Macugen (intraocular)

Overdose

Doses of Macugen up to 10 times the recommended dosage of 0.3 mg have been studied. No additional adverse events have been noted but there is decreased efficacy with doses above 1 mg.

Contraindications

Macugen is contraindicated in patients with ocular or periocular infections.

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

Undesirable effects

Serious adverse events related to the injection procedure occurring in < 1% of intravitreous injections included endophthalmitis , retinal detachment, and iatrogenic traumatic cataract.

The most frequently reported adverse events in patients treated with Macugen 0.3 mg for up to two years were anterior chamber inflammation, blurred vision, cataract, conjunctival hemorrhage, corneal edema, eye discharge, eye irritation, eye pain, hypertension, increased intraocular pressure (IOP), ocular discomfort, punctate keratitis, reduced visual acuity, visual disturbance, vitreous floaters, and vitreous opacities. These events occurred in approximately 10-40% of patients.

The following events were reported in 6-10% of patients receiving Macugen 0.3 mg therapy:

Ocular: blepharitis, conjunctivitis, photopsia, vitreous disorder.

Non-Ocular: bronchitis, diarrhea, dizziness, headache, nausea, urinary tract infection.

The following events were reported in 1-5% of patients receiving Macugen 0.3 mg therapy:

Ocular: allergic conjunctivitis, conjunctival edema, corneal abrasion, corneal deposits, corneal epithelium disorder, endophthalmitis, eye inflammation, eye swelling, eyelid irritation, meibomianitis, mydriasis, periorbital hematoma, retinal edema, vitreous hemorrhage.

Non-Ocular: arthritis, bone spur, carotid artery occlusion, cerebrovascular accident, chest pain, contact dermatitis, contusion, diabetes mellitus, dyspepsia, hearing loss, pleural effusion, transient ischemic attack, urinary retention, vertigo, vomiting.

Anaphylaxis/anaphylactoid reactions, including angioedema, have been identified during postapproval use of Macugen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Therapeutic indications

Macugen is indicated for the treatment of neovascular (wet) age-related macular degeneration.

Pharmacokinetic properties

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.

Name of the medicinal product

Fertility, pregnancy and lactation

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.

Qualitative and quantitative composition

Single-use glass syringe pre-filled with 0.3 mg of Macugen® in a nominal 90 μL solution for intravitreal injection.

Macugen (pegaptanib sodium injection) is supplied in a sterile foil pouch as a single-use glass syringe pre-filled with 0.3 mg of Macugen® in a nominal 90 μL deliverable volume pack. A sterile packaged BD® single use 30G x ½” Precision Glide® Luer Lok® needle is supplied in a separate pouch. The foil pouch and needle are packaged together in a carton
(NDC 68782-001-02).

Store in the refrigerator at 2° to 8°C (36° to 46°F). Do not freeze or shake vigorously.

Manufactured by: Gilead Sciences, Inc 650 Cliffside Drive San Dimas, CA 91773. For: Eyetech Inc. 11360 Jog Road, Suite 200 Palm Beach Gardens, Florida 33418.

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Intravitreous injections, including those with Macugen, have been associated with endophthalmitis. Proper aseptic injection technique should always be utilized when administering Macugen. In addition, patients should be monitored during the week following the injection to permit early treatment, should an infection occur.

Increases in intraocular pressure have been seen within 30 minutes of injection with Macugen. Therefore, intraocular pressure as well as the perfusion of the optic nerve head should be monitored and managed appropriately.

Rare cases of anaphylaxis/anaphylactoid reactions, including angioedema, have been reported in the post-marketing experience following the Macugen intravitreal administration procedure.

Carcinogenicity studies with pegaptanib have not been conducted. No data are available to evaluate male or female mating or fertility indices.

Pegaptanib and its monomer component nucleotides (2'-MA, 2'-MG, 2'-FU, 2'-FC) were evaluated for genotoxicity in a battery of in vitro and in vivo assay systems. Pegaptanib, 2'O-methyladenosine (2'-MA), and 2'-O-methylguanosine (2'-MG) were negative in all assay systems evaluated. 2'-fluorouridine (2'-FU) and 2'-fluorocytidine (2'-FC) were nonclastogenic and were negative in all S. typhimurium tester strains, but produced a non-dose related increase in revertant frequency in a single E. coli tester strain. Pegaptanib, 2'FU, and 2'-FC tested negative in cell transformation assays.

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.

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.

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

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.

Dosage (Posology) and method of administration

FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.

Macugen 0.3 mg should be administered once every six weeks by intravitreous injection into the eye to be treated.

Macugen should be inspected visually for particulate matter and discoloration prior to administration. If visible particulates are observed and/or the liquid in the syringe is discolored, the syringe must not be used.

Administration of the syringe contents involves assembly of the syringe with the administration needle. The injection procedure should be carried out under controlled aseptic conditions, which includes the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). When ready to assemble syringe and administer injection, carefully peel open pouches, remove contents, and place on sterile field. If upon opening the pouch, the plastic clip is missing or not attached to the syringe, the syringe should not be used.

To avoid compromising the sterility of the product, do not pull back on the plunger.

1. Remove the syringe from the plastic clip.
2. Twist off cap.
3. Attach the sterile BD® 30G ½” Precision Glide® administration needle (included) to the syringe by screwing it into the syringe tip. --Another sterile BD® 30G ½” Precision Glide® administration needle may be used in lieu of the one included. Remove the plastic needle shield from the needle.
4. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top of the syringe. SLOWLY depress the plunger to eliminate all the bubbles and to expel the excess drug so that the top edge of the 3rd rib on the plunger stopper aligns with the preprinted black dosing line (See Figure 2, below).
5. Inject the entire contents of the syringe.

PRIOR to Injection

Figure1: Before expelling air bubble and excess drug

READY for Injection

Figure 2: After expelling air bubble and excess drug

The injection procedure should be carried out under controlled aseptic conditions, which includes the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to the injection.

The patient's medical history for hypersensitivity reactions should be evaluated prior to performing the intravitreal procedure.

Following the injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and monitoring during the week following the injection. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay.

No special dosage modification is required for any of the populations that have been studied (i.e. gender, elderly).

The safety and efficacy of Macugen therapy administered to both eyes concurrently have not been studied.

Interaction with other medicinal products and other forms of interaction

Serious adverse events related to the injection procedure occurring in < 1% of intravitreous injections included endophthalmitis , retinal detachment, and iatrogenic traumatic cataract.

The most frequently reported adverse events in patients treated with Macugen 0.3 mg for up to two years were anterior chamber inflammation, blurred vision, cataract, conjunctival hemorrhage, corneal edema, eye discharge, eye irritation, eye pain, hypertension, increased intraocular pressure (IOP), ocular discomfort, punctate keratitis, reduced visual acuity, visual disturbance, vitreous floaters, and vitreous opacities. These events occurred in approximately 10-40% of patients.

The following events were reported in 6-10% of patients receiving Macugen 0.3 mg therapy:

Ocular: blepharitis, conjunctivitis, photopsia, vitreous disorder.

Non-Ocular: bronchitis, diarrhea, dizziness, headache, nausea, urinary tract infection.

The following events were reported in 1-5% of patients receiving Macugen 0.3 mg therapy:

Ocular: allergic conjunctivitis, conjunctival edema, corneal abrasion, corneal deposits, corneal epithelium disorder, endophthalmitis, eye inflammation, eye swelling, eyelid irritation, meibomianitis, mydriasis, periorbital hematoma, retinal edema, vitreous hemorrhage.

Non-Ocular: arthritis, bone spur, carotid artery occlusion, cerebrovascular accident, chest pain, contact dermatitis, contusion, diabetes mellitus, dyspepsia, hearing loss, pleural effusion, transient ischemic attack, urinary retention, vertigo, vomiting.

Anaphylaxis/anaphylactoid reactions, including angioedema, have been identified during postapproval use of Macugen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

No information provided.