ADVERSE REACTIONS SECTION.

Adverse Reactions RYZOLT(TM)was administered to 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. total of 844 patients were exposed to RYZOLT(TM)for 12 weeks, 493 patients for 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. Adverse reactions with an incidence of 1.0% to less than 5.0%Ear and labyrinth disorders: vertigoGastrointestinal disorders: abdominal pain, diarrhea, dry mouth, dyspepsia, upper abdominal painGeneral disorders: fatigue, weaknessInvestigations: weight decreasedMetabolism and nutrition disorders: anorexiaMusculoskeletal and connective tissue disorders: arthralgiaNervous system disorders: headache, tremorPsychiatric disorders: anxiety, insomniaSkin and subcutaneous tissue disorders: pruritus, sweating increasedVascular disorders: hot flushesAdverse reactions with an incidence of less than 1.0%Blood and lymphatic system disorders: anemia, thrombocytopeniaCardiac disorders: bradycardia Eye disorders: blurred vision, visual disturbanceGastrointestinal disorders: abdominal discomfort, abdominal distension, abdominal tenderness, change in bowel habit, constipation aggravated, diverticulitis, diverticulum, dyspepsia aggravated, dysphagia, fecal impaction, gastric irritation, gastritis, gastrointestinal hemorrhage, gastrointestinal irritation, gastro-esophageal reflux disease, lower abdominal pain, pancreatitis aggravated, rectal hemorrhage, rectal prolapse, retching General disorders: asthenia, malaise Hepatobiliary disorders: biliary tract disorder, cholelithiasisImmune system disorders: hypersensitivityInvestigations: alanine aminotransferase decreased, alanine aminotransferase increased, aspartate aminotransferase decreased, aspartate aminotransferase increased, blood amylase increased, blood creatinine increased, blood in stool, blood potassium abnormal, blood pressure increased gamma glutamyltransferase increasedMetabolism and nutrition disorders: appetite decreased, dehydration Nervous system disorders: ataxia, disturbance in attention, dysarthria, gait abnormal, headache aggravated, mental impairment, sedation, seizure, sleep apnea syndrome, syncope, tremorPsychiatric disorders: abnormal behavior, agitation, anxiety, confusion, depression, emotional disturbance, euphoric mood, indifference, irritability, libido decreased, nervousness, sleep disorderRenal and urinary disorders: difficulty in micturition, urinary hesitation, urinary retentionReproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: dyspneaSkin and subcutaneous tissue disorders: allergic dermatitis, cold sweat, dermatitis, night sweats, pallor, generalized pruritus, urticariaVascular disorders: flushing, hypertension, hypotension, orthostatic hypotension.

CLINICAL PHARMACOLOGY SECTION.

Clinical PharmacologyMechanism of ActionRYZOLT(TM) is 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 u-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 O-demethylated metabolite (M1) to mu-opioid receptors. In animal models, M1 is up to 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 in vitro, 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. PharmacokineticsThe analgesic activity of tramadol hydrochloride is due to both parent drug and the M1 metabolite (See CLINICAL PHARMACOLOGY, Mechanism of Action ).RYZOLT(TM) is formulated as racemate and both tramadol and M1 are detected in the circulation.The pharmacokinetics of tramadol and M1 are dose-proportional over 100 to 300 mg dose range in healthy subjects. AbsorptionThe median time to peak plasma concentrations of tramadol and M1 after multiple-dose administration of RYZOLT(TM) 200 mg tablets to healthy subjects are attained at about h and h, respectively (Table and Figure 1). The pharmacokinetic parameter values for RYZOLT(TM) 200 mg administered once daily and tramadol immediate-release 50 mg administered every six hours are provided in Table 1. The relative bioavailability of 200 mg RYZOLT(TM) tablet compared to 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(TM) 200 mg Once Daily and Immediate-Release Tramadol 50 mg Every Hours.Figure 2. Mean M1 Plasma Concentrations at Steady State Following Five Days of Oral Administration of RYZOLT(TM) 200 mg Once Daily and Immediate-Release Tramadol 50 mg Every HoursFood EffectCo-administration with high fat meal did not significantly affect AUC (overall exposure to tramadol); however, Cmax (peak plasma concentration) increased 67% following single 300 mg tablet administration and 54% following single 200 mg tablet administration. RYZOLT(TM) was administered without regard to food in all clinical trials.DistributionThe volume of distribution of tramadol is 2.6 and 2.9 L/kg in males and females, respectively, following 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 ug/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.MetabolismTramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. N-demethylation is mediated by CYP3A4 and CYP2B6. One metabolite (O-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 PRECAUTIONS Drug Interactions ).EliminationTramadol 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(TM), 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. Special PopulationsRenal ImpairmentImpaired renal function results in decreased rate and extent of excretion of tramadol and its active metabolite, M1 in patients taking an immediate-release formulation of tramadol. RYZOLT(TM) has not been studied in patients with renal impairment. The limited availability of dose strengths and once daily dosing of RYZOLT(TM) do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, RYZOLT(TM) should not be used in patients with severe renal impairment (creatinine clearance less than 30 mL/min) (See WARNINGS, Use in Renal and Hepatic Disease and DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during 4-hour dialysis period is less than 7% of the administered dose.Hepatic ImpairmentThe metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both 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(TM) has not been studied in patients with hepatic impairment. The limited availability of dose strengths and once daily dosing of RYZOLT(TM) do not permit the dosing flexibility required for safe use in patients with hepatic impairment. Therefore, RYZOLT(TM) should not be used in patients with hepatic impairment (see WARNINGS, Use in Renal and Hepatic Disease and DOSAGE AND ADMINISTRATION).Geriatric PatientsHealthy 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. hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years (See DOSAGE AND ADMINISTRATION).GenderFollowing 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 single oral dose of immediate-release tramadol, and after adjusting for body weight, females had 12% higher peak tramadol concentration and 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown.Drug InteractionsThe formation of the active metabolite of tramadol, M1, is mediated by CYP2D6, 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. In vitro 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. Johns Wort, with RYZOLT(TM) may affect the metabolism of tramadol leading to altered tramadol exposure (see PRECAUTIONS).QuinidineQuinidineis selective inhibitor of CYP2D6, so that concomitant administration of quinidine and RYZOLT(TM) may result in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown (see PRECAUTIONS). In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.CarbamazepineCarbamazepine, CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have significantly reduced analgesic effect of tramadol. Because of the seizure risk associated with tramadol, concomitant administration of RYZOLT(TM) and carbamazepine is not recommended (see PRECAUTIONS).CimetidineConcomitant administration of tramadol immediate-release tablets with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the RYZOLT(TM) dosage regimen with cimetidine is recommended.Clinical StudiesRYZOLT(TM) 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 reduction of pain and were able to tolerate RYZOLT(TM) during an open-label titration period, were then randomized to RYZOLT(TM) or to placebo for 12 weeks. Sixty-five percent of patients were able to successfully titrate onto RYZOLT(TM). After washout, patients randomized to RYZOLT(TM) were titrated to 200 mg or 300 mg of RYZOLT(TM) 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(TM) arm than the placebo arm due to adverse events (10% vs. 5%, respectively) and more patients discontinuing from the placebo arm than the RYZOLT(TM) arm due to lack of efficacy (10% vs. 8%, respectively). Patients treated with RYZOLT(TM) demonstrated 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 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.. Ryzolt Fig 1. Ryzolt Fig 2. Ryzolt Fig 3.

DOSAGE & ADMINISTRATION SECTION.

Dosage and AdministrationRYZOLT(TM) extended-release tablets should be taken once day. The tablets should be swallowed whole with liquid and not split, chewed, dissolved or crushed. RYZOLT(TM) tablets produce continuous release of active ingredient over 24 hours: repeat dosage within 24 hours is not recommended. Patients Not Currently on Tramadol Immediate-Release Products:Treatment with RYZOLT(TM) should be initiated at 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 or of therapy) to achieve balance between adequate pain control and tolerability for the individual patient. For patients requiring the 300 mg daily dose, titration should take at least 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(TM)should not be administered at 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 total daily dose of RYZOLT(TM)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(TM), some patients maintained on tramadol IR products may not be able to convert to RYZOLT(TM). RYZOLT(TM)should not be administered at dose exceeding 300 mg per day. Do not use RYZOLT(TM) with other tramadol products. (see WARNINGS).Individualization of DoseGood 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.Renal and Hepatic DiseaseRYZOLT(TM) should not be used in patients with:Creatinine clearance less than 30 mL/min, Hepatic impairment. (See WARNINGS, Use in Renal and Hepatic Disease ).Geriatric patients (65 years of age and older)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(TM) 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.. Creatinine clearance less than 30 mL/min, Hepatic impairment.

INFORMATION FOR PATIENTS SECTION.

Information for PatientsPatients should be instructed that:RYZOLT(TM) is for oral use only and should be swallowed whole with sufficient quantity of liquid and not split, chewed, dissolved or crushed. RYZOLT(TM) may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs and triptans) or drugs that significantly reduce the metabolic clearance of tramadol. RYZOLT(TM)should be taken once daily, at approximately the same time every day and that exceeding these instructions can result in respiratory depression, seizures or death. RYZOLT(TM)should not be taken in doses exceeding the maximum recommended daily dose as exceeding these recommendations can result in respiratory depression, seizures or even death (See DOSAGE AND ADMINISTRATION) RYZOLT(TM)may impair the mental and physical abilities required for the performance of potentially hazardous tasks such as driving car or operating machinery. Patients using this drug should be cautioned accordingly. RYZOLT(TM)should not be taken with alcohol-containing beverages. RYZOLT(TM)should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics. Female patients should be instructed to inform the physician if they are pregnant, think they might become pregnant, or are trying to become pregnant (See PRECAUTIONS Pregnancy and Labor and Delivery). Clinical experience suggests that signs and symptoms of withdrawal may be reduced by tapering medication when discontinuing tramadol therapy. Patients should be informed to keep RYZOLT(TM)out of reach of children. Use in Drug and Alcohol Addiction RYZOLT(TM) 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.Drug InteractionsCYP2D6 and CYP3A4 Inhibitors: Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see CLINICAL PHARMACOLOGY, Pharmacokinetics), such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome.Serotonergic Drugs: There have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and 2-adrenergic blockers. Caution is advised when RYZOLT(TM) is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is reversible non-selective MAOI), lithium, or St. Johns Wort. If concomitant treatment of RYZOLT(TM) with drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Triptans: Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when RYZOLT(TM)is coadministered with triptan. If concomitant treatment of RYZOLT(TM)with triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Use with CarbamazepinePatients taking carbamazepine, CYP3A4inducer, may have significantly reduced analgesic effect. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of RYZOLT(TM)and carbamazepine is not recommended.Use with QuinidineTramadol is metabolized to M1 by CYP2D6. Quinidineis selective inhibitor of that isoenzyme, so that concomitant administration of quinidine and tramadol products results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.Use with Digoxin and WarfarinPost-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.Interaction With Central Nervous System (CNS) DepressantsRYZOLT(TM) should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. RYZOLT(TM) increases the risk of CNS and respiratory depression in these patients.Potential of Other Drugs to Affect TramadolIn vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.Tramadol is partially metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. Johns Wort, with RYZOLT(TM)may affect the metabolism of tramadol leading to altered tramadol exposure.Potential for Tramadol to Affect Other Drugs In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when administered concomitantly at therapeutic doses. Tramadol is mild inducer of selected drug metabolism pathways measured in animals.Carcinogenesis, Mutagenesis and Impairment of FertilityA slight, but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in 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 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.PregnancyTeratogenic Effects: Pregnancy Category 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), 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 EffectsTramadol 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 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(TM) 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 DeliveryRYZOLT(TM) 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(TM), if any, on the later growth, development and functional maturation of the child is unknown.Nursing MotherRYZOLT(TM)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 single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 ug of tramadol (0.1% of the maternal dose) and 27 ug of M1.Pediatric UseThe safety and efficacy of RYZOLT(TM)in patients under 16 years of age has not been established. The use of RYZOLT(TM)in the pediatric population is not recommended.Geriatric UseIn 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(TM)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 (less than 65 years of age), except constipation for which the incidence was higher in older patients. RYZOLT(TM)should be used with caution in patients older than 75 years of age (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).. RYZOLT(TM) is for oral use only and should be swallowed whole with sufficient quantity of liquid and not split, chewed, dissolved or crushed. RYZOLT(TM) may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs and triptans) or drugs that significantly reduce the metabolic clearance of tramadol. RYZOLT(TM)should be taken once daily, at approximately the same time every day and that exceeding these instructions can result in respiratory depression, seizures or death. RYZOLT(TM)should not be taken in doses exceeding the maximum recommended daily dose as exceeding these recommendations can result in respiratory depression, seizures or even death (See DOSAGE AND ADMINISTRATION) RYZOLT(TM)may impair the mental and physical abilities required for the performance of potentially hazardous tasks such as driving car or operating machinery. Patients using this drug should be cautioned accordingly. RYZOLT(TM)should not be taken with alcohol-containing beverages. RYZOLT(TM)should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics. Female patients should be instructed to inform the physician if they are pregnant, think they might become pregnant, or are trying to become pregnant (See PRECAUTIONS Pregnancy and Labor and Delivery). Clinical experience suggests that signs and symptoms of withdrawal may be reduced by tapering medication when discontinuing tramadol therapy. Patients should be informed to keep RYZOLT(TM)out of reach of children.

WARNINGS SECTION.

WarningsSeizure RiskSeizures 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.), orOther opioids.Administration of RYZOLT(TM) 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, orOther drugs that reduce the seizure threshold.Risk of convulsions may also be increased in patients with epilepsy, those with history of seizures, or in patients with 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 RiskDo not prescribe RYZOLT(TM) for patients who are suicidal or addiction-prone. Prescribe RYZOLT(TM) with caution for patients taking tranquilizers or antidepressant drugs and for patients who use alcohol in excess. Serious potential consequences of overdosage with RYZOLT(TM) 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 RiskThe development of potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including RYZOLT(TM), 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 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 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 ReactionsSerious 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 history of anaphylactoid reactions to other opioids may be at increased risk and therefore should not receive RYZOLT(TM) (See CONTRAINDICATIONS).Respiratory DepressionRYZOLT(TM) 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(TM) 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 TraumaRYZOLT(TM) 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 high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving RYZOLT(TM) (See Respiratory Depression).Use in Ambulatory PatientsRYZOLT(TM) may impair the mental and physical abilities required for the performance of potentially hazardous tasks such as driving car or operating machinery. Patients using this drug should be cautioned accordingly. Use with MAO Inhibitors and Serotonin Re-uptake InhibitorsRYZOLT(TM) 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.WithdrawalWithdrawal symptoms may occur if RYZOLT(TM)is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. In 12 week study, 325 patients were followed for and days after discontinuation of treatment with RYZOLT(TM). 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(TM) met the DSM-IV criteria for 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 OpioidsTramadol 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(TM)in situations where the healthcare professional is concerned about risk of misuse, abuse, or diversion.RYZOLT(TM) could be abused by breaking, crushing, chewing, or dissolving the product which can result in the uncontrolled delivery of the opioid, and as consequence poses 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 AbuseTramadol 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.Drug Abuse and AddictionAbuseRYZOLT(TM) is mu-agonist opioid. Tramadol, like other opioids used in analgesia, can be abused and is subject to criminal diversion. Addiction is 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 treatable disease, utilizing 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(TM), 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(TM) is intended for oral use only. The crushed tablet poses 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.DependenceTolerance is the need for increasing doses of opioids to maintain 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 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 patient is on continuous opioid therapy.Risk of OverdosageSerious potential consequences of overdosage with RYZOLT(TM) 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).. Selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics),. Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or. Other opioids.. 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.