FDA Safety Changes: Janumet, WelChol, Rituxan  CME

News Author: Yael Waknine
CME Author: Yael Waknine
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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.

May 7, 2008 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of the risk for hypersensitivity reactions in patients receiving sitagliptin as part of a combination antidiabetic product, the risk for hypertriglyceridemia in patients with type 2 diabetes receiving colesevelam HCl therapy, and the risk for severe and potentially fatal infusion reactions in patients receiving rituximab intravenous infusion.

Sitagliptin Component of Janumet Linked to Reports of Hypersensitivity Reactions

On January 2, the FDA approved safety labeling revisions for sitagliptin plus metformin HCl tablets (Janumet; Merck & Co, Inc) to warn of the risk for hypersensitivity reactions.

Postmarketing reports have linked use of sitagliptin to serious hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative skin conditions such as Stevens-Johnson syndrome. These events have occurred within the first 3 months of therapy, sometimes after the first dose.

The FDA notes that the voluntary nature of adverse event reporting precludes an estimation of event frequency or determination of a causal role for the drug. If a hypersensitivity reaction is suspected, other potential causes should be evaluated and alternative antidiabetic therapy instituted if necessary. Once a serious hypersensitivity reaction has occurred in relationship to treatment, patients should not be rechallenged with sitagliptin.

Patients should be informed that allergic reactions have been reported during postmarketing use of sitagliptin, a product component. Treatment should be discontinued and a healthcare clinician contacted for symptoms of an allergic reaction, including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty breathing or swallowing.

Sitagliptin plus metformin tablets are indicated for use with diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus that is inadequately controlled with either component alone or in patients who are already receiving both components separately.

Colesevelam HCl (WelChol) Linked to Risk for Hypertriglyceridemia in Patients With Diabetes

On January 18, the FDA approved safety labeling revisions for colesevelam HCl tablets (WelChol; marketed by Daiichi Sankyo, Inc, under license from Genzyme Corp) to warn of the risk for increased triglyceride (TG) levels in patients receiving treatment of type 2 diabetes, a new indication.

As with other bile sequestrants, colesevelam can increase TG serum concentrations. Although the effect has been small in clinical trials of primary hyperlipidemia (median increase vs placebo, 5%), greater increases were observed when colesevelam was added to sulfonylureas or insulin in patients with type 2 diabetes (median increase vs sulfonylurea alone, 18%; vs insulin alone, 22%).

The FDA notes that hypertriglyceridemia of sufficient severity can cause acute pancreatitis; long-term effects on the risk for coronary artery disease remain unclear. For patients with type 2 diabetes, the effect of colesevelam on low-density lipoprotein cholesterol may be attenuated by TG effects and a smaller reduction in non–high-density lipoprotein cholesterol vs low-density lipoprotein cholesterol.

Because most patients in colesevelam clinical trials had baseline TG levels of more than 300 mg/dL, it is unknown whether uncontrolled baseline hypertriglyceridemia can lead to greater increases in serum TG levels during therapy. Caution is therefore advised when treating patients with TG levels greater than 300 mg/dL.

Lipid parameters, including TG levels and non–high-density lipoprotein cholesterol, should be obtained before colesevelam therapy is initiated and periodically thereafter. Treatment should be discontinued in patients in whom TG levels are more than 500 mg/dL or if hypertriglyceridemia-induced pancreatitis develops.

Colesevelam is indicated as an adjunct to diet and exercise in the treatment of primary hyperlipidemia (alone or with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) and improvement of glycemic control in patients with type 2 diabetes mellitus.

Rituximab Infusion (Rituxan) Requires Premedication for Infusion Reactions

On January 25, the FDA approved safety labeling revisions for rituximab intravenous injection (Rituxan; Genentech, Inc, and Biogen Idec, Inc) to provide revised information regarding the risk for severe, including fatal, infusion reactions.

Reports indicate that severe reactions typically occur during the first infusion, with time to onset ranging from 30 to 120 minutes. Reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and anaphylactoid events.

The FDA advises that patients be premedicated with an antihistamine and acetaminophen before rituximab dosing. Medical management (eg, glucocorticoids, epinephrine, bronchodilators, and oxygen) should be initiated if infusion reactions occur.

Once symptoms have resolved, the severity of the infusion reaction and required interventions should be considered when deciding whether to resume the infusion. If restarted, the infusion rate should be reduced by at least 50%.

Close monitoring is advised for patients with preexisting cardiac or pulmonary conditions, those who experienced previous cardiopulmonary adverse reactions, and in patients with high numbers of circulating malignant cells.

Rituximab intravenous infusion is indicated for the treatment of non-Hodgkin's lymphoma and rheumatoid arthritis.

Janumet Prescribing Information

WelChol Prescribing Information

Rituxan Prescribing Information

Pearls for Practice

• The sitagliptin component of sitagliptin plus metformin HCl tablets has been linked to reports of serious hypersensitivity reactions that occur during the first 3 months of therapy, sometimes after the first dose. Patients who have these reactions should not be rechallenged with the drug.
• Use of colesevelam HCl with sulfonylureas or insulin in patients with diabetes is linked to greater increases in triglyceride levels vs patients receiving treatment of hyperlipidemia (mean increase, 18% and 22% vs 5%). Caution is advised in patients with triglyceride levels of more than 300 mg/dL; therapy is contraindicated if these levels are more than 500 mg/dL.
• Rituximab intravenous infusion is linked to a risk for severe and potentially fatal infusion reactions that typically occur during the first infusion with onset of 30 to 120 minutes; premedication with an antihistamine and acetaminophen is advised. If an infusion reaction occurs, the severity of the reaction and required interventions should be considered when deciding whether to resume the infusion, with a minimum 50% reduction in flow rate.

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