avatrombopag (Rx)

Brand and Other Names:Doptelet
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 20mg

Thrombocytopenia

Patients with chronic liver disease

  • Indicated for thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a procedure
  • Initiate 10-13 days before the scheduled procedure
  • Patients should undergo their procedure 5-8 days after the last dose
  • Dose based on pre-procedure platelet count
    • Platelet count <40 x109/L: 60 mg PO qDay x 5 days
    • Platelet count 40 to <50 x109/L: 40 mg PO qDay x 5 days

Patients with chronic immune thrombocytopenia

  • Indicated for thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment
  • Use lowest dose needed to achieve and maintain a platelet count ≥50 x109/L to reduce the risk for bleeding
  • Initial dose: 20 mg PO qDay; not to exceed 40 mg PO qDay

Dosage Modifications

Chronic ITP

  • Dose adjustments by platelet count
    • Platelet count <50 x109/L after ≥2 weeks: Increase by 1 dose level; wait 2 wk to assess effects before further adjustment
    • Platelet count 200-400 x109/L: Decrease 1 dose level; wait 2 wk to assess effects before further adjustment
    • Platelet count >400 x109/L: Stop treatment and increase platelet monitoring to twice weekly; may restart by decreasing 1 dose level when platelets <150 x109/L
    • Platelet count <50 x109/L after 4 weeks at 40 mg/day: Discontinue treatment
    • Platelet count >400 x109/L after 2 weeks at 20 mg/week: Discontinue treatment
  • Dose levels for titration
    • Dose level 6: 40 mg qDay
    • Dose level 5: 40 mg 3x/week AND 20 mg on the 4 remaining days each week
    • Dose level 4: 20 mg qDay
    • Dose level 3: 20 mg 3x/week
    • Dose level 2: 20 mg 2x/week OR 40 mg qWeek
    • Dose level 1: 20 mg qWeek
  • Discontinue treatment
    • Platelet count does not increase ≥50 x109/L after 4 weeks at 40 mg qDay (maximum dose)
    • Platelet count is >400 x109/L after 2 weeks at 20 mg qWeek
  • Coadministration of dual CYP2C9 and CYP3A4 inhibitors or inducers
    • Moderate or strong dual inhibitors of CYP2C9 and CYP3A4: Start avatrombopag 20 mg 3x/week
    • Moderate or strong dual inducers of CYP2C9 and CYP3A4: Start avatrombopag 40 mg qDay

Renal impairment

  • Mild-to-moderate (CrCl ≥30 mL/min): No dose adjustment required; minimally excreted by the kidneys
  • Severe (CrCl <30 mL/min) or hemodialysis: Unknown

Hepatic impairment

  • Child-Turcotte-Pugh grades A, B, or C or MELD score 4-23: No clinically meaningful effects on the pharmacokinetics

Dosing Considerations

Do not administer in an attempt to normalize platelet counts

Chronic liver disease

  • Obtain platelet count before initiating therapy and on the day of a procedure

Chronic ITP

  • After initiating, assess platelet count weekly until ≥50 x109/L achieved, and then monthly thereafter
  • Obtain platelet counts weekly for at least 4 weeks following discontinuation

Chemotherapy-Induced Thrombocytopenia (Orphan)

Orphan designation for treatment of chemotherapy-induced thrombocytopenia (CIT)

Sponsor

  • Dova Pharmaceuticals, Inc; 240 Leigh Farm Road,Suite 245; Durham, North Carolina 27707

Safety and efficacy not established

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Interactions

Interaction Checker

and avatrombopag

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Contraindicated (0)

              Serious - Use Alternative (9)

              • abametapir

                abametapir will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.

              • amobarbital

                amobarbital will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • fexinidazole

                fexinidazole will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

              • lonafarnib

                lonafarnib will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration with sensitive CYP3A substrates. If coadministration unavoidable, monitor for adverse reactions and reduce CYP3A substrate dose in accordance with product labeling.

              • ritonavir

                ritonavir will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • sotorasib

                sotorasib will decrease the level or effect of avatrombopag by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If use is unavoidable, refer to the prescribing information of the P-gp substrate for dosage modifications.

              • tepotinib

                tepotinib will increase the level or effect of avatrombopag by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If concomitant use unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.

              • tucatinib

                tucatinib will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.

              • voxelotor

                voxelotor will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.

              Monitor Closely (25)

              • amiodarone

                amiodarone will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inhibitor requires a decreased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • belzutifan

                belzutifan will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If unable to avoid coadministration of belzutifan with sensitive CYP3A4 substrates, consider increasing the sensitive CYP3A4 substrate dose in accordance with its prescribing information.

              • berotralstat

                berotralstat will increase the level or effect of avatrombopag by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor or titrate P-gp substrate dose if coadministered.

              • bosentan

                bosentan will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inducer requires an increased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • carbamazepine

                carbamazepine will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inducer requires an increased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • cenobamate

                cenobamate will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.

              • ceritinib

                ceritinib will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inhibitor requires a decreased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • cobicistat

                cobicistat will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inhibitor requires a decreased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • elagolix

                elagolix will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.

              • enzalutamide

                enzalutamide will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inducer requires an increased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • fluconazole

                fluconazole will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inhibitor requires a decreased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • fosphenytoin

                fosphenytoin will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inducer requires an increased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • istradefylline

                istradefylline will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.

              • ketoconazole

                ketoconazole will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inhibitor requires a decreased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • mifepristone

                mifepristone will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, reduce starting dose of avatrombopag to 20 mg PO 3 times weekly when used concomitantly with mifepristone; in patients starting mifepristone while receiving avatrombopag, monitor platelet counts and adjust avatrombopag dose as necessary; coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inhibitor requires a decreased avatrombopag starting dose. Refer to manufacturer recommendations.

              • phenobarbital

                phenobarbital will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inducer requires an increased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • phenytoin

                phenytoin will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inducer requires an increased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • primidone

                primidone will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inducer requires an increased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • rifampin

                rifampin will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inducer requires an increased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • rifapentine

                rifapentine will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inducer requires an increased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • rucaparib

                rucaparib will increase the level or effect of avatrombopag by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP2C9 substrates, if clinically indicated.

              • secobarbital

                secobarbital will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inducer requires an increased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              • tazemetostat

                tazemetostat will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • tucatinib

                tucatinib will increase the level or effect of avatrombopag by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.

              • voriconazole

                voriconazole will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inhibitor requires a decreased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

              Minor (1)

              • ribociclib

                ribociclib will increase the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

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              Adverse Effects

              >10%

              Chronic liver disease

              • Pyrexia (8-11%)

              Chronic ITP

              • Headache (31%)
              • Fatigue (28%)
              • Contusion (26%)
              • Epistaxis (19%)
              • Upper respiratory tract infection (15%)
              • Arthralgia (13%)
              • Gingival bleeding (13%)
              • Petechiae (11%)

              1-10%

              Chronic liver disease

              • Abdominal pain (6-7%)
              • Nausea (6-7%)
              • Fatigue (3-4%)
              • Peripheral edema (2-4%)

              Chronic ITP

              • Nasopharyngitis (10%)
              • Headache (1.6%)

              <1%

              Chronic liver disease

              • Anemia (0.4%)
              • Pyrexia (0.4%)
              • Myalgia (0.4%)

              Frequency Not Defined

              Chronic liver disease

              • Hyponatremia

              Postmarketing Reports

              Immune system disorders: Hypersensitivity reactions including pruritus, rash, choking sensation, erythema, pharyngeal edema, pruritus generalized, rash macular, swelling face, and swollen tongue

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              Warnings

              Contraindications

              None

              Cautions

              Thrombotic/thromboembolic complications

              • Thrombopoietin (TPO) receptor agonists associated with thrombotic and thromboembolic complications in patients with chronic liver disease or chronic ITP
              • Portal vein thrombosis reported with chronic liver disease in patients treated with thrombopoietin (TPO) receptor agonists (ADAPT-1 and ADAPT-2 clinical trials)
              • Consider the potential increased thrombotic risk when administering to patients with known risk factors for thromboembolism, including genetic prothrombotic conditions (eg, factor V Leiden, prothrombin 20210A, antithrombin deficiency, or protein C or S deficiency)
              • Not to be administered to patients with chronic liver disease or chronic immune thrombocytopenia in an attempt to normalize platelet counts; thromboembolic events (arterial or venous) reported
              • Monitor platelet counts and follow dosing guidelines to achieve target platelet counts; monitor patients receiving therapy for signs and symptoms of thromboembolic events and institute treatment promptly

              Drug interaction overview

              • Avatrombopag is a CYP2C9 and CYP3A4 substrate; it inhibits organic anion transporter (OAT) 3 and breast cancer resistance protein (BCRP)
              • Moderate or strong dual CYP2C9 and CYP3A4 inhibitors
                • Coadministration with a moderate or strong dual CYP2C9 and CYP3A4 inhibitor increases avatrombopag AUC, which may increase the risk of avatrombopag toxicities
                • If starting a moderate or strong dual CYP2C9 and CYP3A4 inhibitor during treatment, monitor platelet counts and adjust avatrombopag dose as necessary
              • Moderate or strong dual CYP2C9 and CYP3A4 inducers
                • Coadministration with a moderate or strong dual CYP2C9 and CYP3A4 inducers decreases avatrombopag AUC, which may reduce efficacy of avatrombopag
                • If starting a moderate or strong dual CYP2C9 and CYP3A4 inducer during treatment, monitor platelet counts and adjust avatrombopag dose as necessary
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              Pregnancy

              Pregnancy

              Based on findings from animal reproduction studies, may cause fetal harm when administered to pregnant women

              Animal data

              • In animal reproduction studies, administration resulted in adverse developmental outcomes when administered during organogenesis in rabbits and during organogenesis and the lactation period in rats
              • These findings were observed at exposures based on AUC substantially higher than AUC observed in patients at a dose of 60 mg qDay
              • Advise pregnant women of the potential risk to a fetus

              Lactation

              No data are available regarding the presence of the drug in human milk, the effects on the breastfed child, or the effects on milk production

              In studies, avatrombopag was present in the milk of lactating rats; when a drug is present in animal milk, it is likely the drug will be present in human milk

              Owing to the potential for serious adverse reactions in a breastfed child, breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose

              Clinical considerations

              • Interrupt breastfeeding and pump and discard breast milk in lactating women receiving avatrombopag for brief periods (eg, before an invasive procedure) during treatment and for 2 weeks after the last dose in order to minimize exposure to a breastfed child

              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

              Second-generation orally administered thrombopoietin receptor agonist (TPO-RA)

              Stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, resulting in an increased production of platelets

              Does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production

              Absorption

              Peak plasma time: 5-6 hr

              Peak plasma concentration: 166 ng/mL

              AUC: 4198 ng·hr/mL

              Systemic exposure variability reduced by 40-60% when administered with food

              Distribution

              Protein bound: >96%

              Vd: 180 L

              Metabolism

              Metabolized primarily by CYP2C9 and CYP3A4

              Elimination

              Half-life: 19 hr

              Clearance: 6.9 L/hr

              Excretion: 88% feces (34% unchanged); 6% urine

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              Administration

              Oral Administration

              Take with food

              Chronic liver disease: Administer for 5 consecutive days; all 5 doses should be completed

              Missed dose

              • In the case of a missed dose, administer next dose as soon as possible
              • Do not take 2 doses at one time to make up for a missed dose; take the next dose at the usual time the next day

              Storage

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

              Store in original package

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              Images

              BRAND FORM. UNIT PRICE PILL IMAGE
              Doptelet (10 tab pack) oral
              -
              20 mg tablet
              Doptelet (15 tab pack) oral
              -
              20 mg tablet
              Doptelet (30 tab pack) oral
              -
              20 mg tablet

              Copyright © 2010 First DataBank, Inc.

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              Patient Handout

              A Patient Handout is not currently available for this monograph.
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              Formulary

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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.
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              NC NOT COVERED – Drugs that are not covered by the plan.
              Code Definition
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              Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.