Hydrocodone and Acetaminophen Oral Solution

Risk of Accidental Overdose and Death due to Medication Errors

Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with Hydrocodone Bitartrate and Acetaminophen Oral Solutions of different concentrations, when prescribing, dispensing, and administering Hydrocodone Bitartrate and Acetaminophen Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately. Always use a calibrated measuring device when administering Hydrocodone Bitartrate and Acetaminophen Oral Solution to ensure the dose is measured and administered accurately.

Addiction, Abuse, and Misuse

Hydrocodone Bitartrate and Acetaminophen Oral Solution contains hydrocodone, a Schedule II controlled substance.  As an opioid, Hydrocodone Bitartrate and Acetaminophen Oral Solution 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 Hydrocodone Bitartrate and Acetaminophen Oral Solution.  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 Oral Solution, and monitor all patients receiving Hydrocodone Bitartrate and Acetaminophen Oral Solution 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 Oral Solution, but use in such patients necessitates intensive counseling about the risks and proper use of Hydrocodone Bitartrate and Acetaminophen Oral Solution 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 Oral Solution.  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 PRECAUTIONS; Information for Patients].  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 Oral Solution, the risk is greatest during the initiation of therapy or following a dosage increase.  Follow 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 Oral Solution.

To reduce the risk of respiratory depression, proper dosing and titration of Hydrocodone Bitartrate and Acetaminophen Oral Solution are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the Hydrocodone Bitartrate and Acetaminophen Oral Solution dosage when converting patients from another opioid product can result in a fatal overdose.

Accidental ingestion of Hydrocodone Bitartrate and Acetaminophen Oral Solution especially by children, can result in respiratory depression and death due to an overdose of Hydrocodone Bitartrate and Acetaminophen Oral Solution.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Hydrocodone Bitartrate and Acetaminophen Oral Solution 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 PRECAUTIONS; Information for Patients, Pregnancy].

Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of Hydrocodone Bitartrate and Acetaminophen Oral Solution 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, 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 Oral Solution is achieved .  Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Hydrocodone Bitartrate and Acetaminophen Oral Solution-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions.  When using Hydrocodone Bitartrate and Acetaminophen Oral Solution with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Hydrocodone Bitartrate and Acetaminophen Oral Solution-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Hydrocodone Bitartrate and Acetaminophen Oral Solution until stable drug effects are achieved [see PRECAUTIONS; Drug Interactions].

Concomitant use of Hydrocodone Bitartrate and Acetaminophen Oral Solution 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 Bitartrate and Acetaminophen Oral Solution.  When using Hydrocodone Bitartrate and Acetaminophen Oral Solution 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 PRECAUTIONS; Drug Interactions].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Hydrocodone Bitartrate and Acetaminophen Oral Solution 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 PRECAUTIONS; 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 Hydrocodone Bitartrate and Acetaminophen Oral Solution 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 PRECAUTIONS; Drug Interactions, Information for Patients].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Hydrocodone Bitartrate and Acetaminophen Oral Solution 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 Oral Solution-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 Oral Solution [see WARNINGS; Life Threatening Respiratory Depression] .

Elderly, Cachetic, 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 Oral Solution and when Hydrocodone Bitartrate and Acetaminophen Oral Solution is 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.

Adrenal Insufficiency

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.

Severe Hypotension

Hydrocodone Bitartrate and Acetaminophen Oral Solution 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 PRECAUTIONS; Drug Interactions]. Follow these patients for signs of hypotension after initiating or titrating the dosage of hydrocodone and acetaminophen tablets and oral solution. In patients with circulatory shock hydrocodone and acetaminophen tablets and oral solution may cause vasodilatation that can further reduce cardiac output and blood pressure. Avoid the use of Hydrocodone Bitartrate and Acetaminophen Oral Solution with circulatory shock.

Hepatotoxicity

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 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 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.

Hypersensitivity/Anaphylaxis

There have been postmarketing 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 Oral Solution immediately and seek medical care if they experience these symptoms. Do not prescribe Hydrocodone Bitartrate and Acetaminophen Oral Solution for patients with acetaminophen allergy [see PRECAUTIONS; Information for Patients/Caregivers].

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 CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), hydrocodone and acetaminophen tablets and oral solution may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Follow such patients for signs of sedation and respiratory depression, particularly when initiating therapy with hydrocodone and acetaminophen tablets and oral solution.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of hydrocodone and acetaminophen tablets and oral solution in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions

Hydrocodone Bitartrate and Acetaminophen Oral Solution is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.

The administration of Hydrocodone and Acetaminophen Oral Solution or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

The hydrocodone in Hydrocodone and Acetaminophen Oral Solution may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Follow patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders

The hydrocodone in Hydrocodone Bitartrate and Acetaminophen Oral Solution 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 Oral Solution therapy.

Withdrawal

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 Oral Solution. 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 Oral Solution, gradually taper the dosage [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue Hydrocodone Bitartrate and Acetaminophen Oral Solution in patients who have been using Hydrocodone Bitartrate and Acetaminophen Oral Solution around the clock for more than 5 days [see DRUG ABUSE AND DEPENDENCE].

The following adverse reactions have been identified during post approval use of hydrocodone and acetaminophen tablets and oral solution.  Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most frequently reported adverse reactions are light-headedness, dizziness, sedation, nausea and vomiting. Other adverse reactions include:

Cardio-Renal: Bradycardia, cardiac arrest, circulatory collapse, renal toxicity, renal tubular necrosis, hypotension.

Central Nervous System/Psychiatric: Anxiety, dizziness, drowsiness, dysphoria, euphoria, fear, general malaise, impairment of mental and physical performance, lethargy, lightheadedness, mental clouding, mood changes, psychological dependence, sedation, somnolence progressing to stupor or coma.

Endocrine: Hypoglycemic coma.

Gastrointestinal System: Abdominal pain, constipation, gastric distress, heartburn, hepatic necrosis, hepatitis, occult blood loss, nausea, peptic ulcer, and vomiting.

Genitourinary System: Spasm of vesical sphincters, ureteral spasm, and urinary retention.

Hematologic: Agranulocytosis, hemolytic anemia, iron deficiency anemia, prolonged bleeding time, thrombocytopenia.

Hypersensitivity: Allergic reactions.

Musculoskeletal: Skeletal muscle flaccidity.

Respiratory Depression: Acute airway obstruction, apnea, dose-related respiratory depression [see OVERDOSAGE], shortness of breath.

Special Senses: Cases of hearing impairment or permanent loss have been reported predominantly in patients with chronic overdose.

Skin: Cold and clammy skin, diaphoresis, pruritus, rash.

• Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

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

• Anaphylaxis: Anaphylaxis has been reported with ingredients contained in hydrocodone and acetaminophen tablets.

• Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY] .

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with a child-resistant closure.

MANUFACTURED BY

Pharmaceutical Associates, Inc.

Greenville, SC 29605

www.paipharma.com 

Rev. 11/16

NDC 0121-0772-04

Hydrocodone Bitartrate and
Acetaminophen Oral Solution
CII

7.5 mg/325 mg per 15 mL

Rx ONLY

4 fl oz (118 mL)

Pharmaceutical Associates, Inc.
Greenville, SC 29605

PHARMACIST:  Dispense the important patient information leaflet with the drug product.  The leaflet is included with the package insert.

Dispense in a tight, light-resistant container with a child-resistant closure. Store at 20°-25°C (68°-77°F).  [See USP Controlled Room Temperature].

WARNING: Keep this and all medications out of the reach of children.

USUAL DOSAGE:  See Package Insert for Complete Dosage Recommendations.

L07720401

R08/14

Delivers 10 mL
NDC 0121-1544-10

HYDROCODONE BITARTRATE
and ACETAMINOPHEN ORAL SOLUTION

CII

5 mg/217 mg per 10 mL

Alcohol 6.7%

FOR INSTITUTIONAL USE ONLY

Usual Dosage: See Package Insert for
Complete Dosage Recommendations.
Rx ONLY
PHARMACEUTICAL ASSOCIATES, INC.
GREENVILLE, SC 29605

A47721003

Delivers 5 mL
NDC 0121-4772-05

HYDROCODONE BITARTRATE CII
and ACETAMINOPHEN ORAL SOLUTION

CII

2.5 mg/108 mg per 5 mL

Alcohol 6.7%

FOR INSTITUTIONAL USE ONLY

Usual Dosage: See Package Insert for
Complete Dosage Recommendations.
Rx ONLY
PHARMACEUTICAL ASSOCIATES, INC.
GREENVILLE, SC 29605

A47720501