Safety Review of Combination OC In Adolescents Raises No New Concerns


ROCKVILLE, MD. No new safety concerns were raised by a review of adverse events reported during a recent 1-year period in adolescents taking a combination oral contraceptive, according to Jean Wendy Temeck, M.D., of the Food and Drug Administration's division of pediatric drug development.

The FDA's review of adverse events reported for Ortho Tri-Cyclen and Ortho Tri-Cyclen Lo, which contain norgestimate and ethinyl estradiol, was conducted between December 2003 and January 2005, the year after the FDA granted marketing exclusivity to the drug. Exclusivity is granted to a drug when companies perform pediatric studies of the product in exchange for a 6-month extension on the patent for the drugs.

In this case, the drug manufacturer, Ortho-McNeil Pharmaceutical Inc., which is based in Raritan, N.J., conducted a placebo-controlled study to determine whether the oral contraceptive improved bone density in adolescent girls who had been diagnosed with anorexia nervosa. The study showed no differences from placebo in increases in hip and lumbar-spine bone mineral density following 1 year of treatment.

Dr. Temek reported the findings at a meeting of the FDA's Pediatric Advisory Committee. The Best Pharmaceuticals for Children Act requires that the FDA's Office of Pediatric Therapeutics review postmarketing adverse event reports made to the FDA's MedWatch adverse event reporting system during the year after a drug receives exclusivity. These reports are then referred to the Pediatric Advisory Committee for a review.

The uses of Ortho Tri-Cyclen for female patients at 16 years of age and younger include dysfunctional uterine bleeding and acne, she said. During the postexclusivity period (Dec. 18, 2003, through Jan. 18, 2005) there were 14 unduplicated pediatric adverse event reports associated with Ortho Tri-Cyclen, including 11 serious reports and no deaths.

The 14 reports included 12 cases in adolescent girls and 2 cases involving infants that had been exposed in utero. Adverse events that were reported more than once were headaches and metrorrhagia, events that are listed in the label of Ortho Tri-Cyclen, and convulsions, an adverse event that is not in the label.

There were four hospitalizations, which included the two in utero exposures. The other two hospitalizations were in a 16-year-old patient with benign intracranial hypertension, an increase in cerebrospinal fluid pressure, and a visual field defect; and in a 14-year-old patient who had cerebral thrombosis and headache. These two patients also were using isotretinoin.

A third patient who was also on isotretinoin, as well as prednisone, was reported to have depression, dizziness, and headache, which are unlabeled events for the oral contraceptive; other symptoms included decreased interest, insomnia, and panic attack.

The labels for isotretinoin and prednisone include the possible risk of increased intracranial pressure, depression, insomnia, emotional instability, dizziness, and headache, Dr. Temeck noted.

Of the two infants who were exposed in utero, one was in a breech presentation and born prematurely, and the baby's mother also had taken penicillin, betamethasone, and alprazolam while pregnant. The second exposed infant was reported to have cerebral artery occlusion, convulsion, apnea, and developmental delay.

There were three adolescents who did report visual adverse events, which are not mentioned in the Ortho Tri-Cyclen product label: a 14-year-old patient also on oxcarbazepine who was reported to have papilledema and cluster headache; a 16-year old patient also on doxycycline and tretinoin, who experienced scotoma, blurred vision, headache and influenza-like illness; and a 16-year old patient also on isotretinoin and prednisone, who had a visual-field defect, in addition to benign intracranial hypertension and increased cerebrospinal fluid pressure. (The label for Ortho Tri-Cyclen does contain a warning of retinal thrombosis.)

The other two serious adverse events that were reported were in one 14-year-old who developed hypertension and another 14-year-old who has dysarthria and hypoesthesia—two events that are not included on the label. Convulsions also were reported in a 15-year-old who had a history of intermittent seizures.

Despite the fact that there were reports of some serious adverse events during this period, “no pattern of new safety concerns” was identified, Dr. Temeck said. Based on the presentation, the advisory panel agreed with the FDA that monitoring of adverse events for these oral contraceptives could be switched to regular monitoring.

Health care professionals and consumers can report any drug- or device-related adverse events to MedWatch by calling 800-332-1088, sending a fax to 800-332-0178, writing to MedWatch, Food and Drug Administration, 5600 Fishers Ln., Rockville, MD 20857-9787; or visiting

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