VIROPTIC is the brand name for trifluridine (also known as trifluorothymidine, F ₃ TdR,F ₃ T), an antiviral drug for topical treatment of epithelial keratitis caused by herpes simplex virus. The chemical name of trifluridine is (alpha),(alpha),(alpha)-trifluorothymidine. The structual formula is:

VIROPTIC sterile ophthalmic solution contains 1% trifluridine in an aqueous solution with acetic acid and sodium acetate (buffers), sodium chloride, and thimerosal 0.001% (added as a preservative). The pH range is 5.5 to 6.0 and osmolality is approximately 283 mOsm.

VIROPTIC Ophthalmic Solution, 1% (trifluridine ophthalmic solution) is indicated for the treatment of primay keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2.

Instill one drop of VIROPTIC Ophthalmic Solution, 1% onto the cornea of the affected eye every 2 hours while awake for a maximum daily dosage of nine drops until the corneal ulcer has completely re-epithelialized. Following re-epithelialization, treatment for an additional 7 days of one drop every 4 hours while awake for a minimum daily dosage of five drops is recommended.

If there are no signs of improvement after 7 days of therapy or complete re-epithelialization has not occurred after 14 days of therapy, other forms of therapy should be considered. Continuous administration of VIROPTIC for periods exceeding 21 days should be avoided because of potential ocular toxicity.

VIROPTIC Ophthalmic Solution, 1% is supplied as a sterile ophthalmic solution in a plastic Drop Dose® dispenser bottle of 7.5 mL (NDC 61570-037-75).

Store under refrigeration 2° to 8°C (36° to 46°F).

Manufactured for: Monarch Pharmaceuticals®, Inc., Bristol, TN 37620

By: Catalytica Pharmaceutical, Inc., Greenville, NC 27835
Monarch Pharmaceuticals®

Date of issue: 10/00
643141
Monarch Pharmaceuticals®

The most frequent adverse reactions reported during controlled clinical trials were mild, transient burning or stinging upon instillation (4.6%) and palpebral edema (2.8%). Other adverse reactions in decreasing order of reported frequency were superficial punctate keratopathy, epithelial keratopathy, hypersensitivity reaction, stromal edema, irritation, keratitis sicca, hyperemia, and increased intraocular pressure.

No Information Provided.

The recommended dosage and frequency of administration should not be exceeded (see DOSAGE AND ADMINISTRATION).

General:   VIROPTIC Ophthalmic Solution, 1% should be prescribed only for patients who have a clinical diagnosis of herpetic keratitis.

VIROPTIC may cause mild local irritation of the conjunctiva and cornea when instilled, but these effects are usually transient.

Although documented in vitro viral resistance to trifluridine has not been reported following multiple exposures to VIROPTIC, the possibility of the development of viral resistance exists.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Mutagenic Potential:  Trifluridine has been shown to exert mutagenic, DNA-damaging and cell-transforming activities in various standard in vitro test systems, and clastogenic activity in Vicia faba cells. It did not induce chromosome aberrations in bone marrow cells of male or female rats following a single subcutaneous dose of 100 mg/kg, but was weakly positive in female, but not in male, rats following daily subcutaneous administration at 700 mg/kg/day for 5 days.

Although the significance of these test results is not clear or fully understood, there exists the possibility that mutagenic agents may cause genetic damage in humans.

Oncogenic Potential:   Lifetime carcinogenicity bioassays in rats and mice given daily subcutaneous doses of trifluridine have been performed. Rats tested at 1.5, 7.5, and 15 mg/kg/day had increased incidences of adenocarcinomas of the intestinal tract and mammary glands, hemangiosarcomas of the spleen and liver, carcinosarcomas of the prostate gland, and granulosa-thecal cell tumors of the ovary. Mice were tested at 1, 5, and 10 mg/kg/day; those given 10 mg/kg/day trifluridine had significantly increased incidences of adenocarcinomas of the intestinal tract and uterus. Those given 10 mg/kg/day also had a significantly increased incidence of testicular atrophy as compared to vehicle control mice.

Pregnancy:  Teratogenic Effects:   Pregnancy Category C. Trifluridine was not teratogenic at doses up to 5 mg/kg/day (23 times the estimated human exposure) when given subcutaneously to rats and rabbits. However, fetal toxicity consisting of delayed ossification of portions of the skeleton occurred at dose levels of 2.5 and 5 mg/kg/day in rats and at 2.5 resorption in rabbits. In both rats and rabbits, 1 mg/kg/day (5 times the estimated human exposure) was a no-effect level. There were no teratogenic or fetotoxic effects after topical application of VIROPTIC Ophthalmic Solution, 1% (approximately 5 times the estimated human exposure) to the eyes of rabbits on the 6th through the 18th days of pregnancy. In a non-standard test, trifluridine solution has been shown to be teratogenic when injected directly into the yolk sac of chicken eggs. There are no adequate and well-controlled studies in pregnant women. VIROPTIC Ophthalmic Solution, 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:   It is unlikely that trifluridine is excreted in human milk after ophthalmic instillation of VIROPTIC because of the relatively small dosage (<=5 mg/day), its dilution in body fluids and its extremely short half-life (approximately 12 minutes). The drug should not be prescribed for nursing mothers unless the potential benefits outweigh the potential risks.

Pediatric Use:   Safety and effectiveness in pediatric patients below six years of age have not been established.

Overdosage by ocular instillation is unlikely because any excess solution should be quickly expelled from the conjunctival sac.

Acute overdosage by accidental oral ingestion of VIROPTIC has not occurred. However, should such ingestion occur, the 75 mg dosage of trifluridine in a 7.5 mL bottle of VIROPTIC is not likely to produce adverse effects. Single intravenous doses of 1.5 to 30 mg/kg/day in children and adults with neoplastic disease produce reversible bone marrow depression as the only potentially serious toxic effect and only after three to five courses of therapy. The acute oral LD ₅₀ in the mouse and rat was 4379 mg/kg or higher.

VIROPTIC Ophthalmic Solution, 1% is contraindicated for patients who develop hypersensitivity reactions or chemical intolerance to trifluridine.

Trifluridine is a fluorinated pyrimidine nucleoside with in vitro and in vivo activity against herpes simplex virus, types 1 and 2 and vacciniavirus. Some strains of adenovirus are also inhibited in vitro.

VIROPTIC is also effective in the treatment of epithelial keratitis that has not responded clinically to the topical administration of idoxuridine or when ocular toxicity or hypersensitivity to idoxuridine has occurred. In a smaller number of patients found to be resistant to topical vidarabine, VIROPTIC was also effective.

Trifluridine interferes with DNA synthesis in cultured mammalian cells. However, its antiviral mechanism of action is not completely known.

In vitro perfusion studies on excised rabbit corneas have shown that trifluridine penetrates the intact cornea as evidenced by recovery of parental drug and its major metabolite, 5-carboxy-2'-deoxyuridine, on the endothelial side of the cornea. Absence of the corneal epithelium enhances the penetration of trifluridine approximately two-fold.

Intraocular penetration of trifluridine occurs after topical instillation of VIROPTIC into human eyes. Decreased corneal integrity or stromal or uveal inflammation may enhance the penetration of trifluridine into the aqueous humor. Unlike the results of ocular penetration of trifluridine in vitro , 5-carboxy-2'-deoxyuridine was not found in detectable concentrations within the aqueous humor of the human eye.

Systemic absorption of trifluridine following therapeutic dosing with VIROPTIC appears to be negligible. No detectable concentrations of trifluridine or 5-carboxy-2'-deoxyuridine were found in the sera of adult healthy normal subjects who had VIROPTIC instilled into their eyes seven times daily for 14 consecutive days.

Clinical Studies:   During a controlled multicenter clinical trial, 92 of 97 (95%) patients (78 of 81 with dendritic and 14 of 16 with geographic ulcers) responded to therapy with VIROPTIC as evidenced by complete corneal re-epithelialization within the 14-day therapy period. Fifty-six of 75 (75%) patients (49 of 58 with dendritic and 7 of 17 with geographic ulcers) responded to idoxuridine therapy. The mean time to corneal re-epithelialization for dendritic ulcers (6 days) and geographic ulcers (7 days) was similar for both therapies.

In other clinical studies. VIROPTIC was evaluated in the treatment of herpes simplex virus keratitis in patients who were unresponsive or intolerant to the topical administration of idoxuridine or vidarabine. VIROPTIC was effective in 138 of 150 (92%) patients (109 of 114 with dendritic and 29 of 36 with geographic ulcers) as evidenced by corneal re-epithelialization. The mean time to corneal re-epithelialization was 6 days for patients with dendritic ulcers and 12 days for patients with geographic ulcers.

The clinical efficacy of VIROPTIC in the treatment of stromal keratitis and uveitis due to herpes simplex virus or ophthalmic infections caused by vacciniavirus and adenovirus has not been established by well-controlled clinical trials. VIROPTIC has not been shown to be effective in the prophylaxis of herpes simplex virus keratoconjunctivitis and epithelial keratitis by well-controlled clinical trials. VIROPTIC is not effective against bacterial, fungal, or chlamydial infections of the cornea or nonviral trophic lesions.

ANIMAL PHARMACOLOGY AND ANIMAL TOXICOLOGY

Corneal wound healing studies in rabbits showed that VIROPTIC did not significantly retard closure of epithelial wounds. However, mild toxic changes such as intracellular edema of the basal cell layer, mild thinning of the overlying epithelium and reduced strength of stromal wounds were observed.

Whereas instillation of VIROPTIC into rabbit eyes during a subchronic toxicity study produced some degree of corneal epithelial thinning, a 12-month chronic toxicity study in rabbits in which VIROPTIC was instilled into eyes in intermittent, multiple, full-therapy courses showed no drug-related changes in the cornea.

No Information Provided.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

TRIFLURIDINE DROPS - OPHTHALMIC

(try-FLEWR-ih-deen)

COMMON BRAND NAME(S): Viroptic

USES: This medication is used to treat herpes infection of the eye. Herpes is a virus that lives in the body quietly until an outbreak is triggered. Trifluridine is not a cure for the infection, but treatment of an outbreak can speed up the healing of the sores/swelling in the eye and lower the risk of complications (e.g., vision loss).

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to treat other eye infections caused by viruses (e.g., vaccinia virus infections).

HOW TO USE: To apply eye drops, wash your hands first. To avoid contamination, do not touch the dropper tip or let it touch your eye or any other surface.

Tilt your head back, look up, and pull down the lower eyelid to make a pouch. Hold the dropper directly over your eye and place 1 drop into the pouch as directed by your doctor. Look down and gently close your eyes for 1 to 2 minutes. Place one finger at the corner of your eye (near the nose) and press gently. This will prevent the medication from draining out. Try not to blink and do not rub your eye. Repeat these steps for your other eye if so directed.

Do not rinse the dropper. Replace the dropper cap after each use.

Use this medication usually every 2 hours while awake until the eye has healed. Do not use more than 9 drops into the eye in a 24-hour period. After healing, use this medication for another 7 days, usually every 4 hours while awake (at least 5 drops per day) or as directed by your doctor.

If you are using another kind of eye medication (e.g., drops or ointments), wait at least 5 to 10 minutes before applying other medications. Use eye drops before eye ointments to allow the drops to enter the eye.

Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same times each day. Continue using it for the full time prescribed. Stopping the medication too early may result in a return of the infection.

Do not use this medication more often or use longer than prescribed because doing so may increase the risk of side effects. This medication should not be used for more than 21 days at a time.

Tell your doctor if your condition worsens, does not improve after 7 days, or does not completely heal after 14 days.

SIDE EFFECTS: Temporary mild burning, stinging, and irritation may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: swelling eyelids, eye pain/redness, feeling as if something is in the eye, persistent blurred vision.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using trifluridine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: other eye problems (e.g., glaucoma).

After you apply this drug, your vision may become temporarily blurred. Use caution while driving, using machinery, or doing any other activity that requires clear vision.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: This medicine may be harmful if swallowed. If swallowing or overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in that case.

Laboratory and/or medical tests (e.g., eye exam) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store in the refrigerator between 36-46 degrees F (2-8 degrees C) away from light. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.