Visudyne™ (Verteporfin) Therapy

Visudyne™ (Verteporfin) Therapy
Visudyne Therapy: Evidence-Based Treatment of CNV Visudyne™ (Verteporfin) Therapy The introduction of Visudyne™ (verteporfin) therapy is likely to lead to changes in the management of many patients with choroidal neovascularization (CNV). This presentation provides an overview of the causes and consequences of CNV, the evidence that supports the use of Visudyne therapy, and the practical issues involved in managing and treating patients with CNV.

Visudyne Therapy: A Two-Step Process
Visudyne Therapy: Evidence-Based Treatment of CNV Visudyne Therapy: A Two-Step Process Step 1 IV administration of a non-toxic, light activated drug Visudyne therapy is part of a new therapeutic platform called photodynamic therapy which involves two key steps. Firstly, patients receive a 10-minute intravenous infusion of Visudyne, which accumulates preferentially in the CNV. Secondly, the drug is activated using a non-thermal laser 15 minutes after the start of the infusion. Step 2 Subsequent activation by a specific wavelength of light using non-thermal diode laser device

Visudyne Therapy: Evidence-Based Treatment of CNV
Visudyne Formulation Visudyne is a light-activated drug: Supplied in single-use 15 mg vials Sterile, lipid-based, freeze-dried, dark-green powder Stored at room temperature (20–25ºC or 68–77ºF) Visudyne is supplied in a single-use 15 mg glass vial as a sterile, lipid-based, freeze-dried, dark-green powder. Visudyne supplies should be stored at room temperature and are intended for intravenous injection only.

Establishing the IV Line
Visudyne Therapy: Evidence-Based Treatment of CNV Establishing the IV Line A free-flowing IV line is established, preferably in the antecubital vein The first step in setting up the infusion equipment is the establishment of a free-flowing IV line, which should be carefully monitored throughout the infusion. It is strongly recommended that the largest vein possible in the arm, preferably the antecubital vein, is used for infusion because vein walls may be fragile in some elderly patients. If a vein other than the antecubital vein is used, it is important that the patient and caregivers are instructed to keep the injection site covered after treatment and to follow the photosensitivity precautions recommended by the treating physician.

Determining GLD and Treatment Spot Size
Visudyne Therapy: Evidence-Based Treatment of CNV Determining GLD and Treatment Spot Size Determine GLD of entire lesion on photographic image Calculate actual GLD on retina Add 1000 µm to allow a 500 µm border around lesion (Ensure full coverage of lesion and allow for small eye movements) Treatment spot should be no closer than 200 µm to edge of optic disc Treatment spot size GLD Copyright protected The treatment procedure is straightforward and identical for all patients eligible for Visudyne therapy irrespective of the cause of CNV. To establish the treatment spot size, the GLD of the lesion on the retina is determined and an extra 1000 µm is added to allow a 500 µm border around the lesion. This ensures that the whole lesion is treated. At this point, it is important to ensure that the treatment spot is no closer than 200 µm to the edge of the optic disc. If the lesion is closer than this, the laser spot should be set to cover as much of the lesion as possible without extending within 200 µm of the optic disc. The size of the treatment spot should not be reduced.

Setting the Laser Enter contact lens magnification Enter the spot size (GLD µm) Start the timer at the beginning of infusion Zeiss Visulas 690s Laser and Visulink PDT adapter Coherent Opal Photoactivator Laser and LaserLink adapter The contact lens magnification is then entered into the laser system, together with the laser spot size. Two laser systems have been approved for use in Visudyne therapy, both of which are equipped with timers that alert the physician when it is time to start the light application. The timer is started at the same time as the Visudyne infusion.

Visudyne Infusion Kit Tubing Filters Needles Catheter Syringes The materials needed to administer the Visudyne infusion can be purchased individually or as a kit. The infusion kit includes the necessary tubing, filters, needles, catheter, and syringes. In addition, sterile water and 5% dextrose for injection (D5W) are needed to reconstitute the Visudyne powder and dilute it to the final 30 mL infusion volume.

Calculating BSA Visudyne is administered at a dose of 6 mg/m2 BSA. The BSA can be determined using a standard nomogram or using a slide-rule, which can be obtained from Novartis Ophthalmics. In this example, the patient is 1.75 m tall and weighs 75 kg, which corresponds to a BSA of 1.88 m2. BSA (e.g.: 1.88 m2) Height Weight

Visudyne Reconstitution
Visudyne Therapy: Evidence-Based Treatment of CNV Visudyne Reconstitution Visudyne is reconstituted with sterile water for injection 7 mL of water is added to the vial to give a volume of 7.5 mL The vial is gently agitated to ensure complete dissolution Solution must be protected from light and used within 4 hours Reconstituted drug has a concentration of 2 mg/mL For a total volume of 7.5 mL of reconstituted drug, 7.0 mL of sterile water for injection has to be added to the Visudyne vial, which should then be gently agitated until the powder is completely dissolved. Saline solution must not be used because it causes Visudyne to precipitate. The reconstituted solution must be protected from light and used within 4 hours. Reconstitution produces an opaque dark-green solution of Visudyne at a concentration of 2 mg/mL.

Calculating the Visudyne Dose
Visudyne Therapy: Evidence-Based Treatment of CNV Calculating the Visudyne Dose Drug dose BSA  6 mg/m2 e.g m2 Total drug dose Reconstituted drug concentration Volume reconstituted drug The total drug dose can be calculated by multiplying the Visudyne dose (6 mg/m2) by the BSA. In the example, multiplying the BSA of 1.88 m2 by 6 gives a total drug dose of mg. The total drug dose is then divided by the concentration of the reconstituted drug (2 mg/mL) to give the volume that should be administered. In this example, dividing by 2 gives a volume of 5.64 mL.  = e.g mg 2 mg/mL e.g mL

Preparing the Infusion
Visudyne Therapy: Evidence-Based Treatment of CNV Preparing the Infusion The appropriate volume of Visudyne solution is withdrawn from the vial The Visudyne solution is transferred to the 30 mL syringe D5W is added to give the final 30 mL volume for infusion The appropriate volume of Visudyne is withdrawn using the same syringe that was used to reconstitute the drug. The Visudyne is transferred through an 18-gauge needle into a 30 mL syringe containing the appropriate quantity of D5W to give the final 30 mL infusion volume.

Infusion Connections Syringe in pump A 1.2 µm filter is fitted to the syringe The syringe is connected to the IV line Infusion tubing The syringe containing the Visudyne solution is inserted into an infusion or syringe pump and connected, via infusion tubing and a filter, to a needle used to obtain venous access. Filters with a mesh size of 1.2 µm were used in the clinical trials to ensure the removal of any particles that did not dissolve. Smaller filters can be used, but they may become clogged. The use of larger filters is not recommended. 18-gauge needles were used in the clinical trials, but other needles can be used provided that they allow the Visudyne solution to flow freely. Venous access Filter Needle

Infusing the Visudyne Solution
Visudyne Therapy: Evidence-Based Treatment of CNV Infusing the Visudyne Solution An infusion or syringe pump delivers the 30 mL of drug over 10 minutes The timer on the laser system is started at the same time as the infusion Physician or nurse must monitor patient throughout 10-minute infusion The infusion or syringe pump delivers the 30 mL Visudyne infusion over 10 minutes at a rate of 3 mL/minute. The timer on the laser system should be started at the same time as the infusion. This counts down from 15 minutes to indicate when light should be applied. If the infusion is interrupted for any reason, and at least half the infusion has been given, the laser light should be applied as close as possible to 15 minutes after the start of the infusion.

Precautions to Avoid Extravasation
Visudyne Therapy: Evidence-Based Treatment of CNV Precautions to Avoid Extravasation Extravasation may cause severe pain, inflammation, swelling, and discoloration of the injection site The IV line should be carefully monitored during treatment and infusion stopped if extravasation is suspected or recognized Even with good technique, extravasation may occur Precautions should be taken to avoid extravasation at the injection site. If extravasation does occur, patients may experience pain or discomfort in the injection arm. Extravasation and injection-site reactions can be avoided if the infusion procedures are strictly adhered to and the patient is carefully monitored throughout the 10-minute infusion. However, extravasation may occur even with good technique, and if it does, or if the patient experiences discomfort or pain, the infusion should be discontinued.

Procedure in the Event of Extravasation
Visudyne Therapy: Evidence-Based Treatment of CNV Procedure in the Event of Extravasation If more than half the dose delivered Proceed with light application, as scheduled (15 minute after start of infusion, even if duration of infusion was less than 10 minutes) If less than half the dose delivered Obtain better venous access Begin light application 15 minutes after restarting infusion Apply cold compress or ice immediately Elevate patient’s arm for 1 day, when possible Protect from light for at least 5 days or as long as skin is swollen or discolored Consult burns specialist or dermatologist if needed If venous access was not obtained after several attempts, treatment can be attempted again after 24 hours The procedure in the event of extravasation depends on the amount of drug that has been infused. If more than half has been delivered, the infusion should be discontinued immediately and light application should be carried out as usual, even if the duration of the infusion was less than 10 minutes. If extravasation occurs before half the solution has been administered, then better venous access should be obtained as soon as possible and the infusion should be restarted using the remaining solution. Light application can begin 15 minutes after restarting the infusion. If, after several attempts, venous access has not been obtained, retreatment must not be attempted for at least 24 hours. The site of extravasation should be treated immediately with a cold compress or ice and, if possible, the patient’s arm should be elevated for 1 day. The extravasation area must be thoroughly protected from direct light until swelling and discoloration of the skin have faded in order to prevent the occurrence of a local burn which could be severe.

Ending the Infusion The pump is turned off The IV line is flushed with 5 mL D5W until all remaining Visudyne is cleared from the line The laser timer will indicate when to begin light application Once the infusion is complete, the pump is turned off and the IV line is flushed with 5 mL D5W until all the remaining Visudyne solution has been cleared from the line. In general, 60 seconds is sufficient to ensure complete flushing of the line, although the amount of D5W required may vary depending on the length of the tubing used.

Positioning Patient and Applying Laser
Visudyne Therapy: Evidence-Based Treatment of CNV Positioning Patient and Applying Laser Patient is positioned at slit lamp immediately after end of infusion Light source: Non thermal diode laser Light is applied 15 minutes after start of infusion Light at 689 nm is delivered via a fiber optic and slit lamp using a contact lens Light dose 600 mW/cm2 83 seconds The light is applied exactly 15 minutes after the start of the 10-minute infusion (as indicated by the timer). So, the physician has about 5 minutes in which to flush and remove the infusion line, position the patient at the slit lamp, and visualize the lesion with respect to the retinal landmarks. Before initiating treatment, the physician should familiarize the patient with the procedure by inserting the contact lens and shining the aiming beam at the lesion. This is particularly useful before the first treatment. It gives the patient the opportunity to become comfortable with the light application. It also helps to familiarize the physician with the patient’s lesion characteristics using the aiming beam illumination. Light is applied at a wavelength of 689 nm via a fiber optic and slit lamp, using a contact lens. Light at an intensity of 600 mW/cm2 is delivered for 83 seconds to give a dose of 50 J/cm2. 50 J/cm2

Visudyne: Light application
Visudyne Therapy: Evidence-Based Treatment of CNV Visudyne: Light application Why 689 nm (red light) ??? Light at this wavelength is not absorbed strongly by naturally present substances The strongest absorption peak is at 400 nm (blue light) Not clinically useful, as this is the same as the absorption peak of oxyhaemoglobin

Concurrent Bilateral Treatment
Visudyne Therapy: Evidence-Based Treatment of CNV Concurrent Bilateral Treatment If the patient has received previous Visudyne treatment with an acceptable safety profile: The first eye (with aggressive lesion) is treated 15 minutes after the start of infusion Immediately after treatment of the first eye, the laser is reset to the parameters of the second eye, with the same light dose, intensity and duration The second eye is treated no later than 20 minutes after the start of infusion If bilateral treatment is indicated and the patient has previously received Visudyne therapy in one eye with an acceptable safety profile, both eyes can be treated concurrently after a single infusion. The most aggressive lesion should be treated first, with light application 15 minutes after the start of the infusion. Immediately after light application to the first eye, the laser settings should be adjusted to introduce treatment parameters for the second eye. The light dose and intensity remain the same as for the first eye, and the light application should be started no later than 20 minutes after the start of the infusion.

Follow-up and Retreatment
Visudyne Therapy: Evidence-Based Treatment of CNV Follow-up and Retreatment Follow-up visits after a treatment should be scheduled at least as often as every 10–14 weeks Fluorescein angiography is required to determine whether leakage has recurred Retreatment is often necessary during the first 2 years Copyright protected After treatment, but before the patient leaves the office, a follow-up visit should be arranged. These examinations should be scheduled at least as often as every 10–14 weeks. Visudyne therapy may consist of a series of treatments, which are administered if there is evidence of fluorescein leakage from CNV at any follow-up visit and there have been no serious adverse events associated with previous treatment. Fluorescein angiography is therefore required at all follow-up visits to determine whether leakage has recurred and whether retreatment is indicated. Retreatment is often necessary during the first 2 years, although the likelihood that it will be required decreases with time: in the TAP Investigation, patients received a mean of 3.4 Visudyne treatments in the first year, decreasing to 2.2 in the second year, and 1.1 in the third year, which was part of the open-label extension to the TAP Investigation. Reference: TAP Study Group 2001a Early phase of angiogram showing recurrent leakage within a hypofluorescent region 3 months after Visudyne therapy

Patient Education Physician needs to manage patient expectations In patients for whom treatment is indicated, Visudyne therapy: Reduces risk of moderate or severe vision loss in AMD Increases likelihood of stable or improved vision in pathologic myopia Retreatment often required at 3-month intervals in first 2 years As well as explaining the treatment process and the necessary precautions, staff members should assist in managing patient expectations. A patient’s satisfaction with treatment will partly be determined by their expectations, so it is important that physicians fully explain the benefits and risks of treatment and that all members of staff reinforce the information. Patients should understand the likely outcomes of Visudyne therapy. For patients with CNV due to AMD, Visudyne therapy reduces the risk of moderate or severe vision loss, although most patients lose some additional vision over 2 years due to the natural course of the disease and only a small number of patients experience improvements in vision. For patients with CNV due to pathologic myopia, Visudyne therapy increases the likelihood of stable or improved vision. Patients will also need to understand that Visudyne therapy consists of several treatments over a period of time. In most cases, patients need to be retreated approximately every 10–14 weeks, with an average of five or six treatments during the first 2 years. Reference: TAP Study Group 2001a

Patient Education Patients should be provided with information to take home Patients should avoid exposure to direct sunlight or strong artificial light (halogen) according to physician’s instructions (Up to 48 hours after t/t) e.g. dental procedure, surgical operating rooms Normal indoor / home light – tube light, bulb light, television light - acceptable The physician should explain the precautions that need to be taken to avoid side effects, particularly to prevent photosensitivity reactions in which the drug causes damage to the skin if it is exposed to light. These precautions include avoiding exposure of the skin to direct sunlight or strong artificial light after treatment according to the physician’s instructions. The patient should be provided with sunglasses and a wristband following treatment. Wristbands are available in relevant languages from local Novartis Ophthalmics affiliates. Patients should be informed that they do not need to stay in the dark, and low levels of indoor lighting, such as watching television, will not cause any harm. When outdoors after treatment, however, they should wear the specially provided dark sunglasses, a wide-brimmed hat, long sleeves, and trousers, as instructed by the physician. As patients will have to wear special dark sunglasses and may experience blurred vision immediately after treatment, they should be accompanied on the day of treatment by a family member or friend. If patients have any questions, concerns, or problems they should contact the treating practice.

Patient Education Patients should wear dark sunglasses, long sleeves and trousers, if they need to go outdoors during the first 48 hours (sunscreens do not protect from photosensitivity reactions) Patients should call with questions, concerns or problems (e.g. sudden decrease in vision, pain at injection site) The physician should explain the precautions that need to be taken to avoid side effects, particularly to prevent photosensitivity reactions in which the drug causes damage to the skin if it is exposed to light. These precautions include avoiding exposure of the skin to direct sunlight or strong artificial light after treatment according to the physician’s instructions. The patient should be provided with sunglasses and a wristband following treatment. Wristbands are available in relevant languages from local Novartis Ophthalmics affiliates. Patients should be informed that they do not need to stay in the dark, and low levels of indoor lighting, such as watching television, will not cause any harm. When outdoors after treatment, however, they should wear the specially provided dark sunglasses, a wide-brimmed hat, long sleeves, and trousers, as instructed by the physician. As patients will have to wear special dark sunglasses and may experience blurred vision immediately after treatment, they should be accompanied on the day of treatment by a family member or friend. If patients have any questions, concerns, or problems they should contact the treating practice.

Low Vision Aids CNV rarely causes total blindness Low vision aids may help many patients to perform daily activities Patients can be reassured that CNV rarely results in total blindness and that low vision aids are available to help them maximize their remaining vision and maintain their independence. It is important that physicians help their patients in both the selection and use of low vision aids. Support and information for patients are available from a number of organizations. These organizations provide a variety of support services for people with vision loss, as well as funding research and promoting public awareness of diseases such as AMD. Further information on Visudyne therapy can also be obtained from the Visudyne web site (

Management of Clinically Relevant Adverse Events
Visudyne Therapy: Evidence-Based Treatment of CNV Management of Clinically Relevant Adverse Events Extravasation Avoidable with proper precautions Infusion-related back pain No adverse sequelae known at this time Resolves within a short time Photosensitivity reactions Treat as sunburn (sunscreen is ineffective) Acute severe vision decrease within 7 days Observation, no retreatment recommended The incidence of clinically relevant adverse events was relatively low in all the ocular clinical trials of Visudyne therapy. Some of the events that did occur at a higher frequency in Visudyne-treated patients, compared with placebo, can usually be avoided if proper precautions are followed. Strict adherence to the infusion protocol can greatly reduce the risk of extravasation of the drug. If extravasation does occur, complications can be avoided in most cases by taking appropriate action, including promptly covering the injection site and taking precautions to avoid exposure to strong light. Infusion-related back pain may occur in a minority of patients but has no known sequelae and resolves rapidly. There is anecdotal evidence to suggest that good hydration, altering the patient’s position (by standing them up, for example), and slowing the infusion rate may be beneficial in avoiding or ameliorating infusion-related back pain. Photosensitivity reactions are avoidable if the proper precautions are followed to avoid exposure to direct sunlight or strong artificial light, while noting that sunscreens are ineffective. Any photosensitivity reactions that do occur should be treated as sunburn. Acute severe vision decrease occurred within 7 days of treatment in a small number of Visudyne-treated patients. Partial recovery of visual acuity was observed in many patients. The recommended course of action in such cases is observation and discontinuation of any further treatments. References: VIP Study Group 2001a; VIP Study Group 2001b; VOH Study Group 2001

Visudyne™ (Verteporfin) Therapy

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