FDA Safety Changes: Strattera, Aptivus, CellCept

Yael Waknine

August 05, 2009

This activity is part of an ongoing CME/CE initiative to provide information on labeling changes reported by the FDA. Activities of this nature will be posted on Medscape on a weekly basis.

August 5, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to warn of the risks for liver injury, orthostatic hypotension, and syncope in patients with attention-deficit/hyperactivity disorder receiving treatment with atomoxetine HCl; potential effects of tipranavir on platelet aggregation and coagulation parameters; and the risk for pure red cell aplasia in patients receiving posttransplant antirejection therapy with mycophenolate mofetil.

Atomoxetine (
Strattera) Linked to Risks for Liver Injury, Orthostatic Hypotension, and Syncope

On June 3, the FDA approved safety labeling revisions for atomoxetine HCl capsules (Strattera; Eli Lilly & Co, Inc) to warn of the risks for liver injury, orthostatic hypotension, and syncope.

Although no evidence of liver injury was observed in clinical trials, postmarketing experience suggests that atomoxetine can cause severe liver injury.

The majority of reported cases occurred within 3 months of treatment initiation; some patients presented with markedly elevated hepatic enzymes (> 20 times the upper limit of normal [ULN]) and jaundice with significantly elevated bilirubin levels (> 2 x ULN), followed by recovery on discontinuation of atomoxetine therapy.

Because severe drug-induced hepatic injury may progress to acute liver failure resulting in death or the need for transplant, liver enzyme levels should be obtained at the first sign or symptom of liver dysfunction such as pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained flu-like symptoms.

Atomoxetine should be permanently discontinued in patients with jaundice or laboratory evidence of liver injury. The FDA notes that laboratory abnormalities may continue to worsen for several weeks after atomoxetine is stopped.

The FDA also warned that atomoxetine should be used with caution in patients with conditions that predispose them to hypotension or are associated with abrupt changes in heart rate or blood pressure.

Orthostatic hypotension and syncope have been reported in patients receiving atomoxetine therapy. In a pooled analysis of child and adolescent trials, 0.2% (12/5596) of atomoxetine-treated patients experienced orthostatic hypotension and 0.8% (46/5596) experienced syncope. In short-term child and adolescent controlled trials, 1.8% (6/340) of atomoxetine-treated patients experienced orthostatic hypotension vs 0.5% (1/207) of those receiving placebo; syncope was not reported.

Atomoxetine is a selective norepinephrine reuptake inhibitor indicated for the treatment of attention-deficit/hyperactivity disorder.

Tipranavir (Aptivus) May Be Linked to Effects on Platelet Aggregation and Coagulation

On June 19, the FDA approved revisions to the safety labeling for tipranavir capsules and oral solution (Aptivus; Boehringer Ingelheim Pharmaceuticals, Inc) to warn of potential effects on platelet aggregation and coagulation.

Ritonavir-boosted tipranavir should be used with caution in patients who may be at risk for increased bleeding from trauma, surgery, or other medical conditions; those receiving medications known to increase the risk of bleeding such as antiplatelet agents and anticoagulants; and patients taking supplemental high doses of vitamin E.

The warning is based in part on data from animal studies, showing that use of tipranavir alone yielded dose-dependent increases in coagulation parameters, bleeding events, and death. Coadministration of tipranavir with vitamin E significantly increased these effects. In vitro experiments also demonstrated that tipranavir inhibited human platelet aggregation at levels consistent with exposures observed in patients receiving ritonavir/tipranavir therapy.

Because tipranavir oral solution contains 116 IU/mL of vitamin E (higher than the Reference Daily Intake of 30 IU for adults, 10 IU for children), patients taking the product should be advised against taking supplemental vitamin E at levels greater than that included in a multivitamin.

Ritonavir-boosted tipranavir is indicated for combination antiretroviral treatment of treatment-experienced patients infected with HIV-1 strains resistant to more than 1 protease inhibitor.

Mycophenolate Mofetil (CellCept) May Be Linked to Risk for Pure Red Cell Aplasia

On June 18, the FDA approved safety labeling revisions for mycophenolate mofetil capsules, tablets, injection, and oral suspension (CellCept; Hoffmann-LaRoche, Inc) to warn of the potential risk for pure red cell aplasia.

According to the FDA, cases of pure red cell aplasia have been reported in patients receiving mycophenolate mofetil along with other immunosuppressive agents. The agency notes that the mechanism for this reaction and the relative contribution of the other agents remain unknown.

In some cases, mycophenolate-induced pure red cell aplasia was reversible with dose reduction or discontinuation of therapy. The FDA notes, however, that reduction of immunosuppression in patients undergoing transplantation may place the transplant graft at risk.

Mycophenolate mofetil with cyclosporine and corticosteroids is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac, or hepatic transplants.

Strattera Prescribing Information

Aptivus Prescribing Information

CellCept Prescribing Information


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