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tramadol hydrochloride
Overview
What is ULTRAM?
ULTRAM (tramadol hydrochloride) tablets are an opioid agonist. The chemical name for tramadol hydrochloride is (±)
-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. The structural formula is:
The molecular weight of tramadol hydrochloride is 299.8. Tramadol hydrochloride is a white, bitter, crystalline and odorless powder. It is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7. ULTRAM tablets contain 50 mg of tramadol hydrochloride and are white in color. Inactive ingredients in the tablet are pregelatinized corn starch, modified starch (corn), hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and carnauba wax.
What does ULTRAM look like?
What are the available doses of ULTRAM?
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What should I talk to my health care provider before I take ULTRAM?
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How should I use ULTRAM?
ULTRAM is indicated for the management of pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
What interacts with ULTRAM?
- ULTRAM is contraindicated for:
- ULTRAM is also contraindicated in patients with:
What are the warnings of ULTRAM?
Addiction, Abuse, and Misuse
ULTRAM contains tramadol, a Schedule IV controlled substance. As an opioid, ULTRAM exposes users to the risks of addiction, abuse, and misuse (see
).
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed ULTRAM. 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 ULTRAM, and monitor all patients receiving ULTRAM 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 ULTRAM, but use in such patients necessitates intensive counseling about the risks and proper use of ULTRAM along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing ULTRAM. 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
. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status (see
). Carbon dioxide (CO
) 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 ULTRAM, 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 ULTRAM.
To reduce the risk of respiratory depression, proper dosing and titration of ULTRAM are essential (see
). Overestimating the ULTRAM 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 ULTRAM, especially by children, can result in respiratory depression and death due to an overdose of tramadol.
Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children
- ULTRAM is contraindicated for all children younger than 12 years of age (see ).
- ULTRAM is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy (see ).
- Avoid the use of ULTRAM in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
- As with adults, when prescribing opioids for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of opioid overdose (see ).
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:
Nursing Mothers
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 the active metabolite -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 ULTRAM 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 ULTRAM (see ).
CYP2D6 Genetic Variability: Ultra-rapid metabolizer
Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., 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, -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 ). Therefore, individuals who are ultra-rapid metabolizers should not use ULTRAM.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of ULTRAM 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 ).
Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes
The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from ULTRAM are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with ULTRAM 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 ).
Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors
The concomitant use of ULTRAM 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 ULTRAM 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 ULTRAM is used in conjunction with inhibitors of CYP2D6 (see ).
Cytochrome P450 3A4 Interaction
The concomitant use of ULTRAM 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 ULTRAM 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 ULTRAM 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 ULTRAM is used in conjunction with inhibitors and inducers of CYP3A4 (see ).
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTRAM 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 ).
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when ULTRAM 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 ).
Serotonin Syndrome Risk
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, particularly 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), 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 ). 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 ULTRAM if serotonin syndrome is suspected.
Increased Risk of Seizure
- Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics),
- Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or
- Other opioids,
- MAO inhibitors (see also ),
- Neuroleptics, or
- Other drugs that reduce the seizure threshold.
Seizures have been reported in patients receiving ULTRAM within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of ULTRAM above the recommended range. Concomitant use of ULTRAM increases the seizure risk in patients taking:
Risk of seizure 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 ULTRAM overdose, naloxone administration may increase the risk of seizure.
Suicide Risk
- Do not prescribe ULTRAM for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed. (see ).
- Prescribe ULTRAM Tablets with caution for patients with a history of misuse and/or are currently taking CNS-active drugs including tranquilizers or antidepressant drugs, alcohol in excess, and patients who suffer from emotional disturbance or depression (see ).
- Inform patients not to exceed the recommended dose and to limit their intake of alcohol (see ).
Adrenal Insufficiency
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of ULTRAM in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
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Monitor such patients closely, particularly when initiating and titrating ULTRAM and when ULTRAM is given concomitantly with other drugs that depress respiration (see ). Alternatively, consider the use of non-opioid analgesics in these patients.
Severe Hypotension
ULTRAM 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 ). Monitor these patients for signs of hypotension after initiating or titrating the dosage of ULTRAM. In patients with circulatory shock, ULTRAM may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ULTRAM in patients with circulatory shock.
Risks of use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
In patients who may be susceptible to the intracranial effects of CO retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ULTRAM may reduce respiratory drive, and the resultant CO retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ULTRAM.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of ULTRAM in patients with impaired consciousness or coma.
Risks of use in Patients with Gastrointestinal Conditions
ULTRAM is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus (see ).
The tramadol in ULTRAM 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.
Anaphylaxis and Other Hypersensitivity Reactions
Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with ULTRAM. 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 ULTRAM (see ). If anaphylaxis or other hypersensitivity occurs, stop administration of ULTRAM immediately, discontinue ULTRAM 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 )
Withdrawal
Avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including ULTRAM. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.
When discontinuing ULTRAM in a physically-dependent patient, gradually taper the dosage (see ). Do not abruptly discontinue ULTRAM in these patients (see ).
Risks of Driving and Operating Machinery
ULTRAM 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 ULTRAM and know how they will react to the medication.
What are the precautions of ULTRAM?
Renal and Hepatic Disease
Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, dosing reduction is recommended (see
). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended (see
).
With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.
Information for Patients
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Addiction, Abuse, and Misuse
Inform patients that the use of ULTRAM, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death (see
). Instruct patients not to share ULTRAM with others and to take steps to protect ULTRAM from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting ULTRAM or when the dosage is increased, and that it can occur even at recommended dosages (see
). Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Accidental Ingestion
Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death (see
). Instruct patients to take steps to store ULTRAM securely and to dispose of unused ULTRAM in accordance with the local state guidelines and/or regulations.
Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children
Advise caregivers that ULTRAM is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children ages 12 to 18 years of age receiving ULTRAM to monitor for signs of respiratory depression (see
).
Interactions with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if ULTRAM is used with benzodiazepines, CNS depressants, including alcohol, or some illicit drugs and not to use these concomitantly unless supervised by a healthcare provider (see
).
Serotonin Syndrome
Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome, and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications (see
).
MAOI Interaction
Inform patients not to take ULTRAM while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking ULTRAM (see
).
Seizures
Inform patients that ULTRAM may cause seizures with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol (see
).
Adrenal Insufficiency
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms (see
).
Important Administration Instructions
Instruct patients how to properly take ULTRAM. (see
)
Hypotension
Inform patients that ULTRAM may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) (see
).
Anaphylaxis
Inform patients that anaphylaxis has been reported with ingredients contained in ULTRAM. Advise patients how to recognize such a reaction and when to seek medical attention (see
).
Pregnancy
Lactation
Advise women that breastfeeding is not recommended during treatment with ULTRAM (see
).
Infertility
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible (see
).
Driving or Operating Heavy Machinery
Inform patients that ULTRAM may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication (see
).
Constipation
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (see
).
Disposal of Unused ULTRAM
Advise patients to throw the unused ULTRAM in the household trash following these steps. 1) Remove the drugs from their original containers and mix with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs). 2) Place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or breaking out of a garbage bag.
Maximum single-dose and 24-hour dose
Advise patients not to exceed the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures and death (see
).
Drug Interactions
Inhibitors of CYP2D6
The concomitant use of ULTRAM and CYP2D6 inhibitors, such as quinidine, fluoxetine, paroxetine and bupropion, 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 ULTRAM 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
)
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 ULTRAM dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Use With Quinidine
Quinidine is a selective inhibitor of CYP2D6, so that concomitant administration of quinidine and ULTRAM results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown.
Inhibitors of CYP3A4
The concomitant use of ULTRAM and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), 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 a CYP3A4 inhibitor is added after a stable dose of ULTRAM is achieved.
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease (see
), resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to tramadol.
If concomitant use is necessary, consider dosage reduction of ULTRAM 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 ULTRAM dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
CYP3A4 Inducers
The concomitant use of ULTRAM and CYP3A4 inducers, such as rifampin, carbamazepine and phenytoin, can decrease the plasma concentration of tramadol resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol (see
).
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression.
Use With Carbamazepine
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 ULTRAM and carbamazepine is not recommended.
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Examples of other CNS depressants include other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, and some illicit drugs.
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit the treatment to the minimum effective dosages and durations. Follow patients closely for signs of respiratory depression and sedation (see
).
Serotonergic Drugs
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Examples of these drugs include, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone), monoamine oxidase (MAO) inhibitors (used to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ULTRAM immediately if serotonin syndrome is suspected.
Monoamine Oxidase Inhibitors (MAOIs)
Do not use ULTRAM in patients taking MAOIs or within 14 days of stopping such treatment.
MAOI interactions with opioids may manifest as serotonin syndrome (see
) or opioid toxicity (e.g., respiratory depression, coma) (see
). Examples of these drugs include, phenelzine, tranylcypromine, linezolid.
Digoxin
Post-marketing surveillance has revealed rare reports of digoxin toxicity. Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times. Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Mixed agonist/antagonist and partial agonist opioid analgesics may reduce the analgesic effect of ULTRAM and/or precipitate withdrawal symptoms. Examples of these drugs include butorphanol, nalbuphine, pentazocine and buprenorphine. Avoid concomitant use of these drugs.
Muscle Relaxants
Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of ULTRAM and/or the muscle relaxant as necessary.
Diuretics
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when ULTRAM is used concomitantly with anticholinergic drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in an NMRI mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg in the drinking water (0.36 times the maximum recommended human daily dosage or MRHD) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No evidence of carcinogenicity was noted in a rat 2-year carcinogenicity study testing oral doses of up to 30 mg/kg in the drinking water, 0.73 times the MRHD).
Mutagenesis
Tramadol was mutagenic in the presence of metabolic activation in the mouse lymphoma assay. Tramadol was not mutagenic in the
bacterial reverse mutation assay using
and
(Ames), the mouse lymphoma assay in the absence of metabolic activation, the
chromosomal aberration assay, or the
micronucleus assay in bone marrow.
Impairment of Fertility
No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats. These dosages are 1.2 and 1.8 times the maximum recommended human daily dose based on body surface area, respectively.
Pregnancy
Risk Summary
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with ULTRAM in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.
In animal reproduction studies, tramadol administration 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 [see
]. Based on animal data, advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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.
Clinical Considerations
Labor or Delivery
ULTRAM 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 induce dependency of the fetus, acute respiratory depression in the newborn and/or psycho-physiologic effects associated with opioid exposure and withdrawal. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Monitor newborns exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
Use of opioid analgesics, including ULTRAM, may impact the duration of labor due to inhibitory actions on uterine contractions or facilitatory actions on cervical dilation.
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 ULTRAM, if any, on the later growth, development, and functional maturation of the child is unknown.
Nursing Mothers
Risk Summary
ULTRAM 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,
-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
. 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 ULTRAM (see
).
Clinical Considerations
If infants are exposed to ULTRAM 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.
Data
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.
Females and Males of Reproductive Potential
Due to effects of androgen deficiency, 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
).
Pediatric Use
- ULTRAM is contraindicated for all children younger than 12 years of age (see ).
- ULTRAM is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy (see ).
- Avoid the use of ULTRAM in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
The safety and effectiveness of ULTRAM in pediatric patients have not been established.
Life-threatening respiratory depression and death have occurred in children who received tramadol (see ). 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:
Geriatric Use
A total of 455 elderly (65 years of age or older) subjects were exposed to ULTRAM in controlled clinical trials. Of those, 145 subjects were 75 years of age and older.
In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.
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 ULTRAM slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression (see ).
Tramadol is 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.
What are the side effects of ULTRAM?
The following serious adverse reactions are described, or described in greater detail, in other sections:
Clinical Trials Experience
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.
ULTRAM was administered to 550 patients during the double-blind or open-label extension periods in U.S. studies of chronic nonmalignant pain. Of these patients, 375 were 65 years old or older. Table 2 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. Although the reactions listed in the table are felt to be probably related to ULTRAM administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication. The overall incidence rates of adverse experiences in these trials were similar for ULTRAM and the active control groups, TYLENOL with Codeine #3 (acetaminophen 300 mg with codeine phosphate 30 mg), and aspirin 325 mg with codeine phosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the ULTRAM groups.
| Up to 7 Days | Up to 30 Days | Up to 90 Days | |
|---|---|---|---|
| Dizziness/Vertigo | 26% | 31% | 33% |
| Nausea | 24% | 34% | 40% |
| Constipation | 24% | 38% | 46% |
| Headache | 18% | 26% | 32% |
| Somnolence | 16% | 23% | 25% |
| Vomiting | 9% | 13% | 17% |
| Pruritus | 8% | 10% | 11% |
| "CNS Stimulation" | 7% | 11% | 14% |
| Asthenia | 6% | 11% | 12% |
| Sweating | 6% | 7% | 9% |
| Dyspepsia | 5% | 9% | 13% |
| Dry Mouth | 5% | 9% | 10% |
| Diarrhea | 5% | 6% | 10% |
Incidence 1% to less than 5% possibly causally related
The following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with ULTRAM exists.
Body as a Whole:
Cardiovascular:
Central Nervous System:
Gastrointestinal:
Musculoskeletal:
Skin:
Special Senses:
Urogenital:
Incidence less than 1%, possibly causally related
The following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials of tramadol and/or reported in post-marketing experience with tramadol-containing products.
Body as a Whole:
Cardiovascular:
Central Nervous System:
Metabolism and Nutrition Disorders:
Respiratory:
Skin:
Special Senses:
Urogenital:
Other adverse experiences, causal relationship unknown
A variety of other adverse events were reported infrequently in patients taking ULTRAM during clinical trials and/or reported in post-marketing experience. A causal relationship between ULTRAM and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.
Cardiovascular:
Central Nervous System:
Gastrointestinal:
Laboratory Abnormalities:
Sensory:
Postmarketing Experience
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.
Androgen deficiency
Cases of androgen deficiency have occurred with chronic use of opioids (see ).
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.
- Addiction, Abuse, and Misuse (see )
- Life-Threatening Respiratory Depression (see )
- Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children (see )
- Neonatal Opioid Withdrawal Syndrome (see )
- Interactions with Benzodiazepines or Other CNS Depressants (see )
- Serotonin Syndrome (see )
- Seizures (see )
- Suicide (see )
- Adrenal Insufficiency (see )
- Severe Hypotension (see )
- Gastrointestinal Adverse Reactions (see )
- Hypersensitivity Reactions (see )
- Withdrawal (see )
What should I look out for while using ULTRAM?
ULTRAM is contraindicated for:
ULTRAM is also contraindicated in patients with:
What might happen if I take too much ULTRAM?
How should I store and handle ULTRAM?
Store lyophilized Activase at controlled room temperature not to exceed 30°C (86°F), or under refrigeration (2-8°C/36-46°F). Protect the lyophilized material during extended storage from excessive exposure to light. If stored between 2-30°C (36-86°F), Activase may be used within 8 hours following reconstitution. Discard any unused solution after administration is complete.Do not use beyond the expiration date stamped on the vial.Store lyophilized Activase at controlled room temperature not to exceed 30°C (86°F), or under refrigeration (2-8°C/36-46°F). Protect the lyophilized material during extended storage from excessive exposure to light. If stored between 2-30°C (36-86°F), Activase may be used within 8 hours following reconstitution. Discard any unused solution after administration is complete.Do not use beyond the expiration date stamped on the vial.ULTRAM (tramadol hydrochloride) Tablets - 50 mg are white, capsule-shaped, coated tablet imprinted "ULTRAM" on one side and "06 59" on the scored side.Bottles of 15 tablets: NDC 55289-650-15ULTRAM (tramadol hydrochloride) Tablets - 50 mg are white, capsule-shaped, coated tablet imprinted "ULTRAM" on one side and "06 59" on the scored side.Bottles of 15 tablets: NDC 55289-650-15
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
ULTRAM contains tramadol, an opioid agonist and inhibitor of norepinephrine and serotonin re-uptake. Although the mode of action is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to µ-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin.
Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the
-demethylated metabolite M1 to µ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see
).
Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin
as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.
Non-Clinical Toxicology
ULTRAM is contraindicated for:ULTRAM is also contraindicated in patients with:
Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, dosing reduction is recommended (see ). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended (see ).
With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.
The following serious adverse reactions are described, or described in greater detail, in other sections:
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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