Acetaminophen and Codeine Oral Solution

Name: Acetaminophen and Codeine Oral Solution

Clinical pharmacology

Mechanism of Action

Codeine is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of codeine have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.

The precise mechanism of the analgesic properties of acetaminophen is not established but is thought to involve central actions.

Pharmacodynamics

Effects on the Central Nervous System

Codeine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Codeine 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.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Codeine 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.

Effects on the Cardiovascular System

Codeine 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.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions]. 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 low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of codeine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing codeine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by them development of tolerance to opioid-related adverse reactions [see Dosage and Administration].

Pharmacokinetics

The behavior of the individual components is described below.

Codeine

Codeine is rapidly absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain. Codeine is about 7 to 25% bound to plasma proteins and does not accumulate in body tissues.

About 70 to 80% of the administered dose of codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (C6G) and via O-demethylation to morphine (about 5 to 10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucurodination of codeine to C6G. Cytochrome P450 2D6 is the major enzyme responsible for conversion of codeine to morphine and P450 3A4 is the major enzyme mediating conversion of codeine to norcodeine. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Morphine and M6G are known to have analgesic activity in humans. The analgesic activity of C6G in humans is unknown. Norcodeine and M3G are generally not considered to possess analgesic properties.

The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces.

At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours.

Acetaminophen

Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. A small fraction (10 to 25%) of acetaminophen is bound to plasma proteins. 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 and subsequent renal excretion of metabolites. Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways. 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.

See OVERDOSAGE for toxicity information.

Contraindications

Acetaminophen and codeine phosphate oral solution is contraindicated in:

• Children less than 12 years of age [see WARNINGS and PRECAUTIONS]. • Postoperative pain management in children of any age who have undergone tonsillectomy and/or adenoidectomy [see WARNINGS and PRECAUTIONS]. • Patients with significant respiratory depression [see WARNINGS] • Patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS] • Postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy [see WARNINGS] • Patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS] • Patients with hypersensitivity to codeine, acetaminophen, or any of the formulation excipients (e.g., anaphylaxis) [see WARNINGS]

Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days

Warnings

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 acetaminophen and codeine phosphate oral solution solutions of different concentrations, when prescribing, dispensing, and administering acetaminophen and codeine phosphate oral solution. Ensure that the dose is communicated clearly and dispensed accurately. A household teaspoon is not an adequate measuring device. Given the inexactitude of the household spoon measure and the risk of mistakenly using a tablespoon instead of a teaspoon, which could lead to overdosage, it is strongly recommended that caregivers obtain and use a calibrated measuring device. Health care providers should recommend a calibrated device that can measure and deliver the prescribed dose accurately, and instruct caregivers to use extreme caution in measuring the dosage [see WARNINGS].

Addiction, Abuse, and Misuse

Acetaminophen and codeine phosphate oral solution contains codeine, a Schedule V controlled substance. As an opioid, acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate oral solution, and monitor all patients receiving acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate oral solution, but use in such patients necessitates intensive counseling about the risks and proper use of acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate oral solution, 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 to 72 hours of initiating therapy with and following dosage increases of acetaminophen and codeine phosphate oral solution.

To reduce the risk of respiratory depression, proper dosing and titration of acetaminophen and codeine phosphate oral solution are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the acetaminophen and codeine phosphate oral solution dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of acetaminophen and codeine phosphate oral solution, especially by children, can result in respiratory depression and death due to an overdose of codeine.

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon postmarketing reports, children less than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect.

Because of the risk of life-threatening respiratory depression and death:

• Acetaminophen and codeine phosphate oral solution is contraindicated for all children younger than 12 years of age [see CONTRAINDICATIONS]. • Acetaminophen and codeine phosphate oral solution is contraindicated for postoperative pain management in pediatric patients of any age undergoing tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS]. • Avoid the use of acetaminophen and codeine phosphate oral solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include postoperative status, obstructive sleep apnea, obesity and other conditions associated with hypoventilation syndromes (e.g. neuromuscular disease), concomitant use of other medications that cause respiratory depression, and severe pulmonary disease. • As with adults, when prescribing codeine for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose.

Nursing Mothers

A death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with acetaminophen and codeine phosphate oral solution.

CYP2D6 Genetic Variability: Ultra-rapid metabolizer

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g.,gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican).These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). Therefore, individuals who are ultra-rapid metabolizers should not use codeine.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of acetaminophen and codeine phosphate 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.

Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with acetaminophen and codeine phosphate oral solution requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.

• Cytochrome P450 3A4 Interaction   The concomitant use of acetaminophen and codeine phosphate oral solution with all cytochrome P450 3A4 inhibitors , such as macrolide antibiotics (e.g., erythromycin), azoleantifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.   The concomitant use of acetaminophen and codeine phosphate oral solution with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal.   Follow patients receiving acetaminophen and codeine phosphate oral solution and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when acetaminophen and codeine phosphate oral solution are used in conjunction with inhibitors and inducers of CYP3A4 [see WARNINGS, PRECAUTIONS; Drug Interactions]. • Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors   The concomitant use of acetaminophen and codeine phosphate oral solution with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal.   Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.   Follow patients receiving acetaminophen and codeine phosphate oral solution and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when acetaminophen and codeine phosphate oral solution are used in conjunction with inhibitors of CYP2D6 [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 acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate 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, Information for Patients, Drug Interactions].

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

The use of acetaminophen and codeine phosphate 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: Acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate 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].

Monitor such patients closely, particularly when initiating and titrating acetaminophen and codeine phosphate oral solution and when acetaminophen and codeine phosphate 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.

Interaction with Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, codeine’s active metabolite including respiratory depression, coma, and confusion. Acetaminophen and codeine phosphate oral solution should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 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

Acetaminophen and codeine phosphate oral solution may cause severe hypotension including 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]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of acetaminophen and codeine phosphate oral solution. In patients with circulatory shock acetaminophen and codeine phosphate oral solution may cause vasodilatation that can further reduce cardiac output and blood pressure. Avoid the use of acetaminophen and codeine phosphate 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 4000 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 4000 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 post-marketing reports of hypersensitivity and anaphylaxis associated with 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 acetaminophen and codeine phosphate oral solution immediately and seek medical care if they experience these symptoms. Do not prescribe acetaminophen and codeine phosphate 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 CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), acetaminophen and codeine phosphate oral solution may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with acetaminophen and codeine phosphate oral solution.

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

Risks of Use in Patients with Gastrointestinal Conditions

Acetaminophen and codeine phosphate oral solution is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.

The administration of acetaminophen and codeine phosphate oral solution or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Acetaminophen and codeine phosphate oral solution may cause spasm of the sphincter of Oddi. Opioids including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders

The codeine in acetaminophen and codeine phosphate 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. Monitor patients with a history of seizure disorders for worsened seizure control during acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate oral solution. In these patients, mixed agonist/antagonist and partial analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

When discontinuing acetaminophen and codeine phosphate oral solution, gradually taper the dosage [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue acetaminophen and codeine phosphate oral solution [see DRUG ABUSE AND DEPENDENCE].

Drug abuse and dependence

Controlled Substance

Acetaminophen and codeine phosphate oral solution contains codeine, a Schedule V controlled substance.

Abuse

Acetaminophen and codeine phosphate oral solution contains codeine, a substance with a high potential for abuse similar to other opioids including, including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Acetaminophen and codeine phosphate oral solution can be abused and is 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. Healthcare 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 addiction.

Acetaminophen and codeine phosphate oral solution, 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 Acetaminophen and Codeine Phosphate Oral Solution

Acetaminophen and codeine phosphate oral solution is for oral use only. Abuse of acetaminophen and codeine phosphate oral solution poses a risk of overdose and death. The risk is increased with concurrent use of acetaminophen and codeine phosphate oral solution with alcohol and other central nervous system depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Dependence

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 usage.

Acetaminophen and codeine phosphate oral solution should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If acetaminophen and codeine phosphate oral solution is 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 rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see PRECAUTIONS; Pregnancy].

Medication Guide

MEDICATION GUIDE

Acetaminophen and Codeine Phosphate (a seet’ a min’ oh fen and koe’ deen fos’fate)

Oral Solution,

50383-079

Acetaminophen and Codeine Phosphate Oral Solution is:

• A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage mild to moderate pain when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

Important information about Acetaminophen and Codeine Phosphate Oral Solution:

• Get emergency help right away if you take too much Acetaminophen and Codeine Phosphate Oral Solution (overdose). When you first start taking Acetaminophen and Codeine Phosphate Oral Solution, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. • Taking Acetaminophen and Codeine Phosphate Oral Solution with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. • Never give anyone else your Acetaminophen and Codeine Phosphate Oral Solution. They could die from taking it. Store Acetaminophen and Codeine Phosphate Oral Solution away from children and in a safe place to prevent stealing or abuse. Selling or giving away Acetaminophen and Codeine Phosphate Oral Solution is against the law.

Important Information Guiding Use in Pediatric Patients:

• Do not give Acetaminophen and Codeine Phosphate Oral Solution to a child younger than 12. • Do not give Acetaminophen and Codeine Phosphate Oral Solution to a child younger than 18 to treat pain after surgery to remove the tonsils and/or adenoids. • Avoid giving Acetaminophen and Codeine Phosphate Oral Solution to children between 12 to 18 years of age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems.

Do not take Acetaminophen and Codeine Phosphate Oral Solution if you have:

• severe asthma, trouble breathing, or other lung problems. • a bowel blockage or have narrowing of the stomach or intestines. • previously had an allergic reactions to codeine or acetaminophen.

Before taking Acetaminophen and Codeine Phosphate Oral Solution, tell your

healthcare provider if you have a history of:

• head injury, seizures • liver, kidney, thyroid problems • problems urinating • pancreas or gallbladder problems • abuse of street or prescription drugs, alcohol addiction, or mental health problems.

Tell your healthcare provider if you are:

• pregnant or planning to become pregnant. Prolonged use of Acetaminophen and Codeine Phosphate Oral Solution during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. • breastfeeding. Not recommended; may harm your baby. • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Acetaminophen and Codeine Phosphate Oral Solution with certain other medicines can cause serious side effects that could lead to death.

When taking Acetaminophen and Codeine Phosphate Oral Solution:

• Do not change your dose. Take Acetaminophen and Codeine Phosphate Oral Solution exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. • Always use a calibrated measuring device for Acetaminophen and Codeine Phosphate Oral Solution to correctly measure your dose. A household teaspoon or tablespoon is not an adequate measuring device. Given the inexactitude of the household spoon measure and the possibility of using a tablespoon instead of a teaspoon, which could lead to overdosage, it is strongly recommended that caregivers obtain and use a calibrated measuring device. • Take your prescribed dose at the same time every day. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. • Call your healthcare provider if the dose you are taking does not control your pain. • If you have been taking Acetaminophen and Codeine Phosphate Oral Solution regularly, do not stop taking Acetaminophen and Codeine Phosphate Oral Solution without talking to your healthcare provider. • After you stop taking Acetaminophen and Codeine Phosphate Oral Solution to properly dispose of the Acetaminophen and Codeine Phosphate Oral Solution flush it down the toilet or dispose of in accordance with local state guidelines and/or regulations.

While taking Acetaminophen and Codeine Phosphate Oral Solution DO NOT:

• Drive or operate heavy machinery, until you know how Acetaminophen and Codeine Phosphate Oral Solution affects you. Acetaminophen and Codeine Phosphate Oral Solution can make you sleepy, dizzy, or lightheaded. • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Acetaminophen and Codeine Phosphate Oral Solution may cause you to overdose and die.

The possible side effects of Acetaminophen and Codeine Phosphate Oral Solution: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain.

Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

• trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, or hands, hives, itching, rash) extreme drowsiness, lightheadedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

These are not all the possible side effects of Acetaminophen and Codeine Phosphate Oral Solution. Call your doctor for medical advice about side effects. You may report side effects to Hi-Tech Pharmacal Co., Inc. at 1-800-262-9010 or FDA at 1-800-FDA-1088. For more information go to dailymed.nlm. nih.gov.

Manufactured by:

Hi-Tech Pharmacal Co., Inc.

Amityville, NY 11701

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: April 2017

Package/label principal display panel

AKORN

Acetaminophen and Codeine Phosphate Oral Solution, USP

120 mg/12 mg per 5 mL

RX only

This is a bulk container. Not intended for household use.

Each 5 mL (teaspoonful) contains:

Acetaminophen …………………… 120 mg

Codeine *Phosphate ……………….. 12 mg

Alcohol ………………………………. 7%

WARNING: May be habit-forming.

Protect from light.

Inactive ingredients: artificial cherry flavor, citric acid, FD&C Yellow No. 6, propylene glycol,purifiedwater, saccharin sodiun, sodium benzoate, and sucrose.

Usaual Dosage:

Adults: 15 mL (1 tablespoonful) every four hours as needed.

Children (7-12 years): Two teaspoonsful (10 mL) three or four times daily.

Children (3-6 years): One teaspoonsful (5 mL) three or four times daily.

Children (under 3 years): Safe dosing has not been established. For prescribing information, see accompanying literature.

Store at 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Protect from light. Do not refrigerate.

Dispense in a tight, light-resistant container as defined in the official compendium.

CAP HAS A PRINTED SAFETY SEAL AROUND THE NESK. DO NOT ACCEPT IF BROKEN OR MISSING.

16 FL OZ (473 mL)

ACETAMINOPHEN AND CODEINE PHOSPHATE 
acetaminophen and codeine phosphate solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:50383-079
Route of Administration ORAL DEA Schedule CV    
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ACETAMINOPHEN (ACETAMINOPHEN) ACETAMINOPHEN 120 mg  in 5 mL
CODEINE PHOSPHATE (CODEINE ANHYDROUS) CODEINE PHOSPHATE 12 mg  in 5 mL
Inactive Ingredients
Ingredient Name Strength
ALCOHOL  
ANHYDROUS CITRIC ACID  
CHERRY  
FD&C YELLOW NO. 6  
PROPYLENE GLYCOL  
SACCHARIN SODIUM  
SODIUM BENZOATE  
SUCROSE  
WATER  
Packaging
# Item Code Package Description
1 NDC:50383-079-16 473 mL in 1 BOTTLE
2 NDC:50383-079-06 4 TRAY in 1 CASE
2 10 CUP, UNIT-DOSE in 1 TRAY
2 NDC:50383-079-05 5 mL in 1 CUP, UNIT-DOSE
3 NDC:50383-079-11 4 TRAY in 1 CASE
3 10 CUP, UNIT-DOSE in 1 TRAY
3 NDC:50383-079-10 10 mL in 1 CUP, UNIT-DOSE
4 NDC:50383-079-13 4 TRAY in 1 CASE
4 10 CUP, UNIT-DOSE in 1 TRAY
4 NDC:50383-079-12 12.5 mL in 1 CUP, UNIT-DOSE
5 NDC:50383-079-17 4 TRAY in 1 CASE
5 10 CUP, UNIT-DOSE in 1 TRAY
5 NDC:50383-079-15 15 mL in 1 CUP, UNIT-DOSE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA040119 04/26/1996
Labeler - Hi-Tech Pharmacal Co. Inc. (101196749)
Establishment
Name Address ID/FEI Operations
Hi-Tech Pharmacal Co. Inc. 101196749 MANUFACTURE(50383-079)
Revised: 08/2017   Hi-Tech Pharmacal Co. Inc.
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