Virson

Contraindications

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What is the most important information I should know about Virson?

Patients with hypersensitivity to Virson, valganciclovir or to any component of Cymevene.

Due to the similarity of the chemical structure of Cymevene and that of aciclovir and valaciclovir, a cross-hypersensitivity reaction between these drugs is possible.

Do not administer by rapid or bolus IV injection. The toxicity of Cymevene may be increased as a result of excessive plasma levels.

IM or SC injection may result in severe tissue irritation due to the high pH (~11) of Virson solutions.

Carcinogenicity, Mutagenicity & Impairment of Fertility: In animal studies, Virson was found to be mutagenic, teratogenic and carcinogenic. Cymevene should therefore be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers.

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia have been observed in patients treated with Cymevene. Therapy should not be initiated if the absolute neutrophil count is <500 cells/microliter or the platelet count is <25,000 cells/microliter or the hemoglobin is <8 g/dL.

Use in pregnancy & lactation: Evaluation of experimental animal studies has shown reproductive toxicity eg, birth defects or other effects on the development of the embryo or fetus, the course of gestation or peri- and postnatal development.

Teratogenicity has been observed in animal studies. Women of childbearing potential should be advised to use effective contraception during treatment. Male patients should be advised to practice barrier contraception during and for at least 90 days following treatment with Cymevene.

The safety of Cymevene for use in human pregnancy has not been established. The use of Cymevene should be avoided in pregnant woman unless the benefit to the mother outweighs the potential risk to the fetus.

Peri- and postnatal development has not been studied with Virson but the possibility of Virson being excreted in the breast milk and causing serious adverse reactions in the nursing infant cannot be discounted. Therefore, a decision should be made to discontinue the drug or discontinue nursing taking into consideration the potential benefit of Cymevene to the nursing mother.

Undesirable effects

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What are the possible side effects of Virson?

Adverse events that occurred during clinical trials of Virson Capsules are summarized below, according to the participating study subject population.

Three controlled, randomized, phase 3 trials comparing Virson-IV and Virson Capsules for maintenance treatment of CMV retinitis have been completed. During these trials, Virson-IV or Virson Capsules were prematurely discontinued in 9% of subjects because of adverse events. In a placebo-controlled, randomized, phase 3 trial of Virson Capsules for prevention of CMV disease in AIDS, treatment was prematurely discontinued because of adverse events, new or worsening intercurrent illness, or laboratory abnormalities in 19.5% of subjects treated with Virson Capsules and 16% of subjects receiving placebo. Laboratory data and adverse events reported during the conduct of these controlled trials are summarized below.

Laboratory Data:

Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis and Prevention of CMV Disease

Adverse events: The following table shows selected adverse events reported in 5% or more of the subjects in three controlled clinical trials during treatment with Virson Capsules (3000 mg/day) and in one controlled clinical trial in which Virson Capsules (3000 mg/day) were compared to placebo for the prevention of CMV disease.

The following events were frequently observed in clinical trials but occurred with equal or greater frequency in placebo-treated subjects: abdominal pain, nausea, flatulence, pneumonia, paresthesia, rash.

Retinal Detachment: Retinal detachment has been observed in subjects with CMV retinitis both before and after initiation of therapy with Virson. Its relationship to therapy with Virson is unknown. Retinal detachment occurred in 8% of patients treated with Virson Capsules. Patients with CMV retinitis should have frequent ophthalmologic evaluations to monitor the status of their retinitis and to detect any other retinal pathology.

There has been one controlled clinical trial of Virson Capsules for the prevention of CMV disease in transplant recipients. Laboratory data and adverse events reported during these trials are summarized below.

Laboratory Data: The following table shows the frequency of granulocytopenia (neutropenia) and thrombocytopenia observed:

The following table shows the frequency of elevated serum creatinine values in these controlled clinical trials:

In 3 out of 4 trials, patients receiving either Virson-IV solution or Virson Capsules had elevated serum creatinine levels when compared to those receiving placebo. Most patients in these studies also received cyclosporine. The mechanism of impairment of renal function is not known. However, careful monitoring of renal function during therapy with Virson Capsules is essential, especially for those patients receiving concomitant agents that may cause nephrotoxicity.

Other adverse events that were thought to be “probably” or “possibly” related to Virson Capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are listed below. These events all occurred in at least 3 subjects.

Body as a Whole: abdomen enlarged, asthenia, chest pain, edema, headache, injection site inflammation, malaise, pain

Digestive System: abnormal liver function test, aphthous stomatitis, constipation, dyspepsia, eructation

Hemic and Lymphatic System: pancytopenia

Respiratory System: cough increased, dyspnea

Nervous System: abnormal dreams, anxiety, confusion, depression, dizziness, dry mouth, insomnia, seizures, somnolence, thinking abnormal, tremor

Skin and Appendages: alopecia, dry skin

Special Senses: abnormal vision, taste perversion, tinnitus, vitreous disorder

Metabolic and Nutritional Disorders: creatinine increased, SGOT increased, SGPT increased, weight loss

Cardiovascular System: hypertension, phlebitis, vasodilatation

Urogenital System: creatinine clearance decreased, kidney failure, kidney function abnormal, urinary frequency

Musculoskeletal System: arthralgia, leg cramps, myalgia, myasthenia

The following adverse events reported in patients receiving Virson may be potentially fatal: gastrointestinal perforation, multiple organ failure, pancreatitis and sepsis.

The following events have been identified during postapproval use of the drug. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either the seriousness, frequency of reporting, the apparent causal connection or a combination of these factors:

acidosis, allergic reaction, anaphylactic reaction, arthritis, bronchospasm, cardiac arrest, cardiac conduction abnormality, cataracts, cholelithiasis, cholestasis, congenital anomaly, dry eyes, dysesthesia, dysphasia, elevated triglyceride levels, encephalopathy, exfoliative dermatitis, extrapyramidal reaction, facial palsy, hallucinations, hemolytic anemia, hemolytic uremic syndrome, hepatic failure, hepatitis, hypercalcemia, hyponatremia, inappropriate serum ADH, infertility, intestinal ulceration, intracranial hypertension, irritability, loss of memory, loss of sense of smell, myelopathy, oculomotor nerve paralysis, peripheral ischemia, pulmonary fibrosis, renal tubular disorder, rhabdomyolysis, Stevens-Johnson syndrome, stroke, testicular hypotrophy, Torsades de Pointes, vasculitis, ventricular tachycardia

Therapeutic indications

The Virson (Virson) Implant is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS).

The diagnosis of CMV retinitis is ophthalmologic and should be made by indirect ophthalmoscopy. Other conditions in the differential diagnosis of CMV retinitis include candidiasis, toxoplasmosis, histoplasmosis, retinal scars, and cotton wool spots, any of which may produce a retinal appearance similar to CMV. For this reason, it is essential that the diagnosis of CMV be established by a physician familiar with the retinal presentation of these conditions. The Virson (Virson) Implant is for intravitreal implantation only.

In a randomized, controlled parallel group trial conducted between May 1993 and December 1994, treatment with the Virson (Virson) Implant was compared to treatment with intravenous Virson (Cytovene-IV; Roche) in 188 patients with AIDS and newly diagnosed CMV retinitis. Patients randomized to the Cytovene-IV treatment group received Cytovene-IV solution at induction doses (5 mg/kg twice daily) for 14 days, followed by maintenance dosing (5 mg/kg once daily). Based on masked assessment of fundus photographs, the median time to progression was approximately 210 days for the Virson (Virson) Implant treatment group compared to approximately 120 days for the intravenous Virson treatment group.

Virson is an antiviral drug. It slows the growth and spread of the cytomegalovirus.

Virson ophthalmic (for the eyes) is used to treat certain viral infections affecting the eyes.

Virson implant (Virson) is used to treat cytomegalovirus (CMV) infection of the eye. This infection usually occurs in patients who have suppressed immune systems such as patients with AIDS and organ transplant patients.

Virson gel (Zirgan) is used to treat eye ulcers caused by the herpes simplex virus.

Virson is not a cure for CMV or herpes. This medication will not treat symptoms of these infections in any other part of the body.

Virson may also be used for purposes not listed in this medication guide.

Name of the medicinal product

Qualitative and quantitative composition

Each vial contains Ganciclovir sodium equivalent to Virson 500 mg and sodium approximately 46 mg (2 mEq).

Special warnings and precautions for use

Use Virson gel as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Virson gel is only for the eye. Do not get it in your nose or mouth. If you get it in these areas, rinse right away with cool water.
• Do not wear contact lenses while you are using Virson gel. Take care of your contact lenses as directed by the manufacturer. Check with your doctor before you use them.
• To use Virson gel in the eye, first, wash your hands. Tilt your head back. Using your index finger, pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close your eyes. Immediately use your finger to apply pressure to the inside corner of the eyelid for 1 to 2 minutes. Do not blink. Remove excess medicine around your eye with a clean, dry tissue, being careful not to touch your eye. Wash your hands to remove any medicine that may be on them.
• To prevent germs from contaminating your medicine, do not touch the applicator tip to any surface, including the eye. Keep the container tightly closed.
• To clear up your infection completely, use Virson gel for the full course of treatment. Keep using it even if you feel better in a few days.
• If you miss a dose of Virson gel, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Virson gel.

Cytomegalovirus disease, prophylaxis (transplant patients): Prevention of cytomegalovirus (CMV) disease in adult transplant recipients at risk for CMV disease.

Cytomegalovirus retinitis (immunocompromised patients): Treatment of CMV retinitis in immunocompromised adult patients, including patients with AIDS.

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, Virson is an effective and recommended agent for the treatment of esophagitis or colitis due to CMV disease in HIV-infected patients.

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, Virson is an effective and recommended agent for the treatment of neurological disease due to CMV disease in HIV-infected patients.

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, Virson is an effective and recommended agent for the secondary prophylaxis of CMV retinitis in HIV-infected patients.

Based on the American Society for Blood and Marrow Transplantation (ASBMT) Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplantation Recipients, Virson is an effective and recommended agent in the preemptive management of CMV in bone marrow transplant recipients.

Based on The Transplantation Society International CMV Consensus Group Guidelines, Virson is an effective and recommended agent in the treatment of CMV disease in solid organ transplant recipient.

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, intravitreal Virson in combination with intravenous acyclovir is an effective and recommended agent in the management of varicella-zoster virus acute retinal necrosis (ARN) in HIV-infected patients.

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, Virson is an effective and recommended agent in the management of this condition in HIV-infected patients.

Dosage (Posology) and method of administration

Dosage: THE RECOMMENDED DOSE FOR Virson Capsules SHOULD NOT BE EXCEEDED.

For Treatment of CMV Retinitis in Patients WithNormal Renal Function:

1. Induction Treatmen t

Virson Capsules should not be used for induction treatment.

2. Maintenance Treatment

Following induction treatment, the recommended maintenance dosage of Virson Capsules is 1000 mg tid with food. Alternatively, the dosing regimen of 500 mg 6 times daily every 3 hours with food, during waking hours, may be used.

For patients who experience progression of CMV retinitis while receiving maintenance treatment with either formulation of Virson, reinduction treatment is recommended.

For the Prevention of CMV Disease in Patients With Advanced HIV Infection andNormalRenal Function:

The recommended prophylactic dose of Virson Capsules is 1000 mg tid with food.

For the Prevention of CMV Disease in Transplant Recipients With Normal Renal Function:

The recommended prophylactic dosage of Virson Capsules is 1000 mg tid with food.

The duration of treatment with Virson Capsules in transplant recipients is dependent upon the duration and degree of immunosuppression. In a controlled clinical trial of liver allograft recipients, treatment with Virson Capsules was continued through week 14 posttransplantation.

Renal Impairment:

In patients with renal impairment, the dose of Virson Capsules should be modified as shown below:

Creatinine clearance for females = 0.85 x male value

Patient Monitoring: Due to the frequency of granulocytopenia, anemia and thrombocytopenia in patients receiving Virson, it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom Virson or other nucleoside analogues have previously resulted in cytopenia, or in whom neutrophil counts are less than 1000 cells/µL at the beginning of treatment. Patients should have serum creatinine or creatinine clearance values followed carefully to allow for dosage adjustments in renally impaired patients.

Reduction of Dose: Dosage reductions in renally impaired patients should be considered for Virson Capsules. Dosage reductions should also be considered for those with neutropenia, anemia and/or thrombocytopenia. Virson should not be administered in patients with severe neutropenia (ANC less than 500/µL) or severe thrombocytopenia (platelets less than 25,000/µL).

Handling and Disposal: Caution should be exercised in the handling of Virson Capsules. Avoid direct contact with the skin or mucous membranes of the powder contained in Virson Capsules. If such contact occurs, wash thoroughly with soap and water; rinse eyes thoroughly with plain water. Virson Capsules should not be opened or crushed.

Because Virson shares some of the properties of antitumor agents (ie, carcinogenicity and mutagenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs. Several guidelines on this subject have been published.

There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Interaction with other medicinal products and other forms of interaction

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What other drugs will affect Virson?

Binding of Virson to plasma proteins is only 1-2% and drug interactions involving binding site displacement are not anticipated.

Didanosine: Didanosine plasma concentrations were found to be consistently raised when given with Virson (both IV and oral). At Virson oral doses of 3 and 6 g/day, an increase in the AUC of didanosine ranging from 84-124% has been observed, and likewise at IV doses of 5 and 10 mg/kg/day, an increase in the AUC of didanosine ranging from 38-67% has been observed. Given the increase in didanosine plasma concentrations in the presence of Virson, patients should be closely monitored for didanosine toxicity (eg, pancreatitis).

Drug Interactions with IV Virson: Imipenem-Cilastatin: Convulsions have been reported in patients who received Virson and imipenem-cilastatin concomitantly.

Mycophenolate Mofetil: Based on the results of a single-dose administration study of recommended doses of oral mycophenolate mofetil (MMF) and IV Virson and the known effects of renal impairment on the pharmacokinetics of MMF and Virson, it is anticipated that co-administration of these agents (which have the potential to compete for renal tubular secretion) will result in increases in phenolic glucuronide of mycophenolic acid (MPAG) and Virson concentration. No substantial alteration of mycophenolic acid (MPA) pharmacokinetics is anticipated and MMF dose adjustment is not required. In patients with renal impairment in which MMF and Virson are co-administered, the dose recommendation of Virson should be observed and patients monitored carefully.