What is Zyvir, and how does it work (mechanism of action)?
Zyvir is an antiviral drug, a synthetic nucleoside analogue, that has inhibitory activity (interferes with viral replication) against the herpes viruses, including herpes simplex 1 and 2 (cold sores and genital herpes), varicella-zoster (shingles and chickenpox), and Epstein-Barr virus (mononucleosis). Viruses take over living cells and reproduce themselves, often at the expense of the host cell. The Zyvir is converted to an active form by the virus itself, and the virus then uses the active form of Zyvir rather than the nucleoside it normally uses to manufacture DNA, a critical component of viral replication. Incorporation of active Zyvir into new viral DNA stops the production of the DNA. Virally infected cells absorb more Zyvir than normal cells and convert more of it to the active form, which prolongs its antiviral activity. The FDA approved Zyvir in March 1982.
Q: Is there an Zyvir ointment?
A: There is an Zyvir (Zovirax) ointment formulation, available in 5% strength. Currently, Zyvir ointment is only available as the brand-name Zovirax Ointment 5%. Zyvir ointment is indicated for the management of initial genital herpes and in limited non-life threatening mucocutaneous herpes simplex virus infections in immunocompromised patients. Zyvir ointment is not indicated for the prevention of viral transmission to other individuals. Zyvir ointment is also not indicated for the prevention of recurrent herpes infections. Zyvir ointment is a prescription ointment that is applied directly to genital herpes lesions and may lessen the duration of the symptoms associated with an initial outbreak. For the management of genital herpes, patients should be instructed regarding appropriate dosage and administration of Zyvir ointment. Patients should be advised to apply a sufficient quantity of Zyvir ointment to adequately cover all lesions and apply every 3 hours, 6 times daily, for 7 days of treatment. The dose size of Zyvir ointment for each application may vary depending on the size of the lesion area. However, the dose size should be approximately Â½ inch ribbon of Zyvir ointment per 4 square inches of surface area, according to the prescribing information. Patients should be advised to wear a rubber glove or finger cot when applying Zyvir ointment to the affected area to avoid spreading the virus. Zyvir ointment should be applied as early as possible after the development of signs and symptoms. During controlled clinical trials, mild pain, including temporary burning and stinging, was reported in approximately 30% of patients with no significant difference between patients receiving Zovirax ointment and patients receiving placebo. Local pruritus was also reported in 4% of patients. Zyvir ointment 5% should be used exactly as prescribed by a health care provider. Patients should be advised not to exceed the recommended dosage, frequency of applications and length of treatment.
Zyvir was shown not to impair fertility or reproduction in groups of 15 male and 30 female mice in a two-generation fertility study. The mice in this study were given Zyvir by gastric intubation at dosage levels of 50, 150 and 450 mg/kg/day. Males were dosed for 64 consecutive days prior to mating and females for 21 days prior to mating.
In a rat fertility study where groups of 20 male and 20 female rats were given 0, 12.5, 25.0 and 50.0 mg/kg/day by subcutaneous injection, Zyvir was shown not to have an effect on mating or fertility. The males were dosed for 60 days prior to mating and until their mating schedule was completed. Female rats were dosed for 14 days prior to mating and until day 7 of pregnancy. At 50 mg/kg/day s.c. there was a statistically significant increase in post-implantation loss, but no concomitant decrease in litter size.
In 25 female rabbits treated subcutaneously with 50 mg/kg/day Zyvir on days 6 to 18 of gestation, there was a statistically significant decrease in implantation efficiency but no concomitant decrease in litter size. There was also a dose-related increase in the number of fetuses with supernumerary ribs in all drug-treated groups. This increase was not dose-related when the incidence of supernumerary ribs per litter was examined.
In 15 female rabbits treated intravenously with 50 mg/kg/day Zyvir on days 6 to 18 of gestation, there was no effect on either implantation efficiency or litter size.
In a rat peri- and postnatal study (20 female rats per group), Zyvir was given subcutaneously at 0, 12.5, 25 and 50 mg/kg/day from 17 days of gestation to 21 days postpartum. At 50 mg/kg/day s.c. there was a statistically significant decrease in the group mean numbers of corpora lutea, total implantation sites and live fetuses in the F1 generation. Although not statistically significant, there was also a dose-related decrease in group mean numbers of live fetuses and implantation sites at 12.5 mg/kg/day and 25 mg/kg/day s.c.
In a dose-range finding study with 5 female rabbits the intravenous administration of Zyvir at a dose of 100 mg/kg/day from days 6 to 8 of pregnancy, a dose known to cause obstructive nephropathy, caused a significant increase in fetal resorptions and a corresponding decrease in litter size. At a maximum tolerated intravenous dose of 50 mg/kg/day in rabbits there were no drug-related reproductive effects.
In a subchronic toxicity study where groups of 20 male and 20 female rats were given intraperitoneal doses of Zyvir at 0, 20, 80 or 320 mg/kg/day for one month, and followed for a one-month postdose period, there was testicular atrophy. Some histologic evidence of recovery of sperm production was evident 30 days postdose, but this was insufficient time to demonstrate full reversibility.
Groups of 25 male and 25 female rats were administered intraperitoneal doses of Zyvir at 0, 5, 20 or 80 mg/kg/day for 6 months. Ten male and 10 female rats in each group were continued undosed for 13 weeks. Testicular atrophy was limited to high-dose rats given 80 mg/kg/day for 6 months. Organ weight data and light microscopy defined full reversibility of the testicular atrophy by the end of the postdose recovery period.
In a 31-day dog study (16 males and 16 females per group) where Zyvir was administered intravenously at levels of 50, 100 and 200 mg/kg/day, testicles were normal in dogs at 50 mg/kg. Doses of 100 or 200 mg/kg/day caused death of some dogs due to cytostatic effects (bone marrow and gastrointestinal epithelium) and aspermic testes or testes with scattered aspermic tubules. It cannot be ruled out that the testicular change may have been primary, however, similar changes can be observed secondary to severe stress in moribund dogs.
What other drugs will affect Zyvir?
Zyvir can harm your kidneys. This effect is increased when you also use certain other medicines, including: probenecid, antivirals, chemotherapy, injected antibiotics, medicine for bowel disorders, medicine to prevent organ transplant rejection, injectable osteoporosis medication, and some pain or arthritis medicines (including aspirin, Tylenol, Advil, and Aleve).
Other drugs may interact with Zyvir, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.
Q: I am in stage 1 of multiple myeloma. I was diagnosed nearly 3 years ago. The last 3 summers I have had attacks of shingles, the 1st year I took 1000 mg of Zyvir daily and avoided the painful stage. Last year I missed the spots as they were on my back and suffered greatly for 2 to 3 months and I am still taking 1000 mg Zyvir per day. Each time I stop the medication the fever returns for a couple of days followed by the first few spots. I am on my 5th lot of Zyvir, starting with 1000 mg per day, increasing to 2,400 per day and 2 weeks ago was prescribed 4000 mg per day for 21 days. I have managed 10 days at this level but there are so many side effects, including kidney pain, so I have reduced to 3 tablets of 800 mg each. I feel less "in a fog" and slightly better already but am afraid when I stop the shingles will return. I am concerned about the side effects. Can you give me advice please? The side effects are basically 90% of the ones mentioned on the leaflet in the box of 800 mg tablets at 5 per day.
A: Shingles is a painful rash that is caused by the same virus (varicella virus) that causes the chickenpox. Only people who were infected with the virus and got chickenpox can get shingles. Unfortunately, people with weakened immune systems, from other diseases like cancer or treatments like chemotherapy, are at much greater risk of developing shingles. Drugs like Zyvir (Zovirax) work to reduce the ability of the virus to multiply and spread in the body. Zyvir has been shown to reduce the duration of infection and the severity of symptoms, but it relies on an individual's immune system to attack the virus. The drug itself does not kill the virus and that is likely the reason you continue to have symptoms and relapses. It is possible that some of the painful effects you are experiencing are the result of complications of shingles. One of these complications is called postherpetic neuralgia, which is the painful, tingling, and stinging pain at the site of the initial rash. There are medications that are used to help treat the pain associated with the nerve damage of shingles. These drugs include the anticonvulsants, such as Neurontin (gabapentin), Lyrica (pregabalin), and Tegretol (carbamazepine) and tricyclic antidepressants like Elavil (amitriptyline). For more specific information, consult with your doctor or pharmacist for guidance based on your health status and current medications, particularly before taking any action. Michelle McDermott, PharmD
Q: Does Zyvir affect kidney disease?
A: Zyvir (Zovirax) is used to decrease pain and speed the healing of sores or blisters in people who have varicella (chickenpox), herpes zoster (shingles; a rash that can occur in people who have had chickenpox in the past), and first-time or repeat outbreaks of genital herpes (a herpes virus infection that causes sores to form around the genitals and rectum from time to time). Zyvir is also sometimes used to prevent outbreaks of genital herpes in people who are infected with the virus. Zyvir is in a class of antiviral medications called synthetic nucleoside analogues. Dosage adjustment is recommended when administering Zyvir to patients with renal impairment. For more specific information, consult with your doctor or pharmacist for guidance based on your health status and current medications, particularly before taking any action. Shereen Gharbia, PharmD
Carcinogenesis, Mutagenesis, Impairment of Fertility
The data presented below include references to peak steady-state plasma Zyvir concentrations observed in humans treated with 800 mg given orally 5 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally 5 times a day (dosing appropriate for treatment of genital herpes). Plasma drug concentrations in animal studies are expressed as multiples of human exposure to Zyvir at the higher and lower dosing schedules (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
Zyvir was tested in lifetime bioassays in rats and mice at single daily doses of up to 450 mg/kg administered by gavage. There was no statistically significant difference in the incidence of tumors between treated and control animals, nor did Zyvir shorten the latency of tumors. Maximum plasma concentrations were 3 to 6 times human levels in the mouse bioassay and 1 to 2 times human levels in the rat bioassay.
Zyvir was tested in 16 in vitro and in vivo genetic toxicity assays. Zyvir was positive in 5 of the assays.
Zyvir did not impair fertility or reproduction in mice (450 mg/kg/day, p.o.) or in rats (25 mg/kg/day, s.c.). In the mouse study, plasma levels were 9 to 18 times human levels, while in the rat study, they were 8 to 15 times human levels. At higher doses (50 mg/kg/day, s.c.) in rats and rabbits (11 to 22 and 16 to 31 times human levels, respectively) implantation efficacy, but not litter size, was decreased. In a rat peri- and post-natal study at 50 mg/kg/day, s.c., there was a statistically significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses.
No testicular abnormalities were seen in dogs given 50 mg/kg/day, IV for 1 month (21 to 41 times human levels) or in dogs given 60 mg/kg/day orally for 1 year (6 to 12 times human levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.