Macugen

1

ANNEX I 

SUMMARY OF PRODUCT CHARACTERISTICS 

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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 
 
 
4.1 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 
 
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) 

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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. 
 
 
4.3 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 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  
 

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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 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. 
 
 
4.7 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, 

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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  
Not known anaphylactic reaction* 

  
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  

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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. 

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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 PROPERTIES 
 
5.1  Pharmacodynamic 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.  

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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) 

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 

 0.3-0.3 0.3-discontinued 

Sham-
sham/sham+ 
discontinued

0.3-0.3          0.3- discontinued 

Sham-
sham/sham+ 
discontinued 

N      67 66 54 66 66           53 
Mean change 
in VA Week 

 6 
   -1.9 -0.0 -4.4 -1.9 -2.0         -3.4 

Mean change 
in VA Week 

12 

 
   -4.3 

 
-2.0 

 
-4.8 

 
-2.8 

 
-2.2 

 
        -4.7 

Mean change 
in VA Week 

54 

 
  -9.6 

 
-4.3 

 
-11.7 

 
-8.0 

 
-7.6 

 
       -15.6 

Mean change 
in VA Week 

102 
 -10.8 -9.7 

 
-13.1 -8.0 -12.7 

 
       -21.1 

 

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(L

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-20
-15
-10
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0.3 mg N=265

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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 ± 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. 

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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. PHARMACEUTICAL PARTICULARS 
 
6.1 List 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 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special 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. 
 
6.5 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 

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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 
 
 
 
 
 
 
 
 
 
 
 

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

 
Dosing line and top edge of 3rd 
rib aligned 

Dosing line 
 
3rd Rib (top edge) 

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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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ANNEX II 
 
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT  

 

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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Pfizer Manufacturing Belgium NV,  
Rijksweg 12  
B-2870 Puurs  
Belgium 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic Safety Update Reports 
 
The marketing authorisation holder shall submit periodic safety update reports for this product 
in accordance with the requirements set out in the list of Union reference dates (EURD list)  
provided for under Article 107c(7) of Directive 2001/83/EC and published on the European 
medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT  
 
 Risk Management Plan (RMP)  
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted:  

 At the request of the European Medicines Agency;  
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.  

 
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same 
time. 
 
 Additional risk minimisation measures 
 
Prior to launch in each Member State the Marketing Authorisation Holder (MAH) shall agree the final 
educational material with the National Competent Authority. 
 
The MAH shall ensure that, following discussions and agreement with the National Competent 
Authorities in each Member State where Macugen is marketed, at launch and after launch all 
ophthalmological clinics where Macugen is expected to be used are provided with an updated 
physician information pack containing the following elements: 

 The Summary of Product Characteristics 
 Physician safety brochure 
 Intravitreal injection procedure video 

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 Intravitreal injection procedure pictogram 
 Patient information  

 
The physician safety brochure should contain the following key elements: 
a) The intravitreal procedure as it was performed in the pivotal clinical studies, along with any 

technical improvements 
b) Use of povidone iodine  
c) Performing lid scrubs 
d) Use of anaesthetic to ensure patient comfort 
e) Sterile techniques to minimize the risk of infection 
f) Use of antibiotics 
g) Techniques for the intravitreal injection 
h) Key signs and symptoms of intravitreal injection related adverse events including endophthalmitis, 

increased intraocular pressure, retinal injury, intraocular haemorrhage, traumatic cataract, 
hypersensitivity and injection of excess volume 

i) Management of intraocular pressure 
j) Management of endophthalmitis 
k) Understanding the risk factors involved in developing endophthalmitis 
l) Reporting of serious adverse events(reminder aid) 
  
The patient information should contain the following key elements: 
m) Key signs and symptoms of serious adverse events associated with the intravitreal injection 

procedure including endophthalmitis, increased intraocular pressure, retinal injury, intraocular 
haemorrhage, traumatic cataract, hypersensitivity and injection of excess volume 

n)  When to seek urgent attention from the health care provider 
 
 

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 16

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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A. LABELLING 

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 18

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Macugen 0.3 mg solution for injection 
pegaptanib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
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. 
 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium chloride, monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, 
sodium hydroxide and hydrochloric acid (for pH adjustment), water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection.  
Delivers a single dose of 0.3 mg in 90 microliters 
Pack of one pre-filled syringe, a plunger stopper and a pre-attached plunger rod. Needle is not 
provided. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only.  
Read the package leaflet before use. 
Intravitreal use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
CAUTION: Expel excess volume before injecting. 
Align the third rib of the plunger stopper with the pre-printed black dosing line. 
 
 
8. EXPIRY DATE 
 
EXP 

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 19

 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
PharmaSwiss Česká republika s.r.o.  
Jankovcova 1569/2c 
170 00 Praha 7  
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/05/325/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted Me

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PRE-FILLED SYRINGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Macugen 0.3 mg injection 
pegaptanib  
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
 
4. BATCH NUMBER 
 
 
5.       CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
Single dose: 0.3 mg/90 µl 
 
 
6. OTHER 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
POUCH containing pre-filled syringe, a plunger stopper and a pre-attached plunger rod 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINSTRATION 
 
Macugen 0.3 mg solution for injection 
pegaptanib 
Intravitreal use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5.       CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
Single dose: 0.3 mg/90 µl 
 
 
6. OTHER 
 
The pouch must not be opened until the patient has been prepared for injection. 
 
CAUTION: Expel excess volume before injecting 
Align the third rib of the plunger stopper with the pre-printed black dosing line. 
 
 

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B. PACKAGE LEAFLET 
 

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Package Leaflet: Information for the patient 
 

Macugen 0.3 mg solution for injection 
Pegaptanib  

 
Read all of this leaflet carefully before you start your treatment with this medicine because it 
contains important information for you. 
 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
1. What Macugen is and what it is used for 
2. What you need to know before you are given Macugen  
3. How you will be given Macugen 
4. Possible side effects 
5. How to store Macugen 
6. Contents of the pack and other information 
 
 
1. What Macugen is and what it is used for 
 
Macugen is a solution which is injected into the eye. Pegaptanib, the active substance of this medicine, 
inhibits the activity of the factor involved in the abnormal formation of new blood vessels in the eye, 
known as Vascular Endothelial Growth Factor165 (VEGF165). 
 
Macugen is used for the treatment of the wet form of age-related macular degeneration (AMD). This 
disease leads to vision loss resulting from damage to the central part of the retina (called the macula), 
at the back of the eye. The macula enables the eye to provide the fine central vision that is needed for 
activities such as driving a car, reading fine print and other similar tasks.  
 
In the wet form of AMD, abnormal blood vessels grow under the retina and macula. These new blood 
vessels may bleed and leak fluid, causing the macula to bulge or lift up, thus distorting or destroying 
central vision. Under these circumstances vision loss may be rapid and severe. Macugen works by 
inhibiting the growth of these abnormal blood vessels and by stemming the bleeding and leakage. The 
medicine is used for the treatment of all types of abnormal blood vessels growth in adult AMD 
patients. 
 
 
2. What you need to know before you are given Macugen 
 
You must not be given Macugen: 
If you are allergic to pegaptanib or any of the other ingredients of this medicine (listed in section 6). 
If you have an active or suspected infection in or around the eye. 
 
Warnings and precautions 
Talk to your doctor before you are given Macugen. 
 
Occasionally, an infection or bleeding in the eye can occur after Macugen injection (in the next two 
weeks). It is important to identify and treat these types of conditions as soon as possible. Please tell 
your doctor immediately if you notice any of the following symptoms: eye pain or increased 
discomfort, worsening eye redness, blurred or decreased vision, increased sensitivity to light, increased 
number of small particles in your vision. If your doctor cannot be reached for any reason, an alternate 
doctor should be contacted immediately. 
 

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In some patients the pressure inside the treated eye may increase for a short period directly after the 
injection. Your doctor may monitor this after each injection. 
 
Soon after the injection serious allergic reactions may occur. The symptoms you might experience and 
the instruction what to do in such cases are described in section 4 of this leaflet.  
 
Children and adolescents 
Macugen should not be used in children and adolescents under 18 years old. 
 
Other medicines and Macugen 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Pregnancy and breast-feeding  
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before Macugen treatment. 
 
 There is no experience of using Macugen in pregnant women. Macugen should not be used during 

pregnancy unless the potential benefit outweighs the potential risk to the unborn child. If you are 
pregnant discuss this with your doctor before treatment with Macugen. 

 Macugen is not recommended during breastfeeding as it is not known whether Macugen passes 
into human milk.  Ask your doctor or pharmacist for advice before starting Macugen treatment. 

 
Driving and using machines 
You may experience temporary visual blurring after receiving Macugen. If you are affected, do not 
drive or use machines until this resolves. 
 
Important information about some of the ingredients of Macugen 
This medicine contains less than 1 mmol sodium (23 mg) per 90 microlitre dose, i.e. essentially 
‘sodium-free’ (see section 6). 
 
3. How you will be given Macugen 
 
All injections of Macugen will be administered by your doctor. 
 
Macugen is administered as a single injection (0.3 mg) into your eye at intervals of 6 weeks (i.e. 
9 times per year). The injection is given into the vitreous of the eye, which is the jelly-like substance 
inside the eye. Your doctor will monitor your condition and recommend how long you should be 
treated with Macugen. 
 
Before the treatment is given your doctor may ask you to use antibiotic eye drops, or to wash your 
eyes carefully. Your doctor will also give you some local anaesthetic (numbing medicine). This will 
reduce or prevent any pain you might have with the injection. 
Please do not forget to tell your doctor if you are known to be allergic to any substance.  
 
After each injection you might be asked to use antibiotic eye drops (or another type of antibiotic 
treatment) to guard against eye infection. 
 
If you have been given more Macugen than you should have 
In the case excess Macugen volume is injected, serious increase in intraocular pressure may occur. 
Whenever you’ll experience vision disturbances, eye discomfort/pain, eye redness or nausea and 
vomiting, immediately refer to your doctor and tell about your symptoms. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects  

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Like all medicines, this medicine can cause side effects, although not everybody gets them.  
Cases of  serious allergic reaction, including anaphylactic reaction and angioedema of which 
symptoms are described below, has been reported soon after the injection. Please seek immediate 
medical help if you experience any of the following soon after the injection: sudden onset of breathing 
difficulty or wheezing, swollen mouth, face, hands or feet, itching skin, fainting, rapid pulse, stomach 
cramps, nausea, vomiting or diarrhoea. Frequency of these side effects cannot be estimated from the 
data available. 
 
Uncommonly, an infection in the internal portion of the eye can occur after two weeks following 
Macugen treatment. The symptoms you might experience are described in section 2 of this leaflet 
("Warnings and precautions"). Please read section 2. It tells you what to do if you have any of these 
symptoms. 
 
Other possible side effects are as follows: 
 
Very common (may affect more than 1 in 10 people) 
 
These side effects are most probably caused by the injection procedure rather than the medicine, and 
include:  

 eye inflammation  
 eye pain  
 increased pressure inside the eye  
 small marks on the eye surface (punctate keratitis)  
 small particles or spots in your vision (vitreous floaters or opacities). 

 
Common (may affect up to 1 in 10 people) 
 
Other common eye side effects reported to be possibly caused by the medicine or by the injection 
procedure include:  

 blurred vision  
 visual disturbance  
 eye discomfort  
 decreased vision 
 increased sensitivity to light, appearance of flashing lights  
 bleeding that occurs around the eye (periorbital bleeding)  
 bloodshot eye (conjunctival haemorrhage)  
 disorder of the jelly portion inside the eye (vitreous disorder), such as displacement or tear 

(vitreous detachment)  
 clouding of the lens (cataract)  
 disorder of the surface of the eye (cornea)  
 swelling or inflammation of the eyelid, swelling of the area on the inside of the eyelid or the 

outer surface of the eye (conjunctiva)  
 eye inflammation, tears, inflammation of the conjunctiva (conjunctivitis), dryness, eye 

discharge, eye irritation, itching of the eye, eye redness or enlargement of the pupil  
 
Other common non-visual side effects reported to be possibly caused by the medicine or by the 
injection procedure include: 

 headache 
 nasal discharge. 

 
Uncommon (may affect up to 1 in 100 people) 
 
Uncommon eye side effects reported to be possibly caused by the medicine or by the injection 
procedure include:  

 inflammation of your eye or of the outer surface of the eye  

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 bleeding in the eye or the internal portion of the eye (vitreous)  
 eye strain 
 inflammation of the central part of the surface of the eye (keratitis)  
 small deposits on the eye or on the surface of the eye (cornea), deposits in the back of the eye,  
 itching of the eyelids  
 disturbance in your eye’s reaction to the light (pupillary reflex impaired)  
 small erosion on the central part of the surface of the eye (cornea)  
 drooping eyelid  
 scar inside the eye (retinal scar)  
 small lump on your eyelid due to inflammation (chalazion)  
 decreased pressure inside the eye  
 injection site reaction, injection site vesicles  
 displacement or tear of a layer in the back of the eye (retina)  
 disorder of the pupil, of the coloured part of the eye (iris)  
 retinal artery occlusion  
 eversion of the eyelid, eye movement disorder, eyelid irritation  
 blood in your eye, discoloured eye, deposit  eye  
 inflammation of the eye (iritis)  
 optic nerve cupping  
 deformation of the pupil  
 occlusion of the vein at the back of the eye  
 discharge of inner jelly of the eye 

 
Uncommon non-visual side effects reported to be possibly caused by the medicine or by the injection 
procedure include:  

 nightmare, depression, deafness, vertigo 
 palpitations, high blood pressure, dilatation of the aorta (the main blood vessel)  
 inflammation of the higher respiratory tract, vomiting, indigestion  
 irritation and inflammation of the skin, hair colour changes, rash, itching,  
 night sweats, back pain, tiredness, shivering, tenderness, chest pain, sudden fever and flu-like 

symptoms (generalised aches and pains) 
 elevation of the liver enzymes, abrasion. 

 
 
There is a small risk of a slight lasting increased pressure inside the eye after repeated injection in the 
eye. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor , pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Macugen 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The 
expiry date refers to the last day of that month. 
 
Store in a refrigerator (2ºC - 8ºC). 
Do not freeze. 
 
The medicine must be discarded if kept at room temperature for more than two weeks. 

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 27

 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information  
 
What Macugen contains 
 
- The active substance is pegaptanib. Each single dose pre-filled syringe delivers a dose of 0.3 mg 

pegaptanib in 90 microlitres. 
 
- The other ingredients are sodium chloride, monobasic sodium phosphate monohydrate, dibasic 

sodium phosphate heptahydrate, sodium hydroxide and hydrochloric acid (for pH adjustment) and 
water for injections. For additional information regarding sodium content of Macugen, see section 
2. 

 
What Macugen looks like and contents of the pack 
 
Macugen solution for injection is supplied in a single dose pack.  
 
Each pack contains a pouch in a carton, containing a pre-filled syringe, Type I glass, filled with 0.25-
0.27 ml of solution, 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.  
 
Marketing Authorisation Holder: 
PharmaSwiss Česká republika s.r.o.  
Jankovcova 1569/2c 
170 00 Praha 7  
Czech Republic 

Manufacturer: 
Pfizer Manufacturing Belgium NV,  
Rijksweg 12  
B-2870 Puurs  
Belgium 
 

 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Bausch & Lomb Pharma nv/sa, Belgium  
Tél/Tel: + 32 (0)3 280 82 84 
 

Lietuva 
PharmaSwiss UAB 
Tel. + 370 5 279 0762 
 

България  
PharmaSwiss EOOD 
Тел.: + 359 2 89 52 110 
 

Luxembourg/Luxemburg 
Bausch & Lomb Pharma nv/sa, Belgium 
Tél/Tel: + 32 (0)3 280 82 84 

Česká republika 
PharmaSwiss Česká republika s.r.o. 
Tel: + 420 234 719 600 
 

Magyarország 
Valeant Pharma Magyarország Kft.  
Tel. +36 1 345 5900 

Danmark 
Bausch & Lomb Nordic AB 
Tlf: 80 88 82 68 
Tlf (fra udlandet): +46 8 616 95 85 
 

Malta 
Laboratoire Chauvin, France 
Tél: + 33 (0)4 67 12 30 30 
 

Deutschland 
Bausch & Lomb GmbH 
Tel: + 49 (0)30 33093 0 

Nederland 
Bausch & Lomb Pharma nv/sa, Belgium 
Tel: + 32 (0)3 280 82 84 

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Eesti 
PharmaSwiss Eesti OÜ 
Tel: +372 6 827 400 
 

Norge 
Bausch & Lomb Nordic AB 
Tlf: 800 19 841 
Fra utlandet Tlf.: +46 8 616 95 85 
 

Ελλάδα 
Pharmaswiss Hellas A.E. 
Τλ: +30 210 8108 460 
 

Österreich 
Bausch & Lomb GmbH 
Tel: + 49 (0)30 33093 0 
 

España 
Bausch & Lomb, S.A. 
Tel: + 34 91 657 63 00 
 

Polska 
Valeant sp. z o.o. sp. j.  
Tel.: +48 17 865  51 00 

France 
Laboratoire Chauvin SAS  
Tél: + 33 (0)4 67 12 30 30 
 

Portugal 
Bausch & Lomb, S.A. (Sucursal Portugal) 
Tel: + 351 21 424 15 10 
 

Hrvatska 
PharmaSwiss d.o.o. 
Tel: +385 1 6311 833 
 

România 
Valeant Pharma S.R.L. 
Tel: +40 374 102 600 
 

Ireland 
Bausch & Lomb UK Ltd. 
Tel: +44 (0) 1748 828864 

Slovenija 
PharmaSwiss d.o.o. 
Tel: + 386 1 2364 700 
 

Ísland 
Bausch & Lomb UK Ltd. 
Sími frá útlöndum: +44 (0) 1748 828864 
 

Slovenská republika 
Valeant Slovakia s.r.o. 
Tel: +421 2 3233 4900 
 

Italia 
Bausch & Lomb-IOM S.p.A. 
Tel: + 39 (0)2 27407300 

Suomi/Finland 
Bausch & Lomb Nordic AB 
Puh./Tel: 0800 773 851  
Ulkomailta/Från utomlands: +46 8 616 95 85 
 

Κύπρος 
Kypropharm Ltd. 
Τηλ: + 357 22 43 46 99 
 

Sverige 
Bausch & Lomb Nordic AB 
Tel: 020 088 3496  
Från utomlands: +46 8 616 95 85 
 

Latvija 
SIA PharmaSwiss Latvia 
Tel: + 371 67502185 
 

United Kingdom 
Bausch & Lomb UK Ltd. 
Tel: +44 (0) 1748 828864 
 

 
This leaflet was last revised in  
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 

 
 
 
 
 
 
 
 
 

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--------------------------------------------------------------------------------------------------------------------------- 

 
The following information is intended for healthcare professionals only: 
 

CAUTION: Since 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 instruction 
below to expel the excess volume before injection.  
 

    Figure 1. Before expelling air bubble and excess drug 
 
 
 
 
 
 
 
 
 
 
 

 
 
(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 
Figure 2, below). The plunger stopper should not be pulled back.  
 
 
              Figure 2. After expelling air bubble and excess drug  
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 

 
Dosing line and top edge of 3rd rib aligned 
 

Dosing line 
 
3rd Rib (top edge) 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET