Revolade Dosage/Direction for Use

Revolade treatment should be initiated by and remain under the supervision of a physician who is experienced in the treatment of haematological diseases or the management of chronic hepatitis C and its complications.
Posology: Revolade dosing requirements must be individualised based on the patient's platelet counts. The objective of treatment with Revolade should not be to normalise platelet counts.
Immune (primary) thrombocytopenia: The lowest dose of Revolade to achieve and maintain a platelet count ≥50,000/μl should be used. Dose adjustments are based upon the platelet count response. Revolade must not be used to normalise platelet counts. In clinical studies, platelet counts generally increased within 1 to 2 weeks after starting Revolade and decreased within 1 to 2 weeks after discontinuation.
Adults and paediatric population aged 6 to 17 years: The recommended starting dose of Revolade is 50 mg once daily. For patients of East-/Southeast-Asian ancestry Revolade should be initiated at a reduced dose of 25 mg once daily (see Pharmacology: Pharmacokinetics under Actions).
Monitoring and dose adjustment: After initiating Revolade, the dose must be adjusted to achieve and maintain a platelet count ≥50,000/μl as necessary to reduce the risk for bleeding. A daily dose of 75 mg must not be exceeded.
Clinical haematology and liver tests should be monitored regularly throughout therapy with Revolade and the dose regimen of Revolade modified based on platelet counts as outlined in Table 11. During therapy with Revolade full blood counts (FBCs), including platelet count and peripheral blood smears, should be assessed weekly until a stable platelet count (≥50,000/μl for at least 4 weeks) has been achieved. FBCs including platelet counts and peripheral blood smears should be obtained monthly thereafter. (See Table 11.)

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Revolade can be administered in addition to other ITP medicinal products. The dose regimen of concomitant ITP medicinal products should be modified, as medically appropriate, to avoid excessive increases in platelet counts during therapy with Revolade.
It is necessary to wait for at least 2 weeks to see the effect of any dose adjustment on the patient's platelet response prior to considering another dose adjustment.
The standard Revolade dose adjustment, either decrease or increase, would be 25 mg once daily.
Discontinuation: Treatment with Revolade should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of Revolade therapy at 75 mg once daily.
Patients should be clinically evaluated periodically and continuation of treatment should be decided on an individual basis by the treating physician. In non-splenectomised patients this should include evaluation relative to splenectomy. The reoccurrence of thrombocytopenia is possible upon discontinuation of treatment (see Precautions).
Chronic hepatitis C (HCV) associated thrombocytopenia: When Revolade is given in combination with antivirals reference should be made to the full summary of product characteristics of the respective coadministered medicinal products for comprehensive details of relevant safety information or contraindications.
In clinical studies, platelet counts generally began to increase within 1 week of starting Revolade. The aim of treatment with Revolade should be to achieve the minimum level of platelet counts needed to initiate antiviral therapy, in adherence to clinical practice recommendations. During antiviral therapy, the aim of treatment should be to keep platelet counts at a level that prevents the risk of bleeding complications, normally around 50,000-75,000/μl. Platelet counts >75,000/μl should be avoided. The lowest dose of Revolade needed to achieve the targets should be used. Dose adjustments are based upon the platelet count response.
Initial dose regimen: Revolade should be initiated at a dose of 25 mg once daily. No dosage adjustment is necessary for HCV patients of East-/Southeast-Asian ancestry or patients with mild hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Monitoring and dose adjustment: The dose of Revolade should be adjusted in 25 mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Platelet counts should be monitored every week prior to starting antiviral therapy. On initiation of antiviral therapy the platelet count may fall, so immediate Revolade dose adjustments should be avoided (see Table 12).
During antiviral therapy, the dose of Revolade should be adjusted as necessary to avoid dose reductions of peginterferon due to decreasing platelet counts that may put patients at risk of bleeding (see Table 12). Platelet counts should be monitored weekly during antiviral therapy until a stable platelet count is achieved, normally around 50,000-75,000/μl. FBCs including platelet counts and peripheral blood smears should be obtained monthly thereafter. Dose reductions on the daily dose by 25 mg should be considered if platelet counts exceed the required target. It is recommended to wait for 2 weeks to assess the effects of this and any subsequent dose adjustments.
A dose of 100 mg Revolade once daily must not be exceeded. (See Table 12.)

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Discontinuation: If after 2 weeks of Revolade therapy at 100 mg the required platelet level to initiate antiviral therapy is not achieved, Revolade should be discontinued.
Revolade treatment should be terminated when antiviral therapy is discontinued unless otherwise justified. Excessive platelet count responses or important liver test abnormalities also necessitate discontinuation.
First-line Severe Aplastic Anemia: Initiate Revolade concurrently with standard immunosuppressive therapy.
Initial Dose Regimen: The recommended initial dose regimen is listed in Table 13. Do not exceed the initial dose of Revolade. (See Table 13.)

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For patients with severe aplastic anemia of East-/Southeast-Asian ancestry or those with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B, C), decrease the initial Revolade dose by 50% as listed in Table 14.
If baseline ALT or AST levels are >6 x ULN, do not initiate Revolade until transaminase levels are <5 x ULN. Determine the initial dose for these patients based on Table 13 or Table 14. (See Tables 14 and 15.)

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Monitoring and Dose Adjustment for Revolade: Perform clinical hematology and liver tests regularly throughout therapy with Revolade. (See Table 16.)

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Table 17 summarises the recommendations for dose interruption, reduction, or discontinuation of Revolade in the management of elevated liver transaminase levels and thromboembolic events. (See Table 17.)

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The total duration of Revolade treatment is 6 months.
Refractory Severe Aplastic Anaemia: Initial dose regimen: Revolade should be initiated at a dose of 50 mg once daily. For patients of East-/Southeast-Asian ancestry or those with hepatic impairment, Revolade should be initiated at a reduced dose of 25 mg once daily (see Pharmacology: Pharmacokinetics under Actions). The treatment should not be initiated when the patient has existing cytogenetic abnormalities of chromosome 7.
Monitoring and dose adjustment: Haematological response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting Revolade (see Pharmacology: Pharmacodynamics under Actions). The dose of Revolade should be adjusted in 50 mg increments every 2 weeks as necessary to achieve the target platelet count ≥50,000/μl. For patients taking 25 mg once daily, the dose should be increased to 50 mg daily before increasing the dose amount by 50 mg. A dose of 150 mg daily must not be exceeded. Clinical haematology and liver tests should be monitored regularly throughout therapy with Revolade and the dosage regimen of Revolade modified based on platelet counts as outlined in Table 18. (See Table 18.)

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Tapering for tri-lineage (white blood cells, red blood cells, and platelets) responders: For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of Revolade may be reduced by 50%.
If counts remain stable after 8 weeks at the reduced dose, then Revolade must be discontinued and blood counts monitored. If platelet counts drop to <30,000/μl, haemoglobin drops to <9 g/dl or absolute neutrophil count (ANC) <0.5 x 10⁹/l Revolade may be reinitiated at the previous effective dose.
Discontinuation: If no haematological response has occurred after 16 weeks of therapy with Revolade, therapy should be discontinued. If new cytogenetic abnormalities are detected, it must be evaluated whether continuation of Revolade is appropriate (see Precautions and Adverse Reactions). Excessive platelet count responses (as outlined in Table 18) or important liver test abnormalities also necessitate discontinuation of Revolade (see Adverse Reactions).
Special populations: Renal impairment: No dose adjustment is necessary in patients with renal impairment. Patients with impaired renal function should use Revolade with caution and close monitoring, for example by testing serum creatinine and/or performing urine analysis (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: Revolade should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see Precautions).
If the use of Revolade is deemed necessary for ITP patients with hepatic impairment, the starting dose must be 25 mg once daily. After initiating the dose of Revolade in patients with hepatic impairment an interval of 3 weeks should be observed before increasing the dose.
No dose adjustment is required for thrombocytopenic patients with chronic HCV and mild hepatic impairment (Child-Pugh score ≤6). Chronic HCV patients and refractory severe aplastic anaemia patients with hepatic impairment should initiate Revolade at a dose of 25 mg once daily (see Pharmacology: Pharmacokinetics under Actions). After initiating the dose of Revolade in patients with hepatic impairment an interval of 2 weeks should be observed before increasing the dose.
There is an increased risk for adverse events, including hepatic decompensation and thromboembolic events (TEEs), in thrombocytopenic patients with advanced chronic liver disease treated with Revolade, either in preparation for invasive procedure or in HCV patients undergoing antiviral therapy (see Precautions and Adverse Reactions).
In a clinical trial in definitive immunosuppressive therapy-naïve severe aplastic anemia patients with baseline AST/ALT >5 x ULN were ineligible to participate. The initial dose of Revolade in patients with hepatic impairment in the first-line setting should be determined as necessary based on clinical judgement, tolerability, and close monitoring of liver function.
Elderly: There are limited data on the use of Revolade in ITP patients aged 65 years and older and no clinical experience in ITP patients aged over 85 years. In the clinical studies of Revolade, overall no clinically significant differences in safety of Revolade were observed between patients aged at least 65 years and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see Pharmacology: Pharmacokinetics under Actions).
There are limited data on the use of Revolade in HCV and SAA patients aged over 75 years. Caution should be exercised in these patients (see Precautions).
East-/Southeast-Asian patients: For adult and paediatric patients of East-/Southeast-Asian ancestry, including those with hepatic impairment, Revolade should be initiated at a dose of 25 mg once daily for the treatment of ITP, HCV-associated thrombocytopenia, and refractory SAA (see Pharmacology: Pharmacokinetics under Actions). For the treatment of patients with first-line SAA refer to Dosage & Administration.
Patient platelet count should continue to be monitored and the standard criteria for further dose modification followed.
Paediatric population: Revolade is not recommended for use in children under the age of one year with ITP due to insufficient data on safety and efficacy. In paediatric clinical trials, subjects between 1 to 5 years of age were administered Revolade as a powder for oral suspension formulation. Revolade is only available as tablets and cannot be used in patients who are unable to swallow Revolade tablets whole. The safety and efficacy of Revolade) has not been established in children and adolescents (<18 years) with chronic HCV related thrombocytopenia or SAA. No data are available.
Method of administration: Oral use.
The tablets should be taken at least two hours before or four hours after any products such as antacids, dairy products (or other calcium containing food products), or mineral supplements containing polyvalent cations (e.g. iron, calcium, magnesium, aluminium, selenium and zinc) (see Interactions and Pharmacology: Pharmacokinetics under Actions).