Liquicet

Os comprimidos de bitartarato de hidrocodona e acetaminofeno são indicados para o tratamento da dor intensa o suficiente para exigir um analgésico opióide e para o qual tratamentos alternativos são inadequados.

Limitações de uso

Devido aos riscos de dependência, abuso e uso indevido, com opioides, mesmo em doses recomendadas, reserve comprimidos de bitartarato de hidrocodona e acetaminofeno para uso em pacientes para os quais opções alternativas de tratamento (por exemplo,.analgésicos não opióides):

• não foram tolerados ou não se espera que sejam tolerados
• não forneceram analgesia adequada ou não se espera que forneçam analgesia adequada

Instruções importantes sobre dosagem e administração

Use a menor dose eficaz pela menor duração, consistente com os objetivos individuais de tratamento do paciente.

Inicie o regime de dosagem para cada paciente individualmente, levando em consideração a gravidade da dor, a resposta do paciente, a experiência prévia do tratamento analgésico e os fatores de risco para dependência, abuso e uso indevido.

Siga os pacientes de perto quanto à depressão respiratória, especialmente nas primeiras 24 a 72 horas após o início da terapia e após aumentos de dose com comprimidos de bitartarato de hidrocodona e acetaminofeno e ajuste a dose de acordo.

Dosagem inicial

Iniciando o tratamento com comprimidos de bitartarato de hidrocodona e acetaminofeno

Conversão de outros opioides para comprimidos de bitartarato de hidrocodona e acetaminofeno

Existe variabilidade inter-paciente na potência de medicamentos opióides e formulações de opióides. Portanto, recomenda-se uma abordagem conservadora ao determinar a dose diária total de bitartarato de hidrocodona e comprimidos de acetaminofeno. É mais seguro subestimar a dose de 24 horas de bitartarato de hidrocodona e comprimidos de acetaminofeno do que superestimar a dose de 24 horas de bitartarato de hidrocodona e comprimidos de acetaminofeno e gerenciar uma reação adversa devido a overdose.

Conversão de comprimidos de bitartarato de hidrocodona e acetaminofeno para hidrocodona de liberação prolongada

A biodisponibilidade relativa do hidrocodona dos comprimidos de bitartarato de hidrocodona e acetaminofeno em comparação com os produtos de hidrocodona de liberação prolongada é desconhecida; portanto, a conversão em produtos de liberação prolongada deve ser acompanhada de observação cuidadosa quanto a sinais de sedação excessiva e depressão respiratória.

Titulação e manutenção da terapia

Titule individualmente os comprimidos de bitartarato de hidrocodona e acetaminofeno para uma dose que forneça analgesia adequada e minimize as reações adversas. Reavaliar continuamente os pacientes que recebem comprimidos de bitartarato de hidrocodona e acetaminofeno para avaliar a manutenção do controle da dor e a incidência relativa de reações adversas, bem como monitorar o desenvolvimento de dependência, abuso ou uso indevido. A comunicação frequente é importante entre o médico, outros membros da equipe de saúde, o paciente e o cuidador / família durante períodos de alteração dos requisitos analgésicos, incluindo a titulação inicial.

Se o nível de dor aumentar após a estabilização da dose, tente identificar a fonte de aumento da dor antes de aumentar a dose de hidrocodona bitartarato e acetaminofeno em comprimidos. Se forem observadas reações adversas opioidrelacionadas inaceitáveis, considere reduzir a dose. Ajuste a dose para obter um equilíbrio adequado entre o tratamento da dor e as reações adversas relacionadas aos opióides.

Descontinuação de comprimidos de bitartarato de hidrocodona e acetaminofeno

Quando um paciente que toma comprimidos de bitartarato de hidrocodona e acetaminofeno regularmente e pode ser fisicamente dependente, não requer mais terapia com comprimidos de bitartarato de hidrocodona e acetaminofeno, afinar a dose gradualmente, de 25% a 50% a cada 2 a 4 dias, enquanto monitora cuidadosamente os sinais e sintomas de abstinência. Se o paciente desenvolver esses sinais ou sintomas, aumente a dose para o nível anterior e diminua mais lentamente, aumentando o intervalo entre as diminuições, diminuindo a quantidade de alteração na dose ou ambas. Não interrompa abruptamente os comprimidos de bitartarato de hidrocodona e acetaminofeno em um paciente fisicamente dependente.

Os comprimidos de bitartarato de hidrocodona e acetaminofeno estão contra-indicados em pacientes com:

• Depressão respiratória significativa
• Asma brônquica aguda ou grave em um ambiente não monitorado ou na ausência de equipamento ressuscitativo
• Obstrução gastrointestinal conhecida ou suspeita, incluindo íleo paralítico Hipersensibilidade ao hidrocodona ou acetaminofeno (por exemplo,.anafilaxia)

WARNINGS

Addiction, Abuse, And Misuse

Hydrocodone bitartrate and acetaminophen tablets contain hydrocodone, a Schedule II controlled substance. As an opioid, hydrocodone bitartrate and acetaminophen tablets expose users to the risks of addiction, abuse, and misuse.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydrocodone bitartrate and acetaminophen tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing hydrocodone bitartrate and acetaminophen tablets, and monitor all patients receiving hydrocodone bitartrate and acetaminophen tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as hydrocodone bitartrate and acetaminophen tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydrocodone bitartrate and acetaminophen tablets along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing hydrocodone bitartrate and acetaminophen tablets. 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. 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. Carbon dioxide (CO₂ ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of hydrocodone bitartrate and acetaminophen tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of hydrocodone bitartrate and acetaminophen tablets.

To reduce the risk of respiratory depression, proper dosing and titration of hydrocodone bitartrate and acetaminophen tablets are essential. Overestimating the hydrocodone bitartrate and acetaminophen tablets dosage when converting patients from another opioid product can result in a fatal overdose.

Accidental ingestion of hydrocodone bitartrate and acetaminophen tablets, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone bitartrate and acetaminophen tablets.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of hydrocodone bitartrate and acetaminophen tablets 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 Concomitant Use Or Discontinuation Of Cytochrome P450 3A4 Inhibitors And Inducers

Concomitant use of hydrocodone bitartrate and acetaminophen tablets with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone bitartrate and acetaminophen tablets and prolong opioid adverse reactions, and which may cause potentially fatal respiratory depression , particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and acetaminophen tablets is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in hydrocodone bitartrate and acetaminophen tablets-treated patients may increase hydrocodone plasma concentrations and prolong opoid adverse reactions. When adding CYP3A4 inhibitors or discontinuing CYP3A4 inducers in hydrocodone bitartrate and acetaminophen tablets-treated patients, follow patients at frequent intervals and consider dosage reduction of hydrocodone bitartrate and acetaminophen tablets until stable drug effects are achieved.

Concomitant use of hydrocodone bitartrate and acetaminophen tablets with CYP3A4 inducers or 2 discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. When using bydrocodone bitartrate and acetaminophen tablets with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, follow patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur.

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of hydrocodone bitartrate and acetaminophen tablets 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.

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when hydrocodone bitartrate and acetaminophen tablets are 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.

Life-Threatening Respiratory Depression In Patients With Chronic Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients

The use of hydrocodone bitartrate and acetaminophen tablets 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

ydrocodone bitartrate and acetaminophen tablet-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of hydrocodone bitartrate and acetaminophen tablets.

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.

Follow such patients closely, particularly when initiating and titrating hydrocodone bitartrate and acetaminophen tablets and when hydrocodone bitartrate and acetaminophen tablets are given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension

Hydrocodone bitartrate and acetaminophen tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Follow these patients for signs of hypotension after initiating or titrating the dosage of hydrocodone bitartrate and acetaminophen tablets. In patients with circulatory shock hydrocodone bitartrate and acetaminophen tablets may cause vasodilatation that can further reduce cardiac output and blood pressure. Avoid the use of hydrocodone bitartrate and acetaminophen tablets with circulatory shock.

Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.

Serious Skin Reactions

Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Hypersensitivity/Anaphylaxis

There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue hydrocodone bitartrate and acetaminophen tablets immediately and seek medical care if they experience these symptoms. Do not prescribe hydrocodone bitartrate and acetaminophen tablets for patients with acetaminophen allergy.

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), hydrocodone bitartrate and acetaminophen tablets may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Follow such patients for signs of sedation and respiratory depression, particularly when initiating therapy with hydrocodone bitartrate and acetaminophen tablets.

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

Risks Of Use In Patients With Gastrointestinal Conditions

Hydrocodone bitartrate and acetaminophen tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.

The administration of hydrocodone bitartrate and acetaminophen tablets or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Hydrocodone may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk Of Seizures In Patients With Seizure Disorders

The hydrocodone in hydrocodone bitartrate and acetaminophen tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Follow patients with a history of seizure disorders for worsened seizure control during hydrocodone bitartrate and acetaminophen tablet therapy.]

Withdrawal

Avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including hydrocodone bitartrate and acetaminophen tablets. In these patients, mixed agonist/antagonist and partial analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

When discontinuing hydrocodone bitartrate and acetaminophen tablets, gradually taper the dosage. Do not abruptly discontinue hydrocodone bitartrate and acetaminophen tablets in patients who have been using hydrocodone bitartrate and acetaminophen tablets around the clock for more than 5 days.

PRECAUTIONS

Risks Of Driving And Operating Machinery

Hydrocodone bitartrate and acetaminophen tablets 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 tablets and know how they will react to the medication.

Information For Patients /Caregivers

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Addiction, Abuse, And Misuse

Inform patients that the use of hydrocodone bitartrate and acetaminophen tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death. Instruct patients not to share hydrocodone bitartrate and acetaminophen tablets with others and to take steps to protect hydrocodone bitartrate and acetaminophen tablets 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 tablets or when the dosage is increased, and that it can occur even at recommended dosages. 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. Instruct patients to take steps to store hydrocodone bitartrate and acetaminophen tablets securely and to dispose of unused hydrocodone bitartrate and acetaminophen tablets 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 tablets are used with benzodiazepines and other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider.

Serotonin Syndrome

Inform patients that hydrocodone bitartrate and acetaminophen tablets 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.

Monoamine Oxidase Inhibitor (MAOI) Interaction

Inform patients to avoid taking hydrocodone bitartrate and acetaminophen tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking hydrocodone bitartrate and acetaminophen tablets.

Adrenal Insufficiency

Inform patients that hydrocodone bitartrate and acetaminophen tablets 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.

Important Administration Instructions

Instruct patients how to properly take hydrocodone bitartrate and acetaminophen tablets.

Maximum Daily Dose Of Acetaminophen

Inform patients not to take more than 4000 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 tablets 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).

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in hydrocodone bitartrate and acetaminophen tablets. Advise patients how to recognize such a reaction and when to seek medical attention.

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that hydrocodone bitartrate and acetaminophen tablets can cause fetal harm and to inform their healthcare provider of a known or suspected 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.

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

Driving Or Operating Heavy Machinery

Inform patients that hydrocodone bitartrate and acetaminophen tablets 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.

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

Disposal Of Unused Hydrocodone Bitartrate And Acetaminophen Tablets

Advise patients to dispose of unused hydrocodone bitartrate and acetaminophen tablets by flushing unused tablets 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/Laboratory Test Interactions

Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term studies to evaluate the carcinogenic potential of the combination of hydrocodone bitartrate and acetaminophen tablets 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.

Pregnancy

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

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, 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.

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 tablets are 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 tablets, 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 tablets and any potential adverse effects on the breastfed infant from hydrocodone bitartrate and acetaminophen tablets or from the underlying maternal condition.

Infants exposed to hydrocodone bitartrate and acetaminophen tablets 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

Safety and effectiveness of hydrocodone bitartrate and acetaminophen tablets in pediatric patients have not been established.

Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to hydrocodone bitartrate and acetaminophen tablets. 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 tablets slowly in geriatric patients and follow closely for signs of central nervous system and respiratory depression.

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 monitor 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 tablets 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 tablets in patients with renal impairment and follow closely for adverse events such as respiratory depression and sedation.

As seguintes reações adversas foram identificadas durante o uso pós-aprovação de hidrocodona e acetaminofeno. Como essas reações são relatadas voluntariamente a partir de uma população de tamanho incerto, nem sempre é possível estimar com segurança sua frequência ou estabelecer uma relação causal com a exposição a medicamentos.

As reações adversas mais frequentemente relatadas são tontura, tontura, sedação, náusea e vômito.

Outras reações adversas incluem:

Sistema nervoso central : Sonolência, nebulosidade mental, letargia, comprometimento do desempenho mental e físico, ansiedade, medo, disforia, dependência psicológica, mudanças de humor.

Sistema Gastrointestinal : Constipação.

Sistema Geniturinário : Espasmo ureteral, espasmo de esfíncteres vesicais e retenção urinária.

Sentidos especiais : Casos de deficiência auditiva ou perda permanente foram relatados predominantemente em pacientes com overdose crônica.

Dermatológico: Erupção cutânea, prurido, síndrome de Stevens-Johnson, necrólise epidérmica tóxica, reações alérgicas.

Hematológico: Trombocitopenia, agranulocitose.

• Síndrome da serotonina: Casos de síndrome da serotonina, uma condição potencialmente fatal, foram relatados durante o uso concomitante de opioides com medicamentos serotoninérgicos.
• Insuficiência adrenal : Casos de insuficiência adrenal foram relatados com o uso de opióides, mais frequentemente após mais de um mês de uso.
• Anafilaxia: Foi relatada anafilaxia com ingredientes contidos nos comprimidos de bitartarato de hidrocodona e acetaminofeno.
• Deficiência de andrógenos : Ocorreram casos de deficiência de andrógenos com o uso crônico de opioides.

Após uma superdosagem aguda, a toxicidade pode resultar de hidrocodona ou acetaminofeno.

Apresentação Clínica

A superdosagem aguda com bitartarato de hidrocodona e comprimidos de acetaminofeno pode ser manifestada por depressão respiratória, sonolência progredindo para estupor ou coma, flacidez muscular esquelética, pele fria e úmida, pupilas com restrições e, em alguns casos, edema pulmonar, bradicardia, hipotensão, parcial ou completa obstrução das vias aéreas, ronco atípico e morte. A midríase marcada em vez de miose pode ser observada com hipóxia em situações de overdose.

Acetaminofeno

A necrose hepática potencialmente fatal dependente da dose é o efeito adverso mais grave da superdosagem com acetaminofeno. Necrose tubular renal, coma hipoglicêmico e defeitos de coagulação também podem ocorrer.

Os primeiros sintomas após uma overdose potencialmente hepatotóxica podem incluir: náusea, vômito, diaforese e mal-estar geral. Evidências clínicas e laboratoriais de toxicidade hepática podem não ser aparentes até 48 a 72 horas após a ingestão.

Tratamento de overdose

Hidrocodona

Em caso de sobredosagem, as prioridades são o restabelecimento de uma patente e vias aéreas protegidas e a instituição de ventilação assistida ou controlada, se necessário. Empregue outras medidas de suporte (incluindo oxigênio e vasopressores) no tratamento de choque circulatório e edema pulmonar, conforme indicado. Parada cardíaca ou arritmias exigirão técnicas avançadas de suporte à vida.

Os antagonistas dos opióides, naloxona ou nalmefeno, são antídotos específicos para depressão respiratória resultantes de overdose de opióides. Para depressão respiratória ou circulatória clinicamente significativa secundária à overdose de bitartarato de hidrocodona e comprimidos de acetaminofeno, administre um antagonista opióide. Antagonistas opióides não devem ser administrados na ausência de depressão respiratória ou circulatória clinicamente significativa secundária à overdose de bitartarato de hidrocodona e comprimidos de acetaminofeno.

Como se espera que a duração da reversão dos opióides seja menor que a duração da ação do hidrocodona em comprimidos de bitartarato de hidrocodona e acetaminofeno, monitore cuidadosamente o paciente até que a respiração espontânea seja restabelecida com segurança. Se a resposta a um antagonista opióide for subótima ou apenas breve por natureza, administre antagonista adicional conforme indicado pelas informações de prescrição do produto.

Em um indivíduo fisicamente dependente de opioides, a administração da dose usual recomendada do antagonista precipitará uma síndrome de abstinência aguda. A gravidade dos sintomas de abstinência experimentados dependerá do grau de dependência física e da dose do antagonista administrado. Se for tomada uma decisão para tratar a depressão respiratória grave no paciente fisicamente dependente, a administração do antagonista deve ser iniciada com cuidado e por titulação com doses menores que o normal do antagonista.

Acetaminofeno

A descontaminação gástrica com carvão ativado deve ser administrada imediatamente antes da N-acetilcisteína (NAC) para diminuir a absorção sistêmica se se souber ou se suspeitar que a ingestão de acetaminofeno ocorreu dentro de algumas horas após a apresentação. Os níveis séricos de acetaminofeno devem ser obtidos imediatamente se o paciente apresentar 4 horas ou mais após a ingestão para avaliar o risco potencial de hepatotoxicidade; os níveis de acetaminofeno desenhados menos de 4 horas após a ingestão podem ser enganosos. Para obter o melhor resultado possível, o NAC deve ser administrado o mais rápido possível, quando houver suspeita de lesão hepática iminente ou em evolução. NAC intravenoso pode ser administrado quando as circunstâncias impedirem a administração oral.

A terapia vigorosa de suporte é necessária em intoxicação grave. Os procedimentos para limitar a absorção contínua do medicamento devem ser prontamente executados, pois a lesão hepática depende da dose e ocorre no início da intoxicação.

Efeitos no sistema nervoso central

A principal ação terapêutica da hidrocodona é a analgesia. O hidrocodona produz depressão respiratória por ação direta em centros respiratórios do tronco cerebral. A depressão respiratória envolve uma redução na capacidade de resposta dos centros respiratórios do tronco cerebral a aumentos na tensão do dióxido de carbono e na estimulação elétrica.

O hidrocodona causa miose, mesmo na escuridão total. Alunos pontuais são um sinal de overdose de opióides, mas não são patognomônicos (por exemplo,., lesões pontinas de origem hemorrágica ou isquêmica podem produzir achados semelhantes). Midríase marcada em vez de miose pode ser vista devido à hipóxia em situações de overdose.

Doses terapêuticas de acetaminofeno têm efeitos insignificantes nos sistemas cardiovascular ou respiratório; no entanto, doses tóxicas podem causar insuficiência circulatória e respiração rápida e superficial.

Efeitos no trato gastrointestinal e outros músculos lisos

O hidrocodona causa uma redução na motilidade associada a um aumento no tônus muscular liso no antro do estômago e do duodeno. A digestão dos alimentos no intestino delgado é retardada e as contrações propulsivas são diminuídas. As ondas peristálticas propulsivas no cólon são diminuídas, enquanto o tom pode ser aumentado até o ponto do espasmo, resultando em constipação. Outros efeitos induzidos por opióides podem incluir uma redução nas secreções biliares e pancreáticas, espasmo do esfíncter de Oddi e elevações transitórias na amilase sérica.

Efeitos no sistema cardiovascular

A hidrocodona produz vasodilatação periférica que pode resultar em hipotensão ou síncope ortostática. Manifestações de liberação de histamina e / ou vasodilatação periférica podem incluir prurido, rubor, olhos vermelhos, sudorese e / ou hipotensão ortostática.

Efeitos no sistema endócrino

Os opióides inibem a secreção do hormônio adrenocorticotrópico (ACTH), cortisol e hormônio luteinizante (LH) em humanos. Eles também estimulam prolactina, secreção de hormônio do crescimento (GH) e secreção pancreática de insulina e glucagon.

O uso crônico de opioides pode influenciar o eixo hipotálamo-hipófise-gonadal, levando à deficiência de andrógenos que pode se manifestar como sintomas de baixa libido, impotência, disfunção erétil, amenorréia ou infertilidade. O papel causal dos opioides na síndrome do hipogonadismo é desconhecido porque os vários estressores médicos, físicos, de estilo de vida e psicológicos que podem influenciar os níveis de hormônios gonadais não foram adequadamente controlados nos estudos realizados até o momento.

Efeitos no sistema imunológico

Foi demonstrado que os opióides têm uma variedade de efeitos nos componentes do sistema imunológico. O significado clínico desses achados é desconhecido. No geral, os efeitos dos opioides parecem ser modestamente imunossupressores.

Relações Concentração-Eficácia

A concentração analgésica efetiva mínima variará amplamente entre os pacientes, especialmente entre os pacientes que foram tratados anteriormente com potentes opióides agonistas. A concentração analgésica efetiva mínima de hidrocodona para qualquer paciente individual pode aumentar ao longo do tempo devido ao aumento da dor, ao desenvolvimento de uma nova síndrome da dor e / ou ao desenvolvimento de tolerância analgésica.

Relações Concentração-Reação Adversa

Existe uma relação entre o aumento da concentração plasmática de hidrocodona e a frequência crescente de reações adversas opióides relacionadas à dose, como náusea, vômito, efeitos do SNC e depressão respiratória. Em pacientes tolerantes a opióides, a situação pode ser alterada pelo desenvolvimento de tolerância a reações adversas relacionadas a opióides.