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RYZOLT™ (tramadol hydrochloride extended-release tablets) was administered to a total of 2707 subjects (2406 patients and 301 healthy volunteers) during clinical studies, including four randomized double-blind studies (treatment ≥ 12 weeks) and two open-label long-term studies (treatment up to 12 months) in patients with moderate to severe pain due to osteoarthritis of the knee. A total of 844 patients were exposed to RYZOLT™ (tramadol hydrochloride extended-release tablets) for 12 weeks, 493 patients for 6 months and 243 patients for 12 months. Treatment emergent adverse events increased with dose from 100 mg to 300 mg in the three twelve-week, randomized, double-blind, placebo-controlled studies (Table 2).
Table 2. Percentage of Patients with Incidence of Adverse
Events ≥ 2% from Three 12-week Placebo-Controlled Studies (MDT3-002, MDT3-003
|ADVERSE EVENTS (MEDRA Preferred Terms)||RYZOLT™||Placebo|
|100 mg N=216||200 mg
| 300 mg
|Nausea||28 (13%)||42 (14%)||76 (14%)||179 (16%)||37 (6%)|
|Constipation||21 (10%)||36 (12%)||52 (10%)||140 (13%)||26 (4%)|
|Dizziness||16 (7%)||28 (9%)||52 (10%)||106 (10%)||18 (3%)|
|Somnolence||11 (5%)||22 (7%)||23 (4%)||77 (7%)||12 (2%)|
|Vomiting||7 (3%)||16 (5%)||31 (6%)||58 (5%)||4 (1%)|
|Pruritus||9 (4%)||15 (5%)||18 (3%)||51 (5%)||7 (1%)|
|Headache||10 (5%)||9 (3%)||15 (3%)||41 (4%)||21 (3%)|
|Sweating increased||1 (0%)||9 (3%)||14 (3%)||35 (3%)||5 (1%)|
|Dry mouth||7 (3%)||13 (4%)||6 (1%)||32 (3%)||8 (1%)|
|Fatigue||6 (3%)||7 (2%)||9 (2%)||26 (2%)||6 (1%)|
|Anorexia||4 (2%)||4 (1%)||10 (2%)||25 (2%)||2 (0%)|
|Vertigo||2 (1%)||3 (1%)||6 (1%)||21 (2%)||3 (0%)|
|Insomnia||2 (1%)||6 (2%)||9 (2%)||18 (2%)||8 (1%)|
|*Due to the difference in study design of MDT3-005, only the results of the double-blind phase of the study are presented and the dose specific results include maintenance period data only.|
The majority of patients who experienced the most common adverse events ( ≥ 5%) reported mild to moderate symptoms. Less than 3% of adverse events were rated as severe. Overall, onset of these adverse events usually occurred within the first two weeks of treatment.
Adverse reactions with an incidence of 1.0% to < 5.0%
Ear and labyrinth disorders: vertigo
General disorders: fatigue, weakness
Investigations: weight decreased
Metabolism and nutrition disorders: anorexia
Musculoskeletal and connective tissue disorders: arthralgia
Nervous system disorders: headache, tremor
Psychiatric disorders:anxiety, insomnia
Skin and subcutaneous tissue disorders: pruritus, sweating increased
Vascular disorders: hot flushes
Adverse reactions with an incidence of < 1.0%
Cardiac disorders: bradycardia
Eye disorders: blurred vision, visual disturbance
Gastrointestinal disorders: abdominal discomfort, abdominal distension, abdominal tenderness, change in bowel habit, constipation aggravated, diverticulitis, diverticulum, dyspepsia aggravated, dysphagia, fecal impaction, gastric irritation, gastritis, gastrointestinal hemorrhage, gastrointestinal irritation, gastro-esophageal reflux disease, lower abdominal pain, pancreatitis aggravated, rectal hemorrhage, rectal prolapse, retching
Hepatobiliary disorders:biliary tract disorder, cholelithiasis
Immune system disorders: hypersensitivity
Investigations: alanine aminotransferase decreased, alanine aminotransferase increased, aspartate aminotransferase decreased, aspartate aminotransferase increased, blood amylase increased, blood creatinine increased, blood in stool, blood potassium abnormal, blood pressure increased gamma glutamyltransferase increased
Metabolism and nutrition disorders: appetite decreased, dehydration
Psychiatric disorders: abnormal behavior, agitation, anxiety, confusion, depression, emotional disturbance, euphoric mood, indifference, irritability, libido decreased, nervousness, sleep disorder
Renal and urinary disorders: difficulty in micturition, urinary hesitation, urinary retention
Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction,
Respiratory, thoracic and mediastinal disorders: dyspnea
Read the Ryzolt (tramadol hydrochloride extended-release tablets) Side Effects Center for a complete guide to possible side effects
CYP2D6 and CYP3A4 Inhibitors: Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see CLINICAL PHARMACOLOGY, Pharmacokinetics), 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.
Serotonergic Drugs: There have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when RYZOLT™ (tramadol hydrochloride extended-release tablets) is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible nonselective MAOI), lithium, or St. John's Wort. If concomitant treatment of RYZOLT™ (tramadol hydrochloride extended-release tablets) 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, Serotonin Syndrome).
Triptans: Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when RYZOLT™ (tramadol hydrochloride extended-release tablets) is coadministered with a triptan. If concomitant treatment of RYZOLT™ (tramadol hydrochloride extended-release tablets) with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).
Use with Carbamazepine
Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of RYZOLT™ (tramadol hydrochloride extended-release tablets) and carbamazepine is not recommended.
Use with Quinidine
Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme, so that concomitant administration of quinidine and tramadol products results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.
Use with Digoxin and Warfarin
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.
Interaction With Central Nervous System (CNS) Depressants
RYZOLT™ (tramadol hydrochloride extended-release tablets) should be used 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. RYZOLT™ (tramadol hydrochloride extended-release tablets) increases the risk of CNS and respiratory depression in these patients.
Potential of Other Drugs to Affect Tramadol
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 partially metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John's Wort, with RYZOLT™ (tramadol hydrochloride extended-release tablets) may affect the metabolism of tramadol leading to altered tramadol exposure.
Potential for Tramadol to Affect Other Drugs
In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when administered concomitantly at therapeutic doses. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.
Drug Abuse And Addiction
RYZOLT™ (tramadol hydrochloride extended-release tablets) is a mu-agonist opioid. Tramadol, like other opioids used in analgesia, can be abused and is subject to criminal diversion.
Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
Concerns about abuse and addiction should not prevent the proper management of pain. However 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.
“Drug-seeking” behavior is very common in addicts and drug abusers. 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” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians 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 and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. RYZOLT™ (tramadol hydrochloride extended-release tablets) , like other opioids, may be diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests 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.
RYZOLT™ (tramadol hydrochloride extended-release tablets) is intended for oral use only. The crushed tablet poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the tablet excipients can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other 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. Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on continuous opioid therapy.
Risk of Overdosage
Serious potential consequences of overdosage with RYZOLT™ (tramadol hydrochloride extended-release tablets) 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)
Read the Ryzolt Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 3/2/2009
Additional Ryzolt Information
Ryzolt - User Reviews
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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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