Doptelet (10 Tab Pack) (avatrombopag maleate)

Dosage of avatrombopag maleate is expressed in terms of avatrombopag.

The avatrombopag product (tablet or sprinkle capsule) selected for use is based on the indication and patient age.

Avatrombopag is commercially available as oral tablets and as sprinkle capsules that contain oral granules; both formulations are administered with food. The sprinkle capsules should not be swallowed whole and the granules should not be chewed or crushed.

The tablets and sprinkle capsules are not substitutable on a mg-to-mg basis. The mixture prepared from the sprinkle capsules is more bioavailable than the tablets. No clinical trial experience is available regarding switching between sprinkle capsule and tablet dosing. Clinicians should monitor platelet counts weekly until count stabilization occurs and adjust dosing as necessary if a formulation is switched.

In order to administer the sprinkle capsules, the capsules should initially be opened and the granules sprinkled on a small amount of soft food (e.g., applesauce, strawberry jelly, plain yogurt) or liquid (e.g., whole or skim milk, orange juice, unflavored pediatric electrolyte solution, water) in a spoon or cup. The granules should be mixed into the soft food or liquid and consumed immediately after preparation. The spoon or cup should be rinsed with the soft food or liquid to ensure administration of the full dose.

The tablets and sprinkle capsules are stored at room temperature (20-25degreesC) with excursions permitted from 15-30degreesC.

No dosing information is available for this tab.

Avatrombopag is metabolized by cytochrome P-450 (CYP) isoenzymes 2C9 and 3A4. In vitro studies indicate that avatrombopag is a weak inducer of CYP2C8 and 2C9 but neither induces CYP isoenzymes 1A, 2B6, 2C, or 3A, nor inhibits CYP isoenzymes 1A, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A.

In vitro studies indicate that avatrombopag inhibits breast cancer resistance protein (BCRP) and organic anion transporter (OAT) 3, but does not inhibit organic anion transporting polypeptide (OATP) 1B or 1B3, organic cation transporter (OCT) 2, or organic anion transporter (OAT) 1.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Avatrombopag/Dual Inducers Of Cyp2c9 And Cyp3a4

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that are both moderate or strong inducers of CYP2C9 and CYP3A4 may increase the metabolism of avatrombopag.(1-2)

CLINICAL EFFECTS: Concurrent use of a dual inducer of CYP2C9 and CYP3A4 may result in decreased levels of and clinical effects of avatrombopag.(1-2)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of avatrombopag recommends dose adjustment of avatrombopag when used with drugs that are dual inducers of CYP2C9 and CYP3A4 in patients with persistent or chronic immune thrombocytopenia (ITP). When starting avatrombopag in a patient 6 years and older with persistent or chronic ITP already taking a dual CYP2C9 and CYP3A4 inducer, increase the dose of avatrombopag to 40 mg once daily. In pediatric patients 1 year to less than 6 years old who are on a dual CYP2C9 and CYP3A4 inducer, increase the starting dose of avatrombopag to 20 mg daily.(1) When starting a dual CYP2C9 and CYP3A4 inducer in a chronic ITP patient already taking avatrombopag, monitor platelet counts and adjust the dose of avatrombopag as needed, according to the prescribing information for avatrombopag.(1) No dose adjustments are required for patients with chronic liver disease.(1)

DISCUSSION: A study of 16 healthy subjects found that coadministration of rifampin (a moderate CYP2C9 and strong CYP3A4 inducer) and avatrombopag led to a 43 % decrease in the area-under-curve (AUC) of avatrombopag compared to avatrombopag administered alone and an approximately 5-fold reduction in the area-under-effect-curve (AUEC). There was no difference in the maximum concentration (Cmax) of avatrombopag or the maximum platelet count (Emax) with or without rifampin.(1-2) Drugs that are both moderate CYP2C9 inducers and strong CYP3A4 inducers linked to this monograph include: carbamazepine, enzalutamide, mavacamten, and rifampin.(1,3-4)

Avatrombopag/Dual Inhibitors Of Cyp2c9 & Cyp3a4

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that are both moderate or strong inhibitors of CYP2C9 and CYP3A4 may inhibit the metabolism of avatrombopag.(1-2)

CLINICAL EFFECTS: Concurrent use of a dual inhibitor of CYP2C9 and CYP3A4 may result in elevated levels of and clinical effects of avatrombopag, including thrombotic or thromboembolic complications.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of avatrombopag recommends dose adjustment of avatrombopag when used with drugs that are dual inhibitors of CYP2C9 and CYP3A4 in patients with persistent or chronic immune thrombocytopenia (ITP). When starting avatrombopag in a patient 6 years and older with persistent or chronic ITP already taking a dual CYP2C9 and CYP3A4 inhibitor, reduce the dose of avatrombopag to 20 mg three times weekly. In pediatric patients 1 year to less than 6 years old who are on a dual CYP2C9 and CYP3A4 inhibitor, reduce the starting dose of avatrombopag to 10 mg three times weekly.(1) When starting a dual CYP2C9 and CYP3A4 inhibitor in a chronic ITP patient already taking avatrombopag, monitor platelet counts and adjust the dose of avatrombopag as needed, according to the prescribing information for avatrombopag.(1) No dose adjustments are required for patients with chronic liver disease.(1)

DISCUSSION: A study of 16 healthy subjects found that coadministration of fluconazole (a moderate inhibitor of CYP2C9 and CYP3A4) with avatrombopag resulted in increased area-under-curve (AUC) and maximum concentration (Cmax) of avatrombopag of 2.16-fold and 1.17-fold, respectively, compared to avatrombopag administered alone.(1,2) The maximum increase in platelet count (Emax) with fluconazole and avatrombopag coadministration was increased by 1.66-fold, and the area-under-effect-curve (AUEC) for platelet count was increased by 1.47-fold.(2)

There are no moderate interactions for this drug.

*None.

• Lactation

• Thrombotic disorder

There are no moderate contraindications for this drug.

Adverse reactions reported in >=3% of adult patients with chronic liver disease receiving avatrombopag include pyrexia, abdominal pain, nausea, headache, fatigue, and peripheral edema.

Adverse reactions reported in >=10% of adult patients with chronic immune thrombocytopenia receiving avatrombopag include headache, fatigue, contusion, epistaxis, upper respiratory tract infection, arthralgia, gingival bleeding, petechiae, and nasopharyngitis.

Adverse reactions reported in >=10% pediatric patients with persistent or chronic immune thrombocytopenia receiving avatrombopag include viral infection, nasopharyngitis, cough, pyrexia, and oropharyngeal pain.

Rare or Very Rare

• Anemia
• Arterial thrombosis
• Choking sensation
• Hypersensitivity drug reaction
• Hyponatremia
• Pharyngeal edema
• Portal vein thrombosis
• Thromboembolic disorder
• Thrombotic disorder
• Tongue swelling

More Frequent

• Acute abdominal pain
• Arthralgia
• Cough
• Epistaxis
• Fatigue
• Fever
• Headache disorder
• Nausea
• Pain in oropharynx
• Peripheral edema
• Pharyngitis
• Upper respiratory infection
• Viral infection

Less Frequent

• Gingival bleeding
• Petechiae

Rare or Very Rare

• Erythema
• Facial edema
• Maculopapular rash
• Myalgia
• Pruritus of skin
• Skin rash

No enhanced messaging available.

Safety and efficacy of avatrombopag tablets have been established in pediatric patients >=6 years of age for the treatment of persistent or chronic immune thrombocytopenia. Safety and efficacy of avatrombopag sprinkle capsules have been established in pediatric patients 1 to <6 years of age for the treatment of persistent or chronic immune thrombocytopenia. The use of the tablet and granule formulations for their respective patient populations is supported by clinical data from a well-controlled study in pediatric patients >=1 year of age.

In animal studies, dose-dependent gastric glandular epithelial degeneration, regenerative hyperplasia, and atrophy were observed in juvenile rats receiving avatrombopag at exposures 14 times the human exposure at the maximum recommended dose. In addition, an increased incidence of background focal mineralization was observed in the kidneys of female rats at exposures 50 times the human exposure at the maximum recommended dose.

Avatrombopag may cause fetal harm if administered to pregnant women based on animal findings. Pregnant women should be apprised of the potential fetal risk.

There are insufficient data available regarding use of avatrombopag in pregnant women to inform a drug-associated risk. Adverse developmental outcomes (e.g., abortion, decreased body weight, increased pup mortality) were observed in animal studies when avatrombopag was administered orally during organogenesis in rabbits, and during organogenesis and the lactation period in rats at dose exposures substantially higher than those observed with the maximum recommended human dosage.

It is not known whether avatrombopag is distributed into human milk; the drug is distributed into milk in rats. Because of the potential for serious adverse reactions to avatrombopag in breast-fed infants, women should be advised not to breast-feed while receiving the drug and for at least 2 weeks after the last dose. If avatrombopag is used for brief periods (i.e., prior to a procedure in patients with chronic liver disease) in a lactating woman, the manufacturer states that breast-feeding should be interrupted and the affected milk discarded during treatment and for 2 weeks after the last dose is administered.

The effects of avatrombopag on breast-fed infants or on milk production are not known.

In clinical studies of chronic liver disease and chronic immune thrombocytopenia, 71 patients >=65 years of age and 12 patients >=75 years of age were treated with avatrombopag. Clinical studies did not include sufficient numbers of patients >=65 years of age to determine whether geriatric patients respond differently than younger adults. Other reported clinical experience has not identified differences in responses between geriatric patients and younger adults.