Data from FDA - Curated by EPG Health - Last updated 21 April 2018

Indication(s)

1 INDICATIONS AND USAGE Tramadol Hydrochloride Extended-Release Capsules are indicated for the management of pain severe enough to require daily, around-the-clock, long term opioid treatment and for which alternative treatment options are inadequate. Limitation of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations [see Warnings and Precautions ( 5.1)] , reserve Tramadol Hydrochloride Extended-Release Capsules for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Tramadol Hydrochloride Extended-Release Capsules are not indicated as an as-needed (prn) analgesic. Tramadol Hydrochloride Extended-Release Capsules are an opioid agonist indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. ( 1) Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve Tramadol Hydrochloride Extended-Release Capsules for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1) Tramadol Hydrochloride Extended-Release Capsules are not indicated as an as-needed (prn) analgesic. ( 1)

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Advisory information

contraindications
4 CONTRAINDICATIONS Tramadol Hydrochloride Extended-Release Capsules are contraindicated for: all children younger than 12 years of age [ see Warnings and Precautions ( 5.3)] post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see Warnings and Precautions ( 5.3) ]. Tramadol Hydrochloride Extended-Release Capsules are also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.2)] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.11)] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.14)] Hypersensitivity to tramadol (e.g., anaphylaxis) [see Warnings and Precautions ( 5.15), Adverse Reactions ( 6)] Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days [see Drug Interactions ( 7)] Children younger than 12 years of age. ( 4) Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. ( 4) Significant respiratory depression. ( 4) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4) Hypersensitivity to tramadol. ( 4) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days. ( 4)
Adverse reactions
6 ADVERSE REACTIONS The following serious or otherwise important adverse reactions are described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1)] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2)] Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions ( 5.3)] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4)] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.6)] Serotonin Syndrome [see Warnings and Precautions ( 5.7)] Seizures [see Warnings and Precautions ( 5.8)] Suicide [see Warnings and Precautions ( 5.9)] Adrenal Insufficiency [ see Warnings and Precautions ( 5.10)] Severe Hypotension [see Warnings and Precautions ( 5.12)] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.14)] Hypersensitivity Reactions [see Warnings and Precautions ( 5.15)] Withdrawal [see Warnings and Precautions ( 5.16)] Most common adverse reactions (incidence ≥ 10% and twice placebo) are nausea, constipation, dry mouth, somnolence, dizziness, and vomiting. ( 6) To report SUSPECTED ADVERSE REACTIONS, contact Trigen Laboratories, LLC at (888) 987-4436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 Hydrochloride Extended-Release Capsules were administered to a total of 1987 patients in clinical trials. These included four double-blind and one long-term, open-label study in patients with osteoarthritis of the hip and knee. A total of 812 patients were 65 years or older. Adverse reactions with doses from 100 mg to 300 mg in the four pooled, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain are presented in the following table (see Table 1). Table 1: Incidence (%) of patients with adverse reaction rates ≥ 5% from four double-blind, placebo controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1917). TRAMADOL HYDROCHLORIDE EXTENDED-RELEASE CAPSULES PLACEBO Preferred Term 100 mg (N=429) n (%) 200 mg (N=434) n (%) 300 mg (N=1054) n (%) (N=646) n (%) Headache 99 (23.1) 96 (22.1) 200 (19.0) 128 (19.8) Nausea 69 (16.1) 93 (21.4) 265 (25.1) 37 (5.7) Somnolence 50 (11.7) 60 (13.8) 170 (16.1) 26 (4.0) Dizziness 41 (9.6) 54 (12.4) 143 (13.6) 31 (4.8) Constipation 40 (9.3) 59 (13.6) 225 (21.3) 27 (4.2) Vomiting 28 (6.5) 45 (10.4) 98 (9.3) 12 (1.9) Arthralgia 23 (5.4) 20 (4.6) 53 (5.0) 33 (5.1) Dry Mouth 20 (4.7) 36 (8.3) 138 (13.1) 22 (3.4) Sweating 18 (4.2) 23 (5.3) 71 (6.7) 4 (0.6) Asthenia 15 (3.5) 26 (6.0) 91 (8.6) 17 (2.6) Pruritus 13 (3.0) 25 (5.8) 77 (7.3) 12 (1.9) Anorexia 9 (2.1) 23 (5.3) 60 (5.7) 1 (0.2) Insomnia 9 (2.1) 9 (2.1) 53 (5.0) 11 (1.7) The following adverse reactions were reported from all chronic pain studies (N=1917). The lists below include adverse reactions not otherwise noted in Table 1. Adverse reactions with incidence rates of 1.0% to <5.0% Cardiac disorders: hypertension Gastrointestinal disorders: dyspepsia, flatulence General disorders: abdominal pain, accidental injury, chills, fever, flu syndrome, neck pain, pelvic pain Investigations: hyperglycemia, urine abnormality Metabolism and nutrition disorders: peripheral edema, weight loss Musculoskeletal, connective tissue and bone disorders: myalgia Nervous system disorders: paresthesia, tremor, withdrawal syndrome Psychiatric disorders: agitation, anxiety, apathy, confusion, depersonalization, depression, euphoria, nervousness Respiratory, thoracic and mediastinal disorders: bronchitis, pharyngitis, rhinitis, sinusitis Skin and subcutaneous tissue disorders: rash Urogenital disorders: prostatic disorder, urinary tract infection Vascular disorders: vasodilatation Adverse reactions with incidence rates of 0.5% to <1.0% at any dose and serious adverse reactions reported in at least two patients. Cardiac disorders: EKG abnormal, hypotension, tachycardia Gastrointestinal disorders: gastroenteritis General disorders: neck rigidity, viral infection Hematologic/Lymphatic disorders; anemia, ecchymoses Metabolism and nutrition disorders: blood urea nitrogen increased, GGT increased, gout, SGPT increased Musculoskeletal disorders: arthritis, arthrosis, joint disorder, leg cramps Nervous system disorders: emotional lability, hyperkinesia, hypertonia, thinking abnormal, twitching, vertigo Respiratory disorders: pneumonia Skin and subcutaneous tissue disorders: hair disorder, skin disorder, urticaria Special Senses: eye disorder, lacrimation disorder Urogenital disorders: cystitis, dysuria, sexual function abnormality, urinary retention 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of tramadol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Tramadol Hydrochloride Extended-Release Capsules. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2)] . QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use. Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in overdose setting.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION To be prescribed only by healthcare providers knowledgeable in use of potent opioids for management of chronic pain. ( 2.1) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. ( 2.1) Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1) Do not exceed a daily dose of 300 mg tramadol. Do not use with other tramadol products. (2.1) For opioid-naïve and opioid non-tolerant patients, Initiate Tramadol Hydrochloride Extended-Release Capsules at a dose of 100 mg once daily, then titrate up by 100 mg increments every 5 days according to need and tolerance. ( 2.2) For patients currently on tramadol IR: Calculate total 24-hr IR dose, and initiate Tramadol Hydrochloride Extended-Release Capsules at a dose rounded down to next lower 100 mg increment; then adjust dose according to need and tolerance. See full prescribing information for instructions on conversion, titration, and maintenance of therapy. ( 2.2, 2.3) Do not abruptly discontinue Tramadol Hydrochloride Extended-Release Capsules in a physically-dependent patient. (2.4) 2.1 Important Dosage and Administration Instructions Tramadol Hydrochloride Extended-Release Capsules should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Do not use Tramadol Hydrochloride Extended-Release Capsules concomitantly with other tramadol products [see Warnings and Precautions ( 5.5), ( 5.13)]. Do not administer Tramadol Hydrochloride Extended-Release Capsules at a dose exceeding 300 mg per day. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Dosage and Administration ( 2.3)] . 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 and Precautions ( 5.1)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with Tramadol Hydrochloride Extended-Release Capsules and adjust the dosage accordingly [see Warnings and Precautions ( 5.2)]. Instruct patients to swallow Tramadol Hydrochloride Extended-Release Capsules whole [see Patient Counseling Information ( 17)], and to take it with liquid. Breaking, chewing, splitting, or dissolving Tramadol Hydrochloride Extended-Release Capsules will result in uncontrolled delivery of tramadol and can lead to overdose or death [see Warnings and Precautions ( 5.1)] . Tramadol Hydrochloride Extended-Release Capsules may be taken without regard to food. It is recommended that Tramadol Hydrochloride Extended-Release Capsules be taken in a consistent manner [see Clinical Pharmacology ( 12.3) ]. 2.2 Initial Dosage Patients Not Currently on a Tramadol Product The initial dose of Tramadol Hydrochloride Extended-Release Capsules are 100 mg once daily. Patients Currently on Tramadol Immediate-Release (IR) Products Calculate the 24-hour tramadol IR dose and initiate a total daily dose of Tramadol Hydrochloride Extended-Release Capsules rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with Tramadol Hydrochloride Extended-Release Capsules, some patients maintained on tramadol IR products may not be able to convert to Tramadol Hydrochloride Extended-Release Capsules. Conversion from Other Opioids to Tramadol Hydrochloride Extended-Release Capsules Discontinue all other around-the-clock opioid drugs when Tramadol Hydrochloride Extended-Release Capsules therapy is initiated. There are no established conversion ratios for conversion from other opioids to Tramadol Hydrochloride Extended-Release Capsules defined by clinical trials. Initiate dosing using Tramadol Hydrochloride Extended-Release Capsules 100 mg once a day. 2.3 Titration and Maintenance of Therapy Individually titrate Tramadol Hydrochloride Extended-Release Capsules by 100 mg every five days to a dose that provides adequate analgesia and minimizes adverse reactions. The maximum daily dose of Tramadol Hydrochloride Extended-Release Capsules 300 mg per day. Continually reevaluate patients receiving Tramadol Hydrochloride Extended-Release Capsules 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 and Precautions ( 5.1)]. 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. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics. Patients who experience breakthrough pain may require a dosage adjustment of Tramadol Hydrochloride Extended-Release Capsules, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Tramadol Hydrochloride Extended-Release Capsules 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. 2.4 Discontinuation of Tramadol Hydrochloride Extended-Release Capsules When a patient no longer requires therapy with Tramadol Hydrochloride Extended-Release Capsules, 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 doses, decreasing the amount of change in dose, or both. Do not abruptly discontinue Tramadol Hydrochloride Extended-Release Capsules [see Warnings and Precautions ( 5.16), Drug Abuse and Dependence ( 9.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1) Lactation: Breastfeeding not recommended. ( 8.2) Severe Hepatic or Renal Impairment: Use not recommended. ( 8.6, 8.7) 8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.3)]. Available data with Tramadol Hydrochloride Extended-Release Capsules 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 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity 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 of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.4)]. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported with tramadol during post-approval use of tramadol immediate-release products. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Tramadol Hydrochloride Extended-Release Capsules are not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Tramadol Hydrochloride Extended-Release Capsules can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. The effect of Tramadol Hydrochloride Extended-Release Capsules, 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/m 2 basis are 1.9, 0.8, and 4.9 times the maximum recommended human daily dosage (MRHD) for mouse, rat and rabbit, respectively. No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily of decreased fetal weights, 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 2.3, 2.6, and 19 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 (1.6 times the MRHD) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (2.6 times the MRHD). 8.2 Lactation Risk Summary Tramadol Hydrochloride Extended-Release Capsules are 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-desmethyl tramadol (M1), are present in human milk. There is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. The M1 metabolite is more potent than tramadol in mu opioid receptor binding [see Clinical Pharmacology ( 12.1)] . Published studies have reported tramadol and M1 in colostrum with administration of tramadol to nursing mothers in the early post-partum period . Women who are ultra-rapid metabolizers of tramadol may have higher than expected serum levels of M1, potentially leading to higher levels of M1 in breast milk that can be dangerous in their breastfed infants. In women with normal tramadol metabolism, the amount of tramadol secreted into human milk is low and dose-dependent. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Tramadol Hydrochloride Extended-Release Capsules. Clinical Considerations If infants are exposed to Tramadol Hydrochloride Extended-Release Capsules 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. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2), Clinical Pharmacology ( 12.2), Nonclinical Pharmacology ( 13.1)] . 8.4 Pediatric Use The safety and effectiveness of Tramadol Hydrochloride Extended-Release Capsules in pediatric patients have not been established. Life-threatening respiratory depression and death have occurred in children who received tramadol [see Warnings and Precautions ( 5.3)] . 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 Hydrochloride Extended-Release Capsules are contraindicated for all children younger than age 12 years of age [see Contraindications ( 4)] . Tramadol Hydrochloride Extended-Release Capsules are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4)] . Avoid the use of Tramadol Hydrochloride Extended-Release Capsules 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. [see Warnings and Precautions ( 5.3)] . 8.5 Geriatric Use Eight hundred and twelve elderly (65 years of age or older) subjects were exposed to Tramadol Hydrochloride Extended-Release Capsules in clinical trials. Of those subjects, two hundred and forty were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: nausea, constipation, somnolence, dizziness, dry mouth, vomiting, asthenia, pruritus, anorexia sweating, fatigue, weakness, postural hypotension and dyspepsia. For this reason, Tramadol Hydrochloride Extended-Release Capsules should be used with great caution in patients older than 75 years of age [see Dosage and Administration ( 2.3)]. 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 Tramadol Hydrochloride Extended-Release Capsules slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.2)] . 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. 8.6 Hepatic Impairment Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. Tramadol Hydrochloride Extended-Release Capsules has not been studied in patients with hepatic impairment. The limited availability of dose strengths of Tramadol Hydrochloride Extended-Release Capsules does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, Tramadol Hydrochloride Extended-Release Capsules should not be used in patients with severe hepatic impairment [see Clinical Pharmacology ( 12.3)]. 8.7 Renal Impairment Tramadol Hydrochloride Extended-Release Capsules has not been studied in patients with renal impairment. Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The limited availability of dose strengths of Tramadol Hydrochloride Extended-Release Capsules does not permit the dosing flexibility required for safe use in patients with severe renal impairment (Child-Pugh Class C). Therefore, Tramadol Hydrochloride Extended-Release Capsules should not be used in patients with severe renal impairment [see Clinical Pharmacology ( 12.3)] .
Pregnancy and lactation
8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2), Clinical Pharmacology ( 12.2), Nonclinical Pharmacology ( 13.1)] .

Interactions

7 DRUG INTERACTIONS Table 2 includes clinically significant drug interactions with Tramadol Hydrochloride Extended-Release Capsules. Table 2: Clinically Significant Drug Interactions with Tramadol Hydrochloride Extended-Release Capsules Inhibitors of CYP2D6 Clinical Impact: The concomitant use of Tramadol Hydrochloride Extended-Release Capsules and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of Tramadol Hydrochloride Extended-Release Capsules are achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology ( 12.3)] . Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering Tramadol Hydrochloride Extended-Release Capsules dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation. Examples Quinidine, fluoxetine, paroxetine and bupropion Inhibitors of CYP3A4 Clinical Impact: The concomitant use of Tramadol Hydrochloride Extended-Release Capsules and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Tramadol Hydrochloride Extended-Release Capsules are achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology ( 12.3)] , resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Intervention: If concomitant use is necessary, consider dosage reduction of Tramadol Hydrochloride Extended-Release Capsules 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 Hydrochloride Extended-Release Capsules dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of Tramadol Hydrochloride Extended-Release Capsules and CYP3A4 inducers can decrease the plasma concentration of tramadol, [see Clinical Pharmacology ( 12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions ( 5.5)] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology ( 12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression. Intervention: If concomitant use is necessary, consider increasing the Tramadol Hydrochloride Extended-Release Capsules dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Tramadol Hydrochloride Extended-Release Capsules dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of Tramadol Hydrochloride Extended-Release Capsules and carbamazepine is not recommended. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.6)] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome . Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Tramadol Hydrochloride Extended-Release Capsules if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions ( 5.8)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2)]. Intervention: Do not use Tramadol Hydrochloride Extended-Release Capsules in patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Tramadol Hydrochloride Extended-Release Capsules and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Tramadol Hydrochloride Extended-Release Capsules and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Tramadol Hydrochloride Extended-Release Capsules are used concomitantly with anticholinergic drugs. Digoxin Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity. Intervention: Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed. Warfarin Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times. Intervention: Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Tramadol Hydrochloride Extended-Release Capsules because they may reduce analgesic effect of Tramadol Hydrochloride Extended-Release Capsules or precipitate withdrawal symptoms. ( 5.16, 7)

More information

Category Value
Authorisation number NDA022370
Agency product number 9N7R477WCK
Orphan designation No
Product NDC 13811-691,13811-690,13811-689
Date Last Revised 10-04-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Trigen Laboratories, LLC
Warnings FULL PRESCRIBING INFORMATION 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 AND OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse Tramadol Hydrochloride Extended-Release Capsules 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 Hydrochloride Extended-Release Capsules and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1)] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Tramadol Hydrochloride Extended-Release Capsules. Monitor for respiratory depression, especially during initiation of Tramadol Hydrochloride Extended-Release Capsules or following a dose increase. Instruct patients to swallow Tramadol Hydrochloride Extended-Release Capsules intact, and not to split, break, chew, crush, or dissolve the contents of the capsules to avoid exposure to a potentially fatal dose of tramadol [see Warnings and Precautions ( 5.2)]. Accidental Ingestion Accidental ingestion of/exposure to even one dose of Tramadol Hydrochloride Extended-Release Capsules especially by children, can result in a fatal overdose of tramadol [see Warnings and Precautions ( 5.2)] . 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 occurred following tonsillectomy and/or adenoidectomy, and at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism [see Warnings and Precautions ( 5.3)] . Tramadol Hydrochloride Extended-Release Capsules are 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 ( 4)] . Avoid the use of Tramadol Hydrochloride Extended-Release Capsules 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 and Precautions ( 5.3)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of Tramadol Hydrochloride Extended-Release Capsules 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 and Precautions ( 5.4)] . 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 Hydrochloride Extended-Release Capsules requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [see Warnings and Precautions ( 5.5), Drug Interactions ( 7)]. 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 and Precautions ( 5.6), Drug Interactions ( 7)] . Reserve concomitant prescribing of Tramadol Hydrochloride Extended-Release Capsules and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. 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 See full prescribing information for complete boxed warning . Tramadol Hydrochloride Extended-Release Capsules exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions. ( 5.1) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow Tramadol Hydrochloride Extended-Release Capsules intact, and not to split, chew, crush, or dissolve content of the capsules to avoid exposure to a potentially fatal dose of tramadol. ( 5.2) Accidental ingestion of Tramadol Hydrochloride Extended-Release Capsules, especially by children, can result in a fatal overdose of tramadol. ( 5.2) 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. ( 5.3) Tramadol Hydrochloride Extended-Release Capsules are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. ( 4) Avoid the use of Tramadol Hydrochloride Extended-Release Capsules 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. ( 5.3) Prolonged use of Tramadol Hydrochloride Extended-Release Capsules during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.4) 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 Hydrochloride Extended-Release Capsules requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1. ( 5.5, 7) 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. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.6, 7)