vidarabine monohydrate ointment Monarch Pharmaceuticals, Inc.
VIRA-A® (Vidarabine Ophthalmic Ointment, USP) 3%
VIRA-A is the trade name for vidarabine (also known as adenine
arabinoside and Ara-A), an antiviral drug for the topical treatment of epithelial
keratitis caused by Herpes simplex virus. The chemical name is 9H-Purin-6-amine,
9-β-D-arabinofuranosyl-, monohydrate. Each gram of the ophthalmic
ointment contains 30 mg of vidarabine monohydrate equivalent to 28.11 mg of
vidarabine in a sterile, inert, petrolatum base.
empirical and structural formulas are:
VIRA-A is rapidly deaminated to arabinosylhypoxanthine (Ara-Hx),
the principal metabolite. Ara-Hx also possesses in
vitro antiviral activity but this activity is less than that of
VIRA-A. Because of the low solubility of VIRA-A, trace amounts of both VIRA-A
and Ara-Hx can be detected in the aqueous humor only if there is an epithelial
defect in the cornea. If the cornea is normal, only trace amounts of Ara-Hx
can be recovered from the aqueous humor.
of VIRA-A should not be expected to occur following ocular administration
and swallowing lacrimal secretions. In laboratory animals, VIRA-A is rapidly
deaminated in the gastrointestinal tract to Ara-Hx.
contrast to topical idoxuridine, VIRA-A demonstrated less cellular toxicity
in the regenerating corneal epithelium of the rabbit.
controlled and uncontrolled clinical trials, an average of seven and nine
days of continuous VIRA-A Ophthalmic Ointment, 3%, therapy was required to
achieve corneal re-epithelialization. In the controlled trials, 70 of 81 subjects
(86%) re-epithelialized at the end of three weeks of therapy. In the uncontrolled
trials, 101 of 142 subjects (71%) re-epithelialized at the end of three weeks.
Seventy-five percent of the subjects in these uncontrolled trials had either
not healed previously or had developed hypersensitivity to topical idoxuridine
Vidarabine is a purine nucleoside obtained from fermentation
cultures of Streptomyces antibioticus. The
antiviral mechanism of action has not been established. Vidarabine appears
to interfere with the early steps of viral DNA synthesis.
has been shown to possess antiviral activity against the following viruses in vitro:
types 1 and 2 Vaccinia Varicella-Zoster
for Rhabdovirus and Oncornavirus, vidarabine does not display in
vitro antiviral activity against other RNA or DNA viruses, including
Tests - No universal, standardized, quantitative in
vitro procedures have as yet been developed to estimate the susceptibility
of viruses to antiviral agents.
INDICATIONS AND USAGE
VIRA-A Ophthalmic Ointment, 3%, is indicated for the treatment
of acute keratoconjunctivitis and recurrent epithelial keratitis due to Herpes
simplex virus types l and 2. The clinical diagnosis of keratitis caused by
Herpes simplex virus is usually established by the presence of typical dendritic
or geographic lesions on slit-lamp examination. It is also effective in superficial
keratitis caused by Herpes simplex virus which has not responded to topical
idoxuridine or when toxic or hypersensitivity reactions due to idoxuridine
have occurred. The effectiveness of VIRA-A Ophthalmic Ointment, 3%, against
stromal keratitis and uveitis due to Herpes simplex virus has not been established.
VIRA-A Ophthalmic Ointment, 3%, is contraindicated in patients
who develop hypersensitivity reactions to it.
Normally, corticosteroids alone are contraindicated in Herpes
simplex virus infections of the eye. If VIRA-A Ophthalmic Ointment, 3%, is
administered concurrently with topical corticosteroid therapy, corticosteroid-induced
ocular side effects must be considered. These include corticosteroid-induced
glaucoma or cataract formation and progression of a bacterial or viral infection.
is not effective against RNA virus or adenoviral ocular infections. It is
also not effective against bacterial, fungal, or chlamydial infections of
the cornea or nonviral trophic ulcers.
resistance to VIRA-A has not been observed, this possibility may exist.
The diagnosis of keratoconjunctivitis due to Herpes simplex
virus should be established clinically prior to prescribing VIRA-A Ophthalmic
Patients should be forewarned that VIRA-A
Ophthalmic Ointment, 3%, like any ophthalmic ointment, may produce a temporary
Chronic parenteral (IM) studies of vidarabine have been conducted
in mice and rats.
In the mouse study, there was a statistically
significant increase in liver tumor incidence among the vidarabine-treated
females. In the same study some vidarabine-treated male mice developed kidney
neoplasia. No renal tumors were found in the vehicle-treated control mice
or the vidarabine-treated female mice.
In the rat study,
intestinal, testicular, and thyroid neoplasia occurred with greater frequency
among the vidarabine-treated animals than in the vehicle-treated controls.
The increases in thyroid adenoma incidence in the high-dose (50 mg/kg) males
and the low-dose (30 mg/kg) females were statistically significant.
megalocytosis, associated with vidarabine treatment, has been found in short
and long-term rodent (rat and mouse) studies. It is not clear whether or not
this represents a preneoplastic change.
Results of in vitro experiments
indicate that vidarabine can be incorporated into mammalian DNA and can induce
mutation in mammalian cells (mouse L5178Y cell line). Thus far, in
vivo studies have not been as conclusive, but there is some evidence
(dominant lethal assay in mice) that vidarabine may be capable of producing
mutagenic effects in male germ cells.
It has also been
reported that vidarabine causes chromosome breaks and gaps when added to human
leukocytes in vitro. While the significance
of these effects in terms of mutagenicity is not fully understood, there is
a well-known correlation between the ability of various agents to produce
such effects and their ability to produce heritable genetic damage.
Pregnancy Category C
VIRA-A parenterally is teratogenic in rats and rabbits. Ten
percent VIRA-A ointment applied to 10% of the body surface during organogenesis
induced fetal abnormalities in rabbits. When 10% VIRA-A ointment was applied
to 2% to 3% of the body surface of rabbits, no fetal abnormalities were found.
This dose greatly exceeds the total recommended ophthalmic dose in humans.
The possibility of embryonic or fetal damage in pregnant women receiving VIRA-A
Ophthalmic Ointment, 3%, is remote. The topical ophthalmic dose is small,
and the drug relatively insoluble. Its ocular penetration is very low. However,
a safe dose for a human embryo or fetus has not been established. There are
no adequate and well-controlled studies in pregnant women. VIRA-A should be
used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
It is not known whether VIRA-A is secreted in human milk.
Because many drugs are excreted in human milk and because of the potential
for tumorigenicity shown for VIRA-A in animal studies, a decision should be
made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother. However, breast milk excretion
is unlikely because VIRA-A is rapidly deaminated in the gastrointestinal tract.
The safety and effectiveness in pediatric patients below
the age of 2 years have not been established.
Lacrimation, foreign body sensation, conjunctival injection,
burning, irritation, superficial punctate keratitis, pain, photophobia, punctal
occlusion, and sensitivity have been reported with VIRA-A Ophthalmic Ointment,
3%. The following have also been reported but appear disease-related: uveitis,
stromal edema, secondary glaucoma, trophic defects, corneal vascularization,
Acute massive overdosage by oral ingestion of the ophthalmic
ointment has not occurred. However, the rapid deamination to arabinosylhypoxanthine
should preclude any difficulty. The oral LD50 for vidarabine is
greater than 5020 mg/kg in mice and rats. No untoward effects should result
from ingestion of the entire contents of the tube.
by ocular instillation is unlikely because any excess should be quickly expelled
from the conjunctival sac.
DOSAGE AND ADMINISTRATION
Administer approximately one-half inch of VIRA-A Ophthalmic
Ointment, 3%, into the lower conjunctival sac five times daily at three-hour
If there are no signs of improvement after
7 days, or complete re-epithelialization has not occurred by 21 days, other
forms of therapy should be considered. Some severe cases may require longer
Too frequent administration should be avoided.
re-epithelialization has occurred, treatment for an additional 7 days at a
reduced dosage (such as twice daily) is recommended in order to prevent recurrence.
following topical antibiotics: gentamicin, erythromycin, chloramphenicol;
or topical steroids: prednisolone or dexamethasone have been administered
concurrently with VIRA-A Ophthalmic Ointment, 3%.
Ointment, 3%, is supplied sterile in ophthalmic ointment tubes of 3.5 g. The
base is a 60:40 mixture of solid and liquid petrolatum.