Inhibitors Of CYP3A4 And CYP2D6
The concomitant use of hydrocodone bitartrate and acetaminophen tablets and CYP3A4 inhibitors, such
as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease
inhibitors (e.g., ritonavir), can increase the plasma concentration of the hydrocodone from hydrocodone
bitartrate and acetaminophen tablets, resulting in increased or prolonged opioid effects. These effects
could be more pronounced with concomitant use of hydrocodone bitartrate and acetaminophen tablets
and both CYP3A4 and CYP2D6 inhibitors, particularly when an inhibitor is added after a stable dose of
hydrocodone bitartrate and acetaminophen tablets is achieved [see WARNINGS].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma
concentration will decrease [see CLINICAL PHARMACOLOGY], resulting in decreased opioid
efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone
bitartrate and acetaminophen tablets.
If concomitant use is necessary, consider dosage reduction of hydrocodone bitartrate and
acetaminophen tablets until stable drug effects are achieved. Follow patients for respiratory depression
and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the
hydrocodone bitartrate and acetaminophen tablets dosage until stable drug effects are achieved. Follow
for signs or symptoms of opioid withdrawal.
Inducers Of CYP3A4
The concomitant use of hydrocodone bitartrate and acetaminophen tablets and CYP3A4 inducers, such
as rifampin, carbamazepine, and phenytoin, can decrease the plasma concentration of hydrocodone [see CLINICAL PHARMACOLOGY], resulting in decreased efficacy or onset of a withdrawal syndrome
in patients who have developed physical dependence to hydrocodone [see WARNINGS].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma
concentration will increase [see CLINICAL PHARMACOLOGY], which could increase or prolong
both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
If concomitant use is necessary, consider increasing the hydrocodone bitartrate and acetaminophen
tablets dosage until stable drug effects are achieved. Follow the patient for signs and symptoms of
opioid withdrawal. If a CYP3A4 inducer is discontinued, consider hydrocodone bitartrate and
acetaminophen tablets dosage reduction and follow for signs of respiratory depression.
Benzodiazepines And Other CNS Depressants
Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS
depressants, such as benzodiazepines and other sedative hypnotics, anxiolytics, and tranquilizers,
muscle relaxants, general anesthetics, antipsychotics, and other opioids, including alcohol, can increase
the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment
options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely
for signs of respiratory depression and sedation [see WARNINGS].
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system,
such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors
(SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the
serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase
(MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and
intravenous methylene blue), has resulted in serotonin syndrome [see PATIENT INFORMATION].
If concomitant use is warranted, carefully follow the patient, particularly during treatment initiation and
dose adjustment. Discontinue hydrocodone bitartrate and acetaminophen tablets if serotonin syndrome is
Monoamine Oxidase Inhibitors (MAOIs)
The concomitant use of opioids and MAOIs, such as phenelzine, tranylcypromine, or linezolid, may
manifest as serotonin syndrome, or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS].
The use of hydrocodone bitartrate and acetaminophen tablets is not recommended for patients taking
MAOIs or within 14 days of stopping such treatment.
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain
while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Mixed Agonist/Antagonist And Partial Agonist Opioid Analgesics
The concomitant use of opioids with other opioid analgesics, such as butorphanol, nalbuphine,
pentazocine, may reduce the analgesic effect of hydrocodone bitartrate and acetaminophen tablets and/or
precipitate withdrawal symptoms.
Advise patient to avoid concomitant use of these drugs.
Hydrocodone bitartrate and acetaminophen tablets may enhance the neuromuscular blocking action of
skeletal muscle relaxants and produce an increased degree of respiratory depression.
If concomitant use is warranted, monitor patients for signs of respiratory depression that may be greater
than otherwise expected and decrease the dosage of hydrocodone bitartrate and acetaminophen tablets
and/or the muscle relaxant as necessary.
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
If concomitant use is warranted, follow patients for signs of diminished diuresis and/or effects on blood
pressure and increase the dosage of the diuretic as needed.
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe
constipation, which may lead to paralytic ileus.
If concomitant use is warranted, follow patients for signs and symptoms of urinary retention or reduced
gastric motility when hydrocodone bitartrate and acetaminophen tablets are used concomitantly with
Drug Abuse And Dependence
Hydrocodone bitartrate and acetaminophen tablets contain hydrocodone, a Schedule II controlled
Hydrocodone bitartrate and acetaminophen tablets contain hydrocodone, a substance with a high
potential for abuse similar to other opioids, including fentanyl, hydromorphone, methadone, morphine,
oxycodone, oxymorphone, and tapentadol, can be abused and are subject to misuse, addiction, and
criminal diversion [see WARNINGS].
All patients treated with opioids require careful monitoring for signs of abuse and addiction, because
use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its
rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after
repeated substance use and includes a strong desire to take the drug, difficulties in controlling its use,
persisting in its use despite harmful consequences, a higher priority given to drug use than to other
activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking
tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate
examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions and
reluctance to provide prior medical records or contact information for other treating healthcare
provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is
common among drug abusers and people suffering from untreated addiction. Preoccupation with
achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care
providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms
of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true
Hydrocodone bitartrate and acetaminophen tablets, like other opioids, can be diverted for non-medical
use into illicit channels of distribution. Careful record-keeping of prescribing information, including
quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and
proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Risks Specific to Abuse of HydrocodoneBitartrate and Acetaminophen Tablets
Hydrocodone bitartrate and acetaminophen tablets are for oral use only. Hydrocodone bitartrate and
acetaminophen tablets pose a risk of overdose and death. The risk is increased with concurrent abuse of
hydrocodone bitartrate and acetaminophen tablets with alcohol and other central nervous system
Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the
need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of
disease progression or other external factors). Tolerance may occur to both the desired and undesired
effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage
reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with
opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g.,
pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence
may not occur to a clinically significant degree until after several days to weeks of continued opioid
Hydrocodone bitartrate and acetaminophen tablets should not be abruptly discontinued in a physically
dependent patient [see DOSAGE AND ADMINISTRATION]. If hydrocodone bitartrate and
acetaminophen tablets are abruptly discontinued in a physically dependent patient, a withdrawal
syndrome may occur. Some or all of the following can characterize this syndrome: restlessness,
lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms
also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps,
insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart
Infants born to mothers physically dependent on opioids will also be physically dependent and may
exhibit respiratory difficulties and withdrawal signs [see PRECAUTIONS; Pregnancy].