Included as part of the PRECAUTIONS section.
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 LAZANDA, 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
To reduce the risk of respiratory depression, proper
dosing and titration of LAZANDA are essential [see DOSAGE AND ADMINISTRATION].
Overestimating the LAZANDA dosage can result in a fatal overdose with the first
dose. The substitution of LAZANDA for any other fentanyl product may result in
fatal overdose [see Risk of Medication Errors].
LAZANDA could be fatal to individuals for whom it is not
prescribed and for those who are not opioid-tolerant.
Accidental ingestion of (or exposure to) even one dose of
LAZANDA, especially by (in) children, can result in respiratory depression and
death due to an overdose of fentanyl [see Increased Risk of Overdose in Children Due to Accidental Ingestion or Exposure].
Increased Risk Of Overdose In Children Due To Accidental
Ingestion Or Exposure
Death has been reported in children who have accidentally
ingested transmucosal immediate -release fentanyl products.
Patients and their caregivers must be informed that
LAZANDA contains a medicine in an amount which can be fatal to a child.
Physicians and dispensing pharmacists must specifically question patients or
caregivers about the presence of children in the home (on a full time or
visiting basis) and counsel them regarding the dangers to children from
Patients and their caregivers must be instructed to keep
both used and unused dosage units out of the reach of children. While all units
should be disposed of immediately after use, partially consumed units represent
a special risk to children. In the event that a unit is not completely consumed
it must be properly disposed as soon as possible [see PATIENT INFORMATION].
Detailed instructions for the proper storage,
administration, disposal, and important instructions for managing an overdose
of LAZANDA are provided in the LAZANDA Medication Guide. Encourage patients to
read this information in its entirety and give them an opportunity to have
their questions answered.
Risks Of Concomitant Use Or Discontinuation Of Cytochrome
P450 3A4 Inhibitors And Inducers
Concomitant use of LAZANDA with a CYP3A4 inhibitor, such
as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.,
ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma
concentrations of fentanyl and prolong opioid adverse reactions, which may
cause potentially fatal respiratory depression [see Increased Risk of Overdose in Children Due to Accidental Ingestion or Exposure], particularly when an inhibitor is added after a
stable dose of LAZANDA is achieved. Similarly, discontinuation of a CYP3A4
inducer, such as rifampin, carbamazepine, and phenytoin, in LAZANDA treated
patients may increase fentanyl plasma concentrations and prolong opioid adverse
reactions. When using LAZANDA with CYP3A4 inhibitors or discontinuing CYP3A4
inducers in LAZANDA treated patients, monitor patients closely at frequent
intervals and consider dosage reduction of LAZANDA until stable drug effects
are achieved [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
Concomitant use of LAZANDA with CYP3A4 inducers or
discontinuation of an CYP3A4 inhibitor could decrease fentanyl plasma
concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal
syndrome in a patient who had developed physical dependence to fentanyl. When
using LAZANDA with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor
patients closely at frequent intervals and consider increasing the opioid
dosage if needed to maintain adequate analgesia or if symptoms of opioid
withdrawal occur [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
Risks From Concomitant Use With Benzodiazepines Or Other
Profound sedation, respiratory depression, coma, and
death may result from the concomitant use of LAZANDA 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 LAZANDA 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].
Risk Of Medication Errors
When prescribing, DO NOT convert a patient to LAZANDA
from any other fentanyl product on a mcg per mcg basis as LAZANDA and other
fentanyl products are not equivalent on a microgram per microgram basis.
LAZANDA is NOT a generic version of other transmucosal
immediate release fentanyl (TIRF) formulations. When dispensing, DO NOT
substitute a LAZANDA prescription for any other TIRF formulation under any
circumstances. Other TIRF formulations and LAZANDA are not equivalent.
Substantial differences exist in the pharmacokinetic profile of LAZANDA
compared to other fentanyl products including other TIRF formulations that
result in clinically important differences in the rate and extent of absorption
of fentanyl. As a result of these differences, the substitution of LAZANDA for
any other fentanyl product may result in a fatal overdose.
There are no safe conversion directions available for
patients on any other fentanyl products. (Note: This includes oral,
transdermal, or parenteral formulations of fentanyl.) Therefore, for opioid
tolerant patients, the initial dose of LAZANDA should always be ONE 100 mcg
spray. Each patient should be individually titrated to provide adequate
analgesia while minimizing side effects [see DOSAGE AND ADMINISTRATION].
Addiction, Abuse, And Misuse
LAZANDA contains fentanyl a Schedule II controlled
substance. As an opioid, LAZANDA 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 LAZANDA. 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 LAZANDA, and monitor all patients receiving
LAZANDA 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 LAZANDA, but use in such patients necessitates
intensive counseling about the risks and proper use of LAZANDA 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 LAZANDA. 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.
Transmucosal Immediate Release Fentanyl (TIRF) Risk
Evaluation And Mitigation Strategy (REMS) Access Program
Because of the risk of misuse, abuse, addiction, and
overdose [see Addiction, Abuse, And Misuse], LAZANDA is available only through a restricted
program under a REMS called the TIRF REMS Access program. Under the TIRF REMS
Access program, outpatients, healthcare professionals who prescribe to
outpatients, pharmacies, and distributors must enroll in the program. For
inpatient administration (e.g. hospitals, hospices, and long-term care
facilities that prescribe for inpatient use) of LAZANDA, patient and prescriber
enrollment is not required.
Required components of the TIRF REMS Access program are:
- Healthcare professionals who prescribe LAZANDA must
review the prescriber educational materials for the TIRF REMS Access program,
enroll in the program, and comply with the REMS requirements.
- To receive LAZANDA, outpatients must understand the risks
and benefits and sign a Patient-Prescriber Agreement.
- Pharmacies that dispense LAZANDA must enroll in the
program and agree to comply with the REMS requirements.
- Wholesalers and distributers that distribute LAZANDA must
enroll in the program and distribute only to authorized pharmacies.
- Further information, including a list of qualified
pharmacies/distributors, is available at www.tirfremsaccess.com or by calling
Neonatal Opioid Withdrawal Syndrome
Prolonged use of LAZANDA 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, PATIENT INFORMATION].
Life-Threatening Respiratory Depression In Patients With Chronic
Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients
The use of LAZANDA 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
LAZANDA-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 LAZANDA [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 LAZANDA and when LAZANDA is given concomitantly with
other drugs that depress respiration [see Life-Threatening Respiratory Depression].
Alternatively, consider the use of non-opioid analgesics
in these patients.
Serotonin Syndrome With Concomitant Use Of Serotonergic
Cases of serotonin syndrome, a potentially
life-threatening condition, have been reported during concomitant use of
fentanyl 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 LAZANDA if serotonin syndrome is suspected.
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
LAZANDA 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 LAZANDA. In patients with circulatory shock, LAZANDA may cause vasodilation that can further reduce cardiac output
and blood pressure. Avoid the use of LAZANDA in patients with circulatory
Risks 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), LAZANDA 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 LAZANDA.
Opioids may also obscure the clinical course in a patient
with a head injury. Avoid the use of LAZANDA in patients with impaired
consciousness or coma.
Risks Of Use In Patients With Gastrointestinal Conditions
LAZANDA is contraindicated in patients with known or
suspected gastrointestinal obstruction, including paralytic ileus.
The fentanyl in LAZANDA 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.
Increased Risk Of Seizures In Patients With Seizure
The fentanyl in LAZANDA may increase the frequency of
seizures in patients with seizure disorders, and may increase the risk of
seizures occurring in other clinical settings associated with seizures. Monitor
patients with a history of seizure disorders for worsened seizure control
during LAZANDA therapy.
Risks Of Driving And Operating Machinery
LAZANDA 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 LAZANDA and know how they will react
to the medication.
Intravenous fentanyl may produce bradycardia. Therefore,
use LAZANDA with caution in patients with bradyarrhythmias.
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Medication Guide).
Inform patients of the risk of
life-threatening respiratory depression, including information that the risk is
greatest when starting LAZANDA 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.
Increased Risk Of Overdose And Death In Children Due To Accidental
- Healthcare providers and dispensing pharmacists must
specifically question patients or caregivers about the presence of children in
the home (on a full time or visiting basis) and counsel them regarding the
dangers to children from inadvertent exposure [see
WARNINGS AND PRECAUTIONS].
- Inform patients and their caregivers that accidental
exposure, especially in children, may result in respiratory depression or death
[see WARNINGS AND
- Instruct patients and their caregivers that in the event
that a LAZANDA unit is not completely consumed, it must be properly disposed as
soon as possible [see DOSAGE AND ADMINISTRATION, PATIENT INFORMATION; Disposal of Unused LAZANDA].
- Instruct patients and
caregivers to keep both used and unused LAZANDA out of the reach of children [see WARNINGS AND PRECAUTIONS].
Interactions With Benzodiazepines
And Other CNS Depressants
Inform patients that
potentially fatal additive effects may occur if LAZANDA is used with
benzodiazepines or other CNS depressants, including alcohol, and not to use
these concomitantly unless supervised by a health care provider [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]
Addiction, Abuse, And Misuse
Inform patients that the use of
LAZANDA, 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 LAZANDA with others and to take steps to protect LAZANDA from theft or
Transmucosal Immediate-Release Fentanyl (TIRF) REMS
Advise patients of the following information pertaining
to the TIRF REMS
- Inform outpatients that they must be enrolled in the TIRF
REMS Access program before they can receive LAZANDA.
- Allow patients the opportunity to ask questions and
discuss any concerns regarding LAZANDA or the TIRF REMS Access program.
- As required by the TIRF REMS Access program, review the
contents of the LAZANDA Medication Guide with every patient before initiating
treatment with LAZANDA.
- Advise the patient that LAZANDA is available only from
pharmacies that are enrolled in the TIRF REMS Access program, and provide them
with the telephone number and website for information on how to obtain the
- Advise the patient that only enrolled healthcare
providers may prescribe LAZANDA.
- Inform the patient that they must sign the
Patient-Prescriber Agreement to acknowledge that they understand the risks of
- Advise patients that they may be requested to participate
in a survey to evaluate the effectiveness of the TIRF REMS Access program [see WARNINGS AND PRECAUTIONS].
Inform patients that opioids could cause a rare but
potentially life-threatening condition resulting from concomitant
administration of serotonergic drugs. Warn patients of the symptoms of
serotonin syndrome and to seek medical attention right away if symptoms
develop. Instruct patients to inform their physicians if they are taking, or
plan to take serotonergic medications. [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Inform patients to avoid taking LAZANDA while using any
drugs that inhibit monoamine oxidase. Patients should not start MAOIs while
taking LAZANDA [see WARNINGS AND PRECAUTIONS; DRUG INTERACTIONS].
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 AND PRECAUTIONS].
Important Administration Instructions
[see DOSAGE AND
- Instruct patients not to take LAZANDA for acute pain,
postoperative pain, pain from injuries, headache, migraine, or any other
short-term pain, even if they have taken other opioid analgesics for these
- Instruct patients on the meaning of opioid tolerance and
LAZANDA is only to be used as a supplemental pain medication for patients with
pain requiring regular opioids, who have developed tolerance to the opioid
medication and who need additional opioid treatment of breakthrough pain
- Instruct patients that if they are not taking an opioid
medication on a regular around-the-clock basis, they should not take LAZANDA.
- Advise patients that LAZANDA contains fentanyl, which is
a pain medication similar to hydromorphone, methadone, morphine, oxycodone,
oxymorphone, hydrocodone, and tapentadol.
- Instruct patients that they MUST wait at least 2 hours
before treating another episode of breakthrough pain with LAZANDA.
- Instruct patients to talk to their doctor if breakthrough
pain is not alleviated or worsens after taking LAZANDA.
- Instruct patients to use LAZANDA exactly as prescribed by
their doctor and not to take LAZANDA more often than prescribed.
- Instruct patients NOT to share LAZANDA and that sharing
LAZANDA with anyone else could result in the other individual's death due to
- Instruct patients and their caregivers that the amount of
fentanyl contained in a bottle can be fatal to a child. Patients and their
caregivers must be instructed to keep LAZANDA in its child-resistant container
at all times and to store it and the pouch securely and out of the reach of
Inform patients that LAZANDA 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 LAZANDA. Advise patients how to recognize such a
reaction and when to seek medical attention [see CONTRAINDICATIONS, ADVERSE
Neonatal Opioid Withdrawal Syndrome
Inform patients that prolonged use of LAZANDA during
pregnancy can result in neonatal opioid withdrawal syndrome, which may be
life-threatening if not recognized and treated [see WARNINGS
AND PRECAUTIONS, Use in Specific Populations].
Inform female patients of reproductive potential that
LAZANDA can cause fetal harm and to inform their 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 [see Use in Specific Populations].
Driving Or Operating Heavy Machinery
Inform patients that LAZANDA 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 LAZANDA
[see Instructions for Use]
- Advise patients to properly dispose of all unused,
partially used and used LAZANDA bottles as soon as no longer needed.
- Instruct patients that, to dispose of LAZANDA properly,
the remaining liquid in all bottles must be sprayed into the pouch provided in
the pack for safe disposal as soon as possible. This includes any unwanted
therapeutic sprays remaining in the bottle. After the counter has advanced to
“8”, the patient should continue to push down on the finger grips a total of
four times in order to expel any residual medicine from the bottle. After the 8
therapeutic sprays have been emitted, the patient will not hear a click and the
counter will not advance beyond “8”; further sprays emitted will not be full
sprays and should always be trapped in the pouch, not used therapeutically.
- Instruct the patient and caregiver to seal the pouch and
to place both the empty bottle and the sealed pouch into the child-resistant
storage container and discard in the trash. LAZANDA must be stored in the
specially provided child-resistant container out of the reach of children until
proper disposal is possible.
- Instruct the patient and caregiver to wash their hands
with soap and water immediately after handling the pouch.
- If the pouch is lost, instruct the patient and caregiver
to use a pouch from another LAZANDA pack to prime and dispose of unused
medicine from the current bottle as well as from the next bottle. If they do
not have an empty pouch available, the patient or caregiver can order one by
calling 1-866-458-6389. They will receive the replacement pouch in the mail
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies in animals to evaluate the carcinogenic
potential of fentanyl have not been conducted.
Fentanyl citrate was not mutagenic in the in vitro Ames
reverse mutation assay in S. typhimurium or E. coli, or the mouse lymphoma mutagenesis assay, and was not clastogenic in the in vivo mouse micronucleus
Impairment Of Fertility
Fentanyl has been shown to impair fertility in rats at
doses of 30 mcg/kg subcutaneously. Conversion to human equivalent doses
indicates this is within the range of the human recommended dosing for LAZANDA.
Use In Specific Populations
Prolonged use of opioid
analgesics during pregnancy may cause neonatal opioid withdrawal syndrome.
Available data with LAZANDA in pregnant women are insufficient to inform a
drug-associated risk for major birth defects and miscarriage.
In animal reproduction studies
fentanyl administration to pregnant rats during organogenesis was embryocidal
at doses within the range of the human recommended dosing for LAZANDA. No
evidence of malformations were noted in animal studies completed to date [see Data].
The estimated background risk
of major birth defects and miscarriage for the indicated population is unknown.
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.
Prolonged use of opioid analgesics during pregnancy for
medical or nonmedical purposes can result in physical dependence in the neonate
and neonatal opioid withdrawal syndrome shortly after birth.
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 of
neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS AND PRECAUTIONS].
Labor or Delivery
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. LAZANDA is not recommended for use in pregnant women
during or immediately prior to labor, when other analgesic techniques are more
appropriate. Opioid analgesics, including LAZANDA, 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.
In women treated acutely with intravenous or epidural
fentanyl during labor, symptoms of neonatal respiratory or neurological
depression were no more frequent than would be expected in infants of untreated
Transient neonatal muscular rigidity has been observed in
infants whose mothers were treated with intravenous fentanyl.
Fentanyl has been shown to embryocidal in pregnant rats
at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of LAZANDA on a
mg/m² basis) and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of LAZANDA
based on a mg/m² basis). There was no evidence of teratogenicity reported.
No evidence of malformations or adverse effects on the
fetus was reported in a published study in which pregnant rats were
administered fentanyl continuously via subcutaneously implanted osmotic
minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to
breeding and throughout pregnancy. The high dose was approximately 6 times the
human dose of 800 mcg LAZANDA per pain episode on a mg/m² basis and produced
mean steady-state plasma levels that are 3 times higher than the mean Cmax observed
following administration of 800 mcg dose of LAZANDA in humans.
Fentanyl is present in breast milk. One published
lactation study reports a relative infant dose of fentanyl of 0.024%. However,
there is insufficient information to determine the effects of fentanyl on the
breastfed infant and the effects of fentanyl on milk production.
Because of the potential for serious adverse reactions,
including excess sedation and respiratory depression in a breastfed infant,
advise patients that breastfeeding is not recommended during treatment with
Monitor infants exposed to LAZANDA 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.
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 LAZANDA have not been
established in patients below the age of 18 years.
Of the 523 opioid tolerant cancer patients with
breakthrough cancer pain in clinical studies of LAZANDA, 148 (28%) were aged 60
years and over. No clinically meaningful difference was noted in the safety
profile of the group aged over 60 years versus that of younger patients in LAZANDA
Elderly patients have been shown to be more sensitive to
the effects of fentanyl when administered intravenously compared with the
younger population. Therefore, exercise caution when individually titrating
LAZANDA in elderly patients to provide adequate efficacy while minimizing risk.
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 LAZANDA slowly in geriatric patients and monitor closely for signs of
central nervous system and respiratory depression [see WARNINGS AND PRECAUTIONS].
Fentanyl 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, care should be taken in dose selection, and
it may be useful to monitor renal function.
Patients With Renal Or Hepatic Impairment
Insufficient information exists to make recommendations
regarding the use of LAZANDA in patients with impaired renal or hepatic
function. Fentanyl is metabolized primarily via the human CYP3A4 isoenzyme
system and the inactive metabolite is mostly eliminated in urine. If the drug
is used in these patients, it is to be used with caution because of the hepatic
metabolism and renal excretion of fentanyl.
It is recommended that LAZANDA be titrated to clinical
effect for all patients with special care taken in patients with severe renal
or hepatic disease.
Both male and female opioid-tolerant cancer patients were
studied for the treatment of breakthrough cancer pain. No clinically relevant
sex differences were observed in adverse events.
Patients With Allergic (Seasonal) Rhinitis
The pharmacokinetic and safety profiles of LAZANDA in
individuals with known allergic (seasonal) rhinitis showed no clinically
meaningful differences in rate or extent of exposure to fentanyl, or in local
tolerability of LAZANDA when compared to Asymptomatic (Unchallenged) state.
However, when treated for their rhinitis with oxymetazoline, LAZANDA absorption
was compromised [see Pharmacokinetics].