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 generally7 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 ≥ 5% from two 12-week placebo-controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1811).

	ULTRAM ER	Placebo
MedDRA Preferred Term	100 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)
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 <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

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 (seeCLINICAL PHARMACOLOGY andDOSAGE 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 (seeCLINICAL PHARMACOLOGY andDOSAGE 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 (seePRECAUTIONS, 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 (seeCLINICAL 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 α2-adrenergic blockers. 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 (seeWarnings, 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 (seeWARNINGS, Serotonin Syndrome Risk).

Use With Carbamazepine

Patients takingcarbamazepine, 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 ofquinidine with ULTRAM ER resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure (seeCLINICAL 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 and 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 (seeDRUG 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 100 µg of tramadol (0.1% of the maternal dose) and 27 µg of 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 andDOSAGE AND ADMINISTRATION).