FENTORA (Page 5 of 14)
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 FENTORA with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue FENTORA 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
FENTORA may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of FENTORA. In patients with circulatory shock, FENTORA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of FENTORA 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), FENTORA 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 FENTORA.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of FENTORA in patients with impaired consciousness or coma.
5.14 Risks of Use in Patients with Gastrointestinal Conditions
FENTORA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The fentanyl in FENTORA 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 FENTORA 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 FENTORA therapy.
5.16 Risks of Driving and Operating Machinery
FENTORA 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 FENTORA and know how they will react to the medication.
5.17 Cardiac Disease
Intravenous fentanyl may produce bradycardia. Therefore, use FENTORA with caution in patients with bradyarrhythmias.
5.18 Application Site Reactions
Application site reactions occurred in 10% of patients in clinical trials and ranged from paresthesia to ulceration and bleeding [see Adverse Reactions (6)].
6 ADVERSE REACTIONS
The following serious adverse reactions are described, or described in greater detail, in other sections:
- Life-Threatening Respiratory Depression [see Warnings and Precautions (5.1)]
- Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.4)]
- Addiction, Abuse, and Misuse [see Warnings and Precautions (5.6)]
- Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.8)]
- Serotonin Syndrome [see Warnings and Precautions (5.10)]
- Adrenal Insufficiency [see Warnings and Precautions (5.11)]
- Severe Hypotension [see Warnings and Precautions (5.12)]
- Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.14)]
- Seizures [see Warnings and Precautions (5.15)]
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 FENTORA has been evaluated in 304 opioid-tolerant cancer patients with breakthrough pain. The average duration of therapy was 76 days with some patients being treated for over 12 months.
The clinical trials of FENTORA were designed to evaluate safety and efficacy in treating patients with cancer and breakthrough pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain.
The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received FENTORA for breakthrough pain along with a concomitant opioid for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of FENTORA therapy or cancer-related symptoms.
Table 2 lists, by maximum dose received, adverse events with an overall frequency of 5% or greater within the total population that occurred during titration. The ability to assign a dose-response relationship to these adverse events is limited by the titration schemes used in these studies.
| System Organ Class MeDRA preferred term, n (%) | 100 mcg (N=45) | 200 mcg (N=34) | 400 mcg (N=53) | 600 mcg (N=56) | 800 mcg (N=113) | Total (N=304)* |
| Gastrointestinal disorders | ||||||
| Nausea | 4 (9) | 5 (15) | 10 (19) | 13 (23) | 18 (16) | 50 (17) |
| Vomiting | 0 | 2 (6) | 2 (4) | 7 (13) | 3 (3) | 14 (5) |
| General disorders and administration site conditions | ||||||
| Fatigue | 3 (7) | 1 (3) | 9 (17) | 1 (2) | 5 (4) | 19 (6) |
| Nervous system disorders | ||||||
| Dizziness | 5 (11) | 2 (6) | 12 (23) | 18 (32) | 21 (19) | 58 (19) |
| Somnolence | 2 (4) | 2 (6) | 6 (12) | 7 (13) | 3 (3) | 20 (7) |
| Headache | 1 (2) | 3 (9) | 4 (8) | 8 (14) | 10 (9) | 26 (9) |
*Three hundred and two (302) patients were included in the safety analysis.
Table 3 lists, by successful dose, adverse events with an overall frequency of ≥5% within the total population that occurred after a successful dose had been determined.
| System Organ Class MeDRA preferred term, n (%) | 100 mcg (N=19) | 200 mcg (N=31) | 400 mcg (N=44) | 600 mcg (N=48) | 800 mcg (N=58) | Total (N=200) |
| Blood and lymphatic system disorders | ||||||
| Anemia | 6 (32) | 4 (13) | 4 (9) | 5 (10) | 7 (13) | 26 (13) |
| Neutropenia | 0 | 2 (6) | 1 (2) | 4 (8) | 4 (7) | 11 (6) |
| Gastrointestinal disorders | ||||||
| Nausea | 8 (42) | 5 (16) | 14 (32) | 13 (27) | 17 (31) | 57 (29) |
| Vomiting | 7 (37) | 5 (16) | 9 (20) | 8 (17) | 11 (20) | 40 (20) |
| Constipation | 5 (26) | 4 (13) | 5 (11) | 4 (8) | 6 (11) | 24 (12) |
| Diarrhea | 3 (16) | 0 | 4 (9) | 3 (6) | 5 (9) | 15 (8) |
| Abdominal pain | 2 (11) | 1 (3) | 4 (9) | 7 (15) | 4 (7) | 18 (9) |
| General disorders and administration site conditions | ||||||
| Edema peripheral | 6 (32) | 5 (16) | 4 (9) | 5 (10) | 3 (5) | 23 (12) |
| Asthenia | 3 (16) | 5 (16) | 2 (5) | 3 (6) | 8 (15) | 21 (11) |
| Fatigue | 3 (16) | 3 (10) | 9 (20) | 9 (19) | 8 (15) | 32 (16) |
| Infections and infestations | ||||||
| Pneumonia | 1 (5) | 5 (16) | 1 (2) | 1 (2) | 4 (7) | 12 (6) |
| Investigations | ||||||
| Weight decreased | 1 (5) | 1 (3) | 3 (7) | 2 (4) | 6 (11) | 13 (7) |
| Metabolism and nutrition disorders | ||||||
| Dehydration | 4 (21) | 0 | 4 (9) | 6 (13) | 7 (13) | 21 (11) |
| Anorexia | 1 (5) | 2 (6) | 4 (9) | 3 (6) | 6 (11) | 16 (8) |
| Hypokalemia | 0 | 2 (6) | 0 | 1 (2) | 8 (15) | 11 (6) |
| Musculoskeletal and connective tissue disorders | ||||||
| Back pain | 2 (11) | 0 | 2 (5) | 3 (6) | 2 (4) | 9 (5) |
| Arthralgia | 0 | 1 (3) | 3 (7) | 4 (8) | 3 (5) | 11 (6) |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | ||||||
| Cancer pain | 3 (16) | 1 (3) | 3 (7) | 2 (4) | 1 (2) | 10 (5) |
| Nervous system disorders | ||||||
| Dizziness | 5 (26) | 3 (10) | 5 (11) | 6 (13) | 6 (11) | 25 (13) |
| Headache | 2 (11) | 1 (3) | 4 (9) | 5 (10) | 8 (15) | 20 (10) |
| Somnolence | 0 | 1 (3) | 4 (9) | 4 (8) | 8 (15) | 17 (9) |
| Psychiatric disorders | ||||||
| Confusional state | 3 (16) | 1 (3) | 2 (5) | 3 (6) | 5 (9) | 14 (7) |
| Depression | 2 (11) | 1 (3) | 4 (9) | 3 (6) | 5 (9) | 15 (8) |
| Insomnia | 2 (11) | 1 (3) | 3 (7) | 2 (4) | 4 (7) | 12 (6) |
| Respiratory, thoracic, and mediastinal disorders | ||||||
| Cough | 1 (5) | 1 (3) | 2 (5) | 4 (8) | 5 (9) | 13 (7) |
| Dyspnea | 1 (5) | 6 (19) | 0 | 7 (15) | 4 (7) | 18 (9) |
In addition, a small number of patients (n=11) with Grade 1 mucositis were included in clinical trials designed to support the safety of FENTORA. There was no evidence of excess toxicity in this subset of patients.
Application Site Reactions: In clinical trials, 10% of all patients exposed to FENTORA reported application site reactions. These reactions ranged from paresthesias to ulceration and bleeding. Application site reactions occurring in ≥1% of patients were pain (4%), ulcer (3%), and irritation (3%). Application site reactions tended to occur early in treatment, were self-limited and only resulted in treatment discontinuation for 2% of patients.
The duration of exposure to FENTORA varied greatly, and included open-label and double-blind studies. The frequencies listed below represent the ≥1% of patients (and not listed in Tables 2 and 3 above) from three clinical trials (titration and post-titration periods combined) who experienced that event while receiving FENTORA. Events are classified by system organ class.
Adverse Events (≥1%)
Blood and Lymphatic System Disorders: Thrombocytopenia, Leukopenia
Cardiac Disorders: Tachycardia
Gastrointestinal Disorders: Stomatitis, Dry Mouth, Dyspepsia, Upper Abdominal Pain, Abdominal Distension, Dysphagia, Gingival Pain, Stomach Discomfort, Gastroesophageal Reflux Disease, Glossodynia, Mouth Ulceration
General Disorders and Administration Site Conditions: Pyrexia, Application Site Pain, Application Site Ulcer, Chest Pain, Chills, Application Site Irritation, Edema, Mucosal Inflammation, Pain
Hepatobiliary Disorders: Jaundice
Infections and Infestations: Oral Candidiasis, Urinary Tract Infection, Cellulitis, Nasopharyngitis, Sinusitis, Upper Respiratory Tract Infection, Influenza, Tooth Abscess
Injury, Poisoning and Procedural Complications: Fall, Spinal Compression Fracture
Investigations: Decreased Hemoglobin, Increased Blood Glucose, Decreased Hematocrit, Decreased Platelet Count
Metabolism and Nutrition Disorders: Decreased Appetite, Hypoalbuminemia, Hypercalcemia, Hypomagnesemia, Hyponatremia, Reduced Oral Intake
Musculoskeletal and Connective Tissue Disorders: Pain in Extremity, Myalgia, Chest Wall Pain, Muscle Spasms, Neck Pain, Shoulder Pain
Nervous System Disorders: Hypoesthesia, Dysgeusia, Lethargy, Peripheral Neuropathy, Paresthesia, Balance Disorder, Migraine, Neuropathy
Psychiatric Disorders: Anxiety, Disorientation, Euphoric Mood, Hallucination, Nervousness
Renal and Urinary Disorders: Renal Failure
Respiratory, Thoracic and Mediastinal Disorders: Pharyngolaryngeal Pain, Exertional Dyspnea, Pleural Effusion, Decreased Breathing Sounds, Wheezing
Skin and Subcutaneous Tissue Disorders: Pruritus, Rash, Hyperhidrosis, Cold Sweat
Vascular Disorders: Hypertension, Hypotension, Pallor, Deep Vein Thrombosis
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