Ultram ER (Page 5 of 7)

Potential for Tramadol to Affect Other Drugs

In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when administered concomitantly at therapeutic doses. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

No carcinogenic effect of tramadol was observed in p53(+/–)-heterozygous mice at oral doses up to 150 mg/kg/day (approximately 2-fold maximum daily human dose [MDHD] of 400 mg/day for a 60 kg adult based on body surface conversion) for 26 weeks and in rats at oral doses up to 75 mg/kg/day for males and 100 mg/kg/day for females (approximately 2-fold MDHD) for two years. However, the excessive decrease in body weight gain observed in the rat study might have reduced their sensitivity to any potential carcinogenic effect of the drug.

Tramadol was not mutagenic in the following assays: a bacterial reverse mutation assay using Salmonella and E. coli , a mouse lymphoma assay (in the absence of metabolic activation), and a bone marrow micronucleus test in mice. Mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.

No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg/day in male and female rats (approximately equivalent to MDHD).

Pregnancy

Teratogenic Effects: Pregnancy Category C

Tramadol was not teratogenic at oral dose levels up to 50 mg/kg/day (approximately equivalent to MDHD) in rats and 100 mg/kg (approximately 5-fold MDHD) in rabbits during organogenesis. However, embryo-fetal lethality, reductions in fetal weight and skeletal ossification, and increased supernumerary ribs were observed at a maternal toxic dose of 140 mg/kg in mice (approximately 2-fold MDHD), 80 mg/kg in rats (2-fold MDHD) or 300 mg/kg in rabbits (approximately 15-fold MDHD).

Non-teratogenic Effects

Tramadol caused a reduction in neonatal body weight and survival at an oral dose of 80 mg/kg (approximately 2-fold MDHD) when rats were treated during late gestation throughout lactation period.

There are no adequate and well-controlled studies in pregnant women. ULTRAM ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing reports with tramadol HCl immediate-release products.

Labor and Delivery

ULTRAM ER should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn (see DRUG ABUSE AND ADDICTION). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women treated with tramadol HCl during labor.

The effect of ULTRAM ER, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers

ULTRAM ER is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100-mg dose of tramadol, the cumulative excretion in breast milk within sixteen hours postdose was 100 µg of tramadol (0.1% of the maternal dose) and 27 µg of M1.

Pediatric Use

The safety and efficacy of ULTRAM ER in patients under 18 years of age have not been established. The use of ULTRAM ER in the pediatric population is not recommended.

Geriatric Use

Nine-hundred-one elderly (65 years of age or older) subjects were exposed to ULTRAM ER in clinical trials. Of those subjects, 156 were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: constipation, fatigue, weakness, postural hypotension and dyspepsia. For this reason, ULTRAM ER should be used with great caution in patients older than 75 years of age (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

ULTRAM ER was administered to a total of 3108 patients during studies conducted in the U.S. These included four double-blind studies in patients with osteoarthritis and/or chronic low back pain and one open-label study in patients with chronic non-malignant pain. A total of 901 patients were 65 years or older. The frequency of adverse events generally increased with doses from 100 mg to 400 mg in the two pooled, twelve-week, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain (see Table 2).

Table 2: Incidence (%) of patients with adverse event rates ≥ 5% from two 12-week placebo-controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1811).
ULTRAM ER Placebo
MedDRA Preferred Term 100 mg(N=403)n (%) 200 mg(N=400)n (%) 300 mg(N=400)n (%) 400 mg(N=202)n (%) (N=406)n (%)
Dizziness(not vertigo) 64 (15.9) 81 (20.3) 90 (22.5) 57 (28.2) 28 (6.9)
Nausea 61 (15.1) 90 (22.5) 102 (25.5) 53 (26.2) 32 (7.9)
Constipation 49 (12.2) 68 (17.0) 85 (21.3) 60 (29.7) 17 (4.2)
Headache 49 (12.2) 62 (15.5) 46 (11.5) 32 (15.8) 43 (10.6)
Somnolence 33 (8.2) 45 (11.3) 29 (7.3) 41 (20.3) 7 (1.7)
Flushing 31 (7.7) 40 (10.0) 35 (8.8) 32 (15.8) 18 (4.4)
Pruritus 25 (6.2) 34 (8.5) 30 (7.5) 24 (11.9) 4 (1.0)
Vomiting 20 (5.0) 29 (7.3) 34 (8.5) 19 (9.4) 11 (2.7)
Insomnia 26 (6.5) 32 (8.0) 36 (9.0) 22 (10.9) 13 (3.2)
Dry Mouth 20 (5.0) 29 (7.3) 39 (9.8) 18 (8.9) 6 (1.5)
Diarrhea 15 (3.7) 27 (6.8) 37 (8.5) 10 (5.0) 17 (4.2)
Asthenia 14 (3.5) 24 (6.0) 26 (6.5) 13 (6.4) 7 (1.7)
Postural hypotension 7 (1.7) 17 (4.3) 8 (2.0) 11 (5.4) 9 (2.2)
Sweating increased 6 (1.5) 8 (2.0) 15 (3.8) 13 (6.4) 1 (0.2)
Anorexia 3 (0.7) 7 (1.8) 21 (5.3) 12 (5.9) 1 (0.2)

The following adverse events were reported from all the chronic pain studies (N=3108).

The lists below include adverse events not otherwise noted in Table 2.

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