Revolade Special Precautions

The effectiveness and safety of Revolade have not been established for use in other thrombocytopenic conditions including chemotherapy-induced thrombocytopenia and myelodysplastic syndromes (MDS).
Hepatic Monitoring: Revolade administration can cause hepatobiliary laboratory abnormalities. In clinical trials with Revolade, increases in ALT, AST and indirect bilirubin were observed (see Adverse Reactions).
These findings were mostly mild (grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate an impaired liver function. In 2 placebo-controlled studies, adverse events of ALT increase were reported in 5.7% and 4% of Revolade- and placebo-treated patients, respectively.
Measure serum ALT, AST and bilirubin prior to initiation of Revolade, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Evaluate abnormal serum liver tests with repeat testing within 3-5 days. If the abnormalities are confirmed, monitor serum liver tests until the abnormalities resolve, stabilize or return to baseline levels. Discontinue Revolade if ALT levels increase (≥3x ULN) and are progressive or persistent for ≥4 weeks, or accompanied by increased direct bilirubin or clinical symptoms of liver injury or evidence for hepatic decompensation.
Exercise caution and close monitoring when administering Revolade to patients with hepatic disease/impairment.
Thrombotic/Thromboembolic (TEE) Complications: Thromboembolic events may occur in patients with ITP. Platelet counts above the normal range present a theoretical risk for TEE complications. In Revolade clinical trials, thromboembolic events were observed at low and normal platelet counts. In ITP studies, 21 TEE events were observed in 17 out of 446 subjects (3.8%). The TEE events included: Embolism including pulmonary embolism, deep vein thrombosis, transient ischemic attack, myocardial infarction, ischemic stroke and suspected prolonged reversible ischemic neurologic deficiency (PRlND).
Use caution when administering Revolade to patients with known risk factors for thromboembolism [eg, factor V Leiden, antithrombin III (ATlll) deficiency, antiphospholipid syndrome]. Platelet counts should be closely monitored and consideration given to reducing the dose or discontinuing Revolade treatment if the platelet counts exceeds the target levels (see Dosage & Administration).
In a controlled study in thrombocytopenic patients with chronic liver disease (n=288) undergoing elective invasive procedures, the risk of thrombotic events was increased in patients treated with Revolade 75 mg once daily for 14 days. Six thrombotic complications were reported within the group that received Revolade and 1 within the placebo group. All of the thrombotic complications reported within the Revolade group were of the portal venous system.
Bleeding Following Discontinuation of Revolade: Following discontinuation of Revolade, platelet counts return to baseline levels within 2 weeks in the majority of patients (see Pharmacokinetics: Clinical Studies under Actions), which increases the bleeding risk and in some cases may lead to bleeding. Platelet counts must be monitored weekly for 4 weeks following discontinuation of Revolade.
Bone Marrow Reticulin Formation and Risk of Bone Marrow Fibrosis: Thrombopoietin receptor agonists, including Revolade, may increase the risk for development or progression of reticulin fibers within the bone marrow.
Prior to initiation of Revolade, examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of Revolade, perform CBC with white blood cell count (WBC) differential monthly. If immature or dysplastic cells are observed, examine peripheral blood smears for new or worsening morphological abnormalities (eg, teardrop and nucleated red blood cells, immature WBC) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with Revolade and consider a bone marrow biopsy, including staining for fibrosis.
Malignancies and Progression of Malignancies: There is a theoretical concern that TPO-R agonists may stimulate the progression of existing hematological malignancies eg, MDS. Across the clinical trials in ITP (n=493), no difference in the incidence of malignancies or hematological malignancies was demonstrated between placebo- and Revolade-treated patients. This is consistent with information derived from nonclinical research, where no malignant cell proliferation has been demonstrated upon co-incubation of Revolade with MDS cell lines, multiple leukemic cell lines and solid tumor cell lines (colon, prostate, ovary and lung).
Cataracts: Cataracts were observed in toxicology studies of Revolade in rodents. The clinical relevance of this finding is unknown. Routine monitoring of patients for cataracts is recommended.
Effects on the Ability to Drive or Operate Machinery: There have been no studies to investigate the effect of Revolade on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology of eltrombopag. The clinical status of the patient and the adverse event profile of Revolade should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor and cognitive skills.
Use in pregnancy & lactation: Eltrombopag was not teratogenic when studied in pregnant rats and rabbits but caused a low incidence of cervical ribs (a fetal variation) and reduced fetal body weight at doses that were maternally toxic.
There are no adequate and well-controlled studies of Revolade in pregnant women. The effect of Revolade on human pregnancy is unknown. Revolade should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.
It is not known whether eltrombopag is excreted in human milk. Revolade is not recommended for nursing mothers unless the expected benefit justifies the potential risk to the infant.
Use in children: The safety and efficacy of Revolade in children have not been established.
Use in the elderly: There are limited data on the use of Revolade in patients ≥65 years. In the clinical studies of Revolade, overall no clinically significant differences in safety of Revolade were observed between subjects at least 65 years and younger subjects. 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.