Get your patient on Tramadol Hydrochloride

Tramadol hydrochloride extended-release capsules is an extended-release formulation intended for once a day dosing in adults aged 18 years and older. The tablets must be swallowed whole with liquid and must not be split, chewed, dissolved or crushed. Chewing, crushing or splitting the tablet could result in the uncontrolled delivery of tramadol, in overdose and death tramadol hydrochloride extended-release capsules [see WARNINGS AND PRECAUTIONS (5.11 ), DRUG ABUSE AND DEPENDENCE (9 ) and, OVERDOSE (10.1 )].

Do not administer tramadol hydrochloride extended-release capsules at a dose exceeding 300 mg per day. Do not use tramadol hydrochloride extended-release capsules more than once daily or concomitantly with other tramadol products [see WARNINGS AND PRECAUTIONS (5.12 )]

Tramadol hydrochloride extended-release capsules Initiate treatment with tramadol hydrochloride extended-release capsules at a dose of 100 mg once daily and titrated up as necessary by 100 mg increments every five days to tramadol hydrochloride extended-release capsules achieve a balance between relief of pain and tolerability.

Calculate the 24-hour tramadol IR dose and initiate a total daily dose of tramadol hydrochloride extended-release capsules rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with tramadol hydrochloride extended-release capsules, some patients maintained on tramadol IR products may not be able to convert to tramadol hydrochloride extended-release capsules.

Initiate dosing of an elderly patient (over 65 years of age) should be initiated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. Tramadol hydrochloride extended-release capsules should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population.

The limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release capsules do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Do not use tramadol hydrochloride extended-release capsules in patients with creatinine clearance less than 30 mL/min [see USE IN SPECIFIC POPULATIONS (8.6 ) and CLINICAL PHARMACOLOGY (12.3 ) ]

The limited availability of dose strengths and once daily dosing of tramdol hydrochloride extended-release capsules do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Do not use tramadol hydrochloride extended-release capsules in patients with severe hepatic impairment (Child-Pugh Class C) [see USE IN SPECIFIC POPULATIONS (8.7 ) and CLINICAL PHARMACOLOGY (12.3 ) ] .

Withdrawal symptoms may occur if tramadol hydrochloride extended-release capsules is discontinued abruptly. Clinical experience with tramadol suggests that withdrawal symptoms may be reduced by tapering tramadol hydrochloride extended-release capsules [see WARNINGS AND PRECAUTIONS (5.10 ) and DRUG ABUSE AND DEPENDENCE (9.3 ) ].

Tramadol hydrochloride extended-release capsules may be taken without regard to food [see CLINICAL PHARMACOLOGY (12.3 )].

Tramadol hydrochloride extended-release capsules should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn [ see Drug Abuse and Dependence (9.1 ) ]. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.

The effect of tramadol hydrochloride extended-release capsules, if any, on the later growth, development, and functional maturation of the child is unknown.

Tramadol hydrochloride extended-release capsules is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1. It is not known whether this drug is excreted in human milk following an oral dose.

The safety and efficacy of tramadol hydrochloride extended-release capsules in patients under 18 years of age have not been established. The use of tramadol hydrochloride extended-release capsules in the pediatric population is not recommended.

In general, caution should be used when selecting the dose for an elderly patient. Usually, dose administration should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy

Eight hundred and twelve elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride extended-release capsules in clinical trials. Of those subjects, two hundred and forty were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: nausea, constipation, somnolence, dizziness, dry mouth, vomiting, asthenia, pruritus, anorexia sweating, fatigue, weakness, postural hypotension and dyspepsia. For this reason, tramadol hydrochloride extended-release capsules should be used with great caution in patients older than 75 years of age [see Dosage and Administration (2.3 )].

Tramadol hydrochloride extended-release capsules has not been studied in patients with renal impairment. Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The limited availability of dose strengths of tramadol hydrochloride extended-release capsules does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, tramadol hydrochloride extended-release capsules should not be used in patients with severe renal impairment [see Dosage and Administration (2.3 ), Warnings and Precautions (5.14) and Clinical Pharmacology (12.3 )] .

Tramadol hydrochloride extended-release capsules has not been studied in patients with hepatic impairment. The limited availability of dose strengths of tramadol hydrochloride extended-release capsules does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, tramadol hydrochloride extended-release capsules should not be used in patients with severe hepatic impairment [see Dosage and Administration (2.3 ), Warnings and Precautions, (5.14) and Clinical Pharmacology (12.3 )].

Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking: [see DRUG INTERACTIONS (7.1 , 7.2 )]

• Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SNRIs) 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 ) and DRUG INTERACTIONS (7 , 1 )],
• Neuroleptics, or
• Other drugs that reduce the seizure threshold.

Risk of seizures 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 overdose, naloxone administration may increase the risk of seizure.

• Do not prescribe tramadol hydrochloride extended-release capsules 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 extended-release capsules with caution for patients with a history of misuse and/or are taking CNS-active drugs including tranquilizers or antidepressant drugs, or alcohol in excess, and patients who suffer from emotional disturbance or depression [see Drug INTERACTIONS (7.4 )].
• Tell your patients not to exceed the recommended dose and to limit their intake of alcohol [see DOSAGE AND ADMINISTRATION (2.1 ) and WARNINGS AND PRECAUTIONS (5.6 )] .

The development of a potentially life-threatening serotonin syndrome may occur with use of tramadol products, including tramadol hydrochloride extended-release capsules, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, with drugs which impair metabolism of serotonin (including MAOIs) and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose. [see CLINICAL PHARMACOLOGY (12.3 )] .

Serotonin syndrome 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) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. 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 anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive tramadol hydrochloride extended-release capsules [see Contraindications (4 )].

Administer tramadol hydrochloride extended-release capsules cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. If large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures [see Warnings and Precautions (5.1 ), Overdosage (10 )] .

Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Use tramadol hydrochloride extended-release capsules with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol hydrochloride extended-release capsules increases the risk of CNS and respiratory depression in these patients. Alcohol-containing beverages should not be consumed by patients using tramadol hydrochloride extended-release capsules [see WARNINGS AND PRECAUTIONS (5.6 ), DRUG INTERACTIONS (7.4 ), and OVERDOSE (10 )] .

Use tramadol hydrochloride extended-release capsules with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol hydrochloride extended-release capsules [see Warnings and Precautions (5.5 )] .

Tramadol hydrochloride extended-release capsules may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Caution patients initiating therapy with tramadol hydrochloride extended-release capsules or those whose dose has been increased to refrain from potentially hazardous activities until it is established that their mental and physical abilities are not significantly impaired.

Use tramadol hydrochloride extended-release capsules with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of tramadol hydrochloride extended-release capsules with MAO inhibitors or SSRI's increases the risk of adverse reactions, including seizure and serotonin syndrome [see Warnings and Precautions (5.1 , 5.3 )] .

Withdrawal symptoms may occur if tramadol hydrochloride extended-release capsules is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience with other formulations of tramadol suggests that withdrawal symptoms may be reduced by tapering tramadol hydrochloride extended-release capsules when discontinuing tramadol therapy.

Tramadol hydrochloride extended-release capsules contains tramadol, an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing tramadol hydrochloride extended-release capsules in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Tramadol hydrochloride extended-release capsules could be abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions (5.13 ), Drug Abuse and Dependence (9 ), and Overdosage (10 )] .

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.

Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Serious potential consequences of overdosage with tramadol hydrochloride extended-release capsules are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment [see Overdosage (10 )].

The administration of tramadol hydrochloride extended-release capsules may complicate the clinical assessment of patients with acute abdominal conditions.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Tramadol hydrochloride extended-release capsules Capsules were administered to a total of 1987 patients in clinical trials. These included four double-blind and one long-term, open-label study in patients with osteoarthritis of the hip and knee. A total of 812 patients were 65 years or older. Adverse reactions with doses from 100 mg to 300 mg in the four pooled, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain are presented in the following table (see Table 1 ).

The following adverse reactions were reported from all chronic pain studies (N=1917). The lists below include adverse reactions not otherwise noted in Table 1 .

Adverse reactions with incidence rates of 1.0% to <5.0%

Cardiac disorders: hypertension

Gastrointestinal disorders: dyspepsia, flatulence

General disorders: abdominal pain, accidental injury, chills, fever, flu syndrome, neck pain, pelvic pain

Investigations: hyperglycemia, urine abnormality

Metabolism and nutrition disorders: peripheral edema, weight loss

Musculoskeletal, connective tissue and bone disorders: myalgia

Nervous system disorders: paresthesia, tremor, withdrawal syndrome

Psychiatric disorders: agitation, anxiety, apathy, confusion, depersonalization, depression, euphoria, nervousness

Respiratory, thoracic and mediastinal disorders: bronchitis, pharyngitis, rhinitis, sinusitis

Skin and subcutaneous tissue disorders: rash

Urogenital disorders: prostatic disorder, urinary tract infection

Vascular disorders : vasodilatation

Adverse reactions with incidence rates of 0.5% to <1.0% at any dose and serious adverse reactions reported in at least two patients.

Cardiac disorders: EKG abnormal, hypotension, tachycardia

Gastrointestinal disorders: gastroenteritis

General disorders: neck rigidity, viral infection

Hematologic/Lymphatic disorders; anemia, ecchymoses

Metabolism and nutrition disorders: blood urea nitrogen increased, GGT increased, gout, SGPT increased

Musculoskeletal disorders: arthritis, arthrosis, joint disorder, leg cramps

Nervous system disorders: emotional lability, hyperkinesia, hypertonia, thinking abnormal, twitching, vertigo

Respiratory disorders : pneumonia

Skin and subcutaneous tissue disorders: hair disorder, skin disorder, urticaria

Special Senses : eye disorder, lacrimation disorder

Urogenital disorders : cystitis, dysuria, sexual function abnormality, urinary retention

Concomitant use of tramadol increases the seizure risk in patients taking SSRI/SNRI antidepressants or anorectics, TCA antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics or other drugs that lower the seizure threshold [ see Warnings and Precautions (5.1 ) ].

Tramadol is metabolized by CYP2D6 to form the active metabolite, O-desmethyl tramadol (M1). In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.

Tramadol is also metabolized by CYP3A4 [ see Clinical Pharmacology (12.3 ) ]. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin with tramadol hydrochloride extended-release capsules may affect the metabolism of tramadol leading to altered tramadol exposure.

Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors, such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome [see Clinical Pharmacology (12.3 )] .

There have been post-marketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when tramadol hydrochloride extended-release capsules is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John's Wort. If concomitant treatment of tramadol hydrochloride extended-release capsules with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions (5.3 )].

Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when tramadol hydrochloride extended-release capsules is co-administered with a triptan. If concomitant treatment of tramadol hydrochloride extended-release capsules with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions (5.3 )].

Tramadol hydrochloride extended-release capsules should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol hydrochloride extended-release capsules increases the risk of CNS and respiratory depression in these patients [see Warnings and Precautions (5.6 )].

Quinidine is a strong inhibitor of CYP2D6. Coadministration of quinidine with an extended-release tramadol product resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure. The clinical consequences of these findings are unknown. [ see Clinical Pharmacology (12.3 ) ]. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.

Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.

Administration of CYP3A4 inducers, such as carbamezepine, rifampin and St. John's Wort, with tramadol hydrochloride extended-release capsules may affect the metabolism of tramadol leading to reduced tramadol exposure [see CLINICAL PHARMACOLOGY (12.3 ) ] .

Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release capsules and carbamazepine is not recommended.

Tramadol hydrochloride extended-release capsules contains tramadol, a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake 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 opiate 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.

Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro , as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in clinical studies.

Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left ventricular function or cardiac index. Orthostatic hypotension has been observed.

The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. Tramadol hydrochloride extended-release capsules is administered as a racemate and both tramadol and M1 are detected in the circulation. The Cmax and AUC of tramadol hydrochloride extended-release capsules Capsules have been observed to be dose-proportional over an oral dose range of 100 to 300 mg in healthy subjects.

Absorption:

After a single dose administration of tramadol hydrochloride extended-release capsules, Tmax occurs around 10-12 hours.

The mean Cmax and AUC of tramadol hydrochloride extended-release capsules Capsules after a 300 mg single dose was 308 ng/mL and 6777 ng•hr/mL, respectively under fasting conditions. Tramadol hydrochloride extended-release capsules Capsules is bioequivalent to a reference extended-release tramadol product following a single 300 mg dose under fasting conditions.

At steady-state, tramadol hydrochloride extended-release capsules at 200 mg has been observed to be bioequivalent to a reference extended-release tramadol product at 200 mg under fasting conditions (Table 2 ). Following administration of tramadol hydrochloride extended-release capsules 200 mg Capsules, steady-state plasma concentrations of both tramadol and M1 are achieved within four days of once daily dosing.

Storage

Dispense in a tight container. Store at 25°C; excursions permitted to 15°C to 30°C (59°F to 86°F). Keep out of reach of children.