Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: PharmaSwiss Česká republika s.r.o., Jankovcova 1569/2c, 170 00 Praha 7, Czech Republic
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active or suspected ocular or periocular infection.
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).
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).
Immediate (on the day of injection) and delayed intravitreous haemorrhages may occur following pegaptanib injections (see section 4.2).
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 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’).
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’.
Drug interaction studies have not been conducted with Macugen. Pegaptanib is metabolised by nucleases and therefore cytochrome P450 mediated drug interactions are unlikely.
Two early clinical studies conducted in patients who received Macugen alone and in combination with PDT (photodynamic therapy) revealed no apparent difference in the plasma pharmacokinetics of pegaptanib.
Pegaptanib has not been studied in pregnant women. Animal studies are insufficient, but have shown reproductive toxicity at high systemic exposure levels (see section 5.3). The potential risk to humans is unknown. The systemic exposure to pegaptanib is expected to be very low after ocular administration. Nevertheless, Macugen should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.
It is not known whether Macugen is excreted in human milk. Macugen is not recommended during breast-feeding.
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.
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.
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.
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.
Not known: anaphylactic reaction*
Uncommon: nightmare, depression
Common: headache
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
Uncommon: deafness, Meniere’s disease aggravated, vertigo
Uncommon: palpitations
Uncommon: hypertension, aortic aneurysm
Common: rhinorrhea
Uncommon: nasopharyngitis
Uncommon: vomiting, dyspepsia
Uncommon: contact dermatitis, eczema, hair colour changes, rash, pruritus, night sweats
Not known: angioedema*
Uncommon: back pain
Uncommon: fatigue, rigors, tenderness, chest pain, influenza like illness
Uncommon: increased gamma-glutamyltransferase activity
Uncommon: abrasion
* Post-marketing experience; see "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.
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 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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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