Tramadol Hydrochloride

Pronunciation

Pronunciation: TRAM-a-dol HYE-droe-KLOR-ide
Class: Opioid analgesic

Trade Names

Conzip
- Capsules, ER, oral 100 mg
- Capsules, ER, oral 200 mg
- Capsules, ER, oral 300 mg

Rybix ODT
- Tablets, disintegrating, oral 50 mg

Ryzolt
- Tablets, ER, oral 100 mg
- Tablets, ER, oral 200 mg
- Tablets, ER, oral 300 mg

Tramadol Hydrochloride
- Capsules, ER, oral 150 mg

Ultram
- Tablets, oral 50 mg

Ultram ER
- Tablets, ER, oral 100 mg
- Tablets, ER, oral 200 mg
- Tablets, ER, oral 300 mg

Ralivia (Canada)
Tridural (Canada)
Zytram XL (Canada)

Pharmacology

Binds to mu-opioid receptors and inhibits reuptake of norepinephrine and serotonin; exact mechanism of action unknown.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Mean absolute bioavailability of tramadol is 75% (immediate release), 85% to 90% ( Ultram ER ), or 95% ( Ryzolt ). T max is 2 h (immediate release), 4 h ( Ryzolt ), and 12 h ( Ultram ER ). Steady-state plasma concentrations of tramadol and the metabolite are achieved within 2 days (immediate release, Ryzolt ) and within 4 days ( Ultram ER ). Food delays T max by 30 min (orally disintegrating tablets). High-fat meals increased T max by 3 h and decreased C max and AUC by 28% and 16%, respectively ( Ultram ER ).

Distribution

Tramadol is 20% protein bound and is independent of concentration up to 10 mcg/mL. Vd is approximately 2.7 L/kg.

Metabolism

Tramadol is extensively metabolized after administration. The major metabolic pathway is N- and O-demethylation and glucuronidation or sulfation in liver. N-demethylation is mediated by CYP3A4 and CYP2B6. The O-demethylated metabolite is M1. Production of M1 is dependent on CYP2D6.

Elimination

30% of a dose is excreted unchanged in urine; 60% is excreted as metabolites. The half-life is 6.3 h for tramadol immediate release and 7.4 h for M1. The half-life is 7.9 h for Ultram ER (6.5 h for Ryzolt ) and 7.5 to 8.8 h for M1.

Special Populations

Renal Function Impairment

In patients with renal impairment, there is a decreased rate and extent of excretion of tramadol and M1. The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose. Ultram ER has not been studied in patients with severe renal impairment (CrCl less than 30 mL/min); Ryzolt has not been studied in patients with renal impairment.

Hepatic Function Impairment

Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis. Tramadol ER has not been studied in patients with hepatic impairment ( Ryzolt ) or in patients with severe hepatic impairment ( Ultram ER).

Elderly

C max is slightly elevated (208 vs 162 ng/mL) and the elimination half-life is prolonged (7 vs 6 h) in subjects 65 to 75 y of age with tramadol immediate release. Tramadol ER has not been studied in patients older than 65 y.

Gender

Absolute bioavailability, AUC, and C max are higher in women than in men. Dosage adjustment is not recommended.

Indications and Usage

Relief of moderate to moderately severe pain (immediate release); relief of moderate to moderately severe chronic pain for patients who require around-the-clock treatment for an extended period of time (ER).

Unlabeled Uses

Premature ejaculation; restless leg syndrome.

Contraindications

Known hypersensitivity to tramadol, any other component of this product, or opioids; in any situation in which opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids, or psychotropic drugs; significant respiratory depression in unmonitored settings or the absence of resuscitative equipment, acute or severe bronchial asthma or hypercapnia in unmonitored settings or the absence of resuscitative equipment ( Ryzolt only).

Dosage and Administration

Immediate-Release Tablets
Adults and Children 17 y and older

PO Start with 25 mg/day in the morning and titrate in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg 4 times daily). Thereafter, increase the dose by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg 4 times daily). After titration, administer 50 to 100 mg every 4 to 6 h as needed for pain relief (max, 400 mg/day).

Elderly

PO Max, 300 mg/day in patients 75 y and older.

Renal Function Impairment (CrCl less than 30 mL/min)

PO Increase the dosing interval to 12 h (max, 200 mg/day).

Hepatic Function Impairment (cirrhosis)

PO 50 mg every 12 h.

Orally Disintegrating Tablets
Adults and Children 17 y and older

PO 50 to 100 mg as needed every 4 to 6 h (max, 400 mg/day). Tolerability can be improved by initiating therapy with a titration regimen. The total daily dosage may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg 4 times daily).

Elderly

PO Max, 300 mg/day in patients 75 y and older.

Renal Function Impairment (CrCl less than 30 mL/min)

PO Increase the dosing interval to 12 h (max, 200 mg/day).

Hepatic Function Impairment (cirrhosis)

PO 50 mg every 12 h.

ER Capsules
Adults and children 18 y and older

PO Start with 100 mg once daily and titrate up as necessary to 150, 200, and 300 mg every 5 days to achieve a balance between relief of pain and tolerability. For patients currently on tramadol immediate-release products, calculate the 24-h tramadol immediate-release dose and initiate a total daily dosage of tramadol ER rounded down to the nearest lowest dose. Subsequently individualize the dose as needed (max, 300 mg/day)

ER Tablets
Adults and Children 17 y and older ( Ryzolt is approved in children 17 y and older; Ultram ER is approved in patients 18 y and older)

PO Start with 100 mg once daily and titrate as needed in 100 mg increments every 2 to 3 days ( Ryzolt ) or every 5 days ( Ultram ER), depending upon tolerability (max, 300 mg/day).

Patients currently on tramadol immediate release

Calculate the 24 h tramadol immediate release dose and start a total dose of tramadol ER rounded down to the next lowest 100 mg increment. Subsequently, individualize the dose as needed.

Renal Function Impairment (CrCl less than 30 mL/min)

Do not administer.

Hepatic Function Impairment

Do not administer Ryzolt to patients with hepatic impairment; do not administer Ultram ER to patients with severe hepatic impairment (Child-Pugh class C).

General Advice

  • Take without regards to meals.
  • ER tablets must be swallowed whole with liquid and must not be chewed, crushed, dissolved, or split.
  • Advise patients not to chew, break, or split the orally disintegrating tablets. Place tablet on the tongue until it completely dissolves and then swallow with saliva. May be taken with or without water.
  • Starting at the lowest possible dose and titrating upward as needed has resulted in increased tolerability and fewer discontinuations.
  • Taper tramadol when discontinuing therapy to reduce the signs and symptoms of withdrawal.
  • Because of limitations in flexibility of the tramadol ER dosage form, some patients maintained on tramadol immediate release may not be able to convert to tramadol ER.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Alpha-2 adrenergic blockers

Increased the risk of serotonin syndrome. Use with caution.

Carbamazepine

May reduce serum tramadol levels, leading to decreased efficacy. Coadministration is not recommended.

CNS depressants (eg, alcohol, anesthetics, narcotics, other opioids, phenothiazines, sedative-hypnotics, tranquilizers)

Risk of CNS and respiratory depression may be increased. Use tramadol with caution and in reduced dosages. Avoid alcohol.

CYP2D6 inhibitors (amitriptyline, fluoxetine, paroxetine, quinidine)

Tramadol plasma levels may be increased; however, the clinical importance of this interaction is not known.

CYP3A4 inducers (eg, rifampin, phenytoin, St. John's wort)

May produce increased clearance of tramadol. Use with caution.

CYP3A4 inhibitors (eg, erythromycin, ketoconazole)

Coadministration may produce increased tramadol concentrations and increase the risk for serious adverse events, including seizures and serotonin syndrome. Use with caution and closely monitor the patient.

Digoxin

Digoxin toxicity has been reported. Monitor patients for signs and symptoms of digoxin toxicity. Adjust the digoxin dose as needed.

Drugs that reduce the seizure threshold, neuroleptics, tiagabine

Risk of seizures may be increased. Use with caution and closely monitor the patient.

Lithium

Serotonin syndrome has been reported. Use with caution and closely monitor the patient, particularly during the start of treatment and dose increases.

MAOIs (eg, linezolid, phenelzine, rasagiline), selective 5-HT 1 receptor agonists (eg, sumatriptan), SSRIs (eg, fluoxetine), SNRIs (eg, venlafaxine), tricyclic antidepressants and other tricyclic compounds (eg, cyclobenzaprine, promethazine)

Concomitant use increases the risk of adverse reactions, including seizures and/or serotonin syndrome. Use with caution and closely monitor the patient, particularly during the start of treatment and dose increases. Coadministration of tramadol and rasagiline is contraindicated.

Warfarin

Anticoagulant effect of warfarin may be increased. Monitor anticoagulant activity and adjust the warfarin dose as needed.

Adverse Reactions

Cardiovascular

Postural hypotension (5%); hot flushes, vasodilation (1% to less than 5%).

CNS

Dizziness/vertigo (33%); headache (32%); somnolence (25%); stimulation (14%); asthenia (12%); insomnia (11%); anxiety, confusion, coordination disturbance, depression, euphoria, fatigue, hypoesthesia, lethargy, malaise, nervousness, paresthesia, restlessness, sleep disorder, tremor, weakness (1% to less than 5%).

Dermatologic

Flushing (16%); pruritus (12%); sweating (9%); dermatitis, rash (1% to less than 5%).

EENT

Blurred vision, miosis, nasal congestion, nasopharyngitis, rhinorrhea, sneezing, sore throat, visual disturbance (1% to less than 5%).

GI

Constipation (46%); nausea (40%); vomiting (17%); dyspepsia (13%); diarrhea, dry mouth (10%); anorexia (6%); abdominal pain, flatulence, upper abdominal pain, viral gastroenteritis (1% to less than 5%).

Genitourinary

Menopausal symptoms, urinary frequency, urinary retention, urinary tract infection (1% to less than 5%).

Metabolic-Nutritional

Decreased appetite, decreased weight (1% to less than 5%).

Musculoskeletal

Arthralgia, back pain, hypertonia, limb pain, neck pain, rigors (1% to less than 5%).

Respiratory

Bronchitis, cough, dyspnea, sinus congestion, sinusitis, upper respiratory tract infection (1% to less than 5%).

Miscellaneous

Chest pain, fall, feeling hot, increased blood CPK, influenza, influenza-like illness, pain, pyrexia (1% to less than 5%).

Precautions

Monitor

Carefully monitor all patients for signs and symptoms of abuse and addiction because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.


Pregnancy

Category C . Long-term use during pregnancy may lead to physical dependence and postpartum withdrawal symptoms in the newborn.

Lactation

Excreted in breast milk. Tramadol is not recommended for obstetrical preoperative medication or for postdelivery analgesia in breast-feeding women.

Children

Safety and efficacy of immediate release formulations and Ryzolt not established in children younger than 16 y; safety and efficacy of Ultram ER not established in children younger than 18 y.

Elderly

Use with caution, usually starting at the low end of the dose range, because of the greater frequency of hepatic, renal, or cardiac function impairment, and of concomitant diseases or other drug therapy. In patients older than 75 y, use great caution when prescribing tramadol ER.

Hypersensitivity

Serious and, rarely, fatal anaphylactoid reactions may occur, often following the first dose.

Renal Function

Do not administer tramadol ER to patients with severe renal impairment (CrCl less than 30 mL/min). Dosage reduction recommended in patients taking immediate-release tramadol with a CrCl less than 30 mL/min.

Hepatic Function

Do not administer Ryzolt to patients with hepatic impairment; do not administer Ultram ER to patients with severe hepatic impairment. Dosage reduction recommended in patients with cirrhosis who are taking immediate-release tramadol.

Hazardous Tasks

May impair mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery.

Acute abdominal conditions

Tramadol may complicate the assessment of acute abdominal conditions.

Drug abuse/dependence

Tramadol can be abused and is subject to criminal diversion.

Head trauma

Use with caution in patients with increased intracranial pressure or head trauma.

Mortality

Tramadol products in excessive doses, either alone or in combination with other CNS depressants, are a cause of drug-related deaths. Fatalities within the first hour of overdose are not uncommon. Many of the tramadol-related deaths occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of other CNS drugs.

Phenylketonuria

Patients with a history of sensitivity to phenylketones may be at increased risk and, therefore, should not receive tramadol orally disintegrating tablets.

Respiratory depression

Use with caution in patients at risk for respiratory depression.

Seizures

Seizures may occur within the recommended dose range. In addition, the risk of convulsions may be increased in patients with epilepsy, history of seizures, or risk of seizures (eg, head trauma).

Serotonin syndrome

Potentially life-threatening serotonin syndrome may develop, particularly when combined with serotonergic agents (eg, SSRIs, SNRIs, triptans).

Suicide risk

Do not use in patients who are suicidal or addiction prone. Use with caution in patients who use alcohol in excess and who suffer from emotional disturbance or depression.

Withdrawal

If tramadol is discontinued abruptly, withdrawal symptoms may occur.

Overdosage

Symptoms

Bradycardia, cardiac arrest, CNS depression, cold and clammy skin, coma, constricted pupils, death, hypotension, lethargy, respiratory depression, seizure, skeletal muscle flaccidity, somnolence.

Patient Information

  • Inform patients that tramadol may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or other drugs that significantly reduce the metabolic clearance of tramadol.
  • Inform patients that tramadol may impair mental or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery.
  • Inform patients not to take tramadol with alcohol-containing beverages.
  • Inform patients to use tramadol with caution when taking medications such as tranquilizers, hypnotics, or other opiate-containing analgesics.
  • Instruct female patients to inform their health care provider if they are pregnant, think they might become pregnant, or are trying to become pregnant.
  • Educate patients regarding the single-dose, 24-hour dose limit and the time interval between doses for immediate-release tablets, and the single-dose, 24-hour dosing regimen for ER tablets. Exceeding these recommendations can result in respiratory depression, seizures, and death.
  • Inform patients that tramadol ER tablets are for oral use only and should be swallowed whole with a sufficient quantity of liquid. Instruct patients not to chew, crush, dissolve, or split the tablets.
  • Advise patients that the signs and symptoms of withdrawal may be reduced by tapering the medication when discontinuing therapy.
  • Advise phenylketonuric patients taking the orally disintegrating tablets that the tablets contain phenylalanine.
  • Advise patients on proper administration of the orally disintegrating tablet.

Copyright © 2009 Wolters Kluwer Health.

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