Macugen - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One pre-filled syringe provides a usable amount to deliver a single dose of 90 microlitres containing pegaptanib sodium, corresponding to 0.3 mg of the free acid form of the oligonucleotide.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection (injection).

The solution is clear and colourless.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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

4.2 Posology and method of administration

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active or suspected ocular or periocular infection.

4.4 Special warnings and prec

Endophtalmitis

Intravitreal injection procedures are associated with a risk of endophthalmitis; in Macugen clinical

itis was 0.1% per injection (see section 4.2).

Increased intraocular pr essure

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.

A post marketing observational study has also reported on a small risk of slow sustained increase in intraocular pressure (see section 4.8).

Intravitreous haemorrhages

Immediate (on the day of injection) and delayed intravitreous haemorrhages may occur following pegaptanib injections (see section 4.2).

Hypersensitivity reactions

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 treatments administered as part of the injection preparation procedure, or to other factors has not been established in these cases.

Systemic effects

Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGF inhibitors and there is a theoretical risk that these may relate to VEGF inhibition. There are limited data on safety in patients with prior history of stroke or transient ischaemic attacks. Caution should be exercised when treating such patients (see section 4.8, heading ‘Product-class-related adverse reactions’).

Overfill volume

Injection of the entire volume of the pre-filled syringe could result in serious adverse events; therefore, the excess volume must be expelled before injection (see sections 4.8 and 6.6).

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

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 pegapt      expected to be very low after ocular administration.

Nevertheless, Macugen should be used duri     gnancy only if the potential benefit to the mother

justifies the potential risk to the foetus.

Breast-feeding

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

Fertility

No human data on the effect of Macugen on fertility are available. In animal studies no effects on male or female fertility in mice were observed. See section 5.3.

4.7 Effects on ability to drive and use machines

Macugen has a minor influence on the ability to drive and use machines due to the possible temporary visual blurring after administration of Macugen by intravitreal injection. Patients should be instructed not to drive or use machines until this has resolved.

4.8 Undesirable effects

Summary of the safety profile

The majority of adverse reactions reported following administration of Macugen are related to the intravitreal injection procedure.

In clinical trials the most frequently reported ocular adverse reactions following injection of Macugen are: anterior chamber inflammation, eye pain, increased intraocular pressure, punctate keratitis, vitreous floaters and vitreous opacities. Less frequently reported serious ocular adverse reactions included endophthalmitis, retinal haemorrhage, vitreous haemorrhage and retinal detachment.

Tabulated list of adverse reactions

The safety data described below summarise all procedure and adverse reactions 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 to <1/10), uncommon (>1/1,000 to <1/100), and not known (cannot be estimated from the available data).

Reports from post-marketing experience are included in italics.

anterior chamber inflammation, eye pain, increased intraocular pressure, punctate keratitis, vitreous floaters and vitreous opacities

abnormal sensation in eye, cataract, conjunctival haemorrhage, conj nctival hyperaemia, conjunctival oedema, conjunctivitis, corneal dystrophy, corneal epithelium defect, corneal epithelium disorder, corneal oedema, dry eye, endophthalmitis, eye discharge, eye inflammation, eye irritation, eye pruritus, eye redness, eye swelling, eyelid oedema, lacrimation increased, macular degeneration, mydriasis, ocular discomfort, ocular hypertension, periorbital haematoma, photophobia, photopsia, retinal haemorrhage, vision blurred, visual acuity reduced, visual disturbance, vitreous detachment, and vitreous disorder

asthenopia, blepharitis, conjunctivitis allergic, corneal deposits, eye haemorrhage, eyelids pruritus, keratitis, vitreous haemorrhage, pupillary reflex impaired, corneal abrasion, retinal exudates, eyelid ptosis, retinal scar, chalazion, corneal erosion, decreased intraocular pressure, injection site reaction, injection site vesicles, retinal detachment, corneal disorder, retinal artery occlusion, retinal tear, ectropion, eye movement disorder, eyelid irritation, hyphaema, pupillary disorder, iris disorder, ocular icterus, anterior uveitis, deposit eye, iritis, optic nerve cupping, pupillary deformity, retinal vein occlusion, and vitreous prolapse

deafness, Meniere's disease aggravated, vertigo

palpitations

Vascular disorders

hypertension, aortic aneurysm

Uncommon

Uncommon

Uncommon

Uncommon

Uncommon

A few cases of arterial thromboembolic events were observed in the pegaptanib clinical trials in patients with AMD, DME, and there were no major differences between the groups treated with pegaptanib compared to control.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Overdose with Macugen has not been reported in clinical trials.

Overdosing with increased injection volume (e.g. when the excess volume in the pre-filled syringe is not expelled before injection) may elevate intraocular pressure (see section 4.8). Treating physician should always expel excess volume of solution according to instructions under the section 6.6.

Therefore, in case of overdose, intraocular pressure should be monitored and if deemed necessary by the treating physician, adequate treatment should be initiated.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Ophthalmologicals, Ocular vascular disorder agents, ATC Code S01LA03.

Mechanism of action

Pegaptanib is a pegylated modified oligonucleotic e 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 progressionof the neovascular (wet) form of AMD.

Pharmacodynamic effects

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.

Clinical efficacy and safety

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; EOP1003 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 0.3 mg showed treatment benefit regar visual acuity as well as age, gender, iris pigmentat

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.

from Baseline to Weeks 6, 12, 54 and 102

of Mean Changes in Visual

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.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Macugen in all subsets of the paediatric population in age-related macular degeneration. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

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 ± apparent plasma half-life of pegaptanib after a 3 mg (10-times the recom 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 pg-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 were 0.03% to 0.15% of those in the vitreous hu

Distribution, biotransformation and elimination:

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 admin ion of a radiolabeled dose of pegaptanib to both eyes of rabbits,

istributed in vitreous humour, retina and aqueous humour. After intravitreal trations of radiolabeled pegaptanib to rabbits, the highest concentrations of ing the eye for the intravitreal dose) were obtained in the kidney. In rabbits, the tide, 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.

5.3 Preclinical safety data

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.

6.1

Sodium chloride

Monobasic sodium phosphate monohydrate

Dibasic sodium phosphate heptahydrate Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

3 years.

ot freeze.

room temperature (below 25°C) before injecting.

This medicinal product should be discarded if kept at room temperature for more than two weeks. To prevent contamination, the syringe should not be removed from the pouch until the patient has been prepared for injection.

6.5 Nature and contents of container

Each pack contains a pouch in a carton containing a 1 ml pre-filled syringe, Type 1 glass, sealed with an elastomeric (brombutyl rubber) 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 (bromobutyl/syn­thetic isoprene) tip cap.

Each pre-filled syringe contains approximately 0.25–0.27 ml of solution.

Each carton contains one pre-filled syringe in a pouch (single dose pack).

The pack is supplied without a needle.

6.6 Special precautions for disposal and other handling

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, that Macugen dose 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 14 inch needle should be attached to the luer lock adaptor, to allow the administration of the medicinal product (see Figure 1, below).

CAUTION: Since the pre-filled syringe contains more medicinal product volume (250–270 microlitres) than the recommended dose (90 microlitres), a part of the volume contained in the syringe has to be discarded prior to the administration. Follow the instructions below to expel the excess volume before injection.

(Actual air bubble formation may vary) ^^3

The syringe should be checked with the needle pointing up for 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.

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 pre-printed black dosing line (See Fig 2, below). The plunger stopper should not be pulled back.

At this point, the remaining content of the syringe should be injected.

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

7. MARKETING AUTHORISATION HOLDER

PharmaSwiss Česká republika s.r.o.

Jankovcova 1569/2c

170 00 Praha 7

Czech Republic

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/05/325/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTH

Date of first authorisation: 31/01/2006

Date of latest renewal: 19/11/2015