Vitrasert, Intravitreal Implant Product Monograph

ACTION AND CLINICAL PHARMACOLOGY

Ganciclovir is a synthetic nucleoside analogue of 2-deoxguanosine that inhibits replication of herpes viruses both in vitro and in vivo. Sensitive human viruses include cytomegalovirus (CMV) herpes simplex virus — 1 and —2 (HSV-1, HSV-2), Epstein —

Barr virus (EBV) and varicella zoster virus (VZV). Clinical studies have been limited to assesstment of efficacy in patients with CMV infection.

Median effective inhibitory doses (ED50) of ganciclovir for human CMV isolates tested in vitro in several cell lines ranged from 0.2 to 3.0 pg/mL. The relationship between in vitro sensitivity of CMV to ganciclovir and clinical response has not been established.

Ganciclovir inhibits mammalian cell proliferation in vitro at higher concentrations (10 to

6Oug/mL), with bone marrow colony forming cells being most sensitive (LD 50?

lOug/mL of those cells tested.

Emergence of viral resistance has been reported based on in vitro 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. Clinical Pharmacokinetics

In a clinical trial of Vitrasert Implants, 26 patients (30 eyes) received a total of 39 primary implants and 12 exchange implants (preformed 32 weeks after the implant was inserted or earlier if progression of CMV retinitis occurred. Because most of the exchanged implants were empty the time the implant actually ran out of drug was unknown, and a precise in vivo release rate could not be calculated. However approximate in-vivo release rates could be determined for the exchanged implants, which ranged from 1.001.i.g/h to more than 1.62 jig/h.

In 14 implants (3 exchanged, 11 autopsy) in which the in-vivo release rate could accurately be calculate, the mean release rate was 1.4Oug/h, with a range from 0.5 to 2.88 jig/h. The mean vitreous drug levels in eight eyes ( 4 collected at the time of retinal detachment surgery: 2 collected from autopsy eyes within 6 hours of death and prior to fixation; 2 colleted from implant exchanges) was 4.11.1g/h

Drug delivery

The implant is non-erodible reservoir drug delivery platform. Devices of this classification have a general mechanism controlling the delivery that is outlined in the following figure.

The drug active agent (i.e. ganciclovir) disolutes from the solid dosage form by the incoming solvent molecules (i.e. water). Once the drug is in solution, the drug or solute can then diffuse across the polymer membrane to the surrounding media. The polymer membrane controls the rate of the diffusion to the surrounding media. This mass transport is described by the following expression, derived from Frick's law.

th = ADICAC dl I

Where Mt, is the mass of drug released after time t, A is the surface area of the diffusion port D, is the diffusion coefficient of the drug in the membrane, K is the partition coefficient, 1 is the thickness of the membrane and AC is the concentration gradient across the membrane. If all the components remain constant, the mass transport is concentration independent and is described as a zero order release. This basis model fits reasonably well for the ganciclovir implant based upon the measured release rate release profiles for the implant test, both short and long term in vitro.

INDICATIONS AND CLINICAL USE

The Vitrasert (ganciclovir) Implant is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency sysdrome (AIDS). The Vitrasert Implant is for intravitreal implantation only.

The dignosis of CMV retinitis is ophthalmologic and should be made by indirect ophthalmoscopy. Other conditions in the differential diagnosis of CMV retinitis include candidiasis, taxoplasmosis, histoplasmosis, retinal scars, and cotton wool spots, any of which may produce a retinal appearance similar to CMV. For this reason, it is essential that the diagnosis of CMV be established by a physician familiar with the retinal presentation of these conditions.

Clinical trials

In a randomized, controlled parallel group trial conducted between May 1993 and

December 1994 treatment with the Vitrasert Implant was compared to treatment with

intravenous ganciclovir (Cytovene —IV Roche), in 188 patients with AIDS and newly diagnosed CMV retinitis. Patients randomized to the Cytovene IV treatment group

received Cytovene IV solution at induction doses (5mg/kg twice daily) for 14 days, followed by maintenance dosing (5mg/kg once daily) Based on masked assessment of fundus photographs the median time to progression was approximately 210 days of the

Vitrasert Implant Treatment group compared to approximately 120 days for the intravenous treatment group.

CONTRAINDICATIONS

The Vitrasert Implant (ganciclovir) is contraindicated in patients with hypersensitivity to ganciclovir or acyclovir, and in patients with any contraindications for intraocular surgery such as external infection or sever thrombocytopenia.

WARNINGS

CMV retinitis may be associated with CMV disease elsewhere in the body. The Vitrasert

Implant (ganciclovir) provides localized therapy limited to the implanted eye. The

Vitrasert Implant does not provide treatment for systemic CMV disease. Patients should be monitored for extraocular CMV disease.

As with other surgical procedure, there is risk involved. Potential complications accompanying intraocular surgery to place the Vitrasert Implant in the vitreous cavity may include, but are not limited to, the following: vitreous loss, vitreous hemorrhage, cataract formation, retinal detachment, uveitis, endophthalmitis, and decrease in visual acuity.

Following implantation of the Vitrasert Implant, nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately two to four weeks post-operatively. This decrease in visual acuity is likely a result of the surgical implantation procedure.

• PRECAUTIONS

  As with all intraocular surgery, sterility of the surgical field and the Vitrasert Implant

  (ganciclovir) should be rigorously maintained. The Vitrasert Implant should be handled only by a suture tab in order to avoid damaging the polymer coatings since this could affect release rate of ganciclovir inside the eye. The Vitrasert Implant should not be resterilized by any method.

  A high level of surgical skill is required for implantation if the Vitrasert Implant. A surgeon should have observed or assisted in surgical implantation of the Vitrasert Implant prior to attempting the procedure.

  Drug Interactions

  No drug interactions have been observed with the Vitrasert Implant. There is limited experience with use of retinal tamponades in conjunction with the Vitrasert Implant.

  Used in Pregnancy:

  Ganciclovir has been shown to be embryotoxic in rabbits and mice following intravenous administration and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered 60mg/kg/day and 108mg/kg/day, respectively. Effects observed in rabbits included: fetal growth retardation, embryolethality, teratogenicity and

  /or maternal toxicity. Teratogenic changes included cleft palate,

  anophthalmia/microphthalmia, aplastic organs (kidney and pancreas, hydrocephaly, and brachynathia. In mice, effects observed were maternal/fetal toxicity and embryolethality.

  Daily intravenous doses of 90mg/kg administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month old male offspring, as well as pathologic changes in the nonglandular region of the stomach.

S

Although each Vitrasert Implant contains from 4.5 to 6.4 mg of ganciclovir, which is released locally in the vitreous, there are no adequate and well controlled studies in pregnant women on the effects of the Vitrasert Implant. Therefore, the Vitrasert Implant should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Impairment offertility

Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses of

90mg/kg/day. Ganciclovir caused decreased fertility in male mice and

hypospermatogenesis in mice and rats following daily oral or intravenous administration of doses ranging from 0.2 — 10mg/kg.

Nursing Mothers

It is now known whether ganciclovir from the Vitrasert Implant is excreted in human milk. Daily intravenous doses of 90mg/kg administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month old offspring, as well as pathologic changes in the non-glandular region of the stomach. Because many drugs are excreted in human milk and, because carcinogenicity and teratogenicity effects occurred in animals treated with ganciclovir, mothers should be instructed to discontinue nursing if they have a Vitrasert Implant.

Pediatric Use

There have been no studies conducted in pediatric patients. Safety and effectiveness was observed, however, in two patients aged 11 and 9 who received the Vitrasert Implant in an open label trial.

Information to Patients

The Vitrasert Implant is not a cure for CMV retinitis, and some immunocompromised patients may continue to experience progession of retinitis with the Vitrasert Implant.

Patients should be advised to have ophthalmologic follow-up examinations of both eyes at appropriate intervals following implantation of the Vitrasert Implant.

As with any surgical procedure, there is a risk involved. Potential complications accompanying intraocular surgery to place the Vitrasert Implant into the vitreous cavity may include, but are not limited to, the following: intraocular infection or inflammation, detachment of the retina, and formation of cataract in the natural crystalline lens.

Following implantation of the Vitrasert Implant (ganciclovir), nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately two to four weeks post-operatively. This decrease in visual acuity is likely a result of the surgical implant procedure.

The Vitrasert Implant (ganciclovir) only treats eyes in which it has been implanted.

Additionally, because CMV is a systemic disease, patients should be monitored for extraocular CMV infections (e.g. pneumonitis, colitis) in the body.

Patients should be advised that ganciclovir has caused decreased sperm production in animals and may cause infertility in humans. Woman of childbearing potential should be advised that ganciclovir causes birth defects, including hypoplastic testes in animals and should not be used during pregnancy.

Patients should be advised that ganciclovir has caused tumors in animals. Although there is no information from human studies, ganciclovir should be considered a potential carcinogen.

ADVERSE REACTIONS

During clinical trials, the most frequent adverse events seen in patients treated with the

Vitrasert Implant ( ganciclovir) involved the eye.

During the first two months following implantation, visual acuity loss of 3 lines or more, vitreous hemorrhage, and retinal detachments occurred in approximately 10-20% of patients. Cataract formation/lens opacities, macular abnormalities, intraocular pressure spikes, optic disk/ nerve changes, hyphemas and uveitis occurred in approximately 1-5%.

Adverse reactions with an incidence of less than 1°/0 were:retinopathy, anterior chamber cell and flare, sychenia, hemorrhage (other than vitreous), cotton wool spots, keratopathy, astigmatism, endophthalmitis, microangiopathy, sclerosis, choroiditis, chemosis, phthisis bulbi, angle closure glaucoma with anterior chamber shallowing, vitreous detachment, vitreous traction, hypotony, severe post operative inflammation, retinal tear, retinal hole,

corneal dellen, choroidal folds, pellet extrusion from scleral wound and gliosis. SYMPTOMS AND TREATMENT OF OVERDOSAGE

There is no information available on the symptoms and treatment of overdosage of ganciclovir from the Vitrasert Implant device in the treated eye. Systemic ganciclovir overdosage from the implant is unlikely to occur.

Henry et al., 1987, investigated serum levels of ganciclovir 48 hours after a 200 j.tg

(0.1mL) intravitreal injection of ganciclovir. In this study, serum levels could not be established since they were below the detection of level of the assay, which was 0.411M.

For this reason, it was considered useful to analyze serum samples for ganciclovir levels after the Vitrasert implantation. In a "worst case scenario", that is if the total amount of ganciclovir contained in an implant (4.5-6.0 mg ) were to be released into the vitreous

(approximately 5mL), all at once, the resulting concentration would be 0.9-1.2mg/mL, or approximately 4.1 p.M. Assuming instantaneous distribution into plasma, with a volume of approximately 3 liters, the resulting concentration would be 1.5-2.0 gg/mL or 6.8 nanoM, which is approximately 60 fold lower than the detection limit of the assay. O

O

DOSAGE AND ADMINISTRATION

Each Vitrasert Implant (ganciclovir) contains a minimum of 4.5mg of ganciclovir, and is designed to release the drug over a 5 to 8 month period of time. Following depletion of ganciclovir from the Vitrasert Implant, as evidenced by progression of retinitis, the

Vitrasert Implant may be removed ad replaced.

PHARMACEUTICAL INFORMATION

A. DRUG SUBSTANCE

Chemical Name

Appearance:

Physical form:

Solubility:

Melting Point:

Boiling Point:

Molecular Weight:

n-octanol water partition

coefficient:

pKa:

CAS No.:

Chemical Formula

Structural formula

9-[[2-hydroxy-1-(hydroxymethypethoxy]methyl]guanine

White to off-white crystalline powder

Solid

4.3mg/mL at 25° C in water. Soluble DMSO

Approximately 250° C with decomposition

Not applicable

255.23

0.022

2.2, 9.4

CAS-82410-32-0

C9H,,N,O,

OH

• PHARMACEUTICAL INFORMATION

  B. COMPOSITION

  Active Ingredient

  Ganciclovir

  Inactive Ingredient

  Magnesium stearate, NF

  Composition of Polymer Coatings

  mg/implant

  4.5-6.4

  0.0015 ± 0.0015

  Polyvinyl alcohol (98% Hydrolized)

  Ethylene Vinyl acetate (40% Hydrolized)

  Composition of Suture Tab

  Polyvinyl alcohol (98% hydrolyzed)

  Raw Materials used in the manufacture of PVA and EVA Films (not present in the finished product)

  Sterile Water for Injection, USP

  *These inactive ingredients are used in the manufacture of the polymer coatings that surround the ganciclovir tablet.

  STABILITY AND STORAGE CONDITIONS

  The Vitrasert Implant (ganciclovir) is to be stored at room temperature, 15° — 30° C (59°-

  86°F) Protect from freezing, excessive heat and light.

  AVAILABILITY OF DOSAGE FORM

  The Vitrasert Implant (ganciclovir) is an intravitreal implant. Each implant contains a minimum of 4.5mg of ganciclovir. Each implant is packaged in individual unit cartons in a sterile tyvek pouch.

INFORMATION FOR THE CONSUMER

The Vitrasert Implant (ganciclovir) is not a cure for CMV retinitis, and some immunocompromised patients may continue to experience progression of retinitis with the vitrasert implant. Patients should beadvised to have ophthalmologic follow-up examination of both eyes at appropriate intervals following implantation of the Vitrasert

Implant.

As with any surgical procedure, there is a risk involved. Potential complications accompanying intraocular surgery to place the Vitrasert Implant into the vitreous cavity may include, but are not limited to, the following: intraocular infection, or inflammation, detachment of the retina, and formation of cataracts in the natural crystalline lens.

Following Implantation of the Vitrasert Implant, nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately two to four weeks post-operatively. This decrease in visual acuity is likely as result of the surgical implant procedure.

The Vitrasert Implant only treats eyes in which it has been implanted. Additionally, because CMV is a systemic disease, patients should be monitored for CMV infection in the untreated, initially disease free eye and for extraocular CMV infections (e.g.

pneumonia, colitis) in the body.

Patients should be advised that ganciclovir has caused decreased sperm production in animals and may cause infertility in humans. Women of childbearing potential should be advised that ganciclovir causes birth defects in animals and should not be used during pregnancy.

Patients should be advised that ganciclovir has caused tumor in animals. Although there is no information from human studies, ganciclovir should be considered a potential

carcinogen.

PHARMACOLOGY

The Vitrasert Implant (ganciclovir) provides for the localized treatment of

cytomegalovirus (CMV) retinitis resulting in minimal systemic exposure compared to currently approved induction and maintenance therapies. Therefore, additional ADME studies of the Vitrasert Implant were not justified.

Local administration of ganciclovir with an intravitreal ganciclovir implant whose putative intraocular delivery is approximately 24-481.tg/day will result in substantially lower systemic concentration than the systemic dosing described in the literature.

Therefore, the phannacokinetics parameters associated with the systemic distribution and fate of ganciclovir should not be affected adversely by localized dosing, and not further pharmacokinetics were performed.

TOXICOLOGY

Both I.V. and oral ganciclovir (Roche: Cytovene) have been approved in Canada for use in treating cytomegalovirus (CMV) retinitis in patients with AIDS. High systemic levels of drug are required to achieve efficacious intravitreal drug levels. The Vitrasert Implant

(ganciclovir) provides efficacious levels of drug in the vitreous through localized delivery. Consequently, the toxicity problems related to the high systemic concentrations required for intravenous or orally administered ganciclovir are eliminated.

Studies focusing on the biocompatibility and toxicity of the implant and its polymer

coating were conducted by the original sponsor (Chiron). These studies are summarized in Table I (Toxicity Studies) and Table 2 (Biocompatibility of the Polymer Films).

Biocompatibility tests were performed according to the "Tripartite Biocompatibility

Guidance for Medical Devices for Internal Devices in Longer Term Contact with Tissue and Tissue Fields" on sandwich films of the PVA and EVA polymers contained in the intravitreal ganciclovir implant. A film of EVA was sandwiched between two films of

PVA. The resulting sandwich film (PVA/EVA/PVA) was cured and processed in a manner equivalent to the processing of the intravitreal ganciclovir implant. _{Table 1} — _Toxi^{city Studies}

_STUDY

SPEC^IES

PURPOSE

_

PROCEDURE

,

RESULTS

Biocompatibility of the

_In_trav_itrea_l Gancⁱc^lovⁱr ^Imp^lan^t

_in _the V_itreou^s o^{f t}he Rabb^it

Ey^e

₍UBTL S_tudy 67074⁾

30 Du^tch

Belted

Rabb^its

To eva_lua^te ^the

b_iocompa_tib^ility o^{f t}he

_in_trav_itreal gancⁱc^lovⁱr

_imp_lan_{t i}n the v^itreou^s

o_{f t}he rabb^it eye ^for 6

mon^th^s

The r_igh_t eye of each rabb^{it i}n

_the _te_st group ⁽12 ma^le and 12

female) was implanted with the

_imp_lan_t. The righ^t eye o^f each

rabb_{it i}n _the con^tro^l group ⁽6

ma_le₎ wa_{s i}mplan^ted w^ith ^the

PVA suture tab. The ^left eye of

each an_imal ^served a^s an

un_trea_ted con^tro^l.

There was an _interⁱm sacrⁱfⁱce

o_f 12 an_ima_ls a^t 3 mon^th^s, and

the rema_inder were sacrⁱfⁱed at 6

month^s.

With the exception of fibrin (noted in all 12 test

an_ima_ls a_{t t}erm_ina_tion^{), t}he gro^ss ocu^lar

re_spon_se_s ob_served durⁱng ^the ^study perⁱod

_improved w_ith _time_. The pre^sence o^{f fi}brⁱn

ob_served bo_th gro_ssly and mⁱcro^scopⁱca^lly^,

_sugge_{st t}ha_t a more _sus^taⁱned ⁱn^flamma^tory

response occurred _in the test eyes than occurred

_in the treated control eyes^. Thⁱs presence of

_fibr_in a_ssoc_ia_ted w_ith the ⁱmp^lan^{t is} con^sidered

to be clinically significant. No other finding can

be a_ttr_ibu_ted _to _imp_lanta^tion w^ith ^the ⁱmp^lan^t.

.

Intrav_itrea_l Sustaⁱned-Re^lease

Ganciclovir (Smith, 1992)

Rabb^its

To eva_lua^te ^the

_tox_ic_ity and re^lea^se^-

rate characterⁱstⁱcs of

_in_trav_itreal gancⁱc^lovⁱr

_imp_lan_ts in rabb^its _Imp_lan_{ts t}ha^t re^lea^sed

ganc_ic_lov_ir at approxⁱma^te^ly

2gg_/hr and 5gg/hr ⁱn v^itro were

_imp_lan_ted _in_to ^the v^itreou^s o^f

rabb_it eye^s. Mean _in_trav_itrea_l gancⁱc^lovⁱr ^leve^ls o^f 9 mg^/L

₍2gg_/hr _imp_lan_t) and 16 mg^/L ⁽5gg^/hr ⁱmp^lan^t)

were ma_in_ta_ined _for more ^than 80 day^s and 42

days_, respect_ive_ly_. The ⁱmp^lants were we^ll

_to_lera_ted _in _the rabb_it eye^, w^ith no evⁱdence o^f _in_traocu_lar _in_flamma^tion ob^servab^le w^ith _ind_irec_t oph_tha_lmo_scopy^. Len^s °pac^ifica^tion wa_s ob_served _in _some rabb^its, however^{, it} cou^ld have been cau_sed by _trauma re^su^lting ^from _frequen_t v_itreou_s samp^ling^, a^s no ^len^s

°pac_if_icat_ion occurred in eⁱther contro^l or 2gg^/hr _imp_lant eyes from wh_ich vⁱtreous samp^les were not co_llected after the rabbⁱt was sacrⁱfⁱced^.

Add_itiona_lly_, no _len_s °pac^ifica^tion wa^s ob^served _in eye_s o_f rabb_its receⁱvⁱng an un^-coa^ted 6 mg pe_lle_t o_f gancⁱc^lovⁱr^. Tab_le 2 -- B_iocompat_ib^ility of Po^lymer F^ilms

_STUDY

AN_IMAL _SPEC^IE^{S a}n^d TE^ST

PURPOSE

RESULTS

ARTICLE

_In_-V_itro Hemo^ly^sis S^tudy

₍Repor_t CB036^-100⁾

Aliquot of 0.1 mL of clot free

b_lood _from a New Zea^land

A_lb_ino Rabb^it

PVA_/EVA_/PVA S^andw^ich F^ilm^s

To de_term_ine _if any _leachab^le^{s f}rom ^the po^lymer^s

wou_ld cau_se hemo^ly^sis

in vitro

_

Te_st ar_tic_le wa^s no^{t f}ound ^to be

hemolytic.

USP _In_tracu^taneou^s

Tox_ic_ity S^tudy

₍Repor_t TU013^-800^/2⁾

2 New Zea_land A^lbⁱno Rabb^its

PVA_/EVA_/PVA S^andw^ich F^ilm^s

To determ_ine _if _leachab^les from the po^lymers

wou_ld cau_se derma_{l i}rr^ita^tion or ^toxⁱc^ity

_fo_llow_ing _in_jec_tion ⁱn^to rabb^{it s}kⁱn

There was no evⁱdence of

significant irritation or toxicity

from the extracts ⁱnjected

_in_tracu_taneous^ly ⁱn^to rabb^its.

USP Systemic Toxicity

S_tudy in Mⁱce

₍Repor_t TU012^-500^/2⁾

20 Mⁱce

PVA_/EVA_/PVA S^andw^ich F^ilm^s

To de_term_ine _sy_stem_ic _toxⁱc^ity o^{f i}n^travenou^s or

intraperitoneal injection of extracts of the

PVA/EVA/PVA sandwich film into mice.

No mor_ta_lity or evⁱdence o^f

significant systemic toxicity

from the extracts were noted^.

Rabb_it Pyrogen S^tudy ^--

Ma_ter_ial Medⁱa^ted

₍Repor_t TU010^-807⁾

3 New Zea_land A^lbⁱno Rabb^its

PVA_/EVA^/PVA

Sandw_ich F_ilm^s ex^trac^ted ⁱn

_ste_ile nonpyrogenⁱc ^sa^line ⁽0^.9%

_so_iduom ch_lor_ide USP ^so^lu^tion⁾

_ To de_term_ine _if any ex^trac^t o^{f t}he

PVA_/EVA_/PVA _sandwⁱch ^film produced a

pyrogen_ic re_spon_se _fo^llowⁱng ⁱn^travenou^s

injection.

_In v_ivo b_io_log_ica_l reac^tiv^ity ^fo^llowⁱng

a _sing_le _in_jec_tion o_{f t}he ex^trac^{t i}n^to rabb^its wa^s

eva_lua^ted^. The _to_ta_l ri^se o^f rabb^it

_tempera_ture_s durⁱng ^the 3 hour

ob_serva_tion perⁱod wa^s w^ithⁱn

acceptable USP limits. The test

ex_trac_t wa^{s j}udged a^s

nonpyrogenⁱc^.

Ame_s Mu_tagenⁱc^ity S^tudy o_f a DMSO Ex^trac^t

₍Repor_t MG019^-211⁾ PVA_/EVA_/PVA Sandwⁱch F^ilm^s ex_trac_ted _in d_ime^thy^{l s}u^lfoxⁱde

₍DMSO⁾ To de_term_ine whe_ther a DMSO ex^trac^t o^f

PVA_/EVA_/PVA _sandwich ^film^s wou^ld cau^se mu_tagen_ic change_{s i}n h_istⁱdⁱne^-dependen^t mu^tan^t _stra_in_s o_{f s}a_lmone^lla ^typhⁱmu^rium^.

The me_thod o_f Ame_s e_t a^{l (}1975⁾ wa^{s f}o^llowed bu_t mod_ified _to u_se _te^st ar^tic^le ex^trac^ts. A DMSO ex_trac^t o^{f t}he _sandw_ich _film^s dⁱd no^t cau^se mu_tagen_ic change^{s i}n ^the _sa_lmone_lla _typhⁱmu^rium ^te^ster _stra_in_s emp^loyed

o

Tab_le 2 — B_iocompa_tib_ility o^f Po^lymer F^ilm^{s (}con^tinued⁾

_STUDY

AN_IMAL SPEC^IE^S

PURPOSE

RESULTS

and TEST ART^ICLE

Ame_s Mu_tagenⁱc^ity S^tudy

o_f a Sa_line Ex^trac^t

₍Repor_t MG019^-212⁾

PVA_/EVA_/PVA S^andw^ich F^ilm^s

ex_trac_ted _in 0^.85% ^sa^line

To de_term_ine when a ^sa^line ex^trac^t o^f

PVA_/EVA_/PVA _sandwich ^film^s wou^ld cau^se

mu_tangen_ic change_{s i}n h^istidⁱne^-dependen^t

mu_tan_{t st}ra_in_s o_{f s}a_lmone^lla ^typhⁱmu^rium^.

The me_thod o_f Ame_s e_t a^{l (}1975⁾ wa^{s f}o^llowed

but modified to use test article extracts.

A _sa_line ex_tract o^{f t}he ^sandwⁱch

_film_s d_id no_t cau^se mu^tagenⁱc

change^{s i}n ^the

sa_lmone^lla

_typh_imur_ium tes^ter s^traⁱns

emp_loyed^.

Cy_tox_ic_ity Te^st U^sing ^the

USP E_lu_tion Me^thod

₍Repor_t MG057^-100⁾

PVA_/EVA_/PVA S^andw^ich F^ilm^s

ex_trac_ted _in 0^.9% ^sodⁱum

ch_lor_ide _irrⁱga^tion USP

Mouse F_ibrob^last ce^lls

To determ_ine _if _leachab_les extracted from the test

ma_ter_ia_l wou_ld cau^se cy^to^toxⁱc^ity^..

The _te_st ex_trac^{t s}howed no

ev_idence of causⁱng ce^{ll l}ysⁱs or

_tox_ic_ity greater ^than a grade 2

(mild reactivity). The negative

con_tro_ls and ^the po^sitive

contro_l performed as

an_ticipa^ted^.

In-Vitro

Inhibition of Cell

G_row^th

₍Repor_t MG028^-100⁾

PVA_/EVA_/PVA S^andw^ich F^ilm^s

extracted in distilled water

Mouse F_ibrob^last ce^lls

To determ_ine _if _leachab^les extracted from the

_sandw_ich _film_s would cau^se ce^ll grow^th

inhibition.

No ev_idence of ce^ll growth

_inh_ib_ition wa^s no^ted^.

De_layed Con^tac^t

Sen_sitiza^tion

₍Repor_t TA006^-300^/2⁾

30 Fema_le A_lbino Guⁱnea Pⁱg^s

PVA_/EVA_/PVA S^andw^ich F^ilm^s

ex_trac_ted _in 0^.9% ^sodⁱum

ch_lor_ide and co^tton^seed o^il

To eva_lua_te _the po_ten_tia^{l t}o cau^se de^layed derma^l

con_tac_{t s}en^sitiza^iton

No ev_idence of cause de^layed

derma_l con_tac_t sen^sitiza^tion ⁱn

_the gu_inea pig wa^s no^ted^.

30_-Day Surgⁱca^l Mu^sc^le

_Imp_lan^ta^tion

₍Repor_ts TU019^-830^,

TH035^-830⁾ 2 New Zea_land A^lbⁱno Rabb^its

PVA/EVA/PVA Sandwich Films To determine the effect of the polymer film on

_liv_ing _tissue w_ith re_spec^{t t}o po^ten^tia^{l f}or cau^sing

local irritation or toxicity. The tissue was then

eva_lua_ted _for ev_idence of ⁱrr^ita^tion and ^toxⁱc^ity^, No _sign_ificant ^tissue con^tac^t

_irr_ita_tion macro^scopⁱca^lly wa^s

no_ted_, and _the _te^st ma^terⁱa^l wa^s

c_la_ssified a_s a nonⁱrr^itan^{t i}n ^the m_icro_scop_ic eva^lua^tion^.

90_-Day Surgⁱca^l Mu^sc^le

_Imp_lan^ta^tion

₍Repor_ts TU019^-890^,

TH035^-800⁾ 3 New Zea_land A^lbⁱno Rabb^its

PVA_/EVA_/PVA Sandwⁱch F^ilm^s To de_term_ine _the e_ffec^t o^{f t}he po^lymer ^film on _liv_ing _tissue w_ith re_spec^t o^t po^ten^tia^{l f}or cau^sing _loca_{l i}rr_ita_tion or _toxic^ity^. The ^tissue wa^{s t}hen eva_lua_ted _for ev_idence of ⁱrr^ita^tion and ^toxⁱc^ity^. No _sign_ificant ^tissue con^tac^t _irr_ita_tion macro^scopⁱca^lly wa^s no_ted_, and _the _te^st ma^terⁱa^l wa^s c_la_ssified a_s a nonⁱrr^itan^{t i}n ^the m_icro_scop_ic eva^lua^tion

24 4 •

1. 26.

   NAmSA Laboratory Report MG028-100: In-Vitro Inhibition of Cell Growth (ICG) One Point

   Assay. PVA/EVA Film. Lot: 233-70. September 16, 1994.

2. 27. NAmSA Laboratory Report TU019-830, TH035-800: Surgical Muscle Implantation Study (with histopathology) in the Rabbit (30 days). PVA/EVA Film. Lot: 233-70. October 21, 1994.
3. 28. NAmSA Laboratory Report TU019-890, TH035-800: Surgical Muscle Implantation Study (with histopathology) in the Rabbit (90 days). PVAJEVA Film. Lot: 233-70. December 2, 1994.
4. 29.

   NAmSA Laboratory Report TA006-300/2: Delayed Contact Sensitization Study (a maximization method) in the Guinea Pig (saline and cottonseed oil extracts). PVA/EVA Film. Lot: 233-70.

   September 26, 1994.

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   5. 34. Data on File, Chiron Vision Study Report GCVI-902-CDS, 31 March 1995.*
   6. 35.

      Data on File, Chiron Vision Vitrasert Study Group. A randomized, controlled multicenter clinical trial of a sustained-release intraocular ganciclovir implant (Vitrasert) in AIDS Patients with newly diagnosed CMV retinitis. Final Report. Study GCV-601-CMV, 8 May 1995.*

      1. 36.

         Data on File, Chiron Vision Vitrasert Study Group. A multicenter study to evaluate the safety of an intravitreal ganciclovir implant in patients with cytomegalovirus retinitis. Interim Study Report.

         Study GCVI-603-CMV, 8 May 1995.*

      2. 37. Chiron Vision Vitrasert Study Group. A multicenter open-label study to evaluate the use of an intravitreal ganciclovir implant in patients with sight-threatening cytomegalovirus retinitis and no central venous access. Interim Study Report GCVI-605-COM, 9 May 1995.*
      3. 38. Cytovene® Package Insert. 02-2913-00-00. 1994 Syntex Laboratories, Inc.
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         Felenstein D, D Amico DJ, Hirsch MS, Neumeyer BS, Cederberg DM, de Miranda P, Schooley RT.

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*Note: A report of these studies will be available upon request.