Dose and duration of therapy should be limited between about 20 and 30 weeks of gestation; use should be avoided at about 30 weeks of gestation and later in pregnancy. Additionally, use is not recommended during or immediately prior to labor.

US FDA pregnancy category: Not assigned.

Risk summary: Based on animal data, this drug may cause fetal harm.
-Use of nonsteroidal anti-inflammatory drugs (NSAIDs) can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.
-Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome; insufficient data available on use of tramadol in pregnant women to inform a drug-related risk.

Comments:
-No data are available on use of this combination drug in pregnant women.
-Pregnant patients should be apprised of the potential harm to the fetus.

Animal studies have revealed evidence of embryofetal lethality and teratogenicity; oral administration of celecoxib and tramadol co-crystal to pregnant rabbits during organogenesis resulted in embryofetal deaths and an increased incidence of vertebral defects at about 4.7 and 0.11 times the dose of celecoxib and tramadol, respectively, at the maximum recommended human dose (MRHD) of this combination drug at 400 mg/day (224 mg of celecoxib and 176 mg of tramadol). The no observed adverse effect level (NOAEL) for embryofetal toxicity was about 3.3 and 0.02 times the MRHD of celecoxib and tramadol, respectively, on an AUC basis. There are no controlled data in human pregnancy with this combination drug; the effects of this combination drug on labor and delivery in pregnant women or on later growth, development, and functional maturation of the child are unknown.

CELECOXIB: Animal studies have revealed evidence of embryofetal lethality and teratogenicity; embryofetal deaths and increased incidence of diaphragmatic hernias were observed in rats administered celecoxib daily during organogenesis at oral doses about 13 times the celecoxib dose of 224 mg at the MRHD of this combination drug. Structural abnormalities (e.g., septal defects, ribs fused, sternebrae fused, sternebrae misshapen) were observed in rabbits given daily oral doses of celecoxib during organogenesis at about 4 times the MRHD. There are no controlled data in human pregnancy.

The available human data do not establish the presence or absence of developmental toxicity related to celecoxib use. In published literature, use of NSAIDs at about 30 weeks gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. In published studies and postmarketing reports, maternal NSAID use at about 20 weeks gestation or later in pregnancy has been associated with fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment; these adverse outcomes were generally seen after days to weeks of therapy, although oligohydramnios has been infrequently reported as soon as 48 hours after starting an NSAID. In many cases (but not all), the decrease in amniotic fluid was transient and reversible with discontinuation of therapy. A limited number of cases have been reported of maternal NSAID use and neonatal renal dysfunction without oligohydramnios (some were irreversible); some cases of neonatal renal dysfunction required treatment with invasive procedures (e.g., exchange transfusion, dialysis). Methodological limitations of these postmarketing studies and reports include lack of control group, limited information regarding dose/duration/timing of drug exposure, and concomitant use of other medications; such limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

TRAMADOL: Animal studies have revealed evidence of embryofetal toxicity and teratogenicity; administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 3.2, 1.4, and 8.2 times the tramadol dose of 176 mg at the MRHD of this combination drug. In a prenatal and postnatal development study, tramadol decreased pup body weight and increased pup mortality at 2.7 and 4.3 times the MRHD, respectively. In a published study, tramadol caused structural abnormalities in the brains of fetuses when administered to female Sprague Dawley rats from gestation days 10 to 21 at 2.7 times the MRHD. Tramadol crosses the placenta; the mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. There are no controlled data in human pregnancy.

Clinical Considerations:
-Fetal/neonatal adverse reactions:
---Celecoxib: Use of NSAIDs should be avoided in women at about 30 weeks gestation and later in pregnancy because NSAIDs (including this combination drug) can cause premature closure of the fetal ductus arteriosus. Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. If an NSAID is needed (including this combination drug) during this time, use should be limited to the lowest effective dose and shortest duration possible; if use of this combination drug extends beyond 48 hours, monitoring with ultrasound for oligohydramnios should be considered. This combination drug should be discontinued (with follow up according to clinical practice) if oligohydramnios occurs.
---Tramadol: Prolonged use of opioid analgesics during pregnancy for medical/nonmedical purposes can result in respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity/abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight; its onset, duration, and severity vary based on specific opioid used, duration of use, timing, and amount of last maternal use and rate of drug elimination by the neonate. Neonates should be observed for signs/symptoms of neonatal opioid withdrawal syndrome and should be managed accordingly. Neonatal seizures, neonatal withdrawal syndrome, fetal death, and stillbirth have been reported during postmarketing experience with tramadol.
-Labor or delivery:
---Celecoxib: There are no studies of this combination drug during labor or delivery; in animal studies, NSAIDs (including celecoxib) inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
---Tramadol: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist (e.g., naloxone) must be available for reversal of opioid induced respiratory depression in the neonate. This combination drug is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics (including this combination drug) can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions; however, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Neonates exposed to opioid analgesics during labor should be monitored for signs of excess sedation and respiratory depression.

Infertility in Females and Males of Reproductive Potential:
-Celecoxib: Based on mechanism of action, the use of prostaglandin-mediated NSAIDs (including celecoxib) may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation; small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Withdrawal of NSAIDs (including celecoxib) should be considered in women who have difficulties conceiving or who are undergoing investigation of infertility.
-Tramadol: Chronic use of opioids may reduce fertility in females and males of reproductive potential; it is not known whether these effects on fertility are reversible. Published studies in adult male rodents report clinically relevant doses of tramadol can produce adverse effects on male reproductive hormones and tissues.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

See references

CELECOXIB:
Limited data in 12 breastfeeding women showed low levels of celecoxib in breast milk; the calculated daily infant dose averaged 10 to 40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a 2-year-old. No adverse events were reported in 2 breastfed infants (aged 17 and 22 months).

At 12 months postpartum (average), 3 mothers who had been taking oral celecoxib (200 mg/day [average 3.27 mg/kg/day]) for several weeks had milk celecoxib levels measured at several times during a 24-hour period; 2 of their breastfed infants (17 and 22 months of age), who were breastfed on demand every 3 to 4 hours during the day and once at night, had blood samples taken 4 hours after a maternal dose. Peak milk levels averaged 139 mcg/L at 2 hours after dosing; celecoxib was undetectable (less than 10 mcg/L) in the plasma of the 2 infants, and by 12 hours after dosing, in milk. No infant side effects were noted by the mothers of the 2 infants. After a single 200 mg oral dose to 2 other mothers, breast milk and maternal serum were collected periodically over an 8-hour period; peak milk levels were 170 mcg/L at 4 hours after dosing in 1 woman and 269 mcg/L at 2 hours after dosing in the other. Based on data from these 5 women, an exclusively breastfed infant would receive 9.8 mcg/kg/day (estimated) or 0.3% of the maternal weight-adjusted dosage.

At 11 months postpartum (average; range: 6.5 to 15 months), 6 women were given a single 200 mg oral dose of celecoxib. Milk samples were collected for 48 hours after dosing; a peak milk level of 200 mcg/L (median; range: 70 to 330 mcg/L) occurred 2 to 4 hours after dosing. Authors calculated that a fully breastfed infant would receive 13 mcg/kg/day (median; range: 11 to 210 mcg/kg) or 0.23% of the maternal weight-adjusted dosage.

Nipple aspirate fluid was collected from 13 nonlactating women taking celecoxib 200 or 400 mg twice a day for 2 weeks; collection times with respect to dosing were not provided. With 200 mg twice a day, 2 women had aspirate celecoxib levels of 1.2 and 1.5 mg/L, and with 400 mg twice a day, 2 women had aspirate celecoxib levels of 0.53 and 8.4 mg/L; celecoxib was undetectable (lower limit of assay not provided) in the nipple aspirate fluid of the other 9 women.

TRAMADOL:
In adults, tramadol has 70% to 100% oral bioavailability and is metabolized to the active O-desmethyltramadol (M1); both tramadol and M1 are present in human milk. Tramadol has a more potent monoamine reuptake inhibitory effect while M1 has a more potent opioid mu-agonist effect (i.e., M1 is more potent than tramadol in mu opioid receptor binding); M1 is about 10% as potent as morphine in mu-opiate binding, although some experts have reported a 450-fold potency difference. Published studies have reported tramadol and M1 in colostrum when tramadol was administered to breastfeeding mothers in the early postpartum period. Women who are ultra-rapid metabolizers (i.e., extensive metabolizers) of tramadol may have higher than expected serum levels of M1, potentially leading to higher levels of M1 in breast milk which can be dangerous in their breastfed infants; the capacity of preterm and newborn infants to metabolize tramadol to M1 is limited. In women with normal tramadol metabolism, the amount of tramadol secreted into human milk is low and dose dependent.

Excretion of tramadol into milk is low and even lower amounts of the active metabolite (M1) are excreted. With usual maternal dosage, the amount excreted into breast milk is much less than the dose that has been given to neonates for analgesia. Studies in breastfed neonates found no adverse effects attributable to tramadol; however, a death occurred in the 8-month-old breastfed infant of a woman addicted to tramadol, although breastfeeding exposure alone might not have accounted for the death. Although tramadol is unlikely to adversely affect nursing infants with usual maternal dosages, the US FDA and the manufacturer of tramadol recommend against using tramadol during breastfeeding; if tramadol is used, infants should be monitored for increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, and a physician should be contacted immediately if any of these occur.

After a single 100 mg IV dose of tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.

Detectable levels (greater than 12 mcg/L) of tramadol were found in samples of breast milk collected 10 hours after a 50 mg maternal dose of IV or oral tramadol; no other clinical details or milk levels were reported.

At 2 to 4 days postpartum, 75 mothers provided 3 milk samples from both breasts during the 6 hours following a dose of oral tramadol (100 mg) after taking at least 4 doses. The milk level of tramadol averaged 748 mcg/L and of M1 averaged 203 mcg/L; these values translate to an infant dosage averaging 112 and 30 mcg/kg/day of the drug and metabolite, respectively. An exclusively breastfed infant would receive maternal weight-adjusted dosages of 2.24% of tramadol and 0.64% of its metabolite. At 2 to 4 days of age, the 75 breastfed infants of the 75 mothers were compared to 75 matched infants; 49% of the mothers taking tramadol and all of the control mothers were taking other opiates (primarily oxycodone) and 61% and 58%, respectively, also were taking a nonsteroidal anti-inflammatory agent (primarily diclofenac). Examination by a pediatrician showed no difference between the groups using the Neurologic and Adaptive Capacity Score.

A hospital in Japan provided postpartum mothers with a combination tablet containing tramadol 37.5 mg and acetaminophen 325 mg every 6 hours for 3 days if a pain medication was requested. A retrospective analysis found that of 148 mothers who received the drug, all infants were breastfed and none of the infants had an adverse reaction (e.g., drowsiness, difficulty breastfeeding, breathing problems); the relatively low dose and short duration of therapy may have reduced the risk of adverse reactions.

Tramadol can increase serum prolactin; however, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.

Breastfeeding is not recommended during use of this drug.

Excreted into human milk: Yes

Comments:
-The effects in the nursing infant are unknown; there is the potential for serious adverse reactions (including excess sedation and respiratory depression) in breastfed infants.
-This combination drug is not recommended for obstetrical preoperative medication or for postdelivery analgesia in nursing mothers because the safety of tramadol in infants and neonates has not been studied.
-If infants are exposed to this drug through breast milk, they should be monitored for excess sedation and respiratory depression; withdrawal symptoms can occur in breastfed infants when maternal use of an opioid analgesic or breastfeeding is stopped.
-Due to low levels of celecoxib in breast milk, amounts ingested by infants are small and not expected to cause any side effects in breastfed infants.

See references