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Clinical Trials Experience

In clinical studies, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of PROMACTA. Other serious adverse reactions included liver test abnormalities and thrombotic/thromboembolic complications [see WARNINGS AND PRECAUTIONS].

The data described below reflect exposure of PROMACTA to 446 patients with chronic ITP aged 18 to 85, of whom 65% were female across the ITP clinical development program including 3 placebo-controlled studies. PROMACTA was administered to 277 patients for at least 6 months and 202 patients for at least 1 year.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 2 presents the most common adverse drug reactions (experienced by ≥ 3% of patients receiving PROMACTA) from the 3 placebo-controlled studies, with a higher incidence in PROMACTA versus placebo.

Table 2: Adverse Reactions ( ≥ 3%) from Three Placebo-Controlled Studies

In the 3 controlled clinical studies, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with PROMACTA and in no patients who received placebo.

Among 299 patients with chronic ITP who received PROMACTA in the single-arm extension study, the adverse reactions occurred in a pattern similar to that seen in the placebo controlled studies. Table 3 presents the most common treatment-related adverse reactions (experienced by ≥ 3% of patients receiving PROMACTA) from the extension study.

Table 3: Treatment-Related Adverse Reactions ( ≥ 3%) from Extension Study

In a placebo-controlled trial of eltrombopag in non-ITP thrombocytopenic patients with chronic liver disease (CLD), six eltrombopag-treated patients and one patient in the placebo group developed portal vein thromboses [see WARNINGS AND PRECAUTIONS].

Cytochrome P450

In vitro studies demonstrate that CYP1A2 and CYP2C8 are involved in the oxidative metabolism of eltrombopag. The significance of coadministration of PROMACTA with 1) moderate or strong inhibitors of CYP1A2 (e.g., ciprofloxacin, fluvoxamine) and CYP2C8 (e.g., gemfibrozil, trimethoprim); 2) inducers of CYP1A2 (e.g., tobacco, omeprazole) and CYP2C8(e.g., rifampin); or 3) other substrates of these CYP enzymes on the systemic exposure of PROMACTA has not been established in clinical studies. Monitor patients for signs and symptoms of excessive eltrombopag exposure when PROMACTA is administered concomitantly with moderate or strong inhibitors of CYP1A2 or CYP2C8.

In vitro, eltrombopag is an inhibitor of CYP2C8 and CYP2C9 using paclitaxel and diclofenac as the probe substrates. A clinical study where PROMACTA 75 mg once daily was administered for 7 days to 24 healthy male subjects did not show inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Probe substrates for CYP2C8 were not evaluated in this study.

Transporters

In vitro studies demonstrate that eltrombopag is an inhibitor of the organic anion transporting polypeptide OATP1B1 and breast cancer resistance protein (BCRP) and can increase the systemic exposure of other drugs that are substrates of these transporters (e.g., benzylpenicillin, atorvastatin, fluvastatin, pravastatin, rosuvastatin, methotrexate, nateglinide, repaglinide, rifampin, doxorubicin). Administration of 75 mg of PROMACTA once daily for5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate, rosuvastatin, to 39 healthy adult subjects increased plasma rosuvastatin AUC0-∞ by 55% and Cmax by 103%.

Use caution when concomitantly administering PROMACTA and drugs that are substrates of OATP1B1 or BCRP. Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with eltrombopag, a dose reduction of rosuvastatin by 50% was recommended for coadministration with eltrombopag.

In vitro studies demonstrate that eltrombopag is a BCRP substrate. The effect of coadministration of PROMACTA with moderate or strong BCRP inhibitors or inducers on the systemic exposure of PROMACTA has not been evaluated in clinical studies. Monitor patients closely for signs or symptoms of excessive exposure to PROMACTA when concomitantly administered with moderate or strong inhibitors of BCRP.

UDP-glucuronosyltransferases (UGTs)

In vitro studies demonstrate that eltrombopag is an inhibitor of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15, enzymes involved in the metabolism of multiple drugs, such as acetaminophen, narcotics, and nonsteroidal anti-inflammatory drugs (NSAIDs). The significance of this inhibition on the potential for increased systemic exposure of drugs that are substrates of these UGTs following coadministration with PROMACTA has not been evaluated in clinical studies. Monitor patients closely for signs or symptoms of excessive exposure to these drugs when concomitantly administered with PROMACTA.

In vitro studies demonstrate that UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag. The significance of coadministration of PROMACTA with moderate or strong inhibitors or inducers on the systemic exposure of PROMACTA has not been evaluated in clinical studies. Monitor patients closely for signs or symptoms of excessive exposure to PROMACTA when concomitantly administered with moderate or strong inhibitors of UGT1A1 or UGT1A3.

Polyvalent Cations (Chelation)

Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. In a clinical study, administration of PROMACTA with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) decreased plasma eltrombopag systemic exposure by approximately 70%. The contribution of sodium alginate to this interaction is not known. PROMACTA must not be taken within 4 hours of any medications or products containing polyvalent cations such as antacids, dairy products, and mineral supplements to avoid significant reduction in PROMACTA absorption due to chelation [see DOSAGE AND ADMINISTRATION].

Last reviewed on RxList: 12/28/2011
This monograph has been modified to include the generic and brand name in many instances.