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Macugen (pegaptanib) – Summary of product characteristics - S01LA03

Updated on site: 08-Oct-2017

Medication nameMacugen
ATC CodeS01LA03
Substancepegaptanib
ManufacturerPharmaSwiss Ceska Republika s.r.o

1.NAME OF THE MEDICINAL PRODUCT

Macugen 0.3 mg solution for injection

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 PARTICULARS

4.1Therapeutic indications

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

4.2Posology and method of administration

Macugen should only be administered by ophthalmologists experienced in intravitreal injections.

Posology

The patient’s medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see section 4.4).

The recommended dose is 0.3 mg pegaptanib, equivalent to 90 microliters, administered once every six weeks (9 injections per year) by intravitreal injection into the affected eye.

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 vitreous haemorrhage and endophthalmitis in the two weeks following the injection. Patients should be instructed to report any symptoms suggestive of these conditions 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.

Special populations

Elderly

No special considerations are needed.

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 impairment

Macugen has not been adequately studied in patients with severe renal impairment. Dose adjustments are not recommended in patients with mild or moderate renal impairment (see section 5.2).

Paediatric population

The safety and efficacy of Macugen in children under 18 years has not yet been established. No data are available.

Method of administration

For intravitreal injection use only.

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). Adequate anaesthesia and a broad-spectrum topical microbicide should be administered prior to the injection.

The pre-filled syringe is supplied with an excess product volume. Injecting the entire volume of the prefilled syringe could result in overdose (see section 4.8 and 4.9). See section 6.6 for instructions to expel the excess volume before injection.

4.3Contraindications

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

4.4Special warnings and precautions for use

Endophtalmitis

Intravitreal injection procedures are associated with a risk of endophthalmitis; in Macugen clinical trials, the incidence of endophthalmitis was 0.1% per injection (see section 4.2).

Increased intraocular pressure

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’.

4.5Interaction 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.

4.6Fertility, 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 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.

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.

4.7Effects 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.

4.8Undesirable 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.

MedDRA system organ class

Adverse reaction

Immune system disorders

anaphylactic reaction*

Not known

Psychiatric disorders

 

Uncommon

nightmare, depression

Nervous system disorders

 

Common

headache

Eye disorders

 

Very common

anterior chamber inflammation, eye pain, increased

 

intraocular pressure, punctate keratitis, vitreous floaters and

 

vitreous opacities

Common

abnormal sensation in eye, cataract, conjunctival

 

haemorrhage, conjunctival 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

Uncommon

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

Ear and labyrinth disorders

 

Uncommon

deafness, Meniere's disease aggravated, vertigo

Cardiac disorders

 

Uncommon

palpitations

Vascular disorders

 

Uncommon

hypertension, aortic aneurysm

Respiratory, thoracic and

 

mediastinal disorders

 

Common

rhinorrhea

Uncommon

nasopharyngitis

Gastrointestinal disorders

 

Uncommon

vomiting, dyspepsia

Skin and subcutaneous tissue

 

disorders

 

Uncommon

contact dermatitis, eczema, hair colour changes, rash,

 

pruritus, night sweats

Not known

angioedema*

Musculoskeletal and connective

 

tissue disorders

 

Uncommon

back pain

General disorders and

 

administration site conditions

 

Uncommon

fatigue, rigors, tenderness, chest pain, influenza like illness

Investigations

 

Uncommon

increased gamma-glutamyltransferase activity

Injury, poisoning and procedural

 

complications

 

Uncommon

abrasion

 

 

* Post-marketing experience; see “Description of selected adverse reactions”

Description of selected adverse reactions

Cases of anaphylaxis/anaphylactoid reactions, including angioedema, have been reported in patients within several hours after administration of pegaptanib along with various medicinal products administered as part of the injection preparation procedure (see sections 4.2 and 4.4).

Cases of serious increase in intraocular pressure have been reported when the excess volume in the pre-filled syringe was not expelled before injection.

Sustained small increases in intraocular pressure (IOP) have also been reported after repeated intravitreal dosing in a post marketing observational study. The odds of increased IOP was increased by a factor of 1.128 for each additional injection (p= 0.0003). No statistical difference was found in the incidence of increased IOP between patients with a history of increased IOP or glaucoma versus patients without.

Product-class-related adverse reactions

In the clinical trial, the overall frequency of non-ocular haemorrhages, an adverse event potentially related to systemic VEGF (vascular endothelial growth factor) inhibition, was slightly increased in intravitreal VEGF inhibitor-treated patients. However, there was no consistent pattern among the different haemorrhages. Arterial thromboembolic events (ATEs) are adverse events potentially related to systemic VEGF inhibition. There is a theoretical risk of arterial thromboembolic including stroke and myocardial infarction events following intravitreal use of VEGF inhibitors.

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.

4.9Overdose

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 PROPERTIES

5.1Pharmacodynamic properties

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

Mechanism of action

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.

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)

Mean Change in VA from Week 0 (Letters)

0.3 mg N=265

 

-5 -10 -15 -20

Weeks

N: number of patients enrolled

Pegaptanib 0.3 mg 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.

Summary of Mean Changes in Visual Acuity from Baseline to Weeks 6, 12, 54 and 102 (LOCF)

 

 

EOP 1003

 

 

EOP 1004

 

 

 

0.3-

Sham-

 

0.3-

Sham-

 

0.3-0.3

sham/sham+

0.3-0.3

sham/sham+

 

discontinued

discontinued

 

 

discontinued

 

discontinued

N

Mean change

 

 

 

 

 

 

in VA Week

-1.9

-0.0

-4.4

-1.9

-2.0

-3.4

 

 

 

 

 

 

Mean change

 

 

 

 

 

 

in VA Week

-4.3

-2.0

-4.8

-2.8

-2.2

-4.7

 

 

 

 

 

 

Mean change

 

 

 

 

 

 

in VA Week

-9.6

-4.3

-11.7

-8.0

-7.6

-15.6

 

 

 

 

 

 

Mean change

 

 

 

 

 

 

in VA Week

-10.8

-9.7

-13.1

-8.0

-12.7

-21.1

 

 

 

 

 

 

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.

5.2Pharmacokinetic 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 ± 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 g·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, 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 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.

5.3Preclinical 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.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Sodium chloride

Monobasic sodium phosphate monohydrate

Dibasic sodium phosphate heptahydrate

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

6.2Incompatibilities

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

6.3Shelf life

3 years.

6.4Special precautions for storage

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

The solution to be injected should reach 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.

6.5Nature 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.

6.6Special 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 ½ 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.

Figure 1. Before expelling air bubble and excess drug

Dosing line

3rd Rib (top edge)

(Actual air bubble formation may vary)

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.

Figure 2. After expelling air bubble and excess drug

Dosing line and top edge of 3rd rib aligned

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 AUTHORISATION

Date of first authorisation: 31/01/2006

Date of latest renewal: 19/11/2015

10.DATE OF REVISION OF THE TEXT

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

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