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The following serious adverse reactions are described, or described in greater detail, in other sections:
- Life-Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS]
- Interactions with Benzodiazepines and other CNS Depressants [see WARNINGS AND PRECAUTIONS]
- Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
- Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
- Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]
- Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS]
- Severe Hypotension [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal Adverse Reactions [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
Clinical Trials 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 longterm 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 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 4 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 4: Percent of Patients with Specific Adverse
Events During Titration in the Clinical Trials (Events in 5% or More of
|System Organ Class||Titration
|Nervous System Disorders|
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
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
Injury, Poisoning and Procedural Complications: Fall
Metabolism and Nutrition Disorders: Dehydration, anorexia
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 5 lists adverse reactions with an overall frequency of 5% or greater for the total safety database subsequent to titration during the clinical trials.
Table 5: Adverse Reactions Subsequent to Titration in
5% or More of Patients
|System Organ Class||Dosing
|General Disorders and Administration Site Conditions|
|Respiratory, Thoracic and Mediastinal Disorders|
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.
Cardiac Disorders: Tachycardia, sinus tachycardia
General Disorders and Administration Site Conditions: Edema peripheral, fatigue, pyrexia, chest pain, drug withdrawal syndrome, chills, irritability, malaise, application site irritation
Injury, Poisoning and Procedural Complications: Contusion
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
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.
The following adverse reactions have been identified during post approval use of fentanyl. 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.
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis: Anaphylaxis has been reported with ingredients contained in SUBSYS.
Read the Subsys (fentanyl sublingual spray) Side Effects Center for a complete guide to possible side effects
Table 6 includes clinically significant drug interactions with SUBSYS.
Table 6: Clinically Significant Drug Interactions with
|Inhibitors of CYP3A4|
|Clinical Impact:||The concomitant use of SUBSYS 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 SUBSYS is achieved [see WARNINGS AND PRECAUTIONS]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see CLINICAL PHARMACOLOGY], 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 SUBSYS until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the SUBSYS dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.|
|Examples||Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)|
|Clinical Impact:||The concomitant use of SUBSYS and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see CLINICAL PHARMACOLOGY], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see WARNINGS AND PRECAUTIONS]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see CLINICAL PHARMACOLOGY], 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 SUBSYS dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider SUBSYS dosage reduction and monitor for signs of respiratory depression.|
|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. Follow patients closely for signs of respiratory depression and sedation [see WARNINGS AND PRECAUTIONS].|
|Examples:||Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.|
|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].|
|Intervention:||If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue SUBSYS 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 effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).|
|Monoamine Oxidase Inhibitors (MAOIs)|
|Clinical Impact:||MAOI interactions with opioids may manifest as serotonin syndrome [see WARNINGS AND PRECAUTIONS] or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS AND PRECAUTIONS].|
|Intervention:||The use of SUBSYS is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.|
|Examples:||phenelzine, tranylcypromine, linezolid|
|Mixed Agonist/Anta||gonist and Partial Agonist Opioid Analgesics|
|Clinical Impact:||May reduce the analgesic effect of SUBSYS and/or precipitate withdrawal symptoms.|
|Intervention:||Avoid concomitant use.|
|Examples:||butorphanol, nalbuphine, pentazocine, buprenorphine,|
|Clinical Impact:||Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.|
|Intervention:||Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of SUBSYS and/or the muscle relaxant as necessary.|
|Clinical Impact:||Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.|
|Intervention:||Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.|
|Clinical Impact:||The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.|
|Intervention:||Monitor patients for signs of urinary retention or reduced gastric motility when SUBSYS is used concomitantly with anticholinergic drugs.|
Drug Abuse And Dependence
SUBSYS contains fentanyl a Schedule II controlled substance.
SUBSYS contains fentanyl, a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. SUBSYS can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS AND PRECAUTIONS].
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.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“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 health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers 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 true addiction.
SUBSYS, like other opioids, can be diverted for non-medical 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 re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Risks Specific To The Abuse Of SUBSYS
SUBSYS is for sublingual transmucosal use only. Abuse of SUBSYS poses a risk of overdose and death. The risk is increased with concurrent abuse of SUBSYS with alcohol and other central nervous system depressants.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/6/2017
Additional Subsys Information
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