Tramadol Er
FDA Label NDC 16590-893

Full FDA labeling including Indications, Dosage, Usage, and Precautions

Structured Product Label

The following Structured Product Label (SPL) was submitted to the FDA by Stat Rx Usa for the product Tramadol Er (NDC 16590-893). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.

This specific version of the label includes detailed information regarding description, clinical pharmacology, indications & usage, contraindications, warnings, drug abuse and dependence, precautions, adverse reactions, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.

Label Section Quick Index

Description

DESCRIPTION

Tramadol hydrochloride is a centrally acting synthetic analgesic in an extended-release formulation. The chemical name is (±) cis-2-[(dimethylamino)methyl]­-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:

Structure (Tramadoler200mgstructure)

Structure (Tramadoler200mgstructure)


The molecular weight of tramadol hydrochloride is 299.8. It is a white, bitter, crystalline and odorless powder that is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7. Tramadol hydrochloride Extended-Release (ER) tablets contain 100 mg or 200 mg of tramadol hydrochloride in an extended-release formulation. The tablets are white to off-white in color and contain the inactive ingredients colloidal silicone dioxide, dibutyl sebacate, ethylcellulose, magnesium stearate, polyvinyl alcohol, povidone K-90, and an imprinting agent, Opacode S-1-17823 black, which contains the following ingredients: shellac, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol, and ammonium hydroxide.


Clinical Pharmacology

CLINICAL PHARMACOLOGYMechanism of Action

Tramadol hydrochloride is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms 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 O-demethylated metabolite M1 to µ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-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. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in the tramadol hydrochloride ER tablets clinical studies.

Apart from analgesia, tramadol administration may produce a constellation of 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.

Pharmacokinetics

The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. Tramadol hydrochloride ER tablet is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation.

The pharmacokinetics of tramadol hydrochloride ER tablets are approximately dose-proportional over a 100 to 400 mg dose range in healthy subjects. The observed tramadol AUC values for the 400 mg dose were 26% higher than predicted based on the AUC values for the 200 mg dose. The clinical significance of this finding has not been studied and is not known.

Absorption

In healthy subjects, the bioavailability of a tramadol hydrochloride ER 200 mg tablet relative to a 50 mg every six hours dosing regimen of the immediate-release dosage form (tramadol hydrochloride) was approximately 85 to 90%. Consistent with the extended-release nature of the formulation, there is a lag time in drug absorption following tramadol hydrochloride ER tablets administration. The mean peak plasma concentrations of tramadol and M1 after administration of tramadol hydrochloride ER tablets to healthy volunteers are attained at about 12 hours and 15 hours, respectively, after dosing (see Table 1 and Figure 2). Following administration of the tramadol hydrochloride ER tablet, steady-state plasma concentrations of both tramadol and M1 are achieved within four days with once daily dosing.

The mean (%CV) pharmacokinetic parameter values for tramadol hydrochloride ER tablet 200 mg administered once daily and tramadol hydrochloride immediate-release 50 mg administered every six hours are provided in Table 1.

Table 1. Mean (%CV) Steady-State Pharmacokinetic Parameter Values (n=32)

AUC 0-24: Area Under the Curve in a 24 hour dosing interval; Cmax: Peak Concentration in a 24 hour dosing interval; Cmin: Trough Concentration in a 24 hour dosing interval; Tmax: Time to Peak Concentration

  TramadolM1 Metabolite  
Pharmacokinetic Parameter Tramadol HCl ER 200 mg Tablet OnceDaily Tramadol HCl50 mg Tablet Every 6 Hours Tramadol HCl ER 200 mgTablet OnceDaily Tramadol HCl50 mgTablet Every 6Hours
AUC0-24 (ng.h/mL) 5975 (34) 6613 (27) 1890 (25) 2095 (26)
Cmax (ng/mL) 335 (35) 383 (21) 95 (24) 104 (24)
Cmin (ng/mL) 187 (37) 228 (32) 69 (30) 82 (27)
Tmax (h) 12 (27) 1.5 (42) 15 (27) 1.9 (57)
% Fluctuation 61 (57) 59 (35) 34 (72) 26 (47)

Figure 2: Mean Steady-State Tramadol (a) and M1 (b) Plasma Concentrations on Day 8 Post Dose after Administration of 200 mg Tramadol Hydrochloride ER Tablet Once Daily and 50 mg Tramadol Hydrochloride Tablets Every 6 Hours.

Chart A (Tramadoler200mgcharta)

Chart A (Tramadoler200mgcharta)



Chart B (Tramadoler200mgchartb)

Chart B (Tramadoler200mgchartb)



Food Effects

After a single dose administration of 200 mg tramadol hydrochloride ER tablet with a high fat meal, the C max and AUC0-∞ of tramadol decreased 28% and 16%, respectively, compared to fasting conditions. Mean Tmax was increased by 3 hour (from 14 hour under fasting conditions to 17 hour under fed conditions). While tramadol hydrochloride ER tablet may be taken without regard to food, it is recommended that it be taken in a consistent manner.

Distribution

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

Metabolism

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

Elimination

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. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 after administration of tramadol hydrochloride ER tablets are approximately 7.9 and 8.8 hours, respectively.

Special Populations Renal

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The pharmacokinetics of tramadol were studied in patients with mild or moderate renal impairment after receiving multiple doses of tramadol hydrochloride ER tablets 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50 to 80 mL/min) or moderate (CLcr: 30 to 50 mL/min) renal impairment in comparison to patients with normal renal function. However, exposure of M1 increased 20 to 40% with increased severity of the renal impairment (from normal to mild and moderate). Tramadol hydrochloride ER tablets have not been studied in patients with severe renal impairment (CLcr  30 mL/min). The limited availability of dose strengths of tramadol hydrochloride ER tablets does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, tramadol hydrochloride ER tablets should not be used in patients with severe renal impairment (see PRECAUTIONS - Use in Renal and Hepatic Disease and DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during a 4 hour dialysis period is less than 7% of the administered dose.

Hepatic

Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of tramadol hydrochloride ER tablets 100 mg. The exposure of plus  minus and minus minus tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients with normal hepatic function. However, exposure of  and ­M1 decreased 50% with increased severity of the hepatic impairment (from normal to mild and moderate). The pharmacokinetics of tramadol after the administration of tramadol hydrochloride ER tablets has not been studied in patients with severe hepatic impairment. After the administration of tramadol immediate-release tablets to patients with advanced cirrhosis of the liver, tramadol area under the plasma concentration time curve was larger and the tramadol and M1 half-lives were longer than subjects with normal hepatic function. The limited availability of dose strengths of tramadol hydrochloride ER tablets does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, tramadol hydrochloride ER tablets should not be used in patients with severe hepatic impairment (see PRECAUTIONS - Use in Renal and Hepatic Disease and DOSAGE AND ADMINISTRATION).

Geriatric

The effect of age on the absorption of tramadol from tramadol hydrochloride ER tablets in patients over the age of 65 years has not been studied and is unknown (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Gender

Based on pooled multiple-dose pharmacokinetics studies for tramadol hydrochloride ER tablets in 166 healthy subjects (111 males and 55 females), the dose-normalized AUC values for tramadol were somewhat higher in females than in males. There was a considerable degree of overlap in values between male and female groups. Dosage adjustment based on gender is not recommended.

Drug Interactions

The formation of the active metabolite, M1, is mediated by CYP2D6. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. Based on a population PK analysis of Phase I studies with immediate-release tablets in healthy subjects, 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 (fluoxetine, norfluoxetine, amitriptyline, and quinidine) 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 tramadol hydrochloride ER tablets may affect the metabolism of tramadol leading to altered tramadol exposure (see PRECAUTIONS - Drug Interactions).

Quinidine

Tramadol is metabolized to M1 by CYP2D6. A study was conducted to examine the effect of quinidine, a selective inhibitor of CYP2D6, on the pharmacokinetics of tramadol by administering 200 mg quinidine two hours before the administration of tramadol hydrochloride ER tablets 100 mg. The results demonstrated that the exposure of tramadol increased 50 to 60% and the exposure of M1 decreased 50 to 60% (see PRECAUTIONS - Drug Interactions). In vitro 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 tramadol hydrochloride ER tablets and carbamazepine is not recommended (see PRECAUTIONS - Drug Interactions).

Cimetidine

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




Contraindications

CONTRAINDICATIONS

Tramadol hydrochloride ER tablets should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. Tramadol hydrochloride ER tablets are contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. Tramadol hydrochloride ER tablets may worsen central nervous system and respiratory depression in these patients

Warnings

WARNINGS

Seizure Risk

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

Drug Abuse And Dependence

DRUG ABUSE AND ADDICTION

Tramadol hydrochloride is a mu-agonist opioid. Tramadol, like other opioids used in analgesia, can be abused and is subject to criminal diversion.

Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.

“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. Tramadol hydrochloride ER tablets, like other opioids, may be diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Tramadol hydrochloride ER tablets are 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.

Risk of Overdosage

Serious potential consequences of overdosage with tramadol hydrochloride ER 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).

Precautions

PRECAUTIONSAcute Abdominal Condition

The administration of tramadol hydrochloride ER 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. Tramadol hydrochloride ER tablets have not been studied in patients with severe renal impairment (CLcr less than 30 mL/min). The limited availability of dose strengths and once daily dosing of tramadol hydrochloride ER tablets does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, tramadol hydrochloride ER tablets should not be used in patients with severe renal impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. The pharmacokinetics of tramadol hydrochloride ER tablets has not been studied in patients with severe hepatic impairment. The limited availability of dose strengths and once daily dosing of tramadol hydrochloride ER tablets does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, tramadol hydrochloride ER tablets should not be used in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

INFORMATION FOR PATIENTS

Adverse Reactions

ADVERSE REACTIONS

Tramadol hydrochloride ER tablets were administered to a total of 3108 patients during studies conducted in the U.S. These included four double-blind studies in patients with osteoarthritis and/or chronic low back pain and one open-label study in patients with chronic non-malignant pain. A total of 901 patients were 65 years or older. The frequency of adverse events generally increased with doses from 100 mg to 400 mg in the two pooled, twelve-week, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain (see Table 2).

Table 2: Incidence (%) of patients with adverse event rates greater than or equal to 5% from two 12 week placebo-controlled studies in patients with moderate to moderately severe chronic pain by dose (N = 1811).
MedDRA Preferred TermTramadol Hydrochloride ER Tablets    Placebo (N=406) n (%)
100 mg (N= 403) n (%)200 mg (N=400) n (%)300 mg (N=400) n (%)400 mg (N=202) n (%)
Dizziness (not vertigo) 64 (15.9) 81 (20.3) 90 (22.5) 57 (28.2) 28 (6.9)
Nausea 61 (15.1) 90 (22.5) 102 (25.5) 53 (26.2) 32 (7.9)
Constipation 49 (12.2) 68 (17.0) 85 (21.3) 60 (29.7) 17 (4.2)
Headache 49 (12.2) 62 (15.5) 46 (11.5) 32 (15.8) 43 (10.6)
Somnolence 33 (8.2) 45 (11.3) 29 (7.3) 41 (20.3) 7 (1.7)
Flushing 31 (7.7) 40 (10.0) 35 (8.8) 32 (15.8) 18 (4.4)
Pruritus 25 (6.2) 34 (8.5) 30 (7.5) 24 (11.9) 4 (1.0)
Vomiting 20 (5.0) 29 (7.3) 34 (8.5) 19 (9.4) 11 (2.7)
Insomnia 26 (6.5) 32 (8.0) 36 (9.0) 22 (10.9) 13 (3.2)
Dry Mouth 20 (5.0) 29 (7.3) 39 (9.8) 18 (8.9) 6 (1.5)
Diarrhea 15 (3.7) 27 (6.8) 37 (8.5) 10 (5.0) 17 (4.2)
Asthenia 14 (3.5) 24 (6.0) 26 (6.5) 13 (6.4) 7 (1.7)
Postural hypotension 7 (1.7) 17 (4.3) 8 (2.0) 11 (5.4) 9 (2.2)
Sweating increased 6 (1.5) 8 (2.0) 15 (3.8) 13 (6.4) 1 (0.2)
Anorexia 3 (0.7) 7 (1.8) 21 (5.3) 12 (5.9) 1 (0.2)

The following adverse events were reported from all the chronic pain studies (N=3108).

The lists below include adverse events not otherwise noted in Table 2.

Adverse events with incidence rates of 1.0% to less than 5.0%

Eye disorders:vision blurred

Gastrointestinal disorders:abdominal pain upper, dyspepsia, abdominal pain, sore throat

General disorders:weakness, pain, feeling hot, influenza like illness, fall, rigors, lethargy, pyrexia, chest pain

Infections and infestations:nasopharyngitis, upper respiratory tract infection, sinusitis, influenza, gastroenteritis viral, urinary tract infection, bronchitis

Investigations:blood creatine phosphokinase increased, weight decreased

Metabolism and nutrition disorders:appetite decreased

Musculoskeletal, connective tissue and bone disorders:arthralgia, back pain, pain in limb, neck pain

Nervous system disorders:tremor, paraesthesia, hypoaesthesia

Psychiatric disorders:nervousness, anxiety, depression, restlessness

Respiratory, thoracic and mediastinal disorders:sneezing, cough, rhinorrhea, nasal congestion, dyspnea, sinus congestion

Skin and subcutaneous tissue disorders:sweating increased, dermatitis

Vascular disorders:hot flashes, vasodilatation

Adverse events with incidence rates of 0.5% to less than 1.0% and serious adverse events reported in at least 2 patients.

Cardiac disorders:palpitations, myocardial infarction

Ear and labyrinth disorders:tinnitus, vertigo

Gastrointestinal disorders:flatulence, toothache, constipation aggravated, appendicitis, pancreatitis

General disorders:feeling jittery, edema lower limb, shivering, joint swelling, malaise, drug withdrawal syndrome, peripheral swelling

Hepato-biliary disorders:cholelithiasis, cholecystitis

Infections and infestations:cellulitis, ear infection, gastroenteritis, pneumonia, viral infection

Injury and poisoning:joint sprain, muscle injury

Investigations:alanine aminotransferase increased, blood pressure increased, aspartate aminotransferase increased, heart rate increased, blood glucose increased, liver function tests abnormal

Musculoskeletal, connective tissue and bone disorders: muscle cramps, muscle spasms, joint stiffness, muscle twitching, myalgia, osteoarthritis aggravated

Nervous system disorders: migraine, sedation, syncope, disturbance in attention, dizziness aggravated

Psychiatric disorders: euphoric mood, irritability, libido decreased, sleep disorder, agitation, disorientation, abnormal dreams

Renal and urinary disorders:difficulty in micturition, urinary frequency, hematuria, dysuria, urinary retention

Respiratory, thoracic and mediastinal disorders:yawning

Skin and subcutaneous tissue disorders:contusion, piloerection, clamminess, night sweats, urticaria

Vascular disorders:hypertension aggravated, hypertension, peripheral ischemia

Overdosage

OVERDOSAGE

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.

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

In the treatment of tramadol overdosage, primary attention should be given to the re­establishment 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 hydrochloride ER tablets 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

Dosage & Administration

DOSAGE AND ADMINISTRATION

Tramadol hydrochloride ER tablets should not be used in patients with:

How Supplied

HOW SUPPLIED

Tramadol hydrochloride extended-release tablets are supplied in the following package and dose strength forms:

100 mg, round, white to off-white tablets, imprinted with “Par821” on one side of the tablet in black ink

Bottle of 30 tablets – NDC 49884-821-11

Bottle of 90 tablets – NDC 49884-821-09

Bottle of 500 tablets – NDC 49884-821-05

200 mg, round, white to off-white tablets, imprinted with “Par822” on one side of the tablet in black ink

Bottle of 30 tablets – NDC 49884-822-11

Bottle of 90 tablets – NDC 49884-822-09

Bottle of 500 tablets – NDC 49884-822-05

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Manufactured by:

Par Pharmaceutical Companies, Inc.

Spring Valley, NY 10977

Issued: 06/09

Clinical Studies

CLINICAL STUDIES

Tramadol hydrochloride ER tablets were studied in patients with chronic, moderate to moderately severe pain due to osteoarthritis and/or low back pain in four 12 week, randomized, double-blind, placebo-controlled trials. To qualify for inclusion into these studies, patients were required to have moderate to moderately severe pain as defined by a pain intensity score of ≥40 mm, off previous medications, on a 0 to 100 mm visual analog scale (VAS). Adequate evidence of efficacy was demonstrated in the following two studies:

In one 12 week randomized, double-blind, placebo-controlled study, patients with moderate to moderately severe pain due to osteoarthritis of the knee and/or hip were administered doses from 100 mg to 400 mg daily. Treatment was initiated at 100 mg QD for four days then increased by 100 mg per day increments every five days to the randomized fixed dose. Between 51% and 59% of patients in the tramadol hydrochloride ER tablets treatment groups completed the study and 56% of patients in the placebo group completed the study. Discontinuations due to adverse events were more common in tramadol hydrochloride ER tablets 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with tramadol hydrochloride ER tablets 100 mg and 20% of patients treated with placebo.

Pain, as assessed by the WOMAC Pain subscale, was measured at 1, 2, 3, 6, 9, and 12 weeks and change from baseline assessed. A responder analysis based on the percent change in WOMAC Pain subscale demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups compared to placebo.

In one 12 week randomized, double-blind, placebo-controlled flexible-dosing trial of tramadol hydrochloride ER tablets in patients with osteoarthritis of the knee, patients titrated to an average daily tramadol hydrochloride ER tablets dose of approximately 270 mg/day. Forty-nine percent of patients randomized to tramadol hydrochloride ER tablets completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the tramadol hydrochloride ER tablets treatment group were due to adverse events, accounting for 27% of the early discontinuations in contrast to 7% of the discontinuations from the placebo group. Thirty-four percent of the placebo-treated patients discontinued the study due to lack of efficacy compared to 15% of tramadol hydrochloride ER tablets-treated patients. The tramadol hydrochloride ER tablets group demonstrated a statistically significant decrease in the mean VAS score, and a statistically significant difference in the responder rate, based on the percent change from baseline in the VAS score, measured at 1, 2, 4, 8, and 12 weeks, between patients receiving tramadol hydrochloride ER tablets and placebo.

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