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Ryzolt

WARNINGS

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:

  • Selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics),
  • Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or
  • Other opioids.

Administration of RYZOLT™ (tramadol hydrochloride extended-release tablets) may enhance the seizure risk in patients taking:

  • Monoamine Oxidase (MAO) inhibitors (See also WARNINGS - Use with MAO Inhibitors and Serotonin Re-uptake Inhibitors),
  • Neuroleptics, or
  • Other drugs that reduce the seizure threshold.

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 RYZOLT™ (tramadol hydrochloride extended-release tablets) for patients who are suicidal or addiction-prone. Prescribe RYZOLT™ (tramadol hydrochloride extended-release tablets) with caution for patients taking tranquilizers or antidepressant drugs and for patients who use alcohol in excess. Serious potential consequences of overdosage with RYZOLT™ (tramadol hydrochloride extended-release tablets) are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE).

Serotonin Syndrome risk

The development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including RYZOLT™ (tramadol hydrochloride extended-release tablets) , 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, Pharmacokinetics).

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.

Anaphylactoid Reactions

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 CONTRAINDICATIONS).

Respiratory Depression

RYZOLT™ (tramadol hydrochloride extended-release tablets) 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 WARNINGS, Seizure Risk and OVERDOSAGE).

Interaction with Central Nervous System (CNS) Depressants

RYZOLT™ (tramadol hydrochloride extended-release tablets) should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol increases the risk of CNS and respiratory depression in these patients.

Increased Intracranial Pressure or Head Trauma

RYZOLT™ (tramadol hydrochloride extended-release tablets) 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™ (tramadol hydrochloride extended-release tablets) (See Respiratory Depression).

Use in Ambulatory Patients

RYZOLT™ (tramadol hydrochloride extended-release tablets) 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.

Use with MAO Inhibitors and Serotonin Re-uptake Inhibitors

RYZOLT™ (tramadol hydrochloride extended-release tablets) 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

Withdrawal symptoms may occur if RYZOLT™ (tramadol hydrochloride extended-release tablets) 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™ (tramadol hydrochloride extended-release tablets) . 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™ (tramadol hydrochloride extended-release tablets) 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.

Misuse, Abuse and Diversion of Opioids

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™ (tramadol hydrochloride extended-release tablets) in situations where the healthcare professional is concerned about a risk of misuse, abuse, or diversion.

RYZOLT™ (tramadol hydrochloride extended-release tablets) 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.

PRECAUTIONS

Acute Abdominal Conditions

The administration of RYZOLT™ (tramadol hydrochloride extended-release tablets) may complicate the clinical assessment of patients with acute abdominal conditions.

Use in Renal and Hepatic Disease

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™ (tramadol hydrochloride extended-release tablets) has not been studied in patients with renal impairment. The limited availability of dose strengths and once daily dosing of RYZOLT™ (tramadol hydrochloride extended-release tablets) do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, RYZOLT (tramadol hydrochloride extended-release tablets) ™ should not be used in patients with severe renal impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION)

The metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. RYZOLT™ (tramadol hydrochloride extended-release tablets) has not been studied in patients with hepatic impairment. The limited availability of dose strengths and once daily dosing of RYZOLT™ (tramadol hydrochloride extended-release tablets) 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 CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION)

Use in Drug and Alcohol Addiction

RYZOLT™ (tramadol hydrochloride extended-release tablets) is an opioid with no approved use for the management of addictive disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission is for the management of pain requiring opioid analgesia.

Carcinogenesis, Mutagenesis and Impairment of Fertility

A slight, but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.5 times the maximum daily human dosage of 185 mg/m2) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurred in a rat carcinogenicity study (dosing orally up to 30 mg/kg - 180 mg/m2 equal to the maximum daily human dosage of tramadol).

Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Positive mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Relevance of the finding in humans is unknown.

No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (300 mg/m2) in male rats and 75 mg/kg (450 mg/m2) in female rats. These dosages are 1.6 and 2.4 times the maximum daily human dosage of 185 mg/m2, respectively.

Pregnancy

Teratogenic Effects: Pregnancy Category C

Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg or 360 mg/m2), rats ( ≥ 25 mg/kg or 150 mg/m2) and rabbits ( ≥ 75mg/kg or 900 mg/m2) at maternally toxic dosages, but was not teratogenic at these dose levels. These dosages on an mg/m2 basis are 1.9, 0.8 and 4.9 times the maximum daily human dosage (185 mg/m2) for mouse, rat and rabbit, respectively.

No drug related teratogenic effects were observed in progeny of mice (up to 140 mg/kg or 420 mg/m2), rats (up to 80 mg/kg or 480 mg/m2) or rabbits (up to 300 mg/kg or 3600 mg/m2) treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased supernumerary ribs in maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg (3600 mg/m2), a dose that would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat and rabbit are 2.2, 2.6 and 19.4 times the maximum daily human dosage (185 mg/m2), respectively.

Non-teratogenic Effects

Tramadol was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m2 or 1.6 times the maximum daily human RYZOLT™ (tramadol hydrochloride extended-release tablets) dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m2 or 2.6 times the maximum daily human dose).

There are no adequate and well-controlled studies in pregnant women. RYZOLT™ (tramadol hydrochloride extended-release tablets) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported during post-marketing surveillance of tramadol immediate-release products.

Labor and Delivery

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

The effect of RYZOLT™ (tramadol hydrochloride extended-release tablets) , if any, on the later growth, development and functional maturation of the child is unknown.

Nursing Mother

RYZOLT™ (tramadol hydrochloride extended-release tablets) is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 g of tramadol (0.1% of the maternal dose) and 27 g of M1.

Pediatric Use

The safety and efficacy of RYZOLT™ (tramadol hydrochloride extended-release tablets) in patients under 16 years of age has not been established. The use of RYZOLT™ (tramadol hydrochloride extended-release tablets) in the pediatric population is not recommended.

Geriatric Use

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

In 12-week clinical trials, RYZOLT™ (tramadol hydrochloride extended-release tablets) was administered to 534 patients aged 65 years and older. Of those, 68 patients were 75 years of age and older. Comparable incidence rates of patients experiencing adverse events were observed for patients older than 65 years of age compared with younger patients ( < 65 years of age), except constipation for which the incidence was higher in older patients. RYZOLT™ (tramadol hydrochloride extended-release tablets) should be used with caution in patients older than 75 years of age (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Last reviewed on RxList: 3/2/2009
This monograph has been modified to include the generic and brand name in many instances.

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