FDA Safety Changes: Celexa, Erbitux, ACE Inhibitors

Yael Waknine

January 05, 2009

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December 3, 2008 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of the risk for bleeding events and hyponatremia associated with citalopram HBr, the potential for severe infusion reactions and dermatologic toxicity in patients receiving cetuximab therapy, and drug interactions between angiotensin-converting enzyme inhibitors and injectable gold therapy.

Concomitant Citalopram HBr ( Celexa) Linked to Bleeding Risk, Hyponatremia

On September 17, the FDA approved safety labeling revisions for the selective serotonin reuptake inhibitor (SSRI) citalopram HBr (Celexa tablets and oral solution; Forest Laboratories, Inc) to warn against concomitant use of drugs that increase the risk for bleeding events and advise of the risk for hyponatremia.

Because platelet release of serotonin plays an important role in hemostasis, use of psychotropic drugs that interfere with serotonin reuptake (such as SSRIs and serotonin-norepinephrine reuptake inhibitors [SNRIs]) may increase the risk for bleeding events. These events have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

This risk has been substantiated by data from case-control and cohort-design epidemiologic studies, which demonstrated an association between use of SSRIs and SNRIs and upper gastrointestinal tract bleeding.

Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may potentiate the risk for bleeding, the FDA warned. Patients receiving warfarin should be carefully monitored when citalopram is initiated or discontinued.

The FDA also warned that hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including citalopram. In many cases, it appears to result from the syndrome of inappropriate antidiuretic hormone secretion and is reversible on discontinuation of therapy. Risk factors may include advanced age and concomitant use of diuretics/volume depletion.

Signs and symptoms of hyponatremia can include headache; difficulty concentrating; memory impairment; confusion; weakness; and unsteadiness, which may lead to falls. More severe and/or acute cases of hyponatremia may manifest as hallucinations, syncope, seizure, coma, respiratory arrest, and death.

The FDA advises initiating appropriate medical intervention and considering discontinuation of citalopram in patients in whom symptomatic hyponatremia develops.

Citalopram is indicated for the treatment of depression.

Cetuximab ( Erbitux) Linked to Risks for Severe Infusion Reactions, Dermatologic Toxicity

On September 12, the FDA approved safety labeling revisions for cetuximab intravenous infusion (Erbitux; ImClone Systems, Inc) to provide updated information regarding the risk for serious infusion reactions and dermatologic toxicity.

The FDA previously warned of infusion reactions requiring medical intervention and immediate, permanent discontinuation of cetuximab that have included rapid onset of airway obstruction (bronchospasm, stridor, and hoarseness), hypotension, and/or cardiac arrest. Shock, loss of consciousness, and myocardial infarction have now been reported also.

Severe (National Cancer Institute grades 3/4) infusion reactions were reported with an incidence of 2% to 5% among 1373 cetuximab-treated patients in clinical trials; approximately 90% of these events occurred with the first infusion despite premedication with antihistamines.

The FDA advises that patients be monitored during the infusion and for 1 hour after its completion. Resuscitation equipment and other agents required to treat anaphylaxis should be readily available, including epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen. Patients requiring treatment for infusion reactions may require a longer monitoring period to confirm resolution of the event.

The agency also warned of the risk for dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, Staphylococcus aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, and cheilitis), and hypertrichosis.

In particular, acneform rash occurred in 76% to 88% (severe rash, 1% - 17%) of cetuximab-treated clinical trial patients, usually presenting within the first 2 weeks of therapy. Although the condition resolved for most patients after cessation of therapy, nearly 50% of cases continued beyond 28 days.

Patients should be instructed to limit sun exposure during treatment and should be monitored for dermatologic toxicities and infectious sequelae.

Cetuximab is indicated for use alone or with other agents in the treatment of squamous cell carcinoma of the head and neck and colorectal cancer.

ACE Inhibitor Drug Interaction With Injectable Gold Linked to Nitritoid Reactions

On September 25, the FDA approved safety labeling revisions for angiotensin-converting enzyme (ACE) inhibitors including enalapril maleate plus hydrochlorothiazide tablets (Vaseretic; Biovail Laboratories, Inc), enalapril tablets (Vasotec; Biovail), and captopril tablets (Capoten; Par Pharmaceutical, Inc) to warn of drug interactions with injectable gold therapy.

According to the FDA, nitritoid reactions have been reported rarely in patients receiving therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy. Symptoms may include facial flushing, nausea, vomiting, and hypotension.

Enalapril plus hydrochlorothiazide and captopril tablets are indicated for the treatment of hypertension. Enalapril tablets are indicated for the treatment of hypertension and symptomatic heart failure.

Celexa Prescribing Information

Erbitux Prescribing Information

Vaseretic Prescribing Information

Vasotec Prescribing Information

Capoten Prescribing Information

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