INSTRUCTIONS FOR USE SECTION.

INSTRUCTION FOR USE. User ManualManufacturer: Biofrontera Pharma GmbHDistributor: Biofrontera Inc.ForewordThank you for choosing the BF-RhodoLED(R) LED lamp for your photodynamic therapy. BF-RhodoLED(R) has been developed in accordance with applicable technical standards to provide high energy efficiency as well as constant light emission at the desired wavelength.Your lamp must be installed and maintained by certified Biofrontera technician and used only in accordance with the instructions in this manual. You may request the latest printed version covering this model from Biofrontera at any time.Our drug Ameluz(R) and medical device BF-RhodoLED(R) have been approved in combination for photodynamic therapy; the only approved use of our lamp is in combination with Ameluz(R) gel. This user manual provides important BF-RhodoLED(R) product details, cautions and warnings, and operating instructions. For Ameluz(R), please use its US prescribing information. The Ameluz(R) prescribing information includes information on how to use the gel along with contraindications, warnings and precautions and dosage and administration.Thorough reading and use of both this user manual and the Ameluz(R) USPI is required prior to treatment.Our combination Ameluz(R)/BF-RhodoLED(R) for photodynamic therapy is only to be used by physicians or healthcare professionals.For further questions about Ameluz(R), BF-RhodoLED(R) or the combination therapy please contact your sales representative or Biofrontera (Ameluz-USbiofrontera.com). See contact information below or visit us at http://www.biofrontera.us.com/Sales representative:Name:Tel.:E-mail:Biofrontera Inc.120 Presidential WaySuite 330Woburn, MA 01801USAPhone: (844) 426-3589Warranty and DisclaimersPlease see the terms and conditions of your contract for this information.ManufacturerBiofrontera Pharma GmbH, Hemmelrather Weg 201, 51377 Leverkusen, Germany1 Intended UseBF-RhodoLED(R) is red light emitting LED lamp which is used exclusively in combination with Ameluz(R) gel for lesion-directed and field-directed treatment of actinic keratoses (AKs) of mild-to-moderate severity on the face and scalp.2 BF-RhodoLED(R) General DescriptionBF-RhodoLED(R) is comprised of three main components, the lamp head, the easily adjustable scissor arm, and the mobile frame with castors for smooth transport. In addition, the lamp has convenient touchscreen monitor, storage shelf, aids for positioning the lamp head and variable speed patient fan that can be regulated throughout the treatment.3 Warnings and PrecautionsThe BF-RhodoLED(R) has been developed for use in photodynamic therapy in combination with Ameluz(R)gel (excitation wavelength approx. 635 nm). Any other use or combination of use is prohibited.During PDT side-effects such as application site erythema, pain, irritation, edema, pruritus, exfoliation, scab, induration and vesicles may occur. For further information please see Ameluz(R) USPI chapter 6.The user manual must be read carefully prior to using the BF-RhodoLED(R).The BF-RhodoLED(R) may only be used by healthcare professionals who have received adequate training in its use.To avoid eye irritation, glare, or injury, protective eye equipment must be used by patient, healthcare providers and any person present during the illumination period.Neither the BF-RhodoLED(R) nor the power supply unit should be exposed to excessive mechanical stress or serviced by unauthorized personnel. Assembly and servicing may only be carried out by Biofrontera certified professionals.Risk of trapping fingers The mobility of the adjustable scissor arm may be obstructed by objects placed in or near slotsDepending on positioning, the scissor arm slots below each connecting portion of the scissor arm and to the right of the support rail can cause fingers or objects to become trapped. When transporting or adjusting the lamp please ensure that fingers or other objects are NOT placed in or near the slots (see Figure 1).Beware of TippingIf the castors are in locked position, the lamp will tip over if exposed to lateral force. Leaning against the device or using it for support is not permitted.Do not place the lamp on uneven or unstable surfaces.Do not place heavy objects on the storage shelf (maximum load up to kg) or use for sitting, leaning or pushing, as this can lead to the device tipping over.In order to avoid the risk of electrical shock, the device may only be connected to power supply with grounded connection.Neither the BF-RhodoLED(R) nor its touchscreen monitor may come into contact with water as this may lead to severe damage or electrical shock (exception: cleaning with damp cloth).The plexiglass plate on the lamp head may NOT be touched during or directly after treatment as, in the event of faulty operation, the maximum temperature can reach approx. 73 (163.4 F).The BF-RhodoLED(R) should be operated and housed indoors in areas with temperatures between 0C and 40C (32F and 104F), and relative humidity of 10 to 90 %.Medical electronic devices require special precautionary measures with regard to the electro-magnetic compatibility (EMC); to avoid elect-magnetic disturbances, please do not place the device close to other electrical devices.There is risk of tripping over the power cord or the lamp base. When transporting or when device is not in use, unplug and keep the power cord wound around the star knobs.Ensure that the touchscreen monitor is always returned to the fixture intended for this purpose, located on the storage shelf. Storing the touchscreen monitor by hanging it can lead to damage to the spiral cord and the plug fitting.The touchscreen monitor should not be exposed to strong external pressure or sharp objects.A person trained in operation of the BF-RhodoLED(R) must always be present during treatment. Both the maintenance and the assembly of the BF-RhodoLED(R) and its components (including the opening of individual components) may only be carried out by authorized personnel. In the event of servicing or assembly being carried out by any other party, Biofrontera assumes no responsibility or liability regarding the safety or use of the device.Figure 1: The scissor arm in parked position. Arrows indicate potential points where fingers can get trapped. (The appearance of devices from batches 001 to 003 slightly differs. Appearance and location of the labels remain unaltered).4 BF-RhodoLED(R) Technical Description4.1 Light Emitting Diodes (LEDs)The light-field of the BF-RhodoLED(R) consists of total of 128 LEDs and lenses (arranged in rectangle), which emit uniform, bundled, visible red light with typical peak wavelength of approximately 635 nm. The half-band width of the lamp is 20 nm.Figure 2: Typical emission spectrum of the LEDs of the BF-RhodoLED(R). Insert: Fluorescence excitation spectrum of PPIX in cells 0, and mm below the tissue surface (Moan et al., 1996)The BF-RhodoLED(R) LEDs are calibrated so that the skin being treated receives light dosage of approximately 37 J/cm2 under the following conditions:Illumination time of 10 minutesTreatment distance of 5-8 cm (Optimum cm)The illumination area of the LED lamp is x 18 cm. As the intensity decreases towards the edge of this area, the effective treatment area is reduced to x 16 cm.4.2 Lamp ComponentsThe BF-RhodoLED(R) LED lamp consists of the following components (Figure 3):Lamp head with holding bracketScissor armStorage shelf with control unit (touchscreen monitor)Mobile frame and lamp base (include support rail, castors and power supply)Figure 3: BF-RhodoLED(R) main components. (The appearance of devices from batches 001 to 003 slightly differs.)The swivel range to the left and right of the vertical rail is +/- 24. The lamp head can be adjusted horizontally and vertically and tilted sideways. The scissor arm with internal gas springs allows seamless adjustment of the lamp head to any position. Eye Protection In order to avoid eye irritation, glare or injury, protective eye equipment must be used by patient, healthcare providers and any person present during the illumination period. Do not stare into the light source The operator and other persons present must wear protective glasses with visible light transmission (VLT) of approximately 10%. The patient must wear eye protection such as disposable eye protection pads or eye caps with an optical density for visible light of or higher. Both options are effective and comfortable for use during treatment. Note: Eyewear is not part of the medical device. Please carefully read any accompanying usage information before using any eye protection. In order to avoid eye irritation, glare or injury, protective eye equipment must be used by patient, healthcare providers and any person present during the illumination period.6 BF-RhodoLED(R) PDT Summarized Step-by-Step InstructionsThese instructions should be used in conjunction with detailed operating instructions below (chapter 7). The section texts and numbers listed next to the instruction refer to the detailed instructions and/or descriptions that correspond with each step. Note: Every user of the BF-RhodoLED has to be trained in operating the device. The initial training is provided by Biofrontera during set-up of the BF-RhodoLED. Recurrent training is not mandatory but can be provided by Biofrontera employees. Before treating patient with Ameluz, please ensure that BF-RhodoLED is in good working order.STEP 1)Plug in lamp.STEP 2)Turn on the lamp and wait for home screen to appear (see chapter 7.3).STEP 3)Check the proper functioning of the BF-RhodoLED(R).STEP 4)Treat the affected skin area: Application, incubation and removal of the topical medication following the USPI of Ameluz(R).STEP 5)Position patient comfortably and place protective eyewear on patient (see chapter 5).STEP 6)Position the lamp and adjust the lamp head over the skin area to be treated (distance 5-8 cm) (see chapter 7.5.1).STEP 7)Put on protective eyewear and make sure anyone remaining in the treatment room also wears protective eyewear (see chapter 5).STEP 8)Start treatment by pressing Treatment on the home screen, press Start on the treatment screen, and press Start once again in the profile screen. The illumination period of 10 minutes begins (see chapter 7.5.3).Remind the patient to remain still throughout the illumination period.If sound tone during treatment is activated, explain the beep sequence to the patient.If the patient needs break, press Break on the profile standard screen. To resume treatment, press Start on the profile standard screen (see chapter 7.5.3).To abort the illumination, press Stop on the profile standard screen.Adjust fan speed as needed by patient by pressing plus or minus 1% or 10% on the profile standard screen.Stay with the patient at all times during the illumination period.STEP 9)At the end of the illumination period, remove patients protective eyewear and follow further instructions in the Ameluz(R) USPI.7 Detailed Operating InstructionsNote: Every user of the BF-RhodoLED has to be trained in operating the device. The initial training is provided by Biofrontera during set-up of the BF-RhodoLED. Recurrent training is not mandatory but can be provided by Biofrontera employees. The device must be protected against unauthorized use. In order to avoid eye irritation, glare or injury, protective eye equipment must be used by patient, healthcare providers and any person present during the illumination period.7.1 Transport of the lampThe transportation of the lamp shall be done when the scissor arm is completely folded. During transportation one hand shall hold on to the support rail or storage shelf while the other hand holds the scissor arm (Figure 4).Figure 4: Transport of the lamp. (The appearance of devices from batches 001 to 003 slightly differs.)7.2 Movement area of the scissor arm and the lamp headThe scissor arm has swivel range of +/- 24 degrees to the left and right. The swivel range is limited by pin at the connection between scissor arm/ support rail and scissor arm/ lamp head (Figure 5).The lamp head can be adjusted horizontally and vertically and tilted sideways, as it has swivel range of +/- 90 degrees in all three dimensions.Figure 5: Limiting pins of the scissor arm and the lamp head. (The appearance of devices from batches 001 to 003 slightly differs. Appearance and location of the labels remain unaltered.)7.3 Turning the Lamp On or Off Note: Before turning on the lamp, the power cord must be plugged in. After connecting, the lamp can be turned on and used following the instructions below.The on-off switch is located on the left side of the touchscreen monitor, close to its spiral cord. With the lamp plugged in, press the button to start the device.Important: This push button can also be used to turn the lamp off. Switching off the lamp can also be done by pressing the switch off button on the touchscreen (see chapter 7.4.2 Home Screen).Figure 6: Touchscreen monitor7.4 Touchscreen Monitor and MenuWhen using the touchscreen, please firmly press the center of the buttons shown on the screen to ensure it is read correctly by the software. Do not press too quickly, the input may not be read by the software. The touchscreen can be used while wearing commercially available examination gloves.7.4.1 Start ScreenThe Biofrontera corporate logo and software version are displayed during the LED lamp operating system start-up (Figure 7). The operating system takes approximately 30 seconds to load.Figure 7: Start screen7.4.2 Home ScreenThe home screen appears after the operating system has loaded. From the home screen you can select Treatment, Settings or Service (Figure 8). In the Treatment menu only one treatment profile profile standard is available. The illumination time and light intensity of this program are fixed (see 7.5.2 for further information). The Settings menu allows adjustment of language, time, date, audio signals and power saving settings (see 7.6 for further information). The Service menu may only be accessed by authorized personnel. You can turn the LED lamp off by pressing the button.Figure 8: Home screen7.5 Conducting TreatmentPrior to treating patient with Ameluz please ensure that BF-RhodoLED is in good working order. Before starting treatment, make sure the lamp is set-up in accordance with the operating instructions described in the following sections.7.5.1 Distance IndicatorPosition the lamp head over the skin area to be treated at distance of 5-8 cm. Use the adjustable distance indicator and graduated scale bar to help measure and aid in achieving the correct distance (Figure 9).Figure 9: Positioning of the lamp head to the treated skin area7.5.2 Adjustment LightTo further aid positioning, use the adjustment light. On the touchscreen, press the following buttons in sequence (starting in the home screen): Treatment (Figure 8), Adjust (Figure 11) and Start Adjustment (Figure 12). The adjustment light shows what the field of illumination will be during treatment but at lower intensity (6x16 cm, approx. 2.4 6.3 inches). When finished, press Stop adjustment and then Back (Figure 11) to return to the treatment menu (Figure 10).Figure 10: Treatment menuFigure 11: Start and Stop adjustment7.5.3 Treatment MenuPress treatment to enter the treatment menu (Figure 8). The standard illumination profile is depicted in graph in the treatment menu. The x- and y-axis specify the treatment duration and light intensity respectively (Figure 12).Figure 12: Treatment menuIn the treatment menu (Figure 12), press the Start button to access the profile standard screen.7.5.4 Profile Standard MenuIn the profile screen menu, press Start to begin treatment (Figure 13). You can interrupt the treatment at any time by pressing the Break button. Press the Start button to resume the treatment. Abort the current treatment by pressing the Stop button.If you press Stop prior to the end of the total treatment time, 10 minutes, the clock will reset and any interim treatment time will be not be saved. After pressing Stop or upon completion of the full 10 minute treatment the software will automatically return you to the treatment menu.The remaining treatment time is displayed to the right of the graph and the red vertical line within the graph indicates the time that has elapsed.Figure 13: Profile standard7.5.5 Audio Signals during TreatmentDuring treatment the patient will hear audio signals, beep indicating 25 %, beeps indicating 50 and beeps indicating 75 of the PDT is completed, and upon treatment completion the lamp will stop the illumination and beeps will be heard (see also chapter 7.6.2).7.5.6 Patient fanYou can control the speed of the patient fan both before and during treatment with the plus and minus buttons, in increments of % or 10 %. The patient fan continues to run when the treatment is paused (Break). The fan can be stopped by pressing Stop but be aware the treatment will also be aborted and any elapsed treatment time will not be saved. 7.6 Settings Menu The settings menu is invoked (Figure 14) by pressing the Settings button in the home screen view (see Figure 12).Figure 14: Settings menuYou can configure the following parameters in this menu:LanguageSignalsEnergy service (Power management)Switch back to the home screen menu via the Back button.7.6.1 Language SettingsSelect language by tapping on the desired language. Use the arrow keys to scroll through the list. Confirm the selected language with the OK button (Figure 15). Switch back to the settings menu without saving changes by pressing the Back button instead of OK.Figure 15: Language setting7.6.2 Sound SettingsActivate and deactivate the audio signals for typing, warnings and sounds during the treatment. To do this, select the desired fields. check mark means the sound is on.Confirm with the OK button (Figure 16) to save your settings or close the menu via the Back button to discard the setting.If Turn off sound is activated, all signal tones are switched off.Important Note: Warning sounds will be emitted if an error occurs during operation of the lamp.Figure 16: Sound setting7.6.3 Energy Service (Power Management)Providing the standby function is not manually deactivated via the check box Never turn off lamp automatically located near the bottom of the screen, the lamp will turn off after 10 minutes of non-use (Figure 17). You can change this time span in the menu Energy service via the plus and minus buttons. The settings are confirmed with the OK button and rejected with the Back button. In both cases you will return to the settings menu.Figure 17: Energy managementIf the configured time expires, request appears for 10 seconds asking if you wish to prevent shut down. The LED lamp turns off automatically afterwards.7.7 Service MenuAuthorization is required to access the service menu. Only authorized personnel can access the service menu. Error Messages The BF-RhodoLED(R) has an integrated monitoring function. In the event of malfunction, an error message will appear in the message display. Possible error messages are set out in the table below.Error messagePossible causes Measures Lamp overheatedThe temperature of the surrounding environment is too high.The ventilators or ventilator slots are blocked.The air inlets or outlets are adversely affected.Wait until the standard temperature has been reached.Check the ventilator and test the air inlets and outlets. Remove any visible foreign objects which may be present.In case of continuing impairment of cooling please contact your local sales representative or Biofrontera.Lamp errorPlease inform your supplier.Some of the LEDs have failed.Further treatments may be carried out. However, please contact your local sales representative or Biofrontera immediately.Communication errorCable break in the touchscreen monitor spiral cord.Poor contact between the touchscreen monitor connection plug and the conduit box.Confirm the communication error. Treatments can be continued in the treatment menu by pressing the Start button.Please contact your local sales representative or Biofrontera.Lamp not calibratedThe lamp is not calibrated.Improper calibration.The lamp has to be calibrated. Please contact your local sales representative or Biofrontera immediately.Fehler-Nr.: 0084 Please inform your supplier.A temperature sensor has failed.The lamp head has to be repaired. Please contact your local sales representative or Biofrontera.Firmware of light head is faulty or missingPlease inform your supplier.An Update of the firmware has to be performed.An update of the firmware has to be performed. Please contact your local sales representative or Biofrontera.If your LED lamp no longer functions properly for some unknown reason, proceed as follows:Unplug the power supply for half minute and then plug back into the outlet (This action prompts software reboot).Turn the lamp back on using the touchscreen monitor and verify functionality.Should the problem persist, please contact your sales representative or Biofrontera. The lamp may not be used until the problem has been rectified.For all other malfunctions and difficulties with operation please contact your sales representative or Biofrontera. You will find the contact details on page 2.9 ServicingServicing may only be performed by Biofrontera-authorized personnel. If servicing is done by third parties, BF-RhodoLED warranty is void and Biofrontera cannot be held responsible for potential malfunctions or damages of the device.During service, the gas springs (gas pressure springs and gas traction springs) in the scissor arm as well as the general safety condition of the BF-RhodoLED(R) are checked.Contact your sales representative or Biofrontera to schedule all service appointments.10 Maintenance and CleaningThe device may under no circumstances be cleaned with aggressive cleaning agents or solvents (e.g. acetone), as these promote wear and tear of the surface (paint coating), safety signs and graduated scale bar as well as the logo. Please avoid allowing any penetration of liquids into the lamp, BF-RhodoLED(R) is not waterproof and the electronics inside may be damaged.Always unplug the lamp prior to cleaning and please observe the following cleaning practices:Daily:Wipe the plexiglass screen located on the bottom of the lamp head with damp soft cloth (e. g. microfiber cloth).Weekly:Wipe the entire lamp with soft, dry or damp cloth. Do not use very wet or dripping cleaning cloth. The unit is not waterproof and damage could occur.Please observe the following checks:Monthly:Check lamp for obvious visible damage such as damaged cables, worn off labeling, cracks on the lamp housing, etc.11 Disposal InstructionsFollow all local and governmental disposal laws and regulations when disposing of the BF-RhodoLED(R).12 Technical Data12.1 Electrical connectorsPower supply unit:Primary wide-range input 120-240 VACSecondary safety extra-low voltage output 48 VDCSecondary standby voltage output VDCMother board for voltage management and control:Supply voltage input 48 VDCStandby voltage input VDC plus Standby contactRS485 interfaceOutput supply voltage HMI board 24 VDC4 ports LED board 8-pin (2 LED circuits, temperature (3-pin))4 connector ventilator (2-pin)LED board:2 ports mother board 8-pin (2 LED circuits, temperature (3-pin))Human Machine Interface (HMI) for operation:Supply voltage input 24 VDCRS485 interface12.2 SpecificationTypeBF-RhodoLED(R) Medical device class III; Device of protection class 1CertificationCSA certifiedSoftware Version No.1.4USCANService life of the lampApprox. yearsShelf life1.5 yearsNumber of LEDs128Typical peak wavelength635 nm +- nmLight dose (6 cm distance, 10 min)Approx. 37 J/ cm2 Typical irradiance61 mW/cm2 +/- 15 %Max irradiance77 mW/cm2 +/- 15 (at cm treatment distance)Illuminated areaAn area of 8x18 (approx. 3.1 7.1 inches) cm is illuminated. The effective treatment area is 6x16 cm (approx. 2.4 6.3 inches).Max. deviation of the intensity over the treatment areaApprox. 15 %Transport and storage conditionsTemperature: -30C to +60C (-22F to +140F)Atmospheric pressure: 500 hPa 1060 hPaRelative humidity: 10% 90%, non-condensingOperating conditionsTemperature: 0C to +40C (32F to +104F)Atmospheric pressure: 500 hPa 1060 hPaOperational altitude: <= 2000 above NNRelative humidity: 10% 90%, non-condensingThis PDT lamp is suitable for continuous operation.Operating voltage120-240 VAC, 50/60 HzOutput voltage48 VDCPower consumptionIn calibrated normal operation: approx. 140 VAIn standby mode: approx. 85 VAOver-voltage categoryIIDegree of contamination2Material group (CTI)IIIbProtection classIP20Size of the lamp95 62 168 cm (37 24 66 inches)Devices of batch 001 to 003: 127 56 168 cm (50 22 66 inches)Total lamp weightApprox. 52 kg (115 lbs)Devices of batch 001 to 003: approx. 48 kg (106 lbs)For further information please directly contact Biofrontera. 13 Labeling and Symbols 13.1 Labeling on the LampThe product sticker is located on the reverse side of the lamp base (see Figure 18). It contains manufacturer and product specifications (classification, serial and order number and the power supply used) as well as IP (Ingress) protection. In addition, unique device identifier label is placed next to the product sticker.Figure 18: Product and UDI label. (The appearance of devices from batches 001 to 003 slightly differs. Appearance and location of the labels remain unaltered.)Labels with safety instructions, special disposal instructions and further instructions are represented in the following figures.Figure 19: Instructions and notes on the lamp headFigure 20: Instructions on the storage shelf. (The appearance of devices from batches 001 to 003 slightly differs. Appearance and location of the labels remain unaltered.)Figure 21: Instructions on the scissors arm (The appearance of devices from batches 001 to 003 slightly differs. Appearance and location of the labels remain unaltered.)Instructions for existing ground connector connections (see Figure 22) are located:Next to the grounding screws, which are located within and next to the power supply cover box beneath the mobile castor, respectivelyOn the power supply cover box (see Figure 23)Figure 22: Instructions for ground connector connectionFigure 23: BF-RhodoLED(R). (The appearance of devices from batches 001 to 003 slightly differs. Appearance and location of the labels remain unaltered.)Instructions on the existing potential compensator conductor is located on the carrier bar beneath the potential compensator conductor (see Figure 24).Figure 24: Potential compensator conductor. (The appearance of devices from batches 001 to 003 slightly differs. Appearance and location of the labels remain unaltered.)All depicted symbols are summarized in table in section 13.2 Explanation of symbols.13.2 Description of SymbolsSymbolDescriptionEye protection is required.IP20IP (Ingress Protection):Protection class of the housing against contact, foreign bodies and water2 against ingress of solid foreign bodies >= 12,5 mm and larger0 Not protected against waterTechnical and electric devices must not be disposed of with household waste. Please pay attention to the applicable disposal instructions found in the user manual.Symbol for existing ground connector connectionsFollow the instructions for useGeneral warning signs:Assembly and servicing may ONLY be performed by BiofronteraOnly transport lamp in the park positionThe mobility of the extension and scissors arm may be obstructed by objectsCaution: heavy, do NOT lift alone.NEVER place this unit on an unstable, uneven surfaceWarning sign risk of trapping fingersSymbol for existing potential compensation conductorPlease do not stand on or push. There is risk that the device may fall over through of the force applied.Please do not sit on the equipment. There is risk that the device may fall over through the force applied.13.3 Labeling on the PackagingAttention: Protect from moisture and keep dryAttention: Do not throw the package, damage possibleAttention: Please transport and store at -30C/ -22F to +60C/ 140F, relative humidity of 10 to 90 and at an atmospheric pressure of 500 hPa (5 kPa) 1060 hPa (10,6 kPa).This side up Caution, one end of the package is heavyo Contains lithium metal battery (optionally, not required starting from batch 007)Version 2.1-US 29.10.2019. Illumination time of 10 minutes. Treatment distance of 5-8 cm (Optimum cm). Lamp head with holding bracket. Scissor arm. Storage shelf with control unit (touchscreen monitor). Mobile frame and lamp base (include support rail, castors and power supply). Language. Signals. Energy service (Power management). The temperature of the surrounding environment is too high.. The ventilators or ventilator slots are blocked.. The air inlets or outlets are adversely affected.. Some of the LEDs have failed.. Cable break in the touchscreen monitor spiral cord.. Poor contact between the touchscreen monitor connection plug and the conduit box.. The lamp is not calibrated.. Improper calibration.. temperature sensor has failed.. An Update of the firmware has to be performed.. Unplug the power supply for half minute and then plug back into the outlet (This action prompts software reboot).. Turn the lamp back on using the touchscreen monitor and verify functionality.. Primary wide-range input 120-240 VAC. Secondary safety extra-low voltage output 48 VDC. Secondary standby voltage output VDC. Supply voltage input 48 VDC. Standby voltage input VDC plus Standby contact. RS485 interface. Output supply voltage HMI board 24 VDC. x ports LED board 8-pin (2 LED circuits, temperature (3-pin)). x connector ventilator (2-pin). x ports mother board 8-pin (2 LED circuits, temperature (3-pin)). Supply voltage input 24 VDC. RS485 interface. Next to the grounding screws, which are located within and next to the power supply cover box beneath the mobile castor, respectively. On the power supply cover box (see Figure 23). Assembly and servicing may ONLY be performed by Biofrontera. Only transport lamp in the park position. The mobility of the extension and scissors arm may be obstructed by objects. Caution: heavy, do NOT lift alone.. NEVER place this unit on an unstable, uneven surface. Attention: Protect from moisture and keep dry. Attention: Do not throw the package, damage possible. Attention: Please transport and store at -30C/ -22F to +60C/ 140F, relative humidity of 10 to 90 and at an atmospheric pressure of 500 hPa (5 kPa) 1060 hPa (10,6 kPa).. This side up. Symbol 01. Symbol 02. Symbol 03. Symbol 04. Symbol 05. Symbol 06. Symbol 07. Symbol 08. Symbol 09. Symbol 10. Symbol 11. Symbol 12. Symbol 13. Symbol 14. Figure 01. Figure 02. Figure 03. Figure 04. Figure 05. Figure 06. Figure 07. Figure 08. Figure 09a. Figure 09b. Figure 10. Figure 11. Figure 12. Figure 13. Figure 14. Figure 15. Figure 18. Figure 19. Figure 20. Figure 21. Figure 22. Figure 23. Figure 24. Figure 25. Figure 26. Icon 02. Cover 01.

ADVERSE REACTIONS SECTION.

6. ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the labeling:Hypersensitivity [see Warnings and Precautions (5.1) ].Transient Amnestic Episodes [see Warnings and Precautions (5.2)].Risk of BF-RhodoLED or RhodoLED XL Lamp Induced Eye Injury [see Warnings and Precautions (5.3)].Increased Photosensitivity [see Warnings and Precautions (5.4)].Risk of Bleeding in Patients with Coagulation Disorders [see Warnings and Precautions (5.5)].Ophthalmic Adverse Reactions [see Warnings and Precautions (5.6)].Risk of Mucous Membrane Irritation [see Warnings and Precautions (5.7)].. Hypersensitivity [see Warnings and Precautions (5.1) ].. Transient Amnestic Episodes [see Warnings and Precautions (5.2)].. Risk of BF-RhodoLED or RhodoLED XL Lamp Induced Eye Injury [see Warnings and Precautions (5.3)].. Increased Photosensitivity [see Warnings and Precautions (5.4)].. Risk of Bleeding in Patients with Coagulation Disorders [see Warnings and Precautions (5.5)].. Ophthalmic Adverse Reactions [see Warnings and Precautions (5.6)].. Risk of Mucous Membrane Irritation [see Warnings and Precautions (5.7)].. Most common adverse reactions (>=10%) were application site erythema, pain/burning, irritation, edema, pruritus, exfoliation, scab, induration, and vesicles (6.1).To report SUSPECTED ADVERSE REACTIONS, contact Biofrontera Inc. at 1-844-829-7434 or FDA at 1-800-332-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The clinical program for AMELUZ included three double-blind and placebo-controlled trials (Trials 1, 2, and 3), enrolling total of 299 subjects that were treated with narrow band light. Trial subjects were adults greater than or equal to 49 years of age, and the majority had Fitzpatrick skin type I, II, or III. No subjects had Fitzpatrick skin type or VI. Approximately 86% of subjects were male, and all subjects were Caucasian.For all trials, the enrolled subjects had mild to moderate AKs (Olsen grade and 2) with to lesions on the face and scalp. Overall, 87 placebo-treated subjects (n=16, n=32, n=39) and 212 AMELUZ-treated subjects (n=32, n=55, and n=125) were illuminated with BF-RhodoLED or similar narrow spectrum lamps.Local skin reactions at the application site were observed in about 99.5% of subjects treated with AMELUZ and narrow spectrum lamps. The most frequent adverse reactions during and after PDT were application site erythema, pain, burning, irritation, edema, pruritus, exfoliation, scab, induration, and vesicles.Most adverse reactions occurred during illumination or shortly afterwards, were generally of mild or moderate intensity, and lasted for to days in most cases; in some cases, however, they persisted for to weeks or even longer. Severe pain/burning occurred in up to 30% of subjects. In one case, the adverse reactions required interruption or discontinuation of the illumination.The incidence of common (>=1%, <10%) and very common (>=10%) adverse reactions in randomized, multicenter trials at the application site are presented in Table 1.Table 1: Incidence of Adverse Reactions Occurring at >=1% of the AMELUZ Group and More Frequently than the Vehicle Group in the Actinic Keratosis Trials at the Application SiteAdverse reactionVehiclen=87AMELUZn=212Adverse reactions at theapplication siteErythemaPain/BurningIrritationEdemaPruritusExfoliationScabIndurationVesiclesParesthesiaHyperalgesiaReactionDiscomfortErosionDischargeBleedingPustules34 (39%)26 (30%)17 (20%)3 (3%)14 (16%)4 (5%)2 (2%)0 (0%)1 (1%)2 (2%)0 (0%)2 (2%)0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)195 (92%)195 (92%)153 (72%)75 (35%)72 (34%)41 (19%)41 (19%)26 (12%)25 (12%)18 (9%)13 (6%)8 (4%)7 (3%)6 (3%)4 (2%)3 (1%)3 (1%)Common (>=1%, <10%) adverse reactions not at the application site for AMELUZ were headache, skin exfoliation, chills and eyelid edema.Less common (>=0.1%, <1%) adverse reactions at the application site for AMELUZ were hemorrhage and swelling. The adverse reactions not at the application site were blister, feeling hot, pruritus, pyrexia, scab, nervousness, pain, petechiae, rash pustular, skin erosion and ulcer.In clinical trial designed to investigate the sensitization potential of aminolevulinic acid with 216 healthy subjects, 13 subjects (6%) developed allergic contact dermatitis after continuous exposure for 21 days with doses of aminolevulinic acid that were higher than doses normally used in the treatment of AK.. 6.2 Postmarketing Experience. The following adverse reactions have been reported during post-approval use of AMELUZ. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Skin and subcutaneous tissue disorders: allergic dermatitis, application site inflammation, application site discoloration.Eye disorders: eye irritation, diplopia, ocular hyperemia, photophobia, and blurred vision.General disorders and administration site conditions: fatigue.Immune System disorders: hypersensitivity.Nervous system disorders: dysaesthesia, transient amnestic episodes.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies to evaluate the carcinogenic potential of AMELUZ or aminolevulinic acid have not been performed.Aminolevulinic acid revealed no evidence of mutagenic or clastogenic potential based on the results of three in vitro genotoxicity tests (Ames assay, HPRT test in V79 cells, and Human lymphocyte chromosomal aberration assay) and one in vivo genotoxicity test (mouse micronucleus assay). These genotoxicity studies were conducted without exposure to light. There is literature report that indicates that aminolevulinic acid may cause genotoxic effects in the presence and in the absence of activating light. These genotoxic effects are likely caused by the formation of reactive oxygen species.Animal fertility studies have not been conducted with aminolevulinic acid because of the negligible systemic absorption of aminolevulinic acid in humans following topical administration of AMELUZ under maximal clinical use conditions.

CLINICAL PHARMACOLOGY SECTION.

12. CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Photoactivation following topical application of AMELUZ occurs when aminolevulinic acid (prodrug) is metabolized to protoporphyrin IX (PpIX), photoactive compound which accumulates in the skin. When exposed to red light of suitable wavelength and energy, PpIX is activated resulting in an excited state of porphyrin molecules. In the presence of oxygen, reactive oxygen species are formed which causes damage to cellular components, and eventually destroys the cells. AMELUZ photodynamic therapy of AK lesions utilizes photoactivation of topically applied AMELUZ resulting from BF-RhodoLED or RhodoLED XL illumination, which provides red light of narrow spectrum and light dose of approximately 37 J/cm2.. 12.2 Pharmacodynamics. The pharmacodynamics of AMELUZ in the treatment of actinic keratosis are unknown.. 12.3 Pharmacokinetics Pharmacokinetics (PK) of aminolevulinic acid and PpIX was evaluated in trial of 12 adult subjects with mild to moderate AK with at least 10 AK lesions on the face or forehead. single dose of one entire tube of AMELUZ (2 grams) was applied under occlusion for hours followed by PDT to total area of 20 cm2. The mean +- SD baseline plasma aminolevulinic acid and PpIX concentrations were 20.16 +- 16.53 ng/mL and 3.27 +- 2.40 ng/mL, respectively. In most subjects, an up to 2.5-fold increase of aminolevulinic acid plasma concentrations was observed during the first hours after AMELUZ application. The mean +- SD area under the concentration time curve (AUC0-t) and maximum concentration (Cmax) for baseline corrected aminolevulinic acid (n=12) were 142.83 +- 75.50 ng.h/mL and 27.19 +- 20.02 ng/mL, respectively. The median Tmax (time at which Cmax occurred) was hours.The majority (about 55%) of the PpIX concentrations were below the limit of quantification (LOQ 1 ng/mL) and baseline corrected values were negative in all subjects except for one. The baseline corrected AUC0-t and Cmax in the single subject was 0.07 ng.h/mL and 0.29 ng/mL, respectively. PK of aminolevulinic acid and PpIX following treatment on the scalp was not evaluated.

CLINICAL STUDIES SECTION.

14. CLINICAL STUDIES. The efficacy and safety of AMELUZ in combination with PDT using narrow spectrum (red light lamp) source were evaluated in three randomized, multicenter trials (Trials 1, 2, and 3). Trials and were vehicle-controlled and double-blind. Trial was double-blind with respect to vehicle and observer-blind regarding the active comparator arm. All clinical trials included follow-up assessment after and 12 months.In these trials, 212 subjects with to mild to moderate AK lesions on the face/forehead and/or bald scalp were treated with AMELUZ and narrow band spectrum lamp. Subjects ranged from 49 to 87 years of age (mean 71 years), and 92% had Fitzpatrick skin type I, II, or III. No subjects had Fitzpatrick skin type or VI. Approximately 86% of subjects were male, and all subjects were Caucasian.All sessions were comprised of lesion preparation to roughen the surface and remove crusts, application of AMELUZ with occlusion for hours, and removal of the residual gel. Subsequently, the entire treatment area was illuminated with narrow spectrum red light source, lamp of either 630 nm or 633 nm and light dose of approximately 37 J/cm2. In Trial 3, illumination was performed with BF-RhodoLED, red light source with narrow spectrum around 635 nm and light dose of approximately 37 J/cm2.In all trials, the lesions that were not completely cleared 12 weeks after the initial treatment were treated second time with an identical regimen. In the trials, 42% (88/212) of subjects needed second treatment.The primary endpoint for all trials was complete clearance 12 weeks after the last PDT. The results of Trials 1, and are presented in Table 2.Table 2: Complete Clearance 12 Weeks After the Last Narrow Spectrum PDT in Subjects with Actinic KeratosesAMELUZVehicleTrial 1106/125 (85%)5/39 (13%)Trial 227/32 (84%)2/16 (13%)Trial 350/55 (91%)7/32 (22%)Subjects who achieved complete clearance at 12 weeks after the last PDT entered 12-month follow-up period. In the three trials, subjects who received AMELUZ with the narrowband PDT and achieved complete clearance 12 weeks after the last PDT had recurrence rates of 14%, 11%, and 25%, respectively (at months) and 40%, 22%, and 37%, respectively (at 12 months).Recurrence was defined as the percentage of subjects with at least one recurrent lesion during the 6-month or 12-month follow-up period in subjects with completely cleared lesions 12 weeks after the last PDT.

CONTRAINDICATIONS SECTION.

4. CONTRAINDICATIONS. AMELUZ is contraindicated in patients with:Known hypersensitivity to porphyrins.Known hypersensitivity to any of the components of AMELUZ, which includes soybean phosphatidylcholine [see Warnings and Precautions (5.1)].Porphyria. AMELUZ use may cause uncontrolled phototoxic effects [see Warnings and Precautions (5.4)].Photodermatoses. PDT may worsen the phototoxic or photoallergic reactions [see Warnings and Precautions (5.4)].. Known hypersensitivity to porphyrins.. Known hypersensitivity to any of the components of AMELUZ, which includes soybean phosphatidylcholine [see Warnings and Precautions (5.1)].. Porphyria. AMELUZ use may cause uncontrolled phototoxic effects [see Warnings and Precautions (5.4)].. Photodermatoses. PDT may worsen the phototoxic or photoallergic reactions [see Warnings and Precautions (5.4)].. Known hypersensitivity to porphyrins (4).Known hypersensitivity to any component of AMELUZ, which includes soybean phosphatidylcholine (4).Porphyria (4).Photodermatoses (4).. Known hypersensitivity to porphyrins (4).. Known hypersensitivity to any component of AMELUZ, which includes soybean phosphatidylcholine (4).. Porphyria (4).. Photodermatoses (4).

DESCRIPTION SECTION.

11. DESCRIPTION. AMELUZ (aminolevulinic acid hydrochloride) topical gel, 10% is non-sterile white-to-yellowish gel. The gel formulation contains nanoemulsion.Aminolevulinic acid, porphyrin precursor, is white to off-white crystalline solid. It is readily soluble in water, methanol, and dimethylformamide. Its chemical name is 5-amino-4-oxo-pentanoic acid hydrochloride, molecular weight is 167.59 and molecular formula is C5H9NO3.HCl. The structural formula of aminolevulinic acid hydrochloride is represented below:Each gram of AMELUZ contains 100 mg of aminolevulinic acid hydrochloride (equivalent to 78 mg aminolevulinic acid) as the active ingredient and the following inactive ingredients: xanthan gum, soybean phosphatidylcholine, polysorbate 80, medium-chain triglycerides, isopropyl alcohol, dibasic sodium phosphate, monobasic sodium phosphate, propylene glycol, sodium benzoate and purified water.. ALA.HCl Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2. DOSAGE AND ADMINISTRATION. Administer AMELUZ only by health care provider (2.1).AMELUZ is for topical use only (2.1).Photodynamic therapy with AMELUZ involves preparation of lesions, application of the product, occlusion and illumination with BF-RhodoLED or RhodoLED XL lamp (2.2).Retreat lesions that have not completely resolved months after the initial treatment (2.1).See BF-RhodoLED or RhodoLED XL user manual for detailed lamp safety and operating instructions (2.1).. Administer AMELUZ only by health care provider (2.1).. AMELUZ is for topical use only (2.1).. Photodynamic therapy with AMELUZ involves preparation of lesions, application of the product, occlusion and illumination with BF-RhodoLED or RhodoLED XL lamp (2.2).. Retreat lesions that have not completely resolved months after the initial treatment (2.1).. See BF-RhodoLED or RhodoLED XL user manual for detailed lamp safety and operating instructions (2.1).. 2.1 Important Administration Information. AMELUZ, in conjunction with lesion preparation, is only to be administered by health care provider.AMELUZ is for topical use only. Not for ophthalmic, oral, or intravaginal use.Treat single lesions or an entire field affected by multiple lesions with AMELUZ, in combination with red light photodynamic therapy (PDT). PDT requires administration of both AMELUZ and BF-RhodoLED or RhodoLED XL light. Retreat lesions that have not completely resolved after months after the initial treatment.Refer to BF-RhodoLED or RhodoLED XL user manual for detailed lamp safety and operating instructions. Both patient and medical personnel conducting the PDT should adhere to all safety instructions.. 2.2 Dosage and Administration Instructions. PDT is multi-stage process:Step 1. Preparation of LesionsBefore applying AMELUZ, carefully wipe all lesions with an ethanol or isopropanol-soaked cotton pad to ensure degreasing of the skin. Figure 1A: Degreasing the skinThereafter, remove any scaling and crusts and gently roughen all lesion surfaces, taking care to avoid bleeding. Figure 1B: Removal of scales and crustStep 2. Application of AMELUZUse glove protected fingertips or spatula to apply AMELUZ. Apply gel approximately mm thick and include approximately mm of the surrounding skin. Use sufficient amount of gel to cover the single lesions or if multiple lesions, the entire area. Application area should not exceed 20 cm2 and no more than grams of AMELUZ (one tube) should be used at one time. The gel can be applied to healthy skin around the lesions. Avoid application near mucous membranes such as the eyes, nostrils, mouth, and ears (keep distance of cm from these areas). In case of accidental contact with these areas, thoroughly rinse with water. Allow the gel to dry for approximately 10 minutes before applying occlusive dressing. Figure 2: Drug applicationStep 3. Occlusion for HoursCover the area where the gel has been applied with light-blocking, occlusive dressing. Following hours of occlusion, remove the dressing and wipe off any remaining gel. Figure 3: OcclusionStep 4. Illumination with Red LightDuring illumination, patient and medical personnel need to wear suitable protective eyewear.Immediately after removing occlusion and any remaining gel, illuminate the treatment area with the BF-RhodoLED or RhodoLED XL lamp. BF-RhodoLED and RhodoLED XL lamps are red light sources with narrow spectrum around 635 nm that deliver light dose of approximately 37 J/cm2 within 10 minutes. Calibration by the operator is not needed; the illumination time is calculated automatically.Either the BF-RhodoLED or RhodoLED XL lamp can be used:BF-RhodoLED has an effective treatment area of x 16 cm when an area of x 18 cm is illuminated. Position the lamp head 5-8 cm from the skins surface. Larger areas can be illuminated in several steps.RhodoLED XL has curved configuration with an effective treatment area up to 23 29 cm. Position the lamp head of the RhodoLED XL 11-14 cm from the skins surface. This usually allows full-face illumination with the use of panels. The smallest recommended number of panels to be used are adjacent panels (see chapter 8.4.6 of RhodoLED XL user manual).Healthy untreated skin surrounding the AK lesions does not need protection during illumination. Figure 4A: Illumination with BF-RhodoLED Figure 4B: Illumination with RhodoLED XLIf for any reason, the lesions cannot be illuminated within hours after AMELUZ application, rinse off the gel with saline and water. For days, protect the lesion sites and surrounding skin from sunlight or prolonged or intense light (e.g., tanning beds, sun lamps).. BF-RhodoLED has an effective treatment area of x 16 cm when an area of x 18 cm is illuminated. Position the lamp head 5-8 cm from the skins surface. Larger areas can be illuminated in several steps.. RhodoLED XL has curved configuration with an effective treatment area up to 23 29 cm. Position the lamp head of the RhodoLED XL 11-14 cm from the skins surface. This usually allows full-face illumination with the use of panels. The smallest recommended number of panels to be used are adjacent panels (see chapter 8.4.6 of RhodoLED XL user manual).. Figure 1A: Degreasing of the skin. Figure 1B: Figure 1B: Removal of scales and crusts. Figure 2: Drug application. Figure 3: Occlusion. Figure 4A: Illumination. Figure 4B: Illumination.

DOSAGE FORMS & STRENGTHS SECTION.

3. DOSAGE FORMS AND STRENGTHS. Each gram of AMELUZ topical gel, 10% contains 100 mg of aminolevulinic acid hydrochloride (equivalent to 78 mg of aminolevulinic acid).. Gel: 10% (3).

DRUG INTERACTIONS SECTION.

7. DRUG INTERACTIONS. There have been no formal studies of the interaction of AMELUZ with other drugs. It is possible that concomitant use of other known photosensitizing agents such as St. Johns wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulphonamides, quinolones and tetracyclines may enhance the phototoxic reaction to PDT [see Warnings and Precautions (5.3)].. Concomitant use of the following medications may enhance the phototoxic reaction to photodynamic therapy: St. Johns wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulphonamides, quinolones, and tetracyclines (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 384 subjects exposed to AMELUZ in randomized, multicenter clinical trials, 83% (318/384) of the subjects were 65 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

HOW SUPPLIED SECTION.

16. HOW SUPPLIED/STORAGE AND HANDLING. AMELUZ (aminolevulinic acid hydrochloride) topical gel, 10% is white-to-yellowish gel. The drug product is supplied in an aluminum tube with white, high density polyethylene (HDPE) screw cap. Each tube contains g of gel.NDC 70621-101-01 g tubeNDC 70621-101-10 Cardbox containing one g tubeNDC 70621-101-20 Cardbox containing ten g tubesStore AMELUZ in refrigerator, 2C 8C (36F 46F). Excursions permitted to 15C 30C (59F 86F).After opening, AMELUZ can be stored for up to 12 weeks in refrigerator at 2C 8C (36F 46F) if the tube is tightly closed.

INDICATIONS & USAGE SECTION.

1. INDICATIONS AND USAGE. AMELUZ, in combination with photodynamic therapy (PDT) using BF-RhodoLED(R) or RhodoLED(R) XL lamp, narrowband, red light illumination source, is indicated for lesion-directed and field-directed treatment of actinic keratoses (AKs) of mild-to-moderate severity on the face and scalp.. AMELUZ, porphyrin precursor, in combination with photodynamic therapy using BF-RhodoLED or RhodoLED XL lamp, is indicated for the lesion-directed and field-directed treatment of actinic keratoses of mild-to-moderate severity on the face and scalp (1).

INFORMATION FOR PATIENTS SECTION.

17. PATIENT COUNSELING INFORMATION. Inform patients of the following:. Hypersensitivity. Hypersensitivity has been reported with use of AMELUZ. Inform patients and their caregivers that AMELUZ may cause hypersensitivity potentially including severe courses (anaphylaxis) [see Warnings and Precautions (5.1)].. Transient amnestic episodes. Transient amnestic episodes have been reported with use of AMELUZ in combination with photodynamic therapy. Advise patients and their families or caregivers to contact their healthcare provider if memory impairment, confusion, or disorientation is observed [see Warnings and Precautions (5.2)].. Photosensitivity. Advise patients that for approximately 48 hours following treatment to avoid exposure to sunlight, and prolonged or intense light on the treated lesion sites and surrounding skin.Advise patients to avoid certain medications that may enhance the phototoxic reaction to PDT [see Warnings and Precautions (5.4) and Drug Interactions (7)]. Common adverse reactions. Inform patients that treatment with AMELUZ in combination with PDT may result in adverse reactions which include local skin reactions at the application site such as erythema, pain/burning, irritation, edema, pruritus, exfoliation, induration, scab, and vesicles [see Clinical Trial Experience (6.1)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryNo data are available regarding the presence of aminolevulinic acid in human milk, the effects of aminolevulinic acid on the breastfed infant or on milk production. However, breastfeeding is not expected to result in exposure of the child to the drug due to the negligible systemic absorption of aminolevulinic acid in humans following topical administration of AMELUZ under maximal clinical use conditions [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for AMELUZ and any potential adverse effects on the breastfeeding child from AMELUZ or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Photoactivation following topical application of AMELUZ occurs when aminolevulinic acid (prodrug) is metabolized to protoporphyrin IX (PpIX), photoactive compound which accumulates in the skin. When exposed to red light of suitable wavelength and energy, PpIX is activated resulting in an excited state of porphyrin molecules. In the presence of oxygen, reactive oxygen species are formed which causes damage to cellular components, and eventually destroys the cells. AMELUZ photodynamic therapy of AK lesions utilizes photoactivation of topically applied AMELUZ resulting from BF-RhodoLED or RhodoLED XL illumination, which provides red light of narrow spectrum and light dose of approximately 37 J/cm2.

NONCLINICAL TOXICOLOGY SECTION.

13. NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies to evaluate the carcinogenic potential of AMELUZ or aminolevulinic acid have not been performed.Aminolevulinic acid revealed no evidence of mutagenic or clastogenic potential based on the results of three in vitro genotoxicity tests (Ames assay, HPRT test in V79 cells, and Human lymphocyte chromosomal aberration assay) and one in vivo genotoxicity test (mouse micronucleus assay). These genotoxicity studies were conducted without exposure to light. There is literature report that indicates that aminolevulinic acid may cause genotoxic effects in the presence and in the absence of activating light. These genotoxic effects are likely caused by the formation of reactive oxygen species.Animal fertility studies have not been conducted with aminolevulinic acid because of the negligible systemic absorption of aminolevulinic acid in humans following topical administration of AMELUZ under maximal clinical use conditions.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL OUTER PACKAGING. Outer Packaging, single CartonNDC 70621-101-10Ameluz(R) Rx Only(aminolevulinic acid HCl) topical gel, 10%Use contents within months after opening. Discard after: / .Store refrigerated 2-8C (36-46F), excursions permitted to 15-30C (59-86F).Keep out of the sight and reach of children.See package insert for dosage information. Net Wt. gDistributed By: Biofrontera Inc.120 Presidential Way, Suite 330Woburn, MA 01801Product of SwitzerlandFor Topical Use Only with BF-RhodoLED(R) or RhodoLED(R) XL lampHealthcare Professionals OnlyIngredients: Each gram of Ameluz Gel contains 100 mg of the active ingredient, aminolevulinic acid hydrochloride (equivalent to 78 mg of aminolevulinic acid) and the following inactive ingredients: xanthan gum, soybean phosphatidylcholine, polysorbate 80, medium-chain triglyceride, isopropyl alcohol, dibasic sodium phosphate, monobasic sodium phosphate, propylene glycol, sodium benzoate and purified waterOuter Packaging, Physicians SampleNDC 70621-101-30Ameluz(R) Rx OnlyPhysicians SampleNot for sale(aminolevulinic acid HCl) topical gel, 10%Use contents within months after opening. Discard after: / .Store refrigerated 2-8C (36-46F), excursions permitted to 15-30C (59-86F).Keep out of the sight and reach of children.See package insert for dosage information. Net Wt. gDistributed By: Biofrontera Inc.120 Presidential Way, Suite 330Woburn, MA 01801Product of SwitzerlandFor Topical Use Only with BF-RhodoLED(R) lamp or RhodoLED(R) XL lampHealthcare Professionals OnlyIngredients: Each gram of Ameluz Gel contains 100 mg of the active ingredient, aminolevulinic acid hydrochloride (equivalent to 78 mg of aminolevulinic acid) and the following inactive ingredients: xanthan gum, soybean phosphatidylcholine, polysorbate 80, medium-chain triglyceride, isopropyl alcohol, dibasic sodium phosphate, monobasic sodium phosphate, propylene glycol, sodium benzoate and purified waterOuter Packaging, Multipack10 tubes with Net Wt. 2g each NDC 70621-101-20Ameluz(R) Rx Only(aminolevulinic acid HCl) topical gel, 10%For Topical Use Only with BF-RhodoLED(R) lamp or RhodoLED(R) XL lampHealthcare Professionals OnlySee package insert for dosage information.Distributed By: Biofrontera Inc.120 Presidential Way, Suite 330Woburn, MA 01801Product of Switzerland10 tubes with Net Wt. 2g each NDC 70621-101-20Ameluz(R) Rx Only(aminolevulinic acid HCl) topical gel, 10%Use contents within months after opening the individual tube.Place the enclosed Discard after: / .tag on tube once opened.Store refrigerated 2-8C (36-46F), excursions permitted to 15-30C (59-86F).Keep out of the sight and reach of children.See package insert for dosage information.Ingredients:Each gram of Ameluz Gel contains 100 mg of the active ingredient, aminolevulinic acid hydrochloride (equivalent to 78 mg of aminolevulinic acid) and the following inactive ingredients: xanthan gum, soybean phosphatidylcholine, polysorbate 80, medium-chain triglyceride, isopropyl alcohol, dibasic sodium phosphate, monobasic sodium phosphate, propylene glycol, sodium benzoate and purified waterDistributed By: Biofrontera Inc.120 Presidential Way, Suite 330Woburn, MA 01801Product of Switzerland. figure6.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness in pediatric patients below the age of 18 have not been established. AK is not condition generally seen in the pediatric population.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The pharmacodynamics of AMELUZ in the treatment of actinic keratosis are unknown.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Pharmacokinetics (PK) of aminolevulinic acid and PpIX was evaluated in trial of 12 adult subjects with mild to moderate AK with at least 10 AK lesions on the face or forehead. single dose of one entire tube of AMELUZ (2 grams) was applied under occlusion for hours followed by PDT to total area of 20 cm2. The mean +- SD baseline plasma aminolevulinic acid and PpIX concentrations were 20.16 +- 16.53 ng/mL and 3.27 +- 2.40 ng/mL, respectively. In most subjects, an up to 2.5-fold increase of aminolevulinic acid plasma concentrations was observed during the first hours after AMELUZ application. The mean +- SD area under the concentration time curve (AUC0-t) and maximum concentration (Cmax) for baseline corrected aminolevulinic acid (n=12) were 142.83 +- 75.50 ng.h/mL and 27.19 +- 20.02 ng/mL, respectively. The median Tmax (time at which Cmax occurred) was hours.The majority (about 55%) of the PpIX concentrations were below the limit of quantification (LOQ 1 ng/mL) and baseline corrected values were negative in all subjects except for one. The baseline corrected AUC0-t and Cmax in the single subject was 0.07 ng.h/mL and 0.29 ng/mL, respectively. PK of aminolevulinic acid and PpIX following treatment on the scalp was not evaluated.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on AMELUZ use in pregnant women to inform drug associated risk. Animal reproduction studies were not conducted with aminolevulinic acid. Systemic absorption of aminolevulinic acid in humans is negligible following topical administration of AMELUZ under maximal clinical use conditions [see Clinical Pharmacology (12.3)]. It is not expected that maternal use of AMELUZ will result in fetal exposure to the drug.The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Hypersensitivity (5.1) 05/2021Dosage and Administration, Dosage and Administration Instructions (2.2) 10/2021.

SPL UNCLASSIFIED SECTION.

2.1 Important Administration Information. AMELUZ, in conjunction with lesion preparation, is only to be administered by health care provider.AMELUZ is for topical use only. Not for ophthalmic, oral, or intravaginal use.Treat single lesions or an entire field affected by multiple lesions with AMELUZ, in combination with red light photodynamic therapy (PDT). PDT requires administration of both AMELUZ and BF-RhodoLED or RhodoLED XL light. Retreat lesions that have not completely resolved after months after the initial treatment.Refer to BF-RhodoLED or RhodoLED XL user manual for detailed lamp safety and operating instructions. Both patient and medical personnel conducting the PDT should adhere to all safety instructions.

USE IN SPECIFIC POPULATIONS SECTION.

8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy. Risk SummaryThere are no available data on AMELUZ use in pregnant women to inform drug associated risk. Animal reproduction studies were not conducted with aminolevulinic acid. Systemic absorption of aminolevulinic acid in humans is negligible following topical administration of AMELUZ under maximal clinical use conditions [see Clinical Pharmacology (12.3)]. It is not expected that maternal use of AMELUZ will result in fetal exposure to the drug.The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. 8.2 Lactation. Risk SummaryNo data are available regarding the presence of aminolevulinic acid in human milk, the effects of aminolevulinic acid on the breastfed infant or on milk production. However, breastfeeding is not expected to result in exposure of the child to the drug due to the negligible systemic absorption of aminolevulinic acid in humans following topical administration of AMELUZ under maximal clinical use conditions [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for AMELUZ and any potential adverse effects on the breastfeeding child from AMELUZ or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients below the age of 18 have not been established. AK is not condition generally seen in the pediatric population.. 8.5 Geriatric Use. Of the 384 subjects exposed to AMELUZ in randomized, multicenter clinical trials, 83% (318/384) of the subjects were 65 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

WARNINGS AND PRECAUTIONS SECTION.

5. WARNINGS AND PRECAUTIONS. Hypersensitivity reactions have been reported with the use of AMELUZ prior to photodynamic therapy (PDT). AMELUZ should be washed off and appropriate therapy instituted (5.1).Transient Amnestic Episodes have been reported with use of AMELUZ in combination with PDT. If patients experience amnesia or confusion, discontinue treatment and contact healthcare provider (5.2).Risk of Eye Injury: Patients and healthcare providers must wear protective eyewear before operating BF-RhodoLED or RhodoLED XL lamp (5.3).Photosensitivity: Protect treated lesions from sunlight exposure for 48 hours post treatment (5.4).Risk of Bleeding: Special care should be taken to avoid bleeding during lesion preparation in patients with inherited or acquired coagulation disorders (5.5).Ophthalmic Adverse Reactions: Avoid direct contact of AMELUZ with the eyes (5.6).Mucous Membrane Irritation: Avoid direct contact of AMELUZ with the mucous membranes (5.7).. Hypersensitivity reactions have been reported with the use of AMELUZ prior to photodynamic therapy (PDT). AMELUZ should be washed off and appropriate therapy instituted (5.1).. Transient Amnestic Episodes have been reported with use of AMELUZ in combination with PDT. If patients experience amnesia or confusion, discontinue treatment and contact healthcare provider (5.2).. Risk of Eye Injury: Patients and healthcare providers must wear protective eyewear before operating BF-RhodoLED or RhodoLED XL lamp (5.3).. Photosensitivity: Protect treated lesions from sunlight exposure for 48 hours post treatment (5.4).. Risk of Bleeding: Special care should be taken to avoid bleeding during lesion preparation in patients with inherited or acquired coagulation disorders (5.5).. Ophthalmic Adverse Reactions: Avoid direct contact of AMELUZ with the eyes (5.6).. Mucous Membrane Irritation: Avoid direct contact of AMELUZ with the mucous membranes (5.7).. 5.1 Hypersensitivity. Several cases of hypersensitivity were reported during postmarketing use of AMELUZ prior to PDT illumination [see Adverse Reactions (6.2) ]. If allergic reactions occur, clean the area of skin where the product was applied and institute appropriate therapy. Inform patients and their caregivers that AMELUZ may cause hypersensitivity, potentially including severe courses (anaphylaxis).. 5.2 Transient Amnestic Episodes. Transient amnestic episodes have been reported during postmarketing use of AMELUZ in combination with photodynamic therapy. Inform patients and their caregivers that AMELUZ in combination with photodynamic therapy may cause transient amnestic episodes. Advise them to contact the healthcare provider if the patient develops amnesia after treatment.. 5.3 Risk of BF-RhodoLED or RhodoLED XL Lamp Induced Eye Injury. BF-RhodoLED or RhodoLED XL lamp may cause eye irritation, glare, or injury. Before operating the lamp, personnel must refer to the user manual for specific warnings, cautions, and instructions. Eye exposure to the BF-RhodoLED or RhodoLED XL light must be prevented. Protective eye equipment must be used by patient, healthcare providers and any person present during the illumination period. Avoid staring directly into the light source [see Dosage and Administration (2)].. 5.4 Increased Photosensitivity. AMELUZ increases photosensitivity. Avoid sunlight, prolonged or intense light (e.g., tanning beds, sun lamps) on lesions and surrounding skin treated with AMELUZ for approximately 48 hours following treatment, whether exposed to illumination or not. Concomitant use of AMELUZ with other known photosensitizing agents may increase the risk of phototoxic reaction to PDT [see Drug Interactions (7)].. 5.5 Risk of Bleeding in Patients with Coagulation Disorders. AMELUZ has not been tested on patients with inherited or acquired coagulation disorders.Special care should be taken to avoid bleeding during lesion preparation in such patients [see Dosage and Administration (2)]. Any bleeding must be stopped before application of the gel.. 5.6 Ophthalmic Adverse Reactions. Eyelid edema has occurred with AMELUZ application. AMELUZ can cause ophthalmic adverse reactions. AMELUZ is intended for topical use only. Do not apply AMELUZ into the eyes. Rinse eyes with water in case of accidental contact.. 5.7 Risk of Mucous Membrane Irritation. AMELUZ can cause mucous membrane irritation. AMELUZ is intended for topical use only. Do not apply AMELUZ to the mucous membranes. Rinse with water in case of accidental contact.