Risks of Driving and Operating Machinery
Hydrocodone Bitartrate and Acetaminophen Oral Solution may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Hydrocodone Bitartrate and Acetaminophen Oral Solution and know how they will react to the medication [see PRECAUTIONS; Information for Patients/Caregivers].
Information for Patients
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Medication Errors
Instruct patients how to measure and take the correct dose of Hydrocodone Bitartrate and Acetaminophen Oral Solution and to always use a calibrated measuring device when administering Hydrocodone Bitartrate and Acetaminophen Oral Solution to ensure the dose is measured and administered accurately [see WARNINGS].
If the prescribed concentration is changed, instruct patients on how to correctly measure the new dose to avoid errors which could result in accidental overdose and death.
Addiction, Abuse, and Misuse
Inform patients that the use of Hydrocodone Bitartrate and Acetaminophen Oral Solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS]. Instruct patients not to share Hydrocodone Bitartrate and Acetaminophen Oral Solution with others and to take steps to protect Hydrocodone Bitartrate and Acetaminophen Oral Solution from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Hydrocodone Bitartrate and Acetaminophen Oral Solution or when the dosage is increased, and that it can occur even at recommended dosages [see WARNINGS]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Accidental Ingestion
Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see WARNINGS]. Instruct patients to take steps to store securely and to dispose of unused Hydrocodone Bitartrate and Acetaminophen Oral Solution by flushing down the toilet.
Interactions with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if Hydrocodone Bitartrate and Acetaminophen Oral Solution is used with benzodiazepines and other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see WARNINGS, PRECAUTIONS; Drug Interactions] .
Serotonin Syndrome
Inform patients that Hydrocodone Bitartrate and Acetaminophen Oral Solution could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see PRECAUTIONS; Drug Interactions].
Monoamine Oxidase Inhibitor (MAOI) Interaction
Inform patients to avoid taking Hydrocodone Bitartrate and Acetaminophen Oral Solution while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Hydrocodone Bitartrate and Acetaminophen Oral Solution [see PRECAUTIONS; Drug Interactions].
Adrenal Insufficiency
Inform patients that Hydrocodone Bitartrate and Acetaminophen Oral Solution opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS].
Important Administration Instructions
Instruct patients how to properly measure and take Hydrocodone Bitartrate and Acetaminophen Oral Solution [see DOSAGE AND ADMINISTRATION, WARNINGS].
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- Advise patients to always use the enclosed calibrated oral syringe/dosing cup when administering Hydrocodone Bitartrate and Acetaminophen Oral Solution to ensure the dose is measured and administered accurately [see WARNINGS].
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- Advise patients never to use household teaspoons or tablespoons to measure Hydrocodone Bitartrate and Acetaminophen Oral Solution.
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- Advise patients not to adjust the dose of Hydrocodone Bitartrate and Acetaminophen Oral Solution without consulting with a physician or other healthcare professional.
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- If patients have been receiving treatment with Hydrocodone Bitartrate and Acetaminophen Oral Solution for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose as abrupt discontinuation of the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication [see DOSAGE AND ADMINISTRATION].
Maximum Daily Dose of Acetaminophen
Inform patients to not take more than 4,000 milligrams of acetaminophen per day. Advise patients to call their prescriber if they take more than the recommended dose.
Hypotension
Inform patients that Hydrocodone Bitartrate and Acetaminophen Oral Solution may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see WARNINGS].
Anaphylaxis
Inform patients that anaphylaxis has been reported with ingredients contained in Hydrocodone Bitartrate and Acetaminophen Oral Solution. Advise patients how to recognize such a reaction and when to seek medical attention [see CONTRAINDICATIONS, ADVERSE REACTIONS] .
Pregnancy
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of Hydrocodone Bitartrate and Acetaminophen Oral Solution during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS, PRECAUTIONS; Pregnancy].
Embryo-Fetal Toxicity
Inform female patients of reproductive potential that Hydrocodone Bitartrate and Acetaminophen Oral Solution can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see PRECAUTIONS; Pregnancy].
Lactation
Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see PRECAUTIONS; Nursing Mothers].
Infertility
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS] .
Driving or Operating Heavy Machinery
Inform patients that Hydrocodone Bitartrate and Acetaminophen Oral Solution may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see WARNINGS].
Constipation
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY].
Disposal of Unused Hydrocodone Bitartrate and Acetaminophen Oral Solution
Advise patients to dispose of unused Hydrocodone Bitartrate and Acetaminophen Oral Solution by flushing unused Hydrocodone Bitartrate and Acetaminophen Oral Solution down the toilet.
Laboratory Tests
In patients with severe hepatic or renal disease, effects of therapy should be followed with serial liver and/or renal function tests.
Drug Interactions
Inhibitors of CYP3A4 and CYP2D6
The concomitant use of Hydrocodone Bitartrate and Acetaminophen Oral Solution and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone from Hydrocodone Bitartrate and Acetaminophen Oral Solution, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Hydrocodone Bitartrate and Acetaminophen Oral Solution and both CYP3A4 and CYP2D6 inhibitors, particularly when an inhibitor is added after a stable dose of Hydrocodone Bitartrate and Acetaminophen Oral Solution is achieved [see WARNINGS].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, hydrocodone plasma concentration will decrease [see CLINICAL PHARMACOLOGY], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to Hydrocodone Bitartrate and Acetaminophen Oral Solution.
If concomitant use is necessary, consider dosage reduction of Hydrocodone Bitartrate and Acetaminophen Oral Solution until stable drug effects are achieved. Follow patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Hydrocodone Bitartrate and Acetaminophen Oral Solution dosage until stable drug effects are achieved. Follow patients for signs or symptoms of opioid withdrawal.
Inducers of CYP3A4
The concomitant use of Hydrocodone Bitartrate and Acetaminophen Oral Solution and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, can decrease the plasma concentration of hydrocodone [see CLINICAL PHARMACOLOGY], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to Hydrocodone Bitartrate and Acetaminophen Oral Solution [see WARNINGS].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see CLINICAL PHARMACOLOGY], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
If concomitant use is necessary, consider increasing the Hydrocodone Bitartrate and Acetaminophen Oral Solution dosage until stable drug effects are achieved [see DOSAGE AND ADMINISTRATION]. Follow for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Hydrocodone Bitartrate and Acetaminophen Oral Solution dosage reduction and monitor for signs of respiratory depression.
Benzodiazepines and Other CNS Depressants
Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants such as benzodiazepines and other sedative hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see WARNINGS].
Serotonergic Drugs
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome. [see PRECAUTIONS; Information for Patients].
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Hydrocodone Bitartrate and Acetaminophen Oral Solution if serotonin syndrome is suspected.
Monoamine Oxidase Inhibitors (MAOIs)
The concomitant use of opioids and MAOIs, such as phenelzine, tranylcypromine, or linezolid, may manifest as serotonin syndrome, or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS].
The use of Hydrocodone Bitartrate and Acetaminophen Oral Solution is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
The concomitant use of opioids with other opioid analgesics, such as butorphanol, nalbuphine, pentazocine, may reduce the analgesic effect of Hydrocodone Bitartrate and Acetaminophen Oral Solution and/or precipitate withdrawal symptoms.
Advise patient to avoid concomitant use of these drugs.
Muscle Relaxants
Hydrocodone Bitartrate and Acetaminophen Oral Solution may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
If concomitant use is warranted, follow patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Hydrocodone Bitartrate and Acetaminophen Oral Solution and/or the muscle relaxant as necessary.
Diuretics
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
If concomitant use is warranted, monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
If concomitant use is warranted, follow patients for signs of urinary retention or reduced gastric motility when Hydrocodone Bitartrate and Acetaminophen Oral Solution are used concomitantly with anticholinergic drugs.
Drug/Laboratory Test Interactions
Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleactic acid.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term studies to evaluate the carcinogenic potential of the combination of Hydrocodone Bitartrate and Acetaminophen Oral Solution have not been conducted.
Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 0.8 times the maximum human daily dose (MHDD) of 4 grams/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats that received up to 0.7 times or mice at up to 1.2-1.4 times the MHDD, based on a body surface area comparison.
Mutagenesis
In the published literature, acetaminophen has been reported to be clastogenic when administered at 1500 mg/kg/day to the rat model (3.6-times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.8-times the MHDD, based on a body surface area comparison), suggesting a threshold effect.
Impairment of Fertility
In studies conducted by the National Toxicology Program, fertility assessments with acetaminophen have been completed in Swiss CD-1 mice via a continuous breeding study. There were no effects on fertility parameters in mice consuming up to 1.7 times the MHDD of acetaminophen, based on a body surface area comparison. Although there was no effect on sperm motility or sperm density in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming 1.78 times the MHDD (based on a body surface comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing.
Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 1.2 times the MHDD and greater (based on a body surface comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses. These effects appear to increase with the duration of treatment. The clinical significance of these findings is not known.
Infertility
Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS].
Teratogenic Effects
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Hydrocodone Bitartrate and Acetaminophen Oral Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Fetal/Neonatal Adverse Reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS].
Labor or Delivery
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Hydrocodone Bitartrate and Acetaminophen Oral Solution is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Hydrocodone Bitartrate and Acetaminophen Oral Solution, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
Nursing Mothers
Hydrocodone is present in human milk.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Hydrocodone Bitartrate and Acetaminophen Oral Solution and any potential adverse effects on the breastfed infant from Hydrocodone Bitartrate and Acetaminophen Oral Solution or from the underlying maternal condition.
Infants exposed to Hydrocodone Bitartrate and Acetaminophen Oral Solution through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.
Pediatric Use
The safety and effectiveness of Hydrocodone Bitartrate and Acetaminophen Oral Solution in the pediatric population below the age of two years have not been established. Use of Hydrocodone Bitartrate and Acetaminophen Oral Solution in the pediatric patients over the age of 2 years is supported by evidence from adequate and well controlled studies of hydrocodone and acetaminophen combination products in adults, along with additional data which support the development of metabolic pathways in children two years of age and over [see DOSAGE AND ADMINISTRATION] for pediatric dosage information.
Geriatric Use
Elderly patients (aged 65 years or older) may have increased sensitivity to Hydrocodone Bitartrate and Acetaminophen Oral Solution. In general, use caution when selecting a dosage for an elderly patient, 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.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Hydrocodone Bitartrate and Acetaminophen Oral Solution slowly in geriatric patients and follow closely for signs of central nervous system and respiratory depression [see WARNINGS].
Hydrocodone and acetaminophen are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to follow renal function.
Hepatic Impairment
Patients with hepatic impairment may have higher plasma hydrocodone concentrations than those with normal function. Use a low initial dose of Hydrocodone Bitartrate and Acetaminophen Oral Solution in patients with hepatic impairment and follow closely for adverse events such as respiratory depression and sedation.
Renal Impairment
Patients with renal impairment may have higher plasma hydrocodone concentrations than those with normal function. Use a low initial dose Hydrocodone Bitartrate and Acetaminophen Oral Solution in patients with renal impairment and follow closely for adverse events such as respiratory depression and sedation.
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