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Clinical Studies Experience
The safety of ONSOLIS has been evaluated in 306 opioid tolerant patients with breakthrough cancer pain in the efficacy study and an open-label safety study. The mean duration of therapy was 115 days, with 32 patients treated for more than 1 year.
The adverse reactions seen with ONSOLIS are typical opioid side effects in a population with cancer. Frequently, opioid-associated adverse reactions will cease or decrease in intensity with continued use of ONSOLIS. Expect opioid side effects and manage them accordingly.
The most serious adverse reactions associated with all opioids including ONSOLIS are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms of respiratory depression.
Because the clinical trials of ONSOLIS were designed to evaluate safety and efficacy in treating patients with breakthrough pain associated with cancer, all patients were also taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse event among patients who received ONSOLIS 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 ONSOLIS therapy, or cancer-related symptoms. Adverse reactions are included regardless of severity.
Because clinical trials are conducted under widely varying conditions, adverse event 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.
Table 1 lists, by maximum dose received, adverse reactions with an overall frequency of 5% or greater that occurred during titration. The ability to assign a dose-response relationship to these adverse reactions is limited by the titration schedules used in these studies. Adverse reactions are listed in descending order of frequency within each body system.
Table 1 : Adverse Reactions Which Occurred During
Titration at a Frequency of ≥ 5%
|System Organ Class, Preferred Term, n (%)||ONSOLIS Dose (mcg)||Total
| > 1200
|Nausea||16 (5)||12 (5)||6 (3)||5 (4)||4 (5)||0||42 (14)|
|Vomiting||7(2)||9 (4)||8 (4)||2 (1)||0||0||26 (8)|
|Nervous System Disorders|
|Dizziness||5 (2)||5 (2)||6 (3)||2 (1)||4 (5)||0||22 (7)|
|Somnolence||6 (2)||2 (1)||4 (2)||2 (1)||4 (5)||1 (11)||17 (6)|
Table 2 lists, by successful dose, adverse reactions with an overall frequency of ≥ 5% that occurred during long-term treatment (i.e., the double-blind or open-label maintenance periods).
Table 2 : Adverse Reactions Which Occurred During
Long-Term Treatment at a Frequency of ≥ 5%
|System Organ Class, Preferred Term, n (%)||ONSOLIS Dose (mcg)||Total
| > 1200
|Nausea||2 (9)||6 (10)||8 (10)||12(13)||26 (32)||4 (14)||56 (26)|
|Vomiting||1 (4)||5 (8)||9 (11)||8 (9)||23 (28)||3 (11)||45 (21)|
|Constipation||2 (9)||4 (7)||4 (5)||4 (4)||6 (7)||4 (14)||23(11)|
|Diarrhea||1 (4)||1 (2)||4 (5)||4 (4)||10 (12)||0||19 (9)|
|Dry mouth||1 (4)||4 (7)||3 (4)||2 (2)||3 (4)||1 (4)||14 (7)|
|Abdominal pain||0||0||3 (4)||1 (1)||7 (9)||1 (4)||11 (5)|
|Asthenia||0||6 (10)||3 (4)||8 (9)||7 (9)||4 (14)||28(13)|
|Fatigue||2 (9)||6 (10)||1 (1)||7 (8)||7 (9)||3 (11)||25(12)|
|Weight decreased||3 (13)||0||2 (3)||5 (5)||5 (6)||1 (4)||15 (7)|
|Dehydration||1 (4)||4 (7)||6 (8)||5 (5)||10 (12)||3 (11)||28(13)|
|Decreased appetite||0||4 (7)||4 (5)||6 (7)||2 (2)||2 (7)||18 (8)|
|Anorexia||2 (9)||1 (2)||3 (4)||4 (4)||6 (7)||1 (4)||17 (8)|
|Dizziness||2 (9)||4 (7)||2 (3)||3 (3)||10 (12)||2 (7)||23(11)|
|Headache||2 (9)||1 (2)||3 (4)||9 (10)||7 (9)||0||20 (9)|
|Somnolence||2 (9)||0||4 (5)||2 (2)||3 (4)||3 (11)||14 (7)|
|Confusional state||1 (4)||0||4 (5)||4 (4)||6 (7)||4 (14)||18 (8)|
|Depression||0||3 (5)||1 (1)||4 (4)||7 (9)||3 (11)||18 (8)|
|Insomnia||0||2 (3)||2 (3)||3 (3)||4 (5)||2 (7)||12 (6)|
|Anxiety||1 (4)||1 (2)||2 (3)||3 (3)||3 (4)||1 (4)||11 (5)|
|Dyspnea||3 (13)||4 (7)||3 (4)||8 (9)||6 (7)||3 (11)||26 (12)|
|Cough||1 (4)||0||3 (4)||5 (5)||6 (7)||1 (4)||15 (7)|
|Hypotension||0||3 (5)||3 (4)||1 (1)||3 (4)||1 (4)||11 (5)|
In a mucositis study, a group of patients (n=7) with Grade 1 oral mucositis and a matched group of control patients (n=7) without oral mucositis were included in a clinical trial designed to support the safety of ONSOLIS. The adverse event profile was similar in both subsets of patients. There was no evidence that ONSOLIS caused or worsened oral mucosal irritation or pain in either study group.
The duration of exposure to ONSOLIS varied greatly, and included open-label and double-blind studies. The adverse reactions listed below represent those that were reported by ≥ 1% of patients from two clinical trials (the titration and post-titration periods) while receiving ONSOLIS. Events are classified by system organ class.
Cardiac disorders: tachycardia
Eye disorders: vision blurred, diplopia
Injury, poisoning and procedural complications: fall, contusion Investigations: weight decreased, blood pressure increased
Metabolism and nutrition disorders: dehydration, decreased appetite, anorexia
Psychiatric disorders: confusional state, depression, insomnia, anxiety, hallucination, agitation, mental status changes
Renal and urinary disorders: urinary retention
Respiratory, thoracic and mediastinal disorders: dyspnea, cough
Skin and subcutaneous tissue disorders: pruritus, rash
Read the Onsolis (fentanyl buccal soluble film) Side Effects Center for a complete guide to possible side effects
Fentanyl is metabolized mainly via the human CYP3A4 isoenzyme system; therefore potential interactions may occur when ONSOLIS is given concurrently with agents that affect CYP3A4 activity.
The concomitant use of ONSOLIS with CYP3A4 inhibitors (e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil, or cimetidine) may result in a potentially dangerous increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving ONSOLIS who begin therapy with, or increase the dose of, CYP3A4 inhibitors should be carefully monitored for signs of opioid toxicity over an extended period of time. Dosage increase should be done conservatively [see WARNINGS AND PRECAUTIONS].
The concomitant use of ONSOLIS 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 ONSOLIS. Patients receiving ONSOLIS who stop therapy with, or decrease the dose of, CYP3A4 inducers should be monitored for signs of increased ONSOLIS activity and the dose of ONSOLIS should be adjusted accordingly.
Drug Abuse And Dependence
Fentanyl is a Schedule II controlled substance that can produce drug dependence of the morphine type. ONSOLIS may be subject to misuse, abuse and addiction.
Abuse And Addiction
Manage the handling of ONSOLIS to minimize the risk of abuse, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law [see HOW SUPPLIED and Storage and Handling].
Concerns about abuse and addiction 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 ONSOLIS may be abused 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.
Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse of this product.
Guide the administration of ONSOLIS by the response of the patient.
Physical dependence is not ordinarily a concern when one is treating a patient with chronic cancer pain, and fear of tolerance and physical dependence should not deter using doses that adequately relieve the pain.
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.
Last reviewed on RxList: 1/26/2015
This monograph has been modified to include the generic and brand name in many instances.
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