Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Hydrocodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope.
They also stimulate prolactin, growth hormone GH secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as symptoms as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. 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.
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. There is a relationship between increasing hydrocodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.
Following a 10 mg oral dose of hydrocodone administered to five adult male subjects, the mean peak concentration was Maximum serum levels were achieved at 1. Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation and 6-keto reduction to the corresponding 6-a- and 6-p-hydroxymetabolites. CYP3A4 mediated N-demethylation to norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2D6 mediated O-demethylation to hydromorphone.
Hydromorphone is formed from the O-demethylation of hydrocodone and may contribute to the total analgesic effect of hydrocodone. Hydrocodone and its metabolites are eliminated primarily in the kidneys. Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues.
The plasma half-life is 1. Elimination of acetaminophen is principally by liver metabolism conjugation 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, Pdependent, 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.
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 LORTAB ELIXIR.
Ensure that the dose is communicated clearly and dispensed accurately. Addiction can occur at recommended dosages and if the drug is misused or abused.
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. The potential for these risks should not, however, prevent the proper management of pain in any given patient.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. 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. Healthcare providers are strongly encouraged to do all of the following:. The FDA Blueprint can be found at www. 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. Carbon dioxide CO 2 retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Opioids can cause sleep-related breathing disorders including central sleep apnea CSA and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with LORTAB ELIXIR.
Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines e.
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of other CNS depressants, a history of opioid use disorder, or prior opioid overdose.
The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members including children or other close contacts at risk for accidental ingestion or overdose. 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. 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. 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 patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined.
Elderly, Cachectic, 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 ].
Alternatively, consider the use of non-opioid analgesics in these patients. 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. 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.
Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4, 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, milligrams of acetaminophen per day, even if they feel well.
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. 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.
In patients who may be susceptible to the intracranial effects of CO 2 retention e. Opioids may also obscure the clinical course in a patient with a head injury. Opioids may cause increases in serum amylase. Follow patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that they can visit www. 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.
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting LORTAB ELIXIR or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling or getting emergency medical help right away in the event of a known or suspected overdose [see WARNINGS; Life-Threatening Respiratory Depression ].
Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Inform patients to not take more than milligrams of acetaminophen per day.
Advise patients to call their prescriber if they take more than the recommended dose. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur e.
Advise nursing mothers to monitor infants for increased sleepiness more than usual , breathing difficulties, or limpness. Inform patients that chronic use of opioids may cause reduced fertility. Follow patients for respiratory depression and sedation at frequent intervals. Follow patients for signs or symptoms of opioid withdrawal. Follow for signs of opioid withdrawal. 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. 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. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.
The concomitant use of opioids and MAOIs, such as phenelzine, tranylcypromine, or linezolid, may manifest as serotonin syndrome, or opioid toxicity e.
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. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS ]. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid. Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen.
Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 0.
In contrast, there was no evidence of carcinogenic activity in male rats that received up to 0. 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. 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.
Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 1. These effects appear to increase with the duration of treatment. The clinical significance of these findings is not known. Chronic use of opioids may cause reduced fertility in females and males of reproductive potential.
There are no adequate and well-controlled studies in pregnant women. 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.
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. 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.
Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 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. 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. Patients with hepatic impairment may have higher plasma hydrocodone concentrations than those with normal function. Patients with renal impairment may have higher plasma hydrocodone concentrations than those with normal function.
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. 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. Special Senses: Cases of hearing impairment or permanent loss have been reported predominantly in patients with chronic overdose.
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. 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. Health care 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. 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. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. 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 is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting 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.
Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Rapid discontinuationhas also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. Following an acute overdosage, toxicity may result from hydrocodone or acetaminophen.
Acute overdosage with LORTAB ELIXIR can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death.
Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect of acetaminophen overdosage. Renal tubular necrosis, hypoglycemic coma and coagulation defects 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 case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures including oxygen and vasopressors in the management of circulatory shock and pulmonary edema as indicated.
Cardiac arrest or arrhythmias will require advanced life-support techniques. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. If too much of this medicine is taken for a long time, it may become habit-forming causing mental or physical dependence or cause an overdose. Large amounts of acetaminophen may cause liver damage. It is very important that you understand the rules of the Opioid Analgesic REMS program to prevent addiction, abuse, and misuse of hydrocodone and acetaminophen combination.
This medicine should also come with a Medication Guide and patient information leaflet. Read and follow these instructions carefully. Read it again each time you refill your prescription in case there is new information. Ask your doctor if you have any questions. Measure the oral liquid with a marked measuring spoon, oral syringe, dropper, or medicine cup.
The average household teaspoon may not hold the right amount of liquid. Carefully check the labels of all other medicines you are using, because they may also contain acetaminophen. It is not safe to use more than 4 grams 4, milligrams of acetaminophen in one day 24 hours.
The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so. The amount of medicine that you take depends on the strength of the medicine.
Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine. If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.
Do not double doses. Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing. Hydrocodone can cause serious unwanted effects or fatal overdose if taken by children, pets, or adults who are not used to strong narcotic pain medicines. Make sure you store the medicine in a safe and secure place to prevent others from getting it.
Drop off any unused narcotic medicine at a drug take-back location right away. If you do not have a drug take-back location near you, flush any unused narcotic medicine down the toilet. Check your local drug store and clinics for take-back locations.
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