May 29, 2017
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Lazanda

"While the dangers of "second-hand exposure" are well known and have been studied, contamination is not being regularly monitored at the administration level, according to a new report released by MindMetre Research, a United Kingdom–based indepen"...

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Lazanda




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 LAZANDA.

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 inadvertent exposure.

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 CNS Depressants

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 INTERACTIONS].

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 1-866-822-1483.

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 Drugs

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.

Adrenal Insufficiency

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.

Severe Hypotension

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 shock.

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 Disorders

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.

Cardiac Disease

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).

Life-Threatening Respiratory Depression

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 Exposure
  • 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 PRECAUTIONS].
  • 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 misuse.

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 drug.
  • 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 LAZANDA.
  • 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].
Serotonin Syndrome

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].

MAOI Interaction

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].

Adrenal Insufficiency

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 ADMINISTRATION]

  • 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 conditions.
  • 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 episodes.
  • 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 overdose.
  • 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 children.
Hypotension

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].

Anaphylaxis

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 REACTIONS].

Pregnancy

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].

Embryo-Fetal Toxicity

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].

Lactation

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].

Infertility

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].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see ADVERSE REACTIONS].

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of fentanyl have not been conducted.

Mutagenesis

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 assay.

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

Pregnancy

Risk Summary

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.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

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.

Data

Human Data

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 mothers.

Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.

Animal Data

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.

Lactation

Risk Summary

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 LAZANDA.

Clinical Considerations

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

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 [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Nonclinical Toxicology].

Pediatric Use

The safety and efficacy of LAZANDA have not been established in patients below the age of 18 years.

Geriatric Use

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 clinical trials.

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.

Sex

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].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/31/2017

Warnings
Precautions

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