Included as part of the PRECAUTIONS section.
Addiction, Abuse And Misuse
ULTRACET contains tramadol, a Schedule IV controlled
substance. As an opioid, ULTRACET exposes users to the risks of addiction,
abuse, and misuse [see Drug Abuse and Dependence].
Although the risk of addiction in any individual is
unknown, it can occur in patients appropriately prescribed ULTRACET. Addiction
can occur at recommended dosages and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse,
or misuse prior to prescribing ULTRACET, and monitor all patients receiving
ULTRACET for the development of these behaviors and conditions. Risks are
increased in patients with a personal or family history of substance abuse
(including drug or alcohol abuse or addiction) or mental illness (e.g., major
depression). The potential for these risks should not, however, prevent the
proper management of pain in any given patient. Patients at increased risk may
be prescribed opioids such as ULTRACET, but use in such patients necessitates
intensive counseling about the risks and proper use of ULTRACET along with
intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with
addiction disorders and are subject to criminal diversion. Consider these risks
when prescribing or dispensing ULTRACET. Strategies to reduce these risks
include prescribing the drug in the smallest appropriate quantity and advising
the patient on the proper disposal of unused drug [see PATIENT INFORMATION]. Contact local state professional licensing board or state
controlled substances authority for information on how to prevent and detect
abuse or diversion of this product.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression
has been reported with the use of opioids, even when used as recommended.
Respiratory depression, if not immediately recognized and treated, may lead to
respiratory arrest and death. Management of respiratory depression may include
close observation, supportive measures, and use of opioid antagonists,
depending on the patient's clinical status [see OVERDOSAGE]. Carbon
dioxide (CO2) retention from opioid-induced respiratory depression can
exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory
depression can occur at any time during the use of ULTRACET, the risk is
greatest during the initiation of therapy or following a dosage increase. Monitor
patients closely for respiratory depression, especially within the first 24-72
hours of initiating therapy with and following dosage increases of ULTRACET.
To reduce the risk of respiratory depression, proper
dosing and titration of ULTRACET are essential [see DOSAGE AND
ADMINISTRATION]. Overestimating the ULTRACET dosage when converting
patients from another opioid product can result in a fatal overdose with the
Accidental ingestion of even one dose of ULTRACET,
especially by children, can result in respiratory depression and death due to
an overdose of tramadol.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of ULTRACET during pregnancy can result in
withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid
withdrawal syndrome in adults, may be life-threatening if not recognized and
treated, and requires management according to protocols developed by
neonatology experts. Observe newborns for signs of neonatal opioid withdrawal
syndrome and manage accordingly. Advise pregnant women using opioids for a
prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure
that appropriate treatment will be available [see Use in Specific
Populations and PATIENT INFORMATION].
Risks Of Interactions With Drugs Affecting Cytochrome
The effects of concomitant use or discontinuation of
cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of
tramadol and M1 from ULTRACET are complex. Use of cytochrome P450 3A4 inducers,
3A4 inhibitors, or 2D6 inhibitors with ULTRACET requires careful consideration of
the effects on the parent drug, tramadol, which is a weak serotonin and
norepinephrine reuptake inhibitor and μ-opioid agonist, and the active
metabolite, M1, which is more potent than tramadol in μ- opioid receptor
binding [see DRUG INTERACTIONS].
Risks Of Concomitant Use Or Discontinuation Of Cytochrome
P450 2D6 Inhibitors
The concomitant use of ULTRACET with all cytochrome P450
2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in
tramadol plasma levels and a decrease in the levels of the active metabolite,
M1. A decrease in M1 exposure in patients who have developed physical
dependence to tramadol, may result in signs and symptoms of opioid withdrawal
and reduced efficacy. The effect of increased tramadol levels may be an
increased risk for serious adverse events including seizures and serotonin
Discontinuation of a concomitantly used cytochrome P450
2D6 inhibitor may result in a decrease in tramadol plasma levels and an
increase in active metabolite M1 levels, which could increase or prolong adverse
reactions related to opioid toxicity and may cause potentially fatal
Follow patients receiving ULTRACET and any CYP2D6
inhibitor for the risk of serious adverse events including seizures and
serotonin syndrome, signs and symptoms that may reflect opioid toxicity, and
opioid withdrawal when ULTRACET is used in conjunction with inhibitors of
CYP2D6 [see DRUG INTERACTIONS].
Cytochrome P450 3A4 Interaction
The concomitant use of ULTRACET with cytochrome P450 3A4
inhibitors, such as macrolide antibiotics (e.g., erythromycin),
azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g.,
ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin,
carbamazepine, and phenytoin, may result in an increase in tramadol plasma
concentrations, which could increase or prolong adverse reactions, increase the
risk for serious adverse events including seizures and serotonin syndrome, and
may cause potentially fatal respiratory depression.
The concomitant use of ULTRACET with all cytochrome P450
3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result
in lower tramadol levels. This may be associated with a decrease in efficacy,
and in some patients, may result in signs and symptoms of opioid withdrawal.
Follow patients receiving ULTRACET and any CYP3A4
inhibitor or inducer for the risk for serious adverse events including seizures
and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and
opioid withdrawal when ULTRACET is used in conjunction with inhibitors and
inducers of CYP3A4 [see DRUG INTERACTIONS].
ULTRACET contains tramadol hydrochloride and
acetaminophen. Acetaminophen has been associated with cases of acute liver
failure, at times resulting in liver transplant and death. Most of the cases of
liver injury are associated with the use of acetaminophen at doses that exceed
4,000 milligrams per day, and often involve more than one acetaminophen-containing
product. The excessive intake of acetaminophen may be intentional to cause
self-harm or unintentional as patients attempt to obtain more pain relief or
unknowingly take other acetaminophen-containing products.
The risk of acute liver failure is higher in individuals
with underlying liver disease and in individuals who ingest alcohol while
Instruct patients to look for acetaminophen or APAP on
package labels and not to use more than one product that contains
acetaminophen. Instruct patients to seek medical attention immediately upon ingestion
of more than 4,000 milligrams of acetaminophen per day, even if they feel well.
Risks From Concomitant Use With Benzodiazepines Or Other
Profound sedation, respiratory depression, coma, and
death may result from the concomitant use of ULTRACET with benzodiazepines or
other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics,
anxiolytics, tranquilizers, muscle relaxants, general anesthetics,
antipsychotics, other opioids, alcohol). Because of these risks, reserve
concomitant prescribing of these drugs for use in patients for whom alternative
treatment options are inadequate.
Observational studies have demonstrated that concomitant
use of opioid analgesics and benzodiazepines increases the risk of drug-related
mortality compared to use of opioid analgesics alone. Because of similar
pharmacological properties, it is reasonable to expect similar risk with the
concomitant use of other CNS depressant drugs with opioid analgesics [see DRUG
If the decision is made to prescribe a benzodiazepine or
other CNS depressant concomitantly with an opioid analgesic, prescribe the
lowest effective dosages and minimum durations of concomitant use. In patients
already receiving an opioid analgesic, prescribe a lower initial dose of the
benzodiazepine or other CNS depressant than indicated in the absence of an
opioid, and titrate based on clinical response. If an opioid analgesic is
initiated in a patient already taking a benzodiazepine or other CNS depressant,
prescribe a lower initial dose of the opioid analgesic, and titrate based on
clinical response. Follow patients closely for signs and symptoms of
respiratory depression and sedation.
Advise both patients and caregivers about the risks of
respiratory depression and sedation when ULTRACET is used with benzodiazepines
or other CNS depressants (including alcohol and illicit drugs). Advise patients
not to drive or operate heavy machinery until the effects of concomitant use of
the benzodiazepine or other CNS depressant have been determined. Screen
patients for risk of substance use disorders, including opioid abuse and
misuse, and warn them of the risk for overdose and death associated with the
use of additional CNS depressants including alcohol and illicit drugs [see
DRUG INTERACTIONS, PATIENT INFORMATION].
Serotonin Syndrome Risk
Cases of serotonin syndrome, a potentially
life-threatening condition, have been reported with the use of tramadol, including
ULTRACET, during concomitant use with serotonergic drugs.
Serotonergic drugs include selective serotonin reuptake
inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs),
tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs
that affect the serotonergic neurotransmitter system (e.g., mirtazapine,
trazodone, tramadol), and drugs that impair metabolism of serotonin (including
MAO inhibitors, both those intended to treat psychiatric disorders and also
others, such as linezolid and intravenous methylene blue) [see DRUG
INTERACTIONS]. This may occur within the recommended dosage range.
Serotonin syndrome symptoms 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, rigidity), and/or gastrointestinal symptoms
(e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs
within several hours to a few days of concomitant use, but may occur later than
that. Discontinue ULTRACET if serotonin syndrome is suspected.
Increased Risk Of Seizures
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
Concomitant use of tramadol increases the seizure risk in
patients taking: [see DRUG INTERACTIONS].
- Selective serotonin re-uptake inhibitors (SSRIs) and
Serotonin-norepinephrine re-uptake inhibitors (SNRIs) antidepressants or
- Tricyclic antidepressants (TCAs), and other tricyclic
compounds (e.g., cyclobenzaprine, promethazine, etc.),
- Other opioids,
- MAO inhibitors [see Serotonin Syndrome Risk, and DRUG
- Neuroleptics, or
- Other drugs that reduce the seizure threshold.
Risk of seizures 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,
In tramadol overdose, naloxone administration may
increase the risk of seizure.
- Do not prescribe ULTRACET for patients who are suicidal
or addiction-prone. Consideration should be given to the use of non-narcotic
analgesics in patients who are suicidal or depressed [see Drug Abuse and
- Prescribe ULTRACET with caution for patients with a
history of misuse and/or are currently taking CNS-active drugs including
tranquilizers, or antidepressant drugs, or alcohol in excess, and patients who
suffer from emotional disturbance or depression [see DRUG INTERACTIONS].
- Inform patients not to exceed the recommended dose and to
limit their intake of alcohol [see DOSAGE AND ADMINISTRATION, Hepatotoxicity and Risks From Concomitant Use With Benzodiazepines Or Other
Cases of adrenal insufficiency have been reported with
opioid use, more often following greater than one month of use. Presentation of
adrenal insufficiency may include non-specific symptoms and signs including
nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood
pressure. If adrenal insufficiency is suspected, confirm the diagnosis with
diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed,
treat with physiologic replacement doses of corticosteroids. Wean the patient
off of the opioid to allow adrenal function to recover and continue
corticosteroid treatment until adrenal function recovers. Other opioids may be tried
as some cases reported use of a different opioid without recurrence of adrenal
insufficiency. The information available does not identify any particular opioids
as being more likely to be associated with adrenal insufficiency.
Life-Threatening Respiratory Depression In Patients With Chronic
Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients
The use of ULTRACET in patients with acute or severe
bronchial asthma in an unmonitored setting or in the absence of resuscitative
equipment is contraindicated [see CONTRAINDICATIONS
Patients With Chronic Pulmonary Disease
ULTRACET-treated patients with significant chronic obstructive
pulmonary disease or cor pulmonale, and those with a substantially decreased
respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory
depression are at increased risk of decreased respiratory drive including
apnea, even at recommended dosages of ULTRACET [see Life-Threatening Respiratory Depression].
Elderly, Cachectic, Or Debilitated Patients
Life-threatening respiratory depression is more likely to
occur in elderly, cachectic, or debilitated patients because they may have
altered pharmacokinetics, or altered clearance, compared to younger, healthier
patients [see Life-Threatening Respiratory Depression].
Monitor such patients closely, particularly when
initiating and titrating ULTRACET and when ULTRACET is given concomitantly with
other drugs that depress respiration [see Hepatotoxicity , DRUG
INTERACTIONS]. Alternatively, consider the use of non-opioid analgesics in these
ULTRACET may cause severe hypotension including
orthostatic hypotension and syncope in ambulatory patients. There is increased
risk in patients whose ability to maintain blood pressure has already been compromised
by a reduced blood volume or concurrent administration of certain CNS depressant
drugs (e.g., phenothiazines or general anesthetics) [see DRUG INTERACTIONS].
Monitor these patients for signs of hypotension after initiating or titrating
the dosage of ULTRACET. In patients with circulatory shock, ULTRACET may cause
vasodilation that can further reduce cardiac output and blood pressure. Avoid
the use of ULTRACET in patients with circulatory shock.
Risk Of Use In Patients With Increased Intracranial
Pressure, Brain Tumors, Head Injury, Or Impaired Consciousness
In patients who may be susceptible to the intracranial
effects of CO2 retention (e.g., those with evidence of increased intracranial
pressure or brain tumors), ULTRACET may reduce respiratory drive, and the resultant
CO2 retention can further increase intracranial pressure. Monitor such patients
for signs of sedation and respiratory depression, particularly when initiating
therapy with ULTRACET.
Opioids may also obscure the clinical course in a patient
with a head injury. Avoid the use of ULTRACET in patients with impaired
consciousness or coma.
Serious Skin Reactions
Rarely, acetaminophen may cause serious skin reactions
such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson
Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.
Patients should be informed about the signs of serious skin reactions, and use
of the drug should be discontinued at the first appearance of skin rash or any
other sign of hypersensitivity.
Risk Of Use In Patients With Gastrointestinal Conditions
ULTRACET is contraindicated in patients with known or
suspected gastrointestinal obstruction, including paralytic ileus [see
The tramadol in ULTRACET may cause spasm of the sphincter
of Oddi. Opioids may cause increases in serum amylase. Monitor patients with
biliary tract disease, including acute pancreatitis, for worsening symptoms.
Anaphylaxis And Other Hypersensitivity Reactions
Serious and rarely fatal anaphylactic 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 ULTRACET. If anaphylaxis or other hypersensitivity occurs,
stop administration of ULTRACET immediately, discontinue ULTRACET permanently,
and do not rechallenge with any formulation of tramadol. Advise patients to
seek immediate medical attention if they experience any symptoms of a
hypersensitivity reaction [see CONTRAINDICATIONS, PATIENT INFORMATION].
There have been postmarketing reports of hypersensitivity
and anaphylaxis associated with the use of acetaminophen. Clinical signs
included swelling of the face, mouth, and throat, respiratory distress, urticaria,
rash, pruritus, and vomiting. There were infrequent reports of life-threatening
anaphylaxis requiring emergency medical attention. Instruct patients to
discontinue ULTRACET immediately and seek medical care if they experience these
symptoms. Do not prescribe ULTRACET for patients with acetaminophen allergy.
Increased Risk Of Hepatotoxicity With Concomitant Use Of Other
Due to the potential for acetaminophen hepatotoxicity at
doses higher than the recommended dose, ULTRACET should not be used
concomitantly with other acetaminophen containing products.
Avoid the use of mixed agonist/antagonist (e.g.,
pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g.,
buprenorphine) analgesics in patients who are receiving a full opioid agonist
analgesic, including ULTRACET. In these patients, mixed agonist/antagonist and
partial agonist analgesics may reduce the analgesic effect and/or precipitate
withdrawal symptoms [see DRUG INTERACTIONS
When discontinuing ULTRACET, in opioid-dependent
patients, gradually taper the dosage [see DOSAGE AND ADMINISTRATION]. Do
not abruptly discontinue ULTRACET [see Drug Abuse and Dependence].
Driving And Operating Machinery
ULTRACET may impair the mental or physical abilities needed
to perform potentially hazardous activities such as driving a car or operating
machinery. Warn patients not to drive or operate dangerous machinery unless
they are tolerant to the effects of ULTRACET and know how they will react to
the medication [see PATIENT INFORMATION].
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Addiction, Abuse, And Misuse
Inform patients that the use of ULTRACET, even when taken
as recommended, can result in addiction, abuse, and misuse, which can lead to
overdose and death [see WARNINGS AND PRECAUTIONS]. Instruct patients not
to share ULTRACET with others and to take steps to protect ULTRACET from theft
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening
respiratory depression, including information that the risk is greatest when
starting ULTRACET or when the dosage is increased, and that it can occur even
at recommended dosages [see WARNINGS AND PRECAUTIONS]. Advise patients
how to recognize respiratory depression and to seek medical attention if
breathing difficulties develop.
Inform patients that accidental ingestion, especially by
children, may result in respiratory depression or death [see WARNINGS AND
PRECAUTIONS]. Instruct patients to take steps to store ULTRACET securely and
to dispose of unused ULTRACET in accordance with the local state guidelines
Interactions With Benzodiazepines And Other CNS
Inform patients and caregivers that potentially fatal
additive effects may occur if ULTRACET is used with benzodiazepines or other
CNS depressants, including alcohol, and not to use these concomitantly unless
supervised by a healthcare provider [see WARNINGS AND PRECAUTIONS, DRUG
Inform patients that tramadol could cause a rare but
potentially life-threatening condition, particularly during concomitant use
with serotonergic drugs. Warn patients of the symptoms and signs of serotonin syndrome
and to seek medical attention right away if symptoms develop. Instruct patients
to inform their healthcare provider if they are taking, or plan to take
serotonergic medications [see WARNINGS AND PRECAUTIONS].
Inform patients not to take ULTRACET while using any
drugs that inhibit monoamine oxidase. Patients should not start MAOIs while
taking ULTRACET [see DRUG INTERACTIONS].
Inform patients that ULTRACET may cause seizures with
concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans)
or drugs that significantly reduce the metabolic clearance of tramadol [see WARNINGS
Inform patients that opioids could cause adrenal
insufficiency, a potentially life-threatening condition. Adrenal insufficiency
may present with non-specific symptoms and signs such as nausea, vomiting, anorexia,
fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek
medical attention if they experience a constellation of these symptoms [see WARNINGS
Important Administration Instructions
Instruct patients how to properly take ULTRACET [see
DOSAGE AND ADMINISTRATION].
- Do not adjust the dose of ULTRACET without consulting
with a physician or other healthcare provider.
- Do not take more than 4000 milligrams of acetaminophen
per day and to call their healthcare provider if they took more than the
Inform patients that ULTRACET may cause orthostatic
hypotension and syncope. Instruct patients how to recognize symptoms of low
blood pressure and how to reduce the risk of serious consequences should
hypotension occur (e.g., sit or lie down, carefully rise from a sitting or
lying position) [see WARNINGS AND PRECAUTIONS].
Inform patients that anaphylaxis have been reported with
ingredients contained in ULTRACET. Advise patients how to recognize such a
reaction and when to seek medical attention [see CONTRAINDICATIONS, WARNINGS
AND PRECAUTIONS, ADVERSE REACTIONS].
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that
ULTRACET should not be used for more than 5 days and that prolonged use of
opioids such as ULTRACET, during pregnancy can result in neonatal opioid
withdrawal syndrome, which may be life-threatening if not recognized and
treated [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].
Inform female patients of reproductive potential that
ULTRACET can cause fetal harm and to inform the healthcare provider of a known
or suspected pregnancy [see Use in Specific Populations
Advise nursing mothers to monitor infants for increased
sleepiness (more than usual), breathing difficulties, or limpness. Instruct
nursing mothers to seek immediate medical care if they notice these signs [see
Use in Specific Populations].
Inform patients that chronic use of opioids may cause
reduced fertility. It is not known whether these effects on fertility are
reversible [Use in Specific Populations (8.3)].
Driving Or Operating Heavy Machinery
Inform patients that ULTRACET may impair the ability to
perform potentially hazardous activities such as driving a car or operating
heavy machinery. Advise patients not to perform such tasks until they know how
they will react to the medication [see WARNINGS AND PRECAUTIONS].
Advise patients of the potential for severe constipation,
including management instructions and when to seek medical attention [see ADVERSE
Disposal Of Unused ULTRACET
Advise patients to throw the unused ULTRACET in the
household trash following these steps. 1) Remove the drugs from their original
containers and mix with an undesirable substance, such as used coffee grounds
or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable
to people who may intentionally go through the trash seeking drugs). 2) Place
the mixture in a sealable bag, empty can, or other container to prevent the
drug from leaking or breaking out of a garbage bag.
Maximum Daily Acetaminophen Use
Advise patients not to take more than 4,000 milligrams of
acetaminophen per day and call their doctor if they have taken more than the
recommended dose [see WARNINGS AND PRECAUTIONS].
Use With Other Acetaminophen-Containing Products
Advise patients not to take ULTRACET in combination with
other tramadol or acetaminophencontaining products, including over-the-counter
preparations [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
There are no animal or laboratory studies on the
combination product (tramadol and acetaminophen) to evaluate carcinogenesis,
mutagenesis, or impairment of fertility. Data on the individual components are described
A slight but statistically significant increase in two
common murine tumors, pulmonary and hepatic, was observed in an NMRI mouse
carcinogenicity study, particularly in aged mice. Mice were dosed orally up to
30 mg/kg in the drinking water (0.5 times the maximum recommended daily human
dosage or MRHD) for approximately two years, although the study was not done
with the Maximum Tolerated Dose. This finding is not believed to suggest risk
in humans. No evidence of carcinogenicity was noted in a rat 2-year
carcinogenicity study testing oral doses of up to 30 mg/kg in the drinking
water (1 times the MRHD).
Long-term studies in mice and rats have been completed by
the National Toxicology Program to evaluate the carcinogenic potential of
acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed
a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated equivocal
evidence of carcinogenic activity based on increased incidences of mononuclear
cell leukemia at 1.2 times the maximum human daily dose (MHDD) of 2.6
grams/day, based on a body surface area comparison. In contrast, there was no
evidence of carcinogenic activity in male rats (1.1 times) or mice (1.9-2.2
times the MHDD, based on a body surface area comparison).
Tramadol was mutagenic in the presence of metabolic
activation in the mouse lymphoma assay. Tramadol was not mutagenic in the in
vitro bacterial reverse mutation assay using Salmonella and E. coli (Ames), the
mouse lymphoma assay in the absence of metabolic activation, the in vitro chromosomal
aberration assay, or the in vivo micronucleus assay in bone marrow.
Acetaminophen was not mutagenic in the bacterial reverse
mutation assay (Ames test). In contrast, acetaminophen tested positive for
induction of sister chromatid exchanges and chromosomal aberrations in in vitro
assays using Chinese hamster ovary cells. In the published literature,
acetaminophen has been reported to be clastogenic when administered a dose of
1500 mg/kg/day to the rat model (3.6-times the MHDD, based on a body surface
area comparison). In contrast, no clastogenicity was noted at a dose of 750
mg/kg/day (2.8-times the MHDD, based on a body surface area comparison),
suggesting a threshold effect.
Impairment Of Fertility
No effects on fertility were observed for tramadol at
oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats. These
dosages are 1.6 and 2.4 times the MRHD [see Use in Specific Populations].
In studies of acetaminophen conducted by the National
Toxicology Program, fertility assessments have been completed in Swiss mice via
a continuous breeding study. There were no effects on fertility parameters in
mice consuming up to 1.7 times the MHDD of acetaminophen, based on a body
surface area comparison. Although there was no effect on sperm motility or
sperm density in the epididymis, there was a significant increase in the
percentage of abnormal sperm in mice consuming 1.7 times the MHDD (based on a
body surface area comparison) and there was a reduction in the number of mating
pairs producing a fifth litter at this dose, suggesting the potential for
cumulative toxicity with chronic administration of acetaminophen near the upper
limit of daily dosing.
Published studies in rodents report that oral
acetaminophen treatment of male animals at doses that are 1.2 times the MHDD
and greater (based on a body surface area comparison) result in decreased testicular
weights, reduced spermatogenesis, reduced fertility, and reduced implantation
sites in females given the same doses. These effects appear to increase with
the duration of treatment. The clinical significance of these findings is not
Use In Specific Populations
Prolonged use of opioid analgesics during pregnancy may
cause neonatal opioid withdrawal syndrome [see WARNINGS AND PRECAUTIONS].
Available data with ULTRACET in pregnant women are insufficient to inform a
drug-associated risk for major birth defects and miscarriage.
In animal reproduction studies, the combination of
tramadol and acetaminophen decreased fetal weights and increased supernumerary
ribs at 1.6 times the maximum recommended human daily dosage (MRHD). In
separate animal reproduction studies, tramadol administration alone during
organogenesis decreased fetal weights and reduced ossification in mice, rats,
and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily
dosage (MRHD). Tramadol decreased pup body weight and increased pup mortality
at 1.2 and 1.9 times the MRHD.
Reproductive and developmental studies in rats and mice
from the published literature identified adverse events at clinically relevant
doses with acetaminophen. Treatment of pregnant rats with doses of acetaminophen
approximately 1.3 times the maximum human daily dose (MRHD) showed evidence of fetotoxicity
and increases in bone variations in the fetuses. In another study, necrosis was
observed in the liver and kidney of both pregnant rats and fetuses at doses
approximately 1.9 times the MHDD. In mice treated with acetaminophen at doses
within the clinical dosing range, cumulative adverse effects on reproduction
were seen in a continuous breeding study. A reduction in number of litters of
the parental mating pair was observed as well as retarded growth and abnormal
sperm in their offspring and reduced birth weight in the next generation [see Data].
Based on animal data, advise pregnant women of the potential risk to a fetus.
All pregnancies have a background risk of birth defect,
loss, or other adverse outcomes. In the U.S. general population, the estimated
background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2-4% and 15-20%, respectively.
Fetal/Neonatal Adverse Reactions
Prolonged use of opioid analgesics during pregnancy for
medical or nonmedical purposes can result in respiratory depression and
physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly
Neonatal opioid withdrawal syndrome presents as
irritability, hyperactivity and abnormal sleep pattern, high pitched cry,
tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and
severity of neonatal opioid withdrawal syndrome vary based on the specific
opioid used, duration of use, timing and amount of last maternal use, and rate
of elimination of the drug by the newborn. Observe newborns for symptoms and
signs of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS
Neonatal seizures, neonatal withdrawal syndrome, fetal
death and stillbirth have been reported with tramadol hydrochloride during
Labor or Delivery
ULTRACET is not recommended for use in pregnant women
during or immediately prior to labor, when other analgesic techniques are more
appropriate. Opioids cross the placenta and may produce respiratory depression
and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone,
must be available for reversal of opioid induced respiratory depression in the
neonate. ULTRACET is not recommended for use in pregnant women during or
immediately prior to labor, when other analgesic techniques are more
appropriate. Opioid analgesics, including ULTRACET, can prolong labor through
actions which temporarily reduce the strength, duration, and frequency of
uterine contractions. However, this effect is not consistent and may be offset
by an increased rate of cervical dilation, which tends to shorten labor.
Monitor neonates exposed to opioid analgesics during labor for signs of excess
sedation and respiratory depression.
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 given tramadol during labor.
The effect of ULTRACET, if any, on the later growth,
development, and functional maturation of the child is unknown.
No drug-related teratogenic effects were observed in the
progeny of rats treated orally with tramadol and acetaminophen. The
tramadol/acetaminophen combination product was shown to be embryotoxic and fetotoxic
in rats at a maternally toxic dose, 50/434 mg/kg tramadol/acetaminophen (1.6
times the maximum daily human tramadol/acetaminophen dosage), but was not
teratogenic at this dose level. Embryo and fetal toxicity consisted of
decreased fetal weights and increased supernumerary ribs. Tramadol has been
shown to be embryotoxic and fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and
rabbits (75 mg/kg) at maternally toxic dosages, but was not teratogenic at
these dose levels. These doses on a mg/m2 basis are 1.9, 0.8, and 4.9 times the
maximum recommended human daily dosage (MRHD) for mouse, rat and rabbit,
No drug-related teratogenic effects were observed in
progeny of mice (up to 140 mg/kg), rats (up to 80 mg/kg) or rabbits (up to 300
mg/kg) treated with tramadol by various routes. Embryo and fetal toxicity consisted
primarily of decreased fetal weights, skeletal ossification and increased
supernumerary ribs at maternally toxic dose levels. Transient delays in
developmental or behavioral parameters were also seen in pups from rat dams
allowed to deliver. Embryo and fetal lethality were reported only in one rabbit
study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the
rabbit. The dosages listed for mouse, rat and rabbit are 2.3, 2.6, and 19 times
the MRHD, respectively.
Tramadol alone was evaluated in peri- and post-natal
studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50
mg/kg (300 mg/m2 or 1.6 times the maximum daily human tramadol dosage) or
greater had decreased weights, and pup survival was decreased early in
lactation at 80 mg/kg (480 mg/m2 or 2.6 times the maximum daily human tramadol
Studies in pregnant rats that received oral acetaminophen
during organogenesis at doses up to 1.3 times the maximum human daily dose
(MHDD = 2.6 grams/day, based on a body surface area comparison) showed evidence
of fetotoxicity (reduced fetal weight and length) and a dose-related increase
in bone variations (reduced ossification and rudimentary rib changes). Offspring
had no evidence of external, visceral, or skeletal malformations.
When pregnant rats received oral acetaminophen throughout
gestation at doses of 1.9-times the MHDD (based on a body surface area
comparison), areas of necrosis occurred in both the liver and kidney of pregnant
rats and fetuses. These effects did not occur in animals that received oral
acetaminophen at doses 0.5-times the MHDD, based on a body surface area
In a continuous breeding study, pregnant mice received
0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day).
These doses are approximately 0.7, 1.3, and 2.7 times the MHDD, respectively,
based on a body surface area comparison. A dose-related reduction in body
weights of fourth and fifth litter offspring of the treated mating pair
occurred during lactation and post-weaning at all doses. Animals in the high
dose group had a reduced number of litters per mating pair, male offspring with
an increased percentage of abnormal sperm, and reduced birth weights in the
next generation pups.
ULTRACET 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.
Monitor infants exposed to ULTRACET through breast milk
for excess sedation and respiratory depression. Withdrawal symptoms can occur
in breastfed infants when maternal administration of an opioid analgesic is
stopped, or when breast-feeding is stopped.
Following a single IV 100 mg dose of tramadol, the
cumulative excretion in breast milk within 16 hours post dose was 100 mcg of
tramadol (0.1% of the maternal dose) and 27 mcg of M1.
Females And Males Of Reproductive Potential
Chronic use of opioids may cause reduced fertility in
females and males of reproductive potential. It is not known whether these
effects on fertility are reversible [see ADVERSE REACTIONS, CLINICAL
PHARMACOLOGY, Nonclinical Toxicology
The safety and efficacy of ULTRACET in patients under 18
years of age have not been established. The use of ULTRACET in the pediatric
population is not recommended.
Elderly patients (aged 65 years or older) may have
increased sensitivity to tramadol. In general, use caution when selecting a
dosage for an elderly patient, 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.
Respiratory depression is the chief risk for elderly
patients treated with opioids, and has occurred after large initial doses were
administered to patients who were not opioid-tolerant or when opioids were co-administered
with other agents that depress respiration. Titrate the dosage of ULTRACET
slowly in geriatric patients and monitor closely for signs of central nervous
system and respiratory depression [see WARNINGS AND PRECAUTIONS].
Tramadol and acetaminophen are known to be substantially
excreted by the kidney, and the risk of adverse reactions to this drug may be
greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function.
The pharmacokinetics and tolerability of ULTRACET in
patients with impaired hepatic function have not been studied. Based on
information using tramadol immediate-release tablets in subjects with advanced
cirrhosis of the liver, tramadol exposure was higher and half-lives of tramadol
and active metabolite M1 were longer than in subjects with normal hepatic
function [see CLINICAL PHARMACOLOGY].
As tramadol and acetaminophen are both extensively metabolized
by the liver, the use of ULTRACET in patients with hepatic impairment is not
recommended [see WARNINGS AND PRECAUTIONS].
The pharmacokinetics and tolerability of ULTRACET in
patients with renal impairment has not been studied. Based on studies using
tramadol extended-release tablets, the excretion of tramadol and metabolite M1
is reduced in patients with creatinine clearance of less than 30 mL/min. In
patients with creatinine clearances of less than 30 mL/min, it is recommended
that the dosage of ULTRACET not exceed 2 tablets every 12 hours. [see 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 based on studies using
tramadol alone. Monitor closely for signs of respiratory depression, sedation,
Tramadol clearance was 20% higher in female subjects
compared to males in four Phase 1 studies of ULTRACET in 50 male and 34 female
healthy subjects. The clinical significance of this difference is unknown.