Valtrex

Valaciclovir HCl.

Pharmacology: Pharmacodynamics: Mechanism of Action: Valaciclovir, an antiviral, is the L-valine ester of aciclovir. Aciclovir is a purine (guanine) nucleoside analogue.
Valaciclovir is rapidly and almost completely converted in man to aciclovir and valine, probably by the enzyme referred to as valaciclovir hydrolase.
Aciclovir is a specific inhibitor of the herpes viruses with in vitro activity against herpes simplex viruses (HSV) types 1 and 2, varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpes virus 6 (HHV-6). Aciclovir inhibits herpes virus deoxyribonucleic acid (DNA) synthesis once it has been phosphorylated to the active triphosphate form.
The 1st stage of phosphorylation requires the activity of a virus-specific enzyme. In the case of HSV, VZV and EBV, this enzyme is the viral thymidine kinase (TK) which is only present in virus-infected cells. Selectivity is maintained in CMV with phosphorylation, at least in part, being mediated through the phosphotransferase gene product of UL97. This requirement for activation of aciclovir by a virus-specific enzyme largely explains its selectivity.
The phosphorylation process is completed (conversion from mono- to triphosphate) by cellular kinases. Aciclovir triphosphate competitively inhibits the virus DNA polymerase and incorporation of this nucleoside analogue result in obligate chain termination, halting virus deoxyribonucleic acid (DNA) synthesis and thus blocking virus replication.
Pharmacodynamic Effects: Resistance is normally due to a thymidine kinase-deficient phenotype which results in a virus that is profoundly disadvantaged in the natural host. Infrequently, reduced sensitivity to aciclovir has been described as a result of subtle alterations in either the virus thymidine kinase or DNA polymerase. The virulence of these variants resembles that of the wild-type virus.
Extensive monitoring of clinical HSV and VZV isolates from patients receiving aciclovir therapy or prophylaxis has revealed that the virus with reduced sensitivity to aciclovir is extremely rare in the immunocompetent and is only found infrequently in severely immunocompromised individuals eg, organ or bone marrow transplant recipients, patients receiving chemotherapy for malignant disease and people infected with the human immunodeficiency virus (HIV).
Pharmacokinetics: Absorption: After oral administration, valaciclovir is well-absorbed and rapidly, almost completely, converted to aciclovir and valine. This conversion is probably mediated by an enzyme isolated from human liver referred to as valaciclovir hydrolase.
The bioavailability of aciclovir from valaciclovir 1000 mg is 54% and is not reduced by food. Valaciclovir pharmacokinetics are not dose-proportional. The rate and extent of absorption decrease with increasing dose, resulting in a less than proportional increase in peak plasma concentration (C_max) over the therapeutic dose range and a reduced bioavailability at doses >500 mg. Mean peak aciclovir concentrations are 10-37 micromoles (2.2-8.3 mcg/mL) following single doses of valaciclovir 250-2000 mg to healthy subjects with normal renal function, and occur at a median time of 1-2 hrs post-dose.
Peak plasma concentrations of valaciclovir are only 4% of aciclovir levels, occurring at a median time of 30-100 min post-dose and are at or below the limit of quantification 3 hrs after dosing. The valaciclovir and aciclovir pharmacokinetic profiles are similar after single and repeat dosing.
Herpes zoster and herpes simplex do not significantly alter the pharmacokinetics of valaciclovir and aciclovir after oral administration of valaciclovir.
Distribution: Binding of valaciclovir to plasma proteins is very low (15%). Cerebrospinal fluid (CSF) penetration, determined by CSF/plasma area under the concentration-time curve (AUC) ratio, is about 25% for aciclovir and the metabolite 8-hydroxy-aciclovir (8-OH-ACV), and about 2.5% for the metabolite 9-(carboxymethoxy)methylguanine (CMMG) (see Special Patient Populations as follows).
Metabolism: After oral administration, valaciclovir is converted to aciclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Aciclovir is converted to a small extent to the metabolites 9-CMMG by alcohol and aldehyde dehydrogenase and to 8-OH-ACV by aldehyde oxidase. Approximately 88% of the total combined plasma exposure is attributable to aciclovir, 11% to CMMG and 1% to 8-OH-ACV. Neither valaciclovir nor aciclovir is metabolized by cytochrome P-450 enzymes.
Elimination: In patients with normal renal function, the plasma elimination t_½ of aciclovir after both single and multiple dosing with valaciclovir is approximately 3 hrs. Less than 1% of the administered dose of valaciclovir is recovered in the urine as unchanged drug. Valaciclovir is eliminated in the urine principally as aciclovir (>80% of the recovered dose) and the known aciclovir metabolite, 9-CMMG.
Special Patient Populations: Renal Impairment: The elimination of aciclovir is correlated to renal function and exposure to aciclovir will increase with increased renal impairment. In patients with end-stage renal disease, the average elimination t_½ of aciclovir after Valtrex administration is approximately 14 hrs, compared with about 3 hrs for normal renal function (see Dosage & Administration).
Exposure to aciclovir and its metabolites CMMG and 8-OH-ACV in plasma and CSF was evaluated at steady state after multiple-dose valaciclovir administration in 6 subjects with normal renal function [mean creatinine clearance (CrCl) of 111 mL/min, range: 91-144 mL/min] receiving 2000 mg every 6 hrs and 3 subjects with severe renal impairment (mean CrCl of 26 mL/min, range: 17-31 mL/min) receiving 1500 mg every 12 hrs.
In plasma, as well as CSF, concentrations of aciclovir, CMMG and 8-OH-ACV were on average 2, 4 and 5-6 times higher, respectively, in severe renal impairment compared with normal renal function. There was no difference in the extent of CSF penetration (as determined by CSF/plasma AUC ratio) for aciclovir, CMMG and 8-OH-ACV between the 2 populations (see Distribution as previously mentioned).
Hepatic Impairment: Pharmacokinetic data indicate that hepatic impairment decreases the rate of conversion of valaciclovir to aciclovir but not the extent of conversion. Aciclovir t_½ is not affected.
Pregnant Women: In a study of the pharmacokinetics of valaciclovir and aciclovir during late pregnancy, the steady state daily aciclovir AUC following valaciclovir 1000 mg daily was approximately 2 times greater than that observed with oral aciclovir at 1200 mg daily.
See Use in lactation under Precautions for information on transfer into breast milk.
HIV Infection: In patients with HIV infection, the disposition and pharmacokinetic characteristics of aciclovir after oral administration of single or multiple doses of valaciclovir 1000 mg or 2000 mg are unaltered compared with healthy subjects.
Organ Transplantation: In transplant recipients receiving valaciclovir 2000 mg 4 times daily, aciclovir peak concentrations are similar to or greater than those in healthy volunteers receiving the same dose. The estimated daily AUCs are appreciably greater.
Toxicology: Preclinical Safety Data: The results of mutagenicity tests in vitro and in vivo indicate that valaciclovir is unlikely to pose a genetic risk to humans.
Valaciclovir was not carcinogenic in bioassays performed in mice and rats.
Valaciclovir did not affect fertility in male or female rats dosed by the oral route.
At high parenteral doses of aciclovir testicular atrophy and aspermatogenesis have been observed in rats and dogs.
Valaciclovir was not teratogenic in rats or rabbits. It is almost completely metabolized to aciclovir. Subcutaneous (SC) administration of aciclovir in internationally accepted tests did not produce teratogenic effects in rats or rabbits. In additional studies in rats, fetal abnormalities were observed at SC doses that produced plasma levels of 100 mcg/mL and maternal toxicity.

Treatment of herpes zoster (shingles). Valtrex accelerates the resolution of pain; it reduces the duration of and the proportion of patients with zoster-associated pain which includes acute and post-herpetic neuralgia.
Treatment of herpes simplex infections of the skin and mucous membranes, including initial and recurrent genital herpes.
Treatment of herpes labialis (cold sores).
Prevention (suppression) of recurrent herpes simplex infections of the skin and mucous membranes, including genital herpes.
Reduces transmission of genital herpes when taken as suppressive therapy and combined with safer sex practices.
Prophylaxis of cytomegalovirus (CMV) infection and disease following organ transplantation. CMV prophylaxis with Valtrex reduces acute graft rejection (renal transplant patients), opportunistic infections and other herpes virus infections (HSV, VZV).

Adults: Herpes Zoster (Shingles) Including Ophthalmic Zoster: 1000 mg to be taken 3 times daily for 7 days.
Herpes Simplex Infections: Immunocompetent Adults and Adolescents ≥12 years: 500 mg to be taken twice daily.
For recurrent episodes, treatment should be for 3 or 5 days. For initial episodes, which can be more severe, treatment may have to be extended from 5-10 days. Dosing should begin as early as possible. For recurrent episodes of herpes simplex, this should ideally be during the prodromal period or immediately when the 1st signs or symptoms appear. Valtrex can prevent lesion development when taken at the 1st signs and symptoms of an HSV recurrence.
Alternatively, for herpes labialis (cold sores), Valtrex 2 g twice daily for 1 day is an effective treatment. The 2nd dose should be taken about 12 hrs (no sooner than 6 hrs) after the 1st dose. When using this dosing regimen, treatment should not exceed 1 day since this has been shown not to provide additional clinical benefit. Therapy should be initiated at the earliest symptom of a cold sore (eg, tingling, itching or burning).
Prevention (Suppression) of Recurrences of Herpes Simplex Infections: Immunocompetent Adults and Adolescents ≥12 years: In immunocompetent patients, 500 mg to be taken once daily.
Some patient with very frequent recurrences (eg, ≥10 recurrences/year) may gain additional benefit from the daily dose of 500 mg being taken as a divided dose (250 mg twice daily).
Immunocompromised Adults: For immunocompromised patients, the dose is 500 mg twice daily.
Reduction of Transmission of Genital Herpes: In immunocompetent heterosexual adults with ≤9 recurrences/year, Valtrex 500 mg to be taken once daily by the infected partner.
There are no data on the reduction of transmission in other patient populations.
Prophylaxis of Cytomegalovirus Infection and Disease: The dosage of Valtrex in adults and adolescents (from 12 years) is 2 g 4 times daily to be initiated as early as possible post-transplant. This dose should be reduced according to CrCl (see Renal Impairment as follows).
The duration of treatment will usually be 90 days but may need to be extended in high risk patients.
Elderly: The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly (see Renal Impairment as follows).
Adequate hydration should be maintained.
Renal Impairment: Caution is advised when administering valaciclovir to patients with impaired renal function. Adequate hydration should be maintained.
The dosage of Valtrex should be reduced in patients with significantly impaired renal function as shown in the table as follows: See table.

Click on icon to see table/diagram/image

In patients on intermittent hemodialysis, the Valtrex dosage recommended for patients with a CrCl <15 mL/min should be used. This should be administered after the hemodialysis has been performed.
The CrCl should be monitored frequently, especially during periods when renal function is changing rapidly eg, immediately after transplantation or engraftment. The Valtrex dosage should be adjusted accordingly.
Hepatic Impairment: Studies with Valtrex 1 g unit dose show that dose modification is not required in patients with mild or moderate cirrhosis (hepatic synthetic function maintained). Pharmacokinetic data in patients with advanced cirrhosis (impaired hepatic synthetic function and evidence of portal-systemic shunting) do not indicate the need for dosage adjustment; however, clinical experience is limited. For higher doses, (≥4 g/day), see Precautions.

Symptoms: Acute renal failure and neurological symptoms including confusion, hallucinations, agitation, decreased consciousness and coma have been reported in patients receiving overdoses of valaciclovir. Nausea and vomiting may also occur. Caution is required to prevent inadvertent overdosing. Many of the reported cases involved renally impaired and elderly patients receiving repeated overdoses due to lack of appropriate dosage reduction.
Treatment: Patients should be observed closely for signs of toxicity. Hemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.

Known hypersensitivity to valaciclovir, aciclovir or to any of the excipients of Valtrex.

Hydration Status: Care should be taken to ensure adequate fluid intake in patients who are at risk of dehydration, particularly the elderly.
Elderly and Patients with Renal Impairment: Aciclovir is eliminated be renal clearance, therefore, the dose of valaciclovir must be reduced in patients with renal impairment (see Dosage & Administration). Elderly patients are likely to have reduced renal function and therefore, the need for dose reduction must be considered in this group of patients. Both elderly patients and patients with renal impairment are at increased risk of developing neurological side effects and should be closely monitored for evidence of these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment (see Adverse Reactions).
Use of Higher Doses of Valtrex in Hepatic Impairment and Liver Transplantation: There are no data available on the use of higher doses of Valtrex (≥4 g/day) in patients with liver disease. Caution should therefore be exercised when administering higher doses of Valtrex to these patients. Specific studies of Valtrex have not been conducted in liver transplantation; however, high-dose aciclovir prophylaxis has been shown to reduce CMV infection and disease.
Use in Genital Herpes: Suppressive therapy with Valtrex reduces the risk of transmitting genital herpes. It does not cure genital herpes or completely eliminate the risk of transmission. In addition to therapy with Valtrex, it is recommended that patients use safer sex practices.
Effects on the Ability to Drive or Operate Machinery: The clinical status of the patient and the adverse event profile of Valtrex should be borne in mind when considering the patient's ability to drive or operate machinery. There have been no studies to investigate the effect of valaciclovir on driving performance or the ability to operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of the active substance.
Impairment of Fertility: In animal studies, Valtrex did not affect fertility. However, high parenteral doses of aciclovir caused testicular effects in rats and dogs (see Toxicology: Preclinical Safety Data under Pharmacology under Actions).
No human fertility studies were performed with Valtrex, but no changes in sperm count, motility or morphology were reported in 20 patients after 6 months of daily treatment with 400 mg to 1 g aciclovir.
Use in Pregnancy: There are limited data on the use of Valtrex in pregnancy. It should only be used in pregnancy if the potential benefits of treatment outweigh the potential risk.
Pregnancy registries have documented the pregnancy outcomes in women exposed to Valtrex or to any formulation of Zovirax, (aciclovir, the active metabolite of valaciclovir); 111 and 1246 outcomes (29 and 756 exposed during the 1st trimester of pregnancy), respectively, were obtained from women prospectively registered. The findings of the aciclovir pregnancy registry have not shown an increase in the number of birth defects amongst aciclovir-exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause. Given the small number of women enrolled into the valaciclovir pregnancy registry, reliable and definitive conclusions could not be reached regarding the safety of valaciclovir in pregnancy (see Pharmacology: Pharmacokinetics under Actions).
Use in Lactation: Aciclovir, the principle metabolite of valaciclovir, is excreted in breast milk. Following oral administration of Valtrex 500 mg, C_max in breast milk ranged from 0.5-2.3 (median 1.4) times the corresponding maternal aciclovir serum concentrations. The aciclovir breast milk to maternal serum AUC ratios ranged from 1.4-2.6 (median 2.2). The median aciclovir concentration in breast milk was 2.24 mcg/mL (9.95 micromoles). With a maternal Valtrex dosage of 500 mg twice daily, this level would expose a nursing infant to a daily oral aciclovir dosage of about 0.61 mg/kg/day. The elimination t_½ of aciclovir from breast milk was similar to that for serum.
Unchanged valaciclovir was not detected in maternal serum, breast milk or infant urine.
Caution is advised if Valtrex is to be administered to a nursing woman. However, Zovirax is used to treat neonatal herpes simplex at IV doses of 30 mg/kg/day.
Use in Children: There are no data available on the use of Valtrex in children.

Use in Pregnancy: There are limited data on the use of Valtrex in pregnancy. It should only be used in pregnancy if the potential benefits of treatment outweigh the potential risk.
Pregnancy registries have documented the pregnancy outcomes in women exposed to Valtrex or to any formulation of Zovirax, (aciclovir, the active metabolite of valaciclovir); 111 and 1246 outcomes (29 and 756 exposed during the 1st trimester of pregnancy), respectively, were obtained from women prospectively registered. The findings of the aciclovir pregnancy registry have not shown an increase in the number of birth defects amongst aciclovir-exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause. Given the small number of women enrolled into the valaciclovir pregnancy registry, reliable and definitive conclusions could not be reached regarding the safety of valaciclovir in pregnancy (see Pharmacology: Pharmacokinetics under Actions).
Use in Lactation: Aciclovir, the principle metabolite of valaciclovir, is excreted in breast milk. Following oral administration of Valtrex 500 mg, C_max in breast milk ranged from 0.5-2.3 (median 1.4) times the corresponding maternal aciclovir serum concentrations. The aciclovir breast milk to maternal serum AUC ratios ranged from 1.4-2.6 (median 2.2). The median aciclovir concentration in breast milk was 2.24 mcg/mL (9.95 micromoles). With a maternal Valtrex dosage of 500 mg twice daily, this level would expose a nursing infant to a daily oral aciclovir dosage of about 0.61 mg/kg/day. The elimination t_½ of aciclovir from breast milk was similar to that for serum.
Unchanged valaciclovir was not detected in maternal serum, breast milk or infant urine.
Caution is advised if Valtrex is to be administered to a nursing woman. However, Zovirax is used to treat neonatal herpes simplex at IV doses of 30 mg/kg/day.

Adverse reactions are listed as follows by MedDRA body system organ class and by frequency.
The frequency categories used are: Very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10,000 and <1/1000); and very rare (<1/10,000).
Clinical trial data have been used to assign frequency categories to adverse reactions if, in the trials, there was an evidence of an association with Valtrex (ie, there was a statistically significant difference between the incidence in patients taking Valtrex and placebo). For all other adverse events, spontaneous post-marketing data have been used as a basis for allocating frequency.
Clinical Trial Data: Nervous System Disorders: Common: Headache.
Gastrointestinal Disorders: Common: Nausea.
Post-Marketing Data: Blood and Lymphatic System Disorders: Very Rare: Leukopenia, thrombocytopenia.
Leukopenia is mainly reported in immunocompromised patients.
Immune System Disorders: Very Rare: Anaphylaxis.
Psychiatric and Nervous System Disorders: Rare: Dizziness, confusion, hallucinations, decreased consciousness. Very Rare: Agitation, tremor, ataxia, dysarthria, psychotic symptoms, convulsions, encephalopathy and coma.
The previously mentioned events are generally reversible and usually seen in patients with renal impairment or with other predisposing factors (see Precautions). In organ transplant patients receiving high doses (8 g daily) of Valtrex for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Dyspnea.
Gastrointestinal Disorders: Rare: Abdominal discomfort, vomiting, diarrhea.
Hepatobiliary Disorders: Very Rare: Reversible increases in liver function tests. These are occasionally described as hepatitis.
Skin and Subcutaneous Tissue Disorders: Uncommon: Rashes including photosensitivity. Rare: Pruritus. Very Rare: Urticaria, angioedema.
Renal and Urinary Disorders: Rare: Renal impairment. Very Rare: Acute renal failure, renal pain. Renal pain may be associated with renal failure.
Others: There have been reports of renal insufficiency, microangiopathic hemolytic anemia and thrombocytopenia (sometimes in combination) in severely immunocompromised patients, particularly those with advanced HIV disease, receiving high doses (8 g daily) of Valtrex for prolonged periods in clinical trials. These findings have been observed in patients not treated with Valtrex who have the same underlying or concurrent conditions.

No clinically significant interactions have been identified.
Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase aciclovir plasma concentrations following Valtrex administration.
Following valaciclovir 1 g, cimetidine and probenecid increase the AUC of aciclovir by this mechanism and reduce aciclovir renal clearance. However, no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.
In patients receiving higher doses of Valtrex (≥4 g/day), caution is required during concurrent administration with drugs which compete with aciclovir for elimination because of the potential for increased plasma levels of 1 or both drugs or their metabolites. Increases in plasma AUCs of aciclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant agent used in transplant patients, have been shown when the drugs are co-administered.
Care is also required (with monitoring for changes in renal function) if administering high-dose of Valtrex ≥4 g with drugs which affect other aspects of renal physiology (eg, cyclosporin, tacrolimus).

Store at temperatures not exceeding 30°C.

Antivirals

J05AB11 - valaciclovir ; Belongs to the class of nucleosides and nucleotides excluding reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.

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