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O C U L A R
PHARMACOLOGY
Intravitreal Inserts
Dr. Sonia Rani John DNB, Dr. Meena Chakrabarti MS, Dr. Valsa Stephan MS, Dr. Arup Chakrabarti MS
Advances in biomedical engineering and ocular surgical
techniques has encouraged the development of
sustained release drug delivery implants to treat a
variety of ophthalmic diseases. Polymer based drug
delivery implants placed in the vitreous cavity have
great efficacy in treating posterior segment diseases
such as cytomegalovirus retinitis, uveitis, diabetic
macular edema etc.Intermediate, posterior and
panuveitis are typically the more severe forms of uveitis,
resulting in highest incidence of visual loss 1. These
forms of uveitis often require long–term systemic
treatment with oral corticosteroids, often in conjunction
with other immuno modulating therapy (IMT). Side
effects of oral corticosteroids are many and can be life
threatening 2,3; thus reduction of corticosteroid usage
with the help of IMT is a primary goal in uveitis
treatment strategy. While IMT and targeted biological
agents are increasingly used as corticosteroid – sparing
therapy 4, the fluocinolone acetonide implant is the first
and currently the only sustained – release intra ocular
implant approved by the FDA for the long term control
of non infectious posterior uveitis (Fig. 1)5. Its efficacy
has been well documented. The multicentre uveitis
steroid treatment (MUST) trial compares the efficacy
of standardized systemic therapy vs. fluocinolone
acetonide implant therapy for the treatment of severe
cases of intermediate uveitis, posterior uveitis or pan
uveitis 6,7.
RETISERT (Fluocinolone Acetonide
Intravitreal Implant)
Fluocinolone acetonide intravitreal implant is indicated
for the treatment of chronic non- infectious uveitis
affecting the posterior segment of the eye. The drug
substance is the synthetic corticosteroid, fluocinolone
acetonide. It is less soluble in aqueous solution than
dexamethasone (Fig. 2).
The fluocinolone acetonide implant is a sustained
release system (Fig. 3) designed to deliver fluocinolone
Fig. 1: Cut section of the globe showing an intravitreal insert
insitu.
Chakrabarti Eye Care Centre, Kochulloor, Trivandrum 695 011
E-mail: [email protected]
Fig. 2: Actual size of a Retisert Implant
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Kerala Journal of Ophthalmology
Vol. XXI, No. 1
medication to control inflammation. Thus the
fluocinolone acetonide implant is superior to
intravitreal triamcinolone injection for uveitis.
Implanted eyes had a higher incidence of IOP elevation
( > 10 mm Hg) than non implanted eyes and surgical
mode of intervention was required in 40 % of implanted
eyes vs. 2 % of non implanted eyes to control the
intraocular pressure.
Fig. 3: Size of various intravitreal implants compared to the
size of a dollar coin.
acetonide over 30 months. Each implant consists of a
silicone elastomer containing fluocinolone acetonide
0.59 mg . It delivers drug at an initial rate of 0.6
micrograms / day over the first month, decreasing to a
steady rate of 0.3 – 0.4 micrograms / day over
approximately 30 months 8,9. In patients with non
infectious posterior uveitis (NIPU), the implant reduces
inflammation and preserves visual acuity over an
extended period. Its most common side effects include
elevated IOP and development of cataract 10.
Recently Callanan et al 11 published the 3-year clinical
trial results from the Fluocinolone Acetonide Uveitis
study group. The purpose of this multi center,
randomized study was to evaluate the safety and
efficacy of 0.59 mg and 2.1 mg fluocinolone acetonide
implants in NIPU. Uveitis recurrence in implanted eyes
was reduced from 62 % to 4 %, 10.1 % and 20 % at 1,
2 and 3 years following implantation, respectively, for
the 0.59 mg treatment group and from 58 % to 7 %,
17 % and 41 % respectively for the 2.1 mg treatment
group. The rate of uveitis recurrence was low during
the period corresponding to the active life of the implant
but began to increase towards the end of the drug
delivery period. There was no difference in the post
implantation uveitis recurrence rates between the 2
groups during the first 2 years following implantation,
but there was a significant difference during the third
post implantation year, which was thought to be
secondary to faster drug delivery with the original
2.1 mg implant. The need for adjunctive therapy to
manage uveitis was significantly reduced after
implantation, with 80 % reduction in the use of systemic
Chich et al 12 reported recently that fluocinolone
acetonide implant insertion can be combined safely with
phacoemulsification and IOL implantation in the same
surgical sitting in eyes with uveitis. Other applications
for fluocinolone acetonide implants such as for macular
oedema associated with central retinal vein occlusion
13
and diabetes melitus 14 have been reported.
Clinical Pharmacology: Corticosteroids inhibit the
inflammatory response to a variety of inciting agents
and probably delay or slow healing. They inhibit edema,
fibrin deposition, capillary dilation, leukocyte migration,
capillary proliferation, fibroblast proliferation,
deposition of collagen and scar formation associated
with inflammation. Corticosteroids act by the induction
of phospholipase A2 inhibiting proteins, collectively
called lipocortins. It is postulated that these proteins
control the biosynthesis of potent mediators of
inflammation such as prostaglandins and leukotrienes
by inhibiting the release of their common predecessor
arachidonic acid. Arachidonic acid is released from
membrane phospholipids by phospholipase A2.
Pharmacokinetics: In a subset of patients who
received the intravitreal implant and had blood
samples taken at various times after implantation,
plasma levels of fluocinolone acetonide were below
the limit of detection (0.2 ng/ml) at all times. When
aqueous and vitreous humor samples were assayed for
fluocinolone acetonide in another subset of patients,
detectable concentrations of fluocinolone acetonide
was seen throughout the observation interval (upto
34 months), the concentrations were highly variable,
ranging from below the limit of detection (0.2 ng / ml )
to 589 ng / ml.
Medidur : The Medidur (Alimera) implant also
contains flucocinolone, but it is much smaller. It is a
reservoir implant, but it is not sutured to the eye wall
and is allowed to float freely in the vitreous space.
March 2009
Sonia Rani John et al. - Intravitreal Inserts
Posurdex : Posurdex biogradable dexamethasone
implant (Allergan) is a different concept. It’s
biogradable system is not reservoir based, it uses
polymer and drug mixed together and the drug releases
over time. As the polymer degrades, the drug is
released.
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Dosage and Administration: Each vitrasert
implant contains a minimum of 4.5 mg of ganciclovir
and is designed to release the drug over a 6 to 8 month
period of time. The rate of release is approximately 1
μg/hr. Following depletion of ganciclovir from the
implant, as evidenced by progression of retinitis, the
implant may be removed and replaced.
Contraindications and Complications of
Intravitreal Implants :
Fig. 4: The Vitrasert Implant insitu.
VITRASERT (Ganciclovir Intravitreal
Implant)
Vitrasert implant contains a minimum of 4.5 mg of the
antiviral drug ganciclovir. The implant is designed to
release ganciclovir at a rate of approximately 1 μg / hr
over a 6-8 month period (Fig.4).
Pharmacology: Ganciclovir is a synthetic nucleoside
analogue of 2 – deoxyguanosine that inhibits replication
of herpes viruses both in vitro and in vivo. Sensitive
human viruses include cytomegalovirus (CMV), herpes
simplex virus 1 and 2, Epstein Barr virus (EBV) and
varicella zoster virus.
Emergence of viral resistance has been reported based
on invitro sensitivity testing of CMV isolates from
patients receiving intravenous ganciclovir treatment.
The prevalence of resistant isolates is unknown and
there is a possibility that some patients may be infected
with strains of CMV resistant to ganciclovir. Therefore,
the possibility of viral resistance should be considered
in patients who show poor clinical response.
As with any surgical procedure, potential complications
accompanying intra ocular surgery to place the implant
into the vitreous cavity include cataract, increased intra
ocular pressure, vitreous loss, vitreous haemorrhage,
retinal detachment, choroidal detachment, temporary
reduction in visual acuity, endophthalmitis, hypotony
and wound dehiscence. Following implantation of the
implant, most patients experience an immediate and
temporary reduction in visual acuity in the implanted
eye which lasts for approximately two to four weeks
postoperatively. All the patients should be monitored
for elevated IOP regularly.
Retisert is contraindicated in most viral diseases of the
cornea and conjunctiva including epithelial herpes
simplex keratitis, vaccinia and varicella and also in
mycobacterial infections of the eye and other fungal
infections.
Ganciclovir has the potential to cause temporary or
permanent suppression of fertility in women and
temporary or permanent inhibition of spermatogenesis
in men. Vitrasert is contradicted in pregnant and
lactating women. Safety and effectiveness in pediatric
patients below 12 years age have not been established.
VITRAVENE
(Fomivirsen
Intravitreal Implant)
Sodium
Vitravene is indicated for the local treatment of
cytomegalovirus (CMV) retinitis in patients with AIDS
who are intolerant to or have a contradiction to other
treatment for CMV retinitis.
Indications: Vitrasert is indicated for the treatment
of confirmed CMV in patients with AIDS.
Conclusion
Vitrasert implant is contraindicated in patients with
hypersensitivity to ganciclovir or acyclovir.
Traditional treatment routes cannot obtain sufficient
therapeutic concentrations for treatment of posterior
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Kerala Journal of Ophthalmology
segment diseases of the eye due to anatomic and
physiologic protective mechanisms such as blood retinal
barrier. For ideal drug treatment, the drug should reach
the target tissue directly and at the desired time and
concentration. For this purpose, liposomes, biodegradable
polymers and non degradable implants have been
developed in the last 20 years. Liposomes did not
proceed beyond limited clinical studies due to a great
deal of disadvantages. The most important disadvantage
of non degradable implants are the need for surgery
and wide incisions. Biodegradable polymers produce
the best results due to properties like ease of
implantation, no need to remove and excellent
bioavailability. Thus intravitreal implants provide safe
and effective therapy. Promising efficacy results show
a significant reduction in recurrence rate and
improvement in visual acuity.
5.
Jaffe GJ, et al. Flucocinolone acetonide implant
(Retisert) for non infectious posterior uveitis: thirtyfour-weeks result of a multicenter randomized clinical
study. Ophthalmology 2006;113(6): 1020-1027.
6.
Jaffe G J, et al. Flucocinolone acetonide sustained drug
delivery device to treat severe uveitis. Ophthalmology
2000; 107 (11):2024-2033.
7.
Jaffe GJ, et al. Long-term follow-up results of a pilot
trial of a Flucocinolone acetonide implant to treat
posterior uveitis. Ophthalmology 2005; 112(7): 11921198.
8.
Mohammed DA. Sweet BV, Enler SG. Retisert: is the
new advance in treatment of uveitis a good one? Ann
Pharmacother. 2007; 41 (3):449-454.
9.
Haupert CL, Jaffe GJ. New and emerging treatments
for patients with uveitis. Int Ophthalmol Clin.2000; 40
(2):205-220.
10.
Jaffe G J. Reimplantation of a fluocinolone acetonide
sustained drug delivery implant for chronic uveitis.
Am J Ophthalmol.2008; 145 (4): 667-675.
11.
Callanan DG, et al. Treatment of posterior uveitis
with fluocinolone acetonide implant: three-year
clinical trial results. Arch Ophthalmol. Accepted for
publication.
12.
Cheich JJ, Carlson AN, Jaffe GJ. Combined fluocinolone
acetonide intraocular delivery system insertion,
phacoemulsification, and intraocular lens implantation
for severe uveitis. Am J Ophthalmol. 2008.
13.
Ramachandran R.S et al. Fluococinolone acetonide
sustained drug delivery device for chronic central retinal
vein occlusion: 12 – month results. Am J Ophthalmol
2008; 146 (2):285-291 et al.
14.
Schwartz SG, Flynn HW Jr, Pharmacotherapies for
diabetic retinopathy: present and future. Exp. Diabetes
Res.2007; 52487.
References:
1.
Durrani OM, et al. Degree, duration, and causes of visual
loss in uveitis. Br.J Ophthalmol.2004; 88(9):1159-1162.
2.
Suttorp-Schulten MS, Rothova A. The possible impact
of uveitis in blindness: a literature survey. Br J
Ophthalmol.1996;80 (9):844-848.
3.
Rothova A, et al. Causes and frequency of blindness in
patients with intraocular inflammatory disease.
Br.J.Ophthalmol 1996;80 (4):332-336.
4.
Jabs DA, et al. Guidelines for the use of immunosuppressive
drugs in patients with ocular inflammatory disorders:
recommendation of an expert panel. Am J Ophthalmol.
2000; 130 (4):492-513.
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