Leptofen

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Leptofen uses

Leptofen consists of Droperidol, Fentanyl.

Droperidol:


INDICATIONS AND USAGE

Leptofen (Droperidol) injection is indicated to reduce the incidenceof nausea and vomiting associated with surgical and diagnostic procedures.

CONTRAINDICATIONS

Leptofen (Droperidol) is contraindicated in patients with known or suspectedQT prolongation (i.e., QTc interval greater than 440 msec for males or 450msec for females). This would include patients with congenital long QT syndrome.

Droperidolis contraindicated in patients with known hypersensitivity to the drug.

Droperidolis not recommended for any use other than for the treatment of perioperativenausea and vomiting in patients for whom other treatments are ineffectiveor inappropriate.

WARNINGS

Leptofen (Droperidol) should be administered with extreme caution inthe presence of risk factors for development of prolonged QT syndrome, suchas: 1) clinically significant bradycardia (less than 50 bpm), 2) anyclinically significant cardiac disease, 3) treatment with Class I and ClassIII antiarrhythmics, 4) treatment with monoamine oxidase inhibitors (MAOI’s),5) concomitant treatment with other drug products known to prolong the QTinterval, and 6) electrolyte imbalance,in particular hypokalemia and hypomagnesemia, or concomitant treatment withdrugs (e.g., diuretics) that may cause electrolyte imbalance.

Effects on Cardiac Conduction:

Adose-dependent prolongation of the QT interval was observed within 10 minutesof Leptofen (Droperidol) administration in a study of 40 patients without known cardiacdisease who underwent extracranial head and neck surgery. Significant QT prolongationwas observed at all three dose levels evaluated, with 0.1, 0.175, and 0.25mg/kg associated with prolongation of median QTc by 37, 44, and 59 msec,respectively.

Cases of QT prolongation and serious arrhythmias (e.g., torsade de pointes, ventricular arrhythmias, cardiac arrest, and death)have been observed during post-marketing treatment with Leptofen (Droperidol). Some caseshave occurred in patients with no known risk factors and at doses at or belowrecommended doses. There has been at least one case of nonfatal torsade depointes confirmed by rechallenge.

Based on these reports,all patients should undergo a 12-lead ECG prior to administration of droperidolto determine if a prolonged QT interval (i.e., QTc greater than 440 msec formales or 450 msec for females) is present. If there is a prolonged QT interval,droperidol should NOT be administered. For patients in whom the potential benefit of Leptofen (Droperidol) treatment is feltto outweigh the risks of potentially serious arrhythmias, ECG monitoring shouldbe performed prior to treatment and continued for 2-3 hours after completingtreatment to monitor for arrhythmias.

FLUIDSAND OTHER COUNTERMEASURES TO MANAGE HYPOTENSION SHOULD BE READILY AVAILABLE.

As with other CNS depressant drugs, patientswho have received Leptofen (Droperidol) should have appropriate surveillance.

Itis recommended that opioids, when required, initially be used in reduced doses.

Aswith other neuroleptic agents, very rare reports of neuroleptic malignantsyndrome (altered consciousness, muscle rigidity and autonomic instability)have occurred in patients who have received Leptofen (Droperidol).

Sinceit may be difficult to distinguish neuroleptic malignant syndrome from malignanthyperpyrexia in the perioperative period, prompt treatment with dantroleneshould be considered if increases in temperature, heart rate or carbon dioxideproduction occur.

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PRECAUTIONS

General: The initial dose of Leptofen should be appropriately reduced in elderly, debilitated and other poor-risk patients. The effect of the initial dose should be considered in determining incremental doses.

Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics, can alter respiration by blocking intercostal nerves and can cause peripheral vasodilatation and hypotension because of sympathetic blockade. Through other mechanisms, Leptofen (Droperidol) can also alter circulation. Therefore, when Leptofen (Droperidol) is used to supplement these forms of anesthesia, the anesthetist should be familiar with the physiological alterations involved, and be prepared to manage them in the patients elected for these forms of anesthesia.

If hypotension occurs, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy. Repositioning the patient to improve venous return to the heart should be considered when operative conditions permit. It should be noted that in spinal and peridural anesthesia, tilting the patient into a head-down position may result in a higher level of anesthesia than is desirable, as well as impair venous return to the heart. Care should be exercised in the moving and positioning of patients because of a possibility of orthostatic hypotension. If volume expansion with fluids plus these other countermeasures do not correct the hypotension, then the administration of pressor agents other than epinephrine should be considered. Epinephrine may paradoxically decrease the blood pressure in patients treated with Leptofen (Droperidol) due to the alpha-adrenergic blocking action of Leptofen (Droperidol).

Since Leptofen (Droperidol) may decrease pulmonary arterial pressure, this fact should be considered by those who conduct diagnostic or surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient.

Vital signs and ECG should be monitored routinely.

When the EEG is used for postoperative monitoring, it may be found that the EEG pattern returns to normal slowly.

Impaired Hepatic or Renal Function: Leptofen (Droperidol) should be administered with caution to patients with liver and kidney dysfunction because of the importance of these organs in the metabolism and excretion of drugs.

Pheochromocytoma: In patients with diagnosed/ suspected pheochromocytoma, severe hypertension and tachycardia have been observed after the administration of Leptofen (Droperidol).

Drug Interactions:

Potentially ArrhythmogenicAgents: Any drug known to have the potential to prolong the QT intervalshould not be used together with Leptofen (Droperidol). Possible pharmacodynamic interactionscan occur between Leptofen (Droperidol) and potentially arrhythmogenic agents such asclass I or III antiarrhythmics, antihistamines that prolong the QT interval,antimalarials, calcium channel blockers, neuroleptics that prolong the QTinterval, and antidepressants.

Caution should be usedwhen patients are taking concomitant drugs known to induce hypokalemia orhypomagnesemia as they may precipitate QT prolongation and interact with Leptofen (Droperidol).These would include diuretics, laxatives and supraphysiological use of steroidhormones with mineralocorticoid potential.

CNS Depressant Drugs: Other CNS depressantdrugs (e.g., barbiturates, tranquilizers, opioids and general anesthetics)have additive or potentiating effects with Leptofen (Droperidol). Following the administrationof Leptofen (Droperidol), the dose of other CNS depressant drugs should be reduced.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity studies have been carried out with Leptofen (Droperidol). The micronucleus test in female rats revealed no mutagenic effects in single oral doses as high as 160 mg/kg. An oral study in rats (Segment I) revealed no impairment of fertility in either males or females at 0.63, 2.5 and 10 mg/kg doses (approximately 2, 9 and 36 times maximum recommended human I.V./I.M. dosage).

Pregnancy - Category C: Leptofen (Droperidol) administered intravenously has been shown to cause a slight increase in mortality of the newborn rat at 4.4 times the upper human dose. At 44 times the upper human dose, mortality rate was comparable to that for control animals. Following intramuscular administration, increased mortality of the offspring at 1.8 times the upper human dose is attributed to CNS depression in the dams who neglected to remove placentae from their offspring. Leptofen (Droperidol) has not been shown to be teratogenic in animals. There are no adequate and well-controlled studies in pregnant women. Leptofen (Droperidol) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery: There are insufficient data to support the use of Leptofen (Droperidol) in labor and delivery. Therefore, such use is not recommended.

Nursing Mothers: It is not known whether Leptofen (Droperidol) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Leptofen (Droperidol) is administered to a nursing mother.

Pediatric Use: The safety of Leptofen (Droperidol) in children younger than two years of age has not been established.

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ADVERSE REACTIONS

QT interval prolongation, torsade de pointes, cardiac arrest,and ventricular tachycardia have been reported in patients treated with Leptofen (Droperidol).Some of these cases were associated with death. Some cases occurred in patientswith no known risk factors, and some were associated with Leptofen (Droperidol) dosesat or below recommended doses.

Physicians should bealert to palpitations, syncope, or other symptoms suggestive of episodes ofirregular cardiac rhythm in patients taking Leptofen (Droperidol) and promptly evaluatesuch cases.

Themost common somatic adverse reactions reported to occur with Leptofen (Droperidol) aremild to moderate hypotension and tachycardia, but these effects usually subsidewithout treatment. If hypotension occurs and is severe or persists, the possibilityof hypovolemia should be considered and managed with appropriate parenteralfluid therapy.

The most common behavioral adverse effectsof Leptofen (Droperidol) include dysphoria, postoperative drowsiness, restlessness, hyperactivityand anxiety, which can either be the result of an inadequate dosage (lackof adequate treatment effect) or of an adverse drug reaction (part of thesymptom complex of akathisia).

Care should be takento search for extrapyramidal signs and symptoms (dystonia, akathisia, oculogyriccrisis) to differentiate these different clinical conditions. When extrapyramidalsymptoms are the cause, they can usually be controlled with anticholinergicagents.

Postoperative hallucinatory episodes (sometimesassociated with transient periods of mental depression) have also been reported.

Otherless common reported adverse reactions include anaphylaxis, dizziness, chillsand/or shivering, laryngospasm and bronchospasm.

Elevatedblood pressure, with or without pre-existing hypertension, has been reportedfollowing administration of Leptofen (Droperidol) combined with fentanyl citrate or otherparenteral analgesics. This might be due to unexplained alterations in sympatheticactivity following large doses; however, it is also frequently attributedto anesthetic or surgical stimulation during light anesthesia.

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OVERDOSAGE

Manifestations: The manifestationsof Leptofen (Droperidol) overdosage are an extension of its pharmacologic actions andmay include QT prolongation and serious arrhythmias (e.g. torsade de pointes).

Treatment: In the presence of hypoventilation orapnea, oxygen should be administered and respiration should be assisted orcontrolled as indicated. A patent airway must be maintained; an oropharyngealairway or endotracheal tube might be indicated. The patient should be carefullyobserved for 24 hours; body warmth and adequate fluid intake should be maintained. If hypotension occurs and is severe or persists, the possibility of hypovolemiashould be considered and managed with appropriate parenteral fluid therapy..

If significant extrapyramidal reactionsoccur, in the context of an overdose, an anticholinergic should be administered.

Theintravenous Median Lethal Dose is 20 ― 43 mg/kg in mice; 30 mg/kg inrats; and 25 mg/kg in dogs and 11 ― 13 mg/kg in rabbits. Theintramuscular Median Lethal Dose of Leptofen (Droperidol) is 195 mg/kg in mice; 104 ―110 mg/kg in rats; 97 mg/kg in rabbits and 200 mg/kg in guinea pigs.

DOSAGE AND ADMINISTRATION

Dosage should be individualized. Some of the factors to beconsidered in determining dose are age, body weight, physical status, underlyingpathological condition, use of other drugs, the type of anesthesia to be used,and the surgical procedure involved.

Vital signs andECG should be monitored routinely.

AdultDosage: The maximum recommended initial dose of Leptofen (Droperidol) is 2.5mg I.M. or slow I.V. Additional 1.25 mg doses of Leptofen (Droperidol) may be administeredto achieve the desired effect. However, additional doses should be administeredwith caution, and only if the potential benefit outweighs the potential risk.

Pediatric

Dosage: For children two to 12 yearsof age, the maximum recommended initial dose is 0.1 mg/kg, taking into accountthe patient’s age and other clinical factors. However, additional dosesshould be administered with caution, and only if the potential benefit outweighsthe potential risk.

Parenteral drug products should be inspectedvisually for particulate matter and discoloration prior to administration,whenever solution and container permit. If such abnormalities are observed,the drug should not be administered.

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HOW SUPPLIED

Leptofen (Droperidol) Injection, USP 2.5 mg/mL is supplied in 2 mL (5 mg) single-dose ampuls packaged in cartons of ten (List No. 1187).

Store at 20 to 25°C (68 to 77°F).

Protect from light.

REFERENCES


  • Saarnivaara L, Klemola UM, Lindgren L, et al. QT interval of the ECG, heart rate and arterial pressure using propofol, methohexital or midazolam for induction of anesthesia. Acta Anaesthesiol Scand 1990: 34: 276-81.


  • Schmeling WT, Warltier DC, McDonald DJ, et al. Prolongation of the QT interval by enflurane, isoflurane, and halothane in humans. Anesth Analg 1991:72:137-44.


  • Späth G. Torsade des pointe oder die andere Ursache des plötz-lichen Herztodes. Wien: Ueberreuter, 1998.


  • Riley DC, Schmeling WT, Al-Wathiqui MH, et al. Prolongation of the QT-interval by volatile anesthetics in chronically instrumented dogs. Anesth Analg 1988: 67: 741-9.


  • McConachie I, Keaveny JP, Healy TF, et al. Effects of anaesthesia on the QT-interval. Br J Anaesth 1989: 63: 558-60.


  • Lawrence KR, Nasraway SA. Conduction disturbances associated with administration of butyrophenone antipsychotics in the critically ill: a review of the literature. Pharmacotherapy 1997: 17(3): 531-7.


  • Lischke V, Behne M, Doelken P, et al. Leptofen (Droperidol) causes a dose-dependent prolongation of the QT interval. Anesth Analg 1994: 79: 983-6.



Revised: October, 2004

© Hospira 2004 EN-0531 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

RL-0634

Fentanyl:


1. INDICATIONS AND USAGE

Leptofen (Fentanyl) 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 , reserve Leptofen (Fentanyl) 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.

Leptofen (Fentanyl) 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. Leptofen (Fentanyl) is for use only in patients in the hospital. Discontinue treatment with Leptofen (Fentanyl) before patients leave the hospital.
  • For use after patients have been titrated to an acceptable level of analgesia using alternate opioid analgesics.

Leptofen (Fentanyl) contains Leptofen (Fentanyl), an opioid agonist. Leptofen (Fentanyl) 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. ( 1)

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Leptofen (Fentanyl) 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

Leptofen (Fentanyl) is:

  • Only for use in patients who are alert enough and have adequate cognitive ability to understand the directions for use. ( 1)
  • Not for home use. Leptofen (Fentanyl) is for use only in patients in the hospital. Discontinue treatment with Leptofen (Fentanyl) before patients leave the hospital. ( 1)
  • For use after patients have been titrated to an acceptable level of analgesia using alternate opioid analgesics. ( 1)

2. DOSAGE AND ADMINISTRATION

  • Do not use more than one Leptofen at a time. ( 2.1)
  • Patients should be titrated to comfort before initiating Leptofen (Fentanyl). ( 2.2)
  • For transdermal use only. Apply one Leptofen (Fentanyl) to intact, non-irritated, and non-irradiated skin on the chest or upper outer arm. ( 2.2, 2.3)
  • Each Leptofen (Fentanyl) operates up to 24 hours or 80 doses, whichever comes first. Leptofen (Fentanyl) may be used for a maximum of 72 hours of therapy for acute postoperative pain, with each subsequent Leptofen (Fentanyl) applied to a different skin site. ( 2.2, 2.3 )
  • See full prescribing information for detailed instructions concerning administration, disposal and discontinuation of Leptofen (Fentanyl). ( 2.3, 2.4, 2.5, 2.6 )
  • See Leptofen (Fentanyl) Important Device Instructions for additional details including troubleshooting device malfunction.
  • Do not stop Leptofen (Fentanyl) abruptly in a physically dependent patient. ( 2.5)

2.1 Important Administration Instructions

Leptofen (Fentanyl) IS FOR HOSPITAL USE ONLY BY PATIENTS UNDER MEDICAL SUPERVISION AND DIRECTION. PRIOR TO THE PATIENT LEAVING THE HOSPITAL, MEDICAL PERSONNEL MUST REMOVE Leptofen (Fentanyl) AND DISPOSE OF IT PROPERLY .

ONLY THE PATIENT MAY ACTIVATE Leptofen (Fentanyl).

ONLY ONE Leptofen (Fentanyl) MAY BE APPLIED AT A TIME. If inadequate analgesia is achieved with one Leptofen (Fentanyl), either provide additional supplemental analgesic medication or replace with an alternate analgesic medication.

Leptofen (Fentanyl) should be prescribed only by persons knowledgeable in the administration of potent opioids and in the management of patients receiving potent opioids for treatment of pain. Patients treated with Leptofen (Fentanyl) should be under the supervision of medical personnel with expertise in the detection and management of hypoventilation including close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status .

Remove and properly dispose of Leptofen (Fentanyl) prior to MRI, cardioversion, defibrillation, or diathermy .

To reduce the risk for shock, avoid contact with synthetic materials (such as carpeted flooring) while assembling Leptofen (Fentanyl) and avoid exposing Leptofen (Fentanyl) to electronic security systems .

Depending on the rated maximum output power and frequency of the transmitter, the recommended separation distance between Leptofen (Fentanyl) and communications equipment or a Radio Frequency Identification (RFID) transmitter ranges between 0.12 and 23 meters .

See Leptofen (Fentanyl) Important Device Instructions for additional details, including information on troubleshooting device malfunction, recommended separation distances, and electromagnetic compatibility

2.2 Dosage

Leptofen is for use only after patients have been titrated to an acceptable level of analgesia using another opioid analgesic. Apply one Leptofen (Fentanyl) to healthy, unbroken/intact, non-irritated, and non-irradiated skin on the chest or upper outer arm ONLY.

Leptofen (Fentanyl) provides a 40 mcg dose of Leptofen (Fentanyl) per activation. It is important to instruct patients how to operate Leptofen (Fentanyl) to self-administer doses of Leptofen (Fentanyl) as needed to manage their acute, short-term, postoperative pain. Allow only the patient to self-administer doses of Leptofen (Fentanyl). Each on-demand dose is delivered over a 10-minute period.

To initiate administration of Leptofen (Fentanyl), the patient must press and release the button twice within 3 seconds. One single audible beep indicates the start of delivery of each dose. The green light will start blinking rapidly and the digital display will alternate between a walking circle and the number of doses delivered. When the 10-minute dose is complete, the green light will blink at a slow rate and the display will show the number of doses delivered.

Figure 1A: Leptofen (Fentanyl) Components

Figure 1B: Assembled Leptofen (Fentanyl)

A maximum of six 40-mcg doses per hour can be administered by Leptofen (Fentanyl). The maximum amount of Leptofen (Fentanyl) that can be administered from a single Leptofen (Fentanyl) over 24 hours is 3.2 mg (eighty 40-mcg doses). Each Leptofen (Fentanyl) operates up to 24 hours or 80 doses, whichever comes first. Use one Leptofen (Fentanyl) at a time for up to 24 hours or 80 doses, whichever comes first. Leptofen (Fentanyl) may be used for a maximum of 3 days (72 hours) of therapy for acute postoperative pain, with each subsequent Leptofen (Fentanyl) applied to a different skin site .

After the 24 hours have elapsed, or 80 doses have been delivered, Leptofen (Fentanyl) will not deliver any additional doses. The light and audible beep will not function. The digital display will continue to show the number of doses delivered for an additional 12 hours. If the patient tries to initiate a dose, Leptofen (Fentanyl) will ignore the dose request.

Figure 1a Figure 1b

2.3 Administration of Leptofen (Fentanyl)

For SINGLE-USE only: operates up to 24 hours or 80 doses, whichever comes first.

FOR TRANSDERMAL USE ONLY

Preparation of Patient Site

1. Choose healthy, unbroken skin on the upper outer arm or chest ONLY. Leptofen (Fentanyl) may only be applied to one of the three sites shown in Figure 2.

2. Clip excessive hair if necessary. Do not shave as this may irritate skin.

3. Clean the site with alcohol and let it dry. Do not use soaps, lotions, or other agents.

Assembly of Leptofen (Fentanyl)

DO NOT USE Leptofen (Fentanyl) IF THE SEAL ON THE TRAY OR DRUG UNIT POUCH IS BROKEN OR DAMAGED.

ALWAYS WEAR GLOVES WHEN HANDLING Leptofen (Fentanyl).

Complete these steps before applying Leptofen (Fentanyl) to the patient:

  • Open the tray by peeling back the tray lid. Remove the foil (drug) pouch and the Controller. Open the pouch containing the Drug Unit starting at the pre-cut notch and then carefully tearing along the top of the pouch.
  • Remove the Drug Unit from the pouch and place on a hard, flat surface.
  • Align the matching shapes of the Controller and the Drug Unit.
  • Press on both ends of the device to ensure that the snaps at both ends are fully engaged. You should hear one or two clicks when the snaps are fully engaged.
  • Once assembled, the digital display of the Controller will complete a short self-test during which there will be one audible beep, the red light will blink once, and the digital display will flash the number “88”. At the end of the self-test, the display will show the number “0” and a green light will blink at a slow rate to indicate Leptofen (Fentanyl) is ready for application.

Application of Leptofen (Fentanyl)

ALWAYS WEAR GLOVES WHEN HANDLING Leptofen (Fentanyl).

Peel off and discard only the clear plastic liner covering the adhesive and hydrogels. Take care not to pull on the red tab while removing the clear plastic liner when preparing to apply Leptofen (Fentanyl) to the patient. The red tab is only to be used when separating Leptofen (Fentanyl) for disposal .

Press and hold Leptofen (Fentanyl) firmly in place, with the sticky side down, onto patient’s skin for at least 15 seconds. Press with your fingers around the edges to be sure Leptofen (Fentanyl) adheres to the skin. Do not press the dosing button.

Occasionally, Leptofen (Fentanyl) may loosen from the skin; if this occurs, secure it to patient’s skin by pressing the edges with fingers or securing with a non-allergenic tape to be sure that all edges make complete contact with the skin. If using tape, apply tape along the long edges to secure Leptofen (Fentanyl) to patient’s skin. Do not tape over the button, the light, or the digital display. Do not tape if evidence of blistered or broken skin.

After taping, if Leptofen (Fentanyl) beeps again, remove and dispose. Place a new Leptofen (Fentanyl) on a different skin site. Each Leptofen (Fentanyl) may be used for up to 24 hours from the time it is assembled or until 80 doses have been administered, whichever comes first.

Operation of Leptofen (Fentanyl)

A recessed button is located on the top housing of Leptofen (Fentanyl). To initiate administration of a Leptofen (Fentanyl) dose, the patient must press and release the button twice within 3 seconds. Leptofen (Fentanyl) should only be activated by the patient. One single audible beep indicates the start of delivery of each dose. The green light will start blinking rapidly and the digital display will alternate between a walking circle and the number of doses delivered.

Each dose will be delivered over 10-minutes. During this time Leptofen (Fentanyl) is locked-out and will not respond to additional button presses. When the 10-minute dose is complete, the green light will return to a slow rate of blinking and the display will show the number of doses delivered. Leptofen (Fentanyl) is now ready to be used again by the patient. The next dose cannot begin until the previous 10‑minute delivery cycle is complete. Pressing the button during delivery of a dose will not result in additional drug being administered.

A healthcare professional must observe the first dose administered to ensure that the patient understands how to operate Leptofen (Fentanyl) and that Leptofen (Fentanyl) is working properly.

Each Leptofen (Fentanyl) will cease functioning at the end of 24 hours of use, or after 80 doses have been administered, whichever comes first. The green light will turn off and the number of doses delivered will flash on and off. The flashing digital display may be turned off by pressing and holding the dosing button for 6 seconds.

See Leptofen (Fentanyl) Important Device Instructions for additional details, including information on troubleshooting device malfunction.

Removal of Leptofen (Fentanyl)

ALWAYS WEAR GLOVES WHEN HANDLING Leptofen (Fentanyl).

Leptofen (Fentanyl) may be removed at any time. However, once Leptofen (Fentanyl) has been removed, the same Leptofen (Fentanyl) must not be reapplied.

At the end of 24 hours of use, or after 80 doses have been delivered, Leptofen (Fentanyl) will deactivate and should be removed from the patient’s skin. With gloves on, remove Leptofen (Fentanyl) from the patient.

Leptofen (Fentanyl) contains two hydrogels, one of which contains Leptofen (Fentanyl) . Ensure both hydrogels remain with the removed Leptofen (Fentanyl). If the hydrogel becomes separated from Leptofen (Fentanyl) during removal, use gloves or tweezers to remove the hydrogel from the skin and properly dispose of in accordance with state and federal regulations for controlled substances. If the patient requires additional analgesia a new Leptofen (Fentanyl) should be applied. In this case, Leptofen (Fentanyl) should be applied to a new skin site on the upper outer arm or chest.

One of the hydrogels contains Leptofen (Fentanyl); take care not to touch the exposed hydrogel compartments or the adhesive. If a hydrogel drug reservoir is touched accidentally, rinse the area thoroughly with water (do not use soap).

Fig 2 Fig 3abcde image of removing liner Fig 4c Fig 5 Fig 6

2.4 Disposal of Leptofen

ALWAYS WEAR GLOVES WHEN HANDLING Leptofen (Fentanyl).

Contact with the hydrogels contained in Leptofen (Fentanyl) can result in a fatal overdose of Leptofen (Fentanyl). Handle the used Leptofen (Fentanyl) by the sides and top while avoiding contact with the hydrogel. Dispose of Leptofen (Fentanyl) in accordance with state and federal regulations for controlled substances. The used red bottom housing of Leptofen (Fentanyl) contains a significant amount of Leptofen (Fentanyl) that could cause a fatal overdose of Leptofen (Fentanyl).

To dispose of a used Leptofen (Fentanyl):

  • With gloves on, pull the red tab to separate the red bottom housing containing Leptofen (Fentanyl) from Leptofen (Fentanyl).
  • Fold the red housing in half with the sticky side facing in.
  • Dispose of the folded over red housing containing the residual Leptofen (Fentanyl) per the institution’s procedures for disposal of Schedule II drugs or by flushing it down the toilet.
  • Hold down dosing button until the display goes blank and then dispose of the remaining part of Leptofen (Fentanyl) containing electronics in waste designated for batteries.

Fig 7ab

2.5 Discontinuation of Leptofen

To discontinue use of Leptofen (Fentanyl), remove and dispose of Leptofen (Fentanyl) according to the preceding directions. Do not abruptly discontinue Leptofen (Fentanyl) in a physically-dependent patient .

2.6 Conversion from Leptofen to Alternate Analgesics

Upon discontinuation of Leptofen (Fentanyl), if upon evaluation, conversion to an alternate analgesic is required, titrate the dose of the new analgesic, based upon the patient’s report of pain, until adequate analgesia has been obtained, keeping in mind that the serum Leptofen (Fentanyl) concentration will decrease slowly following removal of Leptofen (Fentanyl) . During the period of converting analgesics, monitor the patient for signs of respiratory and central nervous system depression.

3. DOSAGE FORMS AND STRENGTHS

Iontophoretic transdermal system provides up to 80 doses (40 mcg each) of Leptofen (Fentanyl) per activation on-demand .

Iontophoretic transdermal system provides up to 80 doses (40 mcg each) of Leptofen (Fentanyl) per activation on-demand. ( 3)

4. CONTRAINDICATIONS

Leptofen (Fentanyl) is contraindicated in patients with:

  • Significant respiratory depression
  • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
  • Known or suspected gastrointestinal obstruction, including paralytic ileus
  • Hypersensitivity to Leptofen (Fentanyl), cetylpyridinium chloride (e.g., Cepacol®), or any components of Leptofen (Fentanyl) .
  • Significant respiratory depression. ( 4)
  • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4)
  • Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4)
  • Hypersensitivity to Leptofen (Fentanyl), cetylpyridinium chloride (e.g., Cepacol ®), or any components of Leptofen (Fentanyl). ( 4)

5. WARNINGS AND PRECAUTIONS

  • Risk of Injury during MRI: Leptofen contains metal parts and must be removed before an MRI. ( 5.6)
  • Risk of Use During Other Procedures (cardioversion, defibrillation, X-ray, CT, diathermy): Remove Leptofen (Fentanyl) before these procedures. ( 5.7)
  • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, and Debilitated Patients: Monitor closely, particularly during initiation. ( 5.8)
  • Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue Leptofen (Fentanyl) if serotonin syndrome is suspected. ( 5.9)
  • Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.10)
  • Severe Hypotension: Monitor during dosage initiation. Avoid use of Leptofen (Fentanyl) in patients with circulatory shock. ( 5.11)
  • Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Leptofen (Fentanyl) in patients with impaired consciousness or coma. ( 5.12)

5.1 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including Leptofen (Fentanyl), even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status . Carbon dioxide (CO 2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Leptofen (Fentanyl), the risk is greatest during the initiation of therapy. Monitor patients closely for respiratory depression, especially within the first 24‑72 hours of initiating therapy with Leptofen (Fentanyl).

Accidental exposure to the hydrogel component of Leptofen (Fentanyl), especially in children, can result in respiratory depression and death due to an overdose of Leptofen (Fentanyl).

Following accidental contact with Leptofen (Fentanyl) or its components, immediately rinse the affected area thoroughly with water. Do not use soap, alcohol, or other solvent because they may enhance the drug’s ability to penetrate the skin. The individual exposed should be monitored for signs of respiratory or central nervous system depression.

If Leptofen (Fentanyl) is not handled correctly using gloves, healthcare professionals are at risk of accidental exposure to a fatal overdose of Leptofen (Fentanyl).

Leptofen (Fentanyl) is for hospital use only. Use of Leptofen (Fentanyl) outside of the hospital setting can lead to accidental exposure in others for whom it is not prescribed, causing fatal respiratory depression. Prior to the patient leaving the hospital, medical personnel must remove Leptofen (Fentanyl) and dispose of it properly.

5.2 Leptofen Risk Evaluation and Mitigation Strategy (REMS) Program

Leptofen (Fentanyl) is available only through a restricted program under a REMS called the Leptofen (Fentanyl) REMS Program because of the risk of respiratory depression resulting from accidental exposure .

Notable requirements of the Leptofen (Fentanyl) REMS Program include the following:

  • Healthcare facilities that dispense and administer Leptofen (Fentanyl) must be certified in the Leptofen (Fentanyl) REMS program and comply with the REMS requirements.
  • Hospitals must only dispense Leptofen (Fentanyl) for hospital use.

Further information about the Leptofen (Fentanyl) REMS Program is available at www.ionsysrems.com, or by calling 1-877-488-6835.

5.3 Addiction, Abuse, and Misuse

Leptofen contains Leptofen (Fentanyl), a Schedule II controlled substance. As an opioid, Leptofen (Fentanyl) exposes users to the risks of addiction, abuse, and misuse .

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Leptofen (Fentanyl). Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse, prior to prescribing Leptofen (Fentanyl), and monitor all patients receiving Leptofen (Fentanyl) for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids, such as Leptofen (Fentanyl), but use in such patients necessitates intensive counseling about the risks and proper use of Leptofen (Fentanyl) along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Leptofen (Fentanyl). Contact local State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

5.4 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of Leptofen (Fentanyl) with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of Leptofen (Fentanyl), and prolong opioid adverse reactions, depression , particularly when an inhibitor is added after a stable dose of Leptofen (Fentanyl) is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in IONSYS-treated patients may increase Leptofen (Fentanyl) plasma concentrations and prolong opioid adverse reactions. When using Leptofen (Fentanyl) with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in IONSYS-treated patients, monitor patients closely at frequent intervals for respiratory depression and sedation .

Concomitant use of Leptofen (Fentanyl) with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease Leptofen (Fentanyl) plasma concentrations, decrease opioid efficacy or, possibly lead to a withdrawal syndrome in a patient who had developed physical dependence to Leptofen (Fentanyl). When using Leptofen (Fentanyl) with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur .

5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Leptofen with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics .

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

5.6 Risk of Injury during Magnetic Resonance Imaging (MRI) Procedure

The Leptofen (Fentanyl) device is considered MR Unsafe. Leptofen (Fentanyl) contains metal parts and must be removed and properly disposed of before an MRI procedure to avoid injury to the patient and damage to Leptofen (Fentanyl). It is unknown if exposure to an MRI procedure increases release of Leptofen (Fentanyl) from Leptofen (Fentanyl). Monitor any patients wearing Leptofen (Fentanyl) with inadvertent exposure to an MRI for signs of central nervous system and respiratory depression.

5.7 Risk of Leptofen Use during Other Procedures or Near Certain Equipment

Cardioversion, Defibrillation, Radiographic Imaging Procedures other than MRI, or Diathermy

Use of Leptofen (Fentanyl) during cardioversion, defibrillation, X-ray, CT, or diathermy can damage Leptofen (Fentanyl) from the strong electromagnetic fields set up by these procedures. Leptofen (Fentanyl) contains radio-opaque components and may interfere with an X-ray image or CT scan. Remove and properly dispose of Leptofen (Fentanyl) prior to cardioversion, defibrillation, X-ray, CT, or diathermy .

Synthetic Materials and Electronic Security Systems

Avoid contact with synthetic materials (such as carpeted flooring) to reduce the possibility of electrostatic discharge and damage to Leptofen (Fentanyl). Avoid exposing Leptofen (Fentanyl) to electronic security systems to reduce the possibility of damage to Leptofen (Fentanyl). See Leptofen (Fentanyl) Important Device Instructions for additional details.

Communications Equipment and Radio Frequency Identification Transmitters

Use of Leptofen (Fentanyl) near communications equipment (e.g., base stations for radio telephones and land mobile radios, amateur radio, AM and FM radio broadcast and TV broadcast Radio) and Radio Frequency Identification (RFID) transmitters can damage Leptofen (Fentanyl). Depending on the rated maximum output power and frequency of the transmitter, the recommended separation distance between Leptofen (Fentanyl) and communications equipment or the RFID transmitter ranges between 0.12 and 23 meters. See Leptofen (Fentanyl) Important Device Instructions for detailed instructions regarding recommended separation distances.

Other Electromechanical Devices Including Pacemakers or Electrical Monitoring Equipment

The low-level electrical current provided by Leptofen (Fentanyl) does not result in electromagnetic interference with other electromechanical devices like pacemakers or electrical monitoring equipment.

If exposure to the procedures listed above, electronic security systems, electrostatic discharge, communications equipment, or RFID transmitters occurs, and if Leptofen (Fentanyl) does not appear to function normally , remove Leptofen (Fentanyl) and replace with a new Leptofen (Fentanyl). See Leptofen (Fentanyl) Important Device Instructions for additional details including information on troubleshooting device malfunction and electromagnetic compatibility.

5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Leptofen in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: IONSYS-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at the recommended dosage of Leptofen (Fentanyl) .

Elderly, Cachectic, or Debilitated Patients: Life -threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Monitor such patients closely; particularly when initiating Leptofen (Fentanyl) and when Leptofen (Fentanyl) is used concomitantly with other drugs that depress respiration . Alternatively, consider the use of non-opioid analgesics in these patients.

5.9 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Leptofen (Fentanyl), the active opioid ingredient of Leptofen (Fentanyl), with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) . This may occur at the recommended dosage.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue Leptofen (Fentanyl) if serotonin syndrome is suspected.

5.10 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.11 Severe Hypotension

Leptofen may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) . Monitor these patients for signs of hypotension after initiating Leptofen (Fentanyl). In patients with circulatory shock, Leptofen (Fentanyl) may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Leptofen (Fentanyl) in patients with circulatory shock.

5.12 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors). Leptofen (Fentanyl) may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Leptofen (Fentanyl).

Opioids may also obscure the clinical course in a patient with a head injury.

Avoid the use of Leptofen (Fentanyl) in patients with impaired consciousness or coma. Leptofen (Fentanyl) is not suitable for use in patients who are not alert and able to follow directions.

5.13 Risks of Use in Patients with Gastrointestinal Conditions

Leptofen is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The Leptofen (Fentanyl) in Leptofen (Fentanyl) may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

5.14 Increased Risk of Seizures in Patients with Seizure Disorders

The Leptofen (Fentanyl) in Leptofen (Fentanyl) may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Leptofen (Fentanyl) therapy.

5.15 Topical Skin Reactions

Topical skin reactions may occur with use of Leptofen (Fentanyl) and are typically limited to the application site area. If a severe skin reaction is observed, remove Leptofen (Fentanyl) and discontinue further use.

5.16 Bradycardia

Leptofen (Fentanyl) may produce bradycardia in some patients. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with Leptofen (Fentanyl).

5.17 Withdrawal

Avoid the use of mixed agonist/antagonist or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Leptofen (Fentanyl). In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

Do not abruptly discontinue Leptofen (Fentanyl) .

5.18 Hepatic Impairment

Insufficient data are available on the use of Leptofen (Fentanyl) in patients with impaired hepatic function. Since Leptofen (Fentanyl) is eliminated by hepatic metabolism and Leptofen (Fentanyl) clearance may decrease in patients with hepatic disease, monitor patients with hepatic impairment for signs of sedation and respiratory depression .

5.19 Renal Impairment

A clinical pharmacology study with intravenous Leptofen in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low Leptofen (Fentanyl) clearance. Monitor for signs of sedation and respiratory depression in patients with renal impairment .

5.20 Neonatal Opioid Withdrawal Syndrome

Prolonged use of Leptofen (Fentanyl) during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life‑threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available .

6. ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

  • Life-Threatening respiratory Depression
  • Addiction, Abuse, and Misuse
  • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.5)]
  • Serotonin Syndrome [see Warnings and Precautions ( 5.9)]
  • Adrenal Insufficiency [see Warnings and Precautions ( 5.10)]
  • Severe Hypotension [see Warnings and Precautions ( 5.11)]
  • Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.13)]
  • Seizures
  • Withdrawal
  • Neonatal Opioid Withdrawal Syndrome

Most common adverse reactions (frequency ≥ 2%) were headache, hypotension, nausea, vomiting, anemia, dizziness, application site reaction-erythema, pruritus, and urinary retention. ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact The Medicines Company at 1-877-488-6835 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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.

In controlled and uncontrolled studies, the safety of Leptofen (Fentanyl) 40 mcg was evaluated in a total of 2114 patients with acute postoperative pain requiring opioid analgesia.

The most common adverse reactions (≥ 2%) in the placebo-controlled studies, regardless of relationship to study medication, are listed in Table 1.

Adverse Reactions

Leptofen (Fentanyl)

(n=475)

Placebo

(n=316)

Body as a Whole
Headache

9%

7%
Cardiovascular System

Hypotension


2%


<1%

Digestive System
Nausea

39%


22%


Vomiting


12%


6%

Hemic and Lymphatic System

Anemia


3%


<1%

Nervous System
Dizziness

3%


1%

Skin System
Application site reaction- Erythema

14%

2%

Pruritus


6%


<1%

Urogenital System
Urinary retention

3%


<1%


NOTE: Patients reported as having "Nausea and vomiting" are included in "Nausea" and "Vomiting" in Table 1.

Other Adverse Reactions

Other adverse reactions that were reported (excluding adverse reactions listed in Table 1) in 4 active comparator trials vs. IV PCA morphine in patients treated with Leptofen (Fentanyl) (n=1288) are described below:

Body as a Whole: abdominal pain, back pain, extremity pain, chest pain, chills, abdomen enlarged, asthenia, abscess, hypothermia

Cardiovascular System: syncope, postural hypotension, vasodilation, hypertension, atrial fibrillation, bradycardia, tachycardia, bigeminy, arrhythmia, myocardial infarct

Digestive System: constipation, flatulence, dyspepsia, ileus, dry mouth, diarrhea

Metabolic and Nutritional System: peripheral edema, healing abnormal, edema, dehydration

Musculoskeletal System: leg cramps and myalgia

Nervous System : insomnia, anxiety, somnolence, confusion, paresthesia, hypesthesia, nervousness, agitation, abnormal dreams, tremor

Respiratory System: hypoxia, hypoventilation, dyspnea, apnea, cough increased, asthma, hiccup, atelectasis, rhinitis, hyperventilation

Skin System: application site reactions including: itching, vesicles, papules/pustules, edema, pain, burning, dry and flaky skin, and vesiculobullous rash, wound site oozing/bleeding, wound site inflammation/erythema, rash, sweating

Special Senses: abnormal vision-blurred vision

Urogenital System: urination impaired, hematuria, urinary tract infection, urinary urgency, dysuria

Scheduled observation of the skin approximately 24 hours after Leptofen (Fentanyl) removal was included in several studies. Some redness at the skin sites was observed in approximately 60% of patients at this observation. The skin findings included erythema, edema, and papules. The majority of these events were categorized as mild. Two patients were noted to have hyperpigmentation lasting 2-3 weeks at the application site. Three patients noted a rectangular mark at the application site, which persisted for up to 3 months after study completion.

6.2 Post Marketing Experience

The following adverse reactions have been identified during post approval use of Leptofen (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.

The most commonly observed events were related to application site reactions which included urticaria, application site discharge, erosion, hyperesthesia, pustules, rash and scab, application site bleeding, application site infection, and necrosis.

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 Leptofen (Fentanyl).

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids .

7. DRUG INTERACTIONS

Table 2 includes clinically significant drug interactions with Leptofen (Fentanyl).

Inhibitors of CYP3A4
Clinical Impact:

The concomitant use of Leptofen (Fentanyl) and CYP3A4 inhibitors can increase the plasma concentration of Leptofen (Fentanyl), resulting in increased or prolonged opioid effects .

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the Leptofen (Fentanyl) plasma concentration will decrease , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to Leptofen (Fentanyl).

Intervention:

If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, monitor for signs of opioid withdrawal.

Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice.
CYP3A4 Inducers
Clinical Impact:

The concomitant use of Leptofen (Fentanyl) and CYP3A4 inducers can decrease the plasma concentration of Leptofen (Fentanyl) , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to Leptofen (Fentanyl) .

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the Leptofen (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, monitor for signs of opioid withdrawal.

If a CYP3A4 inducer is discontinued, 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 and other CNS depressants, including alcohol, can increase the risk of hypotension, 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 Drugs
Clinical 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. Discontinue Leptofen (Fentanyl) 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 affect 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 Leptofen (Fentanyl) is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of Leptofen (Fentanyl) and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact: Leptofen (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 the muscle relaxant as necessary.
Diuretics
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.
Anticholinergic Drugs
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 Leptofen (Fentanyl) is used concomitantly with anticholinergic drugs.

Mixed Agonist/Antagonist and Partial Agonist Analgesics: Avoid use with Leptofen (Fentanyl) because they may reduce the analgesic effect of Leptofen (Fentanyl) or precipitate withdrawal. ( 7)

8. USE IN SPECIFIC POPULATIONS

Hepatic impairment and/or renal impairment: Monitor for signs of sedation and respiratory depression.

8.1 Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome . Available data with Leptofen (Fentanyl) 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 Leptofen (Fentanyl) in pregnant women. Limited published data on Leptofen (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.

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 .

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. Leptofen (Fentanyl) is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Leptofen (Fentanyl), 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 Leptofen (Fentanyl) on embryo-fetal development were studied in rat and rabbit models.

Published literature reports that administration of Leptofen (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 Leptofen (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 Leptofen (Fentanyl) (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from Gestation Day 6 to 18. Leptofen (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 Leptofen (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 Leptofen (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. Leptofen (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 Leptofen (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.

8.2 Lactation

Risk Summary

Limited published literature reports that Leptofen 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 Leptofen (Fentanyl) and any potential effects on the breastfed infant from Leptofen (Fentanyl) or from the underlying maternal condition.

Clinical Considerations

Infants exposed to Leptofen (Fentanyl) 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.

8.3 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 .

8.4 Pediatric Use

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

8.5 Geriatric Use

Leptofen (Fentanyl) 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 Leptofen (Fentanyl) 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 Leptofen (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 .

Leptofen (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.

8.6 Hepatic Impairment

Insufficient data are available on the use of Leptofen in patients with impaired hepatic function. Since Leptofen (Fentanyl) is eliminated by hepatic metabolism and Leptofen (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 Leptofen (Fentanyl).

8.7 Renal Impairment

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

9. DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Leptofen contains Leptofen (Fentanyl), a Schedule II controlled substance.

9.2 Abuse

Leptofen (Fentanyl) contains Leptofen (Fentanyl), a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Leptofen (Fentanyl) 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 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.

Leptofen (Fentanyl), 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 Leptofen (Fentanyl)

Leptofen (Fentanyl) is for transdermal use only for patients in the hospital. Abuse of Leptofen (Fentanyl) poses a risk of overdose and death. This risk is increased with concurrent abuse of Leptofen (Fentanyl) and alcohol and other central nervous system depressants . Contact with residual Leptofen (Fentanyl) in hydrogel of the device can result in fatal overdose.

9.3 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.

Leptofen (Fentanyl) should not be abruptly discontinued in a physically dependent patient . If Leptofen (Fentanyl) 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 .

10. OVERDOSAGE

Clinical Presentation

Acute overdose with Leptofen (Fentanyl) can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations .

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The opioid antagonists naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to Leptofen (Fentanyl) overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to Leptofen (Fentanyl) overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of Leptofen (Fentanyl) in Leptofen (Fentanyl), carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist may precipitate acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

11. DESCRIPTION

11.1 Chemical Characteristics of Drug Substance and Product

Leptofen (fentanyl iontophoretic transdermal system) is a patient-controlled iontophoretic transdermal system providing on-demand systemic delivery of Leptofen (Fentanyl), an opioid agonist, for up to 24 hours or a maximum of 80 doses, whichever comes first.

The chemical name is propanamide, N-phenyl-N-[1-(2-phenylethyl)-4- piperidinyl] monohydrochloride. The structural formula is:

The molecular weight of Leptofen (Fentanyl) hydrochloride is 372.93, and the empirical formula is C 22H 28N 2O·HCl. The n-octanol:water partition coefficient is 860:1; the pKa is 8.4.

The active ingredient in Leptofen (Fentanyl) is Leptofen (Fentanyl). Leptofen (Fentanyl) contains 10.8 mg of Leptofen (Fentanyl) hydrochloride equivalent to 9.7 mg of Leptofen (Fentanyl). Leptofen (Fentanyl) is designed to deliver a 40 mcg dose of Leptofen (Fentanyl) (equivalent to 44.4 mcg of Leptofen (Fentanyl) hydrochloride) over a 10-minute period upon each activation of the dose button .

The inactive ingredients in the Leptofen (Fentanyl) hydrogels consist of cetylpyridinium chloride, USP; citric acid, USP; polacrilin; polyvinyl alcohol; sodium citrate, USP; sodium chloride, USP; sodium hydroxide; and purified water, USP.

Chemical Structure

11.2 System Components and Structure

Each Leptofen (Fentanyl) is composed of a plastic top housing that contains the battery and electronics and a red plastic bottom housing containing two hydrogel reservoirs and a polyisobutylene skin adhesive. Only one of the hydrogels (the anode, located under the dosing button) contains Leptofen (Fentanyl) HCl, along with inactive ingredients. The other hydrogel (the cathode) contains only pharmacologically inactive ingredients. The bottom housing has a red tab that is used for Leptofen (Fentanyl) removal from the skin and during disposal . A siliconized clear, plastic release liner covers the hydrogels and must be removed and discarded prior to placement on the skin. Leptofen (Fentanyl) is powered by a 3-volt lithium battery.

Figure 8 Leptofen (Fentanyl) ® (fentanyl iontophoretic transdermal system)

Figure of Leptofen (Fentanyl) Unit

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Leptofen contains Leptofen (Fentanyl), an opioid agonist whose principal therapeutic action is analgesia. Leptofen (Fentanyl) interacts predominantly with the μ-opioid receptor. These μ-binding sites are discretely distributed in the human brain, spinal cord, and other tissues.

12.2 Pharmacodynamics

Effects on Central Nervous System

Leptofen (Fentanyl) produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Leptofen (Fentanyl) causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on Gastrointestinal Tract and Other Smooth Muscle

Leptofen (Fentanyl) causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Leptofen (Fentanyl) produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon .

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date .

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

When patients titrated themselves to analgesic effect with Leptofen (Fentanyl), serum concentrations were in the range of 0.4 to 1.5 ng/mL over the 24-hour dosing period.

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of Leptofen (Fentanyl) for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance .

Concentration–Adverse Reaction Relationships

There is a relationship between increasing Leptofen (Fentanyl) plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.

12.3 Pharmacokinetics

Unless otherwise specified, the clinical pharmacology studies described in this section were performed in healthy adult volunteers. Volunteers were administered naltrexone to antagonize the opioid effects of Leptofen (Fentanyl).

Absorption

At the initiation of each dose, an electrical current is activated for 10 minutes, which moves a dose of Leptofen (Fentanyl) from the drug-containing reservoir through the skin and into the systemic circulation. Compared to IV Leptofen (Fentanyl) administration, Leptofen (Fentanyl) concentrations in blood increase slowly with Leptofen (Fentanyl) activation and continue to increase for approximately 5 minutes after the completion of each 10-minute dose.

The systemic absorption of Leptofen (Fentanyl) from Leptofen (Fentanyl) increases as a function of time, and this increase appears to be independent of frequency of dosing. At treatment initiation, the amount of Leptofen (Fentanyl) absorbed is expected to be approximately 16 mcg. In clinical pharmacokinetic studies, on-demand dosing was initiated immediately after Leptofen (Fentanyl) application. This resulted in absorption of a 40 mcg Leptofen (Fentanyl) dose by about 10 hours post treatment initiation. Thereafter, a 40 mcg dose of Leptofen (Fentanyl) is delivered with each activation.

After delivery of the maximum number of doses in the shortest possible time period (80 consecutive doses delivered over approximately 13 hours), the average Leptofen (Fentanyl) serum concentration was 1.94 ± 0.43 ng/mL. Pharmacokinetic data from illustrative dosing regimens are represented in Table 3. When Leptofen (Fentanyl) was applied without activating the current, the average absorption rate for Leptofen (Fentanyl) over 24 hours was 2.3 mcg/h.

Inter-subject variability in Leptofen (Fentanyl) AUC following Leptofen (Fentanyl) treatment (33%) was comparable to IV Leptofen (Fentanyl) treatment (28%).

The delivery of Leptofen (Fentanyl) from Leptofen (Fentanyl) is similar whether applied on the upper outer arm or the chest. When Leptofen (Fentanyl) is placed on the lower inner arm, the delivery of Leptofen (Fentanyl) is approximately 20% lower. Other application sites have not been evaluated.

Figure 9: Serum Leptofen (Fentanyl) Concentration Following 40 mcg Leptofen (Fentanyl) ® (fentanyl) Compared to IV Leptofen (Fentanyl)

A: First Hour of a Representative Treatment *

B: Last Hour and Upon Termination of a Representative Treatment *

* Leptofen (Fentanyl) ® 40 mcg: 2 sequential doses over 20 minutes every hour for 23 hours and 20 minutes; IV: 80 mcg dose over 20 minutes every hour for 23 hours and 20 minutes.

Dosing Regimen
Parameter

48 a doses (two sequential doses every hour for 23 hours and 20 minutes)

80 b sequential doses (one dose every ten minutes for 13 hours and 20 minutes)
AUC per on demand dose (ng/mL) 0.57±0.13 0.51±0.16
Cmax (ng/mL) 1.3±0.3 1.94±0.43

AUC for this dosing regimen is value estimated between 23-24 hours

Average AUC over all doses delivered during the treatment duration (13.33 hours)

a Representative dosing regimen based on number of doses administered by patients in Phase 3 clinical studies

b Maximum theoretical dosing

Distribution

Leptofen (Fentanyl) administered intravenously exhibits a three-compartment disposition model. In healthy volunteers after IV administration, the estimated initial distribution half-life was about 6 minutes; the second distribution half-life was about 1-hour; and the terminal half-life was about 16 hours. The average volume of distribution for Leptofen (Fentanyl) at steady state following IV administration is 833 L.

Mean values for unbound fractions of Leptofen (Fentanyl) in plasma are estimated to be between 13 and 21%. Leptofen (Fentanyl) binds to erythrocytes, α1 acid glycoproteins, and plasma albumin.

Binding is independent of drug concentration over the therapeutic range. Leptofen (Fentanyl) plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in blood pH may alter ionization of Leptofen (Fentanyl) and therefore its distribution between plasma and the central nervous system. Leptofen (Fentanyl) accumulates in the skeletal muscle and fat and is released slowly into the blood.

Elimination

The average clearance in healthy subjects following IV administration was observed to be 53 L/h. A decline in Leptofen (Fentanyl) concentration after termination of treatment and the terminal half-life is similar following IV administration of Leptofen (Fentanyl) and Leptofen (Fentanyl). This suggests a negligible contribution from continued absorption of Leptofen (Fentanyl) remaining in the skin.

Metabolism

In humans, Leptofen (Fentanyl) is metabolized primarily by cytochrome P450 3A4-mediated N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug.

Skin does not metabolize Leptofen (Fentanyl) administered transdermally. This was determined in a human keratinocyte cell assay.

Excretion

Within 72 hours of IV Leptofen (Fentanyl) administration, approximately 75% of the dose is excreted in urine, mostly as metabolites, with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites.

Specific Populations

Age

Age did not affect Leptofen (Fentanyl) absorption from Leptofen (Fentanyl).

Sex

Sex differences have been reported for hepatically metabolized drugs. Generally, those that are metabolized by CYP3A4 appear to be eliminated faster by women in many cases. There have been no reports on gender differences in Leptofen (Fentanyl) pharmacokinetics.

Race

Race did not affect Leptofen (Fentanyl) absorption from Leptofen (Fentanyl).

Hepatic Impairment

No studies specific to Leptofen (Fentanyl) in patients with hepatic impairment have been conducted. In the literature, Leptofen (Fentanyl) appears to be affected more by hepatic blood flow than by hepatocellular function. The plasma concentration time profiles for the control and cirrhotic patients were similar and not significantly different with respective average elimination half-life values of 10.8 mL/min/kg vs. 11.3 mL/min/kg and volume of distribution values of 3.81 L/kg vs. 4.41 L/kg. In addition, the pharmacokinetics of Leptofen (Fentanyl) in patients with end-stage liver disease who were undergoing hemodialysis to those in normal patients was studied. While differences between groups were not statistically significant, Leptofen (Fentanyl) clearance values were reported to be lower for the hepatically impaired patients.

Renal Impairment

No studies specific to Leptofen (Fentanyl) in patients with renal impairment have been conducted. In the literature, the pharmacokinetics of Leptofen (Fentanyl) in patients with severe renal disease was compared to healthy patients. Plasma Leptofen (Fentanyl) concentrations decreased faster following an IV Leptofen (Fentanyl) administration in those with renal disease than in the control group, indicating more rapid clearance in the former. As renal clearance of Leptofen (Fentanyl) is only 10%, a decrease in renal function would not be expected to have a significant effect on the clearance of Leptofen (Fentanyl).

Drug Interaction Studies

CYP3A4 Inhibitors

Leptofen (Fentanyl) is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4). The interaction between ritonavir, a CPY3A4 inhibitor, and Leptofen (Fentanyl) was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was 200 mg three times a day on Day 1 and 300 mg three times a day on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, Leptofen (Fentanyl) was given as a single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of Leptofen (Fentanyl). The results suggested that ritonavir might decrease the clearance of Leptofen (Fentanyl) by 67%, resulting in a 174% (range 52%–420%) increase in Leptofen (Fentanyl) AUC0-∞. The concomitant use of transdermal Leptofen (Fentanyl) with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice) may result in an increase in Leptofen (Fentanyl) plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients receiving Leptofen (Fentanyl) and any CYP3A4 inhibitor for signs of respiratory depression for an extended period of time and discontinue Leptofen (Fentanyl) if warranted .

CYP3A4 Inducers

Co-administration with agents that induce CYP3A4 activity may decrease plasma concentration of Leptofen (Fentanyl) following use of Leptofen (Fentanyl). Discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in Leptofen (Fentanyl) plasma concentration.

First Hour of a Representative Treatment image Last Hour and Upon Termination of a Representative Treatment image

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a two-year carcinogenicity study conducted in rats, Leptofen (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

Leptofen (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 Leptofen (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 Leptofen (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 Leptofen (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 Leptofen (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 Leptofen (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.

14. CLINICAL STUDIES

14.1 Placebo-Controlled Trials

The efficacy and safety of Leptofen (Fentanyl) for treatment of short-term acute pain were evaluated in three placebo-controlled studies in postoperative patients. The patients were predominantly female (70‑83%) and Caucasian (79‑84%), and their mean age was 45‑54 years (range, 18‑90 years). Patients were enrolled while in the recovery room shortly after major surgery (predominantly lower abdominal or orthopedic) if they were expected to require at least 24 hours of parenteral opioid treatment and were not opioid tolerant; their ASA (American Society of Anesthesiologists) physical status was I, II, or III; and their postsurgical recovery was expected to be uncomplicated. Across the trials, 154 patients were ASA I status (21%); 435 patients were ASA II status (60%); and 138 patients were ASA III status (19%). Administration of long-lasting or continuous regional analgesics, or any non-opioid analgesics, was not permitted in the studies. Patients who remained in the studies for three or more hours using Leptofen (Fentanyl) (or the control) for patient-controlled analgesia (PCA) were considered evaluable.

In the immediate postoperative period, patients were titrated to comfort with IV Leptofen (Fentanyl) or morphine per hospital protocol. Once comfortable, patients were randomized and Leptofen (Fentanyl) or matching placebo Leptofen (Fentanyl) was applied. Patients were instructed to use Leptofen (Fentanyl) for pain. Supplemental IV Leptofen (Fentanyl) was administered by bolus injection as needed to achieve comfort up to three hours post-enrollment. The percentage of patients who used rescue medication during these three hours, as well as the mean amount of rescue medication used, is shown in Table 4 below.

Study Leptofen (Fentanyl)

n=454

Placebo

n=273

Study 1 45% (83 mcg) 52% (102 mcg)
Study 2 48% (100 mcg) 55% (95 mcg)
Study 3 34% (78 mcg) 36% (76 mcg)

After Study Hour 3, Leptofen (Fentanyl) alone or the placebo treatment alone was used to provide analgesia. Efficacy demonstrated in all three studies as demonstrated by the last mean pain intensity scores recorded during the 24-hour treatment period are presented in Table 5.

Study Leptofen (Fentanyl)

n=454

Placebo

n=273

p-value
Study 1

(NRS a)


3.4

5.3 <0.0001
Study 2

(VAS b)


31

41 0.0474
Study 3

(VAS b)


21

37 0.0006

a Verbal numerical rating scale 0-10 at 24 hours or at discontinuation

b Visual analogue scale, 0-100 mm at 24 hours or at discontinuation

In each of the three randomized, double-blind, placebo-controlled trials, fewer patients discontinued for lack of efficacy from three hours to twenty-four hours after Leptofen (Fentanyl) application.


Study


Leptofen (Fentanyl)

n=454

Placebo

n=273

p-value
Study 1 27% (64/235) 57% (116/204) <0.0001
Study 2 25% (36/142) 40% (19/47) 0.049
Study 3 8% (6/77) 41% (9/22) 0.0001

The efficacy of Leptofen (Fentanyl) was similar across the range of body mass indices studied (<25 to >40 kg/m 2 Body Mass Index).

Patients who completed 24 hours of Leptofen (Fentanyl) treatment in the controlled studies used a wide range of the available 80 doses, with a mean of 29 doses per patient (range of 0 to 93 doses). The majority of patients (56.5%) used between 11 to 50 doses. One percent of patients required a second Leptofen (Fentanyl) within 24 hours, after exhausting the first Leptofen (Fentanyl).

16. HOW SUPPLIED/STORAGE AND HANDLING

Leptofen (Fentanyl) (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 Leptofen (Fentanyl))

ACCIDENTAL CONTACT WITH THE HYDROGELS (ON THE ADHESIVE SIDE OF Leptofen (Fentanyl)) CAN RESULT IN FATAL OVERDOSE OF Leptofen (Fentanyl). THEREFORE, THE Leptofen (Fentanyl) 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 .

Leptofen (Fentanyl) 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.

17. PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Life-Threatening Respiratory Depression

  • Inform patients of the risk of respiratory depression, including information that the risk is greatest when starting Leptofen (Fentanyl), and that it can occur even at the recommended dosage . Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
  • Advise patients not to leave the hospital with Leptofen (Fentanyl) .
  • Advise patients not to let anyone else activate the dosing button on the Leptofen (Fentanyl) since only the patient knows how much pain he or she is experiencing. Patients should be cautioned that allowing others to activate the device may result in a potentially fatal overdose .

Accidental Exposure

  • Inform patients that accidental exposure, especially in children, may result in respiratory depression or death .
  • Advise patients not to let anyone touch Leptofen (Fentanyl) if it falls off accidentally and to contact their nurse, pharmacist, or doctor immediately. Accidental exposure to the Leptofen (Fentanyl) hydrogel may result in a fatal overdose of Leptofen (Fentanyl).
  • Instruct patients not to remove or reposition Leptofen (Fentanyl) and that Leptofen (Fentanyl) must be removed only by medical personnel .
  • Instruct patients not to touch the sticky side of Leptofen (Fentanyl) and not to touch the gels. Caution patients that Leptofen (Fentanyl) is rapidly absorbed by the eyes and mouth and could be harmful or fatal if absorbed this way. Advise patients to inform a health care provider if accidental exposure occurs and to immediately rinse the affected area with copious amounts of water. Soap, alcohol, or other solvents should not be used because they may enhance permeability .
  • Instruct patients to keep Leptofen (Fentanyl) out of the reach of children at all times .

Addiction, Abuse and Misuse

  • Inform patients that the use of Leptofen (Fentanyl), even when taken as recommended can result in addiction, abuse and misuse, which can lead to overdose and death .

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Leptofen (Fentanyl) is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider .

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life‑threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications .

MAOI Interaction

Inform patients to avoid taking Leptofen (Fentanyl) while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Leptofen (Fentanyl) .

Important Administration Instructions

Advise patients that the level of current (62 microA/cm 2) provided by Leptofen (Fentanyl) is generally imperceptible to the patient.

Anaphylaxis

  • Inform patients that anaphylaxis have been reported with ingredients contained in Leptofen (Fentanyl). Advise patients how to recognize such a reaction and when to seek medical attention .
  • Advise patients to inform the health care provider of any allergies to Leptofen (Fentanyl), cetylpiridinium chloride (e.g., Cepacol®) and or any components of Leptofen (Fentanyl).

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible .

Disposal of Unused Leptofen (Fentanyl)

Advise patients that only their health care provider should remove Leptofen (Fentanyl) from them and properly dispose of Leptofen (Fentanyl) prior to them leaving the hospital.

Manufactured, Distributed and Marketed by:

The Medicines Company

8 Sylvan Way

Parsippany, NJ 07054

Part No. 308-0023 Rev 02

Software Version: 205-0002, SB-SWC-002 Rev. 5, IT101 Controller Software, Version 1.6.715

Printed in USA

Leptofen (Fentanyl) ® Important Device Instructions

1 Explanation of Standardized Medical Device Symbols

Standardized symbols refer to specific warnings, features, or classifications of the device component of IONSYS® (fentanyl iontophoretic transdermal system). See Table 1 for the symbols and meaning of these symbols.

Symbol Meaning
Do not use
Operating instructions
Caution
Dust-protected

Protected against splashing water

Type body floating (BF) applied part*
Electrostatic discharge (ESD) sensitivity
Magnetic resonance (MR) unsafe
Radio frequency (RF) transmitter

*Body floating (BF) refers to a device that comes into contact with the patient’s body and allows for electrical conductivity.

2 System Components and Structure

Each Leptofen (Fentanyl) is composed of a plastic top housing that contains the battery and electronics and a red plastic bottom housing containing two hydrogel reservoirs and a polyisobutylene skin adhesive. Only one of the hydrogels (the anode, located under the dosing button) contains Leptofen (Fentanyl) HCl, along with inactive ingredients. The other hydrogel (the cathode) contains only pharmacologically inactive ingredients. The bottom housing has a red tab that is used only for Leptofen (Fentanyl) removal from the skin and during disposal. A siliconized clear, plastic release liner covers the hydrogels and must be removed and discarded prior to placement on the skin. Leptofen (Fentanyl) is powered by a 3-volt lithium battery.

Figure 1 Leptofen (Fentanyl) ® (fentanyl iontophoretic transdermal system)

3 Leptofen (Fentanyl) TROUBLESHOOTING

Leptofen (Fentanyl) delivers an on-demand dose of Leptofen (Fentanyl) over 10 minutes. The Normal Leptofen (Fentanyl) Feedback table below illustrates normal audible and visual feedback from Leptofen (Fentanyl) upon assembly and during patient use.

Mode Audible Feedback Visual Feedback

(Light)

Visual Feedback

(Digital Display)

Assemble Leptofen (Fentanyl) by snapping the two parts together A single audible beep Light will blink RED momentarily and then start blinking GREEN at a slow rate Display will flash “88” and then transition to steady “0” indicating that Leptofen (Fentanyl) is ready for use and 0 doses have been delivered
Ready Mode: Leptofen (Fentanyl) is ready and awaiting patient request for dose None Light will blink GREEN at a slow rate

Display will show the number of doses delivered (steady; not flashing)

Patient initiates a dose by pressing and releasing the button twice within 3 seconds A single audible beep indicates the start of delivery of each dose The light changes from blinking GREEN at a slow rate to blinking GREEN at a fast rate The display alternates between a walking circle and the number of doses delivered
10-minute dose is complete – Leptofen (Fentanyl) returns to Ready Mode None Light changes from blinking GREEN at a fast rate to blinking GREEN at a slow rate Display will show the number of doses delivered (steady; not flashing)
End of Use: 24 hours or 80 doses have been completed None None. Light will be Off. Display will flash the number of doses delivered

If Leptofen (Fentanyl) does not appear to function immediately, instruct the patient to attempt to initiate a dose again by firmly pressing and releasing the button twice within 3 seconds (i.e., double-press). A single audible beep will be emitted immediately, confirming that Leptofen (Fentanyl) is functional. Anytime during use, if Leptofen (Fentanyl) does not function properly, instruct the patient to call a staff member. Refer to the Error Messages table for possible problems and appropriate course of action. Error messages provide information (e.g., blinking lights, audible beeps) about problems that may occur during operation of Leptofen (Fentanyl).

Error Message/Feedback Probable Cause Action Required
Low battery or defective Leptofen (Fentanyl)
  • Do not use Leptofen (Fentanyl).
  • Dispose of Leptofen (Fentanyl).
  • Place a new Leptofen (Fentanyl) on a different skin site.
Poor skin contact
  • If Leptofen (Fentanyl) appears to be loose or lifting from skin, secure Leptofen (Fentanyl) to patient’s skin by pressing the edges with fingers or securing with non-allergenic tape.
  • If using tape, apply it along the long edges to secure Leptofen (Fentanyl) to patient’s skin. Do not cover button or display.
  • After taping, if Leptofen (Fentanyl) beeps again, remove and dispose. Place a new Leptofen (Fentanyl) on a different skin site.
  • Do not tape if evidence of blistered or broken skin.
System error
  • Remove Leptofen (Fentanyl) from patient.
  • Hold down dosing button until beeping stops and display goes blank.
  • Dispose of Leptofen (Fentanyl).
  • Place a new Leptofen (Fentanyl) on a different skin site.
End of use (24 hours or 80 doses elapsed)
  • Remove Leptofen (Fentanyl) from patient.
  • Hold down dosing button until display goes blank.
  • Dispose of Leptofen (Fentanyl).
  • Place a new Leptofen (Fentanyl) on a different skin site.

Electromagnetic Compatibility testing for Immunity, specifically, Electrostatic Discharge (ESD) testing, demonstrated contact discharges to the hydrogel touch points caused Leptofen (Fentanyl) to shut down in a safe mode in several cases. A safe mode is a mode in which the controller cannot be activated; thereby, unable to dispense the drug. Therefore, Leptofen (Fentanyl) that shut down due to an ESD event are non-operable and deemed defective. These ESD events only occurred during the task of assembling the controller and drug units together.

4 ELECTROMAGNETIC COMPATIBILITY

Leptofen (Fentanyl) is designed to be used only in a hospital environment. In this environment Leptofen (Fentanyl) was not shown to interfere with nearby electronic equipment, and is immune to interference from other electronic equipment. Leptofen (Fentanyl) was tested in compliance with IEC 60601-1-2 at test levels for a hospital environment. Table 4, Table 5, and Table 6 list tests performed and provide guidance on the environment.

Some diagnostic or therapeutic procedures (such as MRI, cardioversion, defibrillation, X-ray, CT, or diathermy), and some electronic security systems can exceed the test levels shown in the tables. Remove Leptofen (Fentanyl) before exposure to MRI, cardioversion, defibrillation, X-ray, CT, or diathermy. Leptofen (Fentanyl) contains radio-opaque components and may interfere with an X-ray image or CT scan. Avoid exposing Leptofen (Fentanyl) to electronic security systems. Electrostatic discharge can exceed the test levels shown in the tables. Avoid contact with synthetic materials (such as carpeted flooring) to reduce the possibility of electrostatic discharge. Communications equipment (such as base stations for radio telephones and land mobile radios, amateur radio, AM and FM radio broadcast and TV broadcast and Radio), and Radio Frequency Identification (RFID) transmitters, can exceed the test levels shown in the tables.

Minimize exposure to sources of electromagnetic radiation by adhering to the separation distances found in Table 6. If exposure to the procedures, electronic security systems, electrostatic discharge, communications equipment, or RFID systems occurs, and if Leptofen (Fentanyl) does not appear to function normally as described in Table 2, Leptofen (Fentanyl) should be removed and replaced with a new Leptofen (Fentanyl).

Leptofen (Fentanyl) is intended for use in the electromagnetic environment specified below. The health care provider should assure that Leptofen (Fentanyl) is used in such an environment.
Emission Test Compliance Electromagnetic Environment - Guidance
RF emissions

CISPR 11

Group 1 Leptofen (Fentanyl) uses RF energy only for its internal function. Therefore, its RF emissions are very low and are not likely to cause any interference in nearby electronic equipment.
RF emissions

CISPR 11

Class B Leptofen (Fentanyl) is suitable for use in all establishments, including domestic establishments and those directly connected to the public low-voltage power supply network that supplies buildings used for domestic purposes. NOTE: Leptofen (Fentanyl) is indicated for hospital use only.
Leptofen (Fentanyl) is intended for use in the electromagnetic environment specified below. The health care provider should assure that Leptofen (Fentanyl) is used in such an environment.

Immunity Test

IEC 60601

Test Level

Compliance Level Electromagnetic Environment - Guidance
Electrostatic

Discharge (ESD)

IEC 61000-4-2

± 6kV contact

± 8kV air

± 6kV contact

± 8kV air


Floors should be wood, concrete, or ceramic tile. If floors are covered with synthetic material, the relative humidity should be at least 30%.


Power frequency

(50/60Hz) magnetic field

IEC 61000-4-8

3 A/m 3 A/m

Power frequency magnetic fields should be at levels characteristic of a typical location in a typical hospital environment. (a)

Leptofen (Fentanyl) is MR UNSAFE. Remove Leptofen (Fentanyl) before an MRI procedure.


Radiated RF

IEC 61000-4-3

3 V/m

80 MHz to 2.5 GHz

3 V/m

80 MHz to 2.5 GHz


RF communications equipment and RFID transmitters should be used no closer to Leptofen (Fentanyl) than the recommended separation distance calculated from the equation applicable to the frequency of the transmitter.(a)

Recommended separation distance:

Where P is the maximum power output of the transmitter in watts (W) according to the transmitter manufacturer and d is the recommended separation distance in meters (m).

Interference may occur in the vicinity of equipment marked with the following symbol:

(a) Field strengths, as determined by an electromagnetic site survey, must be less than the stated compliance level. Remove Leptofen (Fentanyl) to prevent exposure to field strengths that exceed the stated compliance level.
Leptofen (Fentanyl) is intended for use in an electromagnetic environment in which radiated RF disturbances are controlled. The health care provider can help prevent electromagnetic interference by maintaining a minimum distance (meters) between RF transmitters and Leptofen (Fentanyl) as recommended below, according to the maximum output power (watts) of the transmitter.
Rated maximum output power of transmitter

(watts)

Separation distance according to frequency of transmitter

(meters)

150 kHz to 800 MHz

800 MHz to 2.5 GHz

0.01 0.12 0.23
0.1 0.38 0.73
1 1.2 2.3
10 3.8 7.3
100 12 23

For transmitters rated at a maximum output power not listed above, the recommended separation distance d in meters (m) can be estimated using the equation applicable to the frequency of the transmitter, where P is the maximum output power rating of the transmitter in watts (W) according to the transmitter manufacturer.

NOTE: For 1W RFID transmitters, the recommended separation distance is 2.3 meters.

NOTE: At 800 MHz, the separation distance for the higher frequency range applies.

NOTE: These guidelines may not apply in all situations. Electromagnetic propagation is affected by absorption and reflection from structures, objects, and people.


For questions about Leptofen (Fentanyl), including product returns, call 1-877-488-6835.

Manufactured, Distributed and Marketed by:

The Medicines Company

8 Sylvan Way

Parsippany, NJ 07054

December 2016

Part No. 308-0023 Rev 02

Software Version: 205-0002, SB-SWC-002 Rev. 5, IT101 Controller Software, Version 1.6.715

Printed in USA

no reuse image op instrcutions image caution symbol image splash water and dust protected image Type Body floating image esd image unsafe for MRI image RF Trans symbol Image of Leptofen (Fentanyl) Unit Low battery- defective device error image Pooor skin contact error image System error image End of Use error image esd symbol image MRI unsafe separation distance formula image Radio Frequency Transmitter symbol

Leptofen (Fentanyl) ® Medication Guide

Leptofen (Fentanyl) ® (eye-AHN-sis)

(fentanyl iontophoretic transdermal system) CII

Leptofen (Fentanyl) is:

  • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage acute postoperative pain, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
  • 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.
  • A patient-controlled medicine system that sticks to the skin. It will be applied by your healthcare provider on your upper outer arm or chest.

Important information about Leptofen (Fentanyl):

Get emergency help right away if you use too much Leptofen (Fentanyl), the active ingredient in Leptofen (Fentanyl) (overdose). Only you should press the button on Leptofen (Fentanyl). When you first start using Leptofen (Fentanyl), serious or life-threatening breathing problems that can lead to death may occur.

  • Never give anyone else your Leptofen (Fentanyl). They could die from using it. Store Leptofen (Fentanyl) away from children and in a safe place to prevent stealing or abuse. Selling or giving away Leptofen (Fentanyl) is against the law.
  • Leptofen (Fentanyl) is only for use in the hospital. Do not leave the hospital with Leptofen (Fentanyl) on your skin.
  • Using Leptofen (Fentanyl) with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.

Do not use Leptofen (Fentanyl) if you have:

  • severe asthma, trouble breathing, or other lung problems.
  • a bowel blockage or have narrowing of the stomach or intestines.
  • an allergy to Leptofen (Fentanyl) or Cepacol ® (cetylpyridinium chloride).

Before using Leptofen (Fentanyl), tell your healthcare provider if you have a history of:

  • head injury, seizures
  • liver, kidney, thyroid problems
  • pancreas or gallbladder problems
  • problems urinating
  • abuse of street or prescription drugs, alcohol addiction, or mental health problems.

Tell your healthcare provider if you are:

  • pregnant or planning to become pregnant. Prolonged use of Leptofen (Fentanyl) during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
  • breastfeeding. Leptofen (Fentanyl) passes into breast milk and may harm your baby.
  • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Using Leptofen (Fentanyl) with certain other medicines can cause serious side effects that could lead to death.

Your healthcare provider:

  • will tell you about Leptofen (Fentanyl) and teach you how to use it.
  • will put Leptofen (Fentanyl) on the skin (of your chest or upper outer arm) after your surgery
  • will control pain from your surgery with other pain medicines until you are awake enough to use Leptofen (Fentanyl)
  • will check you for side effects from Leptofen (Fentanyl).
  • must replace your Leptofen (Fentanyl) as needed. You should not replace your Leptofen (Fentanyl) yourself.
  • will remove your Leptofen (Fentanyl) before you leave the hospital. Do not leave the hospital with Leptofen (Fentanyl) on your skin.

How do I use Leptofen (Fentanyl)?

  • You can push the Leptofen (Fentanyl) dosing button when you are experiencing pain or just before you do an activity that may increase your pain - such as physical therapy or getting out of bed.
  • To get a dose of pain medicine from Leptofen (Fentanyl), press and release the dosing button twice within 3 seconds.

  • When you push the dosing button you will hear a single beep and the green light will start blinking quickly. The green light will continue to blink quickly for the 10 minutes it takes to deliver a dose of Leptofen (Fentanyl).
  • During this time, Leptofen (Fentanyl) will not deliver another dose even if you press the dosing button again.
  • Leptofen (Fentanyl) can only be activated every 10 minutes.
  • When Leptofen (Fentanyl) is finished delivering a dose, the green light will start blinking slowly. This means you can give yourself more pain medicine, if needed. Just press and release the dosing button twice within 3 seconds like you did before. The digital display will tell your healthcare provider how many doses you have received. Each Leptofen (Fentanyl) may be used for up to 24 hours or a maximum of 80 doses, whichever comes first.
  • If Leptofen (Fentanyl) starts beeping at any time tell your healthcare provider right away.

Your healthcare provider will check your Leptofen (Fentanyl) to make sure it is working properly.

When using Leptofen (Fentanyl):

  • Tell your healthcare provider if the dose you are using does not control your pain.
  • Do not let anyone else press the Leptofen (Fentanyl) dosing button for you. You are the only person who should push the dosing button.
  • Do not touch Leptofen (Fentanyl) if it falls off of your skin. Tell your healthcare provider right away if your Leptofen (Fentanyl) comes off of your skin. Rinse your hands with water (do not use soap) right away if you accidentally touch the sticky side of Leptofen (Fentanyl), and tell your healthcare provider right away.
  • Do not let others touch Leptofen (Fentanyl).
  • Do not remove or replace Leptofen (Fentanyl) yourself.
  • Do not leave the hospital with Leptofen (Fentanyl) on your skin. Make sure your healthcare provider removes your Leptofen (Fentanyl) before you leave the hospital.
  • Leptofen (Fentanyl) is MR Unsafe and should not be brought into an MRI environment.

Tell your healthcare provider right away if:

  • you have any questions about Leptofen (Fentanyl)
  • you are still having pain
  • Leptofen (Fentanyl) falls off your skin
  • you have trouble using Leptofen (Fentanyl)

While using Leptofen (Fentanyl) DO NOT:

  • Drive or operate heavy machinery, until you know how Leptofen (Fentanyl) affects you. Leptofen (Fentanyl) can make you sleepy, dizzy, or lightheaded.
  • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Leptofen (Fentanyl) may cause you to overdose and die.

The possible side effects of Leptofen (Fentanyl):

  • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Tell your healthcare provider if you have any of these symptoms and they are severe.

Tell your health care provider immediately 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 Leptofen (Fentanyl). Ask 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.

Manufactured, Distributed and Marketed by:

The Medicines Company

8 Sylvan Way

Parsippany, NJ 07054

December 2016

Part No. 308-0023 Rev 02

Software Version 205-0002, SB-SWC-002 Rev. 5, IT101 Controller Software, Version 1.6.715

Printed in USA

This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 12/2016

Leptofen (Fentanyl) device image press and release dosing button image

Instructions for Use and Disposal


Leptofen (Fentanyl) ®

Leptofen (Fentanyl) iontophoretic transdermal system, 40mcg/activation

For single use only. Up to 24 hours or 80 doses, whichever comes first.

Refer to the Prescribing Information (PI) and the following educational materials for more information about Leptofen (Fentanyl):

  • Leptofen (Fentanyl) Medication Guide
  • Leptofen (Fentanyl) REMS Safety Brochure: Guide for Nurses and Pharmacists

1. Prepare Patient Site

! ONLY 1 Leptofen (Fentanyl) system should be applied at any given time.

  • Choose healthy, unbroken skin on the upper outer arm or chest ONLY ( see Figure 1a).
  • Clip excessive hair if necessary.

    Do not shave-this irritates skin.

  • Clean with alcohol and let dry.

    Do not use soaps, lotions, or other agents.

  • When replacing an Leptofen (Fentanyl) system, the new system must be applied to a different site on the upper outer arm or chest.

2. Assemble Leptofen (Fentanyl)

! Always wear gloves when handling Leptofen (Fentanyl).

! Complete this step before applying Leptofen (Fentanyl) to patient.

  • Peel back tray lid ( see Figure 2a). Remove foil pouch and the controller.
  • Remove drug unit from foil pouch and place on a hard, flat surface ( see Figure 2b).

Continued on next panel.


2. Assemble Leptofen (Fentanyl) (cont.)

  • Align the matching shapes ( see Figure 2c).
  • Press on both ends of the device to ensure that snaps at both ends are fully engaged ( see Figure 2d).
  • Wait for system to complete self-test and the digital display to read “0” ( see Figure 2e).

3. Train Patient on Proper Use of Leptofen (Fentanyl)

! Refer to the Leptofen (Fentanyl) Medication Guide to counsel your patient on the safe use of Leptofen (Fentanyl).



4. Apply Leptofen (Fentanyl) to Patient

! Always wear gloves when handling Leptofen (Fentanyl).

  • Peel off clear liner and apply Leptofen (Fentanyl) to the prepared site ( see Figure 4a).
  • Press and hold Leptofen (Fentanyl) onto patient for 15 seconds by pressing the edges with fingers ( see Figure 4b). Do not press dosing button.
  • If Leptofen (Fentanyl) is not securely adhered, see Leptofen (Fentanyl) Troubleshooting – Poor skin contact.

NOTE: Ensure proper display orientation by reading "Doses Delivered" printed below the digital display.


5. Verify Proper Use of Leptofen (Fentanyl)

! Remember that ONLY the patient should press the dosing button.

! Remove before MRI or radiographic procedures as medically necessary.

  • Patient will initiate a dose by pressing and releasing the button twice in 3 seconds.
  • Each dose will be delivered over 10 minutes. During this time Leptofen (Fentanyl) is locked-out and will not respond to additional button presses.
  • During the 10 minutes the light will blink green at a fast rate and the display will alternate between a walking circle and the number of doses delivered ( see Figure 5).

6. Remove Leptofen (Fentanyl) from Patient and Dispose

! Follow your institution’s procedures for handling narcotics or refer to the PI for more information.

! Always wear gloves when handling Leptofen (Fentanyl).

! Important: If drug gel contacts your skin, thoroughly rinse area with water. Do not use soap.

  • With gloves on, remove Leptofen (Fentanyl) from the patient ( see Figure 6a).
  • Pull the red tab to separate the red housing containing the drug ( see Figure 6b).
  • Fold the red housing in half and dispose per your institution’s procedures or flush down the toilet ( see Figure 6c).
  • Hold down dosing button until display goes blank and dispose in waste designated for batteries.

Leptofen (Fentanyl) Troubleshooting

After successful assembly or anytime during use:

If you see or hear this… then do this:

Poor Skin Contact

  • If Leptofen (Fentanyl) appears to be loose or lifting from skin, secure it to patient’s skin by pressing the edges with fingers or securing with nonallergenic tape.
  • If using tape, apply it along the long edges to secure Leptofen (Fentanyl) to patient’s skin. Do not cover the button or display .
  • After taping, If Leptofen (Fentanyl) beeps again, remove and dispose. Place a new Leptofen (Fentanyl) on a different skin site.
  • Do not tape if evidence of blistered or broken skin .

Low Battery or Defective System

  • Do not use the system .
  • Dispose of Leptofen (Fentanyl) per instructions in section 6.
  • Place a new Leptofen (Fentanyl) on a different skin site.

System Error

  • Remove from patient.
  • Hold down dosing button until beeping stops and display goes blank.
  • Dispose of Leptofen (Fentanyl) per instructions in section 6.
  • Place a new Leptofen (Fentanyl) on a different skin site.

End-of-Use (80 doses or 24 hours)

  • Remove from patient.
  • Hold down dosing button until display goes blank.
  • Dispose of Leptofen (Fentanyl) per instructions in section 6.
  • Place a new Leptofen (Fentanyl) on a different skin site.
The Medicines Company

8 Sylvan Way

Parsippany, NJ 07054

Phone: 1-877-488-6835

Fax: 1-877-488-8601


Part Number 308-0024

Rev 02

Leptofen (Fentanyl) product image Patient site image product assembly fig 2a-b image product assembly fig 2c-d-e image remove liner hold on to patient for 15 secs proper use - verify fig 5 image remove product from patient site fig 6a-b-c image poor contact - audible-visual alarms image Low battery-defective unit - audible-visual alarms image System errror - audible-visual alarms image End of use - audible-visual alarms image

PRINCIPAL DISPLAY PANEL - Leptofen (Fentanyl) ® - Carton

Leptofen (Fentanyl) ® CII

(fentanyl iontophoretic transdermal system)

The

Medicines

Company

NDC 65293-011-06

Contains 6 Systems

Rx Only

Storage

Store at 25ºC (77ºF)

Excursion permitted to 15-30ºC (59-86ºF)

Store in the original tray

DO NOT USE IF SEAL ON TRAY OR POUCH IS BROKEN OR DAMAGED

Dosage and Administration

For transdermal use

Use immediately after removal from pouch

See accompanying product literature

Each activation delivers 40 mcg of Leptofen (Fentanyl) over 10 minutes. No more than 6 doses/hour can be delivered. A maximum of 80 doses/system can be delivered over 24 hours

See full Prescribing Information for disposal instructions

Dispense the enclosed Medication Guide to each patient.

carton principal panel

PRINCIPAL DISPLAY PANEL - Leptofen (Fentanyl) ® - Label

Leptofen (Fentanyl) ® CII

(fentanyl iontophoretic transdermal system)

40 mcg/activation

(equivalent to Leptofen (Fentanyl) HCl 44.4 mcg)

For hospital use only

Each activation delivers 40 mcg of Leptofen (Fentanyl) over 10 minutes. No more than 6 doses can be delivered in one hour. Maximum of 80 doses/system over 24 hours. Each system contains 10.8 mg Leptofen (Fentanyl) HCl

NDC 65293-011-01

Tray contains one Drug Unit and one Controller

Rx Only

Store in the original tray

Store at 25ºC (77ºF) Excursion permitted to 15-30ºC (59-86ºF)

DO NOT USE IF SEAL ON TRAY OR POUCH IS BROKEN OR DAMAGED

KEEP OUT OF REACH OF CHILDREN

See full Prescribing Information for disposal instructions

Dispense the enclosed Medication Guide to each patient.

Do Not Reuse

Operating Instructions

Electrostatic Discharge (ESD) Sensitivity

Dust-protected Protected against splashing water

MR Unsafe

TYPE BF APPLIED PART

Caution

Manufactured, Distributed and Marketed by:

The Medicines Company

Parsippany, NJ 07054

Leptofen pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Leptofen available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Leptofen destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Leptofen Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Leptofen pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."RECUVYRA (FENTANYL) SOLUTION [ELANCO ANIMAL HEALTH CO]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."DROPERIDOL INJECTION, SOLUTION [HOSPIRA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."FENTANYL: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Leptofen?

Depending on the reaction of the Leptofen after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Leptofen not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Leptofen addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Leptofen, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Leptofen consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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