Approved Drug Label (PDF)
5
Warnings and Precautions
5.1
Addiction, Abuse, and Misuse
Additions
and/or revisions underlined:
… 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. Consider
prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2),
Warnings and Precautions (5.3)].
5.3 Life-Threatening Respiratory Depression
Additions and/or revisions underlined:
… Accidental
ingestion of even one dose of ULTRACET, especially by children, can result in
respiratory depression and death due to an overdose of tramadol.
Educate patients
and caregivers on how to recognize respiratory depression and emphasize the
importance of calling 911 or getting emergency medical help right away in the
event of a known or suspected overdose [see
Patient Counseling Information (17)].
Opioids can cause
sleep-related breathing disorders including central sleep apnea (CSA) and
sleep-related hypoxemia. Opioid use increases the risk of CSA in a
dose-dependent fashion. In patients who present with CSA, consider decreasing
the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)].
Newly added information:
Patient Access to Naloxone
for the Emergency Treatment of Opioid Overdose
Discuss the
availability of naloxone for the emergency treatment of opioid overdose with
the patient and caregiver and assess the potential need for access to naloxone,
both when initiating and renewing treatment with ULTRACET. Inform patients and
caregivers about the various ways to obtain naloxone as permitted by individual
state naloxone dispensing and prescribing requirements or guidelines (e.g., by
prescription, directly from a pharmacist, or as part of a community-based
program). Educate patients and caregivers on how to recognize respiratory
depression and emphasize the importance of calling 911 or getting emergency
medical help, even if naloxone is administered [see Patient Counseling Information (17)].
Consider
prescribing naloxone, based on the patient’s risk factors for overdose, such as
concomitant use of CNS depressants, a history of opioid use disorder, or prior
opioid overdose. The presence of risk factors for overdose should not prevent the
proper management of pain in any given patient. Also consider prescribing
naloxone if the patient has household members (including children) or other
close contacts at risk for accidental ingestion or overdose. If naloxone is
prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions (5.1, 5.8),
Patient Counseling Information (17)].
5.8 Risks from Concomitant Use with Benzodiazepines or
Other CNS Depressants
Additions and/or revisions underlined:
… 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.
If concomitant use
is warranted, consider prescribing naloxone for the emergency treatment of
opioid overdose [see Dosage and
Administration (2.2), Warnings and Precautions (5.4)].
7
Drug Interactions
Table 2:
Clinically Significant Drug Interactions with ULTRACET
Benzodiazepines
and Other Central Nervous System (CNS) Depressants
Under Intervention, the
following language is added:
If concomitant use is warranted, consider prescribing naloxone for the
emergency treatment of opioid overdose [see Dosage and Administration (2.2),
Warnings and Precautions (5.1, 5.3, 5.8)].
Muscle Relaxants
Under Intervention, the
following language is added:
Due to the risk of respiratory depression with concomitant use of
skeletal muscle relaxants and opioids, consider prescribing naloxone for the
emergency treatment of opioid overdose [see Dosage and Administration (2.2),
Warnings and Precautions (5.3, 5.8)]
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Important information about ULTRACET:
Additions and/or revisions underlined:
Get emergency help
or call 911 right away if you take too much ULTRACET (overdose). When you first
start taking ULTRACET, when your dose is changed, or if you take too much
(overdose), serious or life-threatening breathing problems that can lead to
death may occur. Talk to your healthcare provider about naloxone, a medicine
for the emergency treatment of an opioid overdose.
Before
taking ULTRACET, tell your healthcare provider if you have a history of:
abuse
of street or prescription drugs, alcohol addiction, opioid overdose, or
mental health problems.
Tell
your healthcare provider if you are:
Get emergency
medical help or call 911 right away if you have: …
PATIENT COUNSELING INFORMATION
Life-Threatening
Respiratory Depression
Newly added information:
Educate patients
and caregivers on how to recognize respiratory depression and emphasize the
importance of calling 911 or getting emergency medical help right away in the
event of a known or suspected overdose [see
Warnings and Precautions (5.3)].
Newly added information:
Patient Access to
Naloxone for the Emergency Treatment of Opioid Overdose
Discuss with the
patient and caregiver the availability of naloxone for the emergency treatment
of opioid overdose, both when initiating and renewing treatment with ULTRACET.
Inform patients and caregivers about the various ways to obtain naloxone as permitted
by individual state naloxone dispensing and prescribing requirements or
guidelines (e.g., by prescription, directly from a pharmacist, or as part of a
community-based program) [see Dosage and
Administrations (2.2), Warnings and Precautions (5.3)].Educate patients and
caregivers on how to recognize the signs and symptoms of an overdose.
Explain to
patients and caregivers that naloxone’s effects are temporary, and that they
must call 911 or get emergency medical help right away in all cases of known or
suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].
If naloxone is
prescribed, also advise patients and caregivers:
How
to treat with naloxone in the event of an opioid overdose
To
tell family and friends about their naloxone and to keep it in a place where
family and friends can access it in an emergency
To
read the Patient Information (or other educational material) that will come
with their naloxone. Emphasize the importance of doing this before an opioid
emergency happens, so the patient and caregiver will know what to do.
Approved Drug Label (PDF)
Boxed Warning
(Extensive
additions)
WARNING: ADDICTION, ABUSE, AND MISUSE;
LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID
WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450
ISOENZYMES; HEPATOTOXICITY; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES
OR OTHER CNS DEPRESSANTS
See full prescribing information for complete
boxed warning.
•
ULTRACET exposes users to the risks of
addiction, abuse and misuse, which can lead to overdose and death. Assess each
patient’s risk prior to prescribing ULTRACET, and monitor regularly for these
behaviors or conditions.
•
Serious, life-threatening, or fatal
respiratory depression may occur. Monitor closely, especially during initiation
or following a dose increase.
•
Accidental ingestion of ULTRACET,
especially by children, can result in a fatal overdose of tramadol.
•
Prolonged use of ULTRACET, during
pregnancy can result in neonatal opioid withdrawal syndrome, which may be life
threatening if not recognized and treated If prolonged opioid use is required
in a pregnant woman, advise the patient of the risk of neonatal opioid
withdrawal syndrome and ensure that appropriate treatment will be available.
•
The effects of concomitant use or
discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6
inhibitors with tramadol 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, and the active metabolite, M1.
•
ULTRACET contains 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.
•
Concomitant use of opioids with
benzodiazepines or other central nervous system (CNS) depressants, including
alcohol, may result in profound sedation, respiratory depression, coma, and
death. Reserve concomitant prescribing for use in patients for whom alternative
treatment options are inadequate; limit dosages and durations to the minimum
required; and follow patients for signs and symptoms of respiratory depression
and sedation.
4
Contraindications
(additions
underlined)
ULTRACET is contraindicated in
patients with:
•
Significant respiratory depression.
•
Acute or
severe bronchial asthma in an unmonitored setting or in the absence of
resuscitative equipment.
•
Patients with
known or suspected gastrointestinal obstruction, including paralytic ileus.
•
Hypersensitivity to
tramadol, acetaminophen, any other component of this product.
•
Concurrent use
of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days
5
Warnings and Precautions
5.1 Addiction, Abuse and Misuse
(subsection
added)
ULTRACET contains tramadol, a
Schedule IV controlled substance. As an opioid, ULTRACET exposes users to the
risks of addiction, abuse, and misuse.
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. 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.
5.10 Adrenal Insufficiency
(subsection
added)
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.
5.11 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
(subsection
added)
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.
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.
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.
Monitor such patients closely,
particularly when initiating and titrating ULTRACET and when ULTRACET is given
concomitantly with other drugs that depress respiration. Alternatively,
consider the use of non-opioid analgesics in these patients.
5.12 Severe Hypotension
(subsection
added)
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) .
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.
5.13 Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousnes
(revisions
and additions underlined)
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.
5.15 Risk of Use in Patients with Gastrointestinal Conditions
(subsection
added)
ULTRACET is contraindicated in
patients with known or suspected gastrointestinal obstruction, including
paralytic ileus.
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.
5.16 Anaphylaxis and Other Hypersensitivity Reactions
(additions
underlined)
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.
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.
5.17 Increased Risk of Hepatotoxicity with Concomitant Use of Other Acetaminophen-containing Products
(subsection revised)
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.
5.18 Withdrawal
(subsection
added)
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.
When discontinuing ULTRACET, in
opioid-dependent patients, gradually taper the dosage.Do not abruptly
discontinue ULTRACET.
5.19 Driving and Operating Machinery
(subsection
added)
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.
5.2 Life-Threatening Respiratory Depression
(subsection
added)
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. 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.
Overestimating the ULTRACET dosage when converting patients from another opioid
product can result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of ULTRACET,
especially by children, can result in respiratory depression and death due to
an overdose of tramadol.
5.3 Neonatal Opioid Withdrawal Syndrome
(subsection
added)
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.
5.4 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes
(subsection
added)
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 .
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
syndrome.
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 respiratory depression.
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. 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.
5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
(subsection
added)
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.
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.
5.7 Serotonin Syndrome Risk
(subsection
added)
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 MAOinhibitors, both
those intended to treat psychiatric disorders and also others, such as
linezolid and intravenous methylene blue). 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.
5.8 Increased Risk of Seizures
(additions
underlined)
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 (SSRIs) and Serotonin-norepinephrine re-uptake inhibitors (SNRIs)
antidepressants or anorectics,
•
Tricyclic
antidepressants (TCAs), and other tricyclic
•
compounds (e.g.,
cyclobenzaprine, promethazine, etc.),
•
Other opioids,
•
MAO inhibitors
•
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, CNS infections).
In tramadol
overdose, naloxone administration may increase the risk of seizure.
5.9 Suicide Risk
(additions
underlined)
·
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.
·
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
•
·
Inform
patients not to exceed the recommended dose and to limit their intake of
alcohol
6
Adverse Reactions
6.1 Clinical Trials Experience
(additions
underlined)
Because clinical
trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates
in the clinical trials of another drug and may not reflect the rates observed
in practice.
6.2 Postmarketing Experience
(subsection
added)
The following
adverse reactions have
been identified during
post approval use
of tramadol-containing products. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug
exposure.
Serotonin syndrome: Cases of
serotonin syndrome, a potentially life-threatening condition, have been
reported during concomitant use of opioids with serotonergic drugs.
Adrenal insufficiency: Cases of
adrenal insufficiency have been reported with opioid use, more often following
greater than one month of use.
Anaphylaxis: Anaphylaxis has
been reported with ingredients contained in ULTRACET. Androgen deficiency:
Cases of androgen deficiency have occurred with chronic use of opioids
Eye disorders – miosis, mydriasis
Metabolism and nutrition disorders – Cases of hypoglycemia have been reported very
rarely in patients taking tramadol. Most reports were in patients with
predisposing risk factors, including diabetes or renal insufficiency, or in
elderly patients.
Nervous system disorders – movement disorder, speech disorder
Psychiatric
disorders – delirium
(additions
underlined0
The following
serious adverse reactions are discussed, or described in greater detail, in
other sections:
·
Addiction, Abuse,
and Misuse
·
Life-Threatening
Respiratory Depression
·
Neonatal
Opioid Withdrawal Syndrome
·
Hepatotoxicity
Interactions with Benzodiazepines and
Other CNS Depressants
·
Serotonin
Syndrome
·
Seizures
·
Suicide
·
Adrenal
Insufficiency
·
Severe Hypotension
·
Gastrointestinal Adverse Reactions
·
Hypersensitivity Reactions
·
Withdrawal
7
Drug Interactions
(Extensive
additions and revisions, please refer to Table 2 in label)
8
Use in Specific Populations
8.1 Pregnancy
(PLLR
conversion, please refer to label)
8.2 Lactation
(PLLR
conversion)
Risk Summary
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.
Clinical
Considerations
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.
Data
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.
8.3 Females and Males of Reproductive Potential
(PLLR
conversion)
Infertility
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.
8.4 Pediatric Use
(addition
underlined)
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.
8.5 Geriatric Use
(additions
and revisions underlined)
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.
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.
8.6 Hepatic Impairment
(additions
underlined)
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.
As tramadol and
acetaminophen are both extensively metabolized by the liver, the use of
ULTRACET in patients with hepatic impairment is not recommended.
8.7 Renal Impairment
(additions
underlined)
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.)]. 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, and hypotension.
8.8 Sex
(subsection
added)
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(new
section and extensive information, please refer to label)
Medication Guide
(new
section, please refer to label)
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