Addiction, Abuse, And Misuse
Hydrocodone bitartrate and acetaminophen tablets contain
hydrocodone, a Schedule II controlled substance. As an opioid, hydrocodone
bitartrate and acetaminophen tablets expose 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 hydrocodone
bitartrate and acetaminophen tablets. Addiction can occur at recommended dosages
and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse,
or misuse prior to prescribing hydrocodone bitartrate and acetaminophen
tablets, and monitor all patients receiving hydrocodone bitartrate and acetaminophen
tablets 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 hydrocodone bitartrate and acetaminophen tablets,
but use in such patients necessitates intensive counseling about the risks and
proper use of hydrocodone bitartrate and acetaminophen tablets along with
intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with
addiction disorders and are subject to criminal diversion. Consider these risks
when prescribing or dispensing hydrocodone bitartrate and acetaminophen
tablets. 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 hydrocodone bitartrate and
acetaminophen tablets, 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 hydrocodone bitartrate and acetaminophen
To reduce the risk of respiratory depression, proper
dosing and titration of hydrocodone bitartrate and acetaminophen tablets are
essential [see DOSAGE AND ADMINISTRATION]. Overestimating the hydrocodone
bitartrate and acetaminophen tablets dosage when converting patients from
another opioid product can result in a fatal overdose.
Accidental ingestion of hydrocodone bitartrate and
acetaminophen tablets, especially by children, can result in respiratory
depression and death due to an overdose of hydrocodone bitartrate and acetaminophen
Neonatal Opioid Withdrawal Syndrome
Prolonged use of hydrocodone bitartrate and acetaminophen
tablets 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 PATIENT INFORMATION].
Risks Of Concomitant Use Or Discontinuation Of Cytochrome
P450 3A4 Inhibitors And Inducers
Concomitant use of hydrocodone bitartrate and
acetaminophen tablets 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 bitartrate and acetaminophen tablets and prolong opioid adverse
reactions, and which may cause potentially fatal respiratory depression [see WARNINGS],
particularly when an inhibitor is added after a stable dose of hydrocodone
bitartrate and acetaminophen tablets is achieved. Similarly, discontinuation of
a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in
hydrocodone bitartrate and acetaminophen tablets-treated patients may increase
hydrocodone plasma concentrations and prolong opoid adverse reactions. When
adding CYP3A4 inhibitors or discontinuing CYP3A4 inducers in hydrocodone bitartrate
and acetaminophen tablets-treated patients, follow patients at frequent
intervals and consider dosage reduction of hydrocodone bitartrate and acetaminophen
tablets until stable drug effects are achieved [see DRUG
Concomitant use of hydrocodone bitartrate and
acetaminophen tablets 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 hydrocodone bitartrate
and acetaminophen tablets with CYP3A4 inducers or discontinuing CYP3A4
inhibitors, follow patients 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].
Risks From Concomitant Use With Benzodiazepines Or Other
Profound sedation, respiratory depression, coma, and
death may result from the concomitant use of hydrocodone bitartrate and
acetaminophen tablets 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.Â 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 hydrocodone bitartrate and
acetaminophen tablets are 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 hydrocodone bitartrate and acetaminophen
tablets 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
Hydrocodone bitartrate and acetaminophen tablet-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 hydrocodone
bitartrate and acetaminophen tablets [see WARNINGS; Life-Threatening
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 WARNINGS; Life-Threatening Respiratory Depression].
Follow such patients closely, particularly when
initiating and titrating hydrocodone bitartrate and acetaminophen tablets and
when hydrocodone bitartrate and acetaminophen tablets are given concomitantly
with other drugs that depress respiration [see WARNINGS; 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
Hydrocodone bitartrate and acetaminophen tablets 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]. Follow these patients for
signs of hypotension after initiating or titrating the dosage of hydrocodone
bitartrate and acetaminophen tablets. In patients with circulatory shock
hydrocodone bitartrate and acetaminophen tablets may cause vasodilatation that
can further reduce cardiac output and blood pressure. Avoid the use of
hydrocodone bitartrate and acetaminophen tablets with circulatory shock.
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 4,000 milligrams per day, and often involve more than one
acetaminophen-containing product. 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
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 4,000 milligrams of acetaminophen per day, even if they feel well.
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.
Patients should be informed about the signs of serious skin reactions, and use
of the drug should be discontinued at the first appearance of skin rash or any
other sign of hypersensitivity.
There have been post-marketing reports of
hypersensitivity and anaphylaxis associated with the 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 hydrocodone bitartrate and acetaminophen
tablets immediately and seek medical care if they experience these symptoms. Do
not prescribe hydrocodone bitartrate and acetaminophen tablets for patients
with acetaminophen allergy [see PATIENT INFORMATION.]
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), hydrocodone bitartrate and
acetaminophen tablets may reduce respiratory drive, and the resultant CO2
retention can further increase intracranial pressure. Follow such patients for
signs of sedation and respiratory depression, particularly when initiating therapy
with hydrocodone bitartrate and acetaminophen tablets.
Opioids may also obscure the clinical course in a patient
with a head injury. Avoid the use of hydrocodone bitartrate and acetaminophen
tablets in patients with impaired consciousness or coma.
Risks Of Use In Patients With Gastrointestinal Conditions
Hydrocodone bitartrate and acetaminophen tablets are
contraindicated in patients with gastrointestinal obstruction, including
The administration of hydrocodone bitartrate and
acetaminophen tablets or other opioids may obscure the diagnosis or clinical
course in patients with acute abdominal conditions.
Hydrocodone 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 worsening symptoms.
Increased Risk Of Seizures In Patients With Seizure
The hydrocodone in hydrocodone bitartrate and
acetaminophen tablets 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. Follow patients with a history of seizure
disorders for worsened seizure control during hydrocodone bitartrate and
acetaminophen tablet 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 hydrocodone bitartrate and acetaminophen tablets. In these
patients, mixed agonist/antagonist and partial analgesics may reduce the
analgesic effect and/or precipitate withdrawal symptoms.
When discontinuing hydrocodone bitartrate and acetaminophen
tablets, gradually taper the dosage [see DOSAGE AND ADMINISTRATION]. Do
not abruptly discontinue hydrocodone bitartrate and acetaminophen tablets [see Drug
Abuse And Dependence] in patients who have been using hydrocodone
bitartrate and acetaminophen tablets around the clock for more than 5 days.