ULTRAM ER
(tramadol HCI) Extended-Release Tablets
Clean Proposed Labeling Text
ULTRAM® ER
(tramadol HCI) Extended-Release Tablets
Rx only
Prescribing Information
DESCRIPTION
ULTRAM® ER (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.
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 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 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, leftventricular
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
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.
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 10 μg/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 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.
INDICATIONS AND 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
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:
• Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics),
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g.,
cyclobenzaprine, promethazine, etc.), or
• Other opioids.
Administration of tramadol may enhance the seizure risk in patients taking:
• MAO inhibitors (see also WARNINGS - Use with MAO Inhibitors),
• Neuroleptics, or
• Other drugs that reduce the seizure threshold.
Risk of convulsions may also increase in patients with epilepsy, those with a history
of seizures, or in patients with a recognized risk for seizure (such as head trauma,
metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol
overdose, naloxone administration may increase the risk of seizure.
Suicide Risk
• Do not prescribe ULTRAM ER for patients who are suicidal or addiction-prone.
• Prescribe ULTRAM ER with caution for patients taking tranquilizers or
antidepressant drugs and patients who use alcohol in excess.
• Tell your patients not to exceed the recommended dose and to limit their intake
of alcohol.
Anaphylactoid Reactions
Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving
therapy with tramadol. When these events do occur it is often following the first dose.
Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema,
toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of
anaphylactoid reactions to codeine and other opioids may be at increased risk and
therefore should not receive ULTRAM ER (see CONTRAINDICATIONS).
Respiratory Depression
Administer ULTRAM ER 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
ULTRAM ER 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. ULTRAM ER increases the risk of
CNS and respiratory depression in these patients.
Increased Intracranial Pressure or Head Trauma
ULTRAM ER should be used with caution in patients with increased intracranial pressure
or head injury. The respiratory depressant effects of opioids include carbon dioxide
retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly
exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol
may obscure the existence, extent, or course of intracranial pathology. Clinicians should
also maintain a high index of suspicion for adverse drug reaction when evaluating altered
mental status in these patients if they are receiving ULTRAM ER. (see WARNINGS -
Respiratory Depression.)
Use in Ambulatory Patients
ULTRAM ER may impair the mental and or physical abilities required for the
performance of potentially hazardous tasks such as driving a car or operating machinery.
The patient using this drug should be cautioned accordingly.
Use With MAO Inhibitors and Serotonin Re-uptake Inhibitors
Use ULTRAM ER with great caution in patients taking monoamine oxidase inhibitors.
Animal studies have shown increased deaths with combined administration. Concomitant
use of ULTRAM ER with MAO inhibitors or SSRIs increases the risk of adverse events,
including seizure and serotonin syndrome.
Withdrawal
Withdrawal symptoms may occur if ULTRAM ER is discontinued abruptly. These
symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors,
diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical
experience suggests that withdrawal symptoms may be reduced by tapering ULTRAM
ER.
Misuse, Abuse and Diversion of Opioids
Tramadol is an opioid agonist of the morphine-type. Such drugs are sought by drug
abusers and people with addiction disorders and are subject to criminal diversion.
Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This
should be considered when prescribing or dispensing ULTRAM ER in situations where
the physician or pharmacist is concerned about an increased risk of misuse, abuse, or
diversion.
ULTRAM ER could be abused by crushing, chewing, snorting, or injecting the dissolved
product. These practices will result in the uncontrolled delivery of the opioid and pose a
significant risk to the abuser that could result in overdose and death (see WARNINGS
and DRUG ABUSE AND ADDICTION).
Concerns about abuse, addiction, and diversion should not prevent the proper
management of pain. The development of addiction to opioid analgesics in properly
managed patients with pain has been reported to be rare. However, data are not available
to establish the true incidence of addiction in chronic pain patients.
Healthcare professionals should contact their State Professional Licensing Board, or State
Controlled Substances Authority for information on how to prevent and detect abuse or
diversion of this product.
Interactions with Alcohol and Drugs of Abuse
Tramadol may be expected to have additive effects when used in conjunction with
alcohol, other opioids, or illicit drugs that cause central nervous system depression.
DRUG ABUSE AND ADDICTION
ULTRAM® ER 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 nonmedical
purposes, often in combination with other psychoactive substances. ULTRAM
ER, 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.
ULTRAM ER is 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 ULTRAM ER 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
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 SRIs, NRIs, and
triptans) or drugs that significantly reduce the metabolic clearance of tramadol.
•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 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 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 (see
WARNINGS – Serotonin Syndrome).
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 ).
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 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 (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 postdelivery
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 and DOSAGE AND
ADMINISTRATION).
DOSAGE AND ADMINISTRATION
ULTRAM ER should not be used in patients with:
• creatinine clearance less than 30 mL/min,
• severe hepatic impairment (Child-Pugh Class C)
(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.
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.
