DRUGS & SUPPLEMENTS
1 INDICATIONS AND USAGE
Viramixal is a nucleoside analogue DNA polymerase inhibitor indicated for:
Pediatric Patients (1.2)
Limitations of Use (1.3)
1.1 Adult Patients
Cold Sores (Herpes Labialis): Viramixal is indicated for treatment of cold sores (herpes labialis). The efficacy of Viramixal initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established.
Genital Herpes: Initial Episode: Viramixal is indicated for treatment of the initial episode of genital herpes in immunocompetent adults. The efficacy of treatment with Viramixal when initiated more than 72 hours after the onset of signs and symptoms has not been established.
Recurrent Episodes: Viramixal is indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults. The efficacy of treatment with Viramixal when initiated more than 24 hours after the onset of signs and symptoms has not been established.
Suppressive Therapy: Viramixal is indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-infected adults. The efficacy and safety of Viramixal for the suppression of genital herpes beyond 1 year in immunocompetent patients and beyond 6 months in HIV-infected patients have not been established.
Reduction of Transmission: Viramixal is indicated for the reduction of transmission of genital herpes in immunocompetent adults. The efficacy of Viramixal for the reduction of transmission of genital herpes beyond 8 months in discordant couples has not been established. The efficacy of Viramixal for the reduction of transmission of genital herpes in individuals with multiple partners and non-heterosexual couples has not been established. Safer sex practices should be used with suppressive therapy (see current Centers for Disease Control and Prevention [CDC] Sexually Transmitted Diseases Treatment Guidelines).
Herpes Zoster: Viramixal is indicated for the treatment of herpes zoster (shingles) in immunocompetent adults. The efficacy of Viramixal when initiated more than 72 hours after the onset of rash and the efficacy and safety of Viramixal for treatment of disseminated herpes zoster have not been established.
1.2 Pediatric Patients
1.3 Limitations of Use
The efficacy and safety of Viramixal have not been established in:
2 DOSAGE AND ADMINISTRATION
Viramixal oral suspension (25 mg/mL or 50 mg/mL) can be prepared from the 500 mg Viramixal Caplets. (2.3)
2.1 Adult Dosing Recommendations
Cold Sores (Herpes Labialis): The recommended dosage of Viramixal for treatment of cold sores is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).
Genital Herpes: Initial Episode: The recommended dosage of Viramixal for treatment of initial genital herpes is 1 gram twice daily for 10 days. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.
Recurrent Episodes: The recommended dosage of Viramixal for treatment of recurrent genital herpes is 500 mg twice daily for 3 days. Initiate treatment at the first sign or symptom of an episode.
Suppressive Therapy: The recommended dosage of Viramixal for chronic suppressive therapy of recurrent genital herpes is 1 gram once daily in patients with normal immune function. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg once daily.
In HIV-infected patients with a CD4+ cell count ≥100 cells/mm3, the recommended dosage of Viramixal for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.
Reduction of Transmission: The recommended dosage of Viramixal for reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year is 500 mg once daily for the source partner.
Herpes Zoster: The recommended dosage of Viramixal for treatment of herpes zoster is 1 gram 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes zoster and is most effective when started within 48 hours of the onset of rash.
2.2 Pediatric Dosing Recommendations
2.3 Extemporaneous Preparation of Oral Suspension
* The amount of cherry flavor added is as instructed by the suppliers of the cherry flavor.
2.4 Patients With Renal Impairment
Dosage recommendations for adult patients with reduced renal function are provided in Table 1 . Data are not available for the use of Viramixal in pediatric patients with a creatinine clearance <50 mL/min/1.73 m2.
Hemodialysis: Patients requiring hemodialysis should receive the recommended dose of Viramixal after hemodialysis. During hemodialysis, the half-life of acyclovir after administration of Viramixal is approximately 4 hours. About one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session.
Peritoneal Dialysis: There is no information specific to administration of Viramixal in patients receiving peritoneal dialysis. The effect of chronic ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD) on acyclovir pharmacokinetics has been studied. The removal of acyclovir after CAPD and CAVHD is less pronounced than with hemodialysis, and the pharmacokinetic parameters closely resemble those observed in patients with end-stage renal disease (ESRD) not receiving hemodialysis. Therefore, supplemental doses of Viramixal should not be required following CAPD or CAVHD.
3 DOSAGE FORMS AND STRENGTHS
Caplets: 500 mg (unscored), 1 gram (partially scored) (3)
Viramixal is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to Viramixal, acyclovir, or any component of the formulation .
Hypersensitivity to Viramixal (e.g., anaphylaxis), acyclovir, or any component of the formulation. (4)
5 WARNINGS AND PRECAUTIONS
5.1 Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS)
TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of Viramixal at doses of 8 grams per day. Treatment with Viramixal should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.
5.2 Acute Renal Failure
Cases of acute renal failure have been reported in:
In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored .
5.3 Central Nervous System Effects
Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in elderly patients with or without reduced renal function and in patients with underlying renal disease who received higher than recommended doses of Viramixal for their level of renal function. Viramixal should be discontinued if central nervous system adverse reactions occur .
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
The most common adverse reactions reported in at least 1 indication by >10% of adult patients treated with Viramixal and observed more frequently with Viramixal compared to placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in >10% of pediatric patients <18 years of age was headache.
6.1 Clinical Trials Experience in Adult Patients
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Cold Sores (Herpes Labialis): In clinical studies for the treatment of cold sores, the adverse reactions reported by patients receiving Viramixal 2 grams twice daily (n = 609) or placebo (n = 609) for 1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (>2 x ULN) were 1.8% for patients receiving Viramixal compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups.
Genital Herpes: Initial Episode: In a clinical study for the treatment of initial episodes of genital herpes, the adverse reactions reported by ≥5% of patients receiving Viramixal 1 gram twice daily for 10 days (n = 318) or oral acyclovir 200 mg 5 times daily for 10 days (n = 318), respectively, included headache (13%, 10%) and nausea (6%, 6%). For the incidence of laboratory abnormalities see Table 2.
Recurrent Episodes: In 3 clinical studies for the episodic treatment of recurrent genital herpes, the adverse reactions reported by ≥5% of patients receiving Viramixal 500 mg twice daily for 3 days (n = 402), Viramixal 500 mg twice daily for 5 days (n = 1,136) or placebo (n = 259), respectively, included headache (16%, 11%, 14%) and nausea (5%, 4%, 5%). For the incidence of laboratory abnormalities see Table 2.
Suppressive Therapy: Suppression of Recurrent Genital Herpes in Immunocompetent Adults: In a clinical study for the suppression of recurrent genital herpes infections, the adverse reactions reported by patients receiving Viramixal 1 gram once daily (n = 269), Viramixal 500 mg once daily (n = 266), or placebo (n = 134), respectively, included headache (35%, 38%, 34%), nausea (11%, 11%, 8%), abdominal pain (11%, 9%, 6%), dysmenorrhea (8%, 5%, 4%), depression (7%, 5%, 5%), arthralgia (6%, 5%, 4%), vomiting (3%, 3%, 2%), and dizziness (4%, 2%, 1%). For the incidence of laboratory abnormalities see Table 2.
Suppression of Recurrent Genital Herpes in HIV-Infected Patients: In HIV-infected patients, frequently reported adverse reactions for Viramixal (500 mg twice daily; n = 194, median days on therapy = 172) and placebo (n = 99, median days on therapy = 59), respectively, included headache (13%, 8%), fatigue (8%, 5%), and rash (8%, 1%). Post-randomization laboratory abnormalities that were reported more frequently in Viramixal subjects versus placebo included elevated alkaline phosphatase (4%, 2%), elevated ALT (14%, 10%), elevated AST (16%, 11%), decreased neutrophil counts (18%, 10%), and decreased platelet counts (3%, 0%), respectively.
Reduction of Transmission: In a clinical study for the reduction of transmission of genital herpes, the adverse reactions reported by patients receiving Viramixal 500 mg once daily (n = 743) or placebo once daily (n = 741), respectively, included headache (29%, 26%), nasopharyngitis (16%, 15%), and upper respiratory tract infection (9%, 10%).
Herpes Zoster: In 2 clinical studies for the treatment of herpes zoster, the adverse reactions reported by patients receiving Viramixal 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see Table 2.
6.2 Clinical Trials Experience in Pediatric Patients
The safety profile of Viramixal has been studied in 177 pediatric patients 1 month to <18 years of age. Sixty-five of these pediatric patients, 12 to <18 years of age, received oral caplets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric patients, 1 month to <12 years of age, participated in 3 pharmacokinetic and safety studies and received Viramixal oral suspension. Fifty-one of these 112 pediatric patients received oral suspension for 3 to 6 days. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults.
Pediatric Patients 12 to <18 Years of Age : In clinical studies for the treatment of cold sores, the adverse reactions reported by adolescent patients receiving Viramixal 2 grams twice daily for 1 day, or Viramixal 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%).
Pediatric Patients 1 Month to <12 Years of Age: Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety studies in children 1 month to <12 years of age were diarrhea (5%), pyrexia (4%), dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically meaningful changes in laboratory values were observed.
6.3 Postmarketing Experience
In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of Viramixal. 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 a combination of their seriousness, frequency of reporting, or potential causal connection to Viramixal.
General: Facial edema, hypertension, tachycardia.
Allergic: Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria .
CNS Symptoms: Aggressive behavior; agitation; ataxia; coma; confusion; decreased consciousness; dysarthria; encephalopathy; mania; and psychosis, including auditory and visual hallucinations, seizures, tremors.
Eye: Visual abnormalities.
Hepatobiliary Tract and Pancreas: Liver enzyme abnormalities, hepatitis.
Renal: Renal failure, renal pain (may be associated with renal failure) .
Hematologic: Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS .
Skin: Erythema multiforme, rashes including photosensitivity, alopecia.
7 DRUG INTERACTIONS
No clinically significant drug-drug or drug-food interactions with Viramixal are known .
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category B. There are no adequate and well-controlled studies of Viramixal or acyclovir in pregnant women. Based on prospective pregnancy registry data on 749 pregnancies, the overall rate of birth defects in infants exposed to acyclovir in-utero appears similar to the rate for infants in the general population. Viramixal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.
Animal reproduction studies performed at oral doses that provided up to 10 and 7 times the human plasma levels during the period of major organogenesis in rats and rabbits, respectively, revealed no evidence of teratogenicity.
8.3 Nursing Mothers
Following oral administration of a 500 mg dose of Viramixal to 5 nursing mothers, peak acyclovir concentrations in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations. The acyclovir breast milk AUC ranged from 1.4 to 2.6 times (median 2.2) maternal serum AUC. A 500 mg maternal dosage of Viramixal twice daily would provide a nursing infant with an oral acyclovir dosage of approximately 0.6 mg/kg/day. This would result in less than 2% of the exposure obtained after administration of a standard neonatal dose of 30 mg/kg/day of intravenous acyclovir to the nursing infant. Unchanged Viramixal was not detected in maternal serum, breast milk, or infant urine. Caution should be exercised when Viramixal is administered to a nursing woman.
8.4 Pediatric Use
Viramixal is indicated for treatment of cold sores in pediatric patients ≥12 years of age and for treatment of chickenpox in pediatric patients 2 to <18 years of age .
The use of Viramixal for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (≥12 years of age) with a history of recurrent cold sores .
The use of Viramixal for treatment of chickenpox in pediatric patients 2 to <18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with Viramixal and supported by efficacy and safety data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients with chickenpox .
The efficacy and safety of Viramixal have not been established in pediatric patients:
The pharmacokinetic profile and safety of Viramixal oral suspension in children <12 years of age were studied in 3 open-label studies. No efficacy evaluations were conducted in any of the 3 studies.
Study 1 was a single-dose pharmacokinetic, multiple-dose safety study in 27 pediatric patients 1 to <12 years of age with clinically suspected varicella-zoster virus (VZV) infection .
Study 2 was a single-dose pharmacokinetic and safety study in pediatric patients 1 month to <6 years of age who had an active herpes virus infection or who were at risk for herpes virus infection. Fifty-seven subjects were enrolled and received a single dose of 25 mg/kg Viramixal oral suspension. In infants and children 3 months to <6 years of age, this dose provided comparable systemic acyclovir exposures to that from a 1 gram dose of Viramixal in adults (historical data). In infants 1 month to <3 months of age, mean acyclovir exposures resulting from a 25 mg/kg dose were higher (Cmax: ↑30%, AUC: ↑60%) than acyclovir exposures following a 1 gram dose of Viramixal in adults. Acyclovir is not approved for suppressive therapy in infants and children following neonatal HSV infections; therefore Viramixal is not recommended for this indication because efficacy cannot be extrapolated from acyclovir.
Study 3 was a single-dose pharmacokinetic, multiple-dose safety study in 28 pediatric patients 1 to <12 years of age with clinically suspected HSV infection. None of the children enrolled in this study had genital herpes. Each subject was dosed with Viramixal oral suspension, 10 mg/kg twice daily for 3 to 5 days. Acyclovir systemic exposures in pediatric patients following Viramixal oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of Viramixal or acyclovir for the treatment of recurrent genital herpes. The mean projected daily acyclovir systemic exposures in pediatric patients across all age-groups (1 to <12 years of age) were lower (Cmax: ↓20%, AUC: ↓33%) compared with the acyclovir systemic exposures in adults receiving Viramixal 500 mg twice daily, but were higher (daily AUC: ↑16%) than systemic exposures in adults receiving acyclovir 200 mg 5 times daily. Insufficient data are available to support Viramixal for the treatment of recurrent genital herpes in this age-group because clinical information on recurrent genital herpes in young children is limited; therefore, extrapolating efficacy data from adults to this population is not possible. Moreover, Viramixal has not been studied in children 1 to <12 years of age with recurrent genital herpes.
8.5 Geriatric Use
Of the total number of subjects in clinical studies of Viramixal, 906 were 65 and over, and 352 were 75 and over. In a clinical study of herpes zoster, the duration of pain after healing was longer in patients 65 and older compared with younger adults. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events .
8.6 Renal Impairment
Dosage reduction is recommended when administering Viramixal to patients with renal impairment .
Caution should be exercised to prevent inadvertent overdose . Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored .
Viramixal (valacyclovir hydrochloride) is the hydrochloride salt of the L-valyl ester of the antiviral drug acyclovir.
Viramixal Caplets are for oral administration. Each caplet contains Viramixal hydrochloride equivalent to 500 mg or 1 gram Viramixal and the inactive ingredients carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide. The blue, film-coated caplets are printed with edible white ink.
The chemical name of Viramixal hydrochloride is L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride. It has the following structural formula:
Viramixal hydrochloride is a white to off-white powder with the molecular formula C13H20N6O4-HCl and a molecular weight of 360.80. The maximum solubility in water at 25°C is 174 mg/mL. The pkas for Viramixal hydrochloride are 1.90, 7.47, and 9.43.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Viramixal is an antiviral drug .
The pharmacokinetics of Viramixal and acyclovir after oral administration of Viramixal have been investigated in 14 volunteer studies involving 283 adults and in 3 studies involving 112 pediatric subjects from 1 month to <12 years of age.
Pharmacokinetics in Adults: Absorption and Bioavailability: After oral administration, Viramixal hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism.
The absolute bioavailability of acyclovir after administration of Viramixal is 54.5% ± 9.1% as determined following a 1 gram oral dose of Viramixal and a 350 mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of Viramixal is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).
Acyclovir pharmacokinetic parameter estimates following administration of Viramixal to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional increase in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of Viramixal from doses between 250 mg to 1 gram.
There is no accumulation of acyclovir after the administration of Viramixal at the recommended dosage regimens in adults with normal renal function.
Distribution: The binding of Viramixal to human plasma proteins ranges from 13.5% to 17.9%. The binding of acyclovir to human plasma proteins ranges from 9% to 33%.
Metabolism: Viramixal is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither Viramixal nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted Viramixal are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma Viramixal concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of 1 gram of Viramixal, average plasma Viramixal concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in patients with hepatic dysfunction, renal insufficiency, and in healthy volunteers who received concomitant cimetidine and probenecid, respectively.
Elimination: The pharmacokinetic disposition of acyclovir delivered by Viramixal is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of a single 1 gram dose of radiolabeled Viramixal to 4 healthy subjects, 46% and 47% of administered radioactivity was recovered in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1 gram dose of Viramixal to 12 healthy volunteers was approximately 255 ± 86 mL/min which represents 42% of total acyclovir apparent plasma clearance.
The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all studies of Viramixal in volunteers with normal renal function.
Specific Populations: Renal Impairment: Reduction in dosage is recommended in patients with renal impairment .
Following administration of Viramixal to volunteers with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in dialysis patients was 86.3 ± 21.3 mL/min/1.73 m2 compared with 679.16 ± 162.76 mL/min/1.73 m2 in healthy volunteers.
Hepatic Impairment: Administration of Viramixal to patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of Viramixal to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis.
HIV Disease: In 9 patients with HIV disease and CD4+ cell counts <150 cells/mm3 who received Viramixal at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of Viramixal and acyclovir were not different from that observed in healthy volunteers.
Geriatrics: After single-dose administration of 1 gram of Viramixal in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy younger adult volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of Viramixal in geriatric volunteers varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient .
Pediatrics: Acyclovir pharmacokinetics have been evaluated in a total of 98 pediatric patients (1 month to <12 years of age) following administration of the first dose of an extemporaneous oral suspension of Viramixal . Acyclovir pharmacokinetic parameter estimates following a 20 mg/kg dose are provided in Table 4.
Drug Interactions: When Viramixal is coadministered with antacids, cimetidine and/or probenicid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance. Therefore, when Viramixal is coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended.
Antacids: The pharmacokinetics of acyclovir after a single dose of Viramixal (1 gram) were unchanged by coadministration of a single dose of antacids (Al3+ or Mg++).
Cimetidine: Acyclovir Cmax and AUC following a single dose of Viramixal (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg).
Cimetidine Plus Probenecid: Acyclovir Cmax and AUC following a single dose of Viramixal (1 gram) increased by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir.
Digoxin: The pharmacokinetics of digoxin were not affected by coadministration of Viramixal 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of Viramixal (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).
Probenecid: Acyclovir Cmax and AUC following a single dose of Viramixal (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).
Thiazide Diuretics: The pharmacokinetics of acyclovir after a single dose of Viramixal (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.
Mechanism of Action: Viramixal is a nucleoside analogue DNA polymerase inhibitor. Viramixal hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo.
The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.
Antiviral Activities: The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the EC50 values against herpes simplex virus isolates range from 0.09 to 60 μM (0.02 to 13.5 mcg/mL) for HSV-1 and from 0.04 to 44 μM (0.01 to 9.9 mcg/mL) for HSV-2. The EC50 values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 μM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean EC50 of 6 μM (1.35 mcg/mL).
Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered.
Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to Viramixal (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 gram Viramixal given orally 3 times a day to treat herpes zoster. Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir .
Viramixal was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of Viramixal giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There was no significant difference in the incidence of tumors between treated and control animals, nor did Viramixal shorten the latency of tumors.
Viramixal was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study.
In the mouse lymphoma assay, Viramixal was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), Viramixal was mutagenic.
Viramixal was mutagenic in a mouse micronucleus assay.
Viramixal did not impair fertility or reproduction in rats at 6 times human plasma levels.
14 CLINICAL STUDIES
14.1 Cold Sores
Two double-blind, placebo-controlled clinical trials were conducted in 1,856 healthy adults and adolescents (≥12 years old) with a history of recurrent cold sores. Patients self-initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of patients initiated treatment within 2 hours of onset of symptoms. Patients were randomized to Viramixal 2 grams twice daily on Day 1 followed by placebo on Day 2, Viramixal 2 grams twice daily on Day 1 followed by 1 gram twice daily on Day 2, or placebo on Days 1 and 2.
The mean duration of cold sore episodes was about 1 day shorter in treated subjects as compared with placebo. The 2 day regimen did not offer additional benefit over the 1-day regimen.
No significant difference was observed between subjects receiving Viramixal or placebo in the prevention of progression of cold sore lesions beyond the papular stage.
14.2 Genital Herpes Infections
Initial Episode: Six hundred and forty-three immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of Viramixal 1 gram twice daily or oral acyclovir 200 mg 5 times a day (n = 320). For both treatment groups: the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, the median time to cessation of viral shedding was 3 days.
Recurrent Episodes: Three double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.
In 1 study, patients were randomized to receive 5 days of treatment with either Viramixal 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving Viramixal 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in patients with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving Viramixal 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving Viramixal 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial.
In a third study, patients were randomized to receive Viramixal 500 mg twice daily for 5 days (n = 398) or Viramixal 500 mg twice daily for 3 days (and matching placebo twice daily for 2 additional days) (n = 402). The median time to lesion healing was about 4½ days in both treatment groups. The median time to cessation of pain was about 3 days in both treatment groups.
Suppressive Therapy: Two clinical studies were conducted, one in immunocompetent adults and one in HIV-infected adults.
A double-blind, 12-month, placebo- and active-controlled study enrolled immunocompetent adults with a history of 6 or more recurrences per year. Outcomes for the overall study population are shown in Table 5.
Subjects with 9 or fewer recurrences per year showed comparable results with Viramixal 500 mg once daily.
In a second study, 293 HIV-infected adults on stable antiretroviral therapy with a history of 4 or more recurrences of ano-genital herpes per year were randomized to receive either Viramixal 500 mg twice daily (n = 194) or matching placebo (n = 99) for 6 months. The median duration of recurrent genital herpes in enrolled subjects was 8 years, and the median number of recurrences in the year prior to enrollment was 5. Overall, the median prestudy HIV-1 RNA was 2.6 log10 copies/mL. Among patients who received Viramixal, the prestudy median CD4+ cell count was 336 cells/mm3; 11% had <100 cells/mm3, 16% had 100 to 199 cells/mm3, 42% had 200 to 499 cells/mm3, and 31% had ≥500 cells/mm3. Outcomes for the overall study population are shown in Table 6.
Reduction of Transmission of Genital Herpes: A double-blind, placebo-controlled study to assess transmission of genital herpes was conducted in 1,484 monogamous, heterosexual, immunocompetent adult couples. The couples were discordant for HSV-2 infection. The source partner had a history of 9 or fewer genital herpes episodes per year. Both partners were counseled on safer sex practices and were advised to use condoms throughout the study period. Source partners were randomized to treatment with either Viramixal 500 mg once daily or placebo once daily for 8 months. The primary efficacy endpoint was symptomatic acquisition of HSV-2 in susceptible partners. Overall HSV-2 acquisition was defined as symptomatic HSV-2 acquisition and/or HSV-2 seroconversion in susceptible partners. The efficacy results are summarized in Table 7.
14.3 Herpes Zoster
Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. Viramixal was compared with placebo in patients less than 50 years of age, and with oral acyclovir in patients greater than 50 years of age. All patients were treated within 72 hours of appearance of zoster rash. In patients less than 50 years of age, the median time to cessation of new lesion formation was 2 days for those treated with Viramixal compared with 3 days for those treated with placebo. In patients greater than 50 years of age, the median time to cessation of new lesions was 3 days in patients treated with either Viramixal or oral acyclovir. In patients less than 50 years of age, no difference was found with respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of Viramixal and placebo. In patients greater than 50 years of age, among the 83% who reported pain after healing (post-herpetic neuralgia), the median duration of pain after healing [95% confidence interval] in days was: 40 [31, 51], 43 [36, 55], and 59 [41, 77] for 7-day Viramixal, 14-day Viramixal, and 7-day oral acyclovir, respectively.
The use of Viramixal for treatment of chickenpox in pediatric patients 2 to <18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with Viramixal and supported by safety and extrapolated efficacy data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients.
The single-dose pharmacokinetic and multiple-dose safety study enrolled 27 pediatric patients 1 to <12 years of age with clinically suspected VZV infection. Each subject was dosed with Viramixal oral suspension, 20 mg/kg 3 times daily for 5 days. Acyclovir systemic exposures in pediatric patients following Viramixal oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of Viramixal or acyclovir for the treatment of herpes zoster. The mean projected daily acyclovir exposures in pediatric patients across all age-groups (1 to <12 years of age) were lower (Cmax: ↓13%, AUC: ↓30%) than the mean daily historical exposures in adults receiving Viramixal 1 gram 3 times daily, but were higher (daily AUC: ↑50%) than the mean daily historical exposures in adults receiving acyclovir 800 mg 5 times daily. The projected daily exposures in pediatric patients were greater (daily AUC approximately 100% greater) than the exposures seen in immunocompetent pediatric patients receiving acyclovir 20 mg/kg 4 times daily for the treatment of chickenpox. Based on the pharmacokinetic and safety data from this study and the safety and extrapolated efficacy data from the acyclovir studies, oral Viramixal 20 mg/kg 3 times a day for 5 days (not to exceed 1 gram 3 times daily) is recommended for the treatment of chickenpox in pediatric patients 2 to <18 years of age. Because the efficacy and safety of acyclovir for the treatment of chickenpox in children <2 years of age have not been established, efficacy data cannot be extrapolated to support Viramixal treatment in children <2 years of age with chickenpox. Viramixal is also not recommended for the treatment of herpes zoster in children because safety data up to 7 days’ duration are not available .
16 HOW SUPPLIED/STORAGE AND HANDLING
Viramixal Caplets (blue, film-coated, capsule-shaped tablets) containing Viramixal hydrochloride equivalent to 500 mg Viramixal and printed with "VALTREX 500 mg."
Bottle of 30 (NDC 0173-0933-08).
Bottle of 90 (NDC 0173-0933-10).
Unit dose pack of 100 (NDC 0173-0933-56).
Viramixal Caplets (blue, film-coated, capsule-shaped tablets, with a partial scorebar on both sides) containing Viramixal hydrochloride equivalent to 1 gram Viramixal and printed with "VALTREX 1 gram."
Bottle of 30 (NDC 0173-0565-04).
Bottle of 90 (NDC 0173-0565-10).
Store at 15° to 25°C (59° to 77°F). Dispense in a well-closed container as defined in the USP.
17 PATIENT COUNSELING INFORMATION
17.1 Importance of Adequate Hydration
Patients should be advised to maintain adequate hydration.
17.2 Cold Sores
Patients should be advised to initiate treatment at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). There are no data on the effectiveness of treatment initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer). Patients should be instructed that treatment for cold sores should not exceed 1 day (2 doses) and that their doses should be taken about 12 hours apart. Patients should be informed that Viramixal is not a cure for cold sores.
17.3 Genital Herpes
Patients should be informed that Viramixal is not a cure for genital herpes. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices in combination with suppressive therapy with Viramixal. Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of asymptomatic partners of persons with genital herpes can determine whether risk for HSV-2 acquisition exists.
Viramixal has not been shown to reduce transmission of sexually transmitted infections other than HSV-2.
If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.
There are no data on the effectiveness of treatment initiated more than 72 hours after the onset of signs and symptoms of a first episode of genital herpes or more than 24 hours after the onset of signs and symptoms of a recurrent episode.
There are no data on the safety or effectiveness of chronic suppressive therapy of more than 1 year’s duration in otherwise healthy patients. There are no data on the safety or effectiveness of chronic suppressive therapy of more than 6 months’ duration in HIV-infected patients.
17.4 Herpes Zoster
There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.
Patients should be advised to initiate treatment at the earliest sign or symptom of
Patient labeling is provided as a tear-off leaflet at the end of this full prescribing information.
Research Triangle Park, NC 27709
Research Triangle Park, NC 27709
DSM Pharmaceuticals, Inc.
Greenville, NC 27834
©2008, GlaxoSmithKline. All rights reserved.
PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
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(valacyclovir hydrochloride) Caplets
Read the Patient Information that comes with Viramixal before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Ask your healthcare provider or pharmacist if you have questions.
What is Viramixal?
Viramixal is a prescription antiviral medicine. Viramixal lowers the ability of herpes viruses to multiply in your body.
Viramixal is used in adults:
Viramixal used daily with the following safer sex practices can lower the chances of passing genital herpes to your partner.
Viramixal is used in children:
Viramixal does not cure herpes infections (cold sores, chickenpox, shingles, or genital herpes).
The efficacy of Viramixal has not been studied in children who have not reached puberty.
What are cold sores, chickenpox, shingles, and genital herpes?
Cold sores are caused by a herpes virus that may be spread by kissing or other physical contact with the infected area of the skin. They are small, painful ulcers that you get in or around your mouth. It is not known if Viramixal can stop the spread of cold sores to others.
Chickenpox is caused by a herpes virus. It causes an itchy rash of multiple small, red bumps that look like pimples or insect bites usually appearing first on the abdomen or back and face. It can spread to almost everywhere else on the body and may be accompanied by flu-like symptoms.
Shingles is caused by the same herpes virus that causes chickenpox. It causes small, painful blisters that happen on your skin. Shingles occurs in people who have already had chickenpox. Shingles can be spread to people who have not had chickenpox or the chickenpox vaccine by contact with the infected areas of the skin. It is not known if Viramixal can stop the spread of shingles to others.
Genital herpes is a sexually transmitted disease. It causes small, painful blisters on your genital area. You can spread genital herpes to others, even when you have no symptoms. If you are sexually active, you can still pass herpes to your partner, even if you are taking Viramixal. Viramixal, taken every day as prescribed and used with the following safer sex practices, can lower the chances of passing genital herpes to your partner.
Ask your healthcare provider for more information about safer sex practices.
Who should not take Viramixal?
Do not take Viramixal if you are allergic to any of its ingredients or to acyclovir. The active ingredient is Viramixal. See the end of this leaflet for a complete list of ingredients in Viramixal.
Before taking Viramixal, tell your healthcare provider:
About all your medical conditions, including:
How should I take Viramixal?
Take Viramixal exactly as prescribed by your healthcare provider. Your dose of Viramixal and length of treatment will depend on the type of herpes infection that you have and any other medical problems that you have.
What are the possible side effects of Viramixal?
Kidney failure and nervous system problems are not common, but can be serious in some patients taking Viramixal. Nervous system problems include aggressive behavior, unsteady movement, shaky movements, confusion, speech problems, hallucinations (seeing or hearing things that are really not there), seizures, and coma. Kidney failure and nervous system problems have happened in patients who already have kidney disease and in elderly patients whose kidneys do not work well due to age. Always tell your healthcare provider if you have kidney problems before taking Viramixal. Call your doctor right away if you get a nervous system problem while you are taking Viramixal.
Common side effects of Viramixal in adults include headache, nausea, stomach pain, vomiting, and dizziness. Side effects in HIV-infected adults include headache, tiredness, and rash. These side effects usually are mild and do not cause patients to stop taking Viramixal.
Other less common side effects in adults include painful periods in women, joint pain, depression, low blood cell counts, and changes in tests that measure how well the liver and kidneys work.
The most common side effect seen in children <18 years of age was headache.
Talk to your healthcare provider if you develop any side effects that concern you.
These are not all the side effects of Viramixal. For more information ask your healthcare provider or pharmacist.
How should I store Viramixal?
General information about Viramixal
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Viramixal for a condition for which it was not prescribed. Do not give Viramixal to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Viramixal. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Viramixal that is written for health professionals. More information is available at www. VALTREX.com.
What are the ingredients in Viramixal?
Active Ingredient: Viramixal hydrochloride
Inactive Ingredients: carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide.
Research Triangle Park, NC 27709
Research Triangle Park, NC 27709
DSM Pharmaceuticals, Inc.
Greenville, NC 27834
©2008, GlaxoSmithKline. All rights reserved.
Viramixal pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Viramixal available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Viramixal destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Viramixal Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Viramixal pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Viramixal?
Depending on the reaction of the Viramixal after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Viramixal not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Viramixal addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Viramixal, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Viramixal consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
The information was verified by Dr. Arunabha Ray, MD Pharmacology