Included as part of the PRECAUTIONS section.
Addiction, Abuse, And Misuse
TARGINIQ ER contains oxycodone, a Schedule II controlled
substance. As an opioid, TARGINIQ ER exposes users to the risks of addiction,
abuse, and misuse. Because extended-release products such as TARGINIQ ER
deliver the opioid over an extended period of time, there is a greater risk for
overdose and death due to the larger amount of oxycodone present [see Drug
Abuse and Dependence].
Although the risk of addiction in any individual is
unknown, it can occur in patients appropriately prescribed TARGINIQ ER.
Addiction can occur at recommended doses and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse or
misuse, prior to prescribing TARGINIQ ER, and monitor all patients receiving
TARGINIQ ER for the development of these behaviors and conditions. Risks are
increased in patients with a personal or family history of substance abuse
(including drug or alcohol abuse or addiction) or mental illness (e.g., major
depression). The potential for these risks should not, however, prevent the
proper management of pain in any given patient. Patients at increased risk may
be prescribed opioids such as TARGINIQ ER, but use in such patients
necessitates intensive counseling about the risks and proper use of TARGINIQ ER
along with intensive monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of TARGINIQ ER by crushing, chewing,
snorting, or injecting the dissolved product will result in the uncontrolled
delivery of oxycodone and can result in overdose and death [see OVERDOSAGE].
Opioids are sought by drug abusers and people with
addiction disorders and are subject to criminal diversion. Consider these risks
when prescribing or dispensing TARGINIQ ER. Strategies to reduce these risks
include prescribing the drug in the smallest appropriate quantity and advising
the patient on the proper disposal of unused drug [see PATIENT INFORMATION]. Contact local state professional licensing board or state
controlled substances authority for information on how to prevent and detect
abuse or diversion of this product.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory
depression has been reported with the use of opioids, even when used as
recommended. Respiratory depression, if not immediately recognized and treated,
may lead to respiratory arrest and death. Management of respiratory depression
may include close observation, supportive measures, and use of opioid
antagonists, depending on the patient's clinical status [see OVERDOSAGE].
Carbon dioxide (CO2) retention from opioid-induced respiratory depression can
exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory
depression can occur at any time during the use of TARGINIQ ER, the risk is
greatest during the initiation of therapy or following a dosage increase.
Monitor patients closely for respiratory depression, especially within the
first 24-72 hours of initiating therapy and following dosage increases of
To reduce the risk of respiratory depression, proper
dosing and titration of TARGINIQ ER are essential [see DOSAGE AND
ADMINISTRATION]. Overestimating the TARGINIQ ER dosage when converting
patients from another opioid product can result in a fatal overdose with the
Accidental ingestion of even one dose of TARGINIQ ER,
especially by children, can result in respiratory depression and death due to
an overdose of oxycodone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of TARGINIQ ER during pregnancy can result
in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike
opioid withdrawal syndrome in adults, may be life-threatening if not recognized
and treated, and requires management according to protocols developed by
neonatology experts. Observe newborns for signs of neonatal opioid withdrawal
syndrome and manage accordingly. Advise pregnant women using opioids for a
prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure
that appropriate treatment will be available [see Use in Specific
Populations, PATIENT INFORMATION].
Risks Of Concomitant Use Or Discontinuation Of Cytochrome
P450 3A4 Inhibitors And Inducers
Concomitant use of TARGINIQ ER with a CYP3A4 inhibitor,
such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents
(e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase
plasma concentrations of oxycodone and prolong opioid adverse reactions, which
may cause potentially fatal respiratory depression [see Life-Threatening Respiratory Depression], particularly when an inhibitor is added after a stable dose
of TARGINIQ ER is achieved. Similarly, discontinuation of a CYP3A4 inducer,
such as rifampin, carbamazepine, and phenytoin, in TARGINIQ ER-treated patients
may increase oxycodone plasma concentrations and prolong opioid adverse
reactions. When using TARGINIQ ER with CYP3A4 inhibitors or discontinuing
CYP3A4 inducers in TARGINIQ ER-treated patients, monitor patients closely at
frequent intervals and consider dosage reduction of TARGINIQ ER until stable
drug effects are achieved [see DRUG INTERACTIONS].
Concomitant use of TARGINIQ ER with CYP3A4 inducers or discontinuation
of an CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease
opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who
had developed physical dependence to oxycodone. When using TARGINIQ ER with
CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at
frequent intervals and consider increasing the opioid dosage if needed to
maintain adequate analgesia or if symptoms of opioid withdrawal occur [see
Risks From Concomitant Use With Benzodiazepines, Or Other
Profound sedation, respiratory depression coma, and death
may result from the concomitant use of TARGINIQ ER with benzodiazepines or
other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics,
anxiolytics, tranquilizers, muscle relaxants, general anesthetics,
antipsychotics, other opioids, alcohol). Because of these risks, reserve
concomitant prescribing of these drugs for use in patients for whom alternative
treatment options are inadequate.
Observational studies have demonstrated that concomitant
use of opioid analgesics and benzodiazepines increases the risk of drug-related
mortality compared to use of opioid analgesics alone. Because of similar
pharmacological properties, it is reasonable to expect similar risk with the
concomitant use of other CNS depressant drugs with opioid analgesics [see
If the decision is made to prescribe a benzodiazepine or
other CNS depressant concomitantly with an opioid analgesic, prescribe the
lowest effective dosages and minimum durations of concomitant use. In patients
already receiving an opioid analgesic, prescribe a lower initial dose of the
benzodiazepine or other CNS depressant than indicated in the absence of an
opioid, and titrate based on clinical response. If an opioid analgesic is
initiated in a patient already taking a benzodiazepine or other CNS depressant,
prescribe a lower initial dose of the opioid analgesic, and titrate based on
clinical response. Follow patients closely for signs and symptoms of
respiratory depression and sedation.
Advise both patients and caregivers about the risks of
respiratory depression and sedation when TARGINIQ ER is used with
benzodiazepines or other CNS depressants (including alcohol and illicit drugs).
Advise patients not to drive or operate heavy machinery until the effects of
concomitant use of the benzodiazepine or other CNS depressant have been
determined. Screen patients for risk of substance use disorders, including
opioid abuse and misuse, and warn them of the risk for overdose and death
associated with the use of additional CNS depressants including alcohol and
illicit drugs [see DRUG INTERACTIONS, PATIENT INFORMATION].
Life-Threatening Respiratory Depression In Patients With Chronic
Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients
The use of TARGINIQ ER in patients with acute or severe
bronchial asthma in an unmonitored setting or in the absence of resuscitative
equipment is contraindicated.
Patients With Chronic Pulmonary Disease
TARGINIQ ER-treated patients with significant chronic
obstructive pulmonary disease or cor pulmonale, and those with a substantially
decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing
respiratory depression are at increased risk of decreased respiratory drive
including apnea, even at recommended dosages of TARGINIQ ER [see Life-Threatening Respiratory Depression].
Elderly, Cachectic, Or Debilitated Patients
Life-threatening respiratory depression is more likely to
occur in elderly, cachectic, or debilitated patients because they may have
altered pharmacokinetics or altered clearance compared to younger, healthier
patients [see Life-Threatening Respiratory Depression].
Monitor such patients closely, particularly when
initiating and titrating TARGIIQ ER and when TARGINIQ ER is given concomitantly
with other drugs that depress respiration [see Life-Threatening Respiratory Depression].
Alternatively, consider the use of non-opioid analgesics in these patients.
Cases of adrenal insufficiency have been reported with
opioid use, more often following greater than one month of use. Presentation of
adrenal insufficiency may include non-specific symptoms and signs including
nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood
pressure. If adrenal insufficiency is suspected, confirm the diagnosis with
diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed,
treat with physiologic replacement doses of corticosteroids. Wean the patient
off of the opioid to allow adrenal function to recover and continue
corticosteroid treatment until adrenal function recovers. Other opioids may be
tried as some cases reported use of a different opioid without recurrence of
adrenal insufficiency. The information available does not identify any
particular opioids as being more likely to be associated with adrenal
TARGINIQ ER may cause severe hypotension, including
orthostatic hypotension and syncope in ambulatory patients. There is an
increased risk in patients whose ability to maintain blood pressure has already
been compromised by a reduced blood volume or concurrent administration of
certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see
DRUG INTERACTIONS]. Monitor these patients for signs of hypotension
after initiating or titrating the dosage of TARGINIQ ER. In patients with
circulatory shock, TARGINIQ ER may cause vasodilation that can further reduce
cardiac output and blood pressure. Avoid the use of TARGINIQ ER in patients
with circulatory shock.
Risks Of Use In Patients With Increased Intracranial
Pressure, Brain Tumors, Head Injury or Impaired Consciousness
In patients who may be susceptible to the intracranial
effects of CO2 retention (e.g., those with evidence of increased intracranial
pressure or brain tumors), TARGINIQ ER may reduce respiratory drive, and the
resultant CO2 retention can further increase intracranial pressure. Monitor
such patients for signs of sedation and respiratory depression, particularly
when initiating therapy with TARGINIQ ER.
Opioids may also obscure the clinical course in a patient
with a head injury. Avoid the use of TARGINIQ ER in patients with impaired
consciousness or coma.
Risks Of Use In Patients With Gastrointestinal Conditions
TARGINIQ ER is contraindicated in patients with known or
suspected gastrointestinal obstruction, including paralytic ileus.
The oxycodone in TARGINIQ ER may cause spasm of the
sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor
patients with biliary tract disease, including acute pancreatitis, for
Increased Risk Of Seizures In Patients With Seizure
The oxycodone in TARGINIQ ER may increase the frequency
of seizures in patients with seizure disorders, and may increase the risk of
seizures occurring in other clinical settings associated with seizures. Monitor
patients with a history of seizure disorders for worsened seizure control
during TARGINIQ ER therapy.
Avoid the use of mixed agonist/antagonist (e.g..,
pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g.,
buprenorphine) analgesics in patients who are receiving a full opioid agonist
analgesic, including TARGINIQ ER. In these patients, mixed agonist/antagonist
and partial agonist analgesics may reduce the analgesic effect and/or may
precipitate withdrawal symptoms.
When discontinuing TARGINIQ ER, gradually taper the
dosage [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue
TARGINIQ ER [see Drug Abuse and Dependence].
Symptoms of opioid withdrawal occurred in some patients
in clinical trials [see ADVERSE REACTIONS]. Symptoms included but were
not limited to hyperhidrosis, chills, diarrhea, abdominal pain, anxiety,
irritability, and yawning. Monitor patients for symptoms of opioid withdrawal.
In opioid-tolerant patients, if symptoms of opioid withdrawal occur following
conversion to TARGINIQ ER or following dose escalation, consider lowering the
dose to determine whether symptoms are reduced.
Parenteral use of naloxone has been associated with
abrupt and complete reversal of opioid effects leading to withdrawal symptoms
(e.g., abdominal cramping, muscle aches, sweating, anxiety, nausea, vomiting,
diarrhea). Several instances of hypotension, hypertension, ventricular
tachycardia and fibrillation, and pulmonary edema have been associated with
parenteral naloxone used postoperatively.
Risks Of Driving And Operating Machinery
TARGINIQ ER may impair the mental or physical abilities
needed to perform potentially hazardous activities such as driving a car or
operating machinery. Warn patients not to drive or operate dangerous machinery
unless they are tolerant to the effects of TARGINIQ ER and know how they will
react to the medication [see PATIENT INFORMATION].
Not every urine drug test for “opioids” or “opiates”
detects oxycodone reliably, especially those designed for in-office use.
Further, many laboratories will report urine drug concentrations below a specified
“cut-off” value as “negative”. Therefore, if urine testing for oxycodone is considered
in the clinical management of an individual patient, ensure that the
sensitivity and specificity of the assay is appropriate, and consider the
limitations of the testing used when interpreting results.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Addiction, Abuse, And Misuse
Inform patients that the use of TARGINIQ ER, even when
taken as recommended, can result in addiction, abuse, and misuse, which can
lead to overdose and death [see WARNINGS AND PRECAUTIONS]. Instruct
patients not to share TARGINIQ ER with others and to take steps to protect
TARGINIQ ER from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening
respiratory depression including information that the risk is greatest when
starting TARGINIQ ER or when the dose is increased and that it can occur even
at recommended dosages [see WARNINGS AND PRECAUTIONS]. Advise patients
how to recognize respiratory depression and to seek medical attention if
breathing difficulties develop.
Inform patients that accidental ingestion, especially by
children, may result in respiratory depression or death [see WARNINGS AND
PRECAUTIONS]. Instruct patients to take steps to store TARGINIQ ER securely
and to dispose of unused TARGINIQ ER by flushing the tablets down the toilet.
Interaction With Benzodiazepines And Other CNS
Inform patients and caregivers that potentially fatal
additive effects may occur if TARGINIQ ER is used with benzodiazepines or other
CNS depressants, including alcohol, and not to use these concomitantly unless
supervised by a healthcare provider [see WARNINGS AND PRECAUTIONS, DRUG
Inform patients that opioids could cause a rare but
potentially life-threatening condition resulting from concomitant
administration of serotonergic drugs. Warn patients of the symptoms of
serotonin syndrome and to seek medical attention right away if symptoms
develop. Instruct patients to inform their physicians if they are taking, or
plan to take serotonergic medications [see DRUG INTERACTIONS].
Inform patients to avoid taking TARGINIQ ER while using
any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while
taking TARGINIQ ER.
Inform patients that opioids could cause adrenal
insufficiency, a potentially life-threatening condition. Adrenal insufficiency
may present with non-specific symptoms and signs such as nausea, vomiting,
anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients
to seek medical attention if they experience a constellation of these symptoms [see
WARNINGS AND PRECAUTIONS].
Important Administration Instructions
Instruct patients how to properly take TARGINIQ ER,
including the following:
- TARGINIQ ER is designed to work properly only if
swallowed intact. Taking cut, broken, chewed, crushed, or dissolved TARGINIQ ER
tablets can result in a fatal overdose or other serious side effects (e.g.,
withdrawal symptoms) [see DOSAGE AND ADMINISTRATION].
- Do not discontinue TARGINIQ ER without first discussing
the need for a tapering regimen with the prescriber [see DOSAGE AND
Inform patients that TARGINIQ ER may cause orthostatic
hypotension and syncope. Instruct patients how to recognize symptoms of low
blood pressure and how to reduce the risk of serious consequences should
hypotension occur (e.g., sit or lie down, carefully rise from a sitting or
lying position) [see WARNINGS AND PRECAUTIONS].
Inform patients that anaphylaxis has been reported with
ingredients contained in TARGINIQ ER. Advise patients how to recognize such a
reaction and when to seek medical attention [see CONTRAINDICATIONS, ADVERSE
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that
prolonged use of TARGINIQ ER during pregnancy can result in neonatal opioid
withdrawal syndrome, which may be life-threatening if not recognized and
treated [see WARNINGS AND PRECAUTIONS, Use in Specific Populations].
Inform female patients of reproductive potential that
TARGINIQ ER can cause fetal harm and to inform the healthcare provider of a
known or suspected pregnancy [see Use in Specific Populations].
Advise patients that breastfeeding is not recommended
during treatment with TARGINIQ ER [see Use in Specific Populations]
Inform patients that chronic use of opioids may cause
reduced fertility. It is not known whether these effects on fertility are
reversible ÃÂ [see Use in Specific Populations].
Opioid Withdrawal Symptoms
Advise patients that TARGINIQ ER may be associated with
symptoms possibly related to opioid withdrawal, including sweating, tremors,
anxiety, chills, diarrhea, abdominal pain, irritability, and yawning, and to
contact their prescriber if these symptoms occur.
Driving Or Operating Heavy Machinery
Inform patients that TARGINIQ ER may impair the ability
to perform potentially hazardous activities such as driving a car or operating
heavy machinery. Advise patients not to perform such tasks until they know how
they will react to the medication.
Advise patients of the potential for severe constipation,
including management instructions and when to seek medical attention [see ADVERSE
Disposal Of Unused TARGINIQ ER
Advise patients to flush the unused tablets down the
toilet when TARGINIQ ER is no longer needed.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies have not been conducted with
oxycodone alone or the oxycodone and naloxone combination.
Naloxone was tested in two carcinogenicity studies in
rats and transgenic mice. Naloxone was not carcinogenic in a 2-year rat
bioassay at doses as high as 100 mg/kg/day (24-times the maximum recommended
daily dose of 40 mg naloxone/day on a mg/m&sup basis).
Naloxone did not produce evidence of carcinogenic
potential in the Tg.rasH2 mouse model.
Oxycodone was genotoxic in the mouse lymphoma assay.
Clastogenicity was observed with oxycodone in the presence of metabolic
activation in one chromosomal aberration assay in human lymphocytes at concentrations
greater than or equal to 1250 mcg/mL at 24 but not 48 hours of exposure. In a
second chromosomal aberration assay with human lymphocytes, no structural
clastogenicity was observed either with or without metabolic activation;
however, in the absence of metabolic activation, oxycodone increased numerical
chromosomal aberrations (polyploidy). Oxycodone was not genotoxic in the
following assays: Ames S. typhimurium and E. coli test with and
without metabolic activation at concentrations up to 5000 μg/plate,
chromosomal aberration test in human lymphocytes (in the absence of metabolic
activation) at concentrations up to 1500 μg/mL, and with activation after
48 hours of exposure at concentrations up to 5000 μg/mL, and in the in
vivo bone marrow micronucleus assay in mice (at plasma levels up to 48
Naloxone was genotoxic in the mouse lymphoma assay.
Naloxone produced a non-dose-related increase in chromosomal aberrations in the
presence of metabolic activation that was statistically significant at
concentrations of 375 and 1500 mcg/mL but not at 750 or 3000 mcg/mL. In
contrast, naloxone was not mutagenic in the S. typhimurium/E. coli
bacterial mutagenicity test with or without metabolic activation nor was it
genotoxic in in vivo mouse bone marrow micronucleus test at a dose of 500
Impairment Of Fertility
Fertility studies to evaluate the combination of
oxycodone and naloxone have not been conducted. In a study of reproductive
performance, rats were administered a once daily gavage dose of the vehicle or
oxycodone hydrochloride doses up to 8 mg/kg (equivalent to the maximum
recommended daily dose of 80 mg/day on a mg/m&sup basis). Male rats were dosed for
28 days before cohabitation with females, during the cohabitation and until
necropsy (2-3 weeks post-cohabitation). Females were dosed for 14 days before
cohabitation with males, during cohabitation and up to Gestation Day 6.
Oxycodone hydrochloride did not affect reproductive function in male or female
Oral administration of naloxone to male and female rats
at dosages as high as 800 mg/kg/day had no effect on fertility or general
reproductive performance (approximately 192-times the maximum recommended daily
dose of 40 mg naloxone/day, on a mg/m&sup basis).
Use In Specific Populations
Prolonged use of opioid analgesics during pregnancy may
cause neonatal opioid withdrawal [see WARNINGS AND PRECAUTIONS]. 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%,
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
Labor Or Delivery
Opioids cross the placenta and may produce respiratory
depression and psycho-physiologiceffects 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 notrecommended for use in
women during or immediately prior to labor, when use of shorter
actinganalgesics or other analgesic techniques are more appropriate. Opioid
analgesics, includingTARGINIQ ER, can prolong labor through actions which
temporarily reduce the strength, duration, and frequency of uterine
contractions. However, this effect is not consistent and maybe 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
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/m&sup 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/m&sup 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/m&sup 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/m&sup basis).
Naloxone 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
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/m&sup 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.
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.
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.
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].
Safety and effectiveness of TARGINIQ ER in pediatric
patients below the age of 18 years have not been established.
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
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.
A clinical trial has shown that plasma concentrations of
both oxycodone and naloxone are elevated in patients with hepatic impairment.
Naloxone concentrations were affected to a higher degree than oxycodone. When
administering TARGINIQ ER to patients with mild hepatic impairment, a dosage
adjustment is recommended [see DOSAGE AND ADMINISTRATION]. Monitor
patients closely for signs of central nervous system or respiratory depression
due to elevated levels of oxycodone and for signs of withdrawal due to elevated
levels of naloxone. TARGINIQ ER is contraindicated in patients with moderate
and severe hepatic impairment [see CLINICAL PHARMACOLOGY].
A clinical trial has shown that plasma concentrations of
both oxycodone and naloxone are elevated in patients with renal impairment.
Naloxone concentrations were affected to a higher degree than oxycodone. When
administering TARGINIQ ER to patients with renal impairment, a dosage reduction
is recommended [see DOSAGE AND ADMINISTRATION]. Monitor patients closely
for signs of central nervous system or respiratory depression due to elevated
levels of oxycodone and for signs of withdrawal due to elevated levels of
naloxone. As patients with severe renal impairment may be at greater risk for
opioid withdrawal-related adverse events, consider using alternative products
without naloxone [see CLINICAL PHARMACOLOGY].