Verteporfin (Parenteral-Local )

VA CLASSIFICATION
Primary: OP900

Commonly used brand name(s): Visudyne.

Another commonly used name is:
benzoporphyrin derivative^{03}{04}{05}
.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Macular degeneration therapy adjunct—

Photosensitizer—

Photodynamic therapy—

Indications

Accepted

Macular degeneration (treatment)—Verteporfin is indicated for treatment of age-related macular degeneration in patients with predominantly classic subfoveal choroidal neovascularization.^{01}{08}

Pathologic myopia (treatment)—Verteporfin is indicated for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related pathologic myopia.^{10}{09}

Ocular histoplasmosis, presumed (treatment)¹—Verteporfin is indicated for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related presumed ocular histoplasmosis.^{09}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    718.8^{01}

Mechanism of action/Effect:

Verteporfin is a photosensitizing agent composed of two regioisomers.^{01} It accumulates preferentially in neovasculature, including choroidal neovasculature.^{01} Activation of verteporfin by nonthermal light (689 nanometers wavelength) in the presence of oxygen generates highly reactive, short-lived singlet oxygen and reactive oxygen radicals.^{01} The activated particles cause local damage to neovascular endothelium and subsequent vessel occlusion.^{01} Damaged endothelium releases procoagulant and vasoactive factors causing platelet aggregation, fibrin clot formation, and vasoconstriction.^{01} These factors contribute to the temporary occlusion of choroidal neovascularization.^{01}

Animal models indicate verteporfin is also present in the retina.^{01} Therefore, collateral damage may be caused to retinal structures following photoactivation in humans, including the retinal pigmented epithelium and outer nuclear layer of the retina.^{01}

Distribution:

Verteporfin is transported in the plasma primarily by lipoproteins.^{01} Verteporfin is distributed into most normal and neoplastic tissues of the body, but is retained longer in tumors as well as the skin, liver, kidney, spleen, and wound-healing tissue.^{02}

Biotransformation:

Metabolism to the diacid metabolite is limited and occurs to a small extent by liver and plasma esterases.^{01} NADPH-dependent liver enzyme systems, including the cytochrome P450 isozymes, do not appear to play a role in the metabolism of verteporfin.^{01}


Half-life:

Terminal elimination—5 to 6 hours.^{01}

Half-life has been shown to be significantly increased (by approximately 20%) in patients with mild hepatic insufficiency.^{01}

Elimination:
    Verteporfin is eliminated primarily by the fecal route.^{01} Less than 0.01% of the dose is recovered in the urine.^{01}


Precautions to Consider

Carcinogenicity/Mutagenicity

No studies have been performed to specifically evaluate the carcinogenic potential of verteporfin.^{01} As a class, photodynamic therapy 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, and mutations.^{01} Other photodynamic therapeutic agents have been shown to increase the incidence of sister chromatid exchanges in Chinese hamster ovary cells with visible light and in Chinese hamster lung fibroblasts irradiated with near-UV light, increase mutations and DNA-protein cross linking in mouse L5178 cells, and increase DNA-strand breaks in malignant human cervical carcinoma cells, but not in normal cells.^{01} It is not known how the potential for DNA damage with photodynamic therapy agents translates into human risk.^{01}

Pregnancy/Reproduction
Fertility—
No effect on fertility has been observed in male or female rats administered verteporfin up to 10 milligrams per kilogram of body weight per day (mg/kg/day) (approximately 60- and 40-fold human exposure at 6 mg per square meter of body surface area (mg/m ²) based on AUC_inf in male and female rats, respectively).^{01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. Studies in animals have shown that verteporfin causes adverse effects on the fetus.^{01}

Rat fetuses of dams administered verteporfin intravenously at ³ 10 mg/kg/day during organogenesis (approximately 40-fold human exposure at 6 mg/m² based on AUC_inf in female rats) exhibited an increase in the incidence of anophthalmia/microphthalmia.^{01} Rat fetuses of dams administered 25 mg/kg/day (approximately 125-fold the human exposure at 6 mg/m² based on AUC_inf in female rats) had an increased incidence of wavy ribs and fetal alterations.^{01}

A decrease in body weight gain and food consumption was observed in pregnant rabbits administered verteporfin at ³ 10 mg/kg/day during organogenesis.^{01} The No Observed Adverse Effect Level (NOAEL) for maternal toxicity was 3 mg/kg/day (approximately 7-fold human exposure at 6 mg/m ² based on AUC_inf).^{01} No teratogenic effects were observed in rabbits at doses of up to 10 mg/kg/day.^{01}

FDA Pregnancy Category C^{01}

Breast-feeding

It not known whether verteporfin is distributed into breast milk.^{01}However, problems in humans have not been documented.

Pediatrics

No information is available on the relationship of age to the effects of verteporfin in pediatric patients. Safety and efficacy have not been established.^{01}


Geriatrics


Approximately 90% of patients treated with verteporfin in clinical efficacy trials were over 65 years old.^{01} A reduced treatment effect was observed with increasing age (³ 75 years).^{01}

Surgical

If emergency surgery is necessary within 48 hours after treatment, as much of the internal tissue as possible in addition to the eyes and skin should be protected from intense light.^{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Calcium channel blocking agents or
» Polymyxin B or
» Radiation therapy    (concurrent use may increase the rate of uptake of verteporfin by the vascular endothelium^{01})


» Medications that decrease blood clotting, vasoconstriction, or platelet aggregation, such as:
Thromboxane A ₂ inhibitors    (concurrent use may decrease the efficacy of photodynamic therapy^{01})


» Medications that decrease active oxygen species or scavenge radicals, such as:
Beta-carotene or
Dimethyl sulfoxide (DMSO) or
Ethanol or
Formate or
Mannitol    (concurrent use may decrease the activity of photodynamic therapy^{01})


» Photosensitizing agents, other, including:
Griseofulvin or
Phenothiazines or
Sulfonamides or
Sulfonylurea hypoglycemic agents or
Tetracyclines or
Thiazide diuretics    (concurrent use may increase photosensitivity^{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Albuminuria or
Creatinine, serum or
Hepatic function test values    (may be elevated^{01})


White blood cell count    (may be increased or decreased^{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Porphyria    (cutaneous photosensitivity may be increased)


» Previous hypersensitivity reaction to verteporfin
Risk-benefit should be considered when the following medical problems exist
Hepatic dysfunction, moderate to severe    (consider therapy with verteporfin in these patients carefully as there is no clinical experience^{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
(10–20%)
    
Visual disturbances, including blurred vision, decreased visual acuity, and visual field defects^{01} (blurred vision or other change in vision)

Incidence less frequent
(1–10%)
    
Anemia^{01} (pale skin; troubled breathing, exertional; unusual bleeding or bruising; unusual tiredness or weakness)
    
atrial fibrillation^{01} (fast or irregular heartbeat; dizziness; fainting)
    
cataracts^{01} (blurred vision; decrease in vision)
    
conjunctivitis or conjunctival injection^{01}{07} (itching, redness, or other irritation of eye)
    
eye hemorrhage^{01} (eye pain; decrease in vision )
    
gastrointestinal cancers^{01}{07}
    
hypertension^{01} (dull nervousness ; pounding in the ears; slow or fast heartbeat )
    
decrease in vision, severe^{01} — a severe vision decrease equivalent of 4 lines or more within 7 days after treatment^{07}has been reported in 1–4% of patients; partial recovery of vision was observed in many patients
    
peripheral vascular disorder^{01}{07}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
(10–20%)
    
Injection site reaction^{01} (bleeding; blistering; burning; coldness; discoloration of skin; feeling of pressure; infection ; itching; numbness; pain ; rash; redness; scarring ; stinging; swelling; tenderness; tingling; ulceration; warmth)
    
headache^{01}

Incidence less frequent
(1–10%)
    
Albuminuria^{01} (cloudy urine)
    
arthralgia^{01} (pain, swelling, or redness in joints; muscle pain or stiffness; difficulty in moving)
    
asthenia^{01} (loss of strength or energy)
    
back pain^{01} —occurs primarily during infusion of verteporfin
    
constipation^{01}
    
decreased hearing^{01}
    
diplopia^{{01} {01}}(double vision )
    
dry eyes^{01}
    
eczema^{01} (skin rash)
    
fever^{01}
    
flu-like syndrome^{01} or pneumonia^{01}{07} (chills; cough; diarrhea; fever; general feeling of discomfort or illness; joint pain; loss of appetite ; nausea; runny nose; shivering; sore throat; sweating; trouble sleeping; vomiting)
    
hypesthesia^{01} (decreased sensitivity to touch)
    
lacrimation disorder^{01}{07} (tearing)
    
nausea^{01}{07}
    
pharyngitis (throat congestion; hoarseness ; tender, swollen glands in neck; trouble in swallowing; voice changes)
    
photosensitivity^{01} (increased sensitivity of eyes or skin to sunlight; redness or other discoloration of skin; severe sunburn)— photosensitivity reactions occurred in the form of skin sunburn following exposure to sunlight
    
prostatic disorder^{01} (pelvic discomfort; difficult or painful urination)
    
sleep disturbance^{01} (trouble in sleeping)
    
varicose veins^{01}
    
vertigo^{{01} {01}}( dizziness or light-headedness; feeling of constant movement of self or surroundings)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
An overdose of verteporfin and/or light in the treated eye may result in nonperfusion of normal retinal vessels with the possibility of a severe decrease in vision which could be permanent.^{01} An overdose of verteporfin will also result in the prolongation of the period during which the patient remains photosensitive to bright light.^{01}

Treatment of overdose
In the instance of overdose, it is recommended to extend the photosensitivity precautions for a time proportional to the overdose.^{01}


Supportive care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Verteporfin (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Not recommended for use during pregnancy because of maternal and fetotoxic effects in animal studies





Use in the elderly—A reduced treatment effect was observed with increasing age, for patients ³ 75 years

Surgical
If emergency surgery is necessary within 48 hours after treatment, as much of the internal tissue as possible in addition to the eyes and skin should be protected from intense light
Other medications, especially calcium channel blocking agents; polymyxin B; radiation therapy; medications that decrease blood clotting, vasoconstriction, or platelet aggregation; medications that decrease active oxygen species or scavenge radicals; other photosensitizing agents
Other medical problems, especially porphyria and hypersensitivity reaction to verteporfin

Proper use of this medication

» Proper dosing

Precautions while using this medication
» Ocular sensitivity to sunlight or other bright lights for 5 days; using dark sunglasses as protection

» Avoiding exposure of skin to sunlight and other bright lights (e.g., tanning salons, bright halogen lighting, and high-power lighting used in surgical operating rooms or dental offices) for 5 days after administration because of the risk of dermal photosensitivity reactions; sunscreen products will not protect against such reactions; calling physician immediately if severe reaction to light occurs

» Not avoiding exposure to ambient indoor light, which helps to clear verteporfin from the skin


Side/adverse effects
Signs of potential side effects, especially vision disturbances, anemia, atrial fibrillation, cataracts, conjunctivitis or conjunctival injection, eye hemorrhage, gastrointestinal cancers, hypertension, decrease in vision (severe), and peripheral vascular disorder


General Dosing Information
Standard care and precautions should be taken in administering the intravenous infusion to avoid extravasation.^{01} If extravasation does occur, stop the infusion immediately and apply cold compresses.^{01} The area surrounding the injection site should be thoroughly protected from direct light until the swelling and discoloration have faded in order to prevent the occurrence of a local burn which could be severe.^{01} Some standard precautions include, but are not limited to:^{01}   • Establishing a free-flowing intravenous line before starting verteporfin infusion, and careful monitoring of the line^{01}
   • For elderly patients, using the largest arm vein possible for the injection, because vein walls of some elderly patients may be fragile^{01}
   • Avoiding small veins in the back of the hand^{01}


Following verteporfin injection, care should be taken to avoid exposure of the skin or eyes to direct sunlight or bright indoor light for five days as patients will become temporarily photosensitive.^{01} A wrist band may be worn by patients to remind them to avoid direct sunlight or bright indoor light for five days. Bright indoor light includes but is not limited to, tanning salons, bright halogen lighting, and high-power lighting used in surgical operating rooms or dental offices.^{01}

If patients must go outdoors in the first five days after treatment with verteporfin, they should protect all parts of their skin and eyes by wearing protective clothing and dark sunglasses.^{01} Ultraviolet sunscreens offer no protection against a photosensitivity reaction because residual verteporfin in the skin is activated by visible light.^{01}

After treatment, patients should not stay in the dark and should be encouraged to expose their skin to ambient indoor light.^{01} This will help inactivate verteporfin through a process known as photobleaching.^{01}

Patients experiencing a severe decrease of vision of four lines or more within one week following treatment should not be retreated at least until their vision completely recovers to pretreatment levels and the potential benefits and risks of subsequent treatment are carefully considered by the physician.^{01}

Controlled trials only allowed treatment of one eye per patient.^{01} For patients presenting for the first time with eligible lesions in both eyes without prior verteporfin therapy, it is prudent to treat one eye (the most aggressive lesion) at the first course.^{01}{06}One week after the first course, if no significant safety issues are identified, the second eye can be treated using the same treatment regimen after a second verteporfin infusion.^{01}

For patients presenting with eligible lesions in both eyes, physicians should evaluate the potential benefits and risks of treating both eyes concurrently.^{01} If the patient has previously received verteporfin therapy in one eye with an acceptable safety profile, both eyes may be treated concurrently after a single administration of verteporfin.^{01} The more aggressive lesion should be treated first, at 15 minutes after the start of the infusion.^{01} Immediately following light application to the first eye, the laser settings should be adjusted to introduce the treatment parameters for the second eye, with the same light dose and intensity as for the first eye, starting no later than 20 minutes from the start of the verteporfin infusion.^{01}

Lesion size determination and spot size determination of the choroidal neovascularization (CNV) are used by the ophthalmologist in preparation for verteporfin photodynamic therapy^{06}{07}:   • The greatest linear dimension (GLD) of the lesion is estimated by fluorescein angiography and color fundus photography.^{01} All classic and occult CNV, blood and/or blocked fluorescence, and any serous detachments of the retinal pigment epithelium should be included for this measurement.^{01}
   • The treatment spot size should be 1000 microns larger than the GLD of the lesion on the retina to allow a 500 micron border ensuring full coverage of the lesion.^{01} The maximum spot size used in clinical trials was 6400 microns.^{01}
   • The nasal edge of the treatment spot must be positioned at least 200 microns from the temporal edge of the optic disc, even if this will result in lack of photoactivation of CNV within 200 microns of the optic nerve.^{01}


Safety considerations for handling this medication
It is important to avoid contact with the skin and eyes during preparation and administration of verteporfin.^{01} Exposed persons should be protected from bright light.^{01}

The use of rubber gloves and eye protection is recommended.^{01}

Verteporfin spills should be wiped up with a damp cloth and all materials should be disposed of properly.^{01}


Parenteral Dosage Forms

VERTEPORFIN FOR INJECTION

Usual Adult Dose
Macular degeneration (treatment) or
Pathologic myopia (treatment) or
Ocular histoplasmosis, presumed (treatment)¹
Intravenous, 6 mg per square meter of body surface area, injected slowly over 10 minutes (3 mL/minute), followed by irradiation with light from a nonthermal diode laser 15 minutes after the start of the infusion.^{{01}{08}{10}{09}}

Note: Lesion size determination and spot size determination of the choroidal neovascularization (CNV) are also performed by the ophthalmologist.^{07}
Re-evaluation of the patient should be done every three months, and if choroidal neovascular leakage is detected on fluorescein angiography, therapy should be repeated.^{01} The safety and efficacy of verteporfin beyond two years have not been established.^{01}
Administration of a course of verteporfin photodynamic therapy occurs in two stages. In the first stage of therapy, verteporfin is administered by slow intravenous injection over a period of 10 minutes.^{01}The second stage of therapy begins 15 minutes after the start of the 10-minute infusion and consists of the application of a 689 nanometer wavelength laser light to the lesion.^{01} The recommended light dose is 50 Joules per square centimeter of neovascular lesion delivered at an intensity of 600 milliwatts per square centimeter.^{01} The light dose is applied for 83 seconds.^{01} The laser light is delivered to the retina as a single circular spot by a fiber optic and a slit lamp using a suitable ophthalmic magnification lens.^{01}
Light dose and intensity, ophthalmic lens magnification factor, and zoom lens setting are important parameters for the appropriate delivery of light to the predetermined treatment spot.^{01} The following laser systems are compatible with verteporfin therapy; each system delivers a stable power output at a wavelength of 689±3 nanometers:^{01}   • Coherent Opal Photoactivator Laser Console and LaserLink Adapter, manufactured by Coherent, Inc., Santa Clara, CA^{01}
   • Zeiss VISULAS 690s laser and VISULINK PDT adapter, manufactured by Carl Zeiss, Inc., Thornwood, NY^{01}

The use of incompatible lasers that do not provide the required characteristics of light for the photoactivation of verteporfin could result in incomplete treatment due to partial photoactivation, overtreatment due to overactivation, or damage to surrounding normal tissue.^{01}



Usual Pediatric Dose
Safety and efficacy have not been established.^{01}

Usual Geriatric Dose
See Usual adult dose.

Strength(s) usually available
U.S.—


15 mg (single-dose vial) (Rx) [Visudyne (lactose) (egg phosphatidylglycerol ) (dimyristoyl phosphatidylcholine) (ascorbyl palmitate) (butylated hydroxytoluene )]^{01}

Canada—


15 mg (single-dose vial) (Rx) [Visudyne (lactose) (egg phosphatidylglycerol ) (dimyristoyl phosphatidylcholine) (ascorbyl palmitate) (butylated hydroxytoluene )]^{08}

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F).^{01}{08}

Preparation of dosage form:
Verteporfin is reconstituted for intravenous administration by adding 7 mL of Sterile Water for Injection to the vial, which makes 7.5 mL containing 2 mg/mL of verteporfin.^{01} The desired volume of reconstituted verteporfin is withdrawn from the vial and diluted with 5% Dextrose for Injection to a total volume of 30 mL for administration by intravenous infusion.^{01}

Stability:
Once reconstituted, verteporfin must be protected from light and used within four hours.^{01}

Note: Verteporfin is an opaque, dark green solution.^{01} The diluted dose volume should be administered using an appropriate syringe pump and in-line filter.^{01}

Developed: 07/07/2000
Revised: 12/17/2001

References

1. Product Information: Visudyne™, verteporfin for injection. QLT PhotoTherapeutics, Seattle, WA, (PI developed 4/2000) reviewed 5/2000.
   

2. Lui H & Anderson RR: Photodynamic therapy in dermatology: recent developments. Dermatol Clin 1993; 11(1):1–13.
   

3. Miller JW, Schmidt-Erfurth U, Sickenberg M et al: Photodynamic therapy with verteporfin for choroidal neovascularization caused by age-related macular degeneration. Arch Ophthalmol 1999; 117:1161–1173.
   

4. Mulroney CM, Glück S, & Ho AD: The use of photodynamic therapy in bone marrow purging. Semin Oncol 1994; 21(6 suppl 15):24–27.
   

5. Levy JG: Photosensitizers in photodynamic therapy. Semin Oncol 1994; 21(6 suppl 15):4–10.
   

6. Telephone communication with manufacturer, Ciba Vision, 6/20/2000.
   

7. Manufacturer comments and telephone communication, Ciba Vision, 8/3/2000.
   

8. Product Information: Visudyne™, verteporfin for injection. QLT Inc., Vancouver, B.C. (PI developed 5/30/2000) reviewed 8/2000.
   

9. Product Information: Visudyne™, verteporfin for injection. Novartis Ophthalmics (Canada) Inc. (PI developed 07/2001) reviewed 12/2001.
   

10. Product Information: Visudyne™, verteporfin for injection. QLT PhotoTherapeutics, Seattle, WA, (PI developed 08/2001) reviewed 12/2001.