indicated for the short-term (no more than 14 days) management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Xodol is classified as a Schedule III controlled substance.

Dosage should not exceed 12 tablets in a 24-hour period.

Benzhydrocodone and Acetaminophen tablets exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions.

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.

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Benzhydrocodone and Acetaminophen tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]:

• Have not been tolerated, or are not expected to be tolerated
• Have not provided adequate analgesia, or are not expected to provide adequate analgesia

Individually titrate Benzhydrocodone and Acetaminophen tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Benzhydrocodone and Acetaminophen tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse.

Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase.

Accidental ingestion of Benzhydrocodone and Acetaminophen tablets, especially by children, can result in a fatal overdose of hydrocodone.

The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure.

Hydrocodone bitartrate and acetaminophen tablets should be used with caution in elderly or debilitated patients and those with severe impairment of hepatic or renal function, hypothyroidism, Addison’s disease, prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind.

Benzhydrocodone and Acetaminophen tablets 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. 

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

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.

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.

Hydrocodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Hydrocodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Hydrocodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

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.

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as symptoms as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

Hydrocodone bitartrate and acetaminophen tablets are contraindicated in patients with:

• Significant respiratory depression 
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment 
• Known or suspected gastrointestinal obstruction, including paralytic ileus

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.

The concomitant use of opioids and MAOIs, such as phenelzine, tranylcypromine, or linezolid, may manifest as serotonin syndrome, or opioid toxicity. The use of hydrocodone bitartrate and acetaminophen tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Inform patients that hydrocodone bitartrate and acetaminophen tablets could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs.

The concomitant use of hydrocodone bitartrate and acetaminophen tablets with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentrations. Monitor patients receiving hydrocodone bitartrate and acetaminophen tablets and any cytochrome P450 3A4 inhibitor or inducer for signs of respiratory depression or sedation.

Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone from Benzhydrocodone and Acetaminophen tablets.

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.

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.

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Prolonged use of hydrocodone bitartrate and acetaminophen tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Inform female patients of reproductive potential that hydrocodone bitartrate and  acetaminophen tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy.

Hydrocodone is present in human milk.

GoToSource

• Use in patients under the age of 18. GoToSource

Sensorineural hearing loss. GoToSource

Sedation, hyperalgesia (increased sensitivity to pain), respiratory depression and constipation. GoToSource

Cognitive impairment and pruritus (severe itching). GoToSource

Liver injury. GoToSource

Decreased sex hormone levels including reduced interest in sex, impotence, or infertility with long-term opioid use, serotonin syndrome, adrenal insufficiency, addiction, overdose and death. GoToSource

Stevens-johnson syndrome, toxic epidermal necrolysis and acute generalized exanthematous pustulosis (severe skin reaction). GoToSource

Hypersensitivity reaction. GoToSource

Prolonged ventricular asystole (cardiac arrest). GoToSource

Lawsuits filed for liver injury and failure.