IONSYS

Clinical safety rating: caution

Comprehensive clinical and safety monograph for IONSYS (IONSYS).

How it works

IONSYS is an iontophoretic delivery system for fentanyl, a mu-opioid receptor agonist. Fentanyl binds to mu-opioid receptors in the CNS, inhibiting ascending pain pathways and altering pain perception and emotional response.

What the body does with it

Metabolism	Fentanyl is primarily metabolized in the liver via CYP3A4 isoenzyme to norfentanyl (inactive) and other metabolites.
Excretion	Renal: approximately 90% as fentanyl metabolites (mainly norfentanyl) and less than 10% as unchanged drug; fecal: less than 10%.
Half-life	Terminal elimination half-life: 16.3 ± 9.1 hours for fentanyl released from IONSYS; accounts for prolonged release from depot and is longer than intravenous fentanyl (3-12 hours).
Protein binding	Approximately 80-85% bound to plasma proteins, mainly alpha-1-acid glycoprotein and albumin.
Volume of Distribution	Volume of distribution at steady state: 4.0 ± 1.2 L/kg; large Vd indicates extensive tissue distribution (including fat and muscle).
Bioavailability	Bioavailability of fentanyl from IONSYS via iontophoresis: approximately 100% relative to intravenous fentanyl (systemic absorption is complete).
Onset of Action	Onset of analgesia: approximately 10-15 minutes after actuation of the iontophoretic system; peak effect at 30-60 minutes.
Duration of Action	Duration of analgesia per dose: approximately 1 hour; system delivers 40 mcg fentanyl per actuation over 10 minutes, with clinical effect lasting 1-2 hours; redosing at 10-minute intervals as needed.

Classification & Brands

Dosing & administration

Apply one 40 mcg fentanyl iontophoretic transdermal system to skin on upper arm or chest; delivers 40 mcg per dose on-demand for up to 24 hours or 80 doses, whichever is shorter. Maximum 2 doses per hour, 6 doses per application. Patient must be opioid-tolerant.

Dosage form	SYSTEM
Renal impairment	No specific dose adjustment; however, fentanyl pharmacokinetics may be altered in severe renal impairment (CrCl <30 mL/min). Use with caution and monitor for adverse effects.
Liver impairment	No specific dose adjustment; consider slower elimination in Child-Pugh C; start with lowest effective dose and monitor closely for respiratory depression.
Pediatric use	Not approved for use in patients under 18 years of age.
Geriatric use	Initiate at lowest effective dose; elderly patients may have reduced clearance and increased sensitivity to fentanyl. Monitor for respiratory depression and avoid use in opioid-naive patients.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for IONSYS (IONSYS).

Breastfeeding	Excreted in breast milk; M/P ratio not reported. Use caution; monitor infant for respiratory depression, sedation, and withdrawal. Limited data; consider benefits vs risks.
Teratogenic Risk	Pregnancy Category C. First trimester: No adequate studies; animal studies show no teratogenicity but embryotoxicity at high doses. Second and third trimesters: Prolonged use may cause neonatal opioid withdrawal syndrome; avoid regular use due to risk of respiratory depression in neonate.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

IONSYS is indicated for use only in adult patients who are already receiving opioid therapy and have demonstrated opioid tolerance. Because of the risk of respiratory depression, IONSYS should be used only in patients who are in a monitored hospital setting and who have continuous monitoring of respiratory status. Accidental exposure to the gel adhesive containing fentanyl may result in fatal respiratory depression. IONSYS should not be used in opioid-naive patients.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Opioid-naive patients","Significant respiratory depression","Acute or severe bronchial asthma","Known or suspected paralytic ileus","Hypersensitivity to fentanyl or any component of the system","Use of monoamine oxidase inhibitors (MAOIs) within 14 days"]

Clinical Precautions

Precautions

["Respiratory depression (especially in opioid-naive patients)","Accidental exposure (can cause fatal respiratory depression)","Application site reactions (e.g., erythema, itching)","Risk of opioid addiction, abuse, and misuse","Risk of serotonin syndrome with concurrent serotonergic drugs","Risk of adrenal insufficiency with prolonged use","Risk of severe hypotension in patients with compromised blood pressure"]

Clinical Tips & Counseling

Drug interactions

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IONSYS

Clinical safety rating: caution

Comprehensive clinical and safety monograph for IONSYS (IONSYS).

How it works

What the body does with it

Metabolism	Fentanyl is primarily metabolized in the liver via CYP3A4 isoenzyme to norfentanyl (inactive) and other metabolites.
Excretion	Renal: approximately 90% as fentanyl metabolites (mainly norfentanyl) and less than 10% as unchanged drug; fecal: less than 10%.
Half-life	Terminal elimination half-life: 16.3 ± 9.1 hours for fentanyl released from IONSYS; accounts for prolonged release from depot and is longer than intravenous fentanyl (3-12 hours).
Protein binding	Approximately 80-85% bound to plasma proteins, mainly alpha-1-acid glycoprotein and albumin.
Volume of Distribution	Volume of distribution at steady state: 4.0 ± 1.2 L/kg; large Vd indicates extensive tissue distribution (including fat and muscle).
Bioavailability	Bioavailability of fentanyl from IONSYS via iontophoresis: approximately 100% relative to intravenous fentanyl (systemic absorption is complete).
Onset of Action	Onset of analgesia: approximately 10-15 minutes after actuation of the iontophoretic system; peak effect at 30-60 minutes.
Duration of Action	Duration of analgesia per dose: approximately 1 hour; system delivers 40 mcg fentanyl per actuation over 10 minutes, with clinical effect lasting 1-2 hours; redosing at 10-minute intervals as needed.

Classification & Brands

Dosing & administration

Dosage form	SYSTEM
Renal impairment	No specific dose adjustment; however, fentanyl pharmacokinetics may be altered in severe renal impairment (CrCl <30 mL/min). Use with caution and monitor for adverse effects.
Liver impairment	No specific dose adjustment; consider slower elimination in Child-Pugh C; start with lowest effective dose and monitor closely for respiratory depression.
Pediatric use	Not approved for use in patients under 18 years of age.
Geriatric use	Initiate at lowest effective dose; elderly patients may have reduced clearance and increased sensitivity to fentanyl. Monitor for respiratory depression and avoid use in opioid-naive patients.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for IONSYS (IONSYS).

Breastfeeding	Excreted in breast milk; M/P ratio not reported. Use caution; monitor infant for respiratory depression, sedation, and withdrawal. Limited data; consider benefits vs risks.
Teratogenic Risk	Pregnancy Category C. First trimester: No adequate studies; animal studies show no teratogenicity but embryotoxicity at high doses. Second and third trimesters: Prolonged use may cause neonatal opioid withdrawal syndrome; avoid regular use due to risk of respiratory depression in neonate.
Fetal Monitoring