RYZOLT

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Overview

What is RYZOLT?

CHNO ·HCl

The molecular weight of tramadol hydrochloride is 299.8. Tramadol hydrochloride is a white crystalline powder that is freely soluble in water and ethanol. RYZOLT™ extended-release tablets are for oral administration and contain 100 mg, 200 mg or 300 mg of tramadol hydrochloride. The tablets are white to off-white in color. The inactive ingredients in the tablet are colloidal silicon dioxide, pregelatinized modified starch, hydrogenated vegetable oil, magnesium stearate, polyvinyl acetate, povidone, sodium lauryl sulfate and xanthan gum.

What does RYZOLT look like?

What are the available doses of RYZOLT?

Sorry No records found.

What should I talk to my health care provider before I take RYZOLT?

Sorry No records found

How should I use RYZOLT?

RYZOLT™ is indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time.

RYZOLT™ extended-release tablets should be taken once a day. The tablets should be swallowed whole with liquid and not split, chewed, dissolved or crushed. RYZOLT™ tablets produce a continuous release of active ingredient over 24 hours: a repeat dosage within 24 hours is not recommended.

Patients Not Currently on Tramadol Immediate-Release Products:

Treatment with RYZOLT™ should be initiated at a dose of 100 mg/day. Daily doses should be titrated by 100 mg/day increments every 2-3 days (i.e., start 200 mg/day on day 3 or 4 of therapy) to achieve a balance between adequate pain control and tolerability for the individual patient. For patients requiring the 300 mg daily dose, titration should take at least 4 days (i.e. 300 mg/day on day 5). The usual daily dose is 200 or 300 mg. The daily dose and titration should be individualized for each patient. Therapy should be continued with the lowest effective dose. RYZOLT™should not be administered at a dose exceeding 300 mg per day.

Clinical experience suggests that signs and symptoms of withdrawal may be reduced by tapering medication when discontinuing tramadol therapy.

Patients Currently on Tramadol Immediate-Release Products:

For patients maintained on tramadol immediate release (IR) products, the 24-hour tramadol IR dose should be calculated and the patient should be initiated on a total daily dose of RYZOLT™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 RYZOLT™, some patients maintained on tramadol IR products may not be able to convert to RYZOLT™. RYZOLT™should not be administered at a dose Do not use RYZOLT™ with other tramadol products. (see ).

Good pain management practice dictates that analgesic dose be individualized according to patient need using the lowest beneficial dose. Studies with tramadol products in adults have shown that starting at the lowest possible dose and titrating upward will result in fewer discontinuations and increased tolerability.

RYZOLT™ should not be used in patients with:

(See ).

In general, dose selection for patients over 65 years of age who may have decreased hepatic or renal function, or other concomitant diseases, should be initiated cautiously, usually starting at the low end of the dosing range. RYZOLT™ should be administered with greater caution at the lowest effective dose in patients over 75 years, due to the potential for greater frequency of adverse events in this population.

What interacts with RYZOLT?

Sorry No Records found

What are the warnings of RYZOLT?

Sorry No Records found

What are the precautions of RYZOLT?

Sorry No Records found

What are the side effects of RYZOLT?

Sorry No records found

What should I look out for while using RYZOLT?

RYZOLT™ should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids.

Seizure Risk

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

Administration of RYZOLT™ may enhance the seizure risk in patients taking:

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

Suicide Risk

Do not prescribe

for patients who are suicidal or addiction-prone.

Serotonin Syndrome Risk

The development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including RYZOLT™, 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, ).

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).

Tramadol products in excessive doses, either alone or in combination with other Central Nervous System (CNS) depressants, including alcohol, are a major cause of drug-related deaths. Fatalities within the first hour of overdosage are not uncommon. Tramadol should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.

Many of the tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. Patients taking tramadol should be warned not to exceed the dose recommended by their physician.

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 other opioids may be at increased risk and therefore should not receive RYZOLT™ (See ).

RYZOLT™ should be administered cautiously in patients at risk for respiratory depression. In these patients, alternative non-opioid analgesics should be considered. When 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).

RYZOLT™ 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. Tramadol increases the risk of CNS and respiratory depression in these patients.

RYZOLT™ should be used 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 RYZOLT™ (See ).

RYZOLT™ may impair the mental and physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Patients using this drug should be cautioned accordingly.

RYZOLT™ should be used with great caution in patients taking MAO inhibitors. Animal studies have shown increased deaths with combined administration of tramadol and MAO inhibitors. Concomitant use of tramadol products with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome.

Withdrawal symptoms may occur if RYZOLT™is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations.

In a 12 week study, 325 patients were followed for 3 and 7 days after discontinuation of treatment with RYZOLT™. The majority of reported post-treatment adverse events including withdrawal symptoms were mild to moderate in nature. Onset of the post-treatment adverse events occurred more frequently within the first three days after treatment was stopped. Less than 1% of patients taking RYZOLT™ met the DSM-IV criteria for a diagnosis of opioid withdrawal.

Clinical experience suggests that signs and symptoms of withdrawal may be reduced by tapering medication when discontinuing tramadol therapy.

Tramadol is 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.

Like other opioid agonists, legal or illicit, tramadol can be abused. This should be considered when prescribing or dispensing RYZOLT™in situations where the healthcare professional is concerned about a risk of misuse, abuse, or diversion.

RYZOLT™ could be abused by breaking, crushing, chewing, or dissolving the product which can result in the uncontrolled delivery of the opioid, and as a consequence poses a significant risk of overdose and death.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.

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.

Interactions with Alcohol and Drugs of Abuse

Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids or drugs, whether legal or illicit, which cause central nervous system depression.

RYZOLT™ 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™, 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™ 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.

Serious potential consequences of overdosage with RYZOLT™ 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 ).

What might happen if I take too much RYZOLT?

Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension and death.

Death due to overdose have been reported with abuse and misuse of tramadol, by ingesting, inhaling, or injecting the crushed tablets. The risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol and other CNS depressants, including other opioids.

In the treatment of tramadol overdosage, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.

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 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.

How should I store and handle RYZOLT?

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light. Keep bottles tightly closed to protect from moisture. It is recommended that the infusion bags be kept in the overwrap until ready to use. Protect infusion bags from freezing.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.RYZOLT™ (tramadol hydrochloride extended-release tablets) are supplied in a number of packages and dose strengths:100-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 100" in black ink on the other side.Bottle of 30 tablets – NDC 59011-334-30Bottle of 90 tablets – NDC 59011-334-90200-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 200" in black ink on the other sideBottle of 30 tablets – NDC 59011-335-30Bottle of 90 tablets – NDC 59011-335-90300-mg, white, beveled edge, round biconvex tablets, plain on one side and printed "PP 300" in black ink on the other sideBottle of 30 tablets – NDC 59011-336-30Bottle of 90 tablets – NDC 59011-336-90Store at 25°C (77°F); excursions permitted between 15-30°C (59 – 86°F). Dispense in a tight, light-resistant container.Warning: keep out of reach of children.Manufactured by: Confab Laboratories IncSaint-Hubert, Quebec, Canada J3Y 3X3 Distributed by:Purdue Pharma L.P.Stamford, CT 06901-3431 Licensed from Labopharm Europe LimitedU.S. Patent 6,607,748; U.S. Patent 5,591,452; U.S. Patent 6,254,887RYZOLT is a trademark of Purdue Pharma L.P.

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Clinical Information

Chemical Structure

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Clinical Pharmacology

RYZOLT™ is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, at least two complementary mechanisms that demonstrate three different types of activity 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 -demethylated metabolite (M1) to mu-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mu-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 as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol.

Apart from analgesia, tramadol hydrochloride administration may produce various 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 hydrochloride is due to both parent drug and the M1 metabolite (See ).

RYZOLT™ is formulated as a racemate and both tramadol and M1 are detected in the circulation.

The pharmacokinetics of tramadol and M1 are dose-proportional over a 100 to 300 mg dose range in healthy subjects.

The median time to peak plasma concentrations of tramadol and M1 after multiple-dose administration of RYZOLT™ 200 mg tablets to healthy subjects are attained at about 4 h and 5 h, respectively (Table 1 and Figure 1).

The pharmacokinetic parameter values for RYZOLT™ 200 mg administered once daily and tramadol immediate-release 50 mg administered every six hours are provided in Table 1. The relative bioavailability of a 200 mg RYZOLT™ tablet compared to a 50 mg immediate-release tablet dosed every six hours was approximately 95% in healthy subjects.

Steady-state plasma concentrations are reached within approximately 48 hours.

Figure 1.Mean Tramadol Plasma Concentrations at Steady State Following Five Days of Oral Administration of RYZOLT™ 200 mg Once Daily and Immediate-Release Tramadol 50 mg Every 6 Hours.

Figure 2. Mean M1 Plasma Concentrations at Steady State Following Five Days of Oral Administration of RYZOLT™ 200 mg Once Daily and Immediate-Release Tramadol 50 mg Every 6 Hours

Co-administration with a high fat meal did not significantly affect AUC (overall exposure to tramadol); however, C (peak plasma concentration) increased 67% following a single 300 mg tablet administration and 54% following a single 200 mg tablet administration. RYZOLT™ was administered without regard to food in all clinical trials.

The volume of distribution of tramadol is 2.6 and 2.9 L/kg in males and females, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20%. Protein binding also appears to be independent of concentration up to 10 µg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.

Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be and demethylation and glucuronidation or sulfation in the liver. -demethylation is mediated by CYP3A4 and CYP2B6. One metabolite (-desmethyltramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition and polymorphism, which may affect the therapeutic response (See ).

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. After single administration of RYZOLT™, the mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.5 ± 1.5 and 7.5 ± 1.4 hours, respectively.

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1 in patients taking an immediate-release formulation of tramadol. RYZOLT™ has not been studied in patients with renal impairment. The limited availability of dose strengths and once daily dosing of RYZOLT™ do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, RYZOLT™ should not be used in patients with severe renal impairment (creatinine clearance less than 30 mL/min) (See ). The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.

The metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve (AUC) for tramadol and longer mean tramadol and M1 elimination half-lives (13 hours for tramadol and 19 hours for M1) after the administration of tramadol immediate-release tablets. RYZOLT™ has not been studied in patients with hepatic impairment. The limited availability of dose strengths and once daily dosing of RYZOLT™ do not permit the dosing flexibility required for safe use in patients with hepatic impairment. Therefore, RYZOLT™ should not be used in patients with hepatic impairment (see ).

Healthy elderly subjects aged 65 to 75 years administered an immediate-release formulation of tramadol, have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, mean maximum plasma concentrations are elevated (208 vs. 162 ng/mL) and the mean elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years (See ).

Following a 100 mg IV dose of tramadol, plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females. Following a single oral dose of immediate-release tramadol, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown.

The formation of the active metabolite of tramadol, M1, is mediated by CYP2D6, a polymorphic enzyme. Approximately 7% of the population has reduced activity of CYP2D6. These individuals are "poor metabolizers" of debrisoquine, dextromethorphan and tricyclic antidepressants, among other drugs. In studies in healthy subjects administered immediate-release tramadol products, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers", while M1 concentrations were 40% lower. drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 (amitriptyline, quinidine and fluoxetine and its metabolite norfluoxetine,) inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown.

Tramadol is also metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John’s Wort, with RYZOLT™ may affect the metabolism of tramadol leading to altered tramadol exposure (see ).

Quinidine

Quinidineis a selective inhibitor of CYP2D6, so that concomitant administration of quinidine and RYZOLT™ may result in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown (see ). drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.

Carbamazepine

Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because of the seizure risk associated with tramadol, concomitant administration of RYZOLT™ and carbamazepine is not recommended (see ).

Cimetidine

Concomitant administration of tramadol immediate-release tablets with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the RYZOLT™ dosage regimen with cimetidine is recommended.

RYZOLT™ was studied in four 12-week, randomized, double-blind, controlled studies in patients with moderate to severe pain due to osteoarthritis. Efficacy was demonstrated in one double-blind, placebo-controlled, randomized withdrawal design study. In this study, patients who experienced a reduction of pain and were able to tolerate RYZOLT™ during an open-label titration period, were then randomized to RYZOLT™ or to placebo for 12 weeks. Sixty-five percent of patients were able to successfully titrate onto RYZOLT™. After a washout, patients randomized to RYZOLT™ were titrated to 200 mg or 300 mg of RYZOLT™ based on tolerability and remained on that dose for the following 12-week period. Approximately 24% of patients discontinued during the randomized period of the study, with more patients discontinuing from the RYZOLT™ arm than the placebo arm due to adverse events (10% vs. 5%, respectively) and more patients discontinuing from the placebo arm than the RYZOLT™ arm due to lack of efficacy (10% vs. 8%, respectively). Patients treated with RYZOLT™ demonstrated a greater improvement in pain intensity, measured on an 11-point numerical rating scale, at the end of treatment compared to patients randomized to placebo. Figure 3 shows the fraction of patients achieving various degree of improvement in pain from baseline to the end of treatment (week 12). The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement.

Figure 3. Proportion of Patients Achieving Various Levels of Pain Relief as Measured by 12-Week Pain Intensity.

Non-Clinical Toxicology

RYZOLT™ should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids.

Seizure Risk

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

Administration of RYZOLT™ may enhance the seizure risk in patients taking:

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

Suicide Risk

Do not prescribe

for patients who are suicidal or addiction-prone.

Serotonin Syndrome Risk

The development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including RYZOLT™, 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, ).

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).

Tramadol products in excessive doses, either alone or in combination with other Central Nervous System (CNS) depressants, including alcohol, are a major cause of drug-related deaths. Fatalities within the first hour of overdosage are not uncommon. Tramadol should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.

Many of the tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. Patients taking tramadol should be warned not to exceed the dose recommended by their physician.

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 other opioids may be at increased risk and therefore should not receive RYZOLT™ (See ).

RYZOLT™ should be administered cautiously in patients at risk for respiratory depression. In these patients, alternative non-opioid analgesics should be considered. When 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).

RYZOLT™ 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. Tramadol increases the risk of CNS and respiratory depression in these patients.

RYZOLT™ should be used 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 RYZOLT™ (See ).

RYZOLT™ may impair the mental and physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Patients using this drug should be cautioned accordingly.

RYZOLT™ should be used with great caution in patients taking MAO inhibitors. Animal studies have shown increased deaths with combined administration of tramadol and MAO inhibitors. Concomitant use of tramadol products with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome.

Withdrawal symptoms may occur if RYZOLT™is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations.

In a 12 week study, 325 patients were followed for 3 and 7 days after discontinuation of treatment with RYZOLT™. The majority of reported post-treatment adverse events including withdrawal symptoms were mild to moderate in nature. Onset of the post-treatment adverse events occurred more frequently within the first three days after treatment was stopped. Less than 1% of patients taking RYZOLT™ met the DSM-IV criteria for a diagnosis of opioid withdrawal.

Clinical experience suggests that signs and symptoms of withdrawal may be reduced by tapering medication when discontinuing tramadol therapy.

Tramadol is 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.

Like other opioid agonists, legal or illicit, tramadol can be abused. This should be considered when prescribing or dispensing RYZOLT™in situations where the healthcare professional is concerned about a risk of misuse, abuse, or diversion.

RYZOLT™ could be abused by breaking, crushing, chewing, or dissolving the product which can result in the uncontrolled delivery of the opioid, and as a consequence poses a significant risk of overdose and death.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.

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.

Interactions with Alcohol and Drugs of Abuse

Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids or drugs, whether legal or illicit, which cause central nervous system depression.

RYZOLT™ 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™, 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™ 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.

Serious potential consequences of overdosage with RYZOLT™ 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 ).

The administration of RYZOLT™ may complicate the clinical assessment of patients with acute abdominal conditions.

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1 in patients taking an immediate-release formulation of tramadol. RYZOLT™ has not been studied in patients with renal impairment. The limited availability of dose strengths and once daily dosing of RYZOLT™ do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, RYZOLT™ should not be used in patients with severe renal impairment (see and ).

The metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. RYZOLT™ has not been studied in patients with hepatic impairment. The limited availability of dose strengths and once daily dosing of RYZOLT™ do not permit the dosing flexibility required for safe use in patients with hepatic impairment. Therefore, RYZOLT™ should not be used in patients with hepatic impairment seeand ).

RYZOLT™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™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.

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.

Ear and labyrinth disorders:

Gastrointestinal disorders:

General disorders

Investigations:

Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders:

Nervous system disorders

Psychiatric disorders

Skin and subcutaneous tissue disorders

Vascular disorders:

Blood and lymphatic system disorders:

Cardiac disorders

Eye disorders:

Gastrointestinal disorders

General disorders

Hepatobiliary disorders:

Immune system disorders:

Investigations

Metabolism and nutrition disorders

Nervous system disorders

Psychiatric disorders

Renal and urinary disorders

Reproductive system and breast disorders

Respiratory, thoracic and mediastinal disorders

Skin and subcutaneous tissue disorders

Vascular disorders

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Overview

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How should I use RYZOLT?

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RYZOLT

Overview

What is RYZOLT?

What does RYZOLT look like?

What are the available doses of RYZOLT?

What should I talk to my health care provider before I take RYZOLT?

How should I use RYZOLT?

What interacts with RYZOLT?

What are the warnings of RYZOLT?

What are the precautions of RYZOLT?

What are the side effects of RYZOLT?

What should I look out for while using RYZOLT?

What might happen if I take too much RYZOLT?

How should I store and handle RYZOLT?

Clinical Information

Chemical Structure

Clinical Pharmacology

Non-Clinical Toxicology

Reference

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

Review

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