Prescription Drugs

CLINICAL PHARMACOLOGYVirology 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.

VITRAVENE (fomivirsen) TM Injection Fomivirsen sodium intravitreal injectable DESCRIPTION Vitravene† (fomivirsen sodium intravitreal injectable) is a sterile, aqueous, preservative-free, bicarbonate-buffered solution for intravitreal injection. Fomivirsen sodium is represented by the following structual formula: Fomivirsen sodium is a phosphorothioate oligonucleotide, twenty-one nucleotides in length, with the following sequence: 5'-GCG TTT GCT CTT CTT CTT GCG-3' The chemical name for fomivirsen sodium is as follows: 2'-Deoxyguanosylyl-(3'->5' O,O -phosphorothioyl)-2'-deoxycytidylyl-(3'->5' O,O -phosphorothioyl)-2'-deoxyguanosylyl-(3'->5' O,O -phosphorothioyl)-thymidylyl-(3'->5' O,O -phosphorothioyl)-thymidylyl-(3'->5' O,O -phos-phorothioyl)-thymidylyl-(3'->5' O,O -phosphorothioyl)-2'-deoxyguanosylyl-(3'->5' O,O -pho-sphorothioyl)-2'-deoxycytidylyl-(3'->5' O,O -phosphorothioyl)-thymidylyl-(3'->5' O,O -pho-sphorothioyl)-2'-deoxycytidylyl-(3'->5' O,O -phosphorothioyl)-thymidylyl-(3'->5' O,O -pho-sphorothioyl)-thymidylyl-(3'->5' O,O -phosphorothioyl)-2'-deoxycytidylyl-(3'->5' O,O -phosphorothioyl)-thymidylyl-(3'->5' O,O -pho-sphorothioyl)-thymidylyl-(3'->5' O,O -phosphorothioyl)-2'-deoxycytidylyl-(3'->5' O,O -phosphorothioyl)-thymidylyl-(3'->5' O,O -pho-sphorothioyl)-thymidylyl-(3'->5' O,O -phosphorothioyl)-2'-deoxyguanosylyl-(3'->5' O,O -phosphorothioyl)-2'-deoxycytidylyl-(3'->5' O,O -phosphorothioyl)-2'-deoxyguanosine, 20-sodium salt. Fomivirsen sodium is a white to off-white, hygroscopic, amorphous powder with a molecular formula of C 204 H 243 N 63 O 114 P 20 S 20 Na 20 and a molecular weight of 7,122. Each mL of Vitravene (fomivirsen) † contains: ACTIVE: Fomivirsen sodium 6.6 mg INACTIVES: Sodium chloride, sodium bicarbonate, sodium carbonate and water for injection. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. Vitravene (fomivirsen) † is formulated to have an osmolality of 290 mOsm/kg, and a pH of 8.7.

PATIENT INFORMATION What is Vitravene (fomivirsen) used for? Vitravene (fomivirsen) is used to treat a virus called cytomegalovirus (CMV). CMV can affect one or both eyes in patients with acquired immunodeficiency syndrome (AIDS) who cannot take other treatment(s) for CMV retinitis or who did not respond to other treatments for CMV retinitis. The diagnosis should be made after a comprehensive eye exam, including indirect ophthalmoscopy. Warning(s) with Vitravene (fomivirsen) : Vitravene (fomivirsen) only works in the eye in which it is injected and does not treat CMV elsewhere in the body. Because CMV may be in other parts of your body and not only in your treated eye, your doctor will monitor you for CMV in the untreated eye or CMV elsewhere in your body (e.g. pneumonitis, colitis). Vitravene (fomivirsen) is not recommended if you have been treated within the last 2-4 weeks with cidofivir (VistideÒ ) because of the increased risk of eye inflammation. General Precautions with Vitravene (fomivirsen) : Vitravene (fomivirsen) is for eye(s) only. Vitravene (fomivirsen) is not a cure for CMV retinitis. CMV retinitis in some patients may get worse during or following Vitravene (fomivirsen) treatment. You should have regular eye exams by your ophthalmologist. Inflammation of the eye (uveitis) occurs in approximately one out of four patients being treated with Vitravene (fomivirsen) . This type of reaction is most common when starting treatment with Vitravene (fomivirsen) . Your doctor may prescribe medication to treat the inflammation and may interrupt Vitravene (fomivirsen) treatment until the inflammation stops. Increased pressure in the eye has been reported as another common side effect of Vitravene (fomivirsen) injections. Your doctor should monitor the pressure in your eye(s) during each visit and treat the increase in pressure if necessary. If you are receiving Vitravene (fomivirsen) , you should have regular follow-up eye exams. HIV-infected patients should continue taking their prescribed antiretroviral medications, unless their doctor tells them otherwise. What should I tell my doctor or health care provider? Tell your health care provider if you are trying to become pregnant, are already pregnant, or are breast-feeding. What are some possible side effects of Vitravene (fomivirsen) ? (This is NOT a complete list of side effects reported with Vitravene (fomivirsen) . Your health care provider can discuss with you a more complete list of side effects.) The most common side effect is eye inflammation. This reaction is most common when starting Vitravene (fomivirsen) and may be treated by your health care provider (See General Precautions). Other side effects that may relate to the eye(s) are: Abnormal vision Swelling around the eye Blurred vision Cataract Bleeding in and around the eye Decreased visual sharpness, clearness, Reduced color vision Eye pain Objects in the field of vision (floaters) Increased eye pressure Sensitivity to light Retinal detachment Swelling of the retina Bleeding of the retina Color changes of the retina Additional non-eye related side effects might include: Stomach pain Low blood count Weakness Diarrhea Fever Headache Infection Nausea Pneumonia Rash Inflammation of the sinuses Vomiting Liver or kidney problems Dehydration Sweating Flu-like symptoms Cough Chest pain For more detailed information about Vitravene (fomivirsen) , ask your health care provider.

OVERDOSE In clinical trials with Vitravene (fomivirsen) †, one patient with advanced CMVR unresponsive to other antivitral treatments was accidentally dosed once bilaterally with 990 µg per eye. Anterior chamber paracentesis was performed bilaterally and vision was retained. CONTRAINDICATIONS Vitravene (fomivirsen) † is contraindicated in those persons who have known hypersensitivity to any component of this preparation.

SIDE EFFECTS 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. DRUG INTERACTIONS The interaction in humans between fomivirsen sodium and other drugs has not been studied. Results from in vitro tests demonstrated no inhibition of anti-HCMV activity of fomivirsen by AZT or ddC.

WARNINGS 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. PRECAUTIONSGeneral FOR OPHTHALMIC USE ONLY. Ocular inflammation (uveitis) including iritis and vitritis has been reported to occur in approximately 1 in 4 patients. Inflammatory reactions are more common during induction dosing. Topical corticosteroids have been useful in the medical management of inflammatory changes, and with both medical management and time, patients may be able to continue to receive intravitreal injections of Vitravene (fomivirsen) † after the inflammation has resolved. Increased intraocular pressure has been commonly reported. The increase is usually a transient event and in most cases the pressure returns to the normal range without any treatment or with temporary use of topical medications. Intraocular pressure should be monitored at each visit and elevations of intraocular pressure, if sustained, should be managed with medications to lower intraocular pressure. Information for patients See PATIENT INFORMATION section. Drug Interactions See DRUG INTERACTION section. Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted to evaluate the carcinogenic potential of fomivirsen sodium. Fomivirsen sodium was not mutagenic in Salmonella/Microsome (Ames) and mouse lymphoma tests or clastogenic in the in vivo mouse micronucleus assay. However, equivocal results were observed in the chromosome aberration tests with Chinese hamster ovary cells. No studies have been conducted to evaluate the potential of fomivirsen sodium to affect fertility. Pregnancy Teratogenic Effects Pregnancy Category C. Animal reproductive studies have not been conducted with fomivirsen sodium. It is also not known whether fomivirsen sodium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. There are no adequate and well-controlled studies in pregnant women. Vitravene (fomivirsen) † should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether fomivirsen sodium is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Vitravene (fomivirsen) †, 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. Pediatric use Safety and effectiveness in pediatric patients have not been established. Geriatric use Clinical studies of Vitravene (fomivirsen) † did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects.