8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1) 8.1 Pregnancy Pregnancy Category C during the first two trimesters of pregnancy; Category X during the third trimester of pregnancy. There are no adequate and well-controlled studies in pregnant women. TREXIMET (sumatriptan and naproxen) should be used during the first and second trimester of pregnancy only if the potential benefit justifies the potential risk to the fetus. TREXIMET should not be used during the third trimester of pregnancy because inhibitors of prostaglandin synthesis (including naproxen) are known to cause premature closure of the ductus arteriosus in humans. In animal studies, administration of sumatriptan and naproxen, alone or in combination, during pregnancy resulted in developmental toxicity (increased incidences of fetal malformations, embryofetal and pup mortality, decreased embryofetal growth) at clinically relevant doses. Oral administration of sumatriptan combined with naproxen sodium (5/9, 25/45, or 50/90 mg/kg/day sumatriptan/naproxen sodium) or each drug alone (50/0 or 0/90 mg/kg/day sumatriptan/naproxen sodium) to pregnant rabbits during the period of organogenesis resulted in increased total incidences of fetal abnormalities at all doses and increased incidences of specific malformations (cardiac interventricular septal defect in the 50/90 mg/kg/day group, fused caudal vertebrae in the 50/0 and 0/90 mg/kg/day groups) and variations (absent intermediate lobe of the lung, irregular ossification of the skull, incompletely ossified sternal centra) at the highest dose of sumatriptan and naproxen alone and in combination. A no-effect dose for developmental toxicity in rabbits was not established. The lowest effect dose was 5/9 mg/kg/day sumatriptan/naproxen sodium, which was associated with plasma exposures (AUC) to sumatriptan and naproxen that were less than those attained at the maximum human daily dose (MHDD) of 170 mg sumatriptan and 1000 mg naproxen sodium (two tablets of TREXIMET 85/500 mg in a 24-hour period). In previous developmental toxicity studies of sumatriptan, oral administration to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel abnormalities and decreased pup survival at doses of 250 mg/kg/day or higher. The highest no-effect dose was 60 mg/kg/day, which is approximately 3 times the MHDD of 170 mg sumatriptan on a mg/m2 basis. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of vascular and skeletal abnormalities at a dose of 50 mg/kg/day and embryolethality at 100 mg/kg/day. The highest no-effect dose of sumatriptan for developmental toxicity in rabbits was 15 mg/kg/day, or approximately 2 times the MHDD of 170 mg sumatriptan on a mg/m2 basis. 8.2 Labor and Delivery Naproxen-containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. 8.3 Nursing Mothers Both active components of TREXIMET, sumatriptan and naproxen, have been reported to be secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from TREXIMET, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness of TREXIMET in pediatric patients under 12 years of age have not been established. The safety and efficacy of TREXIMET for the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in a double-blind, placebo-controlled trial [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. TREXIMET is not recommended for use in elderly patients who have decreased renal function, higher risk for unrecognized CAD, and increases in blood pressure that may be more pronounced in the elderly [see Warnings and Precautions (5.1, 5.2, 5.3, 5.8,5.12) and Clinical Pharmacology (12.3)]. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving TREXIMET [see Warnings and Precautions (5.1)]. 8.6 Renal Impairment TREXIMET is not recommended for use in patients with creatinine clearance less than 30 mL/min. Monitor the serum creatinine or creatinine clearance in patients with mild (CrCl = 60 to 89 mL/min) or moderate (CrCL = 30 to 59 mL/min) renal impairment, preexisting kidney disease, or dehydration [see Warnings and Precautions (5.12) and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment TREXIMET is contraindicated in patients with severe hepatic impairment. For patients with mild or moderate hepatic impairment, the TREXIMET dose should be reduced. [see Contraindications (4), Warnings and Precautions (5.7), and Clinical Pharmacology (12.3)].