Subsys (fentanyl) Pain Medication: Side Effects, Dosage, & Warnings

What is Subsys, and how does it work?

Subsys is:

A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage breakthrough pain in adults (18 years of age and older) with cancer who are already routinely taking other opioid pain medicines around-the-clock for cancer pain. Subsys is started only after you have been taking other opioid pain medicines and your body has become used to them ( you are opioid tolerant). Do not use Subsys if you are not opioid tolerant.
An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

Patients considered opioid tolerant are those who are taking for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, or at least 25 mg oral oxymorphone per day, or at least 60mg oral hydrocodone per day, or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids when taking Subsys.

Limitations Of Use

Not for use in opioid non-tolerant patients.
Not for use in the management of acute or postoperative pain, including headache/migraine, dental pain, or in the emergency room.
As part of the Transmucosal Immediate-Release Fentanyl (TIRF) REMS ACCESS Program, Subsys may be dispensed only to outpatients enrolled in the program. For inpatient administration (e.g. hospitals, hospices, and long-term care facilities that prescribe for inpatient use) of Subsys, patient enrollment is not required.

What are the side effects of Subsys?

The possible side effects of Subsys include:

Constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, weakness, anxiety, depression, rash, trouble sleeping, low red blood cell count, swelling of the arms, hands, legs, and feet. Call your healthcare provider if you have any of these symptoms and they are severe.
Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down.

Get emergency medical help if you have:

trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

These are not all the possible side effects of Subsys. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov.

WARNING

LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; CYTOCHROME P450 3A4 INTERACTION; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS and NEONATAL OPIOID WITHDRAWAL SYNDROME

Life-Threatening Respiratory Depression

Serious, life-threatening, and/or fatal respiratory depression has occurred in patients treated with Subsys, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of Subsys or following a dose increase. The substitution of Subsys for any other fentanyl product may result in fatal overdose.

Due to the risk of respiratory depression, Subsys is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients.

Accidental Ingestion

Accidental ingestion of even one dose of Subsys especially by children, can result in a fatal overdose of fentanyl.

Death has been reported in children who have accidentally ingested transmucosal immediaterelease fentanyl products. Subsys must be kept out of reach of children.

Cytochrome P450 3A4 Interaction

The concomitant use of Subsys with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving Subsys and any CYP3A4 inhibitor or inducer.

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing of Subsys and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
Limit dosages and durations to the minimum required.
Follow patients for signs and symptoms of respiratory depression and sedation.

Risk of Medication Errors

Substantial differences exist in the pharmacokinetic profile of Subsys compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal overdose.

When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to Subsys.
When dispensing, do not substitute a Subsys prescription for other fentanyl products.

Does Subsys cause addiction and withdrawal symptoms?

Addiction, Abuse, and Misuse

Subsys exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death.
Assess each patient's risk prior to prescribing Subsys, and monitor all patients regularly for the development of these behaviors and conditions.

Risk Evaluation and Mitigation Strategy (REMS) Access Program

Because of the risk for misuse, abuse, addiction, and overdose, Subsys is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS).
Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program.
Further information is available at www.TIRFREMSaccess.com or by calling 1-866-822-1483.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Subsys during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Drug Abuse And Dependence

Controlled Substance

Subsys contains fentanyl a Schedule II controlled substance.

Abuse

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.
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.

Dependence

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.

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What is the dosage for Subsys?

Important Dosage And Administration Instructions

Healthcare professionals who prescribe Subsys on an outpatient basis must enroll in the TIRF REMS ACCESS program and comply with the requirements of the REMS to ensure safe use of Subsys.
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose.
Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse.
Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with Subsys and adjust the dosage accordingly.
Instruct patients and caregivers to take steps to store Subsys securely and to properly dispose of unused Subsys as soon as no longer needed.
Other TIRF formulations and Subsys are not equivalent. DO NOT substitute a Subsys prescription for any other TIRF formulation under any circumstances. Do not convert patients on a mcg per mcg basis from any other fentanyl product to Subsys.
Subsys is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products, other than Actiq. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.)
Subsys is NOT a generic version of any other oral transmucosal fentanyl product.

Initial Dosage

Initiate treatment with Subsys for all patients (including those switching from another fentanyl product) using ONE 100 mcg spray sublingually.
Prescribe an initial titration supply of 100 mcg Subsys units, which limits the number of units in the home during titration.
Avoid prescribing a higher dose until patients have used up all units to prevent confusion and possible overdose.

Conversion From Actiq To Subsys

The initial dose of Subsys is always 100 mcg with the only exception of patients already using Actiq.

Table 1. Initial Dosing Recommendations for Patients on ACTIQ

Current ACTIQ Dose
(mcg)Initial Subsys Dose
(mcg)200100 mcg spray400100 mcg spray600200 mcg spray800200 mcg spray1200400 mcg spray1600400 mcg spray

For patients being converted from Actiq, prescribers must use the Initial Dosing Recommendations for Patients on Actiq table below ( Table 1). Patients must be instructed to stop the use of Actiq and dispose of any remaining units.
For patients converting from Actiq doses 400 mcg and below, titration should be initiated with 100 mcg Subsys and should proceed using multiples of this strength.
For patients converting from Actiq doses of 600 and 800 mcg, titration should be initiated with 200 mcg Subsys and should proceed using multiples of this strength.
For patients converting from Actiq doses of 1200 and 1600 mcg, titration should be initiated with 400 mcg Subsys and should proceed using multiples of this strength.

Dosage Modifications In Patients With Oral Mucositis

In cancer patients with mucositis, exposure to Subsys was greater than in patients without mucositis.
For patients with Grade 1 mucositis, the increased maximum serum concentration and overall exposure requires closer monitoring for respiratory depression and central nervous system depression, particularly during initiation of therapy with Subsys.
For patients with Grade 2 mucositis or higher, avoid use of Subsys unless the benefits outweigh the potential risk of respiratory depression from increased exposure.

Titration And Maintenance Of Therapy

Individually titrate Subsys to a dose that provides adequate analgesia and minimizes adverse reactions.

From the 100 mcg initial dose, closely follow patients and change the dosage level until the patient reaches a dose that provides adequate analgesia using a single Subsys dose per breakthrough cancer pain episode with tolerable side effects. Patients should record their use of Subsys over several episodes of breakthrough cancer pain and review their experience with their physicians to determine if a dosage adjustment is warranted.
For each breakthrough pain episode treated, if pain is not relieved after 30 minutes, patients may take ONLY ONE additional dose of the same strength for that episode. Thus patients should take a maximum of two doses of Subsys for any breakthrough pain episode.
Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with Subsys.
If there is a need to titrate to a 200 mcg dose, prescribe 200 mcg Subsys units.
Subsequent titration steps are 400 mcg, 600 mcg, 800 mcg, 1200 mcg and 1600 mcg. See Table 2.
To reduce the risk of overdose during titration, patients should have only one strength of Subsys available at any time.

Table 2. Titration Steps

Subsys DOSEUsing100 mcg1 × 100 mcg unit200 mcg1 × 200 mcg unit400 mcg1 × 400 mcg unit600 mcg1 × 600 mcg unit800 mcg1 × 800 mcg unit1200 mcg2 × 600 mcg unit1600 mcg2 × 800 mcg unit

Subsys Titration Process

Noxafil (posaconazole) dosage relative to a teaspoon

Once titrated to a dose that provides adequate pain relief and tolerable side effects, patients should generally use ONLY ONE Subsys dose of the appropriate strength per breakthrough pain episode.
On those occasions when the breakthrough pain episode is not relieved within 30 minutes after administration of the Subsys dose, the patient may take ONLY ONE additional dose using the same strength for that episode.
Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with Subsys. Once a successful dose has been found, patients should limit consumption to four or fewer doses per day.
Dosage adjustment of Subsys may be required in some patients in order to continue to provide adequate relief of breakthrough pain.
If signs of excessive opioid effects appear following administration of a single Subsys dose, subsequent doses should be decreased.
Generally, only increase the Subsys dose when a single administration of the current dose fails to adequately treat the breakthrough pain episode for several consecutive episodes.
If the patient experiences greater than four breakthrough pain episodes per day, the dose of the maintenance (around-the-clock) opioid used for persistent pain should be re-evaluated. In addition, if pain worsens, re-evaluate the patient for changes in the underlying pain condition.

Discontinuation Of Subsys

For patients no longer requiring opioid therapy, consider discontinuing Subsys along with a gradual downward titration of other opioids to minimize possible withdrawal effects. In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, Subsys therapy can usually be discontinued immediately.

Disposal Of Subsys

Patients and caregivers must be advised to dispose of used unit dose systems immediately after use and any unneeded unit dose systems remaining from a prescription as soon as they are no longer needed.
Consumed units represent a special risk because they are no longer protected by the child resistant blister package, yet may contain enough medicine to be fatal to a child.
Charcoal-lined disposal pouches are provided with every carton dispensed.
A charcoal-lined disposal pouch is to be used by patients or their caregivers to dispose of the contents of any unneeded unit dose systems when they are no longer needed.
Instructions for usage of the charcoal-lined disposal pouch are included in the prescribing information.

What drugs interact with Subsys?

Table 6 includes clinically significant drug interactions with Subsys.

Table 6: Clinically Significant Drug Interactions with Subsys

Inhibitors of CYP3A4Clinical 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. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease, 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.ExamplesMacrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)CYP3A4 InducersClinical Impact:The concomitant use of Subsys and CYP3A4 inducers can decrease the plasma concentration of fentanyl, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase, 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.ExamplesRifampin, carbamazepine, phenytoinBenzodiazepines and other Central Nervous System (CNS) DepressantsClinical 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.Examples:Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.Serotonergic DrugsClinical Impact:The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.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 or opioid toxicity (e.g., respiratory depression, coma).Intervention:The use of Subsys is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.Examples:phenelzine, tranylcypromine, linezolidMixed Agonist/Antagonist and Partial Agonist Opioid AnalgesicsClinical Impact:May reduce the analgesic effect of Subsys and/or precipitate withdrawal symptoms.Intervention:Avoid concomitant use.Examples:butorphanol, nalbuphine, pentazocine, buprenorphine,Muscle RelaxantsClinical 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.DiureticsClinical 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.Anticholinergic DrugsClinical 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.

Is Subsys safe to use while pregnant or breastfeeding?

Prolonged use of Subsys during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.
Subsys can (or may) cause fetal harm. Inform your healthcare provider of a known or suspected pregnancy