Approved Drug Label (PDF)
Boxed Warning
Extensive changes; please refer to label
5
Warnings and Precautions
5.1 Addiction, Abuse and Misuse
Additions and revisions underlined:
Assess each patient’s risk
for opioid addiction, abuse, or misuse prior to prescribing SEGLENTIS, and reassess
all patients receiving SEGLENTIS 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 SEGLENTIS but use in such patients necessitates intensive counseling about the risks and proper use of SEGLENTIS along with frequent reevaluation 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 (5.2)].
Opioids are sought for
nonmedical use and are subject
to diversion from legitimate prescribed use. Consider these risks
when prescribing or dispensing SEGLENTIS. Strategies to reduce
these risks include prescribing the drug in the smallest
appropriate quantity and advising the patient on careful
storage of the drug during the course of treatment and on the proper
disposal of unused drug.
5.10 Opioid-Induced Hyperalgesia and Allodynia
Newly added subsection:
Opioid-induced Hyperalgesia (OIH) occurs when an opioid
analgesic paradoxically causes an increase in pain,
or an increase in sensitivity to pain. This condition differs
from tolerance, which
is the need for increasing doses of opioids to maintain a defined effect
[see Dependence (9.3)].
Symptoms of OIH include (but
may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid
dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These
symptoms may suggest OIH only if there is no evidence of underlying disease
progression, opioid tolerance, opioid withdrawal, or addictive behavior.
Causes of OIH have been
reported, both with short-term and longer-term use of opioid analgesics. Though
the mechanism of OIH is not fully understood, multiple biochemical pathways
have been implicated. Medical literature suggests a strong biologic
plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected
to be experiencing OIH, carefully consider appropriately decreasing the dose of the current
opioid analgesic or opioid rotation
(safely switching the patient to a
different opioid moiety) [see Dosage and Administration (2.4), Warnings and Precautions (5.29)].
5.11 Serotonin Syndrome Risk
Additions and revisions underlined:
Tramadol
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, a component of
SEGLENTIS, particularly 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),
certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that
impair metabolism of serotonin (including monoamine oxidase inhibitors, both those intended to treat
psychiatric disorders and also others, such as linezolid and intravenous
methylene blue) [see Drug Interactions
(7)]. 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) and can be fatal.
5.14 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
Additions and revisions underlined:
Tramadol
. . .
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 Warnings and Precautions (5.2)].
Regularly evaluate such patients closely,
particularly when initiating SEGLENTIS and when
SEGLENTIS is given concomitantly with
other drugs that depress respiration [see Warnings and Precautions (5.2, 5.3),
Drug Interactions (7)]. Alternatively, consider the use of non-opioid
analgesics in these patients.
5.18 Risk of Use in Patients with Gastrointestinal Conditions
Additions and revisions underlined:
Tramadol
SEGLENTIS is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications (4)].
The tramadol in SEGLENTIS may
cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase.
Regularly evaluate patients
with biliary tract disease, including
acute pancreatitis, for worsening symptoms.
5.2 Life-Threatening Respiratory Depression
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Tramadol
Monitor patients closely
for respiratory depression, especially within the first 24-72 hours of
initiating therapy with SEGLENTIS.
5.21 Hypertension
Additions and revisions underlined:
Celecoxib
NSAIDs, including celecoxib, a
component in SEGLENTIS, can lead to new onset of hypertension or worsening of
preexisting hypertension, either of which may contribute to the increased
incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors,
thiazide diuretics or loop diuretics may have impaired response
to these therapies when taking NSAIDs
[see Drug Interactions (7)].
Regularly evaluate blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
5.23 Renal Toxicity and Hyperkalemia
Additions and revisions underlined:
Celecoxib
. . .
Correct volume status
in dehydrated or hypovolemic patients
prior to initiating SEGLENTIS. Regularly
evaluate renal function in patients with renal or hepatic impairment, heart
failure, dehydration, or hypovolemia during use of SEGLENTIS [see Drug Interactions (7)].
5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Additions and revisions underlined:
Tramadol
Profound sedation, respiratory depression,
coma, and death may result from the concomitant use of
SEGLENTIS with benzodiazepines and/or
other CNS depressants, including alcohol (e.g., nonbenzodiazepine sedatives/hypnotics,
anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics,
other opioids).
Inform patients and caregivers of this
potential interaction and educate them on the signs
and symptoms of respiratory depression
(including sedation).
5.32 Hyponatremia
Additions and revisions underlined:
Hyponatremia (serum sodium <
135 mmol/L) has been reported with the use of tramadol, a component of SEGLENTIS, and many cases are severe (sodium level < 120 mmol/L). Most cases of hyponatremia occurred in females over
the age of 65 and within the first week of therapy. In some reports,
hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone
secretion (SIADH). Regularly evaluate for signs and symptoms of
hyponatremia (e.g., confusion, disorientation), during treatment with SEGLENTIS, especially during initiation of therapy.
5.33 Hypoglycemia
Additions and revisions underlined:
Cases of tramadol-associated hypoglycemia have been reported,
some resulting in hospitalization. In most cases, patients had predisposing
risk factors (e.g., diabetes). If hypoglycemia is suspected, regularly evaluate blood glucose levels and consider
drug discontinuation as appropriate [see Dosage and Administration (2.4)].
5.4 Neonatal Opioid Withdrawal Syndrome
Additions and revisions underlined:
Tramadol
Use of SEGLENTIS for an extended period
of time 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 an extended period of time of the risk
of neonatal opioid withdrawal syndrome and ensure that appropriate treatment
will be available [see Use in Specific Populations (8.1)].
5.9 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes
Additions and revisions underlined:
.
. .
Evaluate patients
receiving tramadol and any CYP2D6 inhibitor at frequent intervals for
the risk of serious adverse events including seizures and serotonin syndrome, signs
and symptoms that may reflect opioid toxicity, and opioid withdrawal when SEGLENTIS is used in conjunction with inhibitors
of CYP2D6 [see Drug Interactions (7)].
Evaluate patients
receiving SEGLENTIS and any CYP3A4
inhibitor or inducer
at frequent intervals for the risk for serious adverse events including seizures
and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and
opioid withdrawal when SEGLENTIS is used in conjunction with inhibitors and
inducers of CYP3A4 [see Drug Interactions
(7)].
6
Adverse Reactions
Additions and revisions underlined:
The following serious adverse
reactions are discussed, or described in greater detail,
in other sections:
Addiction, Abuse, and Misuse
[see Warnings and Precautions (5.1)]
Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
Interactions with Benzodiazepines or Other CNS Depressants [see Warnings
and Precautions (5.3)]
Neonatal Opioid
Withdrawal Syndrome [see Warnings
and Precautions (5.4)]
Cardiovascular Thrombotic Events [see Warnings and Precautions (5.6)]
Gastrointestinal Bleeding, Ulceration, and Perforation [see Warnings
and Precautions (5.7)]
Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children [see Warnings and Precautions (5.8)]
Opioid-Induced Hyperalgesia and Allodynia [see Warnings
and Precautions (5.
6.2 Postmarketing Experience
Additions and revisions underlined:
. . .
Androgen Deficiency
Cases of androgen
deficiency have occurred
with use of opioids for an extended
period of time
[see Clinical Pharmacology (12.2)].
. . .
Opioid-Induced Hyperalgesia and Allodynia
Cases of hyperalgesia and allodynia have been reported
with opioid therapy
of any duration [see Warnings and Precautions (5.10)].
7
Drug Interactions
Changes to tables; please refer to label
8
Use in Specific Populations
8.1 Pregnancy
Additions and revisions underlined:
Risk Summary
Based on animal data, advise
pregnant women of the potential
risk to fetus.
Use of opioid
analgesics for an extended period
of time during
pregnancy may cause
neonatal opioid withdrawal
syndrome (see Warnings and Precautions
(5.4)).
. . .
Fetal/Neonatal Adverse Reactions
Tramadol:
Use of opioid analgesics
for an extended period of time during pregnancy for medical or nonmedical purposes
can result in respiratory depression and physical dependence in the neonate and
neonatal opioid withdrawal syndrome shortly after birth.
8.3 Females and Males of Reproductive Potential
Additions and revisions underlined:
Infertility
Tramadol
Use of opioids for an extended period of time
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 (6.2), Clinical
Pharmacology (12.2)].
8.5 Geriatric Use
Additions and revisions underlined:
.
. .
Tramadol
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. Frequently reevaluate the patient for signs
of central nervous system and respiratory depression [see Warnings and Precautions (5.14)].
Tramadol is 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, it may be useful
to regularly evaluate renal function.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and revisions underlined:
. . .
Advise patients and
caregivers that when medicines are no longer needed, they should be disposed of
promptly. Inform patients that medicine take-back options are the preferred way
to safely dispose of most types
of unneeded medicines. If no take back programs
or Drug Enforcement Administration (DEA)-registered collectors are available,
instruct patients to dispose of SEGLENTIS by following these four steps:
Mix SEGLENTIS (do not crush)
with an unpalatable substance such as dirt, cat litter, or used
coffee grounds;
Place the mixture in a container such as a sealed
plastic bag;
Throw the container in the household
trash;
Remove all personal information on the prescription label of the empty bottle.
. . .
Opioid-Induced Hyperalgesia and Allodynia
Inform patients and
caregivers not to increase opioid dosage without first consulting a clinician.
Advise patients to seek medical
attention if they experience symptoms
of hyperalgesia, including worsening pain, increased
sensitivity to pain, or new pain. Inform patients and caregivers not to exceed
the recommended dose of SEGLENTIS [see
Warnings and Precautions (5.10), Adverse Reactions (6.2)].
Serotonin Syndrome
Inform patients
that opioids could cause a rare but potentially life-threatening condition called
serotonin syndrome resulting from concomitant administration of serotonergic drugs.
Pregnancy
Neonatal Opioid
Withdrawal Syndrome
Inform female patients of reproductive potential that use of SEGLENTIS for
an extended period
of time during pregnancy can result in neonatal opioid withdrawal
syndrome, which may be life-threatening if not recognized and treated and that the patient should
inform their healthcare provider if they
have used opioids at any time during their pregnancy, especially near the time
of birth [see Warnings and Precautions
(5.4); Use in Specific Populations (8.1)].
Infertility
Advise patients
that use of opioids for
an extended period
of time may cause reduced
fertility. It is not
known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].
Tell your healthcare provider
if you:
Are pregnant or plan to
become pregnant: Use of SEGLENTIS for an
extended period of time during pregnancy can cause withdrawal symptoms in your
newborn baby that could be life-threatening if not recognized and treated.
Taking SEGLENTIS at about 20 weeks
of pregnancy or later may harm your unborn baby. If you need to take SEGLENTIS
for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider
may need to monitor the amount of fluid in your womb around
your baby. You should not take SEGLENTIS and other NSAIDs
after about 30 weeks of
pregnancy. Tell your healthcare provider if you become pregnant or think
that you may be pregnant.
Are breastfeeding: Not recommended; may harm your baby.
Notice your
pain getting worse. If your pain gets worse after you take SEGLENTIS, do not take more of SEGLENTIS without first talking to your doctor. Talk to your doctor if the pain you have increases, if you feel more sensitive
to pain, or if you have
new pain after taking SEGLENTIS.
. . .
For acute (short-term) pain, you may only need to take SEGLENTIS for a few days. You may have some SEGLENTIS left over that you did not use.
See disposal information at the bottom of this section for directions on how to
safely dispose of SEGLENTIS.
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