Mechanism of Antiviral Action:
Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV) both in vitro 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 vitro, acyclovir triphosphate stops 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.
3) Inactivation of the viral DNA polymerase.
The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK.
After oral administration, valacyclovir 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.
Absorption and Bioavailability: The absolute bioavailability of acyclovir after administration of EXONELLA is 54.5% ± 9.1% as determined following a 1-gram oral dose of EXONELLA to 12 healthy volunteers. Acyclovir bioavailability from the administration of EXONELLA is not altered by administration with food.
There was a lack of dose proportionality in acyclovir maximum concentration (C max ) and area under the acyclovir concentration-time curve (AUC) after single-dose administration of 100 mg, 250 mg, 500 mg, 750 mg, and 1 gram of EXONELLA to 8 healthy volunteers.
There was also a lack of dose proportionality in acyclovir C max and AUC after the multiple-dose administration of 250 mg, 500 mg, and 1 gram of EXONELLA administered 4 times daily for 11 days in parallel groups of 8 healthy volunteers.
There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in healthy volunteers with normal renal function.
Distribution: The binding of valacyclovir to human plasma proteins ranged from 13.5% to 17.9%.
Metabolism: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract. Valacyclovir 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. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of 1 gram of valacyclovir, average plasma valacyclovir 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 plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours with normal renal function.
End-Stage Renal Disease (ESRD): Following administration of EXONELLA 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 to 679.16 ± 162.76 mL/min/1.73 m2 in healthy volunteers.
Reduction in dosage is recommended in patients with renal impairment.
Geriatrics: After single-dose administration of 1 gram of EXONELLA in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared to 2.91 ± 0.63 hours in healthy volunteers. Dosage reduction may be necessary in geriatric patients with reduced renal function.
Pediatrics: Valacyclovir pharmacokinetics have not been evaluated in pediatric patients.
Liver Disease: Administration of EXONELLA 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 valacyclovir 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 advanced HIV disease who received EXONELLA at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy volunteers.
Drug Interactions: The pharmacokinetics of digoxin was not affected by coadministration of EXONELLA 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of EXONELLA (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg), single doses of antacids (Al 3+ or Mg ++ ), or multiple doses of thiazide diuretics. Acyclovir C max and AUC following a single dose of EXONELLA (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg), or by 22% and 49%, respectively, after probenecid (1 gram), or by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir. These effects are not considered to be of clinical significance in subjects with normal renal function.
Therefore, no dosage adjustment is recommended when EXONELLA is coadministered with digoxin, antacids, thiazide diuretics, cimetidine, or probenecid in subjects with normal renal function.
INDICATIONS AND USAGE:
Herpes Zoster: EXONELLA is indicated for the treatment of herpes zoster (shingles).
Genital Herpes: EXONELLA is indicated for the treatment or suppression of genital herpes in immunocompetent individuals and for the suppression of recurrent genital herpes in HIV-infected individuals.
When EXONELLA is used as suppressive therapy in immunocompetent individuals with genital herpes, the risk of heterosexual transmission to susceptible partners is reduced. Safer sex practices should be used with suppressive therapy.
Cold Sores (Herpes Labialis): EXONELLA is indicated for the treatment of cold sores (herpes labialis).
EXONELLA is contraindicated in patients with a known hypersensitivity or intolerance to valacyclovir, acyclovir, or any component of the formulation.
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (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 valacyclovir at doses of 8 grams per day.
Dosage reduction is recommended when administering EXONELLA to patients with renal impairment. Similar caution should be exercised when administering EXONELLA to geriatric patients and patients receiving potentially nephrotoxic agents.
Given the dosage recommendations for treatment of cold sores, special attention should be paid when prescribing EXONELLA for cold sores in patients who are elderly or who have impaired renal function. Treatment should not exceed 1 day (2 doses of 2 grams in 24 hours). Therapy beyond 1 day does not provide additional clinical benefit.
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.
The safety and efficacy of EXONELLA have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients. The safety and efficacy of EXONELLA for suppression of recurrent genital herpes in patients with advanced HIV disease have not been established. The efficacy of EXONELLA for the treatment of genital herpes in HIV-infected patients has not been established. The safety and efficacy of EXONELLA have not been established for the treatment of disseminated herpes zoster.
The efficacy of EXONELLA for reducing transmission of genital herpes has not been established in individuals with multiple partners and non-heterosexual couples.
Information for Patients:
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.
Genital Herpes: Patients should be informed that EXONELLA 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 EXONELLA. 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 with genital herpes can determine whether risk for HSV-2 acquisition exists.
EXONELLA 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 of 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 month' duration in HIV-infected patients.
Cold Sores (Herpes Labialis): Patients should be advised to initiate treatment at the earliest symptom of a cold sore (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 EXONELLA is not a cure for cold sores (herpes labialis).
Pregnancy: EXONELLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: EXONELLA should be administered to a nursing mother with caution and only when indicated.
Pediatric Use: Safety and effectiveness of EXONELLA in pre-pubertal pediatric patients have not been established.
Geriatric Use: 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. With respect to CNS adverse events observed during clinical practice, agitation, hallucinations, confusion, delirium, and encephalopathy were reported more frequently in elderly patients.
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: Elevated creatinine, renal failure.
Hematologic: Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis.
Skin: Erythema multiforme, rashes including photosensitivity, alopecia.
Renal Impairment: Renal failure and CNS symptoms have been reported in patients with renal impairment who received valacyclovir or acyclovir at greater than the recommended dose.
DOSAGE AND ADMINISTRATION:
EXONELLA film coated tablets may be given without regard to meals.
Herpes Zoster: The recommended dosage of EXONELLA for the treatment of herpes zoster is 1 gram orally 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 zoster rash. No data are available on efficacy of treatment started greater than 72 hours after rash onset.
Genital Herpes: Initial Episodes: The recommended dosage of EXONELLA for treatment of initial genital herpes is 1 gram twice daily for 10 days.
There are no data on the effectiveness of treatment with EXONELLA when initiated more than 72 hours after the onset of signs and symptoms. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.
Recurrent Episodes: The recommended dosage of EXONELLA for treatment of recurrent genital herpes is 500 gram twice daily for 3 days.
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 with EXONELLA when initiated more than 24 hours after the onset of signs or symptoms.
Suppressive Therapy: The recommended dosage of EXONELLA for chronic suppressive therapy of recurrent genital herpes is 1 gram once daily. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg once daily. The safety and efficacy of therapy with EXONELLA beyond 1 year have not been established.
In HIV-infected patients, the recommended dosage of EXONELLA for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily. The safety and efficacy of therapy with EXONELLA beyond 6 months in patients with HIV infection have not been established.
Reduction of Transmission: The recommended dosage of EXONELLA 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. Patients should be counseled to use safer sex practices in combination with suppressive therapy with EXONELLA. The efficacy of reducing transmission beyond 8 months in discordant couples has not been established.
Cold Sores (Herpes Labialis): The recommended dosage of EXONELLA for the treatment of cold sores is 2 grams twice daily for 1 day taken about 12 hours apart. Therapy should be initiated 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 with Acute or Chronic Renal Impairment: In patients with reduced renal function, reduction in dosage is recommended.
Hemodialysis: During hemodialysis, the half-life of acyclovir after administration of EXONELLA is approximately 4 hours. About one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Patients requiring hemodialysis should receive the recommended dose of EXONELLA after hemodialysis.
Peritoneal Dialysis: There is no information specific to administration of EXONELLA 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 ESRD ( End-Stage Renal Disease ) not receiving hemodialysis. Therefore, supplemental doses of EXONELLA should not be required following CAPD or CAVHD.
Boxes of 20 film coated tablets.
Store at 15° to 25°C.