Source: FDA, National Drug Code (US) Revision Year: 2022
ULTRACET is contraindicated for:
ULTRACET is also contraindicated in patients with:
ULTRACET contains tramadol, a Schedule IV controlled substance. As an opioid, ULTRACET exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed ULTRACET. 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 ULTRACET, and monitor all patients receiving ULTRACET 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 ULTRACET, but use in such patients necessitates intensive counseling about the risks and proper use of ULTRACET along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing ULTRACET. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. 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.
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. 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 ULTRACET, 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 ULTRACET.
To reduce the risk of respiratory depression, proper dosing and titration of ULTRACET are essential [see Dosage and Administration (2)]. Overestimating the ULTRACET dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of ULTRACET, especially by children, can result in respiratory depression and death due to an overdose of tramadol.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)].
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with ULTRACET. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].
Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions (5.1, 5.8), Patient Counseling Information (17)].
Life-threatening respiratory depression and death have occurred in children who received tramadol. Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to increased exposure to an active metabolite. Based upon postmarketing reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol. Furthermore, children with obstructive sleep apnea who are treated with opioids for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:
Tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers of CYP2D6 substrates being potentially exposed to life-threatening levels of O-desmethyltramadol (M1). At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. A baby nursing from an ultra-rapid metabolizer mother taking ULTRACET could potentially be exposed to high levels of M1, and experience life-threatening respiratory depression. For this reason, breastfeeding is not recommended during treatment with ULTRACET [see Use in Specific Populations (8.2)].
Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1×N or *1/*2×N). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert tramadol into its active metabolite, O-desmethyltramadol (M1), more rapidly and completely than other people. This rapid conversion results in higher than expected serum M1 levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see Overdosage (10)]. Therefore, individuals who are ultra-rapid metabolizers should not use ULTRACET.
Prolonged use of ULTRACET 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 [see Use in Specific Populations (8.1) and Patient Counseling Information (17)].
The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from ULTRACET are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with ULTRACET requires careful consideration of the effects on the parent drug, tramadol, which is a weak serotonin and norepinephrine reuptake inhibitor and µ-opioid agonist, and the active metabolite, M1, which is more potent than tramadol in µ-opioid receptor binding [see Drug Interactions (7)].
The concomitant use of ULTRACET with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in tramadol plasma levels and a decrease in the levels of the active metabolite, M1. A decrease in M1 exposure in patients who have developed physical dependence to tramadol, may result in signs and symptoms of opioid withdrawal and reduced efficacy. The effect of increased tramadol levels may be an increased risk for serious adverse events including seizures and serotonin syndrome.
Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in tramadol plasma levels and an increase in active metabolite M1 levels, which could increase or prolong adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression.
Follow patients receiving ULTRACET and any CYP2D6 inhibitor for the risk of serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity, and opioid withdrawal when ULTRACET is used in conjunction with inhibitors of CYP2D6 [see Drug Interactions (7)].
The concomitant use of ULTRACET with cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in tramadol plasma concentrations, which could increase or prolong adverse reactions, increase the risk for serious adverse events including seizures and serotonin syndrome, and may cause potentially fatal respiratory depression.
The concomitant use of ULTRACET with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower tramadol levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal.
Follow patients receiving ULTRACET and any CYP3A4 inhibitor or inducer for the risk for serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and opioid withdrawal when ULTRACET is used in conjunction with inhibitors and inducers of CYP3A4 [see Drug Interactions (7)].
ULTRACET contains tramadol hydrochloride and acetaminophen. 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.
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTRACET with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].
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.
If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].
Advise both patients and caregivers about the risks of respiratory depression and sedation when ULTRACET is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, including ULTRACET, during concomitant use with serotonergic drugs.
Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue ULTRACET if serotonin syndrome is suspected.
Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous postmarketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range.
Concomitant use of tramadol increases the seizure risk in patients taking: [see Drug Interactions (7)].
Risk of seizures may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections).
In tramadol overdose, naloxone administration may increase the risk of seizure.
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.
The use of ULTRACET in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated [see Contraindications (4)].
Patients with Chronic Pulmonary Disease: ULTRACET-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 ULTRACET [see Warnings and Precautions (5.3)].
Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics, or altered clearance, compared to younger, healthier patients [see Warnings and Precautions (5.3)].
Monitor such patients closely, particularly when initiating and titrating ULTRACET and when ULTRACET is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.8), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.
ULTRACET 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) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of ULTRACET. In patients with circulatory shock, ULTRACET may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ULTRACET in patients with circulatory shock.
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), ULTRACET may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ULTRACET.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of ULTRACET in patients with impaired consciousness or coma.
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.
ULTRACET is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications (4)].
The tramadol in ULTRACET 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.
Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to tramadol and other opioids may be at increased risk and therefore should not receive ULTRACET. If anaphylaxis or other hypersensitivity occurs, stop administration of ULTRACET immediately, discontinue ULTRACET permanently, and do not rechallenge with any formulation of tramadol. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction [see Contraindications (4), Information for Patients (17)].
There have been postmarketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue ULTRACET immediately and seek medical care if they experience these symptoms. Do not prescribe ULTRACET for patients with acetaminophen allergy.
Due to the potential for acetaminophen hepatotoxicity at doses higher than the recommended dose, ULTRACET should not be used concomitantly with other acetaminophen containing products.
Do not abruptly discontinue ULTRACET in a patient physically dependent on opioids. When discontinuing ULTRACET in a physically dependent patient, gradually taper the dosage. Rapid tapering of tramadol and acetaminophen in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5), Drug Abuse and Dependence (9.3)].
Additionally, 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 ULTRACET. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].
ULTRACET 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 ULTRACET and know how they will react to the medication [see Patient Counseling Information (17)].
Hyponatremia (serum sodium <135 mmol/L) has been reported with the use of tramadol, and many cases are severe (sodium level < 120 mmol/L). Most cases of hyponatremia occurred in females over the age of 65 and within the first week of therapy. In some reports, hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Monitor for signs and symptoms of hyponatremia (e.g., confusion, disorientation), during treatment with ULTRACET, especially during initiation of therapy. If signs and symptoms of hyponatremia are present, initiate appropriate treatment (e.g., fluid restriction) and discontinue ULTRACET [see Dosage and Administration: Safe Reduction or Discontinuation of ULTRACET (2.5)].
Cases of tramadol-associated hypoglycemia have been reported, some resulting in hospitalization. In most cases, patients had predisposing risk factors (e.g. diabetes). If hypoglycemia is suspected, monitor blood glucose levels and consider drug discontinuation as appropriate [see Dosage and Administration: Safe Reduction or Discontinuation of ULTRACET (2.5)].
The following serious adverse reactions are discussed, or described in greater detail, in other sections:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most common incidence of treatment-emergent adverse events (≥3.0%) in subjects from clinical trials was constipation, diarrhea, nausea, somnolence, anorexia, dizziness, and sweating increased.
Table 1 shows the incidence rate of treatment-emergent adverse events reported in ≥2.0% of subjects over five days of ULTRACET use in clinical trials (subjects took an average of at least 6 tablets per day).
Table 1. Incidence of Treatment-Emergent Adverse Events (≥2.0%):
| Body System Preferred Term | ULTRACET (N=142) (%) |
|---|---|
| Gastrointestinal System Disorders | |
| Constipation | 6 |
| Diarrhea | 3 |
| Nausea | 3 |
| Dry Mouth | 2 |
| Psychiatric Disorders | |
| Somnolence | 6 |
| Anorexia | 3 |
| Insomnia | 2 |
| Central & Peripheral Nervous System | |
| Dizziness | 3 |
| Skin and Appendages | |
| Sweating Increased | 4 |
| Pruritus | 2 |
| Reproductive Disorders, Male* | |
| Prostatic Disorder | 2 |
* Number of males = 62
The following lists adverse reactions that occurred with an incidence of at least 1% in single-dose or repeated-dose clinical trials of ULTRACET.
Body as a Whole: Asthenia, fatigue, hot flushes
Central and Peripheral Nervous System: Dizziness, headache, tremor
Gastrointestinal System: Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting
Psychiatric Disorders: Anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence
Skin and Appendages: Pruritus, rash, increased sweating
The following lists clinically relevant adverse reactions that occurred with an incidence of less than 1% in ULTRACET clinical trials.
Body as a Whole: Chest pain, rigors, syncope, withdrawal syndrome
Cardiovascular Disorders: Hypertension, aggravated hypertension, hypotension
Central and Peripheral Nervous System: Ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesias, stupor, vertigo
Gastrointestinal System: Dysphagia, melena, tongue edema
Hearing and Vestibular Disorders: Tinnitus
Heart Rate and Rhythm Disorders: Arrhythmia, palpitation, tachycardia
Liver and Biliary System: Hepatic function abnormal
Metabolic and Nutritional Disorders: Weight decrease
Psychiatric Disorders: Amnesia, depersonalization, depression, drug abuse, emotional lability, hallucination, impotence, paroniria, abnormal thinking
Red Blood Cell Disorders: Anemia
Respiratory System: Dyspnea
Urinary System: Albuminuria, micturition disorder, oliguria, urinary retention
Vision Disorders: Abnormal vision
The following adverse reactions have been identified during post-approval use of tramadol-containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis: Anaphylaxis has been reported with ingredients contained in ULTRACET.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].
QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use. Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in the overdose setting.
Eye disorders: miosis, mydriasis
Metabolism and nutrition disorders: Hyponatremia: Cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy [see Warnings and Precautions (5.22)].
Hypoglycemia: Cases of hypoglycemia have been reported in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients [see Warnings and Precautions (5.23)].
Nervous system disorders: movement disorder, speech disorder
Psychiatric disorders: delirium
Other events which have been reported with the use of tramadol products and for which a causal association has not been determined include: vasodilation, orthostatic hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson syndrome/TENS), cognitive dysfunction, difficulty concentrating, depression, suicidal tendency, hepatitis, liver failure, and gastrointestinal bleeding. Reported laboratory abnormalities included elevated creatinine and liver function tests. Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures, and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs.
Table 2 includes clinically significant interactions with ULTRACET.
Table 2. Clinically Significant Drug Interactions with ULTRACET:
| Inhibitors of CYP2D6 | |
| Clinical Impact: | The concomitant use of ULTRACET and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of ULTRACET is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)]. |
| Intervention: | If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering ULTRACET dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation. |
| Examples | Quinidine, fluoxetine, paroxetine and bupropion |
| Inhibitors of CYP3A4 | |
| Clinical Impact: | The concomitant use of ULTRACET and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of ULTRACET is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. |
| Intervention: | If concomitant use is necessary, consider dosage reduction of ULTRACET until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the ULTRACET dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. |
| Examples: | Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
| CYP3A4 Inducers | |
| Clinical Impact: | The concomitant use of ULTRACET and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome. |
| Intervention: | If concomitant use is necessary, consider increasing the ULTRACET dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider ULTRACET dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ULTRACET and carbamazepine is not recommended. |
| Examples: | Rifampin, carbamazepine, phenytoin |
| Benzodiazepines and Other Central Nervous System (CNS) Depressants | |
| Clinical Impact: | Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
| Intervention: | Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.8)]. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3, 5.8)]. |
| Examples: | Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
| Serotonergic Drugs | |
| Clinical Impact: | The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
| Intervention: | If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ULTRACET if serotonin syndrome is suspected. |
| Examples: | Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
| Monoamine Oxidase Inhibitors (MAOIs) | |
| Clinical Impact: | MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.9)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)]. |
| Intervention: | Do not use ULTRACET in patients taking MAOIs or within 14 days of stopping such treatment. |
| Examples: | phenelzine, tranylcypromine, linezolid |
| Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics | |
| Clinical Impact: | May reduce the analgesic effect of ULTRACET and/or precipitate withdrawal symptoms. |
| Intervention: | Avoid concomitant use. |
| Examples: | butorphanol, nalbuphine, pentazocine, buprenorphine |
| Muscle Relaxants | |
| Clinical Impact: | Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
| Intervention: | Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of ULTRACET and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3, 5.8)]. |
| Diuretics | |
| Clinical Impact: | Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
| Intervention: | Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
| Anticholinergic Drugs | |
| Clinical Impact: | The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
| Intervention: | Monitor patients for signs of urinary retention or reduced gastric motility when ULTRACET is used concomitantly with anticholinergic drugs. |
| Digoxin | |
| Clinical Impact: | Postmarketing surveillance of tramadol has revealed rare reports of digoxin toxicity. |
| Intervention: | Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed. |
| Warfarin | |
| Clinical Impact: | Postmarketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times. |
| Intervention: | Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed. |
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.5)]. Available data with ULTRACET in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.
In animal reproduction studies, the combination of tramadol and acetaminophen decreased fetal weights and increased supernumerary ribs at 1.6 times the maximum recommended human daily dosage (MRHD). In separate animal reproduction studies, tramadol administration alone during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD). Tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the MRHD.
Reproductive and developmental studies in rats and mice from the published literature identified adverse events at clinically relevant doses with acetaminophen. Treatment of pregnant rats with doses of acetaminophen approximately 1.3 times the maximum human daily dose (MRHD) showed evidence of fetotoxicity and increases in bone variations in the fetuses. In another study, necrosis was observed in the liver and kidney of both pregnant rats and fetuses at doses approximately 1.9 times the MHDD. In mice treated with acetaminophen at doses within the clinical dosing range, cumulative adverse effects on reproduction were seen in a continuous breeding study. A reduction in number of litters of the parental mating pair was observed as well as retarded growth and abnormal sperm in their offspring and reduced birth weight in the next generation [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms and signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.5)].
Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol hydrochloride during postmarketing.
ULTRACET is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. 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. ULTRACET is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including ULTRACET, 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.
Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.
The effect of ULTRACET, if any, on the later growth, development, and functional maturation of the child is unknown.
No drug-related teratogenic effects were observed in the progeny of rats treated orally with tramadol and acetaminophen. The tramadol/acetaminophen combination product was shown to be embryotoxic and fetotoxic in rats at a maternally toxic dose, 50/434 mg/kg tramadol/acetaminophen (1.6 times the maximum daily human tramadol/acetaminophen dosage), but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at these dose levels. These doses on a mg/m² basis are 1.9, 0.8, and 4.9 times the maximum recommended human daily dosage (MRHD) for mouse, rat and rabbit, respectively.
No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat and rabbit are 2.3, 2.6, and 19 times the MRHD, respectively.
Tramadol alone was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m² or 1.6 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m² or 2.6 times the maximum daily human tramadol dosage).
Studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 1.3 times the maximum human daily dose (MHDD = 2.6 grams/day, based on a body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes). Offspring had no evidence of external, visceral, or skeletal malformations.
When pregnant rats received oral acetaminophen throughout gestation at doses of 1.9-times the MHDD (based on a body surface area comparison), areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses. These effects did not occur in animals that received oral acetaminophen at doses 0.5-times the MHDD, based on a body surface area comparison.
In a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day). These doses are approximately 0.7, 1.3, and 2.7 times the MHDD, respectively, based on a body surface area comparison. A dose-related reduction in body weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at all doses. Animals in the high dose group had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next generation pups.
ULTRACET is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.
Tramadol and its metabolite, O-desmethyltramadol (M1), are present in human milk. There is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. The M1 metabolite is more potent than tramadol in mu opioid receptor binding [see Clinical Pharmacology (12.1)]. Published studies have reported tramadol and M1 in colostrum with administration of tramadol to nursing mothers in the early post-partum period. Women who are ultra-rapid metabolizers of tramadol may have higher than expected serum levels of M1, potentially leading to higher levels of M1 in breast milk that can be dangerous in their breastfed infants. In women with normal tramadol metabolism, the amount of tramadol secreted into human milk is low and dose-dependent. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with ULTRACET.
If infants are exposed to ULTRACET through breast milk, they 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.
Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post dose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.
Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].
The safety and effectiveness of ULTRACET in pediatric patients have not been established.
Life-threatening respiratory depression and death have occurred in children who received tramadol [see Warnings and Precautions (5.4)]. In some of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and one of the children had evidence of being an ultra-rapid metabolizer of tramadol (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6). 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:
Elderly patients (65 years of age or older) may have increased sensitivity to tramadol. 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 ULTRACET slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.3)].
Tramadol 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.
The pharmacokinetics and tolerability of ULTRACET in patients with renal impairment has not been studied. Based on studies using tramadol extended-release tablets, the excretion of tramadol and metabolite M1 is reduced in patients with creatinine clearance of less than 30 mL/min. In patients with creatinine clearances of less than 30 mL/min, it is recommended that the dosage of ULTRACET not exceed 2 tablets every 12 hours [see Dosage and Administration (2.3)]. The total amount of tramadol and M1 removed during a 4 hour dialysis period is less than 7% of the administered dose based on studies using tramadol alone. Monitor closely for signs of respiratory depression, sedation, and hypotension.
The pharmacokinetics and tolerability of ULTRACET in patients with impaired hepatic function have not been studied. Based on information using tramadol immediate-release tablets in subjects with advanced cirrhosis of the liver, tramadol exposure was higher and half-lives of tramadol and active metabolite M1 were longer than in subjects with normal hepatic function [see Clinical Pharmacology (12.3)].
As tramadol and acetaminophen are both extensively metabolized by the liver, the use of ULTRACET in patients with hepatic impairment is not recommended [see Warnings and Precautions (5.7)].
Tramadol clearance was 20% higher in female subjects compared to males in four Phase 1 studies of ULTRACET in 50 male and 34 female healthy subjects. The clinical significance of this difference is unknown.
ULTRACET contains tramadol, a Schedule IV controlled substance.
ULTRACET contains tramadol, a substance with a high potential for abuse similar to other opioids and can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].
All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful, or potentially harmful, consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug seeking” behavior is very common in persons with substance use disorders. Drug seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
ULTRACET, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
ULTRACET is for oral use only. Abuse of ULTRACET poses a risk of overdose and death. The risk is increased with concurrent abuse of ULTRACET with alcohol and other central nervous system depressants.
Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
Do not abruptly discontinue ULTRACET in a patient physically dependent on opioids. Rapid tapering of ULTRACET in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain and suicide.
Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.
When discontinuing opioids, gradually taper the dosage using a patient-specific plan that considers the following: the dose of the opioid the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), Warnings and Precautions (5.20)].
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].
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