July 29, 2016
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Side Effects


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 SUBSYS has been evaluated in a total of 359 opioid-tolerant patients with breakthrough cancer pain. The duration of SUBSYS use varied during the open-label study. Safety data from a long-term extension study showed that the average duration of therapy in the open-label study was 66 days. The maximum duration of therapy was 149 days. The dose range studied in these trials ranged from 100 mcg per dose to 1600 mcg per dose.

The most commonly observed adverse reactions seen with SUBSYS are typical opioid side effects such as nausea, vomiting, somnolence, and constipation. Expect opioid side effects and manage them accordingly.

The most serious adverse reactions associated with all opioids including SUBSYS are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms of respiratory depression.

The most common adverse reaction leading to discontinuation of SUBSYS was nausea. There were also adverse reactions of abdominal distension, anorexia, confusional state, disorientation, somnolence, and constipation.

The clinical trials of SUBSYS 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 SUBSYS for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain.

Table 3 lists adverse reactions with an overall frequency of 5% or greater that occurred during titration in the clinical trials. Adverse reactions are listed in descending order of frequency within each system organ class.

Table 3: Percent of Patients with Specific Adverse Events During Titration in the Clinical Trials (Events in 5% or More of Patients)

System Organ Class Titration
Gastrointestinal Disorders
  Nausea 47 (13.1%)
  Vomiting 37 (10.3%)
  Constipation 18 (5.0%)
Nervous System Disorders
  Somnolence 34 (9.5%)
  Dizziness 26 (7.2%)

The following adverse reactions occurred during titration in the clinical trials with an overall frequency of 1% or greater and are listed in descending order of frequency within each system organ class.

Cardiac Disorders: Tachycardia

Gastrointestinal Disorders: Diarrhea, stomatitis, dry mouth

General Disorders and Administration Site Conditions: Application site irritation, pyrexia, edema peripheral, fatigue, asthenia

Metabolism and Nutrition Disorders: Decreased appetite

Nervous System Disorders: Lethargy, sedation, tremor, headache

Psychiatric Disorders: Depression, confusional state, hallucination, insomnia

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea

Skin and Subcutaneous Tissue Disorders: Pruritus

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

Eye Disorders: Vision blurred, dry eye

Gastrointestinal Disorders: Abdominal pain

Infections and Infestations: Oral candidiasis, cellulitis

Injury, Poisoning and Procedural Complications: Fall

Metabolism and Nutrition Disorders: Dehydration, anorexia

Musculoskeletal and Connective Tissue Disorders: Back pain, arthralgia, joint swelling

Psychiatric Disorders: Anxiety, agitation

Renal and Urinary Disorders: Urinary retention

Respiratory, Thoracic and Mediastinal Disorders: Cough, increased bronchial secretion, dysphonia, pharyngolaryngeal pain

Skin and Subcutaneous Tissue Disorders: Hyperhidrosis

Vascular Disorders: Hot flush

Table 4 lists adverse reactions with an overall frequency of 5% or greater for the total safety database subsequent to titration during the clinical trials.

Table 4: Adverse Reactions Subsequent to Titration in 5% or More of Patients

System Organ Class Dosing
Gastrointestinal Disorders
  Vomiting 43 (16.0%)
  Nausea 28 (10.4%)
  Constipation 28 (10.4%)
General Disorders and Administration Site Conditions
  Asthenia 26 (9.7%)
Respiratory, Thoracic and Mediastinal Disorders
  Dyspnea 28 (10.4%)
Psychiatric Disorders
  Anxiety 16 (5.9%)

A patient was counted only once within each category.

The following adverse reactions occurred during the dosing period of the clinical trial with an overall frequency of 1% or greater and are listed in descending order of frequency within each system organ class.

Blood and Lymphatic System Disorders: Anemia, neutropenia, lymphadenopathy, thrombocytopenia, leukopenia

Cardiac Disorders: Tachycardia, sinus tachycardia

Gastrointestinal Disorders: Diarrhea, stomatitis, abdominal pain, abdominal distension, gastritis, dysphagia, dyspepsia, gastroesophageal reflux disease, ascites, hematemesis

General Disorders and Administration Site Conditions: Edema peripheral, fatigue, pyrexia, chest pain, drug withdrawal syndrome, chills, irritability, malaise, application site irritation

Infections and Infestations: Oral candidiasis, pneumonia, urinary tract infection, oral herpes, gastroenteritis, laryngitis

Injury, Poisoning and Procedural Complications: Contusion

Investigations: Weight decreased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood glucose increased, blood lactate increased

Metabolism and Nutrition Disorders: Anorexia, dehydration, hypokalemia, decreased appetite, hyponatremia, hypocalcemia, hypoalbuminemia, cachexia

Musculoskeletal and Connective Tissue Disorders: Back pain, arthralgia, muscular weakness

Nervous System Disorders: Hypoesthesia, lethargy, sedation, tremor, somnolence, headache, dizziness

Psychiatric Disorders: Depression, restlessness, agitation, confusional state, insomnia, hallucination, disorientation

Renal and Urinary Disorders: hypertension, hypotension

Respiratory, Thoracic and Mediastinal Disorders: Cough, increased bronchial secretion, wheezing, pharyngolaryngeal pain, hypoxia, dyspnea exertional

Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus

In a single-dose mucositis study, a group of patients with Grade 1 or 2 oral mucositis (n=9) and without oral mucositis (n=9) were included in a clinical trial designed to support the safety of SUBSYS. Two of the nine subjects with mucositis (one with Grade 1 and one with Grade 2) reported a burning sensation in the oral mucosa after treatment. Both of these events were considered mild and probably related to treatment. There was no change in grade of mucositis after treatment for any subject.

Read the Subsys (fentanyl sublingual spray) Side Effects Center for a complete guide to possible side effects


Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); therefore potential interactions may occur when SUBSYS is given concurrently with agents that affect CYP3A4 activity.

The concomitant use of SUBSYS with strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone) 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 SUBSYS concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time. Dosage increase should be done conservatively.

The concomitant use of SUBSYS with CYP3A4 inducers (e.g., barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, or troglitazone) may result in a decrease in fentanyl plasma concentrations, which could decrease the efficacy of SUBSYS. Patients receiving SUBSYS who stop therapy with, or decrease the dose of, CYP3A4 inducers should be monitored for signs of increased SUBSYS activity and the dose of SUBSYS should be adjusted accordingly.

Concomitant use of SUBSYS with an MAO inhibitor, or within 14 days of discontinuation, is not recommended [see WARNINGS AND PRECAUTIONS].

Drug Abuse And Dependence

Controlled Substance

Fentanyl is a Schedule II controlled substance that can produce drug dependence of the morphine type. SUBSYS may be subject to misuse, abuse and addiction.

Abuse And Addiction

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. “Drug-seeking” behavior is very common in addicts and drug abusers.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for nonmedical purposes, often in combination with other psychoactive substances. Since SUBSYS may be diverted for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of patients, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Handle SUBSYS appropriately to minimize the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law.

Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.


Opioid analgesics may cause physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine).

Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage.

Tolerance, in which increasingly larger doses are required in order to produce the same degree of analgesia, is initially manifested by a shortened duration of analgesic effect, and subsequently, by decreases in the intensity of analgesia.

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

Last reviewed on RxList: 2/25/2016

Side Effects

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