Approval Date:
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Tramadol Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician
Warning Message
Warning: addiction, abuse and misuse; life-threatening respiratory depression; accidental ingestion; ultra-rapid metabolism of tramadol in children and other life-threatening risk factors for respiratory failure; neonatal opioid withdrawal syndrome; interactions with drugs affecting cytochromeP450isozymes; and interactions with benzodiazepines P450isomeric drugs or other drugs or other drugs “font-family:Times New Roman”>Risks associated with the combination of CNSinhibitors
Addiction, abuse and misuse
Patients and other users of Tramadol Hydrochloride Tablets are at risk for opioid addiction, abuse, and misuse, which can lead to overdose and death. Physicians should assess each patient’s risk prior to prescribing tramadol hydrochloride tablets and regularly monitor for the occurrence of such behaviors and conditions (see Adverse Reactions).
Life-threatening respiratory depression
Severe, life-threatening, or fatal respiratory depression may occur with tramadol hydrochloride tablets. Respiratory depression should be monitored at the beginning of tramadol hydrochloride tablets administration or after a dose increase (see Adverse Reactions).
Accidentally swallowed
Accidental swallowing of Tramadol Hydrochloride tablets, especially in children, may result in death.
Ultra-rapid metabolism of tramadol in children and other risk factors for life-threatening respiratory failure in children. span style=”font-family:Times New Roman”>
Life-threatening respiratory depression and death have occurred in children taking tramadol. Some reported cases occurred after tonsillectomy and/ or adenoidectomy; at least1 case in which it was shownCYP2D6diversity led to children becoming ultra-rapid metabolizers of tramadol hydrochloride. Children under 12years of age and18years of age or younger who underwent tonsillectomy and/or adenoidectomy in childrenis contraindicated (see Contraindications). Avoid Tramadol Hydrochloride Tablets in adolescents12-18 years of age in the presence of other risk factors that may increase susceptibility to the effects of tramadol respiratory depressants (see Adverse Reactions).
Neonatal Opioid Withdrawal Syndrome
Prolonged use of tramadol hydrochloride tablets during pregnancy can lead to neonatal opioid withdrawal syndrome, which can be life-threatening if unrecognized and untreated, and requires treatment according to a neonatologist’s protocol. If a pregnant woman requires long-term opioid use, the patient should be informed of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment is available (see Adverse Reactions).
with effects on cytochromeP450isoenzyme drug interactions
Tramadol and cytochromeP450 3A4inducers, 3A4inhibitors or2D6inhibitors in combination or discontinued is complicated by the effects. CytochromeP450 3A4inducers, 3A4inhibitors or2D6inhibitors with tramadol hydrochloride tablets require careful consideration of the effects of the parent drug tramadol and its active metabolite M1 ( Drug Interactions).
with benzodiazepines or otherRisks associated with the combination of CNSinhibitors
opioids in combination with benzodiazepinesPepperclass drugs or other central nervous system (CNS) depressants including The combination of alcohol can cause profound sedation, respiratory depression, coma, and death (see Adverse Reactions).
For patients with inadequate alternative treatment options, consider combining tramadol hydrochloride tablets and benzodiazepinesand the benzodiazepine class of drugs or otherCNSinhibitors.
Treatment should be limited to the lowest effective dose and duration.
Follow up patients for signs and symptoms of respiratory depression and sedation.
[Drug Name].
Generic Name: Tramadol Hydrochloride Tablets
Trade Name: Chimate
English Name: Tramadol Hydrochloride Tablets
Hanyu Pinyin: Yansuan Qumaduo Pian
[Ingredients
The main ingredient of this product is: Tramadol Hydrochloride.
Chemical name: (±)-(1RS,2RS)-2-[(N,N-dimethylamino)methylene]-1-(3-methoxyphenyl)cyclohexanol hydrochloride.
Chemical structure formula.
Molecular formula: C16H25NO2-HCl
Molecular weight: 299.84
[Properties]White oval film-coated tablets with “101” engraved on one side and “OUYI” engraved on the other side.
[Indication]For the treatment of pain in adults whose pain is severe enough to require opioid analgesics and for whom replacement therapy is inadequate.
[Specification]50mg
[dosage]Orally.
Adults (Age 17 and above)
Important Notes on Dosage and Administration
The lowest dose for the shortest duration based on the patient’s treatment goal (see Precautions).
The dosing regimen should be individualized, taking into account the patient’s pain severity, patient response, history of prior analgesic therapy, and risk factors for addiction, abuse, and misuse (see PRECAUTIONS).
Monitor patients closely for respiratory depression, especially during the first 24-72 hours of treatment initiation and after increasing doses of tramadol hydrochloride, and adjust the dose accordingly (see PRECAUTIONS).
Start Tramadol Hydrochloride Tablets Therapy
For patients with moderate to moderately severe chronic pain who do not require rapid onset of analgesic effects, treatment can be initiated with the following titration regimen to improve tolerability of tramadol hydrochloride tablets: tramadol hydrochloride tablets starting dose is 25 mg daily in the morning, titrated to increase every 3 days 25 mg in divided doses until 100 mg/day is reached (25 mg each time, four times daily). Thereafter, the total daily dose is increased by 50 mg every 3 days until 200 mg/day (50 mg each time, four times daily). After titration, 50 to 100 mg of tramadol hydrochloride tablets may be given every 4 to 6 hours as needed for pain relief, but not more than 400 mg/day.
For patients who require rapid initiation of analgesia and in whom the assessed benefit of dosing outweighs the risk of discontinuation due to adverse effects from higher initial doses, 50 mg-100 mg tramadol hydrochloride tablets may be applied every 4-6 hours as needed for pain relief, but must not exceed 400 mg/day.
Conversion from Tramadol Hydrochloride Tablets to Extended Release Tramadol
The relative bioavailability of tramadol hydrochloride tablets versus extended-release tramadol is unknown, so signs of excessive sedation and respiratory depression must be closely monitored when converting to extended-release formulations.
Dose adjustment in patients with hepatic impairment
The recommended dose for adult patients with cirrhosis is 50 mg every 12 hours.
Dose adjustment for patients with renal impairment
The recommended dosing interval for tramadol hydrochloride tablets is extended to 12 hours and the maximum daily dose is 200 mg in all patients with creatinine clearance less than 30 mL/min. Because only 7% of the dose can be removed by hemodialysis, the Dialysis patients can apply their regular dose on dialysis days.
Dose Adjustment for Elderly Patients
In general, dose selection in elderly patients over 65 years of age should be cautious, usually starting with the lowest dose, which is associated with their reduced hepatic or renal or cardiac function and more co-morbidities and medication use. In elderly patients over 75 years of age, the total dose should not exceed 300 mg/day.
Dose titration and therapeutic maintenance
Individually titrate tramadol hydrochloride tablets to the dose that provides adequate analgesia and minimal adverse effects. Continuously reassess patients on tramadol hydrochloride tablets to evaluate maintenance of pain control and the relative incidence of adverse effects, as well as to monitor for the occurrence of addiction, abuse, or misuse (see Adverse Reactions). Frequent communication between the prescribing physician, other members of the health care team, patient, and caregiver/family is important during changes in analgesic requirements, including during initial dose titration.
If pain levels increase after dose stabilization, an attempt should be made to first identify the source of the pain increase before considering increasing the dose of Tramadol Hydrochloride Tablets. If unacceptable opioid-related adverse effects are observed, consider lowering the dose. Adjust the dose to achieve an appropriate balance between pain management and opioid-associated adverse effects.
Discontinue Tramadol Hydrochloride Tablets
When tramadol hydrochloride tablets are no longer needed for treatment in patients who are taking them regularly and who may be somatically dependent, the dose can be gradually reduced by 25%-50% every 2-4 days while closely monitoring for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, the dose is raised to the previous level and slowly reduced by extending the time interval between dose reductions, reducing the number of dose changes, or a combination of both. In somatically dependent patients, abrupt discontinuation of tramadol hydrochloride tablets is contraindicated (see PRECAUTIONS).
[Adverse Reactions
Addiction, abuse and misuse
Tramadol hydrochloride tablets contain tramadol, which is a controlled substance. As an opioid, Tramadol Hydrochloride Tablets carry a risk of addiction, abuse, and misuse.
Each patient’s risk of opioid addiction, abuse, and misuse should be evaluated prior to prescribing tramadol hydrochloride tablets, and patients should be monitored for the development of such behaviors and conditions. Patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or psychiatric disorders (e.g., major depression) are at increased risk for addiction. However, this should not affect proper pain management for any any patient. Opioids, such as tramadol hydrochloride tablets, may also be prescribed for high-risk patients, but the risk profile and proper administration of tramadol hydrochloride tablets must be reinforced and signs of addiction, abuse, and misuse closely monitored.
When prescribing tramadol hydrochloride tablets, consider the risk of criminal cases for people with substance abuse and addiction seeking opioids, and mitigate this risk by prescribing the smallest appropriate dose of the drug and informing the patient how to properly dispose of unused medications (see Precautions). And contact your local controlled substance regulatory agency for information on how to prevent or monitor the shift to abuse of this class of products.
Life-threatening respiratory depression
Severe, life-threatening, or fatal respiratory depression has been reported during opioid use, even at recommended doses. If not recognized and managed immediately, respiratory depression can lead to respiratory arrest and death. Treatment of respiratory depression includes close observation, supportive measures, and administration of opioid receptor antagonists, depending on the patient’s clinical status (see Overdose). Carbon dioxide (CO2) retention due to opioid-induced respiratory depression can exacerbate the sedative effects of opioids.
Severe, life-threatening, or fatal respiratory depression can occur at any time of tramadol hydrochloride tablet administration, with a higher risk at initiation of therapy or subsequent dose increases. Patients should be monitored closely for respiratory depression, especially during the first 24-72 hours of initiating therapy and after a dose increase of tramadol hydrochloride tablets.
To reduce the risk of respiratory depression, it is especially critical to dose tramadol hydrochloride tablets (see Dosage). Overestimation of tramadol hydrochloride tablets dose in patients switching to tramadol hydrochloride tablets on another opioid can lead to death from first dose overdose.
Even accidental swallowing of 1 dose of tramadol hydrochloride tablets, especially in children, can lead to respiratory depression and even death from tramadol overdose.
Ultra-rapid metabolism of tramadol in children and other risk factors for life-threatening respiratory failure in children
Life-threatening respiratory depression and death have occurred in children taking tramadol. Due to the CYP2D6 genotype (described below), the variable metabolism of tramadol and codeine can lead to increased exposure to an active metabolite. Based on post-marketing reports of tramadol or codeine, children under 12 years of age may be more sensitive to the respiratory depressant effects of tramadol. Furthermore, children with obstructive sleep apnea syndrome who are treated with opioids for pain after tonsillectomy and/or adenoidectomy are particularly sensitive to the respiratory depressant effects of the drug. Because of the risk of life-threatening respiratory depression and death.
Tramadol Hydrochloride Tablets are contraindicated in12years of age in all children (see Contraindications).
As with adults, when prescribing opioids to adolescents When prescribing opioids, physicians should select the lowest effective dose as well as the shortest duration of therapy and inform patients and guardians of these risks and signs of opioid overdose (see Precautions, Medications for Children, Overdose).
Neonatal Opioid Withdrawal Syndrome
Prolonged use of tramadol hydrochloride tablets during pregnancy can lead to withdrawal symptoms in newborns. Unlike opioid withdrawal syndrome in adults, if not recognized and treated, neonatal opioid withdrawal syndrome can be lethal and requires treatment based on protocols developed by neonatologists. Observe for any signs of neonatal opioid withdrawal syndrome and treat accordingly. Inform pregnant women with prolonged opioid use of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate therapy is available (see Precautions).
Co-administration of tramadol hydrochloride tablets and benzodiazepinesPepperclass drugs or otherCNSdepressants (e.g. non-benzodiazepinetype sedatives/anesthetics, anxiolytics, sedatives, myorelaxants, general anesthetics, antipsychotics, other opioids and alcohol) may cause profound sedation, respiratory depression, coma and death . Based on these risks, these medications should be used conservatively in patients for whom alternative therapies are not an option.
Observational studies have shown that the combined use of opioid analgesics and benzodiazepines increases the risk of drug-related death compared with opioid analgesics alone. Because of similar pharmacologic properties, similar risks can reasonably be expected when combining other CNS-inhibiting drugs and opioid analgesics (see PRECAUTIONS, Drug Interactions).
If the decision is made to prescribe a benzodiazepine or other CNS inhibitor in combination with an opioid analgesic, the lowest effective dose and the shortest duration of combination application need to be prescribed. Lower doses of benzodiazepines or other CNS inhibitors should be prescribed in patients already on opioid analgesics compared with those not on opioids, with dose adjustments based on clinical response. Initiate opioid analgesia in patients already on benzodiazepines or other CNS inhibitors, prescribe a lower dose of opioid analgesia and adjust the dose based on clinical response. Closely follow patients for respiratory depression and sedation signs and symptoms.
Patients and guardians should be aware of the risks associated with respiratory depression and sedation when Tramadol Hydrochloride Tablets are used in combination with benzodiazepines or other CNS depressants, including alcohol and prohibited drugs. Patients are advised not to drive or operate heavy machinery until the effects of the concomitant application of benzodiazepines or other CNS depressants wear off. Screen patients for risk of substance abuse, including opioid abuse and misuse, overdose and risk of death associated with co-application of CNS inhibitor use, including alcohol and prohibited drugs (see PRECAUTIONS, Drug Interactions).
When using tramadol, especially in combination5-during the use of serotonergic drugs, cases have been reported of a potentially life-threatening disorder,5-hydroxytryptamine syndrome. 5-hydroxytryptophanergic drugs include selective5-hydroxytryptamine reuptake inhibitors (SSRI), 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants ( TCA), tritanic drugs, 5-HT3receptor antagonists, drugs that affect5-serotonergic neurotransmitter systems (e.g., mirtazapine, trazodone, tramadol), and drugs that interfere with5-hydroxytryptamine metabolism (includingMAO inhibitors, including those used to treat psychiatric disorders and other conditions such as linezolid and intravenous methylene blue) (see PRECAUTIONS, Drug Interactions). This may occur in the recommended dose range.
Symptoms of 5-hydroxytryptamine syndrome may include altered mental status (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, unstable blood pressure, hypothermia), neuromuscular abnormalities (e.g., hyperreflexia, ataxia, rigidity), and/or / or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Symptoms generally occur within a few hours to a few days of co-administration, but may also occur at a later time. Discontinue Tramadol Hydrochloride Tablets if 5-hydroxytryptamine syndrome is suspected.
Seizures
Patients on Tramadol Hydrochloride Tablets within the recommended dosing range have reported seizure symptoms. Postmarketing reports suggest that the risk of seizures increases with higher tramadol hydrochloride doses when the dose is higher than the recommended range. The following drug combinations of tramadol hydrochloride tablets increase the risk of seizures in patients:
selective5-hydroxytryptamine reuptake inhibitors (SSRIantidepressants or appetite suppressants),
tricyclic antidepressants (TCA), and/or other tricyclic compounds (e.g., cyclobenzaprine, isoprostanes, etc.)
Other opioids
MAO Inhibitors,
Antipsychotics
Other seizure-lowering threshold medications.
Patients with epilepsy, patients with a history of seizures, or patients at risk for seizures (eg, head trauma, metabolic disease, alcohol and drug withdrawal, CNS infection) are also at increased risk for seizures. The application of naloxone may increase the risk of seizures in the setting of tramadol hydrochloride tablet overdose.
Suicide
For patients with suicidal or addictive tendencies , prescribing Tramadol Hydrochloride tablets is prohibited. Consider non-narcotic analgesics for patients with suicidal or depressive disorders. (See Precautions).
For abuse and /or currently taking centrally active drugs (including sedatives or antidepressants), drinking excessive amounts of alcohol and suffering from mood disorders or depression, caution should be exercised in prescribing Tramadol hydrochloride tablets (see PRECAUTIONS, Drug Interactions).
Advise patients not to exceed the recommended dose and limit alcohol intake (see Dosage and Administration).
Adrenaline insufficiency
over1months of opioid use are often reported in cases of adrenal insufficiency. The presentation of adrenal insufficiency may refer to nonspecific signs and symptoms, including nausea, vomiting, anorexia, weakness, malaise, dizziness, and hypotension. If adrenal insufficiency is suspected, the diagnosis should be confirmed as soon as possible. If adrenal insufficiency is diagnosed, treatment with physiologic replacement doses of corticosteroids is administered. Patients discontinue opioids to restore adrenal function and continue corticosteroid therapy until adrenal function is restored. Some cases report having tried different opioids in patients without recurrent adrenal insufficiency. The available information does not establish an association between any specific opioid and adrenal insufficiency.
Severe hypotension
In outpatients, tramadol hydrochloride tablets may cause severe hypotension, including postural hypotension and syncope. These patients are at increased risk for impaired blood pressure maintenance when blood volume is reduced or when specific CNS inhibitors (e.g., phenothiazines or general anesthetics) are applied concomitantly to affect overpressure (see PRECAUTIONS, Drug Interactions). Monitor these patients for signs of hypotension when initiating or adjusting the dose of tramadol hydrochloride tablets. In patients experiencing circulatory shock, tramadol hydrochloride tablets may cause vasodilation and further decrease cardiac output and blood pressure. Avoid the use of tramadol hydrochloride tablets in patients experiencing circulatory shock.
Gastrointestinal Adverse Reactions
Tramadol Hydrochloride Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic intestinal obstruction (see Contraindications).
Tramadol in Tramadol Hydrochloride Tablets may cause spasm of the sphincter of Oddi. Opioids may cause an increase in serum amylase. Monitor patients with biliary tract disease, including exacerbation of symptoms of acute pancreatitis.
Allergic and other hypersensitivity reactions
Severe and rare fatal hypersensitivity-like reactions have been reported in patients treated with tramadol hydrochloride tablets. These events always occurred after the first dose. Other reported allergic reactions include pruritus, urticaria, bronchospasm, angioedema, toxic epidermolysis bullosa, and Stevens Johnson syndrome. Patients with a history of allergic reactions to tramadol and other opioid analogs may be at increased risk and therefore should not take tramadol hydrochloride tablets (see Contraindications). If an allergic reaction or other hypersensitivity occurs, discontinue Tramadol Hydrochloride Tablets immediately and discontinue Tramadol Hydrochloride Tablets permanently and do not apply any further Tramadol dosage forms. If the patient experiences any symptoms of hypersensitivity reaction, then the patient is advised to seek immediate medical help. (See Contraindications, Precautions)
When applying the full range of opioid agonist analgesics, including tramadol hydrochloride tablets Avoid applying mixed agonists/ antagonists (e.g., pentazocine, nalbuphine, and buprenorphine) or partial agonists (e.g., buprenorphine) to patients Analgesic. Mixed agonists/antagonists or partial agonists may reduce analgesia in such patients, and “font-family:Times New Roman”>/or trigger their withdrawal symptoms.
Patients with physical dependence should discontinue Tramadol Hydrochloride Tablets at a gradually decreasing dose (see Dosage and Administration). And immediate discontinuation of Tramadol Hydrochloride Tablets is prohibited (see PRECAUTIONS).
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, a drug The incidence of adverse reactions observed in clinical trials cannot be directly compared with the incidence in clinical trials of another drug and may not reflect the incidence observed in practice.
Tramadol hydrochloride tablets were used in 550 patients in a double-blind or open-label extension period in the US study of chronic nonmalignant lesions. Of these patients, 375 were 65 years of age or older. Table 2 reports the cumulative incidence of adverse reactions in the most frequent reactions (5% or higher at 7 days) as of 7, 30, and 90 days. The most frequently reported events occurred in the central nervous system and the gastrointestinal system. Although the reactions listed in the table are likely to be associated with tramadol hydrochloride tablet administration, the reported incidence also includes events due in part to underlying disease or concomitant medication. The overall incidence of adverse experiences in these clinical trials was similar between tramadol hydrochloride tablets and the active controls TYLENOL and codeine #3 (acetaminophen 300 mg and codeine phosphate 30 mg) and aspirin 325 mg and codeine phosphate 30 mg, but the incidence of withdrawal due to adverse events appeared to be higher in the tramadol hydrochloride tablets group.
Table 2: Cumulative Incidence of Adverse Reactions to Tramadol Hydrochloride Tablets in Long-Term Clinical Trials for Non-Malignant Lesion Pain (N=427)
up to 7 daysup to 30 daysMax 90 daysDizziness/vertigo26% 31%33%Nasty24%34%40%Constipation24%38%46%Headache18%26%32%Drowsiness16%23%25%Vomiting9%13%17% Pruritus8%10%11%”CNS Stimulus”17%11%14%Powerless6%11%12%Sweating6%7%9%Indigestion5%9%13% Dry mouth5%9%10%10%Diarrhea5%6%10%1. “CNS stimulation” is a combination of tension, anxiety, agitation, tremors, spasms, excitement, emotional instability, and hallucinations.
The incidence is 1%-<5% and may have a causal correlation of.
The following list of adverse reactions with an incidence of 1%-<5% in clinical trials is potentially causally relevant to Tramadol Hydrochloride Tablets.
Body as a whole: discomfort.
Cardiovascular: vasodilation.
Central nervous system: anxiety, confusion, coordination disorders, euphoria, pupillary constriction, nervousness, and sleep disturbances.
Gastrointestinal: abdominal pain, anorexia, and bloating.
Musculoskeletal: hypertonia.
Skin: rash.
Special sensations: visual disturbances.
Genitourinary system: menopausal symptoms, frequent urination and urinary retention.
Occurrence less than 1%, with possible causal correlation.
The following list of tramadol clinical trials in and or tramadol-containing drugs with a post-marketing experience reporting an incidence of less than1%of adverse reactions.
The body as a whole: accidental injury, allergic reactions, anaphylactic reactions, death, suicidal ideation, weight loss, 5-hydroxytryptamine syndrome (altered mental status, hyperreflexia, fever, chills, tremors, euphoria, sweating, seizures, and coma).
Cardiovascular: postural hypotension, syncope, and tachycardia.
Central nervous system: gait abnormalities, amnesia, cognitive dysfunction, delirium, depression, difficulty concentrating, hallucinations, dyskinesia, sensory abnormalities, seizures, speech disorders, and tremors.
Metabolic and nutritional disorders: Very rare cases of hypoglycemia have been reported in patients taking tramadol. The majority of reports are in patients with prodromal risk factors, including diabetes mellitus or renal insufficiency, or in the elderly.
Respiratory: dyspnea.
Skin: Stevens-Johnson syndrome/neutrophilic epidermal necrolysis relaxation, urticaria, microcysticercosis.
Special senses: taste disturbance, pupillary dilation.
Genitourinary system: difficulty urinating, menstrual irregularities.
Other adverse experiences, causality unknown.
Multiple other adverse events were frequently reported in patients taking tramadol hydrochloride tablets during clinical trials and/or in post-marketing experiences. A causal relationship between tramadol hydrochloride tablets and these events was not established. However, the most significant events are listed below as warning information for physicians.
Cardiovascular: abnormal ECG, hypertension, hypotension, myocardial ischemia, palpitations, pulmonary edema, pulmonary embolism.
Central nervous system: migraine.
Gastrointestinal: gastrointestinal bleeding, hepatitis, stomatitis, and liver failure.
Laboratory abnormalities: increased creatinine, elevated liver enzymes, decreased hemoglobin, and proteinuria.
Sensory: cataracts, deafness, and tinnitus.
Post-marketing experience
5-hydroxytryptamine syndrome: A potentially life-threatening disorder, 5-hydroxytryptamine syndrome, has been reported in cases during concomitant use of tramadol and 5-hydroxytryptaminergic drugs.
Adrenal insufficiency: Cases of adrenal insufficiency have been frequently reported with opioid use for more than 1 month.
Androgen deficiency: Cases of androgen deficiency occur during prolonged opioid use (see Clinical Pharmacology).
QT prolongation/tip-twisting ventricular tachycardia: Cases of QT prolongation and/or tip-twisting ventricular tachycardia have been reported while on tramadol. Many of these case reports were on another drug for QT prolongation, in patients with risk factors for QT prolongation (e.g., hypokalemia) or in the context of overdose.
[Contraindication
Tramadol hydrochloride tablets are contraindicated in.
1. Children under 12 years of age.
2. Postoperative analgesia after tonsillectomy and/or adenoidectomy in children under 18 years of age.
Tramadol hydrochloride tablets are also contraindicated in patients who are.
1. Significant respiratory depression.
2. Acute or severe bronchial asthma when monitoring is not available or when resuscitation equipment is not available.
3, Known or suspected gastrointestinal obstruction, including paralytic intestinal obstruction.
4. Hypersensitivity to tramadol, any component of this product, or opioids.
5. Use of a monoamine oxidase inhibitor (MAOI) or concomitant use with an MAOI within the past 14 days.
6. Patients with suicidal and/or addictive tendencies
[Caution].
Application Restrictions
Even at recommended doses, the use of opioids carries a risk of addiction, abuse, and misuse (see Adverse Reactions), and tramadol hydrochloride tablets should be applied conservatively to the following patients on alternative treatments (e.g., non-opioid analgesics).
intolerant, or expected to be intolerant.
Adequate analgesia was not provided, or is not expected to be provided.
Nephropathy and liver disease
Impaired renal function results in reduced rate and extent of excretion of tramadol and its active metabolite M1. A lower dose is recommended for patients with creatinine clearance less than 30 mL/min (see DOSAGE AND ADMINISTRATION). Tramadol and M1 metabolism is diminished in patients with advanced cirrhosis. In patients with cirrhosis, a lower dose is recommended (see DOSAGE AND ADMINISTRATION).
The half-life of the drug is prolonged in the presence of these disorders and the time to reach steady state is delayed, so it may take several days for blood levels to rise.
Patient Precautions
Patients are advised to read the drug insert carefully.
Addiction, abuse and misuse
Inform patients that tramadol hydrochloride tablets can lead to addiction, abuse, and misuse, as well as overdose and death, even when administered at recommended doses (see ADVERSE REACTIONS). Instruct patients not to share Tramadol Hydrochloride Tablets with others and to take steps to protect Tramadol Hydrochloride Tablets from theft or misuse.
Life-threatening respiratory depression
Inform patients of the risk of life-threatening respiratory depression, which is highest with initial use of tramadol hydrochloride tablets or at increasing doses, and that these conditions can also occur at recommended doses (see Adverse Reactions). Instruct patients on how to recognize respiratory depression and on the importance of seeking immediate medical help if respiratory distress occurs.
Accidental swallowing
Advise patients that accidental swallowing, especially in children, may result in respiratory depression or death (see Adverse Reactions). Instruct patients to take steps for safe storage and handling (see Handling of Unused Tramadol Hydrochloride Tablets) Tramadol Hydrochloride Tablets.
Ultra-rapid Metabolism of Tramadol in Children and Other Risk Factors for Life-Threatening Respiratory Failure in Children
Guardians should be aware that tramadol hydrochloride tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age who have undergone tonsillectomy and/or adenoidectomy. children 12-18 years of age should be monitored for respiratory Signs of depression (see Adverse Reactions).
Interaction with benzodiazepines and other CNS inhibitors
Patients and guardians should be aware that potentially lethal superimposed effects may occur if tramadol hydrochloride tablets are used in combination with benzodiazepines, CNS inhibitors including alcohol, or offending drugs, except under medical supervision, which prohibits Co-administration (see Adverse Reactions, Drug Interactions).
5-hydroxytryptamine syndrome
Inform patients that opioids in combination with 5-hydroxytryptaminergic drugs can cause a rare but potentially life-threatening condition. Warn the patient of the symptoms of 5-hydroxytryptamine syndrome and seek immediate medical help if symptoms occur. Instruct patients to inform their primary care physician, among other things, if they are taking or planning to take 5-hydroxytryptaminergic drugs (see Adverse Reactions).
MAOI Interactions
Inform patients that Tramadol Hydrochloride Tablets are contraindicated when using any drug that inhibits monoamine oxidase. Patients should not start an MAOI while taking tramadol hydrochloride tablets (see Drug Interactions).
Seizures
Inform patients that tramadol hydrochloride tablets may trigger seizures when combined with 5-hydroxytryptaminergic drugs (including SSRIs, SNRIs, and tramadol analogs) or drugs that significantly reduce the metabolic clearance of tramadol (see Adverse Reactions).
Adrenal insufficiency
Inform patients that opioids can cause adrenal insufficiency, which is a potentially life-threatening condition. Adrenal insufficiency may manifest as nonspecific signs and symptoms, such as nausea, vomiting, anorexia, weakness, malaise, dizziness, and hypotension. Advise patients to seek medical help if they develop such symptoms (see Adverse Reactions).
Important Dosing Instructions
Instruct patients on how to properly take Tramadol Hydrochloride Tablets.
Inform patients that dose adjustment of Tramadol Hydrochloride Tablets without consulting a physician is prohibited.
If a patient has been on tramadol hydrochloride tablets for more than a few weeks and is at risk of discontinuing treatment, inform the patient of the importance of safely reducing the dose, as abrupt discontinuation can trigger withdrawal symptoms. Provide a dosing regimen to complete tapering off the drug (see Dosage).
Low blood pressure
Inform patients that Tramadol Hydrochloride Tablets may cause postural hypotension and syncope. Instruct patients how to recognize symptoms of hypotension and how to reduce the risk of serious consequences (e.g., sitting or lying down, rising carefully from a sitting or lying position) (see Adverse Reactions).
Allergic reactions
Inform the patient that an allergic reaction has been reported with the ingredients contained in Tramadol Hydrochloride Tablets. Inform patients how to recognize such reactions and when to seek medical help (see Contraindications, Adverse Reactions).
Neonatal Opioid Withdrawal Syndrome
Advise fertile female patients that prolonged use of tramadol hydrochloride tablets during pregnancy can lead to neonatal opioid withdrawal syndrome, which can be lethal if not recognized and treated, and if the patient is taking opioids during pregnancy inform her primary care physician, especially near delivery. (See Adverse Reactions, Precautions).
Embryo-fetal toxicity
Advise fertile female patients that Tramadol Hydrochloride Tablets may cause fetal damage and that patients should inform their physicians of known or suspected pregnancy.
Nursing Mothers
CYP2D6substrate ultra-rapid metabolizers have the potential to be exposed to life-threatening levels of the active metaboliteOO -family:equivocal”>demethyltramadol (M1) when tramadol occurs in the same polymorphic metabolism as codeine. Death has been reported in at least1 case in infants consuming breast milk with high levels of morphine because the mother is an ultrafast metabolizer of codeine. Nursing infants of mothers of ultrafast metabolizers taking tramadol hydrochloride tablets are at risk for exposure to high levels ofM1 and life-threatening respiratory depression. Therefore, breastfeeding is not recommended during treatment with Tramadol Hydrochloride Tablets.
CYP2D6Gene variability: ultra-fast metabolizers
Some individuals may be affected by specificCYP2D6 genotype (e.g. named *1/*1xNor*1/*2xN of gene replicators) and become ultra-fast metabolizers. The incidence of this CYP2D6 genotype varies considerably, with estimates in Caucasians (Europe, North America) of 1-10% and black (African American) 3-4%, East Asians are1-2%(Chinese, Japanese, and Korean), ethnic-specific/races (i.e., Oceanic, North African, Middle Eastern, Ashkenazi Jewish, Puerto Rican) may be higher than10%. These individuals can convert tramadol to its active metabolite O-demethyltramadol more rapidly and completely than others (M1). This rapid conversion leads to higher than expected serumM1levels. Life-threatening or lethal respiratory depression or signs of overdose (e.g., extreme drowsiness, coma, or shallow breathing) may occur in ultra-rapid metabolizers individuals even at nominal dosing regimens (see Overdose). Therefore, tramadol hydrochloride tablets should not be used in individuals who are ultra-rapid metabolizers.
Risks of combining or discontinuing cytochrome P450 2D6 inhibitors
The combined use of tramadol hydrochloride tablets and all cytochrome P450 2D6 inhibitors (eg, amiodarone, quinidine) may result in increased tramadol blood levels and decreased concentrations of the active metabolite M1. In patients who become physically dependent on tramadol, decreased M1 exposure may lead to signs and symptoms of opioid withdrawal, as well as decreased drug efficacy. Increased concentrations of tramadol may increase the risk of serious adverse events, including seizures and 5-hydroxytryptamine syndrome.
Discontinuation of concomitant application of cytochrome P450 2D6 inhibitors may result in decreased tramadol blood concentrations and increased concentrations of the active metabolite M1, which may increase or prolong adverse effects associated with opioid toxicity and may cause potentially lethal respiratory depression.
Tramadol hydrochloride tablets in combination with CYP2D6 inhibitors track the risk of serious adverse events in patients on tramadol hydrochloride tablets and any CYP2D6 inhibitor, including seizures and 5-hydroxytryptamine syndrome, symptoms that may reflect opioid toxicity, and opioid withdrawal (see Drug Interactions).
Life-threatening respiratory depression in patients with chronic lung disease or in elderly, cachectic, or frail patients
Acute or severe bronchial Tramadol Hydrochloride Tablets are contraindicated in patients with asthma.
Patients with chronic lung disease: Patients with significant chronic lung disease or pulmonary heart disease treated with tramadol hydrochloride tablets, and those with significantly reduced respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, even with the recommended dose of tramadol hydrochloride The risk of reduced respiratory drive, including dyspnea, is increased with the recommended dose of tramadol hydrochloride tablets.
Elderly, cachectic, or frail patients: Life-threatening respiratory depression is more likely to occur in older, cachectic, or frail patients because pharmacokinetics or drug clearance may be altered in these patients compared with younger, healthier patients.
Monitor such patients closely, especially when initiating and adjusting tramadol hydrochloride tablets doses and when tramadol hydrochloride tablets are used concomitantly with other medications that depress respiration. As an option, non-opioid analgesics may be considered in these patients.
Infertility
Inform patients that long-term opioid use may lead to reduced fertility. Whether the effects on fertility are reversible remains unknown.
Driving or operating heavy machinery
Advise patients that Tramadol Hydrochloride Tablets may impair the mental or physical ability needed to perform potentially hazardous activities, such as driving a vehicle or operating machinery. Advise patients not to perform such tasks unless they understand how to respond to the drug.
Constipation
Inform patients about the possibility of severe constipation, including treatment instructions and when to seek medical help (see Adverse Reactions).
Handling of Unused Tramadol Hydrochloride Tablets
Patients should dispose of unused Tramadol Hydrochloride tablets in household garbage as follows: 1. Remove the medication from its original packaging and mix it with unwanted materials, such as used coffee grounds or kitty litter (to make the medication less appealing to children and pets. making it difficult for people interested in finding medications through the trash to identify them). 2. Place the mixture in a Ziploc bag, empty box, or other container to prevent the medication from leaking or falling out of the trash bag.
Maximum single dose and 24-hour dose
Advise patients not to exceed the single dose and 24-hour dose limits and the interval between doses, as exceeding these recommendations can result in respiratory depression, seizures, and death (see DOSAGE AND ADMINISTRATION).
Substance abuse
Tramadol hydrochloride tablets contain tramadol, which, similar to other opioids, is a substance with high potential for abuse. Tramadol hydrochloride tablets can be abused and misuse, addiction and criminal tendencies occur.
All patients treated with opioids need to be closely monitored for signs of abuse and addiction because of the risk of addiction with opioid analgesic products, even with appropriate medical applications.
Prescription drug abuse is the intentional non-therapeutic application of a prescription drug, even if applied only 1 time, to seek its reinforcing psychological or physiological effects.
Drug addiction is a collection of behavioral, cognitive, and physiological phenomena that occur after repeated substance application and include: a strong desire to take the medication, difficulty controlling the taking, continued application even though harmful or potentially harmful consequences are present, a higher priority of medication use over other activities and obligations, an increased tolerability, and occasional organic withdrawal.
Medication-seeking behaviors are very common among individuals with substance use disorders. Medication-seeking strategies include emergency phone calls or visits at the end of the workday, refusal to perform appropriate tests, exams, or referrals, repeated “missing” prescriptions, tampering with prescription medications, and unwillingness to provide previous medical records or contact information for other treating physicians.” Physician shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among substance abusers and those with non-therapeutic addictions. Focusing on obtaining adequate pain relief is also appropriate behavior in patients with poor pain control.
Abuse and addiction are separate and distinct from somatic dependence and tolerance. Pharmacies should be aware that in all addicts, addiction may not be accompanied by concurrent tolerance and somatic dependence symptoms. In addition, opioid abuse can occur in the absence of true addiction.
Similar to other opioids, tramadol hydrochloride tablets can be diverted from non-medical applications to illicit distribution channels. As required by state law, careful record keeping of prescribing information, including quantity, frequency, and follow-up requirements, is strongly recommended.
Appropriate patient evaluations, proper prescribing practices, regular in-assessment of treatment, and proper dispensing and storage are all appropriate measures that can help limit opioid drug abuse.
Specific Risks of Tramadol Hydrochloride Tablets Abuse
Tramadol Hydrochloride Tablets are for oral use only. Abuse of Tramadol Hydrochloride Tablets creates a risk of overdose and death. The risk is increased with concomitant abuse of Tramadol Hydrochloride Tablets and alcohol and other central nervous system depressants.
Extra-gastric drug abuse often leads to the transmission of infectious diseases such as hepatitis and HIV.
Dependence
Tolerance and somatic dependence can both occur during long-term opioid therapy. Tolerance is the need to increase the drug dose to maintain a prescribed effect such as analgesia (without disease progression or other external factors). Tolerance may occur with both intended and unintended effects of the drug and may develop at different rates to achieve different effects.
Somatic dependence leads to withdrawal symptoms after abrupt discontinuation or significant reduction in drug dose. Withdrawal can also be facilitated by taking medications with opioid receptor antagonist activity (e.g., naloxone, nalmefene), mixed receptor agonist/antagonist analgesics (pentazocine, buprenorphine, nalbuphine), or partial receptor agonists (buprenorphine). Clinically significant levels of somatic dependence do not occur until several days to weeks of continued opioid application.
Tramadol hydrochloride tablets should not be abruptly discontinued in somatically dependent patients (see Dosage and Administration). Withdrawal syndrome may occur if tramadol hydrochloride tablets are abruptly discontinued in somatically dependent patients. Some or all of the following symptoms may characterize the syndrome: irritability, lacrimation, runny eyes, yawning, sweating, chills, myalgia, and dilated pupils. Other signs and symptoms may also occur, including: irritability, anxiety, back pain, arthralgia, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Infants born to opioid-substantiated mothers may also become somatically dependent and exhibit respiratory distress and withdrawal signs (see Precautions).
[For pregnant and lactating women
Pregnancy
Risk Overview
Prolonged use of opioid analgesics during pregnancy May cause neonatal opioid withdrawal syndrome. Available data for tramadol hydrochloride tablets in pregnant women are insufficient to provide information on the drug-related risks of major birth defects and miscarriage.
Tramadol applied at 1.4, 0.6, and 3.6 times the maximum recommended human daily dose (MRHD) during organogenesis reduced fetal weight and decreased ossification in mice, rats, and rabbits in animal fertility studies. At 1.2 and 1.9 times the MRHD, tramadol decreased fetal body weight and increased mortality in pups. Based on animal data, pregnant women were informed of the potential risk of this drug to the fetus.
The estimated background risk of major birth defects and miscarriages in the indicated population is unknown. All pregnancies were at background risk for birth defects, weight loss, or other adverse prognosis. In the general population, the estimated background risks for major birth defects and miscarriage in clinically identified pregnancies were 2-4% and 15-20%, respectively.
Clinical Considerations
Adverse Neonatal Reactions
For medical or non-medical purposes during pregnancy Prolonged use of opioid analgesics can lead to respiratory depression and somatic dependence in newborns and lead to neonatal opioid withdrawal syndrome very shortly after birth.
Neonatal opioid withdrawal syndrome can manifest as irritability, hyperactivity, abnormal sleep, high pitched crying, tremors, vomiting, diarrhea, and lack of weight gain. The onset, duration, and severity of neonatal opioid withdrawal syndrome varies based on the specific opioid used, duration of administration, timing and amount of last maternal dose, and the rate of drug elimination in the neonate. Observe for any signs and symptoms of neonatal opioid withdrawal syndrome and manage accordingly (see Adverse Reactions).
Neonatal seizures, neonatal withdrawal syndrome, fetal death, and stillbirth have been reported post-marketing.
Paroxysmal pain or labor
Tramadol hydrochloride tablets are not recommended for use in pregnancy during labor or immediately before labor women, when other analgesic techniques are more appropriate. Opioids can cross the placenta and may induce fetal dependence, neonatal acute respiratory depression and/ or psychological effects associated with opioid exposure and withdrawal. and physiological effects. There must be an available opioid receptor antagonist, such as naloxone, that can reverse opioid-induced respiratory depression in neonates. Monitor for signs of excessive sedation and respiratory depression in neonates exposed to opioid analgesics during bouts of pain.
The use of opioid analgesics, including tramadol hydrochloride tablets, may affect the duration of the bout due to inhibitory activity on uterine contractions or facilitation of cervical extension.
Studies have shown that tramadol can cross the placenta. In 40 women taking tramadol during a bout of pain, the mean ratio of serum tramadol in the umbilical vein compared with the maternal vein was 0.83.
The effects of tramadol hydrochloride tablets on subsequent growth, development, and functional maturation in children are unknown.
Data
Animal data
Studies have shown that, when administered at maternal doses Tramadol is effective in mice (120 mg/kg), rats () family:Times New Roman”>25mg/kg) and rabbits (75mg/kg). span>) were embryotoxic and fetotoxic, but not teratogenic at this dose level. Based on mg/m, these doses are the maximum recommended daily human doses for mice, rats, and rabbits, respectively (MRHD)1.4 of the maximum recommended human daily dose (1.4) for mice, rats, and rabbits, respectively. span>, 0.6and and span>3.6times.
No non-drug related teratogenic effects were observed in the offspring of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol at various routes of administration. Embryonic and fetal toxicity at maternal toxicity dose levels consisted mainly of reduced fetal body weight, reduced skeletal ossification, and increased extra ribs. Developmental delays or behavioral parameters were also seen in female rat pups that were ready for delivery. Embryonic and fetal lethality was reported in only one rabbit study at a dose of 300 mg/kg, which can cause extreme maternal toxicity in rabbits. The registered doses in mice, rats, and rabbits were 1.7, 1.9, and 14.6 times MRHD, respectively.
Tramadol was evaluated in prenatal and postnatal studies in rats. Reduced body weight occurred in female offspring applied at oral (gavage) dose levels of 50 mg/kg (1.2 times MRHD) or higher, and shortened pup survival was observed at 80 mg/kg (1.9 times MRHD) applied during early lactation.
Nursing mothers
Risk Overview
Tramadol Hydrochloride Tablets are not recommended for preoperative obstetric use or postpartum analgesia in nursing mothers because the safety of the drug in infants and newborns has not been studied.
Tramadol and its metabolite, O-desmethyltramadol (M1), are present in human breast milk. No information is available on the effects of the drug on the nursing infant or on the drug’s effect on breast milk. The M1 metabolite is more potent than tramadol in terms of μ-opioid receptor binding (see Clinical Pharmacology). Published studies have reported the presence of tramadol and M1 in colostrum in nursing mothers who applied tramadol in the early postpartum period. women who are ultra-rapid metabolizers of tramadol may have higher than expected M1 serum levels, potentially resulting in higher M1 levels in breast milk that are dangerous for their nursing infants. The amount of tramadol secreted into breast milk is lower in women with normal tramadol metabolism and is dose dependent. Because of the potential for serious adverse effects, including excessive sedation and respiratory depression in nursing infants, patients are advised not to recommend breastfeeding during tramadol hydrochloride tablet therapy (see WARNINGS).
If an infant is exposed to tramadol hydrochloride tablets via breast milk, the The infant is monitored for excessive sedation and respiratory depression. Withdrawal symptoms can occur in nursing infants when maternal opioid analgesia is discontinued or when breastfeeding is discontinued.
Data
Single intravenous =”font-family:Times New Roman”>100mgdose of tramadol after application of the drug Cumulative excretion into breast milk within 16hours100mcgtramadol (0.1%maternal dose) and “font-family:Times New Roman”>27mcg M1.
[Children’s medication
The safety and efficacy of Tramadol Hydrochloride Tablets in pediatric patients is uncertain.
Life-threatening respiratory depression and death have occurred in children taking tramadol (see PRECAUTIONS). In some of the reported cases, these events occurred after tonsillectomy and/or adenoidectomy, and 1 child showed evidence of an ultra-rapid metabolizer of tramadol (ie, multiple copies of the cytochrome P450 isoenzyme 2D6 gene). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of tramadol.
Because of the risk of life-threatening respiratory depression and death.
1. Tramadol Hydrochloride Tablets are contraindicated in all children under 12 years of age.
2. Tramadol Hydrochloride Tablets are contraindicated in the postoperative treatment of children under 18 years of age following tonsillectomy and/or adenoidectomy.
3. Avoid the use of Tramadol Hydrochloride Tablets in adolescents 12-18 years of age who have other risk factors that may increase susceptibility to the effects of tramadol respiratory depressants unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe lung disease, neuromuscular disease, and other drugs that cause respiratory depression when combined.
[Geriatric Use]
Total455 older adults (65 “font-family:equinox”>years or older) subjects in controlled clinical trials with tramadol hydrochloride tablets. Of these, 145 patients were75 years of age or older.
In studies including older patients, the incidence of treatment-limiting adverse events was higher among patients older than 75 years compared with those younger than 65 years. Specifically, 30% of patients older than 75 years of age experienced gastrointestinal therapy drug-limiting adverse events compared with 17% of patients younger than 65 years of age. Constipation led to treatment discontinuation in 10% of patients older than 75 years of age.
Respiratory depression is a major risk in older patients treated with opioids, with larger initial doses used in opioid-intolerant patients or when opioids are co-administered with other agents that depress breathing. Slowly adjust the dose of tramadol hydrochloride tablets in elderly patients and closely monitor for signs of central nervous system and respiratory depression (see Adverse Reactions).
The kidneys are known to excrete tramadol significantly, but the risk of adverse reactions to this drug may be higher in patients with renal impairment. Because renal function is more likely to be reduced in older patients, dose selection should be cautious and monitoring of renal function may be useful.
[Drug Interactions
CYP2D6 inhibitors
Concomitant administration of tramadol hydrochloride tablets and CYP2D6 inhibitors, such as quinidine, fluoxetine, paroxetine, and bupropion, may result in increased tramadol blood levels and decreased M1 blood levels, especially when tramadol hydrochloride tablet steady-state dose after the addition of inhibitors. Because M1 is a highly potent mu-opioid receptor agonist, decreased M1 exposure leads to reduced therapeutic effects and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence. Increased tramadol exposure leads to increased or prolonged therapeutic effects and an increased risk of serious adverse events, including seizures and 5-hydroxytryptamine syndrome.
After discontinuation of CYP2D6 inhibitors, tramadol blood levels decrease and M1 blood levels increase as inhibitor effects decrease, thereby increasing or prolonging therapeutic effects, but also increasing adverse reactions related to opioid toxicity and triggering potentially lethal respiratory depression.
If concomitant CYP2D6 inhibitors are necessary, patients should be closely followed for adverse effects, including opioid withdrawal, seizures, and 5-hydroxytryptamine syndrome.
If CYP2D6 inhibitors are discontinued, reduce the dose of tramadol hydrochloride tablets until a stable drug effect can be achieved. Closely follow patients for adverse events, including respiratory depression and sedation.
Co-administration with quinidine
Quinidine is a CYP2D6-selective inhibitor, so co-administration of quinidine and tramadol hydrochloride tablets results in increased tramadol concentrations and decreased M1 concentrations. These clinical consequences are unknown.
CYP3A4 inhibitors
The combination of tramadol hydrochloride tablets and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole antifungals (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), can increase blood levels of tramadol and may lead to greater metabolism of CYP2D6, and higher M1 levels. Closely follow patients for serious adverse events, including seizures and 5-hydroxytryptamine syndrome, and adverse reactions associated with opioid toxicity, including potentially lethal respiratory depression, especially after reaching stable doses of tramadol hydrochloride tablets with the addition of CYP3A4 inhibitors.
After discontinuation of CYP3A4 inhibitors, tramadol blood levels decrease as the inhibitor effect decreases, resulting in diminished tramadol efficacy or withdrawal symptoms in patients who become somatically dependent on tramadol.
If a combination is necessary, consider lowering the dose of tramadol hydrochloride tablets until a stable drug effect is achieved. Closely follow the patient for seizures and 5-hydroxytryptamine syndrome, as well as signs of respiratory depression and sedation. If the CYP3A4 inhibitor is discontinued, consider increasing the dose of tramadol hydrochloride tablets until a stable drug effect is achieved and follow the patient for signs and symptoms of opioid withdrawal.
CYP3A4 inducers
The combination of tramadol hydrochloride tablets and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, can decrease tramadol blood levels, resulting in decreased efficacy or withdrawal symptoms in patients who develop somatic dependence on tramadol.
After discontinuation of CYP3A4 inducers, tramadol blood levels increase as the inducer effect decreases, thereby increasing or prolonging therapeutic effects and adverse effects, and may cause seizures and 5-hydroxytryptamine syndrome, as well as potentially lethal respiratory depression.
Co-administration with carbamazepine
Carbamazepine is a CYP3A4 inducer that significantly reduces the analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and seizure risk is associated with tramadol, the combination of tramadol hydrochloride tablets and carbamazepine is not recommended.
Benzodiazepines and other central nervous system (CNS) depressants
The combined use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, deep sedation, coma, and death due to pharmacologic stacking effects. Other CNS depressants include other sedatives/hypnotics, anxiolytics, tranquilizers, myorelaxants, general anesthetics, antipsychotics, other opioids, and some banned substances.
The combination of these medications should be used conservatively in patients for whom alternative therapies are not effective. Limit therapeutic agents to the minimum effective dose and duration. Closely follow the patient for respiratory depression and signs of sedation.
5-hydroxytryptaminergic drugs
The combination of opioids and other drugs that affect the 5-hydroxytryptophanergic neurotransmitter system can lead to 5-hydroxytryptamine syndrome. These include selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tretinoin, 5-HT3 receptor antagonists, drugs that affect the 5-hydroxytryptaminergic neurotransmitter system (e.g., mirtazapine, trazodone), and monoamine oxidase (MAO) inhibitors (for treating psychiatric disorders and other conditions, such as linezolid and intravenous methylene blue).
If a combination is necessary, patients should be closely monitored, especially during treatment initiation and dose adjustment. Discontinue Tramadol Hydrochloride Tablets immediately if 5-hydroxytryptamine syndrome is suspected.
Monoamine oxidase inhibitors (MAOI)
Tramadol Hydrochloride Tablets are contraindicated in patients taking an MAOI and within 14 days of discontinuation of this class of therapy.
Interaction of MAOI with opioids may manifest as 5-hydroxytryptamine syndrome or opioid toxicity (e.g., respiratory depression, coma). These drugs include phenelzine, transbenzylamine, and linezolid.
Digoxin
Post-marketing surveillance has shown rare reports of digoxin toxicity. Follow patients for signs of digoxin toxicity and adjust digoxin dosing as needed.
Warfarin
Post-marketing monitoring of tramadol has shown rare reports of altered warfarin effects, including prolonged prothrombin time. Monitor prothrombin time in patients on warfarin, signs of drug interactions, and adjust warfarin dosing as needed.
Mixed agonists/antagonists and partially agonized opioid analgesics
Mixed agonists/antagonists or partially agonistic opioid analgesics may reduce the analgesic effect of tramadol hydrochloride tablets and/or trigger withdrawal symptoms. These medications include buprenorphine, nalbuphine, pentazocine, and buprenorphine. Avoid combination use of these medications.
Muscarinic agents
Tramadol may potentiate the neuromuscular blocking activity of skeletal muscle relaxants and exacerbate the degree of respiratory depression. Monitor patients for symptoms of respiratory depression that may be more severe than expected and reduce the dose of tramadol hydrochloride tablets and/or muscle relaxants if necessary.
Diuretics
Opioids can attenuate diuretic effects by inducing antidiuretic hormone release. Monitor patients for signs of diminished diuretic effect and/or effects on blood pressure and increase the dose of diuretics as needed.
Anticholinergics
Concomitant administration of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation and may lead to paralytic bowel obstruction. Patients should be monitored for signs of urinary retention or decreased gastric motility when Tramadol hydrochloride tablets are used concomitantly with anticholinergic drugs.
Interaction with Drugs Affecting Cytochrome P450 Isozymes
to tramadol and tramadol produced by tramadol hydrochloride tabletsM1concentrations from tramadol combination or discontinuation of cytochromeP450 3A4 inducer,3A4 inducer,inhibitors or2D6inhibitors are complex in their effects. The combined use of cytochromeP450 3A4inducers, 3A4inhibitors or2D6inhibitors with tramadol hydrochloride tablets, the parent drug tramadol, i.e., 5-hydroxytryptamine and norepinephrine, needs to be carefully considered weak inhibitors of reuptake and mu-opioid receptor agonists, and the role of their active metabolitesM1,M1binds more potently to the μ opioid receptor.
[Drug overdose
Clinical Manifestations
Acute overdose of tramadol hydrochloride tablets is characterized by respiratory depression, drowsiness progressing to miosis or coma, skeletal muscle relaxation, cold wet skin, pupil constriction, and in some cases pulmonary edema, tachycardia, prolonged QT interval, hypotension partial or complete airway obstruction, atypical snoring, seizures, and death. When hypoxia occurs with overdose, significant pupil dilation rather than pupil narrowing may be seen.
Death from overdose has been reported with tramadol abuse and misuse. A review of case reports suggests an increased risk of fatal overdose when tramadol is abused with alcohol or other CNS depressants including other opioids.
Overdose management
If overdose occurs, prioritize airway reconstruction and protection and establish adjunctive or controlled ventilation mechanisms. When managing circulatory shock and pulmonary edema, use other supportive measures (including oxygen and vasopressants) as indicated. Advanced life support measures are required for cardiac arrest or severe arrhythmias.
The opioid receptor antagonists naloxone or nalmefene are both specific antidotes to respiratory depression due to opioid overdose. For clinically significant respiratory or circulatory depression secondary to tramadol overdose, an opioid receptor antagonist may be administered. Opioid receptor antagonists should not be used in the absence of clinically significant respiratory or circulatory depression secondary to tramadol overdose.
Naloxone may reverse some, but not all, of the symptoms caused by tramadol overdose. The risk of seizures is also increased by naloxone application. Convulsions in animals following application of toxic doses of tramadol hydrochloride tablets can be suppressed with barbiturates or benzodiazepines, whereas naloxone increases the occurrence of convulsions. Naloxone administration does not alter the lethality of overdose in mice. Hemodialysis is not expected to be helpful in the event of overdose because less than 7% of the applied drug dose is removed during a 4-hour dialysis period.
Because the duration of opioid reversal is expected to be less than the duration of action of tramadol, patients should be monitored carefully until autonomic respiratory effects can be reliably re-established. If the response to opioid receptor antagonists is not optimal or transient, additional receptor antagonists are applied based on the product prescribing information.
In individuals with somatic dependence on opioids, administration of commonly recommended doses of receptor antagonists can result in acute withdrawal syndrome. The severity of the withdrawal syndrome that occurs depends on the degree of somatic dependence and the dose of the receptor antagonist taken. If the decision is made to treat severe respiratory depression in a somatically dependent patient, the receptor antagonist should be administered with caution at the outset, at a dose less than the usual dose of the receptor antagonist.
[Pharmacologic Toxicology
Mechanism of action
Tramadol hydrochloride tablets contain tramadol, an opioid receptor agonist and inhibitor of norepinephrine and 5-hydroxytryptamine reuptake. Although its mode of action is not fully understood, the analgesic effects of tramadol are due to its binding to μ-opioid receptors and the concomitant slight inhibition of norepinephrine and 5-hydroxytryptamine reuptake.
Opioid activity is due to the low affinity of μ-opioid receptor binding to the parent compound and the higher affinity of binding to the O-demethylation metabolite M1. In animal models, M1 produced six times the analgesic effect and 200 times the binding to the μ-opioid receptor than tramadol. In several animal tests, the opioid receptor antagonist naloxone only partially antagonized tramadol-induced analgesia. The degree of analgesia in humans with tramadol and M1 depends on the blood levels of each compound.
Tramadol has been shown to inhibit the reuptake of norepinephrine and 5-hydroxytryptamine in vitro, as have some other opioid analgesics. Tramadol inhibits norepinephrine and 5-hydroxytryptamine in vitro, as do some opioid analgesics. These mechanisms alone may contribute to the overall analgesic effect of tramadol. Analgesic effects in humans occur roughly 1 hour after dosing and peak at 2-3 hours.
Pharmacodynamics
Effects on the central nervous system
Tramadol can produce respiratory depression through direct effects on the brainstem respiratory center. During respiratory depression, the responsiveness of the brainstem respiratory center to both increased carbon dioxide tension and electrical stimulation is reduced.
Tramadol causes pupil narrowing, even in the dark. Pinpoint pupils are a sign of opioid overdose but are not used in the diagnosis of drug overdose (bleeding or ischemic-derived pontine lesions may also produce similar results). In cases of hypoxia due to overdose, significant pupil dilation rather than pupil narrowing can occur.
Actions on the gastrointestinal tract and other smooth muscles
Tramadol reduces the dynamics of elevated smooth muscle tone in the stomach and duodenum. Small intestine food digestion is delayed and propulsive contractions are reduced. Propulsive peristaltic waves in the colon are reduced, while tone may increase to the threshold of spasm that leads to constipation. Other opioid-induced effects may include decreased bile and pancreatic secretions, sphincter of Oddi spasm, and transient elevation of serum amylase.
Effects on the cardiovascular system
Tramadol produces peripheral vasodilation, the latter of which may lead to postural hypotension or syncope. Manifestations of peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or upright hypotension.
The effect of oral tramadol on the QTcF interval was evaluated in a double-blind, randomized, four-crossover, placebo and positive drug (moxifloxacin)-controlled study in 68 adult male and female healthy subjects. At a daily dose of 600 mg (1.5 times the maximum immediate-release daily dose), the study showed no significant effect on the QTcF interval.
Effects on the endocrine system
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. Opioids also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of the insulin good glucagon (see adverse effects).
Long-term opioid use may affect the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency, which manifests as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The role of opioids in hypogonadal clinical syndromes is unclear, as the various medical, physical, lifestyle, and psychological stressors that may affect gonadal hormone levels have not been adequately controlled in the studies conducted to date.
Action on the immune system
Studies have shown various effects of opioids on components of the immune system in vitro and in animal models. The clinical significance of these findings is unclear. In conclusion, opioids appear to have modest immunosuppressive properties.
Concentration Efficacy Relationships
Minimum effective analgesic concentrations varied considerably between patients, particularly in patients previously treated with potent opioid receptor agonists. The minimum effective analgesic concentration of tramadol may increase over time in any individual patient due to worsening pain, development of new pain syndromes, and/or development of analgesic tolerance (see Dosage).
Concentration Adverse Reaction Relationships
Increased tramadol blood levels and increased dosing frequency correlate with increased frequency of opioid dose-related adverse reactions, such as nausea, vomiting, CNS effects, and respiratory depression. This can be modified in opioid-resistant patients by increasing tolerance to opioid-associated adverse reactions (see Dosage).
Carcinogenicity, mutagenicity, and fertility impairment
Carcinogenicity
In the NMRI mouse carcinogenicity study, a mild but statistically significant increase in 2 common rodent tumors, namely lung and liver tumors, was observed, especially in aged mice. Mice were dosed orally with up to 30 mg/kg via water (0.36 times the maximum recommended human daily dose or MRHD) for approximately 2 years, but the maximum tolerated dose was not used in the study. The finding is not suggestive of human risk. A 2-year carcinogenicity study in rats tested a maximum oral dose of 30 mg/kg in drinking water (0.73 times MRHD) and found no evidence of carcinogenicity.
Mutagenicity
Tramadol is mutagenic in the metabolic activation of lymphomas in mice. Tramadol has been shown to be mutagenic in an in vitro bacterial revertant mutation assay using Salmonella and Escherichia coli (Ames), a mouse lymph in the absence of metabolic activation assay, in vitro chromatin aberration assay, or bone marrow in vivo micronucleus assay did not show mutagenicity.
Fertility impairment
Maximum oral dose in male rats50mg/kgand female rats up to75mg/kg Roman”>75 mg/kg, no effect of tramadol on fertility was observed. Based on body surface area comparisons, these doses were roughly 1.2 of the maximum recommended daily human dose and 1.8times.
[Pharmacokinetics
Tramadol hydrochloride tablets are analgesic derived from the parent drug and M1 metabolite (see Pharmacology and Toxicology). Tramadol is a racemate, and the [-] and [+] forms of tramadol and M1 are detectable in the circulation. The linear pharmacokinetics were studied after administration of multiple doses of 50 mg and 100 mg until steady state.
Absorption
100mgThe mean absolute bioavailability of the oral dose was approximately75%. The mean peak blood concentrations of racemic tramadol and M1 occurred in healthy adults dosed with 2and3hours later. In general, after a single or multiple doses, tramadol and M1 of 2 enantiomers follow a parallel time course in vivo, with only a very small differences(approximately10%).
Steady-state blood levels of tramadol and M1 were achieved over 2 days with four daily doses. There was no evidence of self-induced effects (see Figure 1 and Table 1 below).
Figure 1: Mean tramadol and M1 blood concentration profiles after a single 100 mg oral application and 29 100 mg oral applications of tramadol hydrochloride four times daily.
Table 1: Mean (%CV) pharmacokinetic parameters of racemic tramadol and M1 metabolites
population/dosing regimenaMother drug/
MetabolitesPeak concentration
(ng/mL)Time to peak (hours)
Clearance/Fb
(mL/min/Kg)t1/2 (hour)Healthy adults.
100 mg qid, MD p.o.Tramadol
M1592 (30)
110 (29)2.3 (61)
2.4 (46)5.90 (25)c6.7 (15)
7.0 (14)Healthy adults.
100 mg SD p.o.Tramadol
M1308 (25)
55.0 (36)1.6 (63)
3.0 (51)8.50 (31)c5.6 (20)
6.7 (16)Senior, (> 75 years old)
50 mg SD p.o.Tramadol
M1208 (31)d2.1 (19)d6.89 (25)c7.0 (23)dImpaired liver function.
50 mg SD p.o.Tramadol
M1217 (11)
19.4 (12)1.9 (16)
9.8 (20)4.23 (56)c13.3 (11)
18.5 (15)Impaired kidney function.
CLcr 10-30 mL/min
100 mg SD i.v. Tramadol
M1c
cc
c4.23 (54)c10.6 (31)
11.5 (40)Impaired kidney function.
CLcr<5 mL/min
100 mg SD i.v. Tramadol
M1 c
c c
c3.73 (17)c11.0 (29)
16.9 (18) SD = single dose,MD = multiple dose,p.o.= orally,i.v.= intravenously, style=”font-family:Times New Roman”>q.i.d.= four times a day
FRepresents the oral bioavailability of tramadol
Not applicable
Not measured
Food effects
Oral administration of Tramadol Hydrochloride Tablets between meals does not significantly affect the rate and extent of absorption, and therefore Tramadol Hydrochloride Tablets can be applied without regard to food.
Distribution
When given intravenously100 mg, the volume of tramadol distribution in male and female subjects was2.6L/kgand2.9L/kg. The binding of tramadol to human plasma proteins is approximately 20%, and binding also appears to be independent of concentrations up to 10mcg/mLeffect of . Plasma protein binding saturation occurs only at concentrations outside the clinically relevant range.
Clearance
Tramadol is cleared primarily by hepatic metabolism, and metabolites are cleared primarily by the kidneys . After a single100 mg oral dose, the mean (%CV) apparent total clearance was8.50(31)mL/min/kg. The mean terminal plasma clearance half-lives of racemic tramadol and racemicM1 were6.3±1.4and7.4±1.4hours. With multiple doses, the plasma clearance half-life of racemic tramadol increased from approximately 6hours to 7hours.
Metabolism
After oral administration, tramadol is metabolized by multiple pathways, including CYP2D6and CYP3A4, but also through conjugation of maternal drugs and metabolites. Approximately30% of the drug is eliminated from the urine as a prodrug, while60% of the drug is excreted as metabolites. The remainder is excreted as unidentifiable or non-extractable metabolites. The main metabolic pathway occurs in the liverN-andDemethylation and glucosinolation or sulfation of O-. One of the metabolites (O-demethyltramadol, named M1) has pharmacological activity in animal models. The formation of M1depends on CYP2D6, which is itself inhibited and may affect therapeutic response (see PRECAUTIONS, Drug Interactions).
About 7% of the population can have reduced CYP2D6 isoenzyme activity of cytochrome P-450. Among other drugs, these individuals are “hypometabolizers” of isoquinolines, dextromethorphan, and tricyclic antidepressants. Based on the population PK analysis of the Phase I study in healthy subjects, tramadol concentrations were approximately 20% higher in the “hypometabolizers” compared to the “hypermetabolizers”, while M1 concentrations were 40% lower. The combination of CYP2D6 inhibitors, such as fluoxetine, paroxetine and quinidine, can lead to significant drug interactions. In vitro drug interaction studies with human liver microsomes have shown that CYP2D6 inhibitors such as fluoxetine and its metabolites, desmethyl fluoxetine, amitriptyline and quinidine, can inhibit tramadol metabolism to varying degrees, suggesting that co-application of these drugs can lead to increased tramadol concentrations as well as lower M1 concentrations. The full pharmacological effects triggered by the alterations in efficacy or safety are unknown. Combined application of 5-hydroxytryptamine reuptake inhibitors and MAO inhibitors may increase the risk of adverse events, including seizures and serotonin syndrome (see Adverse Reactions).
Excretion
Tramadol metabolites are primarily metabolized by the kidneys.
Special Populations
Liver damage
In patients with advanced cirrhosis, tramadol andM1 metabolism is reduced, resulting in an increase in the area under the tramadol concentration time curve and an increase in tramadol andM1elimination half-life is prolonged (tramadol is13hours, M1is19hours). For patients with cirrhosis, adjustment of the dosing regimen is recommended (see Dosage and Administration).
Renal impairment
Renal impairment leading to tramadol and its active metabolitesM1with reduced rate and extent of excretion. Adjustment of the dosing regimen is recommended in patients with creatinine clearance less than 30 mL/min (see Dosage and Administration). 4hours of tramadol removed during dialysis andM1total was less than 7% of the dose administered.
Age: Elderly
65-75year-old healthy elderly subjects with plasma tramadol concentrations and elimination half-lives comparable to65year-old healthy subjects with plasma tramadol concentrations and elimination half-lives comparable to65similar to healthy subjects under the age of Compared to subjects 65-75years old, 75years of age and older subjects had increased maximum serum concentrations (208and162ng/mL), with an elimination half-life prolonged (7and6hours). Daily dose adjustment is recommended for patients over 75 years of age. family:equivocal”>(see Dosage).
Gender
The absolute bioavailability of tramadol in men was73% and in women 79%. 100 mg Plasma clearance in men after intravenous tramadol application was6.4mL/min/kg and for women5.7mL/min/ kg. After a single oral dose adjusted for body weight, women had a higher peak tramadol concentration compared to men12% and a higher area under the concentration time curve 35%. The clinical significance of these differences is unclear.
Weak/strong metabolizers, CYP2D6
Active MetabolitesM1 through polymorphic enzymesCYP2D6mediated formation. Approximately7% of the population cytochromeP-450metabolic enzyme system of CYP2D6isoenzyme activity was reduced. Among other drugs, these individuals are “low metabolizers of isoquinolines, dextromethorphan, and tricyclic antidepressants”. Based on healthy subjectsIRtabletsPopulationPhase IPKanalysis,”low metabolizers” versus”high metabolizers” compared to approximately20% higher tramadol concentrations20%, whileM1concentration is reduced by40%.
Drug Interaction Studies
Potential effects of tramadol on other drugs
In vitro studies have shown that when tramadol is used in combination drug applications at therapeutic doses Tramadol is unlikely to inhibit the metabolism of other drugs mediated by CYP3A4. Tramadol does not induce auto-metabolism in humans because the maximum blood concentrations observed after multiple oral doses are higher than expected based on single-dose data.
CYP2D6 inhibitors
In vitro drug interaction studies with human liver microsomes have shown that the interaction withCYP2D6inhibitors, such as fluoxetine and paroxetine in combination with amitriptyline, can partially inhibit tramadol metabolism (see Caution; Drug interactions).
Quinidine
Tramadol viaCYP2D6metabolite active metaboliteM1. CYP2D6The selective inhibitor quinidine coadministered with tramadol extended-release tablets resulted in elevated tramadol exposure50-60%, M1reduction in exposureby 50-60%. The clinical consequences of these findings are unclear.
An in vitro drug interaction study was performed on human liver microsomes to assess the effect of the CYP2D6 substrate tramadol on quinidine. The results of this study showed that tramadol had no effect on quinidine metabolism (see Warnings, Precautions; Drug Interactions).
CYP3A4 inhibitors and inducers
Because tramadol is also caused byCYP3A4metabolism, therefore concomitant application with tramadol hydrochloride tabletsCYP3A4inhibitors such as ketoconazole and erythromycin, orCYP3A4inducing agents such as rifampin and St. John’s wort may affect tramadol metabolism, resulting in altered tramadol exposure (see Warnings, Precautions; Drug Interactions).
Cimetidine
TramadolIRtablets with weakCYP3A4concomitant application of the inhibitor cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. No change in the dosing regimen of tramadol hydrochloride tablets is recommended when administered concomitantly with cimetidine.
Carbamazepine
CYP3A4CYP3A4 span style=”font-family:equine”>The inducer carbamazepine can increase tramadol metabolism. The analgesic effect of tramadol is significantly diminished in patients taking carbamazepine. Concomitant application of tramadol hydrochloride tablets and carbamazepine is not recommended.
[Storage] Sealed and stored at room temperature.
[Package] Aluminum foil for pharmaceutical packaging, polyvinyl chloride solid pharmaceutical hard tablets, 12 tablets/board/box.
High density polyethylene bottles for oral solid medication,100tablets/bottle.
[Expiration date] 36 months
[Execution Standard
[Approval number] 国药准字H10960106
Drug Production License No.: 冀20150135
[Manufacturer].
Enterprise name: Shih Pharma Group Ouyi Pharmaceutical Co.
Manufacturing Address: No. 88 Yangzi Road, Shijiazhuang Economic and Technological Development Zone
Postal Code: 052165
Tel: 0311-87886158
Fax number: 0311-87039126
Website: http://www.ouyipharma.com