These Highlights Do Not Include All The Information Needed To Use Tramadol Hydrochloride Oral Solution Safely And Effectively. See Full Prescribing Information For Tramadol Hydrochloride Oral Solution.

RISK OF MEDICATION ERRORS

Ensure accuracy when prescribing, dispensing, and administering tramadol hydrochloride oral solution. Dosing errors due to confusion between mg and mL can result in accidental overdose and death [see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.1)].

Dispense in a tight container. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to30°C (59°F to 86°F). [see USP Controlled Room Temperature].

Store tramadol hydrochloride oral solution securely and dispose of properly [see Patient Counseling Information ( 17)].

Tramadol hydrochloride oral solution contains tramadol, a substance having potential for abuse. Tramadol hydrochloride oral solution can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.2)] .

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful, or potentially harmful, consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Tramadol hydrochloride oral solution, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Tramadol hydrochloride oral solution is an opioid agonist. The chemical name for tramadol hydrochloride is (±) cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. The structural formula is:

The molecular formula of tramadol hydrochloride is C ₁₆H ₂₅NO ₂ · HCl, and the molecular weight is 299.8. Tramadol hydrochloride is a white, bitter, crystalline and odorless powder. It is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7. Tramadol hydrochloride oral solution is a clear, grape flavored liquid containing 5 mg of tramadol hydrochloride per 1 mL (equivalent to tramadol 4.4 mg per 1 mL)

Inactive ingredients include: citric acid, glycerin, grape flavor, propylene glycol, purified water, sodium benzoate, sodium citrate dihydrate, and sucralose.

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of drugs to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Do not abruptly discontinue tramadol hydrochloride oral solution in a patient physically dependent on opioids. Rapid tapering of tramadol hydrochloride oral solution in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing Ttramadol hydrochloride oral solution, gradually taper the dosage using a patient-specific plan that considers the following: the dose of tramadol hydrochloride oral solution the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.18)] .

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations ( 8.1)] .

Do not abruptly discontinue tramadol hydrochloride oral solutionin a patient physically dependent on opioids. When discontinuing tramadol hydrochloride oral solution in a physically dependent patient, gradually taper the dosage. Rapid tapering of tramadol in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration ( 2.5), Drug Abuse and Dependence ( 9.3)] .

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including tramadol hydrochloride oral solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions ( 7)] .

Do not prescribe tramadol hydrochloride oral solution for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed [see Drug Abuse and Dependence ( 9.2)] . Prescribe tramadol hydrochloride oral solution with caution for patients with a history of misuse and/or are currently taking CNS-active drugs including tranquilizers or antidepressant drugs, alcohol in excess, and patients who suffer from emotional disturbance or depression [see Drug Interactions ( 7)] . Inform patients not to exceed the recommended dose and to limit their intake of alcohol [see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.8)] .

Hyponatremia (serum sodium < 135 mmol/L) has been reported with the use of tramadol, and many cases are severe (sodium level < 120 mmol/L). Most cases of hyponatremia occurred in females over the age of 65 and within the first week of therapy. In some reports, hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Monitor for signs and symptoms of hyponatremia (e.g., confusion, disorientation), during treatment with tramadol hydrochloride oral solution, especially during initiation of therapy. If signs and symptoms of hyponatremia are present, initiate appropriate treatment (e.g., fluid restriction) and discontinue tramadol hydrochloride oral solution  [see Dosage and Administration: Safe Reduction or Discontinuation of tramadol hydrochloride oral solution ( 2.5)] .

Cases of tramadol-associated hypoglycemia have been reported, some resulting in hospitalization. In most cases, patients had predisposing risk factors (e.g. diabetes). If hypoglycemia is suspected, monitor blood glucose levels and consider drug discontinuation as appropriate [see Dosage and Administration: Safe Reduction or Discontinuation oftramadol hydrochloride oral solution ( 2.5)] .

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 and Precautions ( 5.5)] . 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 oral solution is contraindicated for all children younger than 12 years of age [see Contraindications ( 4)] .
• Tramadol hydrochloride oral solution is contraindicated for postoperative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4)] .

Avoid the use of tramadol hydrochloride oral solution 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.

A total of 455 elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride in controlled clinical trials. Of those, 145 subjects were 75 years of age and older.

In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of tramadol hydrochloride oral solution slowly in geriatric patients starting at the low end of the dosing range and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.13)] .

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.

Tramadol hydrochloride has been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).

In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50 mg and 75 mg. A dose of 100 mg tramadol hydrochloride tended to provide analgesia superior to codeine sulfate 60 mg, but it was not as effective as the combination of aspirin 650 mg with codeine phosphate 60 mg.

Tramadol hydrochloride has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol hydrochloride. Patients with a variety of chronic painful conditions were studied in double-blind trials of one to three months duration. Average daily doses of approximately 250 mg of tramadol hydrochloride in divided doses were generally comparable to five doses of acetaminophen 300 mg with codeine phosphate 30 mg (TYLENOL with Codeine #3) daily, five doses of aspirin 325 mg with codeine phosphate 30 mg daily, or two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (TYLOX) daily.

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)] .

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 analgesic activity of tramadol hydrochloride oral solution is due to both parent drug and the M1 metabolite [see Clinical Pharmacology ( 12.1, 12.2)] . Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

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 may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions ( 7)] . Monitor these patients for signs of hypotension after initiating or titrating the dosage of tramadol hydrochloride oral solution. In patients with circulatory shock, tramadol hydrochloride oral solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of tramadol hydrochloride oral solution in patients with circulatory shock.

Tramadol hydrochloride oral solution contains tramadol, an opioid agonist and inhibitor of norepinephrine and serotonin re-uptake. Although the mode of action is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to µ-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin.

Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to µ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opioid antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound [see Clinical Pharmacology ( 12.2)] .

Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.

Tramadol hydrochloride oral solution contains tramadol, a Schedule IV controlled substance.

• 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).

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

• 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).

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, particularly during concomitant use with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions ( 7)] . This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue tramadol hydrochloride oral solution if serotonin syndrome is suspected.

Tramadol hydrochloride oral solution is supplied as a clear liquid in 16 oz white, opaque plastic bottles, containing tramadol hydrochloride, 5 mg/mL (equivalent to tramadol 4.4 mg per 1 mL).

The following adverse reactions have been identified during post-approval use of tramadol hydrochloride. 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.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2)] .

QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use. Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in the overdose setting.

Eye disorders – mydriasis

Metabolism and nutrition disorders

Hyponatremia: Cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy [see Warnings and Precautions ( 5.20)] .

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients [see Warnings and Precautions ( 5.21)] .

Nervous system disorders – movement disorder, speech disorder

Psychiatric disorders – delirium

• Pregnancy: May cause fetal harm ( 8.1).
• Lactation: Breastfeeding not recommended ( 8.2).

Seizures have been reported in patients receiving tramadol hydrochloride oral solution within the recommended dosage range. Spontaneous postmarketing reports indicate that seizure risk is increased with doses of tramadol hydrochloride oral solution above the recommended range.

Concomitant use of tramadol hydrochloride oral solution increases the seizure risk in patients taking [see Drug Interactions ( 7)] :

• Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics),
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.),
• Other opioids,
• MAO inhibitors [see Warnings and Precautions ( 5.9), Drug Interactions ( 7)] .
• Neuroleptics, or
• Other drugs that reduce the seizure threshold.

Risk of seizure may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol hydrochloride oral solution overdose, naloxone administration may increase the risk of seizure.

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.

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 on the proper disposal of unused drug [see Patient Counseling Information ( 17)] . Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

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 ( 2.3)] . Metabolism of tramadol and M1 is reduced in patients with severe hepatic impairment based on a study in patients with advanced cirrhosis of the liver. In patients with severe hepatic impairment, dosing reduction is recommended [see Dosage and Administration ( 2.3)] .

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Tramadol hydrochloride oral solution is supplied as a clear, grape flavored liquid containing tramadol HCl, 5 mg/mL.

Supplied in 16 oz (473 mL) white, opaque plastic bottles with a child-resistant cap, NDC 52817-615-16

Tramadol hydrochloride oral solution may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of tramadol hydrochloride oral solution and know how they will react to the medication [see Patient Counseling Information ( 17)] .

Prolonged use of tramadol hydrochloride oral solution during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1), Patient Counseling Information ( 17)] .

Individually titrate tramadol hydrochloride oral solution to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving tramadol hydrochloride oral solution to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as to monitor for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.2)] . 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 oral solution 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.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage ( 10)] . Carbon dioxide (CO ₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of tramadol hydrochloride oral solution, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of tramadol hydrochloride oral solution.

To reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride oral solution are essential [see Dosage and Administration ( 2)] . Overestimating the tramadol hydrochloride oral solution dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of tramadol hydrochloride oral solution, especially by children, can result in respiratory depression and death due to an overdose of tramadol.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17)] .

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.5)] .

• 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)] .

Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with tramadol hydrochloride oral solution. When these events do occur, it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of hypersensitivity reactions to tramadol and other opioids may be at increased risk and therefore should not receive Tramadol Hydrochloride oral solution  [see Contraindications ( 4)] . If anaphylaxis or other hypersensitivity occurs, stop administration of tramadol hydrochloride oral solution immediately, discontinue tramadol hydrochloride oral solution permanently, and do not rechallenge with any formulation of tramadol. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. [see Contraindications ( 4), Patient Counseling Information ( 17)] .

Tramadol hydrochloride oral solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications ( 4)] .

The tramadol in tramadol hydrochloride oral solution may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

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)] .

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG .
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com . FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint .

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from tramadol hydrochloride oral solution are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride oral solution requires careful consideration of the effects on the parent drug, tramadol which is a weak serotonin and norepinephrine reuptake inhibitor and µ-opioid agonist, and the active metabolite, M1, which is more potent than tramadol in µ-opioid receptor binding [see Drug Interactions ( 7)] .

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of tramadol hydrochloride oral solution with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7)] .

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.4)] .

Advise both patients and caregivers about the risks of respiratory depression and sedation when tramadol hydrochloride oral solution is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions ( 7), Patient Counseling Information ( 17)] .

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 naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.2, 5.4, 5.8)] .

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

Do not abruptly discontinue tramadol hydrochloride oral solution in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid- dependent patient taking tramadol hydrochloride oral solution, there are a variety of factors that should be considered, including the dose of tramadol hydrochloride oral solution the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on tramadol hydrochloride oral solution who are physically opioid-dependent, initiate the taper by a small enough increment, (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with a lower dosage strength to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.18), Drug Abuse and Dependence ( 9.3)] .

NDC 52817-615-16

Tramadol hydrochloride oral solution 5 mg/mL (equivalent to tramadol 4.4 mg per 1 mL) CIV

Keep out of reach of children.

Rx only

16 oz. (473 mL)

Life-threatening respiratory depression and death have occurred in children who received tramadol. Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to increased exposure to an active metabolite. Based upon postmarketing reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol. Furthermore, children with obstructive sleep apnea who are treated with opioids for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:

• Tramadol hydrochloride oral solution is contraindicated for all children younger than 12 years of age [see Contraindications ( 4)] .
• Tramadol hydrochloride oral solution is contraindicated for postoperative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4)] .
• Avoid the use of tramadol hydrochloride oral solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
• As with adults, when prescribing opioids for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of opioid overdose [see Use in Specific Populations ( 8.4), Overdosage ( 10)] .

In patients who may be susceptible to the intracranial effects of CO ₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), tramadol hydrochloride oral solution may reduce respiratory drive, and the resultant CO ₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with tramadol hydrochloride oral solution.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of tramadol hydrochloride oral solution in patients with impaired consciousness or coma.

The use of tramadol hydrochloride oral solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, and MISUSE; RISK EVALUATION and MITIGATION STRATEGY (REMS); 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.

• Ensure accuracy when prescribing, dispensing, and administering tramadol hydrochloride oral solution. Dosing errors due to confusion between mg and mL can result in accidental overdose and death. ( 2.1, 5.1)
• Tramadol hydrochloride oral solution exposes users to the risks of addiction, abuse and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing tramadol hydrochloride oral solution, and monitor regularly for these behaviors or conditions. ( 5.2)
• To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. ( 5.3)
• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially during initiation or following a dose increase. ( 5.4)
• Accidental ingestion of tramadol hydrochloride oral solution, especially by children, can result in a fatal overdose of tramadol. ( 5.4)
• 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 ( 5.5).
• Tramadol hydrochloride oral solution is 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 oral solution 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. ( 5.5)
• Prolonged use of tramadol hydrochloride oral solution, 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. ( 5.6)
• 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 oral solution requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1. ( 5.7, 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. ( 5.8, 7)

RISK OF MEDICATION ERRORS

Ensure accuracy when prescribing, dispensing, and administering tramadol hydrochloride oral solution. Dosing errors due to confusion between mg and mL can result in accidental overdose and death [see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.1)].

Dispense in a tight container. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to30°C (59°F to 86°F). [see USP Controlled Room Temperature].

Store tramadol hydrochloride oral solution securely and dispose of properly [see Patient Counseling Information ( 17)].

Tramadol hydrochloride oral solution contains tramadol, a substance having potential for abuse. Tramadol hydrochloride oral solution can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.2)] .

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful, or potentially harmful, consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Tramadol hydrochloride oral solution, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Tramadol hydrochloride oral solution is an opioid agonist. The chemical name for tramadol hydrochloride is (±) cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. The structural formula is:

The molecular formula of tramadol hydrochloride is C ₁₆H ₂₅NO ₂ · HCl, and the molecular weight is 299.8. Tramadol hydrochloride is a white, bitter, crystalline and odorless powder. It is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7. Tramadol hydrochloride oral solution is a clear, grape flavored liquid containing 5 mg of tramadol hydrochloride per 1 mL (equivalent to tramadol 4.4 mg per 1 mL)

Inactive ingredients include: citric acid, glycerin, grape flavor, propylene glycol, purified water, sodium benzoate, sodium citrate dihydrate, and sucralose.

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of drugs to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Do not abruptly discontinue tramadol hydrochloride oral solution in a patient physically dependent on opioids. Rapid tapering of tramadol hydrochloride oral solution in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing Ttramadol hydrochloride oral solution, gradually taper the dosage using a patient-specific plan that considers the following: the dose of tramadol hydrochloride oral solution the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.18)] .

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations ( 8.1)] .

Do not abruptly discontinue tramadol hydrochloride oral solutionin a patient physically dependent on opioids. When discontinuing tramadol hydrochloride oral solution in a physically dependent patient, gradually taper the dosage. Rapid tapering of tramadol in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration ( 2.5), Drug Abuse and Dependence ( 9.3)] .

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including tramadol hydrochloride oral solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions ( 7)] .

Do not prescribe tramadol hydrochloride oral solution for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed [see Drug Abuse and Dependence ( 9.2)] . Prescribe tramadol hydrochloride oral solution with caution for patients with a history of misuse and/or are currently taking CNS-active drugs including tranquilizers or antidepressant drugs, alcohol in excess, and patients who suffer from emotional disturbance or depression [see Drug Interactions ( 7)] . Inform patients not to exceed the recommended dose and to limit their intake of alcohol [see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.8)] .

Hyponatremia (serum sodium < 135 mmol/L) has been reported with the use of tramadol, and many cases are severe (sodium level < 120 mmol/L). Most cases of hyponatremia occurred in females over the age of 65 and within the first week of therapy. In some reports, hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Monitor for signs and symptoms of hyponatremia (e.g., confusion, disorientation), during treatment with tramadol hydrochloride oral solution, especially during initiation of therapy. If signs and symptoms of hyponatremia are present, initiate appropriate treatment (e.g., fluid restriction) and discontinue tramadol hydrochloride oral solution  [see Dosage and Administration: Safe Reduction or Discontinuation of tramadol hydrochloride oral solution ( 2.5)] .

Cases of tramadol-associated hypoglycemia have been reported, some resulting in hospitalization. In most cases, patients had predisposing risk factors (e.g. diabetes). If hypoglycemia is suspected, monitor blood glucose levels and consider drug discontinuation as appropriate [see Dosage and Administration: Safe Reduction or Discontinuation oftramadol hydrochloride oral solution ( 2.5)] .

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 and Precautions ( 5.5)] . 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 oral solution is contraindicated for all children younger than 12 years of age [see Contraindications ( 4)] .
• Tramadol hydrochloride oral solution is contraindicated for postoperative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4)] .

Avoid the use of tramadol hydrochloride oral solution 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.

A total of 455 elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride in controlled clinical trials. Of those, 145 subjects were 75 years of age and older.

In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of tramadol hydrochloride oral solution slowly in geriatric patients starting at the low end of the dosing range and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.13)] .

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.

Tramadol hydrochloride has been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).

In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50 mg and 75 mg. A dose of 100 mg tramadol hydrochloride tended to provide analgesia superior to codeine sulfate 60 mg, but it was not as effective as the combination of aspirin 650 mg with codeine phosphate 60 mg.

Tramadol hydrochloride has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol hydrochloride. Patients with a variety of chronic painful conditions were studied in double-blind trials of one to three months duration. Average daily doses of approximately 250 mg of tramadol hydrochloride in divided doses were generally comparable to five doses of acetaminophen 300 mg with codeine phosphate 30 mg (TYLENOL with Codeine #3) daily, five doses of aspirin 325 mg with codeine phosphate 30 mg daily, or two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (TYLOX) daily.

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)] .

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 analgesic activity of tramadol hydrochloride oral solution is due to both parent drug and the M1 metabolite [see Clinical Pharmacology ( 12.1, 12.2)] . Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

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 may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions ( 7)] . Monitor these patients for signs of hypotension after initiating or titrating the dosage of tramadol hydrochloride oral solution. In patients with circulatory shock, tramadol hydrochloride oral solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of tramadol hydrochloride oral solution in patients with circulatory shock.

Tramadol hydrochloride oral solution contains tramadol, an opioid agonist and inhibitor of norepinephrine and serotonin re-uptake. Although the mode of action is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to µ-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin.

Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to µ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opioid antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound [see Clinical Pharmacology ( 12.2)] .

Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.

Tramadol hydrochloride oral solution contains tramadol, a Schedule IV controlled substance.

• 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).

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

• 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).

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, particularly during concomitant use with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions ( 7)] . This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue tramadol hydrochloride oral solution if serotonin syndrome is suspected.

Tramadol hydrochloride oral solution is supplied as a clear liquid in 16 oz white, opaque plastic bottles, containing tramadol hydrochloride, 5 mg/mL (equivalent to tramadol 4.4 mg per 1 mL).

The following adverse reactions have been identified during post-approval use of tramadol hydrochloride. 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.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2)] .

QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use. Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in the overdose setting.

Eye disorders – mydriasis

Metabolism and nutrition disorders

Hyponatremia: Cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy [see Warnings and Precautions ( 5.20)] .

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients [see Warnings and Precautions ( 5.21)] .

Nervous system disorders – movement disorder, speech disorder

Psychiatric disorders – delirium

• Pregnancy: May cause fetal harm ( 8.1).
• Lactation: Breastfeeding not recommended ( 8.2).

Seizures have been reported in patients receiving tramadol hydrochloride oral solution within the recommended dosage range. Spontaneous postmarketing reports indicate that seizure risk is increased with doses of tramadol hydrochloride oral solution above the recommended range.

Concomitant use of tramadol hydrochloride oral solution increases the seizure risk in patients taking [see Drug Interactions ( 7)] :

• Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics),
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.),
• Other opioids,
• MAO inhibitors [see Warnings and Precautions ( 5.9), Drug Interactions ( 7)] .
• Neuroleptics, or
• Other drugs that reduce the seizure threshold.

Risk of seizure may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol hydrochloride oral solution overdose, naloxone administration may increase the risk of seizure.

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.

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 on the proper disposal of unused drug [see Patient Counseling Information ( 17)] . Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

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 ( 2.3)] . Metabolism of tramadol and M1 is reduced in patients with severe hepatic impairment based on a study in patients with advanced cirrhosis of the liver. In patients with severe hepatic impairment, dosing reduction is recommended [see Dosage and Administration ( 2.3)] .

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Tramadol hydrochloride oral solution is supplied as a clear, grape flavored liquid containing tramadol HCl, 5 mg/mL.

Supplied in 16 oz (473 mL) white, opaque plastic bottles with a child-resistant cap, NDC 52817-615-16

Tramadol hydrochloride oral solution may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of tramadol hydrochloride oral solution and know how they will react to the medication [see Patient Counseling Information ( 17)] .

Prolonged use of tramadol hydrochloride oral solution during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1), Patient Counseling Information ( 17)] .

Individually titrate tramadol hydrochloride oral solution to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving tramadol hydrochloride oral solution to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as to monitor for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.2)] . 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 oral solution 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.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage ( 10)] . Carbon dioxide (CO ₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of tramadol hydrochloride oral solution, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of tramadol hydrochloride oral solution.

To reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride oral solution are essential [see Dosage and Administration ( 2)] . Overestimating the tramadol hydrochloride oral solution dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of tramadol hydrochloride oral solution, especially by children, can result in respiratory depression and death due to an overdose of tramadol.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17)] .

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.5)] .

• 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)] .

Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with tramadol hydrochloride oral solution. When these events do occur, it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of hypersensitivity reactions to tramadol and other opioids may be at increased risk and therefore should not receive Tramadol Hydrochloride oral solution  [see Contraindications ( 4)] . If anaphylaxis or other hypersensitivity occurs, stop administration of tramadol hydrochloride oral solution immediately, discontinue tramadol hydrochloride oral solution permanently, and do not rechallenge with any formulation of tramadol. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. [see Contraindications ( 4), Patient Counseling Information ( 17)] .

Tramadol hydrochloride oral solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications ( 4)] .

The tramadol in tramadol hydrochloride oral solution may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

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)] .

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG .
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com . FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint .

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from tramadol hydrochloride oral solution are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride oral solution requires careful consideration of the effects on the parent drug, tramadol which is a weak serotonin and norepinephrine reuptake inhibitor and µ-opioid agonist, and the active metabolite, M1, which is more potent than tramadol in µ-opioid receptor binding [see Drug Interactions ( 7)] .

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of tramadol hydrochloride oral solution with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7)] .

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.4)] .

Advise both patients and caregivers about the risks of respiratory depression and sedation when tramadol hydrochloride oral solution is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions ( 7), Patient Counseling Information ( 17)] .

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 naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.2, 5.4, 5.8)] .

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

Do not abruptly discontinue tramadol hydrochloride oral solution in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid- dependent patient taking tramadol hydrochloride oral solution, there are a variety of factors that should be considered, including the dose of tramadol hydrochloride oral solution the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on tramadol hydrochloride oral solution who are physically opioid-dependent, initiate the taper by a small enough increment, (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with a lower dosage strength to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.18), Drug Abuse and Dependence ( 9.3)] .

NDC 52817-615-16

Tramadol hydrochloride oral solution 5 mg/mL (equivalent to tramadol 4.4 mg per 1 mL) CIV

Keep out of reach of children.

Rx only

16 oz. (473 mL)

Life-threatening respiratory depression and death have occurred in children who received tramadol. Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to increased exposure to an active metabolite. Based upon postmarketing reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol. Furthermore, children with obstructive sleep apnea who are treated with opioids for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:

• Tramadol hydrochloride oral solution is contraindicated for all children younger than 12 years of age [see Contraindications ( 4)] .
• Tramadol hydrochloride oral solution is contraindicated for postoperative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4)] .
• Avoid the use of tramadol hydrochloride oral solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
• As with adults, when prescribing opioids for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of opioid overdose [see Use in Specific Populations ( 8.4), Overdosage ( 10)] .

In patients who may be susceptible to the intracranial effects of CO ₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), tramadol hydrochloride oral solution may reduce respiratory drive, and the resultant CO ₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with tramadol hydrochloride oral solution.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of tramadol hydrochloride oral solution in patients with impaired consciousness or coma.

The use of tramadol hydrochloride oral solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, and MISUSE; RISK EVALUATION and MITIGATION STRATEGY (REMS); 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.

• Ensure accuracy when prescribing, dispensing, and administering tramadol hydrochloride oral solution. Dosing errors due to confusion between mg and mL can result in accidental overdose and death. ( 2.1, 5.1)
• Tramadol hydrochloride oral solution exposes users to the risks of addiction, abuse and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing tramadol hydrochloride oral solution, and monitor regularly for these behaviors or conditions. ( 5.2)
• To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. ( 5.3)
• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially during initiation or following a dose increase. ( 5.4)
• Accidental ingestion of tramadol hydrochloride oral solution, especially by children, can result in a fatal overdose of tramadol. ( 5.4)
• 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 ( 5.5).
• Tramadol hydrochloride oral solution is 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 oral solution 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. ( 5.5)
• Prolonged use of tramadol hydrochloride oral solution, 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. ( 5.6)
• 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 oral solution requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1. ( 5.7, 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. ( 5.8, 7)