Tramadol Hydrochloride

1 INDICATIONS AND USAGE Tramadol hydrochloride oral solution is indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Tramadol hydrochloride oral solution is an opioid agonist indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate ( 1 ). Limitations of Use ( 1 ) Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses ( 5.2 ), reserve tramadol hydrochloride oral solution 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 ( 1 ). Have not provided adequate analgesia, or are not expected to provide adequate analgesia ( 1 ). Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions ( 5.2 )] , reserve tramadol hydrochloride oral solution 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.

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals ( 2.1 ). 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 ( 2.1 ). Monitor patients closely for respiratory depression, especially within the first 24–72 hours of initiating therapy and following dosage increases with tramadol hydrochloride oral solution and adjust the dosage accordingly ( 2.1 ). Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with tramadol hydrochloride oral solution. Consider prescribing naloxone based on the patient’s risk factors for overdose [ 2.2 , 5.2 , 5.4 , 5.8 ]. Start at 25 mg /day and titrate in 25 mg increments as separate doses every 3 days to reach 100 mg /day (25 mg four times a day). Thereafter 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 oral solution 50 mg to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg /day ( 2.3 , 2.4 ). Severe hepatic impairment : Recommended dose is 50 mg every 12 hours ( 2.3 ). Do not abruptly discontinue tramadol hydrochloride oral solution in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide ( 2.5 ). 2.1 Important Dosage and Administration Instructions Ensure accuracy when prescribing, dispensing, and administering tramadol hydrochloride oral solution to avoid dosing errors due to confusion between mg and mL which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Instruct patients on how to measure and take the correct dose of tramadol hydrochloride oral solution and to use extreme caution when measuring the dose. Strongly advise patients to always use a calibrated oral syringe or other oral dosing device, with metric units of measurements (i.e., mL), to correctly measure the prescribed amount of medication. Inform patients that oral dosing devices may be obtained from their pharmacy and to never use household teaspoons or tablespoons to measure tramadol hydrochloride oral solution [see Patient Counseling Information ( 17 )] . Do not use tramadol hydrochloride oral solution concomitantly with other tramadol-containing products. Do not administer tramadol hydrochloride oral solution at a dose exceeding 400 mg (80 mL) per day. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5.2 )] . 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 ( 5.2 )] . Monitor patients closely for respiratory depression, especially within the first 24–72 hours of initiating therapy and following dosage increases with tramadol hydrochloride oral solution and adjust the dosage accordingly [see Warnings and Precautions ( 5.4 )] . 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with tramadol hydrochloride oral solution [see Warnings and Precautions ( 5.4 ), Patient Counseling Information ( 17 )] . Inform patients and caregivers about the various ways to obtain…

5 WARNINGS AND PRECAUTIONS Serotonin Syndrome : May be life-threatening. Can occur with use of tramadol alone, with concomitant use of serotonergic drugs, with drugs that impair metabolism of serotonin or tramadol ( 5.9 ). Risk of Seizure : Can occur at the recommended dose of tramadol. Concomitant use with other drugs may increase seizure risk. Risk may increase in patients with epilepsy, a history of seizures, and in patients with a recognized risk for seizures ( 5.10 ). Risk of Suicide : Do not prescribe for suicidal or addiction-prone patients ( 5.11 ). Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid ( 5.12 ). Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration ( 5.13 ). Severe Hypotension : Monitor during dosage initiation and titration. Avoid use of tramadol hydrochloride oral solution in patients with circulatory shock ( 5.14 ). Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of tramadol hydrochloride oral solution in patients with impaired consciousness or coma ( 5.15 ). 5.1 Risk of Accidental Overdose and Death due to Medication Errors Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL when prescribing, dispensing, and administering tramadol hydrochloride oral solution. Ensure that the dose is communicated clearly and dispensed accurately. Instruct patients on how to measure and take the correct dose of tramadol hydrochloride oral solution and to use extreme caution when measuring the dose. Strongly advise patients to always use a calibrated oral dosing device that can measure and deliver the prescribed dose accurately and to never use household teaspoons or tablespoons to measure a dose because household teaspoons and tablespoons are not adequate measuring devices [see Patient Counseling Information ( 17 )] . 5.2 Addiction, Abuse and Misuse Tramadol hydrochloride oral solution contains tramadol, a Schedule IV controlled substance. As an opioid, tramadol hydrochloride oral solution exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed tramadol hydrochloride oral solution. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing tramadol hydrochloride oral solution, and monitor all patients receiving tramadol hydrochloride oral solution for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as tramadol hydrochloride oral solution, but use in such patients necessitates intensive counseling about the risks and proper use of tramadol hydrochloride oral solution along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.4 )] . Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing tramadol hydrochloride oral solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient …

4 CONTRAINDICATIONS Tramadol hydrochloride oral solution is contraindicated for: all children younger than 12 years of age [see Warnings and Precautions ( 5.5 )] . postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions ( 5.5 )] . Tramadol hydrochloride oral solution is also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.4 )] . Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.13 )] . Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.16 )] . Hypersensitivity to tramadol, any other component of this product or opioids [see Warnings and Precautions ( 5.17 )] . 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 the absence of resuscitative equipment ( 4 ). Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ). Hypersensitivity to tramadol, any other component of this product or opioids ( 4 ). Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days ( 4 ).

7 DRUG INTERACTIONS Table 2: Clinically Significant Drug Interactions with tramadol hydrochloride oral solution Inhibitors of CYP2D6 Clinical Impact: The concomitant use of tramadol hydrochloride oral solution 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 oral solution 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. This could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, such as 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 oral solution 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 oral solution 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 oral solution is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to tramadol. Intervention: If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride oral solution 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 oral solution 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 oral solution and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures, serotonin syndrome, and/or potentially fatal respiratory depression. Intervention: If concomitant use is necessary, consider increasing the tramadol hydrochloride oral solution dosage u…

8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with tramadol hydrochloride in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics ( see Clinical Considerations) . 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). In a pre- and post-natal development study, tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the MRHD. In a published study, tramadol caused structural abnormalities in the brains of fetuses when administered to female Sprague Dawley rats from Gestation Days 10-21 at a dose comparable to 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 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 and Precautions ( 5.6 )] . Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during postmarketing. 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 oral solution is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including tramadol hydrochloride oral solution, 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, 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 did not cause malformations at these dose levels. These doses on a mg/m 2 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 malformations were observed in progeny of mice (up to…

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.2 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.4 )] Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children [see Warnings and Precautions ( 5.5 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.6 )] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.8 )] Serotonin Syndrome [see Warnings and Precautions ( 5.9 )] Seizures [see Warnings and Precautions ( 5.10 )] Suicide [see Warnings and Precautions ( 5.11 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.12 )] Severe Hypotension [see Warnings and Precautions ( 5.14 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.16 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.17 )] Withdrawal [see Warnings and Precautions ( 5.18 )] The most common incidence of treatment-emergent adverse events (≥15.0%) in patients from clinical trials were dizziness/vertigo, nausea, constipation, headache, somnolence, vomiting and pruritus ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact TruPharma, LLC at 1-877-541-5504 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 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 1 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 hydrochloride 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 hydrochloride 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 hydrochloride groups. Table 1: Cumulative Incidence of Adverse Reactions for Tramadol HCl Tablets in Chronic Trials of Nonmalignant Pain (N=427) 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 CNS Stimulation is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations 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 hydrochloride 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…