Pre-Marketing Clinical Trial Experience

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 most commonly observed adverse events seen with FENTORA are typical of opioid side effects. Opioid side effects should be expected and managed accordingly.

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 5 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.

Table 5. Adverse Events Which Occurred During Titration at a Frequency of ≥ 5%

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 6 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.

Table 6. Adverse Events Which Occurred During Long-Term Treatment at a Frequency of ≥ 5%

System Organ ClassMeDRA 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 (incl 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.

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 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: Anemia, Neutropenia, Thrombocytopenia, Leukopenia

Cardiac Disorders:

Tachycardia

Gastrointestinal Disorders:

Nausea, Vomiting, Constipation, Abdominal Pain, Diarrhea, 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:

Fatigue, Edema Peripheral, Asthenia, Pyrexia, Application Site Pain, Application Site Ulcer, Chest Pain, Chills, Application Site Irritation, Edema, Mucosal Inflammation, Pain

Hepatobiliary Disorders:

Jaundice

Infections and Infestations:

Pneumonia, 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 Weight, Decreased Hemoglobin, Increased Blood Glucose, Decreased Hematocrit, Decreased Platelet Count

Metabolism and Nutrition Disorders:

Dehydration, Anorexia, Hypokalemia, Decreased Appetite, Hypoalbuminemia, Hypercalcemia, Hypomagnesemia, Hyponatremia, Reduced Oral Intake

Musculoskeletal and Connective Tissue Disorders:

Arthralgia, Back Pain, Pain in Extremity, Myalgia, Chest Wall Pain, Muscle Spasms, Neck Pain, Shoulder Pain

Nervous System Disorders:

Dizziness, Headache, Somnolence, Hypoesthesia, Dysgeusia, Lethargy, Peripheral Neuropathy, Paresthesia, Balance Disorder, Migraine, Neuropathy

Psychiatric Disorders:

Confusional State, Depression, Insomnia, Anxiety, Disorientation, Euphoric Mood, Hallucination, Nervousness

Renal and Urinary Disorders:

Renal Failure

Respiratory, Thoracic and Mediastinal Disorders:

Dyspnea, Cough, 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

See WARNINGS.

Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); therefore potential interactions may occur when FENTORA is given concurrently with agents that affect CYP3A4 activity. The concomitant use of FENTORA with strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazadone) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious adverse drug effects including fatal respiratory depression. Patients receiving FENTORA concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time. Dosage increase should be done conservatively. (See PHARMACOKINETICS, Drug Interactions and DOSAGE AND ADMINISTRATION.)

Grapefruit and grapefruit juice decrease CYP3A4 activity, increasing blood concentrations of fentanyl, thus should be avoided.

Drugs that induce cytochrome P450 3A4 activity may have the opposite effects.

Concomitant use of FENTORA with an MAO inhibitor, or within 14 days of discontinuation, is not recommended.