Consumer medicine information

Visudyne

Verteporfin

BRAND INFORMATION

Brand name

Visudyne

Active ingredient

Verteporfin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Visudyne.

What is in this leaflet

This leaflet answers some common questions about Visudyne.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Visudyne against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What Visudyne is used for

Visudyne is used to treat a condition where abnormal blood vessels grow in the back of your eye causing you to lose central vision and impairing your eyesight. The medical name for this condition is subfoveal choroidal neovascularisation.

This condition is caused by a breakdown of the macula. The macula is part of the light sensitive layer at the back of the eye.

This medicine is a light activated drug used in photodynamic therapy (PDT). By itself, it has no effect. It works only when activated by light. It works by stopping the blood flowing to the abnormal vessels.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

It is available only with doctor's prescription.

There is not enough information to recommend the use of this medicine for children.

Before you are given Visudyne

When you must not be given it

You must not be given Visudyne if you have an allergy to:

  • any medicine containing verteporfin
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

You must not be given this medicine if you have:

  • porphyria
  • severe liver disease

Do not breast-feed if you are given this medicine. There is a possibility that your baby may be affected. Your doctor will advise when you can start breastfeeding again.

You must not be given this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged return it to your pharmacist for disposal.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, dyes or preservatives.

Tell your doctor if you have or have had any of the following medical conditions:

  • liver disease
  • gall bladder disease
  • heart disease
  • high blood pressure

Tell your doctor if you have been treated with Visudyne before and you experienced a decrease in vision following this previous treatment. Visudyne has caused a severe decrease in vision shortly after treatment in a small number of patients. If this happened to you, your doctor will discuss the risk and benefit of further treatment with Visudyne.

Tell your doctor if you are pregnant or plan to become pregnant. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you are given Visudyne.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Visudyne may interfere with each other. These include:

  • some antibiotics, including tetracyclines, sulfonamides, griseofulvin and polymixin B
  • phenothiazine medicines used to treat mental disorders
  • some types of tablets used to treat diabetes
  • some diuretic medicines (also called fluid or water tablets)
  • some heart medicines called calcium channel blockers
  • radiation therapy
  • betacarotene included in some vitamin supplements
  • medicine which decrease clotting such as aspirin
  • vasodilators used to widen blood vessels resulting in smooth muscle relaxation
  • alcohol
  • mannitol.

These medicines may affect how well Visudyne works or may increase the chance of side effects such as making your skin or eyes more sensitive to light.

Your doctor and pharmacist have more information on medicines to be careful with or avoid when you are given this medicine.

How Visudyne is given

Your doctor will prepare and administer Visudyne for you.

Follow the directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor for help.

How much is given

The amount of Visudyne you need will be calculated for you and depends on your height and weight.

How it is given

Visudyne is first dissolved in water and then diluted with glucose for a total amount of 30mL infusion solution. This solution is injected slowly, over 10 minutes, into a vein.

At the end of the infusion, your doctor will put a special contact lens onto your eye and treat your eye with light from a special laser.

Follow the instructions from your doctor and keep your eye still while you are being treated with the laser. It takes about 11/2 minutes to deliver the light dose required from the laser to activate Visudyne.

When it is given

Visudyne is given as a single dose. If necessary, it can be repeated every 3 months.

How long to continue treatment

Continue treatment with this medicine for as long as your doctor tells you. This medicine helps to control your eye disease, but does not cure it. It is important to keep having your vision checked by your doctor even if you feel it has improved.

If you forget a treatment

If you miss a Visudyne treatment, you need to contact your doctor to arrange another appointment as soon as possible. If you stop Visudyne treatment, your eye disease may continue to progress.

If you are given too much (overdose)

If you are given more Visudyne than you need, your doctor may ask you to protect yourself from direct sunlight, bright indoor light or surgeon's lamps for a longer period of time than the usual 48 hours. Your doctor will advise for how long you need to do this.

While you are being given Visudyne

Things you must do

If you experience any problems during the treatment, tell your doctor.

If you experience any infusion related problems or symptoms during or following the treatment such as chest pain, , sweating, dizziness, rash, breathlessness, flushing, irregular heartbeat, or seizures, please tell your doctor or nurse immediately, as the infusion may need to be stopped and your condition may need to be treated urgently. Infusion related problems may also include sudden loss of consciousness.

If you have to go outdoors in daylight during the first 48 hours after treatment, you must protect your skin and eyes by wearing protective clothing and dark sunglasses. Avoid exposure to direct sunlight or bright indoor lights such as tanning salons, bright halogen lighting or high power lighting as used by surgeons or dentists. Also avoid prolonged exposure to light-emitting medical devices such as those which measure blood oxygen levels. Wear the wristband which will be given to you to remind you to avoid direct sunlight for 48 hours. Sunscreens offer no protection. When you are given Visudyne, you will become sensitive to bright light for 48 hours after the treatment. Normal indoor lighting is safe. Do not stay in the dark because exposure to normal indoor lighting will help your body eliminate Visudyne more quickly.

If you become pregnant while being treated with this medicine, tell your doctor immediately.

Things you must not do

Do not drive or operate machinery if your vision is poor, either because of your disease or because of the treatment. This medicine may cause temporary problems with vision in some people. If you are affected, do not drive, operate machinery or do anything else that could be dangerous until your vision is normal.

Things to be careful of

If the Visudyne solution comes into direct contact with your skin or eyes, extensively wash the affected area with water. Visudyne contains a small amount of butylated hydroxytoluene (E321). This ingredient is an irritant to the eyes, skin and mucous membranes. If Visudyne is spilled, your doctor or his/her staff will contain the spill and wipe it up with a damp cloth.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are being treated with Visudyne.

This medicine helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • sensitivity of the skin and eyes to light or the sun
  • infusion related back or chest pain which may radiate to other areas including but not limited to the pelvis, shoulders or ribs
  • sunburn
  • nausea, unusual tiredness or weakness
  • itching
  • feeling anxious
  • headache
  • decreased skin sensitivity
  • fever, sweating, hot flushes
  • pain, inflammation, swelling, blistering or leakage into the area surrounding the injection site and possibly death of skin tissue (necrosis) at the injection site. If Visudyne goes outside the vein during injection, it can cause pain, swelling and a change in skin colour in the area of the leakage. If this happens, the injection needs to be stopped and the skin treated with cold compresses and thoroughly protected from light until the skin colour returns to normal. You may need a pain killer.
  • abnormal or decreased vision. Visudyne has caused a severe decrease in vision shortly after treatment in a small number of patients. Partial recovery of vision was observed in some of these patients.

The above side effects are usually mild and short lived.

Tell your doctor as soon as possible if you notice any of the following:

  • eye disorder including spots, sensation of flashing light, loss of vision
  • temporary blindness, or blurred vision, especially when the onset is sudden, severe and is restricted to one eye
  • a change in your field of vision
  • bleeding in the eye with an appearance of a spider's web in the vision
  • severe allergic reactions related to Visudyne infusion including difficulty breathing or swallowing, rash, itching, hives, dizziness or redness of the skin. On rare occasions these reactions may be severe and potentially include seizures.
  • fainting
  • change in heart rate
  • severe upper stomach pain, often with nausea and vomiting
  • yellowing of the skin or eyes
  • severe pain in the abdomen
  • any unusual bleeding
  • signs of a chest infection

The above are serious side effects which may require medical attention.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people. Some of these side effects (for example, changes in cholesterol level, kidney or liver function, or blood pressure) can only be found when your doctor does tests from time to time to check your progress.

After you are given Visudyne

Storage

You will not need to store Visudyne. Your doctor will obtain and keep it for you.

Product description

What it looks like

Visudyne is a green powder in a clear glass vial.

Ingredients

Visudyne contains 15 mg of verteporfin as the active ingredient.

It also contains:

  • lactose
  • dimyristoylphosphatidylcholine
  • egg phosphatidylglycerol sodium
  • ascorbyl palmitate
  • butylated hydroxytoluene

Sponsor

Visudyne is supplied in Australia by:

NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1-800-671-203

Web site: www.novartis.com.au

Date of preparation

This leaflet was prepared in September 2018

AUST R 74902

® = Registered trademark

(vid280918c) based on PI (vid280918i)

Published by MIMS December 2018

BRAND INFORMATION

Brand name

Visudyne

Active ingredient

Verteporfin

Schedule

S4

 

1 Name of Medicine

Verteporfin.

2 Qualitative and Quantitative Composition

Each vial contains 15 mg of verteporfin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Visudyne (verteporfin) is a sterile powder for intravenous infusion.
Verteporfin is a dark green to black powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Visudyne is indicated for the treatment of patients with predominately classic or occult subfoveal choroidal neovascularisation due to age-related macular degeneration (AMD), or with subfoveal choroidal neovascularisation caused by other macular diseases.

4.2 Dose and Method of Administration

Visudyne therapy should only be administered by ophthalmologists experienced in the management of patients with age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis.

Dosage.

General target population. Visudyne treatment is a two-step process. The first step is a 10 minute intravenous infusion of Visudyne at a dose of 6 mg/m2 body surface area, diluted in 30 mL infusion solution (see Section 4.2 Dose and Method of Administration, Instructions for use and handling).
The second step is the light activation of Visudyne 15 minutes after the start of the infusion (see Section 4.2 Dose and Method of Administration, Method of administration).
Patients should be re-evaluated every 3 months. In the event of recurrent CNV leakage, Visudyne treatment should be repeated. In clinical studies, patients have been treated up to 9 times within 2 years.
There are, as yet, no clinical data to support concomitant treatment of the second eye. Controlled trials only allowed treatment of one eye per patient. Therefore, concomitant treatment of both eyes is not recommended.
Special populations.

Renal impairment.

Visudyne has not been studied in patients with renal impairment.

Paediatrics.

Use in the paediatric population has not been investigated. Visudyne is not indicated in this population.

Method of administration.

This medicinal product is intended for intravenous infusion only.
For the light activation, a diode laser generating non-thermal red light (wavelength 689 nanometre) is used via a slit lamp mounted fibre optic device and a suitable contact lens. At the recommended light intensity of 600 mW/cm2 it takes 83 seconds to deliver the required light dose of 50 J/cm2.
The greatest linear dimension of the choroidal neovascular lesion is estimated using fluorescein angiography and fundus photography. Fundus cameras with a magnification within the range of 2.4 to 2.6-fold are recommended.
The treatment spot should cover all neovasculature, blood and/or blocked fluorescence. To ensure treatment of poorly demarcated lesion borders, an additional margin of 500 micrometres should be added around the visible lesion. The nasal edge of the treatment spot must be at least 200 micrometres from the temporal edge of the optic disc. The maximum spot size for the first treatment in the clinical studies was 6400 micrometres. For treatment of lesions that are larger than the maximum treatment spot size, apply the light to the greatest possible area of the active lesion.
It is important to follow the above recommendations to achieve the optimal effect.

Instructions for use and handling.

Reconstitute Visudyne with 7.0 mL water for injections to produce 7.5 mL of a 2.0 mg/mL solution. Reconstituted Visudyne is an opaque dark green solution. It is recommended that reconstituted Visudyne be inspected visually for particulate matter and discolouration prior to administration. For a dose of 6 mg/m2 body surface area (see Section 4.2 Dose and Method of Administration) dilute the required amount of Visudyne solution in 5% glucose for injection to a final volume of 30 mL.
Use in one patient on one occasion only. Contains no antimicrobial preservative.
If material is spilled, it should be contained and wiped up with a damp cloth. Eye and skin contact should be avoided. Use of rubber gloves and eye protection is recommended. All materials should be disposed of properly.

4.3 Contraindications

Visudyne is contraindicated for patients with porphyria or a known hypersensitivity to verteporfin or to any of the excipients of Visudyne, and in patients with severe hepatic impairment.

4.4 Special Warnings and Precautions for Use

Photosensitivity following treatment.

Patients who receive Visudyne will become photosensitive for 48 hours after the infusion and should wear a wrist band to remind them to avoid direct sunlight for 48 hours. During that period, patients should avoid exposure of unprotected skin, eyes or other body organs to direct sunlight or bright indoor light such as tanning salons, bright halogen lighting, or high power lighting in surgery operating rooms or dentist offices. Prolonged exposure to light from light-emitting medical devices such as pulse oximeters should also be avoided for 48 hours following Visudyne administration.
If patients have to go outdoors in daylight during the first 48 hours after treatment, they must protect their skin and eyes by wearing protective clothing and dark sunglasses. Ambient indoor light is safe. UV sunscreens are not effective in protecting against photosensitivity reactions. If emergency surgery is necessary within 48 hours after treatment, as much of the internal tissue as possible should be protected from intense light.

Decrease in visual acuity.

Patients who experience a severe decrease of vision (equivalent to 4 lines or more) within one week after treatment should not be retreated, at least until their vision completely recovers to pretreatment level and the potential benefits and risks of subsequent treatment are carefully considered by the treating physician.

Extravasation.

Extravasation of Visudyne, especially if the area is exposed to light, can cause severe pain, inflammation, swelling, blistering or discolouration at the injection site. The relief of pain may require analgesic treatment. Localised (skin) necrosis at the injection site following extravasation has also been reported. If extravasation occurs, the infusion should be stopped immediately. Protect the affected area thoroughly from bright direct light until swelling and discolouration have disappeared in order to prevent the occurrence of a local burn which could be severe, and put cold compresses on the injection site.
To avoid extravasation, a free-flowing IV line should be established before starting Visudyne infusion and the line should be monitored. The largest possible arm vein, preferably the antecubital, should be used for the infusion and small veins in the back of the hand should be avoided.

Medical supervision during the infusion.

Chest pain, vaso-vagal reactions and hypersensitivity reactions related to Visudyne infusion, have been reported. Both vasovagal and hypersensitivity reactions are associated with general symptoms such as syncope, sweating, dizziness, rash, dyspnoea, flushing and changes in blood pressure and heart rate. On rare occasions these reactions may be severe, and potentially include convulsions. Patients should be under medical supervision during the Visudyne infusion.
Cases of anaphylactic reactions have been observed in patients receiving Visudyne. If an anaphylactic or other serious allergic reaction occurs during or following infusion, administration of Visudyne should be discontinued immediately and appropriate therapy be initiated.

Use in anaesthetised patients.

There are no clinical data on the use of Visudyne in anaesthetised patients.
In sedated or anaesthetised pigs, a Visudyne dose of more than 10 times the recommended dose in patients, given as a bolus injection, caused severe haemodynamic effects including death, probably as a result of complement activation. Pre-dosing with antihistamine (diphenhydramine) diminished these effects, suggesting that histamine may play a role in this process. This effect was not observed in conscious non-sedated pigs, or any other species including man.
Verteporfin, at about 6 times the expected maximum plasma concentration in treated patients, caused a low level (≤ 40%) of complement activation in human blood in vitro. Complement activation tended to be greatest in serum samples from people with anti-cardiolipin (anti-phospholipid) antibodies. No clinically relevant complement activation was reported in five patients treated with verteporfin, but the risk of anaphylactic reactions due to complement activation cannot be excluded. Patients should be supervised during Visudyne infusion and caution should be exercised when Visudyne treatment under general anaesthesia is considered.

Use of incompatible lasers.

Use of incompatible lasers that do not provide the required characteristics of light for the photoactivation of Visudyne could result in incomplete treatment due to partial photoactivation of Visudyne, overtreatment due to overactivation of Visudyne, or damage to surrounding normal tissue.

Use in patients with heart disease or hypertension.

No clinical experience is available in patients with unstable heart disease (class III or IV) and in patients with uncontrolled arterial hypertension.

Use in hepatic impairment.

Verteporfin is cleared by the liver and excreted in the bile. Visudyne therapy should be considered carefully in patients with moderate hepatic impairment or biliary obstruction since no experience has been gained in these patients (see Section 4.3 Contraindications).

Use in the elderly.

Approximately 90% of the patients treated with Visudyne in the clinical efficacy trials were over the age of 65. A reduced treatment effect was seen with increasing age.

Paediatric use.

Safety and effectiveness in paediatric patients have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No specific drug-drug interaction studies have been conducted in humans.
Verteporfin is rapidly eliminated by the liver, mainly as unchanged drug. Metabolism is limited and occurs by liver and plasma esterases. Microsomal cytochrome P450 does not appear to play a role in verteporfin metabolism.
Based on the mechanism of action of verteporfin, many drugs used concomitantly could influence the effect of Visudyne therapy. Possible examples include the following.

Drugs increasing verteporfin uptake in the vascular endothelium.

Agents such as calcium channel blockers, polymyxin B and radiation therapy are known to alter the vascular endothelium and may result in enhanced verteporfin tissue-uptake when used concurrently.

Other photosensitising agents.

It is possible that concomitant use of other photosensitising agents (e.g. tetracyclines, sulfonamides, phenothiazines, sulfonylurea, hypoglycemic agents, thiazide diuretics and griseofulvin) could increase the potential for skin photosensitivity reactions.

Free radical scavengers.

Although there is no clinical evidence, antioxidants (e.g. beta-carotene) or compounds that scavenge free radicals (e.g. dimethyl-sulfoxide (DMSO), ethanol, formate or mannitol) may quench the activated oxygen species generated by verteporfin, resulting in decreased verteporfin activity.

Drugs antagonising blood vessel occlusion.

Drugs that decrease clotting, vasoconstriction or platelet aggregation (e.g. thromboxane A2 inhibitors) could also decrease the efficacy of Visudyne therapy.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effect on male or female fertility was observed in rats following intravenous administration of verteporfin up to 10 mg/kg/day (approximately 60 and 40-fold human exposure at 6 mg/m2 based on AUC(0-∞) in male and female rats, respectively).
(Category B3)
Foetal levels of verteporfin and/or metabolites were about 1% of maternal concentrations after intravenous administration of radiolabelled verteporfin in pregnant rats.
Rat foetuses of dams administered verteporfin for injection intravenously at 25 mg/kg/day during organogenesis showed increased incidences of anophthalmia/ microphthalmia, bent or wavy ribs. The no observed effect level (NOEL) was 10 mg/kg/day for foetal damage (approximately 40-fold the human exposure at 6 mg/m2 based on AUC in female rats) and 2 mg/kg/day for maternal toxicity (approximately 4 fold the human exposure at 6 mg/m2 based on AUC in female rats).
No evidence of foetal toxicity or teratogenic activity was observed in rabbits given verteporfin intravenously at doses up to 10 mg/kg/day, while 25 mg/kg/day was fatal in pregnant rabbits. The NOEL for foetal damage was 10 mg/kg/day (approximately 24-fold the human exposure at 6 mg/m2 based on body surface area) and 3 mg/kg/day for maternal toxicity (approximately 7 fold the human exposure at 6 mg/m2 based on body surface area).
There are no adequate and well-controlled studies in pregnant women. Visudyne should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the foetus.
 It is not known whether Visudyne is excreted in human milk. However, many drugs are excreted in human milk. Visudyne should therefore not be administered to nursing mothers, or breast-feeding should be interrupted.

4.7 Effects on Ability to Drive and Use Machines

Following Visudyne treatment, patients may develop transient visual disturbances such as abnormal vision, vision decrease or visual field defects that may interfere with their ability to drive or use machines. Patients who develop such symptoms should not drive or use machines as long as these symptoms persist.

4.8 Adverse Effects (Undesirable Effects)

Adverse drug reactions from clinical trials (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
In randomised clinical trials in choroidal neovascularisation, mainly in AMD patients, the following additional adverse events were reported. Only those adverse events occurring at an incidence at least 1% higher in Visudyne treated patients compared to placebo are listed:

Events occurring in 10-20% of patients.

Ocular treatment site.

Cataract.

Events occurring in 1-10% of patients.

Ocular treatment site.

Blepharitis.

Body as a whole.

Flu syndrome.

Digestive.

Constipation.

Haemic and lymphatic.

Leucopoenia.

Musculoskeletal.

Arthrosis.

Nervous system.

Sleep disorder.

Respiratory.

Cough.

Skin and appendages.

Skin disorder.

Special senses.

Cataract (untreated eye).

Urogenital.

Prostatic disorder.
The following adverse drug reactions (Table 2) are additional rare undesirable effects in clinical trials or spontaneously reported during post marketing surveillance and suspected to be associated with verteporfin.
Most adverse reactions were mild to moderate and transient in nature. Undesirable effects reported in patients with pathologic myopia and ocular histoplasmosis syndrome were similar to those reported in patients with AMD.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdose of drug and/or light in the treated eye may result in non-selective non-perfusion of normal retinal vessels, with the possibility of severe vision decrease.
Overdose of the drug may result in the prolongation of the period during which the patient remains photosensitive. In such cases, the patient should prolong skin and eye protection from direct sunlight or bright indoor light for a period proportionate with the overdose given.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Visudyne therapy is a two-stage process requiring administration of both verteporfin for injection and nonthermal red light. Verteporfin is used as a light activated drug (photosensitiser). Treatment of diseases using photosensitisers and light activation is called photodynamic therapy (PDT).
Verteporfin is transported in the plasma primarily by lipoproteins. Once verteporfin is activated by light in the presence of oxygen, highly reactive, short lived singlet oxygen and reactive oxygen radicals are generated. Light activation of verteporfin results in local damage to neovascular endothelium, resulting in vessel occlusion. Damaged endothelium is known to release procoagulant and vasoactive factors through the lipo-oxygenase (leukotriene) and cyclo-oxygenase (eicosanoids such as thromboxane) pathways, resulting in platelet aggregation, fibrin clot formation and vasoconstriction. Verteporfin appears to somewhat preferentially accumulate in neovasculature, including choroidal neovasculature. However, animal models indicate that the drug is also present in the retina. Therefore, there may be collateral damage to retinal structures following photoactivation including retinal pigment epithelium and outer nuclear layer of the retina. The temporary occlusion of choroidal neovascularisation (CNV) following Visudyne therapy has been confirmed in humans with fluorescein angiography.

Clinical trials.

Age-related macular degeneration (AMD).

AMD with predominantly classic subfoveal CNV. Treatment of AMD with PDT; TAP studies BPD OCR 002 A and B. Two adequate and well-controlled, double-masked, placebo-controlled, randomised studies were conducted in patients with classic containing subfoveal CNV secondary to age-related macular degeneration (BPD OCR 002 A and B). A total of 609 patients (Visudyne 402, placebo 207) were enrolled in these two studies. A planned analysis of safety and efficacy was conducted at 1 year, with 94% of patients completing that portion of the study. A second analysis was planned at 2 years to establish durability of effect: 87% of patients completed 2 years of follow-up. During these studies, retreatment was allowed every 3 months if fluorescein angiograms showed any recurrence or persistence of leakage. The placebo control (sham treatment) consisted of intravenous administration of glucose 5% in water, followed by light application identical to that used for Visudyne therapy. The primary efficacy variable was responder rate, defined as the proportion of patients who lost less than 15 letters (equivalent to 3 lines) of visual acuity (measured with the EDTRS chart) at 12 months relative to baseline.
The difference between treatment groups statistically favoured Visudyne at the 1-year and 2-year analyses for visual acuity endpoints.
The subgroup of patients with predominantly classic CNV lesions was more likely to exhibit a treatment benefit (N = 242; Visudyne 159, placebo 83). Predominantly classic CNV lesions were defined as those in which the classic component comprised 50% or more of the area of the entire lesion. For the primary efficacy endpoint (percentage of patients who lost less than 3 lines of visual acuity), these patients showed a difference of approximately 28% between treatment groups at both month 12 and 24 (67% for Visudyne patients compared to 40% for placebo patients, p < 0.001 at month 12; and 59% for Visudyne patients compared to 31% for placebo patients, p < 0.001 at month 24). Severe vision loss (≥ 6 lines of visual acuity from baseline) was experienced by only 12% of Visudyne-treated patients compared to 34% of placebo treated patients at month 12, and by 15% of Visudyne-treated patients compared to 36% of placebo patients at month 24.
In patients followed from month 24 onwards and receiving Visudyne treatment as needed in an uncontrolled, open-label extension study (BPD OCR 002 A and B extension study), data suggest that vision outcomes at month 24 may be sustained for up to 60 months. No additional safety concerns were identified in the extension study.
In the BPD OCR 002 A and B extension study in all lesion types, the average number of treatments per year was 3.5 in the first year after diagnosis and 2.4 in the second for the randomised, placebo-controlled phase and 1.3 in the third year, 0.4 in the fourth and 0.1 in the fifth year for the open-label extension phase.
AMD with occult subfoveal CNV. The benefit of the product in the AMD patient population who have occult subfoveal CNV with evidence of recent or ongoing disease progression has not been demonstrated consistently. Two randomised, placebo-controlled, double-masked, multicentre, 24-month studies (BPD OCR 003 AMD, or verteporfin in Photodynamic Therapy of AMD [VIP-AMD], and BPD OCR 013, or Visudyne in Occult Choroidal Neovascularisation [VIO]) were conducted in patients with AMD characterised by occult with no classic subfoveal CNV.

Verteporfin in photodynamic therapy of AMD (VIP-AMD) study BPD OCR 003 AMD.

VIP-AMD was conducted in patients with AMD characterised by occult with no classic subfoveal CNV, or classic containing CNV with a visual acuity score > 73 letters (20/40). 339 patients (225 verteporfin, 114 placebo) were enrolled in this study. The efficacy parameter was the same as in BPD OCR 002 (see above).
For the primary efficacy endpoint (percentage of patients who lost less than 3 lines of visual acuity), a statistically significant difference of 12.9% in favour of Visudyne compared to placebo was observed at month 24 (46.2% i.e. 104 of 225 Visudyne patients, versus 33.3% i.e. 38 of 114 placebo patients, p = 0.023). A group of patients who had occult with no classic lesions (n = 258) showed a statistically significant difference in this same primary efficacy endpoint of 13.7% in favour of Visudyne compared to placebo (45.2% i.e. 75 of 166 Visudyne patients versus 31.5% i.e. 29 of 92 placebo patients, p = 0.032).
Exploratory subgroup analysis suggested that the treatment benefit was greater for occult with no classic patients who presented with either small lesions (< 4 MPS-DA) or lower levels of vision (VA score of < 65 letters) at baseline (n = 187). In those patients, the responder rate difference was 26.2% in favour of Visudyne compared to placebo patients (51.2% i.e. 63 of 123 Visudyne patients versus 25% i.e. 16 of 64 placebo patients lost less than 3 lines of visual acuity at month 24, p < 0.001).

Visudyne in occult choroidal neovascularisation (VIO) study BPD OCR 013.

The VIO study included patients with occult with no classic subfoveal CNV with a visual acuity score of 73-34 letters (20/40-20/200), and patients with lesions > 4 MPS disc areas were to have baseline visual acuity < 65 letters (< 20/50). 364 patients (244 verteporfin, 120 placebo) were enrolled in this study. The efficacy parameter was the same as in BPD OCR 002 and BPD OCR 003 AMD (see above), with an additional endpoint of month 24 defined. Another efficacy parameter was also defined: the proportion of patients who lost less than 30 letters (equivalent to 6 lines) of visual acuity at months 12 and 24 relative to baseline.
The study did not show statistically significant results on the primary efficacy parameter at month 12 (15-letter responder rate 62.7% versus 55.0%, p = 0.150; 30-letter responder rate 84.0% versus 83.3%, p = 0.868) or at month 24 (15 letter responder rate 53.3% versus 47.5%, p = 0.300; 30-letter responder rate 77.5% versus 75.0%, p = 0.602).
A higher percentage of patients who received Visudyne, compared with those who received placebo, experienced adverse events (88.1% versus 81.7%), associated adverse events (23.0% versus 7.5%), events leading to discontinuation (11.9% versus 3.3%) and events leading to death (n = 10 [4.1%] versus n = 1 [0.8%]). No death was considered to be related to treatment.
The safety and efficacy of Visudyne beyond 2 years have not been demonstrated.

Other macular diseases.

Pathologic myopia.

Verteporfin in photodynamic therapy of pathologic myopia (VIP-PM) study BPD OCR 003 PM.

One adequate multicentre, double masked, placebo controlled, randomised study (BPD OCR 003 PM) was conducted in patients with subfoveal CNV caused by pathologic myopia. A total of 120 patients (81 Visudyne, 39 placebo) were enrolled in the study. The posology and retreatments were the same as in the AMD studies. A planned analysis of safety and efficacy was conducted at 12 and 24 months, with 96% and 95% of patients completing each portion of the study, respectively.
At month 12, the difference between treatment groups statistically favoured Visudyne for visual acuity endpoints. For the primary efficacy endpoint (percentage of patients who lost less than 3 lines of visual acuity), these patients showed a difference of approximately 20% between groups (86% for Visudyne versus 67% for placebo, p = 0.011). The percentage of patients who lost less than 1.5 lines was 72% (Visudyne) versus 44% (placebo), showing a difference of 28% between treatment groups (p = 0.003).
At month 24, 79% Visudyne patients versus 72% placebo patients had lost less than 3 lines of visual acuity (p = 0.381). The percentage of patients who lost less than 1.5 lines was 64% for Visudyne and 49% for placebo (p = 0.106).
In patients followed from month 24 onwards (67 patients) and receiving Visudyne treatment as needed in an uncontrolled, open label, extension study (BPD OCR 003 PM extension study), data suggest that vision outcomes at month 24 may be sustained for up to 60 months. Other than 8 Visudyne-treated patients gaining more than 3 lines of vision after 60 months, there were no significant changes in vision in either the treated or placebo group. No additional safety concerns were identified in the extension study.
In the BPD OCR 003 study in pathological myopia, the average number of treatments per year was 3.5 in the first year after diagnosis, 1.8 in the second for the randomised placebo-controlled phase and 0.4 in the third year, 0.2 in the fourth and 0.1 in the fifth year for the open-label extension phase.
Ocular histoplasmosis.

Verteporfin in ocular histoplasmosis (VOH) study BPD OCR 004.

One open-label study (BPD OCR 004) was conducted in patients with ocular histoplasmosis syndrome. A total of 26 patients were treated with Visudyne in the study. The posology and retreatments were the same as in the AMD studies. After Visudyne therapy, visual acuity scores improved 7 or more letters from baseline in 46% of the patients after 24 months of follow-up, with 36% of patients gaining 15 or more letters of visual acuity. These results show that verteporfin therapy demonstrates an improvement in vision compared to the natural progression of the disease, which resulted in loss of vision.
In patients followed from month 24 onward (17 patients) and receiving Visudyne treatment as needed in an uncontrolled, open-label extension study (BPD OCR 004 extension study), data suggest that vision outcomes at month 24 may be sustained for up to 48 months. No additional safety concerns were identified in the extension study.
In the VOH study in presumed ocular histoplasmosis, the average number of treatments per year was 2.9 in the first year after diagnosis, 1.2 in the second, 0.2 in the third and 0.1 in the fourth year.

5.2 Pharmacokinetic Properties

Distribution.

Visudyne exhibits a simple and predictable pharmacokinetic profile. Cmax after a 10 minute infusion of 6 and 12 mg/m2 body surface area in the target population is approximately 1.58 and 3.24 microgram/mL, respectively. These values are somewhat higher (26% for the proposed dose of 6 mg/m2) than those observed in healthy young volunteers (1.18 microgram/mL) and may result in a higher exposure. The clinical relevance of this age related difference is remote as the risk/ benefit assessment determined in the target population is favourable. A maximum 2-fold inter-individual variation in plasma concentrations at Cmax (immediately after the end of the infusion) and at the time of light administration was found for each Visudyne dose administered. Cmax and area under the curve (AUC) values were linearly proportional to dose. The volume of distribution was 0.6 L/kg.
Plasma elimination half-life mean values ranged from 5-6 hours and were similar for both structural isomers.
The mean half-life of verteporfin in subjects with mild hepatic dysfunction was approximately 6.5 hours, while that of normal subjects was close to 4.7 hours. The mean AUC values for subjects with mild hepatic dysfunction were up to 1.4 times greater than those for subjects with normal hepatic function. This difference is not clinically relevant and does not require any dose adjustment for patients with mild hepatic impairment.

Protein binding.

In whole human blood, 90% of verteporfin is associated with plasma and 10% associated with blood cells, of which very little is membrane associated. In human plasma, 90% of verteporfin is associated with plasma lipoprotein fractions and approximately 6% is associated with albumin.

Metabolism.

The ester group of verteporfin is hydrolysed via plasma and hepatic esterases, leading to the formation of benzoporphyrin derivative diacid (BPD-DA). BPD-DA is also a photosensitiser but its systemic exposure is low (5-10% of the verteporfin exposure), suggesting that most of the drug is eliminated unchanged. In vitro studies did not show any significant involvement of oxidative metabolism by cytochrome P450 enzymes.

Excretion.

In rats, approximately 90% of the intravenous dose of 14C-BPD-MA was excreted in the faeces in 7 days, mainly by excretion in the bile. Less than 1% of the radioactivity was excreted in the urine. Only negligible amounts of verteporfin or BPD-DA are recovered in human urine, confirming a biliary excretion. The total body clearance in healthy volunteers was 105 mL/hour/kg and urinary excretion was less than 0.01% of the dose, as verteporfin and BPD-DA.

5.3 Preclinical Safety Data

Genotoxicity.

Photodynamic therapy (PDT) as a class has been reported to result in DNA damage including DNA strand breaks, alkali-labile sites, DNA degradation, and DNA-protein cross links which may result in chromosomal aberrations, sister chromatid exchanges (SCE) and mutations. In addition, other photodynamic therapy agents have been shown to increase the incidence of SCE in Chinese hamster ovary (CHO) cells irradiated with visible light and in Chinese hamster lung fibroblasts irradiated with near UV light, to increase mutations and DNA-protein cross-linking in mouse L5178 cells, and to increase DNA-strand breaks in malignant human cervical carcinoma cells but not in normal cells. Verteporfin was not evaluated in these systems. In other assays verteporfin, with or without metabolic activation (hepatic S9 fraction), and with or without irradiation using white (full spectrum) fluorescent light, showed no evidence of genotoxicity in assays of gene mutation (bacterial and mammalian (CHO) cells) or clastogenic activity (CHO cells in vitro and an in vivo mouse micronucleus test). Verteporfin, with or without irradiation, was also negative in an assay of unscheduled DNA synthesis in rat hepatocytes. It is not known how the potential for DNA damage with PDT agents translates into human risk.

Carcinogenicity.

No studies have been conducted to evaluate the carcinogenic potential of verteporfin.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose, dimyristoylphatidylcholine, egg phosphatidylglycerol sodium, ascorbyl palmitate, butylated hydroxytoluene.

6.2 Incompatibilities

Do not use normal saline or other parenteral solutions. Do not mix Visudyne in the same solution with other drugs.
After reconstitution and dilution protect from light until used and use within a maximum of 4 hours (see Section 4.2 Dose and Method of Administration, Instructions for use and handling). From a microbiological point of view the product should be used immediately.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Keep vial in the outer carton in order to protect from light.

6.5 Nature and Contents of Container

Glass vial, stopper and flip-off seal.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Verteporfin, also referred to as benzoporphyrin derivative monoacids ring A (BPD-MA), consisting of a 1:1 mixture of the equally active structural isomers BPD-MAC and BPD-MAD.
Chemical Name: (±)-trans-18-ethenyl-4,4a-dihydro-3,4-bis(methoxycarbonyl)-4a,8,14,19-tetramethyl-23H,25H-benzo[b]porphine-9,13-dipropanoic acid monomethyl esters. Molecular Formula: C41H42N4O8. Molecular weight: 718.
Verteporfin is soluble in tetrahydrofuran, sparingly soluble in acetonitrile, methanol and methylene chloride and insoluble in water, other than at extremes of pH.

Chemical structure.


CAS number.

129497-78-5.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes