Data from FDA - Curated by EPG Health - Last updated 05 July 2018

Indication(s)

INDICATIONS AND USAGE Tramadol Hydrochloride Tablets, USP are indicated for the management of pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses (see WARNINGS ), reserve tramadol for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: Have not been tolerated, or are not expected to be tolerated. Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

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Advisory information

contraindications
CONTRAINDICATIONS Tramadol hydrochloride tablets are contraindicated for: all children younger than 12 years of age (see WARNINGS ) post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (see WARNINGS ). Tramadol Hydrochloride Tablets are also contraindicated in patients with: Significant respiratory depression (see WARNINGS ). Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (see WARNINGS ). Known or suspected gastrointestinal obstruction, including paralytic ileus (see WARNINGS ). Hypersensitivity to tramadol, any other component of this product or opioids (see WARNINGS ). Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (see PRECAUTIONS; Drug Interactions ).
Special warnings and precautions
PRECAUTIONS 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 DOSAGE AND ADMINISTRATION ). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION ). 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 tramadol, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death (see WARNINGS ). Instruct patients not to share tramadol with others and to take steps to protect tramadol 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 tramadol or when the dosage is increased, and that it can occur even at recommended dosages (see WARNINGS ). 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 WARNINGS ). Instruct patients to take steps to store tramadol securely and to dispose of unused tramadol 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 tramadol 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 tramadol to monitor for signs of respiratory depression (see WARNINGS ). Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if tramadol is used with benzodiazepines, CNS depressants, including alcohol, or some illicit drugs and not to use these concomitantly unless supervised by a health care provider (see WARNINGS, PRECAUTIONS; Drug Interactions ). 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 WARNINGS ). MAOI Interaction Inform patients not to take tramadol while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking tramadol (see PRECAUTIONS: Drug Interactions ). Seizures Inform patients that tramadol 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 WARNINGS ). 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 WARNINGS ). Important Administration Instructions Instruct patients how to properly take tramadol. (see DOSAGE AND ADMINISTRATION, WARNINGS ) Advise patients not to adjust the dose of tramadol without consulting with a physician or other healthcare professional. If patients have been receiving treatment with tramadol for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose as abrupt discontinuation of the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication (see DOSAGE AND ADMINISTRATION ). Hypotension Inform patients that tramadol 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 WARNINGS ). Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in tramadol. Advise patients how to recognize such a reaction and when to seek medical attention (see CONTRAINDICATIONS, ADVERSE REACTIONS ). Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of tramadol during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated and that the patient should inform their healthcare provider if they have used opioids at any time during their pregnancy, especially near the time of birth. (see WARNINGS, PRECAUTIONS; Labor or Delivery ). Embryo-Fetal Toxicity Inform female patients of reproductive potential that tramadol may cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy (see PRECAUTONS; Pregnancy ) . Lactation Advise women that breastfeeding is not recommended during treatment with tramadol (see PRECAUTIONS; Nursing Mothers ). Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible (see PRECAUTIONS ). Driving or Operating Heavy Machinery Inform patients that tramadol 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 WARNINGS ). Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (see ADVERSE REACTIONS ). Disposal of Unused Tramadol Advise patients to throw the unused tramadol 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 DOSAGE AND ADMINISTRATION; WARNINGS ). Drug Interactions Inhibitors of CYP2D6 The concomitant use of tramadol 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 tramadol 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 ) 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 tramadol 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 tramadol 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 tramadol 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 tramadol is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease (see CLINICAL PHARMACOLOGY ), 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 tramadol 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 tramadol dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. CYP3A4 Inducers The concomitant use of tramadol 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 WARNINGS ). 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 tramadol 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 WARNINGS ). 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 tramadol immediately if serotonin syndrome is suspected. Monoamine Oxidase Inhibitors (MAOIs) Do not use tramadol in patients taking MAOIs or within 14 days of stopping such treatment. MAOI interactions with opioids may manifest as serotonin syndrome (see WARNINGS ) or opioid toxicity (e.g., respiratory depression, coma) (see WARNINGS ). 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 tramadol 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 tramadol 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 tramadol 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 in vitro bacterial reverse mutation assay using Salmonella and E. coli (Ames), the mouse lymphoma assay in the absence of metabolic activation, the in vitro chromosomal aberration assay, or the in vivo 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 tramadol 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 Data]. 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 to 4% and 15 to 20%, respectively. Clinical Considerations Neonatal Adverse Reactions 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 can present 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 ). Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing. Labor or Delivery Tramadol 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 tramadol, 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 tramadol, if any, on the later growth, development, and functional maturation of the child is unknown. Data Animal Data 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 1.4, 0.6, and 3.6 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, decreased 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 1.7, 1.9 and 14.6 times the MRHD, respectively. Tramadol was evaluated in pre- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg 1.2 times the MRHD) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (1.9 times the MRHD). Nursing Mothers Risk Summary Tramadol 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) . 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 tramadol (see WARNINGS ). Clinical Considerations If infants are exposed to tramadol 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 breastfeeding 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 Infertility 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 ADVERSE REACTIONS ). Pediatric Use The safety and effectiveness of tramadol in pediatric patients have not been established. Life-threatening respiratory depression and death have occurred in children who received tramadol (see WARNINGS ). 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: Tramadol is contraindicated for all children younger than 12 years of age (see CONTRAINDICATIONS ). Tramadol is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy (see CONTRAINDICATIONS ). Avoid the use of tramadol 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. Geriatric Use A total of 455 elderly (65 years of age or older) subjects were exposed to tramadol 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 coadministered with other agents that depress respiration. Titrate the dosage of tramadol slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression (see WARNINGS ). 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.
Adverse reactions
ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse (see WARNINGS ) Life-Threatening Respiratory Depression (see WARNINGS ) Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children (see WARNINGS ) Neonatal Opioid Withdrawal Syndrome (see WARNINGS ) Interactions with Benzodiazepines or Other CNS Depressants (see WARNINGS ) Serotonin Syndrome (see WARNINGS ) Seizures (see WARNINGS ) Suicide (see WARNINGS ) Adrenal Insufficiency (see WARNINGS ) Severe Hypotension (see WARNINGS ) Gastrointestinal Adverse Reactions (see WARNINGS ) Hypersensitivity Reactions (see WARNINGS ) Withdrawal (see WARNINGS ) 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. Tramadol 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 tramadol 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 tramadol 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 tramadol groups. Table 2:Cumulative Incidence of Adverse Reactions for tramadol in Chronic Trials of Nonmalignant Pain (N=427) 1 “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations 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”1 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 tramadol exists. Body as a Whole: Malaise. Cardiovascular: Vasodilation. Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder. Gastrointestinal: Abdominal pain, Anorexia, Flatulence. Musculoskeletal: Hypertonia. Skin: Rash. Special Senses: Visual disturbance. Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention. 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: Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma). Cardiovascular: Orthostatic hypotension, Syncope, Tachycardia. Central Nervous System: Abnormal gait, Amnesia, Cognitive dysfunction, Delirium, Depression, Difficulty in concentration, Hallucinations, Movement disorder, Paresthesia, Seizure, Speech disorder, Tremor. Metabolism and Nutrition Disorders: Cases of hypoglycemia have been reported very rarely in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients. Respiratory: Dyspnea. Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles. Special Senses: Dysgeusia, Mydriasis. Urogenital: Dysuria, Menstrual disorder. Other adverse experiences, causal relationship unknown: A variety of other adverse events were reported infrequently in patients taking tramadol during clinical trials and/or reported in post-marketing experience. A causal relationship between tramadol and these events has not been determined. However, the most significant events are listed below as alerting information to the physician. Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism. Central Nervous System: Migraine. Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure. Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria. Sensory: Cataracts, Deafness, Tinnitus. 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 CLINICAL PHARMACOLOGY ). 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.

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION Adults (17 years of age and over) Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse (see WARNINGS ). Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with tramadol hydrochloride tablets and adjust the dosage accordingly (see WARNINGS ). Initial Dosage Initiating Treatment with tramadol hydrochloride tablets For patients with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect, the tolerability of tramadol hydrochloride tablets can be improved by initiating therapy with the following titration regimen: the total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg four times a day). After titration, tramadol hydrochloride tablets 50 to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg/day. For the subset of patients for whom rapid onset of analgesic effect is required and for whom the benefits outweigh the risk of discontinuation due to adverse events associated with higher initial doses, tramadol hydrochloride tablets 50 mg to 100 mg can be administered as needed for pain relief every four to six hours, not to exceed 400 mg per day. Conversion from tramadol hydrochloride tablets to Extended-Release tramadol The relative bioavailability of tramadol hydrochloride tablets compared to extended-release tramadol is unknown, so conversion to extended-release formulations must be accompanied by close observation for signs of excessive sedation and respiratory depression. Dosage Modification in Patients with Hepatic Impairment The recommended dose for adult patients with cirrhosis is 50 mg every 12 hours. Dosage Modification in Patients with Renal Impairment In all patients with creatinine clearance less than 30 mL/min, it is recommended that the dosing interval of tramadol hydrochloride tablets be increased to 12 hours, with a maximum daily dose of 200 mg. Since only 7% of an administered dose is removed by hemodialysis, dialysis patients can receive their regular dose on the day of dialysis. Dosage Modification in Geriatric Patients In general, dose selection for an elderly patient over 65 years old should be cautious, 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. For elderly patients over 75 years old, total dose should not exceed 300 mg/day. Titration and Maintenance of Therapy Individually titrate tramadol hydrochloride tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving tramadol hydrochloride tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse (see WARNINGS ). Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the tramadol hydrochloride tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. Discontinuation of tramadol hydrochloride tablets When a patient who has been taking tramadol hydrochloride tablets regularly and may be physically dependent no longer requires therapy with tramadol hydrochloride tablets, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue tramadol hydrochloride tablets in a physically-dependent patient. (see WARNINGS; Drug Abuse and Dependence ).
Pregnancy and lactation
Nursing Mothers Risk Summary Tramadol 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) . 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 tramadol (see WARNINGS ). Clinical Considerations If infants are exposed to tramadol 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 breastfeeding 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.

Interactions

Drug Interactions Inhibitors of CYP2D6 The concomitant use of tramadol 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 tramadol 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 ) 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 tramadol 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 tramadol 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 tramadol 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 tramadol is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease (see CLINICAL PHARMACOLOGY ), 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 tramadol 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 tramadol dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. CYP3A4 Inducers The concomitant use of tramadol 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 WARNINGS ). 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 tramadol 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 WARNINGS ). 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 tramadol immediately if serotonin syndrome is suspected. Monoamine Oxidase Inhibitors (MAOIs) Do not use tramadol in patients taking MAOIs or within 14 days of stopping such treatment. MAOI interactions with opioids may manifest as serotonin syndrome (see WARNINGS ) or opioid toxicity (e.g., respiratory depression, coma) (see WARNINGS ). 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 tramadol 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 tramadol 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 tramadol is used concomitantly with anticholinergic drugs.

More information

Category Value
Authorisation number ANDA090404
Agency product number 9N7R477WCK
Orphan designation No
Product NDC 60760-319
Date Last Revised 28-06-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder St. Mary's Medical Park Pharmacy
Warnings BOXED WARNING ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN;NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS ADDICTION, ABUSE AND MISUSE Tramadol exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing tramadol, and monitor all patients regularly for the development of these behaviors and conditions (see WARNINGS). LIFE-THREATENING RESPIRATORY DEPRESSION Serious, life-threatening, or fatal respiratory depression may occur with use of tramadol. Monitor for respiratory depression, especially during initiation of tramadol or following a dose increase (see WARNINGS). ACCIDENTAL INGESTION Accidental ingestion of tramadol, especially by children, can be fatal. (see WARNINGS). ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism (see WARNINGS). Tramadol is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (see CONTRAINDICATIONS). Avoid the use of tramadol 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 (see WARNINGS). NEONATAL OPIOID WITHDRAWAL SYNDROME Prolonged use of tramadol during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see WARNINGS). INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Tramadol requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 (see WARNINGS, PRECAUTIONS; Drug Interactions). RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (see WARNINGS, PRECAUTIONS; Drug Interactions). Reserve concomitant prescribing of tramadol and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit treatment to the minimum effective dosages and durations. Follow patients for signs and symptoms of respiratory depression and sedation.