Pfizer Healthcare Ireland

Macugen^® 0.3 mg solution for injection

A single dose pre-filled syringe delivers 1.65 mg pegaptanib sodium, corresponding to 0.3 mg of the free acid form of the oligonucleotide, in a nominal volume of 90 microlitres.

For a full list excipients, see section 6.1.

Solution for injection.

The solution is clear and colourless.

Macugen is indicated for the treatment of neovascular (wet) age-related macular degeneration (AMD) (see section 5.1).

FOR INTRAVITREAL USE ONLY.

Treatment with Macugen is for intravitreal injection only and should be administered by ophthalmologists experienced in intravitreal injections.

Macugen 0.3 mg should be administered once every six weeks (9 injections per year) by intravitreal injection into the affected eye.

Macugen should be inspected visually for particulate matter and discoloration prior to administration (see section 6.6).

The injection procedure should be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent) and the availability of sterile paracentesis (if required). The patient's medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see section 4.4). Adequate anaesthesia and a broad-spectrum topical microbicide should be administered prior to the injection.

Following the injection, transient increases in intraocular pressure were seen in Macugen treated patients. Therefore, the perfusion of the optic nerve head and intraocular pressure should be monitored. Moreover patients should be closely monitored for endophthalmitis in the two weeks following the injection. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay (see section 4.4).

After 2 consecutive injections of Macugen, if a patient does not demonstrate a treatment benefit (loss of less than 15 letters of visual acuity) at the 12-week visit, consideration should be given to stopping or withholding Macugen therapy.

Specific patient groups:

Hepatic impairment:

Macugen has not been studied in patients with hepatic impairment.

However, no special considerations are needed in this population (see section 5.2)

Renal insufficiency:

Macugen has not been adequately studied in patients with creatinine clearance < 20 ml/min. No special considerations are needed in patients with creatinine clearance above 20 ml/min (see section 5.2).

Children and adolescents:

Macugen has not been studied in patients below the age of 18 years. Use in children and adolescents is therefore not recommended.

Elderly patients:

No special considerations are needed.

Gender:

No special considerations are needed.

Active or suspected ocular or periocular infection.

Known hypersensitivity to the active substance or to any of the excipients.

As expected with intravitreal injections, transient increases in intraocular pressure may be seen. Therefore, the perfusion of the optic nerve head should be verified and elevation of intraocular pressure should be managed appropriately post injection.

Immediate (on the day of injection) and delayed intravitreous haemorrhages may occur following pegaptanib injections.

Intravitreal injection procedures are associated with a risk of endophthalmitis; in Macugen clinical trials, the incidence of endophthalmitis was 0.1% per injection.

Cases of anaphylaxis/anaphylactoid reactions, including angioedema, have been observed within several hours after the pegaptanib intravitreal administration procedure in the post-marketing experience. A direct relationship to Macugen or any of the various medications administered as part of the injection preparation procedure, or to other factors has not been established in these cases.

Drug interaction studies have not been conducted with Macugen. Pegaptanib is metabolised by nucleases and therefore cytochrome P450 mediated drug interactions are unlikely.

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

Pegaptanib has not been studied in pregnant women. Animal studies are insufficient, but have shown reproductive toxicity at high systemic exposure levels (see section 5.3). The potential risk to humans is unknown. The systemic exposure to pegaptanib is expected to be very low after ocular administration. Nevertheless, Macugen should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.

It is not known whether Macugen is excreted in human milk. Macugen is not recommended during breast-feeding.

Patients may experience temporary visual blurring after receiving Macugen by intravitreal injection. They should not drive or use machines until this has resolved

Macugen was administered to 892 patients in controlled studies for one year (total number of injections = 7545, mean number of injections/patient = 8.5) at doses of 0.3, 1.0 and 3.0 mg. All three doses shared a similar safety profile. In the 295 patients who were treated with the recommended dose of 0.3 mg for one year (total number of injections = 2478, mean number of injections/patient = 8.4), 84% of the patients experienced an adverse event attributed by the investigators as being related to the injection procedure, 3% of the patients experienced a Serious Adverse Event potentially related to the injection procedure, and 1% experienced an adverse event potentially related to the injection procedure that led to study treatment discontinuation. Twenty seven percent (27%) of the patients experienced an adverse event attributed by the investigators as being related to the study drug. Two patients (0.7%) experienced Serious Adverse Events potentially related to study drug. One of these patients had an aortic aneurysm; the other had a retinal detachment and retinal haemorrhage, which led to discontinuation of treatment.

Serious ocular Adverse Events reported in Macugen treated patients included endophthalmitis (12 cases, 1%), retinal haemorrhage (3 cases, <1%), vitreous haemorrhage (2 cases, <1%) and retinal detachment (4 cases, < 1%).

The safety data described below summarise all procedure and drug potentially related adverse events in the 295 patients in the 0.3 mg treatment group. The adverse reactions are listed by system organ class and frequency (very common (1/10), common (1/100 and <1/10), and uncommon (1/1000 and <1/100).

Psychiatric disorders

Nervous system disorders

Eye disorders

These ocular adverse reactions were considered potentially related to treatment with Macugen (either injection procedure or due to Macugen), and for the most part were considered related to the injection procedure.

Ear and labyrinth disorders

Cardiac disorders

Vascular disorders

Respiratory, thoracic and mediastinal disorders

Gastrointestinal disorders

Skin and subcutaneous tissue disorders

Musculoskeletal and connective tissue disorders

General disorders and administration site conditions

Investigations

Injury, poisoning and procedural complications

Three hundred seventy four (374) patients received continuous treatment with Macugen for up to 2 years (128 at 0.3 mg, 126 at 1 mg, and 120 at 3 mg). The overall safety data were consistent with the Year 1 safety data, and no new safety signals emerged. In the 128 patients who were treated with the recommended dose of 0.3 mg for up to 2 years (total number of injections in second year = 913, mean number of injections in the second year = 6.9), there was no evidence of increased in frequency of adverse events compared to those seen during the first year.

Post-Marketing Experience: Rare cases of anaphylaxis/anaphylactoid reactions, including angioedema, have been reported in patients within several hours after administration of pegaptanib along with various medications administered as part of the injection preparation procedure (see sections 4.2 and 4.4).

Overdosage with Macugen has not been reported in clinical trials.

Pharmacotherapeutic group: Ocular Vascular Disorder Agent, ATC code: S01LA03.

Pegaptanib is a pegylated modified oligonucleotide that binds with high specificity and affinity to extracellular Vascular Endothelial Growth Factor (VEGF₁₆₅) inhibiting its activity. VEGF is a secreted protein that induces angiogenesis, vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular (wet) form of AMD. VEGF₁₆₅ is the VEGF isoform preferentially involved in pathological ocular neovascularisation. The selective inhibition in animals with pegaptanib proved as effective at suppressing pathological neovascularisation as pan-VEGF inhibition, however pegaptanib spared the normal vasculature whereas pan-VEGF inhibition did not.

Reductions in the growth of mean total lesion size, choroidal neovascularisation (CNV size), and fluorescein leak size, have been shown in patients with AMD treated with Macugen.

Pegaptanib was studied in two controlled, double-masked, and identically designed randomised studies (EOP1003; EOP1004) in patients with neovascular AMD. A total of 1190 patients were treated (892 pegaptanib, 298 sham (control)) with a median age of 77 years. Patients received a mean of between 8.4-8.6 treatments out of possible 9 total across all treatment arms in the first year.

Patients were randomised to receive sham or 0.3 mg, 1 mg or 3 mg pegaptanib administered as intravitreal injections every 6 weeks for 48 weeks. Verteporfin photodynamic therapy (PDT) was permitted in patients with predominantly classic lesions at the discretion of the investigators.

The two trials enrolled patients, including all neovascular AMD lesion subtypes (25% predominantly classic, 39% occult with no classic and 36% minimally classic), lesion sizes up to 12 disc areas, of which up to 50% could be comprised of subretinal haemorrhage and/or up to 25% fibrotic scar or atrophic damage. Patients had up to one prior PDT and baseline visual acuity in the study eye between 20/40 and 20/320.

At one year, pegaptanib 0.3 mg exhibited a statistically significant treatment benefit for the primary efficacy endpoint; proportion of patients losing less than 15 letters of visual acuity (prespecified pooled analysis, pegaptanib 0.3 mg 70% versus Sham 55%, p = 0.0001; EOP 1003 pegaptanib 0.3 mg 73% versus Sham 59%, p = 0.0105; EOP1004 pegaptanib 0.3 mg 67% versus Sham 52%, p = 0.0031).

Mean Change in Visual Acuity Over Time; Year 1; ITT (LOCF)

Pegaptanib 0.3mg showed treatment benefit regardless of baseline lesion subtype, lesion size and visual acuity as well as age, gender, iris pigmentation and prior and/or baseline PDT usage.

At the end of the first year (week 54), 1053 patients were re-randomized to either continue or discontinue treatment through week 102.

On average, the treatment benefit was maintained at 102 weeks with continuing preservation of visual acuity for patients re-randomized to continue pegaptanib. Patients who were re-randomized to discontinue pegaptanib after one year, lost visual acuity during the second year.

Data over a two-year period indicate that Macugen treatment should be initiated as early as possible. In advanced disease the initiation and continuation of Macugen therapy should consider the potential for useful vision in the eye.

Macugen therapy administered to both eyes concurrently has not been studied.

The safety and efficacy of Macugen beyond two years has not been demonstrated.

Absorption:

In animals, pegaptanib is slowly absorbed into the systemic circulation from the eye after intravitreal 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 in humans. In humans, the average ± standard deviation apparent plasma half-life of pegaptanib after a 3 mg (10-times the recommended dose) monocular dose is 10 ± 4 days.

A mean maximum plasma concentration of about 80 ng/ml occurs within 1 to 4 days after a 3 mg monocular dose in humans. The mean area under the plasma concentration-time curve (AUC) is about 25 μg∙hr/ml at this dose. Pegaptanib does not accumulate in the plasma when administered intravitreally every 6 weeks. At doses below 0.5 mg/eye, pegaptanib plasma concentrations do not likely exceed 10 ng/ml.

The absolute bioavailability of pegaptanib after intravitreal administration has not been assessed in humans, but is approximately 70-100% in rabbits, dogs and monkeys.

In animals that received doses of pegaptanib up to 0.5 mg/eye to both eyes, plasma concentrations were 0.03% to 0.15% of those in the vitreous humour.

Distribution/Metabolism/Excretion:

In mice, rats, rabbits, dogs and monkeys, pegaptanib distributes primarily into plasma volume and is not extensively distributed to peripheral tissues after intravenous administration. Twenty-four hours after intravitreous administration of a radiolabeled dose of pegaptanib to both eyes of rabbits, radioactivity was mainly distributed in vitreous humour, retina and aqueous humour. After intravitreal and intravenous administrations of radiolabeled pegaptanib to rabbits, the highest concentrations of radioactivity (excluding the eye for the intravitreal 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 intravitreal doses. Pegaptanib is metabolised by endo- and exonucleases. In rabbits, pegaptanib is eliminated as parent drug and metabolites primarily in the urine.

Special populations:

Pegaptanib pharmacokinetics is similar in female and male patients and within the age range 50 to 90 years.

Pegaptanib sodium has not been adequately studied in patients with creatinine clearance below 20 ml/min. A decrease in creatinine clearance down to 20 ml/min may be associated with up to a 2.3-fold increase in pegaptanib AUC. No special considerations are needed in patients with creatinine clearance above 20 ml/min who are treated with the recommended dose of pegaptanib sodium 0.3 mg.

Pegaptanib pharmacokinetics have not been studied in patients with hepatic impairment. The systemic exposure is expected to be within a well tolerated range in patients with hepatic impairment, as a 10 fold higher dose (3 mg/eye) was well tolerated.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. There are no studies on the carcinogenic potential of pegaptanib.

Pegaptanib produced no maternal toxicity and no evidence of teratogenicity or foetal mortality in mice at intravenous doses of 1 to 40 mg/kg/day. Reduced body weight (5%) and minimal delayed ossification in forepaw phalanges were observed, only at exposure levels based on AUC of over 300 fold greater than that expected in humans. These finding are therefore considered to be of limited clinical relevance. In the 40 mg/kg/day group, pegaptanib concentrations in the amniotic fluid were 0.05% of the maternal plasma levels. There are no reproductive toxicity studies in rabbits.

No data are available to evaluate male or female mating or fertility indices.

Sodium chloride

Monobasic sodium phosphate monohydrate

Dibasic sodium phosphate heptahydrate

Sodium hydroxide

Hydrochloric acid

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

18 months

Store in a refrigerator (2 ^oC -8^oC). Do not freeze.

Macugen is supplied in a single dose pack.

Each pack contains a pouch in a carton containing a 1 ml pre-filled syringe, Type 1 glass, sealed with an elastomeric plunger stopper and a pre-attached plunger rod, held by a plastic clip. The syringe has a pre-attached polycarbonate plastic luer lock adaptor and the tip is sealed with an elastomeric tip cap.

The pack is supplied without a needle.

Macugen is for single use only. If the solution appears cloudy, particles are observed or if there is evidence of damage to the syringe, or if the plastic clip is missing or not attached to the syringe, Macugen should not be used.

Prior to the administration, the syringe should be removed from the plastic clip and the tip cap removed. A 27 or 30 G x ½ inch needle should be attached to the luer lock adaptor, to allow the administration of the product.

The syringe should be checked with the needle pointing up regarding the presence of bubbles. If there are bubbles, the syringe should be gently tapped with a finger until the bubbles rise to the top of the syringe. Then, the plunger should be slowly pushed up to force the bubbles out of the syringe. The plunger stopper should not be pulled back.

The last rib of the plunger stopper (closest to the plunger rod) should not be pushed past the dose line printed on the syringe. Immediately prior to administration this last rib of the plunger should be aligned with the dose line to ensure the delivery of the appropriate dose. At this point, the entire content of the syringe should be injected.

Macugen should be stored in a refrigerator. The solution to be injected should reach room temperature before injecting. Macugen should be discarded if kept at room temperature for more than two weeks. To prevent contamination, the Macugen syringe should not be removed from the pouch until the patient has been prepared for injection.

Any unused product or waste material should be disposed of in accordance with local requirements.

Pfizer Limited

Ramsgate Road

Sandwich, Kent

CT13 9NJ

United Kingdom

EU/1/05/325/002

31 January 2006

12/2007

POM

Ref: MC4_0

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA): http://www.emea.europa.eu/