Avalet20 mg

Avalet is indicated for the treatment of thrombocytopenia in patients scheduled to undergo a procedure, and for the treatment of chronic immune thrombocytopenia (ITP) in patients who have had an insufficient response to a previous treatment.

Established / FDA-approved uses

• Chronic liver disease (CLD) with thrombocytopenia, prior to a scheduled procedure: Avalet is used short-term (a 5-day course) in adults with chronic liver disease to raise platelet counts high enough to safely undergo a planned invasive or surgical procedure.
• Chronic immune thrombocytopenia (ITP) in adults: Avalet is used for adults with chronic ITP who have had an insufficient response to a previous therapy (e.g., corticosteroids, immunoglobulins, splenectomy).
• Chronic/persistent ITP in children 1 year of age and older: Avalet is also approved for pediatric patients with persistent or chronic ITP who have had an insufficient response to a previous treatment; see Pediatric Uses.

Avalet does not address the underlying cause of thrombocytopenia. It is intended to be used as part of a broader treatment plan, under the supervision of a specialist (hepatologist for chronic liver disease, or hematologist for ITP).

Each film-coated tablet contains Avatrombopag (as avatrombopag maleate) equivalent to 20 mg of avatrombopag base.

Oral granules ("sprinkle" formulation) contain Avatrombopag (as avatrombopag maleate) equivalent to 5 mg or 10 mg of avatrombopag base per packet, for patients unable to swallow tablets.

Tablet and granule formulations of Avatrombopag are not interchangeable on a milligram-for-milligram basis.

Avalet is a small-molecule, orally administered thrombopoietin (TPO) receptor agonist. It works by stimulating the same receptor that the body's natural thrombopoietin uses to signal bone marrow cells to produce platelets, thereby raising platelet counts in people with thrombocytopenia (low platelet counts) related to chronic liver disease or chronic immune thrombocytopenia.

Unlike some earlier oral TPO receptor agonists, Avalet does not require dietary restrictions related to divalent cations and can be taken with a meal.

Avalet belongs to the therapeutic class of thrombopoietin (TPO) receptor agonists, also referred to as platelet growth factor agents or antihemorrhagic/hematopoietic stimulant agents used to increase platelet production.

Pharmacodynamics

Avatrombopag binds to the transmembrane domain of the human thrombopoietin (TPO) receptor on megakaryocyte precursor cells, a binding site distinct from that of endogenous TPO. This interaction activates intracellular JAK/STAT and MAPK/ERK signalling pathways, promoting proliferation and differentiation of megakaryocytes and ultimately increasing platelet production. Avatrombopag acts synergistically with, rather than by competing against, endogenous thrombopoietin. See Mode of Action for a concise mechanistic summary.

Pharmacokinetics

• Absorption: Peak plasma concentrations are reached approximately 5-6 hours after an oral dose taken with food; taking Avatrombopag with food increases absorption and is required (see Administration).
• Distribution: Highly bound to plasma proteins (greater than 96%).
• Metabolism: Metabolized primarily via CYP2C9 and CYP3A4 hepatic pathways.
• Elimination: Elimination half-life is approximately 19 hours; excreted mainly in feces, with a minor renal component.

Avalet must be taken with food. Tablets are swallowed whole and are not interchangeable with the oral granule ("sprinkle") formulation on a milligram-for-milligram basis. Oral granules must be mixed with a small amount of soft food or liquid immediately before use and taken right away. See Dosage and Administration for full instructions and timing relative to a scheduled procedure.

CYP2C9 and CYP3A4 modulators (relevant to the chronic ITP dosing regimen)

Avalet is metabolized by CYP2C9 and CYP3A4. In patients being treated for chronic ITP:

• Dual moderate-to-strong CYP2C9 and CYP3A4 inhibitors (e.g., fluconazole) increase Avalet exposure; a reduced starting dose is recommended and the patient should be monitored more closely for adverse effects, particularly thrombotic risk.
• Dual moderate-to-strong CYP2C9 and CYP3A4 inducers (e.g., rifampin) decrease Avalet exposure; an increased starting dose is recommended, with close monitoring of platelet response.

No dose adjustment for these interactions is recommended for the short, fixed 5-day chronic liver disease/procedure regimen, but the prescriber should still be aware of concomitant use.

Other medicines affecting hemostasis

Concomitant use of anticoagulants or antiplatelet agents may add to the thrombotic risk associated with Avalet (see Precautions and Warnings) and warrants closer clinical monitoring.

Chronic liver disease (short 5-day course before a procedure)

Most common: pyrexia (fever), abdominal pain, nausea/vomiting, headache, fatigue, and peripheral edema.

Chronic ITP - adults

Most common: headache, fatigue, contusion (bruising), epistaxis (nosebleed), petechiae, myalgia (muscle pain), and upper respiratory tract infection.

Chronic/persistent ITP - pediatric patients

Most common: viral infection, pyrexia, cough, oropharyngeal pain (sore throat), upper respiratory tract infection, and vomiting.

Serious adverse effects

With Avalet, thrombotic/thromboembolic events (see Precautions and Warnings) and hepatic decompensation in patients with chronic liver disease have been reported; seek prompt medical attention for symptoms such as leg swelling/pain, chest pain, shortness of breath, or worsening confusion/jaundice.

Pregnancy: There are no adequate, well-controlled studies of Avalet in pregnant women. Animal reproduction studies have shown adverse effects on the fetus at maternal exposures relevant to the recommended human dose. Avalet should be used during pregnancy only if clearly needed and if the potential benefit to the mother justifies the potential risk to the fetus; a physician should always be consulted before use in pregnancy.

Lactation: It is not known whether Avalet passes into human breast milk. Because of the potential for serious adverse reactions in a breastfed infant, it is generally recommended to discontinue breastfeeding during treatment and for approximately two weeks after the last dose; consult a physician regarding infant feeding options.

Thrombotic/thromboembolic events

Avalet, like other thrombopoietin receptor agonists, has been associated with thrombotic and thromboembolic events, including portal vein thrombosis, which is of particular relevance in patients with chronic liver disease - a population that already carries some baseline risk of thrombosis. To reduce this risk, Avalet should be dosed to achieve the platelet count needed for the clinical purpose (safe conduct of a procedure, or reduced bleeding risk in ITP), not to normalize the platelet count.

Hepatic decompensation

Hepatic decompensation has been observed in patients with chronic liver disease receiving thrombopoietin receptor agonists, including Avalet, in some clinical contexts. Patients with chronic liver disease should be monitored clinically for signs of worsening liver function during and after treatment.

Worsening thrombocytopenia after discontinuation

Platelet counts may fall below the pre-treatment baseline after Avalet is stopped, increasing bleeding risk, particularly in ITP; platelet counts should be monitored weekly for at least 4 weeks after discontinuation.

General

Avalet does not treat the underlying cause of thrombocytopenia; it should be used only as part of a broader management plan under the supervision of a hepatologist or hematologist, with regular clinical and laboratory monitoring.

There is limited clinical experience with Avalet overdose. An overdose could be expected to cause an excessive rise in platelet count, which may increase the risk of thrombotic/thromboembolic complications. If an overdose of Avalet is suspected, seek immediate medical attention or contact a poison control center; platelet counts should be monitored closely and supportive care provided by a physician. Do not attempt to manage a suspected overdose at home without medical guidance.

Store Avalet tablets and oral granules at room temperature, between 20°C and 25°C (68°F-77°F); brief excursions outside this range during transport are generally acceptable. Keep tablets in their original blister packaging until immediately before use, protected from excess light and moisture. Keep out of reach of children.

Renal impairment

No dose adjustment of Avalet is required in patients with renal impairment.

Hepatic impairment

Avalet has been specifically studied in patients with chronic liver disease of varying severity for the procedure-related indication; no additional dose adjustment beyond the standard CLD dosing regimen is recommended based on hepatic impairment alone. See Precautions and Warnings for hepatic decompensation monitoring.

Elderly patients

No overall differences in safety or effectiveness of Avalet have been observed between elderly and younger adult patients, though as with any medicine, use with appropriate monitoring in older adults with multiple comorbidities.

Pediatric patients

See Pediatric Uses for age-specific approved use and dosing of Avalet.

For the chronic liver disease/procedure indication, Avalet is used for a short, fixed 5-day course. For chronic ITP (adult and pediatric), Avalet is typically used long-term/chronically at the lowest dose that maintains a platelet count sufficient to reduce bleeding risk, with regular monitoring; treatment should be discontinued if an adequate platelet response is not achieved after 2 weeks at the maximum dose.

Avatrombopag belongs to the drug class of thrombopoietin (TPO) receptor agonists - small-molecule, non-peptide agents that stimulate platelet production, distinct from peptide TPO mimetics and from earlier recombinant thrombopoietin products.

Avatrombopag binds to the transmembrane domain of the thrombopoietin receptor (MPL) on megakaryocytes and their precursors, at a site distinct from the endogenous ligand. This activates downstream JAK2/STAT and MAPK signalling, driving megakaryocyte proliferation and maturation and leading to increased platelet production, without competing with the body's own thrombopoietin.

Avalet is approved for the treatment of chronic/persistent immune thrombocytopenia (ITP) in children 1 year of age and older who have had an insufficient response to a previous treatment.

• 1 to less than 6 years: oral granule ("sprinkle") formulation only, starting at 10 mg once daily, titrated up to a maximum of 20 mg once daily based on platelet response.
• 6 years and older: tablet or oral granule formulation, starting at 20 mg once daily, titrated up to a maximum of 40 mg once daily.

The safety and effectiveness of Avalet for the chronic liver disease/pre-procedure indication have not been established in pediatric patients. Children receiving Avalet should be monitored by a pediatric hematologist, with the same attention to thrombotic risk and platelet-count targets described in Precautions and Warnings.