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
- 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 and Serotonin Re-uptake 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.
- 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.
Serotonin Syndrome Risk
The development of a potentially life-threatening
serotonin syndrome may occur with the use of tramadol products, including
ULTRAM ER, particularly with concomitant use of serotonergic drugs such as
SSRIs, SNRIs, TCAs, MAOIs, and triptans, with drugs which impair metabolism of
serotonin (including MAOIs), and with drugs which impair metabolism of tramadol
(CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose (see
CLINICAL PHARMACOLOGY, Pharmacokinetics).
Serotonin syndrome may include mental-status changes
(e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations
(e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g.,
nausea, vomiting, diarrhea).
Tramadol products in excessive doses, either alone or in
combination with other CNS depressants, including alcohol, are a major cause of
drug-related deaths. Fatalities within the first hour of overdosage are not
uncommon. Tramadol should not be taken in doses higher than those recommended
by the physician. The judicious prescribing of tramadol is essential to the
safe use of this drug. With patients who are depressed or suicidal,
consideration should be given to the use of non-narcotic analgesics. Patients
should be cautioned about the concomitant use of tramadol products and alcohol
because of potentially serious CNS-additive effects of these agents. Because of
its added depressant effects, tramadol should be prescribed with caution for
those patients whose medical condition requires the concomitant administration
of sedatives, tranquilizers, muscle relaxants, antidepressants, or other
CNS-depressant drugs. Patients should be advised of the additive depressant
effects of these combinations.
Many of the tramadol-related deaths have occurred in
patients with previous histories of emotional disturbances or suicidal ideation
or attempts as well as histories of misuse of tranquilizers, alcohol, and other
CNS-active drugs. Some deaths have occurred as a consequence of the accidental
ingestion of excessive quantities of tramadol alone or in combination with
other drugs. Patients taking tramadol should be warned not to exceed the dose
recommended by their physician.
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).
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
Use With MAO Inhibitors And Serotonin Re-uptake
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
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
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 (tramadol hydrochloride) Extended-Release
Tablets are classified as a Schedule IV controlled substance.
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 non-medical
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).