Hydrocodone bitartrate and acetaminophen

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# Overview
Hydrocodone bitartrate and acetaminophen is an opioid narcotic analgesic that is FDA approved for the treatment of moderate to moderately severe pain.   Common adverse reactions include lightheadedness, dizziness, sedation, nausea ,vomiting, rash, pruritus, constipation, drowsiness,mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
- Hydrocodone bitartrate and acetaminophen tablets are indicated for the relief of moderate to moderately severe pain.

# Dosage
- Dosage should be adjusted according to the severity of the pain and response of the patient. However, it should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose-related.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hydrocodone bitartrate and acetaminophen in pediatric patients.

### NonGuideline-Supported Use

# Indications and Dosing
- Pain, Moderate to moderately-severe
- 1 or 2 tablets (hydrocodone bitartrate 5 mg/acetaminophen 325 mg per tablet) orally every 4 to 6 hours as needed; not to exceed total of 12 tablets/day; max acetaminophen (including all other acetaminophen-containing products) 4000 mg/day.
- 1 tablet (hydrocodone bitartrate 7.5 or 10 mg/acetaminophen 325 mg per tablet) orally every 4 to 6 hours as needed; not to exceed total of 6 tablets/day; max acetaminophen (including all other acetaminophen-containing products) 4000 mg/day.
- 1 or 2 tablets (hydrocodone bitartrate 5 mg/acetaminophen 300 mg per tablet) orally every 4 to 6 hours as needed; max 8 tablets/day; max acetaminophen (including all other acetaminophen-containing products) 4000 mg/day.
- 1 tablet (hydrocodone bitartrate 7.5 or 10 mg/acetaminophen 300 mg per tablet) orally every 4 to 6 hours as needed; max 6 tablets/day; max acetaminophen (including all other acetaminophen-containing products) 4000 mg/day.
- Solution: 11.25 mL (hydrocodone bitartrate 7.5 mg/acetaminophen 225 mg) orally every 4 to 6 hours as needed for pain; max 67.5 mL/day (hydrocodone 45 mg/acetaminophen 1350 mg).

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hydrocodone bitartrate and acetaminophen in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Hydrocodone bitartrate and acetaminophen tablet in pediatric patients.

# Contraindications
- This product should not be administered to patients who have previously exhibited hypersensitivity to hydrocodone or acetaminophen.
- Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to hydrocodone

# Warnings
- Respiratory Depression: At high doses or in sensitive patients, hydrocodone may produce dose-related respiratory depression by acting directly on the brain stem respiratory center. Hydrocodone also affects the center that controls respiratory rhythm, and may produce irregular and periodic breathing.
- Head Injury and Increased Intracranial Pressure: 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 preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries.
- Acute Abdominal Conditions: The administration of narcotics may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

# Adverse Reactions

## Clinical Trials Experience
- The most frequently reported adverse reactions are lightheadedness, dizziness, sedation, nausea and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down.
- Other adverse reactions include:
'Central Nervous System':
- Drowsiness
- Mental clouding
- Lethargy
- Impairment of mental and physical performance
- Anxiety
- Fear
- Dysphoria
- Psychic dependence
- Mood changes
'Gastrointestinal System'
- Prolonged administration of hydrocodone bitartrate and acetaminophen tablets may produce constipation.
'Genitourinary System'
- Ureteral spasm
- Spasm of vesical sphincters
- urinary retention
'Respiratory Depression'
- Hydrocodone bitartrate may produce dose-related respiratory depression by acting directly on the brain stem respiratory center .
'Special Senses'
- Cases of hearing impairment or permanent loss have been reported predominantly in patients with chronic overdose.
'Dermatological'
- Skin rash
- Pruritus.
- The following adverse drug events may be borne in mind as potential effects of acetaminophen: allergic reactions, rash, thrombocytopenia, agranulocytosis.

## Postmarketing Experience
There is limited information regarding Hydrocodone bitartrate and acetaminophen Postmarketing Experience in the drug label.

# Drug Interactions
- Patients receiving other narcotic analgesics, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with hydrocodone bitartrate and acetaminophen tablets may exhibit an additive CNS depression. When combined therapy is contemplated, the dose of one or both agents should be reduced.
- The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Teratogenic Effects:
- Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydrocodone bitartrate and acetaminophen tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects:
- Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hydrocodone bitartrate and acetaminophen in women who are pregnant.

### Labor and Delivery
- As with all narcotics, administration of hydrocodone bitartrate and acetaminophen tablets to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used.

### Nursing Mothers
- Acetaminophen is excreted in breast milk in small amounts, but the significance of its effects on nursing infants is not known. It is not known whether hydrocodone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from hydrocodone and acetaminophen, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.

### Geriatic Use
- Clinical studies of hydrocodone bitartrate and acetaminophen tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, 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.
- Hydrocodone and the major metabolites of acetaminophen are known to be substantially excreted by the kidney. Thus the risk of toxic reactions may be greater in patients with impaired renal function due to the accumulation of the parent compound and/or metabolites in the plasma. 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.
- Hydrocodone may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of hydrocodone bitartrate and acetaminophen tablets and observed closely.

### Gender
There is no FDA guidance on the use of Hydrocodone bitartrate and acetaminophen with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Hydrocodone bitartrate and acetaminophen with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Hydrocodone bitartrate and acetaminophen in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Hydrocodone bitartrate and acetaminophen in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Hydrocodone bitartrate and acetaminophen in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Hydrocodone bitartrate and acetaminophen in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
There is limited information regarding Hydrocodone bitartrate and acetaminophen Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Hydrocodone bitartrate and acetaminophen and IV administrations.

# Overdosage
Signs and Symptoms
- Hydrocodone: Serious overdose with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur.
- Acetaminophen: In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and thrombocytopenia may also occur.
- Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.
- In adults, hepatic toxicity has rarely been reported with acute overdoses of less than 10 grams, or fatalities with less than 15 grams
Treatment
- A single or multiple overdose with hydrocodone and acetaminophen is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended.
- Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Vomiting should be induced mechanically, or with syrup of ipecac, if the patient is alert (adequate pharyngeal and laryngeal reflexes). Oral activated charcoal (1 g/kg) should follow gastric emptying. The first dose should be accompanied by an appropriate cathartic. If repeated doses are used, the cathartic might be included with alternate doses as required. Hypotension is usually hypovolemic and should respond to fluids. Vasopressors and other supportive measures should be employed as indicated. A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and, when necessary, to provide assisted respiration.
- Meticulous attention should be given to maintaining adequate pulmonary ventilation. In severe cases of intoxication, peritoneal dialysis, or preferably hemodialysis may be considered. If hypoprothrombinemia occurs due to acetaminophen overdose, vitamin K should be administered intravenously.
- Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid overdose. Naloxone hydrochloride 0.4 mg to 2 mg is given parenterally. Since the duration of action of hydrocodone may exceed that of the naloxone, the patient should be kept under continuous surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression.
- If the dose of acetaminophen may have exceeded 140 mg/kg, acetylcysteine should be administered as early as possible. Serum acetaminophen levels should be obtained, since levels four or more hours following ingestion help predict acetaminophen toxicity. Do not await acetaminophen assay results before initiating treatment. Hepatic enzymes should be obtained initially, and repeated at 24-hour intervals.
- Methemoglobinemia over 30% should be treated with methylene blue by slow intravenous administration.
- The toxic dose for adults for acetaminophen is 10 g

# Pharmacology

## Mechanism of Action
- Hydrocodone is a semisynthetic narcotic analgesic and antitussive with multiple actions qualitatively similar to those of codeine. Most of these involve the central nervous system and smooth muscle. The precise mechanism of action of hydrocodone and other opiates is not known, although it is believed to relate to the existence of opiate receptors in the central nervous system. In addition to analgesia, narcotics may produce drowsiness, changes in mood and mental clouding.
- The analgesic action of acetaminophen involves peripheral influences, but the specific mechanism is as yet undetermined. Antipyretic activity is mediated through hypothalamic heat regulating centers. Acetaminophen inhibits prostaglandin synthetase. Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.

## Structure
- Hydrocodone bitartrate and acetaminophen is supplied in tablet form for oral administration.
- Hydrocodone bitartrate is an opioid analgesic and antitussive and occurs as fine, white crystals or as a crystalline powder. It is affected by light. The chemical name is: 4,5a- Epoxy-3-methoxy-17-methylmorphinan- 6-one tartrate (1:1) hydrate (2:5). It has the following structural formula:
- Acetaminophen, 4-Hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:
- Hydrocodone bitartrate and acetaminophen tablets, USP for oral administration are available in the following strengths
- In addition, each tablet contains the following inactive ingredients: anhydrous lactose, croscarmellose sodium, crospovidone, magnesium stearate,microcrystalline cellulose, povidone, starch, and stearic acid; except the 7.5mg/325mg, 10 mg/325 mg and 10 mg/500 mg tablets do not contain anhydrous lactose.  The 7.5 mg/325 mg tablets include FD and C Yellow # 6 Aluminum Lake; the 7.5 mg/650 mg tablets include FD and C Red #40 Aluminum Lake; the 10 mg/325 mg and 10 mg/750 mg tablets include D and C Yellow # 10 Aluminum Lake; the 10 mg/500 mg tablets include FD and C Blue #2 Aluminum Lake; and the 10 mg/650mg tablets include FD and C Blue #1 Aluminum Lake and D and C Yellow #10 Aluminum Lake.  Meets USP Dissolution Test 1.

## Pharmacodynamics
There is limited information regarding Hydrocodone bitartrate and acetaminophen Pharmacodynamics in the drug label.

## Pharmacokinetics
The behavior of the individual components is described below:
- Hydrocodone: Following a 10 mg oral dose of hydrocodone administered to five adult male subjects, the mean peak concentration was 23.6  5.2 ng/mL. Maximum serum levels were achieved at 1.3  0.3 hours and the half-life was determined to be 3.8  0.3 hours. Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, Ndemethylation and 6-keto reduction to the corresponding 6-a- and 6-b-hydroxy-metabolites. See OVERDOSAGE for toxicity information.
- Acetaminophen: Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug.

## Nonclinical Toxicology
- No adequate studies have been conducted in animals to determine whether hydrocodone or acetaminophen have a potential for carcinogenesis, mutagenesis, or impairment of fertility.

# Clinical Studies
There is limited information regarding Hydrocodone bitartrate and acetaminophen Clinical Studies in the drug label.

# How Supplied
- Hydrocodone bitartrate and acetaminophen tablets, USP are available in the following strengths:

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

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Information for Patients
- Hydrocodone, like all narcotics, may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery; patients should be cautioned accordingly.
- Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this combination product, and should be avoided.
- Hydrocodone may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

# Precautions with Alcohol
Alcohol-Hydrocodone bitartrate and acetaminophen tablet interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
HYDROCODONE ACETAMINOPHEN

# Look-Alike Drug Names
There is limited information regarding Hydrocodone bitartrate and acetaminophen Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price