Fentanyl Citrate


Indications

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 daily for a week or longer. 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 .
As a part of the TIRF REMS Access program, OTFC may be dispensed only to outpatients enrolled in the program . For inpatient administration of OTFC (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required.

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.
Significant respiratory depression .
Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department.
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment .
Known or suspected gastrointestinal obstruction, including paralytic ileus .
Known hypersensitivity to fentanyl or components of OTFC (e.g., anaphylaxis, hypersensitivity) .

adverse reactions

The following serious adverse reactions are described, or described in greater detail, in other sections:

Life-Threatening Respiratory Depression
Interactions with Benzodiazepines and Other CNS Depressants
Addiction, Abuse, and Misuse
Neonatal Opioid Withdrawal Syndrome
Serotonin Syndrome
Adrenal Insufficiency
Severe Hypotension
Gastrointestinal Adverse Reactions
Seizures

6.1 Clinical 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)
*
Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once.

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*

(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

2

3

6

5

4

Skin

Pruritus

1

0

0

5

2

Rash

1

1

0

2

2

Sweating

1

1

2

2

2

Special Senses

Abnormal Vision

1

0

2

0

2

The following adverse reactions not reflected in Table 1 occurred during titration with an overall frequency of 1% or greater and are listed in descending order of frequency within each body system.

Body as a Whole: Pain, fever, abdominal pain, chills, back pain, chest pain, infection

Digestive: Diarrhea, dyspepsia, flatulence

Metabolic and Nutritional: Peripheral edema, dehydration

Nervous: Hypesthesia, migraine

Respiratory: Pharyngitis, cough increased

The following reactions occurred during titration with an overall frequency of less than 1% and are listed in descending order of frequency within each body system.

Body as a Whole: bone pain

Cardiovascular: Deep thrombophlebitis, hypertension, hypotension

Digestive: Anorexia, eructation, fecal impaction, gum hemorrhage, mouth ulceration, oral moniliasis

Hemic and Lymphatic: Anemia, leukopenia

Metabolic and Nutritional: Edema, hypercalcemia, weight loss

Musculoskeletal: Myalgia, pathological fracture, myasthenia

Nervous: Abnormal dreams, urinary retention, agitation, amnesia, emotional lability, euphoria, incoordination, libido decreased, neuropathy, paresthesia, speech disorder

Respiratory: Hemoptysis, pleural effusion, rhinitis, asthma, hiccup, pneumonia, respiratory insufficiency, sputum increased

Skin and Appendages: Alopecia, exfoliative dermatitis

Special Senses: Taste perversion

Urogenital: Vaginal hemorrhage, dysuria, hematuria, urinary incontinence, urinary tract infection

A long-term extension study was conducted in 156 patients with malignancy and breakthrough cancer pain who were treated for an average of 129 days. Data are available for 152 of these patients. Table 2 lists by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during the long-term extension study. Adverse reactions are listed in descending order of frequency within each body system.

Table 2. Percent of Patients with Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Long Term Treatment (Events in 1% or More of Patients)
*
Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once.

Dose Group

Percentage of Patients Reporting Event

200-

600 mcg

(n=98)

800-

1400 mcg

(n=83)

1600

mcg

(n=53)

>1600

mcg

(n=27)

Any

Dose*

(n=152)

Body As A Whole

Asthenia

25

30

17

15

38

Headache

12

17

13

4

20

Accidental Injury

4

6

4

7

9

Hypertonia

2

2

2

0

3

Digestive

Nausea

31

36

25

26

45

Vomiting

21

28

15

7

31

Constipation

14

11

13

4

20

Intestinal Obstruction

0

2

4

0

3

Cardiovascular

Hypertension

1

1

0

0

1

Nervous

Dizziness

12

10

9

0

16

Anxiety

9

8

8

7

15

Somnolence

8

13

8

7

15

Confusion

2

5

13

7

10

Depression

9

4

2

7

9

Insomnia

5

1

8

4

7

Abnormal Gait

5

1

0

0

4

Dry Mouth

3

1

2

4

4

Nervousness

2

2

0

4

3

Stupor

4

1

0

0

3

Vasodilatation

1

1

4

0

3

Thinking Abnormal

2

1

0

0

2

Abnormal Dreams

1

1

0

0

1

Convulsion

0

1

2

0

1

Myoclonus

0

0

4

0

1

Tremor

0

1

2

0

1

Vertigo

0

0

4

0

1

Respiratory

Dyspnea

15

16

8

7

22

Skin

Rash

3

5

8

4

8

Sweating

3

2

2

0

4

Pruritus

2

0

2

0

2

Special Senses

Abnormal Vision

2

2

0

0

3

Urogenital

Urinary Retention

1

2

0

0

2

The following reactions not reflected in Table 2 occurred with an overall frequency of 1% or greater in the long-term extension study and are listed in descending order of frequency within each body system.

Body as a Whole: Pain, fever, back pain, abdominal pain, chest pain, flu syndrome, chills, infection, abdomen enlarged, bone pain, ascites, sepsis, neck pain, viral infection, fungal infection, cachexia, cellulitis, malaise, pelvic pain

Cardiovascular: Deep thrombophlebitis, palpitation, vascular disorder

Digestive: Diarrhea, anorexia, dyspepsia, dysphagia, oral moniliasis, mouth ulceration, rectal disorder, stomatitis, flatulence, gastrointestinal hemorrhage, gingivitis, jaundice, periodontal abscess, eructation, glossitis, rectal hemorrhage

Hemic and Lymphatic: Anemia, leukopenia, thrombocytopenia, ecchymosis, lymphadenopathy, lymphedema, pancytopenia

Metabolic and Nutritional: Peripheral edema, edema, dehydration, weight loss, hyperglycemia, hypokalemia, hypercalcemia, hypomagnesemia

Musculoskeletal: Myalgia, pathological fracture, joint disorder, leg cramps, arthralgia, bone disorder

Nervous: Hypesthesia, paresthesia, hypokinesia, neuropathy, speech disorder, migraine

Respiratory: Cough increased, pharyngitis, pneumonia, rhinitis, sinusitis, bronchitis, epistaxis, asthma, hemoptysis, sputum increased

Skin and Appendages: Skin ulcer, alopecia

Special Senses: Tinnitus, conjunctivitis, ear disorder, taste perversion

Urogenital: Urinary tract infection, urinary incontinence, breast pain, dysuria, hematuria, scrotal edema, hydronephrosis, kidney failure, urinary urgency, urination impaired, breast neoplasm, vaginal hemorrhage, vaginitis

The following reactions occurred with a frequency of less than 1% in the long-term extension study and are listed in descending order of frequency within each body system.

Body as a Whole: Allergic reaction, cyst, face edema, flank pain, granuloma, bacterial infection, mucous membrane disorder, neck rigidity

Cardiovascular: Angina pectoris, hemorrhage, hypotension, peripheral vascular disorder, postural hypotension, tachycardia

Digestive: Cheilitis, esophagitis, fecal incontinence, gastroenteritis, gastrointestinal disorder, gum hemorrhage, hemorrhage of colon, hepatorenal syndrome, liver tenderness, tooth caries, tooth disorder

Hemic and Lymphatic: Bleeding time increased

Metabolic and Nutritional: Acidosis, generalized edema, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, thirst

Musculoskeletal: Arthritis, muscle atrophy, myopathy, synovitis, tendon disorder

Nervous: Acute brain syndrome, agitation, cerebral ischemia, facial paralysis, foot drop, hallucinations, hemiplegia, miosis, subdural hematoma

Respiratory: Hiccup, hyperventilation, lung disorder, pneumothorax, respiratory failure, voice alteration

Skin and Appendages: Herpes zoster, maculopapular rash, skin discoloration, urticaria, vesiculobullous rash

Special Senses: Ear pain, eye hemorrhage, lacrimation disorder, partial permanent deafness, partial transitory deafness

Urogenital: Kidney pain, nocturia, oliguria, polyuria, pyelonephritis

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of OTFC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Digestive:

– Dental decay: Dental decay, including dental caries, tooth loss, and gum line erosion.

Nervous System Disorders:

– Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Endocrine Disorders:

– Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.

Immune System Disorders:

– Anaphylaxis: Anaphylaxis has been reported with ingredients contained in OTFC.

General Disorders and Administration Site Conditions: Application site reactions including irritation, pain, and ulcer, and drug withdrawal syndrome.

warnings and precautions

5.1 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of OTFC, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Oral Transmucosal Fentanyl Citrate (OTFC).

To reduce the risk of respiratory depression, proper dosing and titration of OTFC are essential2)]. Overestimating the OTFC dosage can result in a fatal overdose with the first dose. The substitution of OTFC for any other fentanyl product may result in fatal overdose5.5)].

OTFC could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.

Accidental ingestion of even one dose of OTFC, especially by children, can result in respiratory depression and death due to an overdose of fentanyl5.1, 5.2)].

5.2 Increased Risk of Overdose in Children Due to Accidental Ingestion or Exposure

Death has been reported in children who have accidentally ingested OTFC.

Patients and their caregivers must be informed that OTFC contains a medicine in an amount which can be fatal to a child. Healthcare providers and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure.

Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. While all units should be disposed of immediately after use, partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible17)].

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of OTFC are provided in the OTFC. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.

5.3 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of OTFC with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression5.1)], particularly when an inhibitor is added after a stable dose of OTFC is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in OTFC-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using OTFC with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in OTFC-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of OTFC until stable drug effects are achieved7)].

Concomitant use of OTFC with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using OTFC with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur7)].

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants (including Alcohol)

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OTFC with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when OTFC is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs7) and Patient Counseling Information (17)].

5.5 Risk of Medication Errors

When prescribing, do not convert a patient to OTFC from any other fentanyl product on a mcg per mcg basis as OTFC and other fentanyl products are not equivalent on a microgram per microgram basis.

OTFC is not a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute an OTFC prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and OTFC are not equivalent. Substantial differences exist in the pharmacokinetic profile of OTFC compared to other fentanyl products including other TIRF formulations that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of OTFC for any other fentanyl product may result in a fatal overdose.

There are no safe conversion directions available for patients on any other fentanyl products. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) Therefore, for opioid tolerant patients, the initial dose of OTFC should always be 200 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects.

5.6 Addiction, Abuse, and Misuse

OTFC contains fentanyl, a Schedule II controlled substance. As an opioid, OTFC exposes users to the risks of addiction, abuse, and misuse9)].

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.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing OTFC, and monitor 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 intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing OTFC. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug17)]. 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.

5.7 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program

Because of the risk for misuse, abuse, addiction, and overdose, OTFC is available only through a restricted program called the TIRF REMS Access program. Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe for outpatient use, pharmacies, and distributors must enroll in the program. For inpatient administration (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use) of OTFC, patient and prescriber enrollment is not required.

Required components of the TIRF REMS Access program are:

Healthcare professionals, who prescribe OTFC for outpatient use, must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements.
To receive OTFC, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement.
Pharmacies that dispense OTFC must enroll in the program, and agree to comply with the REMS requirements.
Wholesalers and distributors that distribute OTFC must enroll in the program, and distribute only to authorized pharmacies.
Further information, including a list of qualified pharmacies/distributors, is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

5.8 Neonatal Opioid Withdrawal Syndrome

Prolonged use of OTFC during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of OTFC in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: OTFC-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of OTFC5.1)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients5.1)].

Monitor such patients closely, particularly when initiating and titrating OTFC and when OTFC is given concomitantly with other drugs that depress respiration5.1)]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of OTFC with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue OTFC if serotonin syndrome is suspected.

5.11 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.12 Severe Hypotension

OTFC may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of OTFC. In patients with circulatory shock, OTFC may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the 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

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), OTFC may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with OTFC.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OTFC in patients with impaired consciousness or coma.

5.14 Risks of Use in Patients with Gastrointestinal Conditions

OTFC is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The fentanyl in OTFC may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

5.15 Increased Risk of Seizures in Patients with Seizure Disorders

The fentanyl in OTFC may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during OTFC therapy.

5.16 Risks of Driving and Operating Machinery

OTFC may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of OTFC and know how they will react to the medication.

5.17 Cardiac Disease

Intravenous fentanyl may produce bradycardia. Therefore, use OTFC with caution in patients with bradyarrhythmias.

5.18 MAO Inhibitors

OTFC is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

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 uses 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 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.
Taking OTFC with other medicines that may make you sleepy, such as other pain medicines, 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. Store OTFC away from children and in a safe place to prevent stealing or abuse. Selling or giving away OTFC is against the law.
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 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access program. To receive OTFC, you must:
o
talk to your healthcare provider
o
understand the benefits and risks of OTFC
o
agree to all of the instructions
o
sign the Patient-Prescriber Agreement form
OTFC is only available at pharmacies that are part of the TIRF REMS Access program. Your healthcare provider will let you know the 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 the end of this Medication Guide for a complete list of ingredients in OTFC.
You have short-term pain that you would expect to go away in a few days, such as:
o
pain after surgery
o
headache or migraine
o
dental pain

Before taking Oral Transmucosal Fentanyl Citrate (OTFC), tell your healthcare provider if you have a history of:

troubled breathing or lung problems such as asthma, wheezing, or shortness of breath
head injury, seizures
slow heart rate or other heart problems
low blood pressure
mental problems [including major depression, schizophrenia or hallucinations (seeing or hearing things that are not there)]
problems urinating
liver, kidney, thyroid problems
pancreas or gallbladder problems
abuse of street or prescription drugs, alcohol addiction, or mental health problems
diabetes. Each OTFC unit contains about ½ teaspoon (2 grams) of sugar.

Tell your healthcare provider if you are:

Pregnant or planning to become pregnant. Prolonged use of OTFC during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
breastfeeding. OTFC passes into breast milk and may harm your baby.
taking prescription over-the-counter medicines, vitamins, or herbal supplements. Taking OTFC with certain other medicines can cause serious side effects that could lead to death.

When taking Oral Transmucosal Fentanyl Citrate (OTFC):

Do not change your dose. Take OTFC exactly as prescribed by your healthcare provider.
Your healthcare provider will change the dose until you and your healthcare provider find the right dose for you.
See the detailed Patient Instructions for Use at the end of this Medication Guide for information about how to use OTFC.
Finish the unit completely in 15 minutes to get the most relief. If you finish OTFC too quickly, you will swallow more of the medicine and get less relief.
Do not bite or chew. You will get less relief for your breakthrough cancer pain.
You may drink some water before using OTFC but you should not drink or eat anything while using OTFC.
You must not use more than 2 units of OTFC during each episode of breakthrough cancer pain:
o
Use 1 unit for an episode of breakthrough cancer pain. Finish the unit over 15 minutes.
o
If your breakthrough cancer pain is not relieved 15 minutes after you finished the OTFC unit, use only 1 more unit of OTFC at this time.
o
If your breakthrough pain does not get better after the second unit of OTFC, call your healthcare provider for instructions. Do not use another unit of OTFC at this time.
Wait at least 4 hours before treating a new episode of breakthrough cancer pain with OTFC.
It is important for you to keep taking your around-the-clock opioid pain medicine.
Talk to your healthcare provider if your dose of OTFC does not relieve your breakthrough cancer pain. Your healthcare provider will decide if your dose of OTFC needs to be changed.
Talk to your healthcare provider if you have more than 4 episodes of breakthrough cancer pain per day. The dose of your around-the-clock opioid pain medicine may need to be adjusted.
If you begin to feel dizzy, sick to your stomach, or very sleepy before OTFC is completely dissolved, remove OTFC from your mouth.
Do not stop taking OTFC without talking to your healthcare provider. You could become sick with uncomfortable withdrawal symptoms because your body has become used to these medicines. Physical dependency is not the same as drug addiction.
After you stop taking, or when OTFC is no longer needed, see “ How should I dispose of OTFC units when they are no longer needed?” for proper disposal of OTFC.
DO NOT Drive or operate heavy machinery, until you know how OTFC affects you. OTFC can make you sleepy, dizzy, or lightheaded.
DO NOT Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with OTFC may cause you to overdose and die.
DO NOT Switch from OTFC to other medicines that contain fentanyl without talking to your healthcare provider. The amount of fentanyl in a dose of OTFC is not the same as the amount of fentanyl in other medicines that contain fentanyl. Your healthcare provider will prescribe a starting dose of OTFC that may be different than other fentanyl containing medicines you may have been taking.

The possible side effects of Oral Transmucosal Fentanyl Citrate (OTFC):

constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, weakness, anxiety, depression, rash, trouble sleeping. Call your healthcare provider if you have any of these symptoms and they are severe.
Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down.
OTFC contains sugar. Cavities and tooth decay can happen in people taking OTFC. When taking OTFC, you should talk to your dentist about proper care of your teeth.

Get emergency medical help if you have:

trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.
These symptoms can be a sign that you have used too much OTFC or the dose is too high for you. These symptoms may lead to serious problems or death if not treated right away. If you have any of these symptoms, do not use any more OTFC until you have talked to your healthcare provider.

These are not all the possible side effects of OTFC. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov

How should I store Oral Transmucosal Fentanyl Citrate (OTFC)?

Always keep OTFC in a safe place away from children and from anyone for whom it has not been prescribed. Protect OTFC from theft.
o
You can use the OTFC Child Safety Kit to help you store OTFC and your other medicines out of the reach of children. It is very important that you use the items in the OTFC Child Safety Kit to help protect the children in your home or visiting your home.
o
If you were not offered a Child Safety Kit when you received your medicine, call 888-534-3119.

The OTFC Child Safety Kit contains important information on the safe storage and handling of OTFC.

The Child Safety Kit includes:

A child-resistant lock that you use to secure the storage space where you keep OTFC (See Figure 1).

Figure 1

A portable locking pouch for you to keep a small supply of OTFC nearby. The rest of your OTFC must be kept in a locked storage space.
o
Keep this pouch secured with its lock and keep it out of the reach and sight of children (See Figure 2).

Figure 2

A child-resistant temporary storage bottle (See Figure 3).

Figure 3

Store OTFC at room temperature, 59°F to 86°F (15°C to 30°C) until ready to use.
Do not freeze OTFC.
Keep OTFC in the original sealed child-resistant blister package. Do not open the blister package until you are ready to use OTFC.
Keep OTFC dry.

How should I dispose of Oral Transmucosal Fentanyl Citrate (OTFC) units when they are no longer needed?

Disposing of OTFC units after use:

Partially used OTFC units may contain enough medicine to be harmful or fatal to a child or other adults who have not been prescribed OTFC. You must properly dispose of the OTFC handle right away after use even if there is little or no medicine left on it.

After you have finished the OTFC unit and the medicine is totally gone, throw the handle away in a place that is out of the reach of children.

If any medicine remains on the used OTFC unit after you have finished:

Place the used OTFC unit under hot running water until the medicine is gone, and then throw the handle away out of the reach of children and pets (See Figure 4).

Figure 4

Temporary Storage of Used OTFC Units:

If you did not finish the entire OTFC unit and you cannot dissolve the medicine under hot running water right away, put the used OTFC unit in the temporary storage bottle that you received in the OTFC Child Safety Kit. Push the used OTFC unit into the opening on the top until it falls completely into the bottle. Never leave unused or partially used OTFC units where children or pets can get to them (See Figure 5).

Figure 5

 
Disposing of Used OTFC Units from the Temporary Storage Bottle:

You must dispose of all used OTFC units in the temporary storage bottle at least one time each day, as follows:

 
1.
To open the temporary storage bottle, push down on the cap until you are able to twist the cap to the left to remove it (See Figure 6).

Figure 6

2.
Remove one OTFC unit from the temporary storage bottle. Hold the OTFC by its handle over the toilet bowl.
3.
Using wire-cutting pliers, cut the medicine end off so that it falls into the toilet.
4.
Throw the handle away in a place that is out of the reach of children.
5.
Repeat these 3 steps for each OTFC handle that is in the storage bottle. There should not be more than 4 handles in the temporary storage bottle for 1 day.
6.
Flush the toilet twice.

Do not flush entire unused OTFC units, OTFC handles, or blister packages down the toilet.

Disposing of unopened OTFC units: Dispose of any unopened OTFC units remaining from a prescription as soon as they are no longer needed, as follows:

1.
Remove all OTFC from the locked storage space (See Figure 7).
 
Figure 7
2.
Remove one OTFC unit from its blister package by using scissors to cut off the marked end and then peel back the blister backing (See Figures 8A and 8B).
 
Figure 8A Figure 8B
3.
Hold OTFC by its handle over the toilet bowl. Use wire-cutting pliers to cut the medicine end off so that it falls into the toilet (See Figures 9A and 9B).
 
Figure 9A Figure 9B
4.
Throw the handle away in a place that is out of the reach of children (See Figure 10).
 
Figure 10
5.
Repeat steps 1 through 4 for each OTFC unit.
6.
Flush the toilet twice after the medicine ends from 5 OTFC units have been cut off (See Figure 11). Do not flush more than 5 OTFC units at a time.

Figure 11

Do not flush entire unused OTFC units, OTFC handles, or blister packages down the toilet.

If you need help with disposal of OTFC, call Teva Pharmaceuticals at 1-888-483-8279, or call your local Drug Enforcement Agency (DEA) office.

General information about Oral Transmucosal Fentanyl Citrate (OTFC)

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Use OTFC only for the purpose for which it was prescribed. Do not give OTFC to other people, even if they have the same symptoms you have. OTFC can harm other people and even cause death. Sharing OTFC is against the law.

This Medication Guide summarizes the most important information about OTFC. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about OTFC that is written for healthcare professionals.

For more information about the TIRF REMS Access program, go to www.TIRFREMSAccess.com or call 1-866-822-1483.

What are the ingredients of Oral Transmucosal Fentanyl Citrate (OTFC)?

Active Ingredient: fentanyl citrate

Inactive Ingredients: sugar, citric acid, dibasic sodium phosphate, artificial berry flavor, magnesium stearate, modified food starch and confectioner’s sugar.

Patient Instructions for Use

Before you use OTFC, it is important that you read the Medication Guide and these Patient Instructions for Use. Be sure that you read, understand, and follow these Patient Instructions for Use so that you use OTFC the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use OTFC.

When you get an episode of breakthrough cancer pain, use the dose of OTFC prescribed by your healthcare provider as follows:

You may drink some water before using OTFC but you should not drink or eat anything while using OTFC.
Each unit of OTFC is sealed in its own blister package (See Figure 12). Do not open the blister package until you are ready to use OTFC.

Figure 12

When you are ready to use OTFC, cut open the package using scissors. Peel back the blister backing, and remove the OTFC unit (See Figures 13A and 13B). The end of the unit printed with “FENTANYL” and the strength number of the unit (“200”, “400”, “600”, “800”, “1200”, or “1600”) is the medicine end that is to be placed in your mouth. Hold the OTFC unit by the handle (See Figure 14).
 
Figure 13A Figure 13B

Figure 14

1.
Place the medicine end of the OTFC unit in your mouth between your cheeks and gums and actively suck on the medicine.
2.
Move the medicine end of the OTFC unit around in your mouth, especially along the inside of your cheeks (See Figure 15).

Figure 15

3.
Twirl the handle often.
4.
Finish the OTFC unit completely over 15 minutes to get the most relief. If you finish OTFC too quickly, you will swallow more of the medicine and get less relief.
5.
Do not bite or chew OTFC. You will get less relief for your breakthrough cancer pain.
If you cannot finish all of the medicine on the OTFC unit and cannot dissolve the medicine under hot tap water right away, immediately put the OTFC unit in the temporary storage bottle for safe keeping (See Figure 16).
o
Push the OTFC unit into the opening on the top until it falls completely into the bottle. You must properly dispose of the OTFC unit as soon as you can.

Figure 16

See “How should I dispose of OTFC units when they are no longer needed?” for proper disposal of OTFC.

Distributed by:

 
Teva Pharmaceuticals USA, Inc. call 1-888-483-8279
 
North Wales, PA 19454

Revised 12/2016

OTF-013

OTFMG-013

©2000-2016 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

Printed in USA

This Medication Guide has been approved by the U.S. Food and Drug Administration.

overdosage

Clinical Presentation

Acute overdose with Oral Transmucosal Fentanyl Citrate (OTFC) 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, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

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 techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to fentanyl overdose.

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 antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist 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 antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

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).

Fentanyl Citrate Package Photos

About the Author

Truman Lewis
Truman has been a bureau chief and correspondent in D.C., Los Angeles, Phoenix and elsewhere, reporting for radio, television, print and news services, for more than 30 years. Most recently, he has reported extensively on health and consumer issues for ConsumerAffairs.com and FairfaxNews.com.