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RYZOLT
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.
Clinical Information
Chemical Structure
No Image foundClinical 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.
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Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).