Ionsys

Fentanyl can slow or stop your breathing. Use this device only as directed.

The fentanyl transdermal device is used only while you are in a hospital. A healthcare provider will place the device on your chest or upper arm where you can reach it. A healthcare provider should also remove or replace the device when needed. Do not leave the hospital with a device on your skin.

Fentanyl may be habit-forming, even at regular doses. Never share a transdermal device with another person, especially someone with a history of drug abuse or addiction. MISUSE OF NARCOTIC MEDICINE CAN CAUSE ADDICTION, OVERDOSE, OR DEATH, especially in a person using the medicine without a prescription. Selling or giving away fentanyl is against the law.

To release the medicine from the device, press the dosing button twice. A beep will sound when the dose starts, and a green light will blink for 10 minutes while the dose is delivered. The device can only be activated once every 10 minutes. Tell your doctor if this medicine seems to stop working as well in relieving your pain.

While you are wearing this device, only you should press the dosing button to control your pain. Do not allow others to press the dosing button for you, or you could receive a fatal overdose.

Never allow a family member or visitor to touch or handle the transdermal device. It should be handled only by a healthcare professional. Do not remove or reposition the device yourself. The sticky side of the device contains a high concentration of fentanyl, which could cause a fatal overdose if the medicine gets on your skin. Tell your care provider if the device comes loose or falls off.

The device is worn for 24 hours or until it has delivered 80 doses of fentanyl.

The fentanyl transdermal device may burn your skin if you wear the device during an MRI (magnetic resonance imaging). Certain other medical tests can cause damage to the transdermal device. Remove the device before undergoing an MRI, CT scan, x-ray, or similar test.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. A fentanyl overdose can be fatal. Overdose symptoms may include slow breathing and heart rate, severe drowsiness, muscle weakness, cold and clammy skin, pinpoint pupils, and fainting.

Since a fentanyl transdermal device is applied by a healthcare professional in a hospital setting, it is not likely that you will miss a dose.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of the Duragesic® patch in children 2 years and older. However, pediatric patients must be opioid-tolerant before using a fentanyl patch. Safety and efficacy have not been established in children younger than 2 years.

Appropriate studies have not been performed on the relationship of age to the effects of the Ionsys® patch in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of fentanyl skin patch in the elderly. However, elderly patients are more likely to have drowsiness and age-related lung, kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving fentanyl skin patch in order to avoid serious side effects.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amifampridine
• Mifepristone
• Nalmefene
• Naltrexone
• Safinamide

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acepromazine
• Alefacept
• Alfentanil
• Almotriptan
• Alprazolam
• Amineptine
• Amiodarone
• Amisulpride
• Amitriptyline
• Amitriptylinoxide
• Amobarbital
• Amoxapine
• Amphetamine
• Anileridine
• Aripiprazole
• Asenapine
• Baclofen
• Benperidol
• Benzphetamine
• Blinatumomab
• Boceprevir
• Bromazepam
• Bromopride
• Brompheniramine
• Buprenorphine
• Buspirone
• Butabarbital
• Butorphanol
• Carbamazepine
• Carbinoxamine
• Cariprazine
• Carisoprodol
• Carphenazine
• Ceritinib
• Chloral Hydrate
• Chlordiazepoxide
• Chlorpheniramine
• Chlorpromazine
• Chlorzoxazone
• Citalopram
• Clarithromycin
• Clobazam
• Clomipramine
• Clonazepam
• Clorazepate
• Clozapine
• Cobicistat
• Cocaine
• Codeine
• Conivaptan
• Cyclobenzaprine
• Desipramine
• Desmopressin
• Desvenlafaxine
• Dexmedetomidine
• Dextroamphetamine
• Dextromethorphan
• Dezocine
• Diazepam
• Dibenzepin
• Dichloralphenazone
• Difenoxin
• Dihydrocodeine
• Diphenhydramine
• Diphenoxylate
• Dolasetron
• Donepezil
• Doxepin
• Droperidol
• Duloxetine
• Eletriptan
• Eluxadoline
• Enflurane
• Enzalutamide
• Escitalopram
• Estazolam
• Eszopiclone
• Ethchlorvynol
• Ethopropazine
• Ethylmorphine
• Flibanserin
• Fluoxetine
• Fluphenazine
• Flurazepam
• Fluspirilene
• Fluvoxamine
• Fosphenytoin
• Fospropofol
• Frovatriptan
• Furazolidone
• Golimumab
• Granisetron
• Guselkumab
• Halazepam
• Haloperidol
• Halothane
• Hexobarbital
• Hydrocodone
• Hydromorphone
• Hydroxytryptophan
• Hydroxyzine
• Idelalisib
• Imipramine
• Indinavir
• Iproniazid
• Isocarboxazid
• Isoflurane
• Itraconazole
• Ketamine
• Ketobemidone
• Ketoconazole
• Levomilnacipran
• Levorphanol
• Linezolid
• Lisdexamfetamine
• Lithium
• Lofepramine
• Lopinavir
• Lorazepam
• Lorcaserin
• Loxapine
• Lumacaftor
• Meclizine
• Melitracen
• Melperone
• Meperidine
• Mephobarbital
• Meprobamate
• Meptazinol
• Mesoridazine
• Metaxalone
• Methadone
• Methamphetamine
• Methdilazine
• Methocarbamol
• Methohexital
• Methotrimeprazine
• Methylene Blue
• Midazolam
• Milnacipran
• Mirtazapine
• Mitotane
• Moclobemide
• Molindone
• Moricizine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Naratriptan
• Nefazodone
• Nelfinavir
• Netupitant
• Nialamide
• Nicardipine
• Nicomorphine
• Nifedipine
• Nitrazepam
• Nitrous Oxide
• Nortriptyline
• Olanzapine
• Ondansetron
• Opipramol
• Opium
• Opium Alkaloids
• Orphenadrine
• Oxazepam
• Oxycodone
• Oxymorphone
• Palonosetron
• Papaveretum
• Paregoric
• Paroxetine
• Pazopanib
• Pentazocine
• Pentobarbital
• Perampanel
• Perazine
• Periciazine
• Perphenazine
• Phenelzine
• Phenobarbital
• Phenytoin
• Pimozide
• Piperacetazine
• Pipotiazine
• Piritramide
• Pitolisant
• Posaconazole
• Prazepam
• Primidone
• Procarbazine
• Prochlorperazine
• Promazine
• Promethazine
• Propofol
• Protriptyline
• Quazepam
• Quetiapine
• Ramelteon
• Ranolazine
• Rasagiline
• Remifentanil
• Remoxipride
• Ribociclib
• Rifampin
• Ritonavir
• Rizatriptan
• Saquinavir
• Secobarbital
• Secukinumab
• Selegiline
• Sertindole
• Sertraline
• Sibutramine
• Sodium Oxybate
• St John's Wort
• Sufentanil
• Sulpiride
• Sumatriptan
• Suvorexant
• Tapentadol
• Telaprevir
• Telithromycin
• Temazepam
• Thiethylperazine
• Thiopental
• Thiopropazate
• Thioridazine
• Tianeptine
• Tilidine
• Tizanidine
• Tolonium Chloride
• Topiramate
• Tramadol
• Tranylcypromine
• Trazodone
• Triazolam
• Trifluoperazine
• Trifluperidol
• Triflupromazine
• Trimeprazine
• Trimipramine
• Tryptophan
• Venlafaxine
• Vilazodone
• Voriconazole
• Vortioxetine
• Zaleplon
• Ziprasidone
• Zolmitriptan
• Zolpidem
• Zopiclone
• Zotepine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse, or history of or
• Brain tumor, history of or
• Breathing problems (eg, asthma, apnea, low oxygen levels) or
• Chronic obstructive pulmonary disease (COPD) or
• Cor pulmonale (serious heart condition) or
• Gallbladder disease (eg, gallstones) or
• Depression, history of or
• Drug dependence, including narcotic or illicit drug abuse or dependence, history of or
• Head injury, history of or
• Mental health problems, history of or
• Weakened physical condition—Use with caution. May increase risk for more serious side effects.

• Bradyarrhythmia (slow heart rhythm) or
• Hypotension (low blood pressure) or
• Pancreatitis (inflammation of the pancreas), acute or
• Seizures, history of—Use with caution. May make these conditions worse.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Stomach or bowel blockage (eg, paralytic ileus), known or suspected—Should not be used in patients with this condition.

Use this medicine (Ionsys) as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Your doctor will put on the skin.
• Follow how to use as you have been told by the doctor or read the package insert.
• If you are not sure how to use this medicine, talk with your doctor.
• Do not take this medicine (Ionsys) off or move it from where it has been placed.
• Misuse or abuse of this medicine by placing it in the mouth or chewing, swallowing, injecting, or snorting it can lead to overdose and death.
• If you or anyone else touches the gel, wash the skin with lots of water. Do not use soap.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad dizziness or passing out.
• Feeling confused.
• Very upset stomach or throwing up.
• Very hard stools (constipation).
• Very bad belly pain.
• Feeling very tired or weak.
• Trouble breathing, slow breathing, or shallow breathing.
• Noisy breathing.
• Shortness of breath.
• Chest pain.
• Fast or slow heartbeat.
• Feeling very sleepy.
• Seizures.
• Very bad irritation where this medicine (Ionsys) is used.
• A very bad and sometimes deadly health problem called serotonin syndrome may happen if you take this medicine with drugs for depression, migraines, or certain other drugs. Call your doctor right away if you have agitation; change in balance; confusion; hallucinations; fever; fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.
• Taking an opioid drug like this medicine (Ionsys) may lead to a rare but very bad adrenal gland problem. Call your doctor right away if you have very bad dizziness or passing out, very bad upset stomach or throwing up, or if you feel less hungry, very tired, or very weak.
• Long-term use of an opioid drug like this medicine may lead to lower sex hormone levels. This may lead to signs like change in sex ability in men, no menstrual period in women, lowered interest in sex, or fertility problems. Call your doctor if you have any of these signs.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness.
• Dry mouth.
• Upset stomach or throwing up.
• Hard stools (constipation).
• Loose stools (diarrhea).
• Headache.
• Feeling sleepy.
• Feeling tired or weak.
• Feeling cold.
• Not hungry.
• Not able to sleep.
• Sweating a lot.
• Belly pain.
• Irritation where this medicine (Ionsys) is used.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Ionsys is indicated for the short-term management of acute postoperative pain severe enough to require an opioid analgesic in the hospital and for which alternative treatments are inadequate.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions ( 5.3)] , reserve Ionsys for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]:

• Have not been tolerated, or are not expected to be tolerated,
• Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

Ionsys is:

• Only for use in patients who are alert enough and have adequate cognitive ability to understand the directions for use.
• Not for home use. Ionsys is for use only in patients in the hospital. Discontinue treatment with Ionsys before patients leave the hospital.
• For use after patients have been titrated to an acceptable level of analgesia using alternate opioid analgesics.

Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.20)]. Available data with Ionsys in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

There are no studies with the use of Ionsys in pregnant women. Limited published data on fentanyl use during pregnancy are insufficient to establish any drug-associated risks. In animal reproduction and developmental studies, at doses within the dosing range of humans, there was an increased risk for early embryonic lethality, decreased pup survival, and delays in developmental landmarks of surviving pups [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.20)] .

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Ionsys is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Ionsys, can prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor and respiratory depression. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data

The potential effects of fentanyl on embryo-fetal development were studied in rat and rabbit models.

Published literature reports that administration of fentanyl (0, 0.01, 0.1, or 0.5 mg/kg/day) to pregnant female Sprague-Dawley rats from Gestation Day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of teratogenicity. The high dose is approximately 1.5 times the daily maximum recommended human dose (MRHD) of 3.2 mg/day based on a mg/m 2 body surface area basis and a 60 kg human body weight.

In contrast, the intravenous administration of fentanyl at doses of 0, 0.01, or 0.03 mg/kg (equivalent to 0.03 and 0.09 times, respectively, the MHRD) to pregnant female rats from Gestation Day 6 to 18 resulted in evidence of embryo toxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted.

Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from Gestation Day 6 to 18. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity (decreased body weight and sedation). Under the conditions of the assay, there was no evidence for fentanyl-induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (2.4 times the MRHD).

The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Pregnant female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion (equivalent to 0.08, 0.3, and 1.2 times, respectively, the MRHD) from Gestation Day 6 through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at Post-Natal Day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at Post-Natal Day 28 which recovered by Post-Natal Day 50). No adverse effects were observed at 0.08 times the MRHD.

Lactation

Risk Summary

Limited published literature reports that fentanyl is present in human milk at low levels, which resulted in an estimated infant dose of 0.38% of the maternal weight-adjusted dosage. There are no reports of adverse effects on the breastfed infant and no information on the effects on milk production.

The developmental and health benefits from breastfeeding should be considered along with the mother’s clinical need for Ionsys and any potential effects on the breastfed infant from Ionsys or from the underlying maternal condition.

Clinical Considerations

Infants exposed to Ionsys through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast‑feeding is stopped.

Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2), Clinical Pharmacology ( 12.2), Nonclinical Toxicology ( 13.1)].

Pediatric Use

The efficacy and safety of Ionsys have not been established in pediatric patients under 18 years of age.

Geriatric Use

Ionsys 40 mcg has been studied in 499 patients 65 years or older; 174 of whom were 75 years or older. No major differences in safety or effectiveness were observed between these subjects and younger subjects. However, the incidence of the following events was slightly higher (≥1%) in patients ≥65 years compared with patients who were 18 to 64 years of age: hypotension (4% versus 3%), confusion (2% versus <1%), hypokalemia (3% versus 1%), hypoxia (3% versus 2%), and hypoventilation (2% versus <1%).

In a pharmacokinetic study of Ionsys conducted in 63 healthy volunteers (25 subjects older than 65 years), age did not significantly affect the extent of drug absorption. Literature suggests that the clearance of fentanyl may be reduced and the terminal half-life prolonged in the elderly.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.1)] .

Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hepatic Impairment

Insufficient data are available on the use of Ionsys in patients with impaired hepatic function. Since fentanyl is eliminated by hepatic metabolism and fentanyl clearance may decrease in patients with hepatic disease, monitor patients with hepatic impairment closely for signs of central nervous system and respiratory depression, especially when initiating treatment with Ionsys.

Renal Impairment

Approximately 10% of administered fentanyl is excreted unchanged by the kidney. Insufficient data are available on the use of Ionsys in patients with impaired renal function to determine effects on renal clearance of fentanyl. Monitor patients with renal impairment closely for signs of central nervous system and respiratory depression, especially when initiating treatment with Ionsys.

Controlled Substance

Ionsys contains fentanyl, a Schedule II controlled substance.

Abuse

Ionsys contains fentanyl, a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Ionsys can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.3)].

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 healthcare 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. Healthcare 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.

Ionsys, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity and 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 Abuse of Ionsys

Ionsys is for transdermal use only for patients in the hospital. Abuse of Ionsys poses a risk of overdose and death. This risk is increased with concurrent abuse of Ionsys and alcohol and other central nervous system depressants [see Warnings and Precautions ( 5.1, 5.5) and Drug Interactions ( 7)] . Contact with residual fentanyl in hydrogel of the device can result in fatal overdose.

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 may also 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.

Ionsys should not be abruptly discontinued in a physically dependent patient [see Dosage and Administration ( 2.5)]. If Ionsys is abruptly discontinued in a physically‑dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations ( 8.1)] .

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 0.033 mg/kg/day in males or 0.1 mg/kg/day in females. These lifetime doses in rats are approximately 0.1 and 0.3, respectively, the maximum recommended human dose (MRHD) of 3.2 mg/day by transdermal administration based on a mg/m 2 body surface area comparison and a 60 kg human body weight.

Mutagenesis

Fentanyl is not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay), the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the in vitro chromosomal aberration assays using either human lymphocytes or Chinese hamster ovary cells.

Impairment of Fertility

The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl doses of 0, 0.025, 0.1, or 0.4 mg/kg/day (equivalent to 0.08, 0.3, 1.2 times, respectively, the MHRD) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl doses of 0, 0.025, 0.1, or 0.4 mg/kg/day (equivalent to 0.08, 0.3, 1.2 times, respectively, the MHRD) via continuous intravenous infusion for 14 days prior to mating until Day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.2 times the maximum available daily human dose on a mg/m 2 basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the MRHD for a period of 12 days.

Ionsys (fentanyl iontophoretic transdermal system) is packaged in a sealed tray containing one Controller and one pouched Drug Unit for assembly. For distribution, there are six sealed trays per carton.

NDC 65293-011-01 (each individual tray contains one Drug Unit and one Controller)

NDC 65293-011-06 (carton of six trays containing Ionsys)

ACCIDENTAL CONTACT WITH THE HYDROGELS (ON THE ADHESIVE SIDE OF Ionsys) CAN RESULT IN FATAL OVERDOSE OF FENTANYL. THEREFORE, THE Ionsys MUST ONLY BE HANDLED WHILE WEARING GLOVES.

If there is accidental contact with skin, the affected area should be rinsed thoroughly with water. Do not use soap, alcohol, or other solvents to remove the hydrogel because they may enhance the drug’s ability to penetrate the skin [see Warnings and Precautions ( 5.1)] .

Ionsys should be stored at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). Assemble and use immediately after removal from the individually sealed package. Do not use if the seal on the Tray or Drug Unit pouch is broken or damaged.