TARGINIQ ER (Page 7 of 11)


8.1 Pregnancy

Risk Summary
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal [see Warnings and Precautions (5.3)]. There are no adequate and well-controlled studies with TARGINIQ ER in pregnant women. The naloxone component of TARGINIQ ER may precipitate opioid withdrawal in a fetus due to the immaturity of the fetal blood brain barrier. Animal reproduction studies were not conducted with the combination of oxycodone and naloxone, the components of TARGINIQ ER. However, animal data are available from studies conducted with the individual components. Embryo-fetal toxicity was not observed following oral administration of oxycodone to rats and rabbits during the period of organogenesis at doses equal to or 30 times, respectively, the maximum recommended daily dose (MRDD) of 80 mg oxycodone/day on a body surface area basis. Decreased pup weight was observed in rats with oral administration of oxycodone throughout pregnancy at doses 0.8 times the MRDD dose of 80 mg oxycodone/day. Embryo-fetal toxicity was not observed following oral administration of naloxone (800 mg/kg or 400 mg/kg) to pregnant rats and rabbits, respectively, during organogenesis at doses 192 times the MRDD of 40 mg naloxone/day, on a body surface area basis. In several published studies, treatment of pregnant rats with oxycodone hydrochloride at clinically relevant doses and below resulted in neurobehavioral effects in offspring [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations
Fetal/neonatal adverse reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of narcotic-opioid induced respiratory depression in the neonate. TARGINIQ ER is not recommended for use in women during or immediately prior to labor, when use of shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including TARGINIQ ER, 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. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.


Animal Data
There are no studies examining the reproductive and developmental effects of the combination of oxycodone and naloxone; however, there are data with the individual agents.


Studies with oral doses of oxycodone hydrochloride in rats up to 8 mg/kg/day and rabbits up to 125 mg/kg/day, equivalent to 1 and 30 times the maximum total daily dose of 80 mg oxycodone/day, respectively on a mg/m2 basis, did not reveal evidence of harm to the fetus due to oxycodone. In a pre- and postnatal toxicity study, female rats received oxycodone during gestation and lactation. There were no long-term developmental or reproductive effects in the pups.

Oxycodone hydrochloride was administered orally to female rats during gestation and lactation in a pre- and postnatal toxicity study. There were no drug-related effects on reproductive performance in these females or any long-term developmental or reproductive effects in pups born to these rats. Decreased body weight was found during lactation and the early post-weaning phase in pups nursed by mothers given the highest dose used (6 mg/kg/day, equivalent to approximately 0.8-times the maximum total daily dose of 80 mg/day, on a mg/m2 basis). However, body weight of these pups recovered.

In published studies, offspring of pregnant rats administered oxycodone hydrochloride during gestation have been reported to exhibit neurobehavioral effects including altered stress responses and increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3 times an adult human oral dose of 60 mg/day on a mg/m2 basis), and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human oral dose of 60 mg/day on a mg/m2 basis).


Orally administered naloxone was not teratogenic in the rat or rabbit at the maximum dosages tested (800 mg/kg/day or 400 mg/kg/day, respectively) which were equivalent to approximately 192-times the intake of naloxone at the maximum recommended dose of 40 mg naloxone/day on a mg/m2 basis.

In a peri-/post-natal development study with naloxone in rats, the highest dosage of 800 mg/kg/day (192-times the intake of naloxone at the maximum total daily dose of 40 mg naloxone/day, on a mg/m2 basis) produced mortality and significant toxicity in maternal rats, which was associated with increased pup deaths in the immediate postpartum period. Mild toxic signs were also observed in maternal rats that received 200 mg/kg/day (approximately 48-times the intake of naloxone at the maximum daily dose of 40 mg naloxone on a body surface area basis); however, there were no adverse effects on the pups.

8.2 Lactation

Risk Summary

Oxycodone is present in breast milk. Published lactation studies report variable concentrations of oxycodone in breast milk with administration of immediate-release oxycodone to nursing mothers in the early postpartum period. The lactation studies did not assess breastfed infants for potential adverse reactions. Lactation studies have not been conducted with TARGINIQ ER. It is unknown whether naloxone is present in breast milk. Instruct patients not to undertake nursing while receiving TARGINIQ ER. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with TARGINIQ ER.

Clinical Considerations
Infants exposed to TARGINIQ ER through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. Furthermore, naloxone may precipitate opioid withdrawal in a breast-fed infant.

8.3 Females and Males of Reproductive Potential


Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].

8.4 Pediatric Use

Safety and effectiveness of TARGINIQ ER in pediatric patients below the age of 18 years have not been established.

8.5 Geriatric Use

A prospective study conducted in two age groups (younger: 19-44 years old vs. elderly: 65-77 years old) to assess age effects on the PK of TARGINIQ ER (10 mg/5 mg) demonstrated slightly higher steady-state oxycodone AUC (18% increase), and higher steady-state naloxone AUC (82% increase) for elderly subjects compared with younger subjects. Evaluate elderly patients at frequent intervals and consider TARGINIQ ER dose adjustments until stable drug effects are achieved.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of TARGINIQ ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6)].

Oxycodone and naloxone are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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