Fomivirsen

Vitravene† (fomivirsen sodium intravitreal injectable) is supplied in preservative-free, single-use vials containing 0.25 mL, 6.6 mg/mL. The product is intended for intravitreal injection only.

NDC 58768-902-35

Store between 2-25° C (35-77° F). Protect from excessive heat and light.

Rx only

Manufactured by:
Abbott Laboratories
McPherson, KS 67460

Distributed by:
CIBA Vision®
A Novartis Company
Duluth, GA 30097

This product has been discovered and developed by Isis Pharmaceuticals, Inc., Carlsbad, CA 92008

The most frequently observed adverse experiences have been cases of ocular inflammation (uveitis) including iritis and vitritis. Ocular inflammation has been reported to occur in approximately 1 in 4 patients. Inflammatory reactions are more common during induction dosing. Delaying additional treatment with Vitravene (fomivirsen) † and the use of topical corticosteroids have been useful in the medical management of inflammatory changes (SEE PRECAUTIONS, General).

Adverse experiences reported in approximately 5 to 20% of patients have included:

Ocular: abnormal vision, anterior chamber inflammation, blurred vision, cataract, conjunctival hemorrhage, decreased visual acuity, desaturation of color vision, eye pain, floaters, increased intraocular pressure, photophobia, retinal detachment, retinal edema, retinal hemorrhage, retinal pigment changes, uveitis, vitritis.

Systemic: abdominal pain, anemia, asthenia, diarrhea, fever, headache, infection, nausea, pneumonia, rash, sepsis, sinusitis, systemic CMV, vomiting.

Adverse experiences reported in approximately 2 to 5% of patients have included:

Ocular: application site reaction, conjunctival hyperemia, conjunctivitis, corneal edema, decreased peripheral vision, eye irritation, hypotony, keratic precipitates, optic neuritis, photopsia, retinal vascular disease, visual field defect,vitreous hemorrhage, vitreous opacity.

Systemic: abnormal liver function, abnormal thinking, allergic reactions, anorexia, back pain, bronchitis, cachexia, catheter infection, chest pain, decreased weight, dehydration, depression, dizziness, dyspnea, flu syndrome, increased cough, increased GGTP, kidney failure, lymphoma like reaction, neuropathy, neutropenia, oral monilia, pain, pancreatitis, sweating, thrombocytopenia.

Vitravene (fomivirsen) † is for intravitreal injection use only.

CMV retinitis may be associated with CMV disease elsewhere in the body. Vitravene (fomivirsen) † provides localized therapy limited to the treated eye. The use of Vitravene (fomivirsen) † does not provide treatment for systemic CMV disease. Patients should be monitored for extraocular CMV disease or disease in the contralateral eye.

Vitravene (fomivirsen) † is not recommended for use in patients who have recently (2-4 weeks) been treated with either intravenous or intravitreal cidofovir because of the risk of exaggerated ocular inflammation.

Virology

Mechanism of Action

Fomivirsen is a phosphorothioate oligonucleotide that inhibits human cytomegalovirus (HCMV) replication through an antisense mechanism. The nucleotide sequence of fomivirsen is complementary to a sequence in mRNA transcripts of the major immediate early region 2 (IE2) of HCMV. This region of mRNA encodes several proteins responsible for regulation of viral gene expression that are essential for production of infectious CMV. Binding of fomivirsen to the target mRNA, results in inhibition of IE2 protein synthesis, subsequently inhibiting virus replication.

Resistance

Through persistent selection pressure in vitro it was possible to isolate a clone of HCMV that was 10-fold less sensitive to inhibition of replication than the parent strain. The molecular basis for the resistance has not been elucidated. It is possible that resistant strains may occur in clinical use.

Cross-resistance

The antisense mechanism of action and molecular target of fomivirsen are different from that of inhibitors of HCMV replication, which function by inhibiting the viral DNA polymerase. Fomivirsen was equally potent against 21 independent clinical HCMV isolates, including several that were resistant to ganciclovir, foscarnet and/or cidofovir. Isolates, which are resistant to fomivirsen, may be sensitive to ganciclovir, foscarnet and/or cidofovir.

Pharmacokinetics

The assessment of ocular pharmacokinetic parameters in patients has been limited and is still ongoing.

ANIMAL STUDIES

Ocular Kinetics:   Fomivirsen is cleared from the vitreous in rabbits over the course of 7 to 10 days, by a combination of tissue distribution and metabolism. In the eye, fomivirsen concentrations were greatest in the retina and iris. Fomivirsen was detectable in retina within hours after injection, and concentrations increased over 3 to 5 days.

Metabolism and Elimination:   Metabolism is the primary route of elimination from the eye. Metabolites of fomivirsen are detected in the retina and vitreous in animals. Fomivirsen sodium is metabolized by exonucleases in a process that sequentially removes residues from the terminal ends of the oligonucleotide yielding shortened oligonucleotides and mononucleotide metabolites. Data with related compounds indicate that mononucleotide metabolites are further catabolized similar to endogenous nucleotides and are excreted as low molecular weight metabolites. In rabbits, a small amount of fomivirsen-derived radioactivity was eliminated in urine (16%) or feces (3%) as low molecular weight metabolites. Expired air has been shown to be a major route of excretion for CO 2 generated by catabolism of nucleotides after administration of phosphorothioate oligonucleotides.

Systemic Exposure:   Systemic exposure to fomivirsen following single or repeated intravitreal injection in monkeys was below limits of quantitation (70 [ng ]g/mL in plasma and 350 [ng ]g/g in tissue). In monkeys treated every other week for up to 3 months with fomivirsen there were isolated instances when fomivirsen's metabolites were observed in liver, kidney, and plasma at a concentration near the level of detection (14 [ng ]g/mL in plasma and 70 [ng ]g/g in tissue).

Protein Binding:   Analysis of vitreous samples from treated rabbits and monkeys indicates that approximately 40% of fomivirsen is bound to proteins.

Clinical Studies

Clinical ocular pharmacokinetics studies have not yet been completed.

Limited, open label, controlled clinical studies evaluating the safety and efficacy of Vitravene (fomivirsen) † have been conducted in patients with newly diagnosed CMV retinitis and in patients who have failed previous therapies. Based on the assessment of fundus photographs, the median time to CMV retinitis progression was approximately 80 days in patients receiving a dose of 330 µg. Many of these patients were also receiving protease inhibitor treatment. In the subgroup of newly diagnosed patients who received delayed treatment, most had CMV retinitis progression within two weeks. Head to head comparisons with other medications available to treat CMV retinitis has not been completed.

Fomivirsen is used in the treatment of:

• Cytomegalovirus Retinitis

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Fomivirsen is part of the drug class:

• Opthalmic antivirals