ULTRAM ER- tramadol hydrochloride tablet 
REMEDYREPACK INC.

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DESCRIPTION

ULTRAMER (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:

Figure 1

MM1

The molecular weight of tramadol HCl 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. ULTRAM ER tablets contain 100, 200 or 300 mg of tramadol HCl in an extended-release formulation. The tablets are white to off-white in color and contain the inactive ingredients ethylcellulose, dibutyl sebacate, polyvinyl pyrrolidone, sodium stearyl fumarate, colloidal silicon dioxide, and polyvinyl alcohol.

CLINICAL PHARMACOLOGY

Mechanism of Action

;


ULTRAM ER 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 toreceptors 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 toreceptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent inbinding. 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 ULTRAM ER 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. ULTRAM ER is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation.

The pharmacokinetics of ULTRAM ER are approximately dose-proportional over a 100-400 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 ULTRAM ER 200 mg tablet relative to a 50 mg every six hours dosing regimen of the immediate-release dosage form (ULTRAM) was approximately 85-90%. Consistent with the extended-release nature of the formulation, there is a lag time in drug absorption following ULTRAM ER administration. The mean peak plasma concentrations of tramadol and M1 after administration of ULTRAM ER tablets to healthy volunteers are attained at about 12 h and 15 h, respectively, after dosing (see

>

Table 1

and

Figure 2

). Following administration of the ULTRAM ER, 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 ULTRAM ER 200 mg administered once daily and tramadol HCl immediate-release (ULTRAM) 50 mg administered every six hours
Table 1.

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

Tramadol

M1 Metabolite

Pharma- cokinetic ParameterULTRAM ER 200-mg Tablet Once-DailyULTRAM 50-mg Tablet Every 6 HoursULTRAM ER 200-mg Tablet Once-DailyULTRAM 50-mg Tablet Every 6 Hours

AUC0-24 (ng5975 (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)% Fluctuation61 (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 ULTRAM ER Once-Daily and 50 mg ULTRAM Every 6 Hours.

MM2

MM3

Food Effects


After a single dose administration of 200 mg ULTRAM ER tablet with a high fat meal, the Cmax and AUC0-of tramadol decreased 28% and 16%, respectively, compared to fasting conditions. Mean Tmax was increased by 3 hr (from 14 hr under fasting conditions to 17 hr under fed conditions). While ULTRAM ER 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 10Saturation 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 ULTRAM ER 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 ULTRAM ER 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal impairment in comparison to patients with normal renal function. However, exposure of M1 increased 20-40% with increased severity of the renal impairment (from normal to mild and moderate). ULTRAM ER has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths of ULTRAM ER does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, ULTRAM ER 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 ULTRAM ER 100 mg. The exposure of (+)- and (-)-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 ULTRAM ER 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 ULTRAM ER does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, ULTRAM ER 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 ULTRAM ER 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 ULTRAM ER 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 ULTRAM ER 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 ULTRAM ER 100 mg. The results demonstrated that the exposure of tramadol increased 50-60% and the exposure of M1 decreased 50-60% (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 ULTRAM ER 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 ULTRAM ER dosage regimen with cimetidine is recommended.

CLINICAL STUDIES

ULTRAM ER was 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 ofmm, off previous medications, on a 0100 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 ULTRAM ER 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 the ULTRAM ER 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with ULTRAM ER 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 (see

Figure 3

).
Figure 3

MM4

In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of ULTRAM ER in patients with osteoarthritis of the knee, patients titrated to an average daily ULTRAM ER dose of approximately 270 mg/day. Forty-nine percent of patients randomized to ULTRAM ER completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the ULTRAM ER 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 ULTRAM ER-treated patients. The ULTRAM ER 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 ULTRAM ER and placebo (see

Figure 4

).
Figure 4
MM5

INDICATIONS & USAGE

ULTRAM ER 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.

CONTRAINDICATIONS

ULTRAM ER should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. ULTRAM ER is 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. ULTRAM ER may worsen central nervous system and respiratory depression in these patients.

WARNINGS

PRECAUTIONS

Acute Abdominal Condition

The administration of ULTRAM ER 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. ULTRAM ER has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths and once daily dosing of ULTRAM ER do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, ULTRAM ER 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 ULTRAM ER has not been studied in patients with severe hepatic impairment. The limited availability of dose strengths and once daily dosing of ULTRAM ER do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, ULTRAM ER should not be used in patients with severe hepatic impairment (see

CLINICAL PHARMACOLOGY

and

DOSAGE AND ADMINISTRATION

).

INFORMATION FOR PATIENTS

  • Patients should be informed that ULTRAM ER is for oral use only and should be swallowed whole. The tablets should not be chewed, crushed, or split.
    • Patients should be informed that ULTRAM ER 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.
      • Patients should be informed that ULTRAM ER may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
        • Patients should be informed that ULTRAM ER should not be taken with alcohol containing beverages.
          • Patients should be informed that ULTRAM ER 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 prescriber if they are pregnant, think they might become pregnant, or are trying to become pregnant (see PRECAUTIONS, Labor and Delivery).
              • Patients should be educated regarding the single-dose and 24-hour dosing regimen, as exceeding these recommendations can result in respiratory depression, seizures or death.
              • Use in Drug and Alcohol Addiction

                ULTRAM ER is an opioid with no approved use in 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 INTERACTIONS

CYP2D6 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 andblockers. Caution is advised when ULTRAM ER is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John's Wort. If concomitant treatment of ULTRAM ER with a 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 Risk

).

Triptans: Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when ULTRAM ER is coadministered with a triptan. If concomitant treatment of ULTRAM ER with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see

WARNINGS, Serotonin Syndrome Risk

).
Use With Carbamazepine


Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ULTRAM ER and carbamazepine is not recommended.

Use With Quinidine


Coadministration of quinidine with ULTRAM ER resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure (see

CLINICAL PHARMACOLOGY, Drug Interactions

). The clinical consequences of these findings are unknown.
Use With Digoxin and Warfarin


Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.

Potential for Other Drugs to Affect Tramadol


In 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.

Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John's Wort, with ULTRAM ER may affect the metabolism of tramadol leading to altered tramadol exposure.

Potential for Tramadol to Affect Other Drugs


In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. 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 a mild inducer of selected drug metabolism pathways measured in animals.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY

No carcinogenic effect of tramadol was observed in p53(+/)-heterozygous mice at oral doses up to 150 mg/kg/day (approximately 2-fold maximum daily human dose [MDHD] of 400 mg/day for a 60 kg adult based on body surface conversion) for 26 weeks and in rats at oral doses up to 75 mg/kg/day for males and 100 mg/kg/day for females (approximately 2-fold MDHD) for two years. However, the excessive decrease in body weight gain observed in the rat study might have reduced their sensitivity to any potential carcinogenic effect of the drug.

Tramadol was not mutagenic in the following assays: a bacterial reverse mutation assay using Salmonella and E. coli, a mouse lymphoma assay (in the absence of metabolic activation), and a bone marrow micronucleus test in mice. Mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.

No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg/day in male and female rats (approximately equivalent to MDHD).

PREGNANCY

Teratogenic Effects: Pregnancy Category C


Tramadol was not teratogenic at oral dose levels up to 50 mg/kg/day (approximately equivalent to MDHD) in rats and 100 mg/kg (approximately 5-fold MDHD) in rabbits during organogenesis. However, embryo-fetal lethality, reductions in fetal weight and skeletal ossification, and increased supernumerary ribs were observed at a maternal toxic dose of 140 mg/kg in mice (approximately 2-fold MDHD), 80 mg/kg in rats (2-fold MDHD) or 300 mg/kg in rabbits (approximately 15-fold MDHD).


Non-teratogenic Effects


Tramadol caused a reduction in neonatal body weight and survival at an oral dose of 80 mg/kg (approximately 2-fold MDHD) when rats were treated during late gestation throughout lactation period.

There are no adequate and well-controlled studies in pregnant women. ULTRAM ER 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 still birth have been reported during post-marketing reports with tramadol HCl immediate-release products.

LABOR & DELIVERY

ULTRAM ER 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 treated with tramadol HCl during labor.

The effect of ULTRAM ER, if any, on the later growth, development, and functional maturation of the child is unknown.

NURSING MOTHERS

ULTRAM ER 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 sixteen hours postdose was 100of tramadol (0.1% of the maternal dose) and 27of M1.

PEDIATRIC USE

The safety and efficacy of ULTRAM ER in patients under 18 years of age have not been established. The use of ULTRAM ER in the pediatric population is not recommended.

GERIATRIC USE

Nine-hundred-one elderly (65 years of age or older) subjects were exposed to ULTRAM ER in clinical trials. Of those subjects, 156 were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: constipation, fatigue, weakness, postural hypotension and dyspepsia. For this reason, ULTRAM ER should be used with great caution in patients older than 75 years of age (see

CLINICAL PHARMACOLOGY

and

DOSAGE AND ADMINISTRATION

).

ADVERSE REACTIONS

ULTRAM ER was 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 rates5% from two 12-week placebo-controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1811).

ULTRAM ER

PlaceboMedDRA Preferred Term100 mg (N=403) n (%)200 mg (N=400) n (%)300 mg (N=400) n (%)400 mg (N=202) n (%)(N=406) n (%)

Dizziness (not vertigo)64 (15.9)81 (20.3)90 (22.5)57 (28.2)28 (6.9)Nausea61 (15.1)90 (22.5)102 (25.5)53 (26.2)32 (7.9)Constipation49 (12.2)68 (17.0)85 (21.3)60 (29.7)17 (4.2)Headache49 (12.2)62 (15.5)46 (11.5)32 (15.8)43 (10.6)Somnolence33 (8.2)45 (11.3)29 (7.3)41 (20.3)7 (1.7)Flushing31 (7.7)40 (10.0)35 (8.8)32 (15.8)18 (4.4)Pruritus25 (6.2)34 (8.5)30 (7.5)24 (11.9)4 (1.0)Vomiting20 (5.0)29 (7.3)34 (8.5)19 (9.4)11 (2.7)Insomnia26 (6.5)32 (8.0)36 (9.0)22 (10.9)13 (3.2)Dry Mouth20 (5.0)29 (7.3)39 (9.8)18 (8.9)6 (1.5)Diarrhea15 (3.7)27 (6.8)37 (8.5)10 (5.0)17 (4.2)Asthenia14 (3.5)24 (6.0)26 (6.5)13 (6.4)7 (1.7)Postural hypotension7 (1.7)17 (4.3)8 (2.0)11 (5.4)9 (2.2)Sweating increased6 (1.5)8 (2.0)15 (3.8)13 (6.4)1 (0.2)Anorexia3 (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 <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, paresthesia, hypoesthesia

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 flushes, vasodilatation


Adverse events with incidence rates of 0.5% to <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

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 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 ULTRAM ER 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

ULTRAM ER should not be used in patients with:

  • creatinine clearance less than 30 mL/min,

    (See

    PRECAUTIONS, Use in Renal and Hepatic Disease

    ).

    ULTRAM ER must be swallowed whole and must not be chewed, crushed, or split (see

    WARNINGS, Misuse, Abuse and Diversion of Opioids

    and

    DRUG ABUSE AND ADDICTION

    ).



    Adults (18 years of age and over)
    Patients Not Currently on Tramadol Immediate-Release Products


    For patients not currently treated with tramadol immediate-release (IR) products, ULTRAM ER should be initiated at a dose of 100 mg once daily and titrated up as necessary by 100-mg increments every five days to relief of pain and depending upon tolerability. ULTRAM ER should not be administered at a dose exceeding 300 mg per day.

    • severe hepatic impairment (Child-Pugh Class C)
    • Patients Currently on Tramadol Immediate-Release Products
      For patients maintained on tramadol IR products, calculate the 24-hour tramadol IR dose and initiate a total daily dose of ULTRAM ER 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 ULTRAM ER, some patients maintained on tramadol IR products may not be able to convert to ULTRAM ER. ULTRAM ER should not be administered at a dose exceeding 300 mg per day. The concomitant use of ULTRAM ER with other tramadol products is not recommended (see

      WARNINGS

      ).


      Individualization of Dose


      Good pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Start at the lowest possible dose and titrate upward as tolerated to achieve an adequate effect. Clinical studies of ULTRAM ER have not demonstrated a clinical benefit at a total daily dose exceeding 300 mg.

      In general, dosing of an elderly patient (over 65 years of age) should be initiated cautiously, usually starting 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. ULTRAM ER should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population.

HOW SUPPLIED

ULTRAM ER (tramadol hydrochloride) Extended-release tablets are supplied in the following package and dose strength forms:

100 mg: Round, convex, white to off-white tablets imprinted with "100" over "ER" on one side in black ink

Bottle of 30 tabletsNDC 50458-653-30

200 mg: Round, convex, white to off-white tablets imprinted with "200" over "ER" on one side in black ink

Bottle of 30 tabletsNDC 50458-655-30

300 mg: Round, convex, white to off-white tablets imprinted with "300" over "ER" on one side in black ink

Bottle of 30 tabletsNDC 50458-657-30

STORAGE AND HANDLING

Store at 25(77(59 - 86

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

DRUG: Ultram ER

GENERIC: Tramadol Hydrochloride

DOSAGE: TABLET

ADMINSTRATION: ORAL

NDC: 49349-845-03

STRENGTH:100 mg

COLOR: white

SHAPE: ROUND

SCORE: No score

SIZE: 6 mm

IMPRINT: 20

QTY: 20

MM6

ULTRAM  ER
tramadol hydrochloride tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:49349-845(NDC:50458-653)
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
TRAMADOL HYDROCHLORIDE (UNII: 9N7R477WCK) (TRAMADOL - UNII:39J1LGJ30J) TRAMADOL HYDROCHLORIDE100 mg
Inactive Ingredients
Ingredient NameStrength
DIBUTYL SEBACATE (UNII: 4W5IH7FLNY)  
ETHYLCELLULOSE (100 MPA.S) (UNII: 47MLB0F1MV)  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
POLYVINYL ALCOHOL (UNII: 532B59J990)  
Product Characteristics
ColorwhiteScoreno score
ShapeROUND (TABLET) Size6mm
FlavorImprint Code 100;ER
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:49349-845-0320 in 1 VIAL; Type 0: Not a Combination Product10/25/201610/25/2016
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02169210/25/201610/25/2016
Labeler - REMEDYREPACK INC. (829572556)

Revised: 10/2016
 
REMEDYREPACK INC.