Ganciclovir (Implantation-Ophthalmic)
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VA CLASSIFICATION
Primary: OP900
Commonly used brand name(s): Vitrasert.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antiviral (ophthalmic)—
Indications
Accepted
Cytomegalovirus retinitis (treatment)—Ganciclovir intravitreal implant is indicated for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) {01}. However, ganciclovir therapy is not a cure for CMV retinitis, and progression will occur after all of the medication has been released from the implant {01}.
—The intravitreal implant provides localized treatment only and will not have any effect on extraocular CMV infection {01}.
Note: Viral resistance to ganciclovir has been demonstrated in vitro using CMV isolates from patients receiving the medication intravenously {01}. The possibility of viral resistance should be considered if a poor clinical response occurs {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
255.23 {01}
Solubility
In water at 25 °C: 4.3 mg per mL (mg/mL) {01}.
Mechanism of action/Effect:
Ganciclovir inhibits virus replication {01}.
Duration of action:
The intravitreal implant is designed to release ganciclovir over a period of 5 to 8 months {01}. In one clinical trial, the median time to progression of CMV retinitis after insertion of the implant was 210 days {01}. With the comparison treatment (recommended induction and maintenance doses of intravenous ganciclovir), the median time to progression of CMV retinitis was 120 days {01}.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients hypersensitive to acyclovir may be hypersensitive to ganciclovir also {01}.
Carcinogenicity/Tumorigenicity
Ganciclovir is carcinogenic and tumorigenic in animals and should be considered a potential carcinogen in humans {01}. Mice given oral doses of 20 mg per kg of body weight (mg/kg) per day showed slightly increased incidences of tumors in the preputial and harderian glands in males, forestomach in males and females, and liver in females {01}. Mice given oral doses of 1000 mg/kg per day showed increased incidences of tumors of the preputial gland in males, forestomach in males and females, and reproductive tissues and liver in females {01}. Except for histiocytic sarcoma of the liver, ganciclovir-induced tumors were of vascular or epithelial origin {01}.
Mutagenicity
Ganciclovir was mutagenic in mouse lymphoma cells at concentrations between 50 and 500 micrograms per mL (mcg/mL) and caused DNA damage in human lymphocytes at concentrations between 250 and 2000 mcg/mL {01}. Ganciclovir was clastogenic in the mouse micronucleus assay after intravenous administration of 150 and 500 mg/kg (2.8 and 10 times, respectively, the human exposure after intravenous administration based on the area under the concentration–time curve [AUC]), but not after intravenous administration of 50 mg/kg (exposure approximately equivalent to the human exposure after intravenous administration based on the AUC) {01}. However, no mutagenicity was found in the Ames Salmonella assay with ganciclovir concentrations of 500 to 5000 mcg/mL {01}.
Pregnancy/Reproduction
Fertility—
Systemic ganciclovir causes adverse effects on fertility in animals and may impair fertility in humans {01}. Decreases in mating behavior and fertility occurred in female mice given intravenous doses of 90 mg/kg per day {01}, and fetal resorptions occurred in at least 85% of rabbits and mice given 60 mg/kg per day and 108 mg/kg per day, respectively {01}. Also, decreases in sperm production and fertility occurred in male mice and dogs given oral or intravenous doses ranging from 0.2 to 10 mg/kg per day {01}.
Pregnancy—
Adequate and well-controlled studies with the intravitreous implant have not been done in humans {01}.
Animal studies have shown systemic ganciclovir to be embryotoxic and teratogenic {01}. In rabbits, ganciclovir administration resulted in maternal toxicity, fetal growth retardation, and teratogenic changes including cleft palate, anophthalmia or microphthalmia, aplastic kidney and pancreas, hydrocephaly, and brachygnathia {01}. In mice, ganciclovir caused maternal and fetal toxicity {01}. Also, intravenous administration of 90 mg/kg per day to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in month-old male offspring, and pathologic changes in the forestomach (nonglandular mucosa) of the mothers {01}.
FDA Pregnancy Category C {01}.
Breast-feeding
It is not known whether ganciclovir is distributed into human breast milk {01}. However, because of the carcinogenicity, teratogenicity, and other adverse effects seen in animal studies, it is recommended that breast-feeding be discontinued if the mother receives a ganciclovir intravitreal implant {01}.
Pediatrics
Appropriate studies on the relationship of age to the effects of ganciclovir intravitreal implants have not been done in children younger than 9 years of age. Safety and efficacy have not been established {01}.
Geriatrics
No information is available on the relationship of age to the effects of ganciclovir intravitreal implants in geriatric patients.
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problems exist:
» Any condition in which intraocular surgery is contraindicated{01} , such as:
Infection, external{01}
Thrombocytopenia, severe{01}
» Hypersensitivity to ganciclovir or acyclovir, history of{01}
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Ophthalmologic examinations, postoperative (recommended periodically to detect possible postoperative complications and to detect a progression of cytomegalovirus [CMV] retinitis in cases of drug resistance or after the medication is depleted from the implant {01})
Side/Adverse Effects
Note: Side effects reported in conjunction with insertion of a ganciclovir intravitreous implant are probably due to the surgical procedure, rather than to the medication {01}.
In addition to the side/adverse effects listed below, there is a risk of postoperative infection {01}.
A decrease in visual acuity occurs in the implanted eye immediately after surgery in almost all patients {01}. This effect is temporary and lasts approximately 2 to 4 weeks {01}. This decrease in visual acuity is most likely a result of the surgical implant procedure itself {01}.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent—10 to 20% within the first 2 months after surgery
Hemorrhage, vitreous{01} (seeing floating spots before the eyes)
retinal detachment{01} (seeing flashes or sparks of light, seeing floating spots before the eyes, or a veil or curtain appearing across part of vision)
visual acuity loss of three or more lines{01}{02} (decrease in vision, severe)
Incidence less frequent—1 to 5% within the first 2 months after surgery
Cataract formation or lens opacities{01}
increased intraocular pressure{01}
macular abnormalities{01}
or optic disk or nerve changes{01} (decreased vision or other change in vision)
hyphema{01} (red or bloodshot eye)
uveitis{01}{02} (eye pain, tearing, sensitivity of eye to light, redness of eye, or blurred vision or other change in vision)
Incidence rare—less than 1% within the first 2 months after surgery
Angle closure glaucoma with anterior chamber shallowing{01} (eye pain and blurred vision)
chemosis{01} (swelling of the membrane covering the white part of the eye)
choroidal folds{01}
corneal dellen{01}
keratopathy{01}
phthisis bulbi{01}
retinal hole or tear{01}
synechia{01}
or vitreous detachment or traction{01} (decreased vision or other change in vision)
choroiditis{01}
endophthalmitis{01}
or other severe postoperative inflammation{01} (eye pain, tearing, sensitivity of eye to light, redness of eye, or blurred vision or other change in vision)
gliosis{01}{02} (decreased vision or other change in vision)
hypotony{01}{02} (decreased vision or other change in vision)
pellet extrusion from scleral wound{01} (eye irritation or pain, eye redness, or tearing)
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Visual acuity loss, immediate and temporary{01} (decrease in vision lasting approximately 2 to 4 weeks)—in nearly all patients; most likely a result of the surgical implant procedure itself
Incidence rare—less than 1% within the first 2 months after surgery
Hemorrhage, nonvitreous{01}{02} (red or bloodshot eye)
sclerosis{01}{02}
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ganciclovir (Implantation-Ophthalmic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Description of use
» Describing the surgical procedure for inserting the implant
» Discussing with the patient the possible risks of the surgical procedure, including intraocular infection or inflammation, detachment of the retina, and formation of a cataract in the natural crystalline lens {01}
Before receiving this intravitreal implant
» Conditions affecting use, especially:
Sensitivity to ganciclovir or acyclovir
Carcinogenicity/tumorigenicity
Ganciclovir is carcinogenic and tumorigenic in animals; ganciclovir should be considered a potential carcinogen in humans
Mutagenicity—
Mutagenicity has been demonstrated in various tests
Pregnancy—The risk of adverse effects with the intravitreal implant has not been established; however, systemic ganciclovir is embryotoxic and teratogenic in animals
Breast-feeding—Breast-feeding should be discontinued if an intravitreal implant is inserted because carcinogenicity and other adverse effects have been demonstrated in animals
Use in children—Safety and efficacy in children up to 9 years of age have not been established
Other medical problems, especially any condition in which intraocular surgery is contraindicated, such as external infection or severe thrombocytopenia
Precautions after receiving this intravitreal implant
» Importance of regular ophthalmologic examinations to check for possible postoperative complications and to check for a progression of cytomegalovirus (CMV) retinitis in cases of drug resistance or after the medication is depleted from the implant {01}
» Decrease in visual acuity in the implanted eye is to be expected for the first 2 to 4 weeks after surgery; checking with physician if other vision changes occur or if the decrease in visual acuity worsens, continues for more than 4 weeks, or recurs after improving, since this may indicate postoperative complications
Side/adverse effects
Signs of potential postoperative complications, especially hemorrhage, vitreous; retinal detachment; visual acuity loss of three or more lines; cataract formation or lens opacities, increased intraocular pressure, macular abnormalities, or optic disk or nerve changes; hyphema; uveitis; angle closure glaucoma with anterior chamber shallowing; chemosis; choroidal folds, corneal dellen, keratopathy, phthisis bulbi, retinal hole or tear, synechia, or vitreous detachment or traction; choroiditis, endophthalmitis, or other severe postoperative inflammation; gliosis; hypotony; and pellet extrusion from scleral wound
General Dosing Information
The ganciclovir intravitreal implant should be inserted only by a surgeon who previously has observed or assisted with the procedure {01}. Aseptic technique should be maintained prior to and during the procedure {01}.
The ganciclovir intravitreal implant has been sterilized by an ethylene oxide–freon mixture (a substance that may harm public health and the environment by destroying ozone in the upper atmosphere) {01}. The implant should not be resterilized {01}.
To avoid damaging the polymer coatings, which could result in an increased rate of ganciclovir release from the implant, the product should be handled only by the suture tab {01}.
Safety considerations for handling this medication
Because ganciclovir shares some of the properties of antitumor agents (e.g., carcinogenicity, mutagenicity), consideration should be given to handling and disposing of the implant according to guidelines issued for antineoplastics {01}.
Ophthalmic Dosage Forms
GANCICLOVIR IMPLANTS{03} (INTRAVITREAL)
Usual adult and adolescent dose
Cytomegalovirus retinitis
Intravitreal, one implant inserted surgically into the affected eye {01}. The implant may be removed and replaced when evidence of progression of retinitis indicates that the medication has been depleted from the implant {01}.
Note: The product is designed to release ganciclovir over a period of five to eight months {01}.
Usual pediatric dose
Cytomegalovirus retinitis
Children up to 9 years of age:
Safety and efficacy have not been established {01}.
Children 9 years of age and older:
See Usual adult and adolescent dose {01}.
Strength(s) usually available
U.S.—
4.5 mg (Rx) [Vitrasert{01} (magnesium stearate 0.25%) (polyvinyl alcohol polymer) (ethylene vinyl acetate polymer)]
Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F) {01}, unless otherwise directed by manufacturer. Protect from freezing and from excessive heat and light {01}.
Developed: 08/14/1998
Revised: 08/14/1998
References
- Vitrasert package insert (Chiron Vision—US), Rev 1996, Rec 7/18/96.
- Panel comment, 2/14/97.
- Per USP Nomenclature Committee decision at January 1997 meeting.
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