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Fentanyl Citrate 400 ug Lozenge, 30-count — NDC 0093-7866-65 (Billing 00093-7866-65)

by Teva Pharmaceuticals USA, Inc. · 30 BLISTER PACK in 1 CARTON / 1 LOZENGE in 1 BLISTER PACK

This is a package of 30 lozenges of Fentanyl Citrate 400 ug Lozenge from Teva Pharmaceuticals USA, Inc., no longer marketed (first marketed Dec 2015), no longer in the FDA NDC Directory, this package's marketing ended Aug 2026. It is this product's only package size.

NDC 00093-7866-65
🏷️ FDA NDC (as labeled) 0093-7866-65 billing pads the labeler segment with a zero
Rx only Brand Discontinued CII 🛡 REMS ⚠ Discontinued by firm ⇄ Compare with another NDC
🗂️ FDA directory synced Oct 1, 2026 · this listing last changed Jul 24, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

This page is curated, coded, and maintained by

Compiled from public FDA, CMS, DailyMed, NADAC, and related drug data sources. Editorial policy

NDC database record

One package, one record: these facts belong to NDC 0093-7866-65 alone.

Record
FDA NDC Directory package listing · Human prescription drug
Code segments
0093 labeler · 7866 product · 65 package
Package marketed since
Dec 8, 2015
Package marketing ended
Aug 31, 2026
Sample package
No — commercial package
Billing quantity
30 EA per package
Barcode (UPC-A, from the NDC)
3 0093786665 7
FDA record last changed
Jul 24, 2026
⚠️
Excluded from the active FDA NDC Directory. The labeler reported this product as discontinued, so it is excluded from the active NDC Directory. The listing was last certified through Aug 2026. A label may still appear on DailyMed, but the NDC is no longer in the current FDA NDC Directory. Search the FDA NDC Directory ↗

Identity & classification

Regulatory identifiers FDA, NLM and CMS codes for this package

FDA NDC (as labeled) 0093-7866-65
Product NDC 0093-7866
11-digit billing NDC 00093786665
NCPDP billing unit EA — each (per item)
RxCUI 310293, 310294, 310295, 310297, 313992, 313993
UNII MUN5LYG46H
Application # NDA020747
SPL Set ID 78221eab-66fd-4cd8-9c81-af52eb83671c
Established class (EPC) Opioid Agonist
Mechanism of action Full Opioid Agonists
DEA schedule CII
Marketing category NDA AUTHORIZED GENERIC
Marketing status Discontinued
FDA listing status Discontinued by firm (certified through Aug 2026)
Marketing start 2015-12-08
Marketing end 2026-08-31
Route ORAL, TRANSMUCOSAL
Dosage form LOZENGE
Substance FENTANYL CITRATE

Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification

GPI-14 65100025108455
GPI class fentaNYL Citrate
GCN Seq No 022360
GCN 19206
HICL code 001747
Ingredient (HICL) Fentanyl Citrate
HIC1 code H
Therapeutic class — broad (HIC1) Nervous System (Except Autonomic)
HIC2 code H3
Therapeutic class — intermediate (HIC2) Analgesics
HIC3 code H3A
Therapeutic class — specific (HIC3) Opioid Analgesics
AHFS code 28:08.08.00
AHFS class Opioid Agonists (28:08)
FDB label name FENTANYL CITRATE OTFC 400 MCG
FDB brand name Fentanyl Citrate
Legend status F — Federal legend — prescription drug or device
Quick answers
  • GSN (GCN sequence number): 022360
  • GCN: 19206
  • GPI-14 (Medi-Span): 65100025108455
  • HICL (First Databank): 001747
  • AHFS class code: 28:08.08.00
  • RxCUI (RxNorm): 310293
Why two NDCs? The FDA registers this code as 0093-7866-65 — a 4-4-2 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the labeler segment → 00093-7866-65. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

RxNorm drug class

This medicine belongs to the Opioid Agonist class.

Pharmacologic class Opioid Agonist
Drug family (ATC) Opioid anesthetics, Phenylpiperidine derivatives
How it works Full Opioid Agonists
Where does this data come from?
Therapeutic classes from RxNorm RxClass (U.S. National Library of Medicine) — Established Pharmacologic Class (FDA), ATC drug family (WHO) and mechanism of action, matched by this product’s RxCUI.

Clinical

Label name FENTANYL CITRATE OTFC 400 MCG Ingredient Fentanyl Citrate
📖 What it is MedlinePlus · NLM

Fentanyl is used to treat breakthrough pain (sudden episodes of pain that occur despite round the clock treatment with pain medication) in cancer patients at least 18 years of age (or at least 16 years of age if using Actiq® brand lozenges) who are taking regularly scheduled doses of another narcotic (opiate) pain medication, and who are tolerant (used to the effects of the medication) to narcotic pain medications. Fentanyl is in a class of medications called narcotic (opiate) analgesics. It works by changing the way the brain and nervous system respond to pain. Fentanyl should be used along w...

Read the full MedlinePlus article ↗
📗 Our plain-language guide HelloPharmacist
  • It depends on the form. The patch treats severe, ongoing pain in people already used to opioids. The lozenge treats breakthrough cancer pain, and the injection is used by anesthesi...
  • No. The patch and lozenge are only for people who are already opioid-tolerant. In someone who isn't, they can cause dangerous or fatal slowed breathing.
  • Can I use fentanyl if I've never taken opioids?
  • Please don't without checking with me or your doctor. Alcohol, benzodiazepines and other sedating medicines can cause profound sleepiness, slowed breathing and death.
📖 Read our full Fentanyl guide →
Where does this data come from?
Plain-language summary from MedlinePlus (U.S. National Library of Medicine); supplement & herbal interactions and nutrient depletion data from the Natural Medicines database; our full guide is HelloPharmacist editorial content.

Pricing

A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.

Price systemPer eachPer package
Retail pharmacies payNADAC · weekly Not in the retail survey — common for institutional, discontinued, or low-volume packs.
Medicaid paysCMS SDUD · 12 mo No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data.
Medicare drug plans payPart D · quarterly No Part D plan price is available for this NDC in our data.
ℹ️
No price is published for this exact package yet. CMS surveys NADAC per package size, so a different pack of the same drug often has one.
Where does this data come from?
NADAC (National Average Drug Acquisition Cost) is the CMS weekly pharmacy-acquisition-cost survey — what pharmacies pay. ASP (Average Sales Price) is the CMS Medicare Part B drug-payment file, published quarterly. Medicaid pays is computed by us from CMS State Drug Utilization Data (total reimbursed ÷ units, trailing 12 months) — gross of rebates and inclusive of dispensing fees, so it reflects what Medicaid paid, not an acquisition cost. Medicare drug plans pay is the median negotiated point-of-sale unit cost across plans listing this NDC in the CMS quarterly Prescription Drug Plan pricing files, before rebates. The VA pays is the federal contract price (FSS, and the statutory Big 4 ceiling where listed) from the VA National Acquisition Center pharmaceutical price file. All are free public government data; each measures a different payer, so the figures are not directly comparable.

Packaging — all sizes for this product

Package NDCDescription Marketing startMarketing endStatus
00093-7866-65 You're viewing this Main listing 30 BLISTER PACK in 1 CARTON / 1 LOZENGE in 1 BLISTER PACK 2015-12-08 Aug 31, 2026 Discontinued by firm

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
Fentanyl Citrate 400 ugthis 00093-7866-65 Teva 30 lozenges — — Discontinued —
About this product: this is an authorized generic — the brand-name product marketed without its brand name. Other versions are listed above, least expensive first.
Where does this data come from?
Equivalents are other NDCs of the same ingredient, form and route from the openFDA NDC Directory, ranked least-expensive-first by NADAC. Therapeutic-equivalence (AB) ratings come from the FDA Orange Book; biologics use the FDA Purple Book for biosimilar & interchangeable status.

Availability & generic status

🏛️
2015
On the market since
Dec 2015
📍
2026
Currently FDA-listed
11 years listed
🔒
·
No generic listed yet
brand only
ℹ️No FDA-approved generic found

We did not find an FDA-approved generic match for this exact strength, form and route.

Where does this data come from?
Patents and exclusivity from the FDA Orange Book (small-molecule drugs), refreshed from public FDA data. Generic launch timing is an estimate, not a guarantee.

Inactive Ingredients / Excipients

Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.

We could not link this NDC to a current FDA Structured Product Label. An inactive-ingredient list is therefore not available from this source.
Where does this data come from?
Source: official FDA Structured Product Labeling (SPL) via DailyMed and the openFDA label index. Structured IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.

Inactive ingredient FAQ

Are inactive ingredients the same for every manufacturer?
No. Inactive ingredients can differ by manufacturer, dosage form, strength, and package / product version.
Why might an inactive ingredient be missing?
Some SPLs do not provide a complete structured inactive-ingredient list, and older or unusual labels may only include the information in narrative text.
Can inactive ingredients matter?
Yes. They can matter for allergies, intolerances, dyes, gluten / lactose concerns, preservatives, and formulation differences — but confirm with a pharmacist or the manufacturer when it’s clinically important.

Manufacturer & labeler

LabelerTeva Pharmaceuticals USA, Inc.
Application holderCEPHALON LLC
FDA applicationNDA020747 (NDA AUTHORIZED GENERIC)
Labeler code00093
First marketedDec 2015
DEA scheduleCII
Product typeHuman Prescription Drug
Portfolio504 products on file

More NDCs from Teva Pharmaceuticals USA, Inc. labeler code 00093

The labeler markets the product; the application holder owns the FDA approval. They’re often the same company but can differ (e.g. a repackager or an authorized generic). A mailing address / phone appears here when the manufacturer includes it in the product’s FDA label (not all do).
Where does this data come from?
Labeler, application holder and registered establishment from the FDA openFDA NDC Directory and Drugs@FDA; address/contact from the product’s FDA label.

Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. Very long sections are excerpted here and marked; the full text is on DailyMed (linked in the sources below). Jump with a chip, search within the label, or expand everything.
🚨 Boxed Warning 🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 🔄 Drug Interactions 👥 Use in Specific Populations 🤰 Pregnancy 🧒 Pediatric Use 🧓 Geriatric Use 🆘 Overdosage 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📋 Description 💬 Information for Patients 💬 Medication Guide 🧬 Pharmacokinetics 🧬 Pharmacodynamics 🔬 Clinical Studies 🔒 Drug Abuse and Dependence 🔒 Controlled Substance 🧪 Nonclinical Toxicology 📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 📄 Recent Major Changes 📄 Package Label / Principal Display Panel
🚨 Boxed Warning ~3 min read ▾

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF ORAL TRANSMUCOSAL FENTANYL CITRATE (OTFC) Addiction, Abuse, and Misuse Because the use of OTFC exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 )]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has occurred in patients treated with Oral Transmucosal Fentanyl Citrate (OTFC), including following use in opioid non-tolerant patients and improper dosing.

Evaluate patients for respiratory depression, especially during initiation of OTFC or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of OTFC are essential. The substitution of OTFC for any other fentanyl product may result in fatal overdose [see Warnings and Precautions ( 5.2 )].

Due to the risk of respiratory depression, OTFC is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients [see Contraindications ( 4 )]. Accidental Ingestion Accidental ingestion of even one dose of OTFC, especially by children, can result in a fatal overdose of fentanyl. Death has been reported in children who have accidentally ingested OTFC.

OTFC must be kept out of reach of children [see Warnings and Precautions ( 5.3 )]. Risks From Concomitant Use with Benzodiazepines or Other CNS Depressants 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 of OTFC and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )].

Risk of Medication Errors Substantial differences exist in the pharmacokinetic profile of OTFC compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl and that could result in fatal overdose [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.5 )]. When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to OTFC [see Dosage and Administration ( 2.1 )]. When dispensing, do not substitute an OTFC prescription for other fentanyl products.

Cytochrome P450 3A4 Interaction The concomitant use of OTFC with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Evaluate patients at frequent intervals receiving OTFC and any CYP3A4 inhibitor or inducer [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )].

Risk Evaluation and Mitigation Strategy (REMS) Because of the risk for accidental exposure, misuse, abuse, addiction, and overdose, OTFC is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS, pharmacies, outpatients, and healthcare professionals who prescribe to outpatients must enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require OTFC while hospitalized.

Further information is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483 [see Warnings and Precautions ( 5.7 )]. Neonatal Opioid Withdrawal Syndrome (NOWS) Advise pregnant women using opi… [Excerpted — this section continues on DailyMed.]

🎯 Indications and Usage ~2 min read ▾

1 INDICATIONS AND USAGE Oral Transmucosal Fentanyl Citrate (OTFC) is indicated for the management of breakthrough pain in cancer patients 16 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid.

Patients must remain on around-the-clock opioids when taking OTFC. Limitations of Use: Not for use in opioid non-tolerant patients. Not for use in the management of acute or postoperative pain, including headache/migraine and dental pain [see Contraindications ( 4 )] .

As a part of the TIRF REMS, OTFC may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see Warnings and Precautions ( 5.7 )] . For inpatient administration of OTFC, patient and prescriber enrollment are not required. OTFC is an opioid agonist indicated for the management of breakthrough pain in cancer patients 16 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.

( 1 ) Patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid. Patients must remain on around-the-clock opioids while taking OTFC. Limitations of Use: Not for use in opioid non-tolerant patients.

Not for use in the management of acute or postoperative pain, including headache/migraine or dental pain. ( 4 ) As a part of the TIRF REMS, OTFC may be dispensed by outpatient pharmacies only to outpatients enrolled in the program. ( 5.7 ) For inpatient administration of OTFC, patient and prescriber enrollment are not required.

⏱️ Dosage and Administration ~3 min read ▾

2 DOSAGE AND ADMINISTRATION Patients must require and use around-the-clock opioids when taking OTFC. ( 1 ) OTFC should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals.

Reserve titration to higher doses of OTFC for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with OTFC.

Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver both when initiating and renewing treatment with OTFC, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.4 ) Initial dose of OTFC: 200 mcg.

Prescribe an initial supply of six 200 mcg OTFC units. ( 2.3 ) Individually titrate to a tolerable dose that provides adequate analgesia using single OTFC dosage unit per breakthrough cancer pain episode. ( 2.4 ) No more than two doses can be taken per breakthrough pain episode.

( 2.4 , 2.5 ) Wait at least 4 hours before treating another episode of breakthrough pain with OTFC. ( 2.4 , 2.5 ) Limit consumption to four or fewer units per day once successful dose is found. ( 2.5 ) Periodically reassess patients receiving OTFC to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse.

( 2.5 ) When opioid therapy is no longer required, consider discontinuing OTFC along with a gradual downward of other opioids to minimize possible withdrawal effects. ( 2.7 )

2.1Important Dosage and Administration Instructions Healthcare professionals who prescribe Oral Transmucosal Fentanyl Citrate (OTFC) for outpatients must enroll in the TIRF REMS and comply with the requirements of the REMS to ensure safe use of OTFC [see Warnings and Precautions ( 5.7 )] . Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of OTFC for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] .

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with OTFC. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )]. Instruct patients and caregivers to take steps to store OTFC securely and to properly dispose of unused OTFC as soon as no longer needed [see Warnings and Precautions ( 5.1 , 5.3… [Excerpted — this section continues on DailyMed.]

💊 Dosage Forms and Strengths 91 words ▾

3 DOSAGE FORMS AND STRENGTHS Solid oral transmucosal lozenge: Each dosage unit has white to off-white color and is a solid drug matrix on a handle. Each strength is marked on the individual solid drug matrix and the handle tag. Oral Transmucosal Fentanyl Citrate (OTFC) is available in 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg and 1600 mcg strengths [see How Supplied/Storage and Handling ( 16 )] .

Solid oral transmucosal lozenge: 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, and 1600 mcg. ( 3 )

⛔ Contraindications 195 words ▾

4 CONTRAINDICATIONS Oral Transmucosal Fentanyl Citrate (OTFC) is contraindicated in: Opioid non-tolerant patients: Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients [see Indications and Usage ( 1 ), Warnings and Precautions ( 5.2 )]. Significant respiratory depression [see Warnings and Precautions ( 5.2 )]. Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department [see Indications and Usage ( 1 )] .

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.11 )]. Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.15 )]. Known hypersensitivity to fentanyl or components of OTFC (e.g., anaphylaxis, hypersensitivity) [see Adverse Reactions ( 6.2 )].

Opioid non-tolerant patients. ( 4 ) Significant respiratory depression. ( 4 ) Management of acute or postoperative pain, including headache/migraine and dental pain.

( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Known hypersensitivity to fentanyl or components of OTFC.

( 4 )

⚠️ Warnings and Cautions ~3 min read ▾

5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.9 ) Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration.

Discontinue OTFC if serotonin syndrome is suspected. ( 5.10 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate patients, particularly during initiation and titration. ( 5.11 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.

( 5.12 ) Severe Hypotension : Regularly evaluate patients during dosage initiation and titration. Avoid use of OTFC in patients with circulatory shock. ( 5.13 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression.

Avoid use of OTFC in patients with impaired consciousness or coma. ( 5.14 )

5.1Addiction, Abuse, and Misuse Oral Transmucosal Fentanyl Citrate (OTFC) contains fentanyl, a Schedule II controlled substance. As an opioid, OTFC exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OTFC.

Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6.2 )] .

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing OTFC, and reassess all patients receiving OTFC 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 OTFC, but use in such patients necessitates intensive counseling about the risks and proper use of OTFC along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [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 OTFC. 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 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.

5.2Life-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 overdose reversal agents , depending on the patient’s clinical status [see Overdosage ( 10 )] .

Carbon dioxide (CO 2 ) retentio… [Excerpted — this section continues on DailyMed.]

🤒 Adverse Reactions ~3 min read ▾

6 ADVERSE REACTIONS The following serious adverse reactions are described, 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 and Other CNS Depressants [see Warnings and Precautions ( 5.4 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.8 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.9 )] Serotonin Syndrome [see Warnings and Precautions ( 5.10 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.12 )] Severe Hypotension [see Warnings and Precautions ( 5.13 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.15 )] Seizures [see Warnings and Precautions ( 5.16 )] Most common (frequency ≥5%): nausea, dizziness, somnolence, vomiting, asthenia, and headache, dyspnea, constipation, anxiety, confusion, depression, rash, and insomnia.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Studies Experience 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. The safety of Oral Transmucosal Fentanyl Citrate (OTFC) has been evaluated in 257 opioid-tolerant chronic cancer pain patients. The duration of OTFC use varied during the open-label study.

Some patients were followed for over 21 months. The average duration of therapy in the open-label study was 129 days. The most serious adverse reactions associated with OTFC are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock.

Because the clinical trials of OTFC were designed to evaluate safety and efficacy in treating breakthrough cancer pain, all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received OTFC for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of OTFC therapy, or cancer-related symptoms.

Three short-term clinical trials with similar titration schemes were conducted in 257 patients with malignancy and breakthrough cancer pain. Data are available for 254 of these patients. Table 1 lists, by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during titration.

The ability to assign a dose-response relationship to these adverse reactions is limited by the titration schemes used in these studies. Adverse reactions are listed in descending order of frequency within each body system. Table 1.

Percent of Patients with Specific Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Titration (Events in 1% or More of Patients) Dose Group Percentage of Patients Reporting Event 200- 600 mcg (n=230) 800- 1400 mcg (n=138) 1600 mcg (n=54) >1600 mcg (n=41) Any Dose Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once. (n=254) Body As A Whole Asthenia 6 4 0 7 9 Headache 3 4 6 5 6 Accidental Injury 1 1 4 0 2 Digestive Nausea 14 15 11 22 23 Vomiting 7 6 6 15 12 Constipation 1 4 2 0 4 Nervous Dizziness 10 16 6 15 17 Somnolence 9 9 11 20 17 Confusion 1 6 2 0 4 Anxiety 3 0 2 0 3 Abnormal Gait 0 1 4 0 2 Dry Mouth 1 1 2 0 2 Nervousness 1 1 0 0 2 Vasodilatation 2 0 2 0 2 Hallucinations 0 1 2 2 1 Insomnia 0 1 2 0 1 Thinking Abnormal 0 1 2 0 1 Vertigo 1 0 0 0 1 Respiratory Dyspnea… [Excerpted — this section continues on DailyMed.]

🔄 Drug Interactions ~3 min read ▾

7 DRUG INTERACTIONS Table 3 includes clinically significant drug interactions with Oral Transmucosal Fentanyl Citrate (OTFC). Table 3: Clinically Significant Drug Interactions with OTFC Inhibitors of CYP3A4 Clinical Impact: The concomitant use of OTFC and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of OTFC is achieved [see Warnings and Precautions ( 5.6 )] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.

Intervention: If concomitant use is necessary, consider dosage reduction of OTFC until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the OTFC dosage until stable drug effects are achieved.

Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice CYP3A4 Inducers Clinical Impact: The concomitant use of OTFC and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions ( 5.6 )] .

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the OTFC dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.

If a CYP3A4 inducer is discontinued, consider OTFC dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.4 )] .

Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions ( 5.10 )] . Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment.

Discontinue OTFC if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapin… [Excerpted — this section continues on DailyMed.]

👥 Use in Specific Populations ~3 min read ▾

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Lactation : Not recommended. ( 8.2 ) Renal and Hepatic Impairment : Administer OTFC with caution. ( 8.6 )

8.1Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.8 )] . Available data with Oral Transmucosal Fentanyl Citrate (OTFC) in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and infant associated with use of OTFC for an extended period of time during pregnancy (see Clinical Considerations).

In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data] .

The 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 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time 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 of neonatal withdrawal symptoms usually occurs in the first days after birth.

The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.8 )] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.

An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. OTFC is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including OTFC, 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 (25, 50, or 100 mcg/kg) citrate was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6 to 17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (the no observed effect level of 50 mcg/kg is equivalent to 0.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison).

Fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis… [Excerpted — this section continues on DailyMed.]

🤰 Pregnancy ~3 min read ▾

8.1Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.8 )] . Available data with Oral Transmucosal Fentanyl Citrate (OTFC) in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and infant associated with use of OTFC for an extended period of time during pregnancy (see Clinical Considerations).

In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data] .

The 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 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time 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 of neonatal withdrawal symptoms usually occurs in the first days after birth.

The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.8 )] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.

An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. OTFC is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including OTFC, 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 (25, 50, or 100 mcg/kg) citrate was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6 to 17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (the no observed effect level of 50 mcg/kg is equivalent to 0.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison).

Fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (GD 6-18). Maternal toxicity was noted at doses >100 mcg/kg. No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 3.5 times the exposure of a single human d… [Excerpted — this section continues on DailyMed.]

🧒 Pediatric Use 142 words ▾

8.4Pediatric Use Safety and effectiveness in pediatric patients below 16 years of age have not been established. In a clinical study, 15 opioid-tolerant pediatric patients with breakthrough pain, ranging in age from 5 to 15 years, were treated with OTFC. The study was too small to allow conclusions on safety and efficacy in this patient population.

Twelve of the fifteen opioid-tolerant children and adolescents aged 5 to 15 years in this study received OTFC at doses ranging from 200 mcg to 600 mcg. The mean (CV%; range) dose-normalized (to 200 mcg) C max and AUC 0-8 values were 0.87 ng/mL (51%; 0.42-1.30) and 4.54 ng . h/mL (42%; 2.37-6.0), respectively, for children ages 5 to <11 years old (N = 3) and 0.68 ng/mL (72%; 0.15-1.44) and 8.38 (192%; 0.84-50.78), respectively, for children ages ≥11 to <16 y (N = 9).

🧓 Geriatric Use ~1 min read ▾

8.5Geriatric Use Of the 257 patients in clinical studies of OTFC in breakthrough cancer pain, 61 (24%) were 65 years of age and older, while 15 (6%) were 75 years of age and older. Those patients over the age of 65 years were titrated to a mean dose that was about 200 mcg less than the mean dose titrated to by younger patients. No difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in OTFC 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 OTFC 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 OTFC slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.11 )] . 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 regularly evaluate renal function.

🆘 Overdosage ~1 min read ▾

10 OVERDOSAGE Clinical Presentation Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology ( 12.2 )] . Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication.

Treatment of Overdose In case of overdose, priorities are: removal of the OTFC unit, if still in the mouth, the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures.

For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in OTFC, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the opioid overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.

🧬 Clinical Pharmacology ~3 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.

12.2Pharmacodynamics Effects on the Central Nervous System The precise mechanism of the analgesic action is unknown although fentanyl is known to be a mu- opioid receptor agonist. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug. Fentanyl produces respiratory depression by direct action on brain stem respiratory centers.

The respiratory depression involves a reduction in the responsiveness of the brain stem to both increases in carbon dioxide and electrical stimulation. Fentanyl causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings).

Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased.

Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of the sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on the Cardiovascular System Fentanyl may produce release of histamine with or without associated peripheral vasodilation.

Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2 )] .

They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions ( 6.2 )] . Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6.2 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.

Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Efficacy Relationships The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3- to 5-minute half-life). In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids.

The rate of development of tolerance varies widely among individuals. The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance. Concentration-Adverse Reaction Re… [Excerpted — this section continues on DailyMed.]

🧬 Mechanism of Action 15 words ▾

12.1Mechanism of Action Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.

📦 How Supplied / Storage and Handling 211 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING Oral Transmucosal Fentanyl Citrate (OTFC) is supplied in six dosage strengths. Each unit is individually wrapped in a child-resistant, protective blister package. These blister packages are packed 30 per shelf carton for use when patients have been titrated to the appropriate dose.

Each dosage unit has a white to off-white color. Each individual solid drug matrix is marked with “FENTANYL” and the strength of the unit (“200”, “400”, “600”, “800”, “1200”, or “1600”). The dosage strength is also marked on the handle tag, the blister package and the carton.

See blister package and carton for product information. Dosage Strength (fentanyl base) Carton/Blister Package Color NDC Number 200 mcg Gray NDC 0093-7865-65 400 mcg Blue NDC 0093-7866-65 600 mcg Orange NDC 0093-7867-65 800 mcg Purple NDC 0093-7868-65 1200 mcg Green NDC 0093-7869-65 1600 mcg Burgundy NDC 0093-7870-65 Note: Colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.

Store at 20ºC to 25ºC (68ºF to 77ºF) with excursions permitted between 15°C and 30°C (59°F to 86°F) until ready to use. (See USP Controlled Room Temperature.) Protect OTFC from freezing and moisture. Do not use if the blister package has been opened.

Store OTFC securely and dispose of properly .

📋 Description 180 words ▾

11 DESCRIPTION Oral Transmucosal Fentanyl Citrate (OTFC) (fentanyl citrate) oral transmucosal lozenge is a solid formulation of fentanyl, an opioid agonist, intended for oral transmucosal administration. OTFC is formulated as a white to off-white solid drug matrix on a handle that is fracture resistant (ABS plastic) under normal conditions when used as directed. OTFC is designed to be dissolved slowly in the mouth to facilitate transmucosal absorption.

The handle allows the OTFC unit to be removed from the mouth if signs of excessive opioid effects appear during administration. Active Ingredient: Fentanyl citrate, USP is N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1). Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 816:1) that is freely soluble in organic solvents and sparingly soluble in water (1:40).

The molecular weight of the free base is 336.5 (the citrate salt is 528.6). The pKa of the tertiary nitrogens are 7.3 and 8.4. The compound has the following structural formula: Inactive Ingredients: Hydrated dextrates, citric acid, dibasic sodium phosphate, artificial berry flavor, magnesium stearate, and edible glue (modified food starch and confectioner’s sugar). chemical-structure

💬 Information for Patients ~3 min read ▾

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) . Storage and Disposal of Unused and Used OTFC [see Medication Guide / Instructions for Use]. Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store OTFC securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home .

Inform patients that leaving OTFC unsecured can pose a deadly risk to others in the home [see Warnings and Precautions ( 5.1 , 5.2 ), Drug Abuse and Dependence ( 9.2 )] . Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

Disposal of Used OTFC Units: Instruct patients on proper disposal of completely used and partially used OTFC units as follows: After consumption of the unit is complete and the matrix is totally dissolved, throw away the handle in a trash container that is out of the reach of children. If any of the drug matrix remains on the handle, place the handle under hot running tap water until all of the drug matrix is dissolved, and then dispose of the handle in a place that is out of the reach of children. Dispose of handles in the child-resistant container (as described in steps 1 and 2) at least once a day.

If the patient does not entirely consume the unit and the remaining drug cannot be immediately dissolved under hot running water, the patient or caregiver must temporarily store the OTFC unit in the specially provided child-resistant container out of the reach of children until proper disposal is possible. Disposal of Unopened OTFC Units When No Longer Needed: Patients and members of their household must be advised to dispose of any unopened units remaining from a prescription as soon as they are no longer needed. To dispose of the unused OTFC units: Remove the OTFC unit from its blister package using scissors, and hold the OTFC by its handle over the toilet bowl.

Using wire-cutting pliers cut off the drug matrix end so that it falls into the toilet. Dispose of the handle in a place that is out of the reach of children. Repeat steps 1, 2, and 3 for each OTFC unit.

Flush the toilet twice after 5 units have been cut and deposited into the toilet. Do not flush the entire OTFC units, OTFC handles, blister packages, or cartons down the toilet. Dispose of the handle where children cannot reach it.

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of OTFC are provided in the OTFC Medication Guide . Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered. In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for Teva Pharmaceuticals (1-888-483-8279) or seek assistance from their local DEA office.

Addiction, Abuse, and Misuse Inform patients that the use of OTFC, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.1 )] . Instruct patients not to share OTFC with others and to take steps to protect OTFC from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Oral Transmucosal Fentanyl Citrate (OTFC) or when the dosage is increased, and that it can occur even at recommended dosages.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help r… [Excerpted — this section continues on DailyMed.]

💬 Medication Guide ~3 min read ▾

MEDICATION GUIDE Dispense with Medication Guide available at: www.tevausa.com/medguides Medication Guide Oral Transmucosal Fentanyl Citrate (OTFC) (fentanyl citrate) oral transmucosal lozenge, CII IMPORTANT: Do not use Oral Transmucosal Fentanyl Citrate (OTFC) unless you are regularly using another opioid pain medicine around-the-clock for at least one week or longer for your cancer pain and your body is used to these medicines (this means that you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant.

Keep OTFC in a safe place away from children. Get emergency medical help right away if: a child takes OTFC. OTFC can cause an overdose and death in any child who takes it. an adult who has not been prescribed OTFC uses it. an adult who is not already taking opioids around-the-clock, uses OTFC.

These are medical emergencies that can cause death. If possible, remove OTFC from the mouth. Oral Transmucosal Fentanyl Citrate (OTFC) is: A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage breakthrough pain in adults (16 years of age and older) with cancer who are already routinely taking other opioid pain medicines around-the-clock for cancer pain.

OTFC is started only after you have been taking other opioid pain medicines and your body has become used to them (you are opioid tolerant). Do not use OTFC if you are not opioid tolerant. An opioid pain medicine that can put you at risk for overdose and death.

Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about Oral Transmucosal Fentanyl Citrate (OTFC): Get emergency help or call 911 right away if you take too much OTFC (overdose). When you first start taking OTFC, 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.

Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose. Taking OTFC with other medicines that may make you sleepy, such as other pain medicines, gabapentinoids (gabapentin or pregabalin), anti-depressants, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers, or with alcohol or street drugs can cause severe drowsiness, confusion, breathing problems, coma, and death. Never give anyone else your OTFC.

They could die from taking it. Selling or giving away OTFC is against the law. Store OTFC securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

If you stop taking your around-the-clock opioid pain medicine for your cancer pain, you must stop using OTFC. You may no longer be opioid tolerant. Talk to your healthcare provider about how to treat your pain.

OTFC is available only through a program called the T ransmucosal I mmediate R elease F entanyl (TIRF) R isk E valuation and M itigation S trategy (REMS). To receive OTFC, you must: talk to your healthcare provider understand the benefits and risks of OTFC agree to all of the instructions sign the Patient Enrollment Form OTFC is only available at pharmacies that are part of the TIRF REMS. Your healthcare provider can help you locate a pharmacy closest to your home where you can have your OTFC prescription filled.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. Do not take Oral Transmucosal Fentanyl Citrate (OTFC) if: You are not opioid tolerant.

Opioid tolerant means that you are already taking other opioid pain medicines around-the-clock for at least one week or longer for your cancer pain, and your body is used to these medicines. You have severe asthma, trouble breathing, or other lung problems. You have a bowel blockage or have narrowing of the stomach or intestines.

You are allergic to any of the ingredients in OTFC . See… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacokinetics ~3 min read ▾

12.3Pharmacokinetics Absorption The absorption pharmacokinetics of fentanyl from the oral transmucosal dosage form is a combination of an initial rapid absorption from the buccal mucosa and a more prolonged absorption of swallowed fentanyl from the GI tract. Both the blood fentanyl profile and the bioavailability of fentanyl will vary depending on the fraction of the dose that is absorbed through the oral mucosa and the fraction swallowed. Absolute bioavailability, as determined by area under the concentration-time curve, of 15 mcg/kg in 12 adult males was 50% compared to intravenous fentanyl.

Normally, approximately 25% of the total dose of OTFC is rapidly absorbed from the buccal mucosa and becomes systemically available. The remaining 75% of the total dose is swallowed with the saliva and then is slowly absorbed from the GI tract. About 1/3 of this amount (25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available.

Thus, the generally observed 50% bioavailability of OTFC is divided equally between rapid transmucosal and slower GI absorption. Therefore, a unit dose of OTFC, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed. Dose proportionality among four of the available strengths of OTFC (200, 400, 800, and 1600 mcg) has been demonstrated in a balanced crossover design in adult subjects (n=11).

Mean serum fentanyl levels following these four doses of OTFC are shown in Figure 1. The curves for each dose level are similar in shape with increasing dose levels producing increasing serum fentanyl levels. C max and AUC 0→∞ increased in a dose-dependent manner that is approximately proportional to the OTFC administered.

Figure 1. Mean Serum Fentanyl Concentration (ng/mL) in Adult Subjects Comparing 4 Doses of OTFC The pharmacokinetic parameters of the four strengths of OTFC tested in the dose-proportionality study are shown in Table 4. The mean C max ranged from 0.39 - 2.51 ng/mL.

The median time of maximum plasma concentration (T max ) across these four doses of OTFC varied from 20 - 40 minutes (range of 20 – 480 minutes) as measured after the start of administration. Table 4. Pharmacokinetic Parameters* in Adult Subjects Receiving 200, 400, 800, and 1600 mcg Units of OTFC Pharmacokinetic Parameter 200 mcg 400 mcg 800 mcg 1600 mcg T max , minute median (range) 40 (20-120) 25 (20-240) 25 (20-120) 20 (20-480) C max , ng/mL mean (%CV) 0.39 (23) 0.75 (33) 1.55 (30) 2.51 (23) AUC 0-1440 , ng/mL minute mean (%CV) 102 (65) 243 (67) 573 (64) 1026 (67) t 1/2 , minute mean (%CV) 193 (48) 386 (115) 381 (55) 358 (45) * Based on arterial blood samples.

Distribution Fentanyl is highly lipophilic. Animal data showed that following absorption, fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat. The plasma protein binding of fentanyl is 80-85%.

The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis. The mean volume of distribution at steady state (Vss) was 4 L/kg.

Elimination The total plasma clearance of fentanyl was

0.5L/hr/kg (range 0.3 –

0.7L/hr/kg). The terminal elimination half-life after OTFC administration is about 7 hours. Metabolism Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform.

Norfentanyl was not found to be pharmacologically active in animal studies [see Drug Interactions ( 7 )] . Excretion Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces.

The metabolites are mainly excreted in the urine, while fecal excretion is less important. figure-01

🧬 Pharmacodynamics ~3 min read ▾

12.2Pharmacodynamics Effects on the Central Nervous System The precise mechanism of the analgesic action is unknown although fentanyl is known to be a mu- opioid receptor agonist. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug. Fentanyl produces respiratory depression by direct action on brain stem respiratory centers.

The respiratory depression involves a reduction in the responsiveness of the brain stem to both increases in carbon dioxide and electrical stimulation. Fentanyl causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings).

Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased.

Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of the sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on the Cardiovascular System Fentanyl may produce release of histamine with or without associated peripheral vasodilation.

Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2 )] .

They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions ( 6.2 )] . Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6.2 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.

Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Efficacy Relationships The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3- to 5-minute half-life). In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids.

The rate of development of tolerance varies widely among individuals. The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance. Concentration-Adverse Reaction Relationships There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opi… [Excerpted — this section continues on DailyMed.]

🔬 Clinical Studies ~2 min read ▾

14 CLINICAL STUDIES Oral Transmucosal Fentanyl Citrate (OTFC) was investigated in clinical trials involving 257 opioid tolerant adult cancer patients experiencing breakthrough cancer pain. Breakthrough cancer pain was defined as a transient flare of moderate-to-severe pain occurring in cancer patients experiencing persistent cancer pain otherwise controlled with maintenance doses of opioid medications including at least 60 mg morphine/day, 50 mcg transdermal fentanyl/hour, or an equianalgesic dose of another opioid for a week or longer.

In two dose titration studies 95 of 127 patients (75%) who were on stable doses of either long-acting oral opioids or transdermal fentanyl for their persistent cancer pain titrated to a successful dose of OTFC to treat their breakthrough cancer pain within the dose range offered (200, 400, 600, 800, 1200, and 1600 mcg). A “successful” dose was defined as a dose where one unit of OTFC could be used consistently for at least two consecutive days to treat breakthrough cancer pain without unacceptable side effects. In these studies 11% of patients withdrew due to adverse reactions and 14% withdrew due to other reasons.

The successful dose of OTFC for breakthrough cancer pain was not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain and is thus best determined by dose titration. A double-blind placebo controlled crossover study was performed in cancer patients to evaluate the effectiveness of OTFC for the treatment of breakthrough cancer pain. Of 130 patients who entered the study 92 patients (71%) achieved a successful dose during the titration phase.

The distribution of successful doses is shown in Table 5. Table 5. Successful Dose of OTFC Following Initial Titration OTFC Dose Total No.

(%) (N=92) 200 mcg 13 (14) 400 mcg 19 (21) 600 mcg 14 (15) 800 mcg 18 (20) 1200 mcg 13 (14) 1600 mcg 15 (16) Mean +/- SD 789 +/- 468 mcg On average, patients over 65 years of age titrated to a mean dose that was about 200 mcg less than the mean dose to which younger adult patients were titrated. OTFC was administered beginning at Time 0 minutes and produced more pain relief compared with placebo at 15, 30, 45, and 60 minutes as measured after the start of administration (see Figure 2). The differences were statistically significant.

Figure 2. Pain Relief (PR) Scores (Mean ± SD) During the Double-Blind Phase – All Patients with Evaluable Episodes on Both OTFC and Placebo (N=86) 1 0 minutes = Start of administration of OTFC 2 15 minutes = First time to measure pain relief figure-02

🔒 Drug Abuse and Dependence ~3 min read ▾

9 DRUG ABUSE AND DEPENDENCE

9.1Controlled Substance Oral Transmucosal Fentanyl Citrate (OTFC) contains fentanyl, a Schedule II controlled substance.

9.2Abuse OTFC contains fentanyl, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.1 )]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of OTFC increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of OTFC with alcohol and/or other CNS depressants.

Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Patients at high risk of OTFC abuse include those with a history of prolonged use of any opioid, including products containing fentanyl, those with a history of drug or alcohol abuse, or those who use OTFC in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder.

Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. OTFC, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of OTFC Abuse of OTFC poses a risk of overdose and death. The risk is increased with concurrent use of OTFC with alcohol and/or other CNS depressants.

OTFC is approved for oral transmucosal use only.

9.3Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefen… [Excerpted — this section continues on DailyMed.]

🔒 Controlled Substance 15 words ▾

9.1Controlled Substance Oral Transmucosal Fentanyl Citrate (OTFC) contains fentanyl, a Schedule II controlled substance.

🧪 Nonclinical Toxicology ~2 min read ▾

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Fentanyl was evaluated for carcinogenic potential in a 104-week rat study and in a 6-month Tg.AC transgenic mouse study. In rats, doses up to 50 mcg/kg in males and 100 mcg/kg in females were administered subcutaneously and no treatment-related neoplasms were observed (doses are equivalent to 1.13 and 2.7 times the exposure of a single human dose of 1600 mcg per pain episode, respectively, based on an AUC comparison). In a 26-week transgenic mice model (Tg.AC), at topical doses up to 50 mcg/dose/day, no increase in the occurrence of treatment-related neoplasms was observed.

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 In a fertility study, female rats were administered fentanyl subcutaneously for 14 days prior to mating with untreated males at doses up to 300 mcg/kg and no effects on female fertility were observed. The systemic exposure at the dose of 300 mcg/kg was approximately 4.0-times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison.

Males were administered fentanyl subcutaneously for 28 days prior to mating with untreated females at doses up to 300 mcg/kg. At 300 mcg/kg, adverse effects on sperm parameters, which affected fertility, were observed. These effects included decreased percent mobile sperm, decreased sperm concentrations as well as an increase in the percent abnormal sperm.

The dose in males at which no effects on fertility were observed was 100 mcg/kg, which is approximately 2.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison. Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for OTFC.

📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ~2 min read ▾

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Fentanyl was evaluated for carcinogenic potential in a 104-week rat study and in a 6-month Tg.AC transgenic mouse study. In rats, doses up to 50 mcg/kg in males and 100 mcg/kg in females were administered subcutaneously and no treatment-related neoplasms were observed (doses are equivalent to 1.13 and 2.7 times the exposure of a single human dose of 1600 mcg per pain episode, respectively, based on an AUC comparison). In a 26-week transgenic mice model (Tg.AC), at topical doses up to 50 mcg/dose/day, no increase in the occurrence of treatment-related neoplasms was observed.

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 In a fertility study, female rats were administered fentanyl subcutaneously for 14 days prior to mating with untreated males at doses up to 300 mcg/kg and no effects on female fertility were observed. The systemic exposure at the dose of 300 mcg/kg was approximately 4.0-times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison.

Males were administered fentanyl subcutaneously for 28 days prior to mating with untreated females at doses up to 300 mcg/kg. At 300 mcg/kg, adverse effects on sperm parameters, which affected fertility, were observed. These effects included decreased percent mobile sperm, decreased sperm concentrations as well as an increase in the percent abnormal sperm.

The dose in males at which no effects on fertility were observed was 100 mcg/kg, which is approximately 2.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison. Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for OTFC.

📄 Recent Major Changes 26 words ▾

RECENT MAJOR CHANGES Boxed Warning 1/2026 Dosage and Administration ( 2.2 ) 1/2026 Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.15 ) 1/2026

📄 Package Label / Principal Display Panel ~3 min read ▾

Package/Label Display Panel NDC 0093- 7865 -65 Oral Transmucosal Fentanyl Citrate (OTFC) CII equivalent to 200 mcg fentanyl base Only for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine. PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY DO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS WARNING: Keep out of the reach of children. Accidental ingestion of this medicine by a child could be harmful or fatal.

Partially consumed OTFC must be disposed of properly. Read enclosed OTFC Medication Guide and consult your physician for important warnings and directions. Call 1-888-534-3119 for a free OTFC Child Safety Kit with important additional information about safe use, storage, and disposal of this medicine.

Rx only 30 Units TEVA image

Package/Label Display Panel NDC 0093- 7866 -65 Oral Transmucosal Fentanyl Citrate (OTFC) CII equivalent to 400 mcg fentanyl base Only for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine. PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY DO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS WARNING: Keep out of the reach of children. Accidental ingestion of this medicine by a child could be harmful or fatal.

Partially consumed OTFC must be disposed of properly. Read enclosed OTFC Medication Guide and consult your physician for important warnings and directions. Call 1-888-534-3119 for a free OTFC Child Safety Kit with important additional information about safe use, storage, and disposal of this medicine.

Rx only 30 Units TEVA image

Package/Label Display Panel NDC 0093- 7867 -65 Oral Transmucosal Fentanyl Citrate (OTFC) CII equivalent to 600 mcg fentanyl base Only for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine. PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY DO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS WARNING: Keep out of the reach of children. Accidental ingestion of this medicine by a child could be harmful or fatal.

Partially consumed OTFC must be disposed of properly. Read enclosed OTFC Medication Guide and consult your physician for important warnings and directions. Call 1-888-534-3119 for a free OTFC Child Safety Kit with important additional information about safe use, storage, and disposal of this medicine.

Rx only 30 Units TEVA image

Package/Label Display Panel NDC 0093- 7868 -65 Oral Transmucosal Fentanyl Citrate (OTFC) CII equivalent to 800 mcg fentanyl base Only for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine. PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY DO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS WARNING: Keep out of the reach of children. Accidental ingestion of this medicine by a child could be harmful or fatal.

Partially consumed OTFC must be disposed of properly. Read enclosed OTFC Medication Guide and consult your physician for important warnings and directions. Call 1-888-534-3119 for a free OTFC Child Safety Kit with important additional information about safe use, storage, and disposal of this medicine.

Rx only 30 Units TEVA image

Package/Label Display Panel NDC 0093- 7869 -65 Oral Transmucosal Fentanyl Citrate (OTFC) CII equivalent to 1200 mcg fentanyl base Only for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine. PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY DO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS WARNING: Keep out of the reach of children. Accidental ingestion of this medicine by a child could be harmful or fatal.

Partially consumed OTFC must be disposed of properly. Read enclosed OTFC Medication Guide and consult your physician for important warnings and directions. Call 1-888-534-3119 for a free OTFC Child Safety Kit with important additional information about safe use, storage, and disposal of this medicine.

Rx only 30 Units TEVA image

Package/Label Display Panel NDC 00… [Excerpted — this section continues on DailyMed.]

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗

Medicare Part D spend CMS · PART D · 2026 (Q1)

Medicare Part D (outpatient prescription) spending for Fentanyl Citrate — the program that covers self-administered drugs. 2 manufacturers.
⚠️ Drug-level data: CMS publishes Part D spending by drug, not by NDC — these figures combine every manufacturer, strength and package size sold under the name Fentanyl Citrate. That’s a different level of aggregation than the Medicaid card above, which is specific to this exact 11-digit NDC (pack size included), so the two aren’t directly comparable.
Period
Total Part D spend
$20.6K
Claims incl. refills
4.4K
Beneficiaries
4K
Spend / beneficiary
$5.17
Spend / claim
$4.74
Trend by period
💵 About the dollar figures: spending is what Part D plans paid before confidential manufacturer rebates, so the program’s real net cost is lower. A blank patient count means fewer than 11 people — CMS hides counts that small to protect privacy. Source: CMS Medicare Quarterly Part D Spending by Drug (data.cms.gov), updated quarterly.
🛡
This drug has a REMS — TIRF REMS. A Risk Evaluation & Mitigation Strategy is an FDA-required safety program. It is available only through a restricted program (certified prescribers/pharmacies, enrollment, or required monitoring). See the boxed warning & full label below, and REMS@FDA ↗.

About this NDC listing & data coverage

Finished prescription product No longer marketed (per FDA listing data)
What data is (and isn’t) available for this NDC — tap to expand
NDC identity (package / product / labeler codes) ✓ Available
Labeler ✓ Available
Product & package description ✓ Available
Marketing category & status ✓ Available
Active ingredient / dosage form / route ✓ Available
FDA label (SPL via DailyMed) ✓ Available
Package photos — Not published for this NDC No photo available yet for this listing.
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NADAC pharmacy acquisition price (CMS) — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey.
Orange Book / therapeutic-equivalence data — Not published for this NDC Applies only to products approved under an NDA/ANDA; many listings are out of scope.
HCPCS J-code billing crosswalk — Not published for this NDC Most self-administered / retail products have no J-code — that is normal.
Medicaid utilization (CMS SDUD) — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold.
“Not published” reflects what the public FDA / CMS / NLM sources provide for this exact package code — it is a property of the data feeds, not a judgment about the product.

Questions about this listing

Why is there no price listed?
The pricing shown on our NDC pages comes from CMS NADAC, a voluntary survey of retail community pharmacy invoices. CMS does not publish a NADAC for every NDC — packages outside the retail survey (institutional and hospital products, bulk packages, discontinued items, and many OTC items) may never receive one. A missing price reflects the survey's scope, not this product's actual cost, and does not mean the product is free or unavailable.
What does the discontinued status mean for this NDC?
The labeler reported a marketing end date (or the listing was delisted), so this specific package is no longer actively marketed. Remaining stock may still be dispensed for a time, and the NDC stays valid for historical records and claims — but data feeds (pricing, labeling) typically stop updating for it. Other package sizes or other manufacturers' versions of the same medication may still be marketed — see the equivalents section where available.
Is the NDC printed on the package the same as the 11-digit billing NDC?
Yes, they identify this exact package in different formats. The form printed on the packaging and shown on DailyMed is the one the FDA registered. Insurance claims use a fixed 11-digit 5-4-2 format, so the short segment is padded with a leading zero and the dashes are dropped. The Identity section at the top of this page lists each form of this code.
Who lists this product with the FDA?
Teva Pharmaceuticals USA, Inc. is the labeler of record for this NDC — the company under whose FDA-assigned code the package is listed. The labeler may be the manufacturer itself or a distributor marketing the product under its own code.
Do I need a prescription for this product?
This NDC is listed with FDA as a prescription product, so it is dispensed under a prescriber's order. Your pharmacist can tell you whether any over-the-counter forms of the same medication exist.
This page identifies an FDA-listed package (the NDC) and reports public regulatory and pricing data about the listing. It is reference information, not a medical recommendation — talk to your pharmacist or prescriber about your own medication.
Where does this data come from?
Listing facts (marketing category, packager status, marketing dates) from the FDA openFDA NDC Directory; label availability from DailyMed; pricing coverage from CMS NADAC; equivalence scope from the FDA Orange Book.
← 00093-7769-24 · Teva 00093-7868-65 · Teva →
For educational and professional reference only — not medical advice. Pricing reflects published NADAC and CMS ASP (free public data) and may differ from your acquisition cost; always verify before billing or dispensing.