Included as part of the "PRECAUTIONS" Section
Addiction, Abuse, And Misuse
APADAZ contains benzhydrocodone, a Schedule II controlled substance. As an opioid, APADAZ
exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse And Dependence].
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately
prescribed APADAZ. Addiction can occur at recommended dosages and if the drug is misused or
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing APADAZ, and
monitor all patients receiving APADAZ 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 APADAZ, but use in such patients necessitates intensive counseling about
the risks and proper use of APADAZ along with intensive monitoring for signs of addiction, abuse, and
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal
diversion. Consider these risks when prescribing or dispensing APADAZ. 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.
Opioid Analgesic Risk Evaluation And Mitigation Strategy (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the
Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS)
for these products. Under the requirements of the REMS, drug companies with approved opioid
analgesic products must make REMS-compliant education programs available to healthcare providers.
Healthcare providers are strongly encouraged to do all of the following:
- Complete a REMS-compliant education program offered by an accredited provider of continuing
education (CE) or another education program that includes all the elements of the FDA Education
Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
- Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with
patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling
Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
- Emphasize to patients and their caregivers the importance of reading the Medication Guide that they
will receive from their pharmacist every time an opioid analgesic is dispensed to them.
- Consider using other tools to improve patient, household, and community safety, such as patientprescriber
agreements that reinforce patient-prescriber responsibilities.
To obtain further information on the opioid analgesic REMS and for a list of accredited REMS
CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can
be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.
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 OVERDOSE]. 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
APADAZ, 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
with and following dosage increases of APADAZ.
To reduce the risk of respiratory depression, proper dosing and titration of APADAZ are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the APADAZ dosage when converting patients from
another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of APADAZ, especially by children, can result in respiratory
depression and death due to an overdose of hydrocodone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of APADAZ 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 CYP3A4 Inhibitors And
Concomitant use of APADAZ 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 hydrocodone 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 APADAZ is achieved. Similarly, discontinuation of a CYP3A4
inducer, such as rifampin, carbamazepine, and phenytoin, in APADAZ-treated patients may increase
hydrocodone plasma concentrations and prolong opioid adverse reactions. When using APADAZ with
CYP3A4 inhibitors or discontinuing CYP3A4 inducers in APADAZ-treated patients, monitor patients
closely at frequent intervals and consider dosage reduction of APADAZ until stable drug effects are
achieved [see DRUG INTERACTIONS].
Concomitant use of APADAZ with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could
decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a
withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. When using
APADAZ 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 DRUG INTERACTIONS].
APADAZ contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure,
at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the
use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one
acetaminophen-containing product [see OVERDOSE]. The excessive intake of acetaminophen may be
intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or
unknowingly take other acetaminophen-containing products.
The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals
who ingest alcohol while taking acetaminophen.
Instruct patients to look for “acetaminophen” or “APAP” on package labels and not to use more than one
product that contains acetaminophen. Instruct patients to seek medical attention immediately upon
ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of
APADAZ 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 DRUG INTERACTIONS].
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
APADAZ 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 APADAZ 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
APADAZ-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 APADAZ [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 APADAZ and when APADAZ 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 insufficiency.
APADAZ may cause severe hypotension including orthostatic hypotension and syncope in ambulatory
patients. There is 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 APADAZ.
In patients with circulatory shock, APADAZ may cause vasodilation that can further reduce cardiac
output and blood pressure. Avoid the use of APADAZ in patients with circulatory shock.
Serious Skin Reactions
Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous
pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can
be fatal. Inform patients about the signs of serious skin reactions and discontinue use at the first
appearance of skin rash or any other sign of hypersensitivity.
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), APADAZ 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 APADAZ.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of APADAZ
in patients with impaired consciousness or coma.
There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of
acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress,
urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis
requiring emergency medical attention. Instruct patients to discontinue APADAZ tablets immediately and
seek medical care if they experience these symptoms. Do not prescribe APADAZ tablets for patients
with acetaminophen allergy.
Risks Of Use In Patients With Gastrointestinal Conditions
APADAZ is contraindicated in patients with known or suspected gastrointestinal obstruction, including
The hydrocodone from APADAZ may cause spasm of the sphincter of Oddi. Opioids may cause
increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for
Increased Risk Of Seizures In Patients With Seizure Disorders
The hydrocodone from APADAZ 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
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 APADAZ [see DRUG INTERACTIONS]. In these patients, mixed agonist/antagonist and partial
agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.
When discontinuing APADAZ, gradually taper the dosage [see DOSAGE AND ADMINISTRATION]. Do not
abruptly discontinue APADAZ [see Drug Abuse And Dependence].
Risks Of Driving And Operating Machinery
APADAZ 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 APADAZ and know how they will react to the medication [see PATIENT INFORMATION].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Important Administration Instructions
Instruct patients how to properly take APADAZ [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
- Do not take more than 4,000 milligrams of acetaminophen per day. Call your doctor if you took
more than the recommended dose.
- Use APADAZ exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g.,
- Do not discontinue APADAZ without first discussing the need for a tapering regimen with your
Addiction, Abuse, And Misuse
Inform patients that the use of APADAZ, 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 APADAZ with others and to take steps to protect APADAZ 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 APADAZ or when the dosage 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 APADAZ securely and
to dispose of unused APADAZ by flushing the tablets down the toilet.
Maximum Daily Acetaminophen Use
Advise patients not to take more than 4,000 milligrams of acetaminophen per day and call their doctor if
they have taken more than the recommended dose. Advise patients not to take APADAZ in combination
with other tramadol or acetaminophen-containing products, including over-the- counter preparations
[(see WARNINGS AND PRECAUTIONS].
Interactions With Benzodiazepines And Other CNS Depressants
Inform patients that potentially fatal additive effects may occur if APADAZ is used with
benzodiazepines or other CNS depressants, including alcohol, and not to use these unless supervised by
a healthcare provider [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
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 healthcare
providers if they are taking, or plan to take serotonergic medications [see DRUG INTERACTIONS].
Inform patients to avoid taking APADAZ while using any drugs that inhibit monoamine oxidase. Patients
should not start MAOIs while taking APADAZ [see DRUG INTERACTIONS].
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].
Inform patients that APADAZ 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].
Serious Skin Reactions
Advise patients to stop APADAZ immediately if they develop any type of rash and to contact their
healthcare provider as soon as possible [see WARNINGS AND PRECAUTIONS].
Inform patients that anaphylaxis have been reported with ingredients contained in APADAZ. Advise
patients how to recognize such a reaction and when to seek medical attention [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS ADVERSE REACTIONS].
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of APADAZ 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 APADAZ can cause fetal harm and to inform their
healthcare provider of a known or suspected pregnancy [see Use In Specific Populations].
Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing
difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these
signs [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 [see Use In Specific Populations].
Driving Or Operating Heavy Machinery
Inform patients that APADAZ 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 [see WARNINGS AND PRECAUTIONS].
Advise patients of the potential for severe constipation, including management instructions and when to
seek medical attention [see ADVERSE REACTIONS].
Disposal Of Unused APADAZ
Advise patients to flush the unused tablets down the toilet when APADAZ is no longer needed or to
contact the Drug Enforcement Administration (DEA) to find the location of an authorized collector (1-
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies to evaluate the carcinogenic potential of benzhydrocodone or the combination of
benzhydrocodone and acetaminophen have not been conducted.
Long-term studies in mice and rats have been completed by the National Toxicology Program to
evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats
and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated
equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell
leukemia at 0.8 times the maximum human daily dose (MHDD) of 3.9 grams/day, based on a body
surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats (0.7
times) or mice (1.3-1.5 times the MHDD, based on a body surface area comparison).
Benzhydrocodone was positive in an in vitro mammalian cell chromosome aberration assay in the
presence of a metabolic activation (S9 mix) and negative in the absence of metabolic activation.
Benzhydrocodone was negative in an in vitro bacterial mutation assay as well as in the in vivo rat
micronucleus and comet assays.
Acetaminophen was not mutagenic in the bacterial reverse mutation assay (Ames test). In contrast,
acetaminophen tested positive in the in vitro mouse lymphoma assay and the in vitro chromosomal
aberration assay using human lymphocytes. In the published literature, acetaminophen has been reported
to be clastogenic when administered at 1500 mg/kg/day to the rat model (3.7-times the MHDD, based on
a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day
(1.9-times the MHDD, based on a body surface area comparison), suggesting a threshold effect.
Impairment Of Fertility
No nonclinical fertility studies have been conducted with benzhydrocodone or the combination of
benzhydrocodone and acetaminophen.
In studies conducted by the National Toxicology Program, fertility assessments with acetaminophen
have been completed in Swiss CD-1 mice via a continuous breeding study. There were no effects on
fertility parameters in mice consuming up to 1.8 times the MHDD of acetaminophen, based on a body
surface area comparison. Although there was no effect on sperm motility or sperm density in the
epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming 1.8
times the MHDD (based on a body surface comparison) and there was a reduction in the number of
mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with
chronic administration of acetaminophen near the upper limit of daily dosing.
Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are
1.2 times the MHDD and greater (based on a body surface comparison) result in decreased testicular
weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the
same doses. These effects appear to increase with the duration of treatment.
In a published mouse study, oral administration of 50 mg/kg acetaminophen to pregnant mice from
Gestation Day 7 to delivery (0.06 times the MHDD) reduced the number of primordial follicles in
female offspring and reduced the percentage of full term pregnancies and number of pups born to these
females exposed to acetaminophen in utero.
In a published study, pregnant rats oral administration of 350 mg/kg acetaminophen (0.9 times the
MHDD) from Gestation Day 13 to 21 (dams), reduced the number of germ cells in the fetal ovary and
decreased ovary weight and reduced number of pups per litter in F1 females as well as reduced ovary
weights in F2 females.
Use In Specific Populations
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome
[see WARNINGS AND PRECAUTIONS]. There are no available human data on hydrocodone or APADAZ
use during pregnancy to inform any drug associated risks. However, neonatal opioid withdrawal and
other adverse reactions during pregnancy and labor can occur with use of APADAZ [see Clinical
Published studies with oral acetaminophen use during pregnancy have not reported an association with
major congenital malformations. No reproductive or developmental toxicology studies in animals have
been conducted with benzhydrocodone or the combination of benzhydrocodone and acetaminophen.
Reproductive and developmental studies in rats and mice from the published literature identified
adverse events at clinically relevant doses with acetaminophen. Treatment of pregnant rats with doses of
acetaminophen approximately equal to the maximum human daily dose (MHDD) showed evidence of
fetotoxicity and increases in bone variations in the fetuses. In another study, necrosis was observed in
the liver and kidney of both pregnant rats and fetuses at doses approximately equal to the MHDD. In
mice and rats treated with acetaminophen at doses within the clinical dosing range, cumulative adverse
effects on reproductive capacity were reported. In mice, a reduction in number of litters of the parental
mating pair was observed as well as retarded growth, abnormal sperm in their offspring, and reduced
birth weight in the next generation. In rats, female fertility was decreased following in utero exposure
to acetaminophen [see Data].
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 to 4% and 15 to 20%, respectively.
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].
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 opioid-induced
respiratory depression in the neonate. APADAZ is not recommended for use in pregnant women during
or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid
analgesics, including APADAZ, 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.
Published data from a large population-based prospective cohort study and a population-based, casecontrol
study do not clearly report an association with oral acetaminophen and major birth defects,
miscarriage, or adverse maternal or fetal outcomes when acetaminophen is used during pregnancy.
However, these studies cannot definitely establish the absence of any risk because of methodological
limitations including recall bias.
No reproductive or developmental toxicology studies were conducted with benzhydrocodone or the
combination of benzhydrocodone and acetaminophen. The following data are based on findings from
studies performed with acetaminophen alone.
Studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 0.88 the
maximum human daily dose (MHDD) of 3.9 grams/day based on a body surface area comparison showed
evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations
(reduced ossification and rudimentary rib changes). Offspring had no evidence of external, visceral, or
skeletal malformations. When pregnant rats received oral acetaminophen throughout gestation at doses
of 1.2 times the MHDD (based on a body surface area comparison), areas of necrosis occurred in both
the liver and kidney of pregnant rats and fetuses. These effects did not occur in animals that received
oral acetaminophen at doses 0.3 times the MHDD, based on a body surface area comparison. In a
continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357,
715, or 1430 mg/kg/day). These doses are approximately 0.45, 0.89, and 1.78 times the MHDD,
respectively, based on a body surface area comparison. A dose-related reduction in body weights of
fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at
all doses. Animals in the high dose group had a reduced number of litters per mating pair, male
offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next
Hydrocodone is present in human milk. A published lactation study reports variable concentrations of
hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of
hydrocodone to nursing mothers in the early post-partum period. This lactation study did not assess
breastfed infants for potential adverse drug reactions. There is potential for sedation and respiratory
depression resulting from infant exposure to hydrocodone and its metabolites in breast milk.
Acetaminophen is present in human milk in small quantities after oral administration. Based on data from
more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 to
2% of the maternal dose. There is one well-documented report of a rash in a breastfed infant that
resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen
The developmental and health benefits of breastfeeding should be considered along with the mother’s
clinical need for APADAZ and any potential adverse effects on the breastfed child from APADAZ or
from the underlying maternal condition.
Infants exposed to APADAZ through breast milk should be monitored for excess sedation and
respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal
administration of an opioid analgesic is stopped, or when breastfeeding is stopped.
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, CLINICAL PHARMACOLOGY].
Published animal studies report that oral acetaminophen treatment of male animals at doses that are 1.2
times the MHDD and greater (based on a body surface area comparison) result in decreased testicular
weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the
same doses. Additional published animal studies indicate that acetaminophen exposure in utero adversely impacts reproductive capacity of both male and female offspring at clinically relevant
exposures [see Nonclinical Toxicology].
Safety and effectiveness in pediatric patients below the age of 18 years have not been established.
Elderly patients (aged 65 years or older) may have increased sensitivity to hydrocodone. In general, use
caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing
range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of
concomitant disease or other drug therapy.
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 APADAZ slowly in
geriatric patients and monitor closely for signs of respiratory depression [see WARNINGS AND PRECAUTIONS].
Hydrocodone and acetaminophen 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.
The effect of hepatic impairment on the pharmacokinetics of APADAZ has not been determined. Patients
with hepatic impairment may have higher plasma concentrations than those with normal function. Use a
low initial dose of APADAZ in patients with hepatic impairment or active liver disease and monitor
closely for adverse events such as respiratory depression and hepatotoxicity [see WARNINGS AND PRECAUTIONS].
The effect of renal impairment on the pharmacokinetics of APADAZ has not been determined. Patients
with renal impairment may have higher plasma concentrations than those with normal function. Use a low
initial dose of APADAZ in patients with renal impairment and monitor closely for adverse events such
as respiratory depression.