FDA Safety Changes: Arixtra, Sulfonylureas, Tobramycin

Yael Waknine

October 07, 2009

October 7, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to warn of factors that increase the risk of bleeding in patients receiving treatment with fondaparinux sodium, the risk for hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency with use of sulfonylureas, and the potential for the development of Clostridium difficile–associated diarrhea more than 2 months after completion of antimicrobial therapy.

Fondaparinux (Arixtra) Bleeding Risk Increased in Certain Settings

On August 14, the FDA approved safety labeling revisions for fondaparinux sodium subcutaneous injection (Arixtra; GlaxoSmithKline) to emphasize factors that increase the risk of bleeding.

As with other anticoagulants, use of fondaparinux is linked to a risk for hemorrhage. Extreme caution is advised when treating patients with conditions that increase this risk, such as congenital or acquired bleeding disorders; active ulcerative and angiodysplastic gastrointestinal tract disease; hemorrhagic stroke; uncontrolled arterial hypertension; diabetic retinopathy; or shortly after brain, spinal, or ophthalmologic surgery.

Coadministration of other agents that increase the risk for hemorrhage should also be avoided, unless essential for management of the underlying condition (eg, vitamin K antagonists in venous thromboembolism). Patients receiving combination therapy should be carefully observed for signs and symptoms of bleeding. Isolated cases of elevated activated partial thromboplastin time temporally associated with bleeding events have been reported after administration of fondaparinux with or without concomitant use of other anticoagulants, the FDA noted.

Use of fondaparinux earlier than 6 hours after surgery has also been linked to an increased risk of bleeding; at least 6 to 8 hours should elapse before treatment is initiated.

Because of the increased risk of bleeding in low-weight patients, presurgical use of fondaparinux for deep vein thrombosis (DVT) prophylaxis should be avoided in those weighing less than 50 kg. Use of fondaparinux for the treatment of DVT and pulmonary embolism (PE) should be approached with caution in low-weight patients.

Fondaparinux is also linked to an increased risk of bleeding in patients with impaired renal function because of decreased clearance. Caution and periodic assessment of renal function are advised when treating patients with creatinine clearance ranging from 30 mL/minute to 50 mL/minute; treatment should be discontinued for severe renal impairment (creatinine clearance < 30 mL/minute). The FDA notes that the anticoagulant effect of fondaparinux persists for 2 to 4 days after discontinuation of therapy in patients with normal renal function, a period that may be extended in those with renal impairment.

Fondaparinux is a factor Xa inhibitor (anticoagulant) indicated for the prevention of DVT in patients undergoing hip fracture surgery, hip replacement surgery, knee replacement surgery, or abdominal surgery. It also may be used for the treatment of DVT or acute PE when administered in conjunction with warfarin.

Use of Sulfonylureas Linked to Hemolytic Anemia in Patients with G6PD Deficiency

The FDA approved sulfonylurea class safety labeling revisions for glipizide and glipizide extended-release tablets, micronized glyburide tablets, glipizide/metformin HCl tablets, and glyburide tablets to warn against their use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In August, the labels for Glucotrol and Glucotrol XL (Pfizer, Inc), Glynase (Pfizer, Inc), Metaglip (Bristol-Myers Squibb Co), and Micronase (Pfizer, Inc) were updated.

G6PD deficiency is an X-linked recessive hereditary condition in which red blood cells break down when the body is exposed to the stress of infection or certain drugs. Clinical manifestations include hemolytic anemia, abdominal and/or back pain, dizziness, headache, dyspnea, and palpitations.

Because use of sulfonylureas in patients with G6PD deficiency can lead to hemolytic anemia, alternative agents should be considered. The FDA notes that hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

Sulfonylureas are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Tobramycin Linked to Risk for Posttherapy Clostridium difficile–Associated Diarrhea

On August 10, the FDA approved antimicrobial class safety labeling revisions for tobramycin sulfate injection (APP Pharmaceuticals, Inc) to warn of the risk for Clostridium difficile–associated diarrhea (CDAD) in patients receiving antibiotic therapy.

Use of antimicrobial agents can alter the colon's normal flora, leading to overgrowth of C difficile and subsequent release of toxins A and B that contribute to the development of CDAD. Nearly all antibiotics have been implicated in CDAD, which may range in severity from mild diarrhea to fatal colitis.

Because hypertoxin-producing strains of C difficile can be resistant to antimicrobial therapy, they are associated with increased morbidity and mortality rates and may require colectomy. The FDA advises that CDAD be considered in all patients who present with diarrhea after antibiotic use. Careful examination of medical history is required because of the potential for late-onset disease; cases of CDAD have been reported more than 2 months after completion of an antimicrobial course of therapy.

The FDA notes that current antibiotic therapy for the primary infection may need to be discontinued in patients with known or suspected CDAD. Appropriate fluid and electrolyte management, protein supplementation, antibiotic therapy for C difficile, and surgical evaluation also may be required.

Tobramycin is an aminoglycoside antibiotic indicated for the treatment of serious bacterial infections caused by susceptible microorganisms. Specific uses include septicemia; lower respiratory tract infections; central nervous system infections; intra-abdominal infections; skin, bone, and skin structure infections, and complicated/recurrent urinary tract infections.

Arixtra Prescribing Information

Glucotrol XL Extended Release Tablets Prescribing Information

Glynase PresTab Prescribing Information

Metaglip Prescribing Information

Micronase Prescribing Information

FDA Safety Information

 

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