|
|
|
 |
DESCRIPCION El valaciclovir es el ester del aciclovir con la valina, lo que mejora considerablemente la biodisponibilidad del aciclovir y, como consecuencia permite aumentar los intervalos entre dosis. El valaciclovir se utiliza en el tratamiento de la varicela, herpes zoster, herpes labiales, herpes genital y como profilactico de las infecciones por citomegalovirus en los pacientes con SIDA, o en pacientes inmunodeprimidos Mecanismo de acción: el valaciclovir es transformado rápidamente a aciclovir, el cual inhibe la síntesis del DNA vírico. Para ejercer su efecto, el aciclovir debe ser fosforilado intracelularmente, lo que se consigue mediante una timidina-kinasa vírica que lo transforma en monofosfato. Seguidamente, este monofosfato es convertido a difosfato mediante una una guanilato kinasa celular y finalmente a trifosfato por medio de varias enzimas celulares. Una vez sintetizado el trifosfato de aciclovir este inhibe selectivamente la ADN-polimerasa viral al competir con la deoxiguanosina trifosfato. La inhibición de la sintesis del ADN vírico solo tiene lugar en las células infectadas, mientras que la síntesis del ADN en las células normales no es afectado. La inhibición de la síntesis del ADN viral impide la replicación del virus. El aciclovir es activo frente a varios tipos de virus del herpes simple y frente al virus de la varicela-zoster. La actividad antivírica depende de varios factores, en particular del tiempo transcurrido entre la infección y el tratamiento. La resistencia de los virus herpes y herpes zoster al aciclovir puede producirse por mutación de los genes que codifican la timidina kinasa o la ADN-polimerasa. En el primer caso, una mutación de la timidina kinasa del virus, puede reducir o impedir la formación de la timidina trifosfato y, en consecuencia del aciclovir trifosfato. En el segundo caso, la ADN-polimerasa se hace capaz de diferenciar entre la aciclovir trifosfato u la deoxiguanosina trifosfato por lo que la síntesis de ADN puede llevarse a cabo. Farmacocinética: el valaciclovir se administra por vía oral y es rápidamente absorbido, sin ser esta afectada por la presencia de alimentos en el estómago. En voluntarios sanos, la biodisponibilidad del valaciclovir es de 3.5 a 5 veces mayor. La biodisponibilidad del aciclovir liberado del valaciclovir es del 54% en comparación con sólo el 15% cuando se administra el aciclovir como tal. La administración de dosis repetidas de valaciclovir no reducen las concentraciones plasmáticas del aciclovir, si bien las las concentraciones máximas de este y el AUC no son proporcionales a las dosis. El valaciclovir administrado en dosis de 1 a 4 g cuatro veces al día proporciona unas concentraciones plasmáticas de aciclovir similares a las que producen 5-10 mg/kg de aciclovir intravenoso cada 8 horas. El valaciclovir se une en un 13.5-17.9% a las proteínas del plasma. El valaciclovir es transformado a aciclovir + valina mediante un metabolismo de primer paso y un metabolismo hepático. A su vez, el aciclovir experimenta un metabolización parcila por medio de la alhehido oxidasa, la alcohol deshidrogenasa y la aldehido deshidrogenasa produciendo metabolitos inactivos. Las enzimas de los microsomas hepáticos no intervienen en el metabolismo del valaciclovir o del aciclovir. Las concentraciones plasmáticas de valaciclovir con generalmente bajas y a las 3 horas son prácticamente indetectables. El aciclovir generado se elimina principalmente a través de los riñones. En los pacientes con la función renal normal, la semi-vida de eliminación plasmática del aciclovir esd 2.5 a 3 .3 horeas En los pacientes con enfermedad renal terminal, la semi-vida del aciclovir aumenta hasta las 14 horas. Durante la hemodiálisis, la semi-vida el aciclovir es de unas 4 horas, eliminando el procediniento aproximadamente el tercio del aciclovor en cada sesión. Los pacientes con una aclaramiento de creatinina reducido requieren una reducción de la dosis INDICACIONES Y POSOLOGIA
Administración oral
a) Tratamiento de un primer episodio de herpes genital en pacientes inmunocompetentes Administración oral: Adultos y adolescentes: 1 g dos veces al día durante 10 días comenzando al primer signo o síntoma de las lesiones, preferentemente en las primeras 48 horas. El CDC recomienda la misma dosis durante 7-10 días. Si las lesiones con han cicatrizado por completo a los 10 días, el tratamiento puede prolongarse. No hay evidencia de la efectividad del valaciclovir si se administra más de 72 horas después del inicio los síntomas a) Tratamiento de un herpes genital recurrente en pacientes inmunocompetentes Administración oral
c) Tratamiento de un herpes genital recurrente en pacientes inmunocomprometidos: Oral dosage: Adults: A dose of 1 g PO twice daily for 5 days has been studied. Treatment should be initiated by patients within 12 hours of symptoms.
a) for suppressive therapy of recurrent herpes genitalis in immunocompetent patients: Oral dosage: Adults and adolescents: 1 g PO once daily. In patients with a history of <= 9 recurrences per year, 500 mg PO once daily may be given. The CDC recommends 1 g PO once daily or 250 mg PO twice daily.[1632] Safety and efficacy of valacyclovir beyond 1 year have not been established. b) for secondary prevention of herpes genitalis (i.e., herpes genitalis prophylaxis) in patients with human immunodeficiency virus (HIV) infection†: Oral dosage: Adults: A dose of 500 mg PO twice daily has been studied.
a) In patients with AIDS: Oral dosage: Adults: The CDC does not recommend using valacyclovir for the prevention CMV disease in patients with AIDS.[1446] In a study that compared valacyclovir 2 g PO four times a day with two acyclovir regimens, valacyclovir-treated patients showed a 29% reduction in CMV end-organ disease at one year and a reduction in the risk of CMV disease; however, the trial was discontinued because of an unexpected trend toward earlier mortality at one year in valacyclovir-treated patients (24.3%) compared to those receiving high-dose or low-dose acyclovir (19.5% and 18.8%, respectively). In addition, toxicity and earlier medication discontinuation were more common in patients treated with valacyclovir.[2954] b) In patients following kidney transplantation: Oral dosage: Adults: In a randomized trial, 2 g PO four times a day for 90 days post transplant significantly reduced the incidence of CMV disease in both CMV-seronegative and -seropositive patients. In this study, treatment with valacyclovir was associated with a decreased rate of CMV viremia and viruria, herpes simplex virus disease, and acute graft rejection.[2355] c) In patients following bone marrow transplantation: Oral dosage: Adults: Valacyclovir 1.5—2 g PO two to four times a day, is under investigation in a randomized, double-blind study in comparison acyclovir PO. Therapy with valacyclovir or oral acyclovir follows an initial 28 day IV course of acyclovir for all patients, and continues for 14 weeks. d) In patients following heart transplantation: Oral dosage: Adults: Valacyclovir 2 g PO four times a day, is under investigation in a randomized, double-blind study in comparison with acyclovir PO. Therapy is initiated within 48 hours of allograft and continued to day 90. Maximum Dosage Limits: •Adults: 3 g/day PO. •Elderly: 3 g/day PO. •Adolescents: Maximum dosage information is not available. •Children: Maximum dosage information is not available. Patients with hepatic impairment: No dosage adjustment is necessary. Patients with renal impairment: CrCl >= 50 ml/min: no dosage adjustment needed. CrCl 30—49 ml/min: For herpes zoster, reduce dose to 1 g PO every 12 hours. No dosage adjustments are required for genital herpes. CrCl 10—29 ml/min: For herpes zoster, reduce dose to 1 g PO every 24 hours. For genital herpes, initial treatment should be reduced to 1 g PO every 24 hours, recurrent episode treatment should be reduced to 500 mg PO every 24 hours, and suppressive therapy doses should be reduced to 500 mg every 24 hours (if receiving 1 g PO every day) or 500 mg PO every 48 hours (if receiving 500 mg PO every 24 hours). CrCl < 10 ml/min: For herpes zoster and initial and recurrent episode treatment of genital herpes, reduce dose to 500 mg PO every 24 hours. For suppressive therapy of genital herpes, doses should be reduced to 500 mg every 24 hours (if receiving 1 g PO every day) or 500 mg PO every 48 hours (if receiving 500 mg PO every 24 hours) Intermittent hemodialysis: During hemodialysis, the half-life of acyclovir after administration of valacyclovir is approximately 4 hours. About one-third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Patients should receive the recommended dosage of valacyclovir after each dialysis. Peritoneal dialysis: Supplemental doses are usually not required following chronic ambulatory peritoneal dialysis (CAPD) or continuous arteriovenous hemofiltration/dialysis (CAVHD). CONTRAINDICACIONES El valaciclovir está VALTREX is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation Valacyclovir is not currently approved for use in patients with immunosuppression. Trials regarding the effectiveness of valacyclovir in the treatment and prophylaxis of CMV in renal and bone marrow transplant patients are currently underway. However, in clinical trials using valacyclovir 8 g/day in patients with advanced HIV disease or following allogeneic bone marrow transplantation or renal transplantation, cases of thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) have been reported; some of these cases were fatal. Efficacy of valacyclovir has not been established in immunocompromised patients or in those with disseminated herpes zoster (varicella). The CDC does not recommended valacyclovir for cytomegalovirus (CMV) prophylaxis in patients with acquired immunodeficiency syndrome (AIDS). During clinical studies, there was an unexplained trend towards increased mortality in persons with AIDS treated with valacyclovir for the prevention of CMV infection.[1446] Valacyclovir should be used with caution in patients with renal dysfunction. Patients with renal impairment or renal failure should receive lower doses at longer intervals (see Dosage). Elderly patients are more likely to have impaired renal function and may require lower doses of valacyclovir. Acute renal failure and CNS toxicity have been reported in patients with underlying renal dysfunction who have received inappropriately high doses of valacyclovir for their level of renal function. Patients receiving potentially nephrotoxic drugs together with valacyclovir may have an increased risk of renal dysfunction. In order to prevent crystalluria, patients should be well-hydrated to maintain a high urine volume and avoid dehydration during treatment with valacyclovir. The safe use of valacyclovir in children has not been established. Oral administration of acyclovir has been studied in children over 2 years old. |
|
 |
Valacyclovir has been classified as FDA pregnancy category B. No complete or well-controlled pregnancy studies have been performed in humans. Acyclovir, the active component of valacyclovir, was not found to be teratogenic in standard animal studies. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 756 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy. 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 specific defects or to permit definitive conclusions regarding the safety of acyclovir in pregnant women. Valacyclovir should be avoided during pregnancy unless the potential benefits outweigh the possible risks to the fetus. Possible excretion of valacyclovir into breast milk has not been determined. However, concentrations of acyclovir in breast milk were up to 4 times that of maternal plasma concentrations of acyclovir.[1046] These concentrations would potentially expose the nursing infant to a dose of acyclovir as high as 0.3 mg/kg/day. Valacyclovir should be administered to a woman breast-feeding her infant with caution and only when indicated. | |
| Valacyclovir is rapidly converted to acyclovir and should be used with caution in patients with acyclovir hypersensitivity or ganciclovir hypersensitivity. Patients with moderate or severe hepatic disease have a slower valacyclovir to acyclovir conversion rate. However, the extent of conversion is not affected, or the half-life of acyclovir.No dosage adjustments are recommended for patients with hepatic disease. | ||
INTERACCIONES Following administration of valacyclovir to healthy patients taking cimetidine, probenecid, or a combination of both, an additive increase in acyclovir AUC and peak serum concentration was observed, primarily due to a reduction in the clearance of acyclovir. The clinical significance of these pharmacokinetic interactions is unknown; however, no dosagae adjustments are recommended for patients with normal renal function. In a single case report, the addition of acyclovir to a regimen of phenytoin and valproate led to a clinically significant decrease in phenytoin serum concentrations and loss of seizure control. Adjustments to the phenytoin dose were necessary when acyclovir was added and discontinued. Acyclovir did not appear to affect valproate concentrations in this report.[2906] Until more data are known, clinicians should be prepared to make adjustments in phenytoin or fosphenytoin dosing if acyclovir or valacyclovir therapy is added or discontinued. Patients receiving potentially nephrotoxic drugs together with valacyclovir may have an increased risk of renal dysfunction. |
||
REACCIONES ADVERSAS Las reacciones adversas producidas por el valaciclovir son similares a las que produce el aciclovir The adverse effect profile of valacyclovir is similar to that of acyclovir. The most commonly reported adverse events are headache, nausea/vomiting, dizziness, and abdominal pain. Other less common adverse events include dysmenorrhea, arthralgia, and depression. In clinical trials with valacyclovir (8 g/day for 8—84 weeks), cases of thrombotic thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS) have occurred in patients with advanced HIV disease, and in bone marrow and renal transplant patients. Some of these cases were associated with patient death. In other studies of otherwise healthy patients or in HIV-infected patients for the treatment or suppression of genital herpes using lower doses of valacyclovir (<= 3 g/day) and shorter duration of treatment, there have been no reports of TTP or HUS. During clincial use of valacyclovir, the following severe adverse reactions have been reported to the manufacturer: anaphylactoid reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash (unspecified), and urticaria; confusion; agitation; hallucinations; aggressive behavior; mania; diarrhea; liver enzyme abnormalities; hepatitis; elevated creatinine; renal failure (unspecified); thrombocytopenia; aplastic anemia; erythema multiforme; photosensitivity; facial edema; hypertension; and tachycardia. |
||
| Valacyclovir Valtrex™ | ||
| REFERENCIAS
|
||
| Monografía revisada el 5 de Junio de 2011. Equipo de Redacción de IQB | ||
 |
||
| |
Tratamiento del herpes zoster localizado en sujetos inmunocompetentes