Macugen

Mechanism of Action

Pegaptanib is a selective vascular endothelial growth factor (VEGF) antagonist. VEGF is a secreted protein that selectively binds and activates its receptors located primarily on the surface of vascular endothelial cells. VEGF induces angiogenesis, and increases vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular (wet) form of age-related macular degeneration (AMD), a leading cause of blindness. VEGF has been implicated in blood retinal barrier breakdown and pathological ocular neovascularization.

Pegaptanib is an aptamer, a pegylated modified oligonucleotide, which adopts a three-dimensional conformation that enables it to bind to extracellular VEGF. Under in vitro testing conditions, pegaptanib binds to the major pathological VEGF isoform, extracellular VEGF165, thereby inhibiting VEGF165 binding to its VEGF receptors. The inhibition of VEGF164, the rodent counterpart of human VEGF165, was effective at suppressing pathological neovascularization.

Pharmacokinetics

In animals, pegaptanib is slowly absorbed into the systemic circulation from the eye after intravitreous administration. The rate of absorption from the eye is the rate limiting step in the disposition of pegaptanib in animals and is likely to be the rate limiting step in humans.

In humans, a mean maximum plasma concentration of about 80 ng/mL occurs within 1 to 4 days after a 3 mg monocular dose (10 times the recommended dose). The mean area under the plasma concentration-time curve (AUC) is about 25 μg·hr/mL at this dose.

Pegaptanib is metabolized by nucleases and is generally not affected by the cytochrome P450 system.

Two early clinical studies conducted in patients who received Macugen alone and in combination with photodynamic therapy (PDT) revealed no apparent difference in the plasma pharmacokinetics of pegaptanib.

Twenty-four hours after intravitreous administration of a radiolabeled dose of pegaptanib to both eyes of rabbits, radioactivity was mainly distributed in vitreous fluid, retina, and aqueous fluid. After intravitreous and intravenous administrations of radiolabeled pegaptanib to rabbits, the highest concentrations of radioactivity (excluding the eye for the intravitreous dose) were obtained in the kidney. In rabbits, the component nucleotide, 2'fluorouridine is found in plasma and urine after single radiolabeled pegaptanib intravenous and intravitreous doses. In rabbits, pegaptanib is eliminated as parent drug and metabolites primarily in the urine.

Based on preclinical data, pegaptanib is metabolized by endo- and exonucleases.

In humans, after a 3 mg monocular dose (10 times the recommended dose), the average (± standard deviation) apparent plasma half-life of pegaptanib is 10 (±4) days.

Special Populations

Plasma concentrations do not appear to be affected by age or gender, but have not been studied in patients under the age of 50.

Clinical Studies

Macugen was studied in two controlled, double-masked, and identically designed randomized studies in patients with neovascular AMD. Patients were randomized to receive control (sham treatment) or 0.3 mg, 1 mg or 3 mg Macugen administered as intravitreous injections every 6 weeks for 48 weeks. A total of approximately 1200 patients were enrolled with 892 patients receiving Macugen and 298 receiving a sham injection. The median age of the patients was 77 years. Patients received a mean 8.5 treatments out of a possible 9 total treatments across all treatment arms. Patients were re-randomized between treatment and no treatment during the second year. Patients who continued treatment in year 2 received a mean of 16 treatments out of a possible total 17 overall.

The two trials enrolled patients with neovascular AMD characteristics including classic, occult, and mixed lesions of up to 12 disc areas and baseline visual acuity in the study eye between 20/40 and 20/320. The primary efficacy endpoint was the proportion of patients losing less than 15 letters of visual acuity, from baseline up to 54 week assessment.

Verteporfin PDT usage was permitted at the discretion of the investigators in patients with predominantly classic lesions.

The groups treated with Macugen 0.3 mg exhibited a statistically significant result in both trials for the primary efficacy endpoint at 1 year: Study EOP1003, Macugen 73% vs. Sham 60%; Study EOP1004, Macugen 67% vs. Sham 53%. Concomitant use of PDT overall was low. More sham treated patients (75/296) received PDT than Macugen 0.3 mg treated patients (58/294).

On average, Macugen 0.3 mg treated patients and sham treated patients continued to experience vision loss. However, the rate of vision decline in the Macugen treated group was slower than the rate in the patients who received sham treatment. See Figure 1.

Figure 1 : Mean Visual Acuity: Year 1

At the end of the first year (week 54), approximately 1050 of the original 1200 patients were re-randomized to either continue the same treatment or to discontinue treatment through week 102. See Figure 2.

Macugen was less effective during the second year than during the first year. The percentage of patients losing less than 15 letters from baseline to week 102 was: Study EOP1003, Macugen 38/67 (57%); Sham 30/54 (56%); Study EOP1004, Macugen 40/66 (61%); Sham 18/53 (34%).

Figure 2 : Mean Visual Acuity: Year 2

Dose levels above 0.3 mg did not demonstrate any additional benefit. The safety or efficacy of Macugen beyond 2 years has not been demonstrated.

• Valeant Pharmaceuticals North America LLC

No drug interactions have been studied by the manufacturer. However, you should tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Not all drug interactions are known or reported and new drug interactions are continually being reported.

• Keep all appointments with your doctor. Your doctor will need to examine your eyes to see if you are developing serious side effects during the week following the injection. 

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of pegaptanib in the elderly .

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

In the U.S.

• Macugen

Available Dosage Forms:

• Solution

Therapeutic Class: Ophthalmologic Agent

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of pegaptanib in the pediatric population. Safety and efficacy have not been established .

Geriatric

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of pegaptanib in the elderly .

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Eye infection—Pegaptanib should NOT be used in patients with an infection in or around the eye .

• Glaucoma—This medicine may increase eye pressure after injection. Your doctor will monitor your eye pressure during the week after every injection .

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Eye irritation.
• Seeing floaters.
• Dizziness.
• Loose stools (diarrhea).
• Headache.
• Upset stomach.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Ocular or Periocular Infections

Macugen is contraindicated in patients with ocular or periocular infections.

Hypersensitivity

Macugen is contraindicated in patients with known hypersensitivity to pegaptanib sodium or any other excipient in this product.

Pregnancy

Teratogenic Effects: Pregnancy Category B. Pegaptanib produced no maternal toxicity and no evidence of teratogenicity or fetal mortality in mice at intravenous doses of up to 40 mg/kg/day (about 7,000 times the recommended human monocular ophthalmic dose of 0.3 mg/eye). Pegaptanib crosses the placenta in mice.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether pegaptanib is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Macugen is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Macugen in pediatric patients have not been established.

Geriatric Use

Approximately 94% (834/892) of the patients treated with Macugen were ≥65 years of age and approximately 62% (553/892) were ≥75 years of age. No difference in treatment effect or systemic exposure was seen with increasing age.

Mechanism of Action

Pegaptanib is a selective vascular endothelial growth factor (VEGF) antagonist. VEGF is a secreted protein that selectively binds and activates its receptors located primarily on the surface of vascular endothelial cells. VEGF induces angiogenesis, and increases vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular (wet) form of age-related macular degeneration (AMD), a leading cause of blindness. VEGF has been implicated in blood retinal barrier breakdown and pathological ocular neovascularization.

Pegaptanib is an aptamer, a pegylated modified oligonucleotide, which adopts a three-dimensional conformation that enables it to bind to extracellular VEGF. Under in vitro testing conditions, pegaptanib binds to the major pathological VEGF isoform, extracellular VEGF165, thereby inhibiting VEGF165 binding to its VEGF receptors. The inhibition of VEGF164, the rodent counterpart of human VEGF165, was effective at suppressing pathological neovascularization.

Pharmacokinetics

Absorption

In animals, pegaptanib is slowly absorbed into the systemic circulation from the eye after intravitreous administration. The rate of absorption from the eye is the rate limiting step in the disposition of pegaptanib in animals and is likely to be the rate limiting step in humans.

In humans, a mean maximum plasma concentration of about 80 ng/mL occurs within 1 to 4 days after a 3 mg monocular dose (10 times the recommended dose). The mean area under the plasma concentration-time curve (AUC) is about 25 μg•hr/mL at this dose.

Pegaptanib is metabolized by nucleases and is generally not affected by the cytochrome P450 system.

Two early clinical studies conducted in patients who received Macugen alone and in combination with photodynamic therapy (PDT) revealed no apparent difference in the plasma pharmacokinetics of pegaptanib.

Distribution/Metabolism/Excretion

Twenty-four hours after intravitreous administration of a radiolabeled dose of pegaptanib to both eyes of rabbits, radioactivity was mainly distributed in vitreous fluid, retina, and aqueous fluid. After intravitreous and intravenous administrations of radiolabeled pegaptanib to rabbits, the highest concentrations of radioactivity (excluding the eye for the intravitreous dose) were obtained in the kidney. In rabbits, the component nucleotide, 2'-fluorouridine, is found in plasma and urine after single radiolabeled pegaptanib intravenous and intravitreous doses. In rabbits, pegaptanib is eliminated as parent drug and metabolites primarily in the urine.

Based on preclinical data, pegaptanib is metabolized by endo- and exonucleases.

In humans, after a 3 mg monocular dose (10 times the recommended dose), the average (± standard deviation) apparent plasma half-life of pegaptanib is 10 (±4) days.

Special Populations

Plasma concentrations do not appear to be affected by age or gender, but have not been studied in patients under the age of 50.