratory tract infection (12%)

Miscellaneous: Fever (28%)

1% to 10%: Cardiovascular: Peripheral edema (10%)

<1%, postmarketing, and/or case reports (Limited to important or life-threatening; reported with mono- or combination therapy): Anaphylaxis, febrile neutropenia (Health Canada 2016), hypersensitivity reaction, intestinal perforation, opportunistic infection (such as pneumocystic carinii/jirovecii pneumonia and cytomegalovirus) (Health Canada 2016), Stevens-Johnson syndrome, toxic epidermal necrolysis

ALERT: U.S. Boxed Warning

Hepatotoxicity:

Fatal and/or serious hepatotoxicity occurred in 14% of idelalisib-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue idelalisib as recommended.

Severe diarrhea/colitis:

Fatal and/or serious and severe diarrhea or colitis occurred in 14% of idelalisib-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue idelalisib as recommended.

Pneumonitis:

Fatal and serious pneumonitis can occur in idelalisib-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue idelalisib as recommended.

Intestinal perforation:

Fatal and serious intestinal perforation can occur in idelalisib-treated patients across clinical trials. Discontinue idelalisib for intestinal perforation.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Grade 3 or 4 neutropenia occurred in close to one-third of patients in clinical trials; thrombocytopenia and anemia (any grade) have also been reported. Monitor blood counts at least every 2 weeks for the first 6 months, and at least weekly in patients with neutropenia. May require treatment interruption and dosage reduction.

• Dermatologic toxicity: Severe and/or life-threatening cutaneous/mucocutaneous reactions (grade 3 or higher), including exfoliative dermatitis, rash (generalized, erythematous, macular-papular, pruritic, exfoliative), and skin disorder, have been observed. Toxic epidermal necrolysis (TEN) has been reported (when idelalisib was administered in combination with rituximab and bendamustine). Cases of Stevens Johnson syndrome (SJS) have been reported (some fatal) when idelalisib has been administered in combination with other medications associated with SJS. Monitor closely for dermatologic toxicity and discontinue for severe reactions.

• Gastrointestinal events: [US Boxed Warning]: Serious and/or fatal diarrhea and colitis have been reported. Monitor closely; may require treatment interruption, dosage reduction, and/or discontinuation. Grade 3 or higher diarrhea or colitis have been reported in clinical trials. Diarrhea may occur at any time during therapy and responds poorly to antidiarrheal (antimotility) medications. The median time to resolution of diarrhea was 1 week to 1 month (following therapy interruption); corticosteroids were used in some cases to manage toxicity. Avoid concomitant use with other promotility agents.

• Gastrointestinal perforation: [US Boxed Warning]: Serious and fatal intestinal perforation may occur; discontinue permanently if perforation develops. In some patients, perforation was preceded by moderate to severe diarrhea. Monitor closely for new or worsening abdominal pain, chills, fever, nausea, or vomiting.

• Hepatotoxicity: [US Boxed Warning]: Serious hepatotoxicity (some fatal) has been observed. Monitor hepatic function at baseline and during therapy. May require treatment interruption and/or dosage reduction. ALT/AST elevations >5 times ULN have occurred, and were generally observed during the first 12 weeks of therapy; transaminase elevations were reversible upon therapy interruption. Hepatotoxicity may recur upon rechallenge, even at a reduced dose; discontinue for recurrent hepatotoxicity. Avoid concomitant use with other hepatotoxic agents. Monitor ALT/AST at baseline and every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter, or as clinically necessary. Increase monitoring to weekly if ALT or AST >3 times ULN until resolved. Interrupt therapy if ALT/AST >5 times ULN; monitor LFTs weekly until resolved.

• Hypersensitivity reactions: Serious allergic/hypersensitivity reactions, including anaphylaxis, have been reported. Discontinue permanently for serious reactions and manage appropriately.

• Infections: Decreased overall survival and increased incidences of serious adverse events (usually infections) have been reported with idelalisib when used in combination with other medications used for the treatment of cancer. In March 2016, the manufacturer of idelalisib issued a "Dear Healthcare Provider" letter with the following recommendations (McHutchinson 2016): Idelalisib should not be used as first-line treatment for chronic lymphocytic leukemia. Patients should be advised of the risk of serious and/or fatal infections. Prophylaxis for Pneumocystis jirovecii pneumonia (PCP) should be administered throughout idelalisib treatment (and after discontinuation if infection risk persists). Monitor for cytomegalovirus (CMV) and permanently discontinue idelalisib if evidence of CMV infection or viremia exists. Monitor blood counts at least every 2 weeks during the initial 6 months of idelalisib treatment; monitor weekly in patients with an ANC <1,000/mm 3.

• Pneumonitis: [US Boxed Warning]: Serious and fatal pneumonitis may occur. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. May require therapy interruption or discontinuation. Symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates, or an oxygen saturation decrease of more than 5% should be promptly evaluated. Interrupt therapy for suspected pneumonitis; if diagnosis is confirmed, discontinue idelalisib and administer corticosteroids as appropriate.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Monitoring Parameters

Complete blood counts with differential at least every 2 weeks for the first 6 months, and at least weekly in patients with neutropenia (ANC <1,000/mm3 ), or as clinically necessary; liver function tests at baseline and every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter, or as clinically necessary; monitor for infections (including PCP and CMV); monitor for signs/symptoms of diarrhea/colitis, intestinal perforation, pneumonitis, dermatologic toxicity, and hypersensitivity reactions

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Women of reproductive potential should use effective contraception during therapy and for at least 1 month after treatment discontinuation.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, heartburn, joint pain, lack of appetite, loss of strength and energy, or insomnia. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), severe diarrhea, increase in bowel movements by six or more in a day, chills, severe nausea, vomiting, severe abdominal pain, mouth sores, night sweats, swelling of arms or legs, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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