umbralisib (Rx)

Brand and Other Names:Ukoniq
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet

  • 200mg

Marginal Zone Lymphoma

Indicated for relapsed or refractory marginal zone lymphoma (MZL) in adults who have received ≥1 prior anti-CD20-regimen

800 mg PO qDay

Continue until disease progression or unacceptable toxicity

Follicular Lymphoma

Indicated for relapsed or refractory follicular lymphoma (FL) in adults who have received ≥3 prior lines of systemic therapy

800 mg PO qDay

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Dose reductions for adverse reactions

  • First dose reduction: 600 mg qDay
  • Second dose reduction: 400 mg qDay
  • Unable to tolerate 400 mg/day: Permanently discontinue

Neutropenia

Absolute neutrophil count (ANC) 0.5-1 x 10^9/L
  • Maintain dose
  • If recurs or persistent, then withhold until ANC ≥1 x 109/L, then resume at same dose
ANC <0.5 x 10^9/L
  • Withhold until ANC ≥0.5 x 109/L, then resume at same dose
  • If recurs, then resume at reduced dose

Thrombocytopenia

  • Platelet count 25 to <50 x 109/L with bleeding OR <25 x 109/L
  • Withhold until platelet count ≥25 x 109/L and bleeding resolved (if applicable), then resume at same dose
  • If recurs, withhold until resolved, then resume at reduced dose

Infection

Includes opportunistic infection

  • Grade 3 or 4 infection
  • Withhold until resolved, then resume at same or reduced dose
  • Pneumocystis jirovecii pneumonia (PJP)
    • Suspected PJP: Withhold until evaluated
    • Confirmed PJP: Permanently discontinue
  • Cytomegalovirus (CMV) infection
    • Withhold until infection or viremia resolves, then resume at same or reduced dose
    • Monitor for CMV reactivation by polymerase chain reaction or antigen test at least monthly

Elevated ALT/AST

  • ALT/AST >5x to <20x ULN: Withhold until AST/ALT <3x ULN, then resume at reduced dose
  • ALT/AST >20x ULN: Discontinue

Diarrhea or noninfectious colitis

  • Withhold until resolved, then resume at same or reduced dose
    • Persistent mild or moderate diarrhea (≤6 stools/day over baseline) OR
    • Persistent asymptomatic (Grade 1) colitis
    • If recurs, withhold until resolved, then resume at reduced dose
  • Withhold until resolved, then resume at reduced dose
    • Severe diarrhea (>6 stools/day over baseline) OR
    • Abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs
  • Discontinue
    • Recurrent severe diarrhea or colitis (any grade)
    • Life-threatening diarrhea or noninfectious colitis

Severe cutaneous reactions

  • Severe
    • Withhold until resolved, then resume at reduced dose or discontinue
    • If recurs after rechallenge, discontinue
  • Discontinue
    • Life-threatening cutaneous reactions
    • Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (any grade)

Other adverse reactions

  • Severe: Withhold until resolved, then resume at same or reduced dose
  • Life-threatening: Discontinue

Renal impairment

  • Mild or moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
  • Severe (CrCl <30 mL/min): Not studied

Hepatic impairment

  • Mild (total bilirubin ≤1.5x ULN and any AST): No dosage adjustment necessary
  • Moderate or severe (total bilirubin >1.5x ULN and any AST): Not studied

Dosing Considerations

Verify pregnancy status in females of reproductive potential before initiation

Prophylaxis

  • Provide prophylaxis for PJP during treatment
  • Consider prophylactic antivirals during treatment to prevent CMV infection, including CMV reactivation

Monitoring parameter

  • Hepatic function: Baseline, during treatment
  • Neutrophil counts
    • First 2 months: At least every 2 weeks
    • Patients with neutrophil count <1 x 109: At least weekly

Safety and efficacy not established

No overall differences in efficacy or pharmacokinetics observed between older and younger patients

Patients ≥65 years had higher incidences of serious adverse reactions (including infections) compared with patients <65 years

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Interactions

Interaction Checker

and umbralisib

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            All grades

            • Creatinine increased (79%)
            • Diarrhea (58%)
            • Fatigue (41%)
            • Nausea (38%)
            • Neutrophils decreased (33%)
            • ALT increased (33%)
            • AST increased (32%)
            • Hemoglobin decreased (27%)
            • Musculoskeletal pain (27%)
            • Platelets decreased (26%)
            • Potassium decreased (21%)
            • Vomiting (21%)
            • Upper respiratory tract infection (21%)
            • Abdominal pain (19%)
            • Decreased appetite (19%)
            • Rash (18%)
            • Edema (14%)
            • Insomnia (14%)

            Grade 3 or 4

            • Neutrophil decreased (16%)

            1-10%

            All grades

            • Pyrexia (10%)
            • Urinary tract infection (9%)
            • Dyspnea (7%)
            • Pneumonia (6%)
            • Sepsis (3%)
            • Colitis (2%)

            Grade 3 or 4

            • Diarrhea (10%)
            • ALT increased (8%)
            • AST increased (7%)
            • Platelets decreased (4%)
            • Potassium decreased (4%)
            • Hemoglobin decreased (3%)
            • Rash (3%)
            • Fatigue (3%)
            • Abdominal pain (3%)
            • Musculoskeletal pain (2%)
            • Decreased appetite (2%)

            <1%

            Grade 3 or 4

            • Pneumonitis
            • Exfoliative dermatitis
            • Nausea
            • Vomiting
            • Edema
            • Upper respiratory tract infection
            • Insomnia
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            Warnings

            Contraindications

            None

            Cautions

            Serious neutropenia reported; monitor and consider appropriate supportive care

            Serious diarrhea or noninfectious colitis occurred; monitor for development of diarrhea or colitis and provide supportive care (ie, antidiarrheals, enteric-acting steroids) as appropriate

            Serious hepatotoxicity occurred; median time to onset for grade ≥3 elevated AST/ALT monitor hepatic function

            Contains FD&C yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma); incidence of sensitivity frequently seen in patients who also have aspirin hypersensitivity

            Can cause fetal harm when administered to pregnant females

            Infections

            • Serious, including fatal, infections occurred
            • Monitor for fever, CMV infection, and any new or worsening signs and symptoms of infection
            • Evaluate promptly and treat as needed
            • Provide prophylaxis for Pneumocystis jirovecii pneumonia (PJP) and consider prophylactic antivirals for CMV prevention during treatment

            Severe cutaneous reactions

            • Severe cutaneous reactions, including a fatal case of exfoliative dermatitis
            • Monitor for new or worsening cutaneous reactions
            • Review all concomitant medications and discontinue any potentially contributing medications
            • Provide supportive care as appropriate

            Drug interaction overview

            • Substrate of CYP1A2, CYP2C9, and CYP3A4
            • Inhibits CYP2C8, CYP2C9, CYP2C19, CYP3A4, and P-gp; induces CYP3A4
            • Coadministration with strong CYP3A4 or CYP2C9 inhibitors and inducers: Not studied
            • Coadministration with sensitive substrates of CYP3A4, CYP2C8, CYP2C9 and CYP2C19, or P-gp substrates: Not fully characterized
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            Pregnancy & Lactation

            Pregnancy

            May cause fetal harm when administered to pregnant females

            Data are not available on use in pregnant females

            Verify pregnancy status in females of reproductive potential before initiation

            Animal data

            • Administration to pregnant mice during organogenesis resulted in adverse developmental outcomes (eg, alterations to growth, embryofetal mortality, structural abnormalities) at maternal exposures (AUC) comparable to 800-mg dose

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for 1 month after last dose
            • Males with female partners of reproductive potential: Use effective contraception during treatment and for 1 month after last dose

            Infertility

            • Based on findings from mice and dogs, male fertility may be impaired
            • Trend for reversibility noted in dogs 30 days after last dose

            Lactation

            No data available on presence in milk, effects on breastfed children, or milk production

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Dual inhibitor of phosphatidylinositol-3-kinase (PI3K) delta and casein kinase (CK1) 1-epsilon expressed on malignant B cells

            PI3K-delta plays an important role in supporting cell proliferation and survival, cell differentiation, intercellular trafficking and immunity

            CK1-epsilon is a regulator of oncoprotein translation and has been implicated in the pathogenesis of cancer cells, including lymphoid malignancies

            Absorption

            Peak plasma concentration (steady-state): 7.3 mcg/mL

            Peak plasma time: ~4 hr

            AUC (steady-state): 141 mcg⋅hr/mL

            Effect of food

            • A single dose with a high-fat, high-calorie meal (~917 calories [171 calories from protein, 232 calories from carbohydrate, and 502 calories from fat]) increased AUC and peak plasma concentration

            Distribution

            Protein bound: ≥99.7%

            Vd (central): 312 L

            Mean blood-to-plasma ration: 0.6

            Metabolism

            Metabolized by CYP2C9, CYP3A4, and CYP1A2

            Elimination

            Half-life: 91 hr

            Clearance: 15.5 L/hr

            Excretion: ~81% (feces [17% unchanged]); 3% (urine [0.02% unchanged])

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            Administration

            Oral Administration

            Take with food at same time each day

            Swallow tablet whole; do not crush, break, cut, or chew

            Provide prophylaxis (ie, antivirals) for PJP during treatment

            Missed dose

            • Vomited dose: Skip dose; wait for next scheduled dose
            • Missed dose ≥12 hr from next dose: Take as soon as possible
            • Missed dose <12 hr from next dose: Skip dose; wait for next scheduled dose

            Storage

            Store at 68-77ºF (20-25ºC); excursions permitted to 59-86ºF (15-30ºC)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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