Visudyne

VISUDYNE- verteporfin injection, powder, lyophilized, for solution
QLT Inc.

DESCRIPTION

VISUDYNE® (verteporfin for injection) is a light activated drug used in photodynamic therapy. The finished drug product is a lyophilized dark green cake. Verteporfin is a 1:1 mixture of two regioisomers (I and II), represented by the following structures:

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The chemical names for the verteporfin regioisomers are:

9-methyl (I) and 13-methyl (II) trans-(±)-18-ethenyl-4,4a-dihydro-3,4-bis(methoxycarbonyl)-4a,8,14,19-tetramethyl-23H, 25H-benzo[b ]porphine-9,13-dipropanoate

The molecular formula is C41 H42 N4 O8 with a molecular weight of approximately 718.8.

Each mL of reconstituted VISUDYNE contains:

ACTIVE: Verteporfin, 2 mg

INACTIVES: Lactose, egg phosphatidylglycerol, dimyristoyl phosphatidylcholine, ascorbyl palmitate and butylated hydroxytoluene

CLINICAL PHARMACOLOGY

Mechanism of Action

VISUDYNE (verteporfin for injection) therapy is a two-stage process requiring administration of both verteporfin for injection and nonthermal red light.

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 the retinal pigmented epithelium and outer nuclear layer of the retina. The temporary occlusion of choroidal neovascularization (CNV) following Visudyne therapy has been confirmed in humans by fluorescein angiography.

Pharmacokinetics

Following intravenous infusion, verteporfin exhibits a bi-exponential elimination with a terminal elimination half-life of approximately 5-6 hours. The extent of exposure and the maximal plasma concentration are proportional to the dose between 6 and 20 mg/m2. At the intended dose, pharmacokinetic parameters are not significantly affected by gender.

Verteporfin is metabolized to a small extent to its diacid metabolite by liver and plasma esterases. NADPH-dependent liver enzyme systems (including the cytochrome P450 isozymes) do not appear to play a role in the metabolism of verteporfin. Elimination is by the fecal route, with less than 0.01% of the dose recovered in urine.

In a study of patients with mild hepatic insufficiency (defined as having two abnormal hepatic function tests at enrollment), AUC and Cmax were not significantly different from the control group, half-life however was significantly increased by approximately 20%.

Clinical Studies

Age-Related Macular Degeneration (AMD)

Two adequate and well-controlled, double-masked, placebo-controlled, randomized studies were conducted in patients with classic-containing subfoveal CNV secondary to age-related macular degeneration. A total of 609 patients (VISUDYNE 402, placebo 207) were enrolled in these two studies. 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 Dextrose 5% in Water, followed by light application identical to that used for Visudyne therapy.

The difference between treatment groups statistically favored 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 Months 12 and 24 (67% for VISUDYNE patients compared to 40% for placebo patients, at Month 12; and 59% for VISUDYNE patients compared to 31% for placebo patients, at Month 24). Severe vision loss (≥6 lines of visual acuity from baseline) was experienced by 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-treated patients at Month 24.

Patients with predominantly classic CNV lesions that did not contain occult CNV exhibited the greatest benefit (N=134; VISUDYNE 90, placebo 44). At 1 year, these patients demonstrated a 49% difference between treatment groups when assessed by the <3 lines-lost definition (77% vs. 27%).

Older patients (≥75 years), patients with dark irides, patients with occult lesions or patients with less than 50% classic CNV were less likely to benefit from Visudyne therapy.

The safety and efficacy of VISUDYNE beyond 2 years have not been demonstrated.

Pathologic Myopia

One adequate and well-controlled, double-masked, placebo-controlled, randomized study was conducted in patients with subfoveal CNV secondary to pathologic myopia. A total of 120 patients (VISUDYNE 81, placebo 39) were enrolled in the study. The treatment dosing and retreatments were the same as in the AMD studies. The difference between treatment groups statistically favored VISUDYNE at the 1-year analysis but not at the 2-year analysis for visual acuity endpoints. For the primary efficacy endpoint (percentage of patients who lost less than 3 lines of visual acuity), patients at the 1-year time point showed a difference of approximately 19% between treatment groups (86% for VISUDYNE patients compared to 67% for placebo patients). However, by the 2-year timepoint, the effect was no longer statistically significant (79% for VISUDYNE patients compared to 72% for placebo patients).

Presumed Ocular Histoplasmosis

One open-label study was conducted in patients with subfoveal CNV secondary to presumed ocular histoplasmosis. A total of 26 patients were treated with VISUDYNE in the study. The treatment dosing and retreatments for VISUDYNE were the same as in the AMD studies. Visudyne-treated patients compare favorably with historical control data demonstrating a reduction in the number of episodes of severe visual acuity loss (>6 lines of loss).

Visudyne Indications and Usage

VISUDYNE (verteporfin for injection) therapy is indicated for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis.

There is insufficient evidence to indicate VISUDYNE for the treatment of predominantly occult subfoveal choroidal neovascularization.

CONTRAINDICATIONS

VISUDYNE (verteporfin for injection) is contraindicated for patients with porphyria or a known hypersensitivity to any component of this preparation.

WARNINGS

Following injection with VISUDYNE (verteporfin for injection), care should be taken to avoid exposure of skin or eyes to direct sunlight or bright indoor light for 5 days. In the event of extravasation during infusion, the extravasation area must 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. If emergency surgery is necessary within 48 hours after treatment, as much of the internal tissue as possible should be protected from intense light.

Patients who experience severe decrease of vision of 4 lines or more within 1 week after 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 treating physician.

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.

PRECAUTIONS

General

Standard precautions should be taken during infusion of VISUDYNE (verteporfin for injection) to avoid extravasation. Examples of standard precautions include, but are not limited to:

  • A free-flowing intravenous (IV) line should be established before starting Visudyne infusion and the line should be carefully monitored.

  • Due to the possible fragility of vein walls of some elderly patients, it is strongly recommended that the largest arm vein possible, preferably antecubital, be used for injection.

  • Small veins in the back of the hand should be avoided.

Extravasation of VISUDYNE, especially if the affected area is exposed to light, can cause severe pain, inflammation, swelling or discoloration at the injection site.

If extravasation does occur, the infusion should be stopped immediately. The extravasation area must be thoroughly protected from direct light until swelling and discoloration have faded in order to prevent the occurrence of a local burn, which could be severe. Cold compresses should be applied to the injection site. (see Warnings). Oral medications for pain relief may be administered.

Visudyne therapy should be considered carefully in patients with moderate to severe hepatic impairment or biliary obstruction since there is no clinical experience with verteporfin in such patients.

There is no clinical data related to the use of VISUDYNE in anesthetized patients. At a >10-fold higher dose given by bolus injection to sedated or anesthetized pigs, verteporfin caused severe hemodynamic effects, including death, probably as a result of complement activation. These effects were diminished or abolished by pretreatment with antihistamine and they were not seen in conscious nonsedated pigs. VISUDYNE resulted in a concentration-dependent increase in complement activation in human blood in vitro. At 10 µg/mL (approximately 5 times the expected plasma concentration in human patients), there was mild to moderate complement activation. At ≥100 µg/mL, there was significant complement activation. Signs (chest pain, syncope, dyspnea, and flushing) consistent with complement activation have been observed in <1% of patients administered VISUDYNE. Patients should be supervised during VISUDYNE infusion.

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