Tramadol Hydrochloride

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF TRAMADOL HYDROCHLORIDE TABLETS

BOXED WARNING SECTION

Addiction, Abuse and Misuse Because the use of tramadol hydrochloride tablets exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1) ] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of tramadol hydrochloride tablets, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride tablets are essential [see Warnings and Precautions (5.2) ]. Accidental Ingestion Accidental ingestion of even one dose of tramadol hydrochloride tablets, especially by children, can result in a fatal overdose of tramadol [see Warnings and Precautions (5.5) ] . Risks From Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of tramadol hydrochloride tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3) ; Drug Interactions (7) ] . Neonatal Opioid Withdrawal Syndrome (NOWS) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4) ] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.5) ] . Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism [see Warnings and Precautions (5.6) ] . Tramadol hydrochloride tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4) ] . Avoid the use of tramadol hydrochloride tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol [see Warnings and Precautions (5.6) ] . Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride tablets requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [see Warnings and Precautions (5.7) ; Drug Interactions (7) ] .

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

Tramadol hydrochloride tablets are indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.1) ] , reserve tramadol hydrochloride tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated or are not expected to be tolerated, Have not provided adequate analgesia or are not expected to provide adequate analgesia. Tramadol hydrochloride tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

Tramadol Hydrochloride Tablets USP, 50 mg are supplied as white, round film-coated tablets, debossed “AN” over “627” on one side and scored on other side.

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

Tramadol hydrochloride tablets are contraindicated for: all children younger than 12 years of age [see Warnings and Precautions (5.6) ] . postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.6) ] . Tramadol hydrochloride tablets are also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.2) ] . Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.12) ] . 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) ] .

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children [see Warnings and Precautions (5.6) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4) ] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3) ] Opioid-Induced Hyperalgesia and Allodynia [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 (5.13) ] 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) ]

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

Table 2: Clinically Significant Drug Interactions with Tramadol Hydrochloride Tablets Inhibitors of CYP2D6 Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride tablet is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase. This could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, such as potentially fatal respiratory depression [see Clinical Pharmacology (12.3) ] . Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, evaluate patients at frequent intervals for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride tablets dosage until stable drug effects are achieved. Evaluate patients at frequent intervals for adverse events including respiratory depression and sedation. Examples: Quinidine, fluoxetine, paroxetine and bupropion Inhibitors of CYP3A4 Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride tablet is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3) ] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to tramadol. Intervention: If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride tablet until stable drug effects are achieved. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of seizures, serotonin syndrome, and signs of respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride tablet dosage until stable drug effects are achieved and evaluate patients at frequent intervals for signs and symptoms of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride tablet and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3) ] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures, serotonin syndrome, and/or potentially fatal respiratory depression. Intervention: If concomitant use is necessary, consider increasing the tramadol hydrochloride tablet dosage until stable drug effects are achieved. Assess patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride tablet dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride tablet and carbamazepine is not recommended. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including 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 (5.1 , 5.2 , 5.3 )] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, and alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride tablet immediately if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10) ] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2) ] . Intervention: Do not use tramadol hydrochloride tablet in patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of tramadol hydrochloride tablet and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of tramadol hydrochloride tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) , Warnings and Precautions (5.2 , 5.3 )]. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hor...

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

9 DRUG ABUSE AND DEPENDENCE

DRUG ABUSE AND DEPENDENCE SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

Clinical Presentation Acute overdosage with tramadol hydrochloride tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, QT prolongation, hypotension, partial or complete airway obstruction, atypical snoring, seizures, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Deaths due to overdose have been reported with abuse and misuse of tramadol [see Warnings and Precautions (5.1) ; Drug Abuse and Dependence (9.2) ] . Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or serious arrhythmias will require advanced life-support measures. Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center (where available) to determine the latest recommendations for the management of an overdose. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals, convulsions following the administration of toxic doses of tramadol hydrochloride tablets could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period. Because the duration of opioid reversal is expected to be less than the duration of action of tramadol in tramadol hydrochloride tablets, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

11 DESCRIPTION

DESCRIPTION SECTION

Tramadol hydrochloride tablets USP, for oral use, are 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 weight of tramadol hydrochloride is 299.84. Tramadol hydrochloride, USP is a white or almost white crystalline powder. It is freely soluble in water and in methanol, very slightly soluble in acetone and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7. Tramadol hydrochloride tablets, USP contain 50 mg of tramadol hydrochloride, USP and are white in color. Inactive ingredients in the tablet are hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium starch glycolate, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

Tramadol hydrochloride tablets have 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 tablets 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 tablets have been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol hydrochloride tablets. 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 tablets 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. Titration Trials In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily tramadol hydrochloride tablets dose of 200 mg (50 mg four times per day), attained in 50 mg increments every 3 days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only 4 days or no titration. In a second study with 54 to 59 patients per group, patients who had nausea or vomiting when titrated over 4 days were randomized to re-initiate tramadol hydrochloride tablets therapy using slower titration rates. A 16-day titration schedule, starting with 25 mg every morning and using additional doses in 25 mg increments every third day to 100 mg/day (25 mg four times per day), followed by 50 mg increments in the total daily dose every third day to 200 mg/day (50 mg four times per day), resulted in fewer discontinuations due to nausea or vomiting and fewer discontinuations due to any cause than did a 10-day titration schedule. Figure 2:

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

Tramadol Hydrochloride Tablets USP, 50 mg are supplied as white, round film-coated tablets, debossed “AN” over “627” on one side and scored on other side. They are supplied as follows: Bottles of 15 Tablets NDC: 80425-0501-01 Bottles of 30 Tablets NDC: 80425-0501-02 Bottles of 40 Tablets NDC: 80425-0501-06 Bottles of 60 Tablets NDC: 80425-0501-03 Bottles of 90 Tablets NDC: 80425-0501-04 Bottles of 120 Tablets NDC: 80425-0501-05 Bottles of 180 Tablets NDC: 80425-0501-07 Bottles of 240 Tablets NDC: 80425-0501-08 Dispense in a tight container. Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store tramadol hydrochloride tablets securely and dispose of properly [see Patient Counseling Information (17) ] .

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store tramadol hydrochloride tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving tramadol hydrochloride tablets unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1 , 5.18 ), Drug Abuse and Dependence (9.2) ] . Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that medicine take-back options are the preferred way to safely dispose of most types of unneeded medicines. If no take back programs or Drug Enforcement Administration (DEA)-registered collectors are available, instruct patients to dispose of tramadol hydrochloride tablets by following these four steps: Mix tramadol hydrochloride tablets (do not crush) with an unpalatable substance such as dirt, cat litter, or used coffee grounds; Place the mixture in a container such as a sealed plastic bag; Throw the container in the household trash; Delete all personal information on the prescription label of the empty bottle. Inform patients that they can visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of tramadol hydrochloride tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1) ] . Instruct patients not to share tramadol hydrochloride tablets with others and to take steps to protect tramadol hydrochloride tablets from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting tramadol hydrochloride tablets or when the dosage is increased, and that it can occur even at recommended dosages. 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 Warnings and Precautions (5.2) ] . Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2) ] . Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if tramadol hydrochloride tablets are used with benzodiazepines, CNS depressants, including alcohol, or some illicit drugs and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.3) ; Drug Interactions (7) ] . Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with tramadol hydrochloride. 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) [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) ] . Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [ see Overdosage (10) ]. If naloxone is prescribed, also advise patients and caregivers: How to treat with naloxone in the event of an opioid overdose To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children Advise caregivers that tramadol hydrochloride tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children ages 12 to 18 years of age receiving tramadol hydrochloride tablets to monitor for signs of respiratory depression [see Warnings and Precautions (5.6) ] . Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.8) ; Adverse Reactions (6.2) ] . Maximum single-dose and 24-hour dose Advise patients not to exceed the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures and death [see Dosage and Administration (2) ; Warnings and Precautions (5.2) ] . Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome, and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.9) ] . Seizures Inform patients that tramadol hydrochloride tablets may cause seizures with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol [see Warnings and Precautions (5.10) ] . MAOI Interaction Inform patients not to take tramadol hydrochloride tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking tramadol hydrochloride tablets [see Drug Interactions (7) ] . Important Administration Instructions Instruct patients how to properly take tramadol hydrochloride tablets [see Dosage and Administration (2) ] . Advise patients not to adjust the dose of tramadol hydrochloride tablets without consulting with a physician or other healthcare professional. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue tramadol hydrochloride tablets without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5) ] . Driving or Operating Heavy Machinery Inform patients that tramadol hydrochloride tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.19) ] . Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6) ] . Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.13) ] . Hypotension Inform ...

Medication Guide

SPL MEDGUIDE SECTION

Tramadol Hydrochloride (tram’ a dol hye” droe klor’ ide) Tablets, USP C-IV Tramadol hydrochloride tablets are: A strong prescription pain medicine that contains an opioid (narcotic) that is used for the management pain in adults, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about tramadol hydrochloride tablets: Get emergency help or call 911 right away if you take too many tramadol hydrochloride tablets (overdose). When you first start taking tramadol hydrochloride tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose. Taking tramadol hydrochloride tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your tramadol hydrochloride tablets. They could die from taking it. Selling or giving away tramadol hydrochloride tablets is against the law. Store tramadol hydrochloride tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Important Information Guiding Use in Pediatric Patients: Do not give tramadol hydrochloride tablets to a child younger than 12 years of age. Do not give tramadol hydrochloride tablets to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids. Avoid giving tramadol hydrochloride tablets to children between 12 to 18 years of age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems. Do not take tramadol hydrochloride tablets if you have: Severe asthma, trouble breathing, or other lung problems. A bowel blockage or have narrowing of the stomach or intestines. An allergy to tramadol. Taken a Monoamine Oxidase Inhibitor, MAOI, (medicine used for depression) within the last 14 days. Before taking tramadol hydrochloride tablets, tell your healthcare provider if you have a history of: head injury, seizures liver, kidney, thyroid problems problems urinating pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems. Tell your healthcare provider if you are: noticing your pain getting worse. If your pain gets worse after you take tramadol hydrochloride tablets, do not take more of tramadol hydrochloride tablets without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking tramadol hydrochloride tablets. pregnant or planning to become pregnant . Use of tramadol hydrochloride tablets for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding . Not recommended; it may harm your baby. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking tramadol hydrochloride tablets with certain other medicines can cause serious side effects that could lead to death. When taking tramadol hydrochloride tablets: Do not change your dose. Take tramadol hydrochloride tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. For acute (short-term) pain, you may only need to take tramadol hydrochloride tablets for a few days. You may have some tramadol hydrochloride tablets left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused tramadol hydrochloride tablets. Take your prescribed dose as indicated by your healthcare provider. The maximum dosage is 1 or 2 tablets every 4 to 6 hours, as needed for pain relief. Do not take more than your prescribed dose and do not take more than 8 tablets per day. If you miss a dose, take your next dose at your usual time. Call your healthcare provider if the dose you are taking does not control your pain. If you have been taking tramadol hydrochloride tablets regularly, do not stop taking tramadol hydrochloride tablets without talking to your healthcare provider. Dispose of expired, unwanted, or unused tramadol hydrochloride tablets by taking your drug to an authorized Drug Enforcement Administration (DEA)-registered collector or drug take-back program. If one is not available, you can dispose of tramadol hydrochloride tablets by mixing the product with dirt, cat litter, or coffee grounds; placing the mixture in a sealed plastic bag, and throwing the bag in your trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. While taking tramadol hydrochloride tablets DO NOT: Drive or operate heavy machinery, until you know how tramadol hydrochloride tablets affect you. Tramadol hydrochloride tablets can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with tramadol hydrochloride tablets may cause you to overdose and die. The possible side effects of tramadol hydrochloride tablets: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you have: trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of tramadol hydrochloride tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov. Manufactured by: Amneal Pharmaceuticals Pvt. Ltd. Ahmedabad 382220, INDIA Or Amneal Pharmaceuticals Pvt. Ltd. Oral Solid Dosage Unit Ahmedabad 382213, INDIA Distributed by: Advanced Rx of Tennessee, LLC Glasgow, KY 42141 Rev. 08-2024-01 This Medication Guide has been approved by the U.S. Food and Drug Administration. Dispense with Medication Guide available at: documents.amneal.com/mg/tramadol-tablets-in.pdf

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