FDA Safety Changes: Advair Diskus, Orap, Rocephin

Yael Waknine

May 28, 2009

May 28, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of potential decreases in bone mineral density in patients receiving long-term treatment with fluticasone propionate-salmeterol xinafoate inhalation powder, citalopram HBr and escitalopram oxalate drug interactions with pimozide that can lead to prolongation of the QTc interval, and contraindications to ceftriaxone therapy in neonates.

Long-Term Use of Fluticasone and Salmeterol May Be Linked to Decreases in BMD

The FDA approved class labeling changes for fluticasone propionate and salmeterol xinafoate inhalation powder to advise of new data regarding the risk for decreased bone mineral density (BMD) in patients receiving long-term treatment with inhaled corticosteroids for chronic obstructive pulmonary disease (COPD). On March 31, the label for Advair Diskus (GlaxoSmithKline) was updated.

In a 3-year placebo-controlled study, the effects of fluticasone/salmeterol 250 µg/50 µg and salmeterol 50 µg on BMD were evaluated at baseline and at 6-month intervals; of the 186 patients enrolled, 108 (72 men, 36 women) were observed for the entire 3 years. According to the FDA, conclusions cannot be drawn from this study regarding BMD decline in patients receiving combination vs monotherapy because of the inconsistency of treatment differences across sex and between the lumbar spine and total hip.

However, 7 nontraumatic fractures were reported in 5 patients receiving combination therapy, and 1 nontraumatic fracture occurred in a patient receiving salmeterol alone. None of the fractures occurred in the vertebrae, hip, or long bones.

Fracture risk was also estimated in a survival study of 6184 patients with COPD; the probability of fracture at 3 years was 6.3% for fluticasone and salmeterol 500 µg/50 µg vs 5.4%, 5.1%, and 5.1% for fluticasone alone, salmeterol alone, and placebo, respectively.

The FDA notes that the clinical significance of small changes in BMD on long-term consequences such as fracture remains unknown.

Patients with major risk factors for decreased bone mineral content should be monitored and treated with established standards of care. Risk factors include prolonged immobilization, a family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, and long-term use of drugs that can reduce bone mass (eg, anticonvulsants and oral corticosteroids).

Because patients with COPD often have multiple risk factors for reduced BMD, their status should be assessed before initiating therapy and periodically thereafter. Use of medication to treat or prevent osteoporosis should be considered if significant reductions in BMD are observed and continued treatment with fluticasone/salmeterol is medically necessary.

Fluticasone and salmeterol inhalation powder is a corticosteroid plus long-acting B2 adrenergic receptor agonist combination product indicated for the long-term, twice-daily maintenance treatment of airflow obstruction in patients with COPD, and asthma in patients 4 years and older.

Pimozide (Orap) Contraindicated in Patients Receiving Citalopram or Escitalopram

On April 28, the FDA approved safety labeling revisions for pimozide tablets (Orap; Teva Pharmaceuticals, USA) to warn of a contraindication with citalopram HBr (Celexa; Forest Laboratories, Inc) and its S isomer, escitalopram oxalate (Lexapro; Forest).

The warning was based on data from a controlled study, showing that a single 2-mg dose of pimozide coadministered with racemic citalopram (40 mg taken once daily for 11 days) was linked to a mean increase in QTc values of approximately 10 milliseconds vs pimozide alone; mean pimozide exposure (area under the receiver operating curve and Cmax) were not affected. According to the FDA, the nature of this pharmacodynamic interaction remains unknown.

Pimozide is an antipsychotic drug indicated for the suppression of motor and phonic tics in patients with Tourette's disorder in whom there was failure to respond satisfactorily to standard treatment. It is not intended as a treatment of first choice, nor is it intended for the treatment of tics that are merely annoying or cosmetically troublesome. Pimozide should be reserved for use in patients with Tourette's disorder whose development and/or daily life function is severely compromised by the presence of motor and phonic tics.

Citalopram and escitalopram are selective serotonin reuptake inhibitors indicated for the treatment of depression.

Ceftriaxone Injection (Rocephin) Contraindicated in Neonates Receiving Calcium-Containing Products

In March, the FDA approved safety labeling revisions for ceftriaxone sodium injection for infusion (Rocephin; Roche) to emphasize the potential risks associated with concomitant use of calcium or calcium-containing solutions or products in neonates.

Neonates with hyperbilirubinemia, especially premature infants, should not be treated with ceftriaxone, the FDA warned, noting that in vitro studies have shown that ceftriaxone can displace bilirubin from binding to serum albumin, potentially leading to bilirubin encephalopathy.

In vitro studies using adult and neonatal plasma from umbilical cord blood have demonstrated that neonates also have an increased risk for precipitation of ceftriaxone-calcium.

A small number of fatal reactions with ceftriaxone-calcium precipitates in the lungs and kidneys have been reported in neonates. In some of these cases, the same intravenous line was used for both fluids, and in some, a precipitate was observed. At least 1 fatality was reported in a neonate receiving ceftriaxone and calcium-containing products by different routes at different times. There have been no similar reports in patients other than neonates, the FDA said.

Ceftriaxone is therefore also contraindicated in neonates if they require, or are expected to require, treatment with calcium-containing intravenous solutions, including parenteral nutrition.

Because of the risk for particulate precipitation, ceftriaxone should not be mixed with calcium-containing solutions/products or reconstituted with calcium-containing diluents such as Ringer's or Hartmann's solution. Concomitant administration of ceftriaxone with calcium-containing solutions or products such as parenteral nutrition is likewise contraindicated for all patients, even those receiving treatment via different infusion lines.

In patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid.

Ceftriaxone infusion is a broad-spectrum cephalosporin antibiotic indicated for the treatment of lower respiratory tract infections, urinary tract infections, bacterial septicemia, skin and skin structure infections, bone and joint infections, pelvic inflammatory disease, uncomplicated gonorrhea, intraabdominal infections, acute bacterial otitis media, and meningitis caused by susceptible microorganisms. It also is approved for surgical prophylaxis in patients undergoing certain procedures classified as contaminated or potentially contaminated.

FDA Safety Information

Orap Prescribing Information

Rocephin Prescribing Information

Celexa Prescribing Information


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