英文药名：VALACICLOVIR TABLETS（Valaciclovir Hydrochloride）

中文药名：盐酸伐昔洛韦片
药品介绍
抗病毒化疗药物
批准上市日期：2013年12月
商標名
VALACICLOVIR TABLETS 500mg
一般名：
バラシクロビル塩酸塩
（Valaciclovir Hydrochloride）
化学名：
2-［（2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl）methoxy］ethyl L-valinate monohydrochloride
分子式：
C13H20N6O4・HCl
分子量：
360.80
構造式：

性状：
白色～微黄白色の粉末である．水に溶けやすく，エタノール（99.5）に極めて溶けにくく，アセトニトリルにほとんど溶けない．
取扱い上の注意
安定性試験3）
最終製品を用いた加速試験（40℃，相対湿度75％，6ヶ月）の結果，本剤は通常の市場流通下において3年間安定であることが推測された．
药理毒理
1、药理
代昔洛韦是阿昔洛韦的L-缬氨酸酯。本品口服后吸收迅速并在体内很快转化为阿昔洛韦，其抗病毒作用为阿昔洛韦所发挥，阿昔洛韦进入疱疹感染细胞之后，与脱氧核苷竞争病毒胸腺嘧啶激酶或细胞激酶，药物被磷酸化成活化型无环鸟苷三磷酸酯，作为病毒复制的底物与脱氧鸟嘌呤三磷酸酯竞争病毒DNA多聚酶，从而抑制了病毒DNA合成，显示抗病毒作用。本品体内的抗病毒活性优于阿昔洛韦，对单纯性疱疹病毒I型和II型的治疗指数分别比阿昔洛韦高42.91%和30.13%，对水痘带状疱疹病毒也有很高的疗效，对哺乳动物宿主细胞的毒性很低。
2、毒理
盐酸代昔洛韦大鼠和小鼠灌胃给药的半数致死量（LD50）分别为4.4g/kg和1.51g/kg。由于本品在体内很快转化为阿昔洛韦，其代谢物在体内没有蓄积现象。在不同阶段的长期毒性试验中，本品与阿昔洛韦具有相同的安全性。
适应症
用于治疗水痘带状疱疹及Ⅰ型、Ⅱ型单纯疱疹病毒感染，包括初发和复发生殖器疱疹病毒感染。本品可用于阿昔洛韦的所有适应症。
用法用量
1）单纯疱疹
成年人；口服一天二次，每次一片。
2）带状疱疹
成年人；口服一天三次，每次二片。
3）预防复发性生殖器疱疹
成年人；口服一天一次，每次一片，另外HIV感染加一片（CD4淋巴细胞数100个/ mm3以上）。
4）水痘
口服一天三次，每次二片（孩子体重超过40公斤，并且成年人）
不良反应
常见不良反应为恶心、头痛、头晕、腹痛、痛经、关节痛及抑郁。
其他不良反应有：
全身：面部水肿、高血压、心动过速。
过敏：血管性水肿、呼吸困难、瘙痒症、皮疹、风疹；
中枢神经：攻击性行为、激动、昏迷、脑病、意识模糊、癫狂、精神异常、幻听和幻视；
眼睛：视觉异常；
肝胆：肝酶异常、肝炎；
肾脏：肌酐增加、肾脏衰竭；
血液：血小板减少、贫血；
皮肤：多形性红斑、光敏性皮疹。
禁忌
对本品及阿昔洛韦过敏者禁用
注意事项
1.对更昔洛韦过敏者也可能对本品过敏。
2.脱水或已有肝、肾功能不全者慎用。肾功能不全者在接受本品治疗时，需根据肌酐清除率来校正剂量。
3.严重免疫功能缺陷者长期或多次应用本品治疗后可能引起单纯疱疹病毒和带状疱疹病毒对本品耐药。如单纯疱疹患者应用本品后皮损不见改善者应测试单纯疱疹病毒对本品的敏感性。
4.随访检查：由于生殖器疱疹患者大多易患子宫颈癌，因此患者至少应一年检查一次，以早期发现。
5.一旦疱疹症状与体征出现，应尽早给药。
6.服药期间应给予患者充分的水，防止阿昔洛韦在肾小管内沉淀。
7.一次血液透析可使阿昔洛韦的血药浓度减低60%，因此血液透析后应补给一次剂量。
8.生殖器复发性疱疹感染以间歇短程疗法给药有效。生殖器复发性疱疹的长程疗法也不应超过6个月。
9.本品对单纯疱疹病毒的潜伏感染无明显效果，不能根除病毒。
10.药物不要放在孩童可触及的地方。
11.废弃药品包装不应随意丢弃。
包装规格
片剂
500毫克*42片（6片×7）

生产商：Theo rear Pharma制药（武田薬品销售）
补充说明书
完整处方资料附件：http://www.info.pmda.go.jp/go/pack/6250019F1039_1_02/
Valtrex 500mg film coated tabletsValaciclovir hydrochloride
1. NAME OF THE MEDICINAL PRODUCT
Valtrex 500mg film coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains valaciclovir hydrochloride equivalent to 500 mg valaciclovir
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablets.
White, biconvex, elongated tablet with a white to off-white core, engraved “GX CF1” on one side.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Varicella zoster virus (VZV) infections – herpes zoster
Valtrex is indicated for the treatment of herpes zoster (shingles) and ophthalmic zoster in immunocompetent adults (see section 4.4).
Valtrex is indicated for the treatment of herpes zoster in adult patients with mild or moderate immunosuppression (see section 4.4).
Herpes simplex virus (HSV) infections
Valtrex is indicated
• for the treatment and suppression of HSV infections of the skin and mucous membranes including
• treatment of first-episode of genital herpes in immunocompetent adults and adolescents and in immunocompromised adults
• treatment of recurrences of genital herpes in immunocompetent adults and adolescents, and in immunocompromised adults
• Treatment and suppression of recurrent ocular HSV infections (see section 4.4
• Treatment and suppression of recurrent ocular HSV infections (see section 4.4)
Clinical studies have not been conducted in HSV-infected patients immunocompromised for other causes than HIV-infection (see section 5.1).
Cytomegalovirus (CMV) infections:
Valtrex is indicated for the prophylaxis of CMV infection and disease following solid organ transplantation in adults and adolescents (see section 4.4).
4.2 Posology and method of administration
Varicella zoster virus (VZV) infections – herpes zoster and ophthalmic zoster
Patients should be advised to start treatment as soon as possible after a diagnosis of herpes zoster. There are no data on treatment started more than 72 hours after onset of the zoster rash.
Immunocompetent Adults
The dose in immunocompetent patients is 1000 mg three times daily for seven days (3000 mg total daily dose). This dose should be reduced according to creatinine clearance (see Renal impairment below).
Immunocompromised Adults
The dose in immunocompromised patients is 1000 mg three times daily for at least seven days (3000 mg total daily dose) and for 2 days following crusting of lesions. This dose should be reduced according to creatinine clearance (see Renal impairment below).
In immunocompromised patients, antiviral treatment is suggested for patients presenting within one week of vesicle formation or at any time before full crusting of lesions.
Treatment of herpes simplex virus (HSV) infections in adults and adolescents ( 12 years)
Immunocompetent Adults and Adolescents ( 12 years)
The dose is 500 mg of Valtrex to be taken twice daily (1000 mg total daily dose). This dose should be reduced according to creatinine clearance (see Renal impairment below).
For recurrent episodes, treatment should be for three to five days. For initial episodes, which can be more severe, treatment may have to be extended to ten days. Dosing should begin as early as possible. For recurrent episodes of herpes simplex, this should ideally be during the prodromal period or immediately upon appearance of the first signs or symptoms. Valtrex can prevent lesion development when taken at the first signs and symptoms of an HSV recurrence.
Herpes labialis
For herpes labialis (cold sores), valaciclovir 2000 mg twice daily for one day is effective treatment in adults and adolescents. The second dose should be taken 12 h (no sooner than 6 h) after the first dose. This dose should be reduced according to creatinine clearance (see Renal impairment below). When using this dosing regimen, treatment should not exceed one day, since this has been shown not to provide additional clinical benefit. Therapy should be initiated at the earliest symptom of a cold sore (e.g. tingling, itching or burning).
Immunocompromised Adults
For the treatment of HSV in immunocompromised adults, the dosage is 1000 mg twice daily for at least 5 days, following assessment of the severity of the clinical condition and immunological status of the patient. For initial episodes, which can be more severe, treatment may have to be extended to ten days. Dosing should begin as early as possible. This dose should be reduced according to creatinine clearance (see Renal impairment below). For maximum clinical benefit, the treatment should be started within 48 hours. A strict monitoring of the evolution of lesions is advised.
Suppression of recurrences of herpes simplex virus (HSV) infections in adults and adolescents ( 12 years)
Immunocompetent Adults and Adolescents ( 12 years)
The dose is 500mg of Valtrex to be taken once daily.
Some patients with very frequent recurrences ( 10/year in absence of therapy) may gain additional benefit from the daily dose of 500mg being taken as a divided dose (250 mg twice daily). This dose should be reduced according to creatinine clearance (see Renal impairment below). Treatment should be re-eva luated after 6 to 12 months of therapy.
Immunocompromised Adults
The dose is 500mg of Valtrex twice daily. This dose should be reduced according to creatinine clearance (see Renal impairment below). Treatment should be re-eva luated after 6 to 12 months of therapy.
Prophylaxis of cytomegalovirus (CMV) infection and disease in adults and adolescents ( 12 years)
The dosage of Valtrex is 2000 mg four times a day, to be initiated as early as possible post-transplant. This dose should be reduced according to creatinine clearance (see Renal impairment below).
The duration of treatment will usually be 90 days, but may need to be extended in high risk patients.
Special Populations
Children
The efficacy of Valtrex in children below the age of 12 years has not been eva luated.
Elderly
The possibility of renal impairment in the elderly must be considered and the dose should be adjusted accordingly (see Renal impairment below). Adequate hydration should be maintained.
Renal Impairment
Caution is advised when administering Valtrex to patients with impaired renal function. Adequate hydration should be maintained. The dose of Valtrex should be reduced in patients with impaired renal function as shown in Table 1 below.
In patients on intermittent haemodialysis, the Valtrex dose should be administered after the haemodialysis has been performed. The creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after renal transplantation or engraftment. The Valtrex dosage should be adjusted accordingly.
Hepatic impairment
Studies with a 1000 mg dose of valaciclovir in adult patients show that dose modification is not required in patients with mild or moderate cirrhosis (hepatic synthetic function maintained). Pharmacokinetic data in adult patients with advanced cirrhosis (impaired hepatic synthetic function and evidence of portal-systemic shunting) do not indicate the need for dose adjustment; however, clinical experience is limited. For higher doses (4000 mg or more per day), see section 4.4.
Table 1: DOSAGE ADJUSTMENT FOR RENAL IMPAIRMENT

Therapeutic Indication	Creatinine Clearance (mL/min)	Valaclovir Dosagea
Varicella-Zoster Virus (VZV) Infections
Treatment of herpes zoster (shingles) In immunocompetent and Immunocompromised adults	50 30 to 49 10 to 29 10	1000 mg three times daily 1000 mg twice daily 1000 mg once daily 500 mg once daily
Herpes Simplex Virus (HSV) Infections
Treatment of HSV infections
- Immunocompetent adults and adolescents	30 < 30	500 mg twice daily 500 mg once daily
- Immunocompromised adults	30 < 30	1000 mg twice daily 1000 mg once daily
Treatment of herpes labialis (cold sores) in immunocompetent adults and adolescents (alternative 1-day regimen)	50 30 to 49 10 to 29 <10	2000 mg twice in one day 1000 mg twice in one day 500 mg twice in one day 500 mg single dose
Suppression of HSV infections
- Immunocompetent adults and adolescents	30 < 30	500 mg once dailyb 250 mg once daily
- Immunocompromised adults	30 < 30	500 mg twice daily 500 mg once daily
Cytomegalovirus (CMV) Infections
CMV prophylaxis in solid organ transplant recipients in adults and adolescents	75 50 to <75 25 to <50 10 to <25 <10 or on dialysis	2000 mg four times daily 1500 mg four times daily 1500 mg three times daily 1500 mg twice daily 1500 mg once daily

aFor patients on intermittent haemodialysis, the dose should be given after dialysis on dialysis days.
bFor HSV suppression in immunocompetent subjects with a history of 10 recurrences/year, better results may be obtained with 250 mg twice daily.
4.3 Contraindications
Hypersensitivity to valaciclovir or acyclovir or any of the excipients (see section 6.1).
4.4 Special warnings and precautions for use
Hydration status
Care should be taken to ensure adequate fluid intake in patients who are at risk of dehydration, particularly the elderly.
Use in patients with renal impairment and in elderly patients
Aciclovir is eliminated by renal clearance, therefore the dose of valaciclovir must be reduced in patients with renal impairment (see section 4.2). 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 section 4.8)Use of higher doses of valaciclovir in hepatic impairment and liver transplantation
There are no data available on the use of higher doses of valaciclovir (4000 mg or more per day) in patients with liver disease. Specific studies of valaciclovir have not been conducted in liver transplantation, and hence caution should be exercised when administering daily doses greater than 4000 mg to these patients.
Use for zoster treatment
Clinical response should be closely monitored, particularly in immunocompromised patients. Consideration should be given to intravenous antiviral therapy when response to oral therapy is considered insufficient.
Patients with complicated herpes zoster, i.e. those with visceral involvement, disseminated zoster, motor neuropathies, encephalitis and cerebrovascular complications should be treated with intravenous antiviral therapy.
Moreover, immunocompromised patients with ophthalmic zoster or those with a high risk for disease dissemination and visceral organ involvement should be treated with intravenous antiviral therapy.
Transmission of genital herpes
Patients should be advised to avoid intercourse when symptoms are present even if treatment with an antiviral has been initiated. During suppressive treatment with antiviral agents, the frequency of viral shedding is significantly reduced. However, the risk of transmission is still possible. Therefore, in addition to therapy with valaciclovir, it is recommended that patients use safer sex practices.
Use in ocular HSV infections
Clinical response should be closely monitored in these patients. Consideration should be given to intravenous antiviral therapy when response to oral therapy is unlikely to be sufficient.
Use in CMV infections
Data on the efficacy of valaciclovir from transplant patients (~200) at high risk of CMV disease (e.g. donor CMV-positive/recipient CMV negative or use of anti-thymocyte globulin induction therapy) indicate that valaciclovir should only be used in these patients when safety concerns preclude the use of valganciclovir or ganciclovir.
High dose valaciclovir as required for CMV prophylaxis may result in more frequent adverse events, including CNS abnormalities, than observed with lower doses administered for other indications (see section 4.8). Patients should be closely monitored for changes in renal function, and doses adjusted accordingly (see section 4.2).
4.5 Interaction with other medicinal products and other forms of interaction
The combination of valaciclovir with nephrotoxic medicinal products should be made with caution, especially in subjects with impaired renal function, and warrants regular monitoring of renal function. This applies to concomitant administration with aminoglycosides, organoplatinum compounds, iodinated contrast media, methotrexate, pentamidine, foscarnet, ciclosporin and tacrolimus.
Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion.
Following 1000 mg valaciclovir, cimetidine and probenecid reduce aciclovir renal clearance and increase the AUC of aciclovir by about 25% and 45%, respectively, by inhibition of the active renal secretion of aciclovir. Cimetidine and probenecid taken together with valaciclovir increased aciclovir AUC by about 65%. Other medicinal products (including e.g. tenofovir) administered concurrently that compete with or inhibit active tubular secretion may increase aciclovir concentrations by this mechanism. Similarly, valaciclovir administration may increase plasma concentrations of the concurrently administered substance.
In patients receiving higher aciclovir exposures from valaciclovir (e.g. at doses for zoster treatment or CMV prophylaxis), caution is required during concurrent administration with drugs which inhibit active renal tubular secretion.
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 coadministered. No changes in peak concentrations or AUCs are observed with co-administration of valaciclovir and mycophenolate mofetil in healthy volunteers. There is limited clinical experience with the use of this combination.
4.6 Pregnancy and lactation
Pregnancy
A limited amount of data on the use of valaciclovir and a moderate amount of data on the use of aciclovir in pregnancy is available from pregnancy registries (which have documented the pregnancy outcomes in women exposed to valaciclovir or to oral or intravenous aciclovir (the active metabolite of valaciclovir); 111 and 1246 outcomes (29 and 756 exposed during the first trimester of pregnancy, respectively) and postmarketing experience indicate no malformative or foeto/neonatal toxicity. Animal studies do not show reproductive toxicity for valaciclovir (see section 5.3). Valaciclovir should only be used in pregnancy if the potential benefits of treatment outweigh the potential risk.
Breastfeeding
Aciclovir, the principle metabolite of valaciclovir, is excreted in breast milk. However, at therapeutic doses of valaciclovir, no effects on the breastfed newborns/infants are anticipated since the dose ingested by the child is less than 2% of the therapeutic dose of intravenous aciclovir for treatment of neonatal herpes (see Section 5.2). Valaciclovir should be used with caution during breast feeding and only when clinically indicated.
Fertility
Valaciclovir did not affect fertility in rats dosed by the oral route. At high parenteral doses of aciclovir testicular atrophy and aspermatogenesis have been observed in rats and dogs. No human fertility studies were performed with valaciclovir, but no changes in sperm count, motility or morphology were reported in 20 patients after 6 months of daily treatment with 400 to 1000 mg aciclovir.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. The clinical status of the patient and the adverse reaction profile of Valtrex should be borne in mind when considering the patient's ability to drive or operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of the active substance.
4.8 Undesirable effects
The most common adverse reactions (ARs) reported in at least one indication by patients treated with Valtrex in clinical trials were headache and nausea. More serious ARs such as thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome, acute renal failure and neurological disorders are discussed in greater detail in other sections of the label.
Undesirable effects are listed below by body system organ class and by frequency.
The following frequency categories are used for classification of adverse effects:
Very common
  1/10,
Common
  1/100 and < 1/10,
Uncommon
  1/1,000 and < 1/100,
Rare
  1/10,000 and < 1/1,000,
Very rare
 < 1/10,000.
Clinical trial data have been used to assign frequency categories to ARs if, in the trials, there was evidence of an association with valaciclovir.
For ARs identified from postmarketing experience, but not observed in clinical trials, the most conservative value of point estimate ('rule of three') has been used to assign the AR frequency category. For ARs identified as associated with valaciclovir from post-marketing experience, and observed in clinical trials, study incidence has been used to assign the AR frequency category. The clinical trial safety database is based on 5855 subjects to valaciclovir in clinical trials covering multiple indications (treatment of herpes zoster, treatment/suppression of genital herpes & treatment of cold sores).
Clinical Trial Data
Nervous system disorders
Very common:
 Headache.
Gastrointestinal disorders
Common:
 Nausea.
Post Marketing Data
Blood and lymphatic system disorders
Uncommon:
 Leucopenia, thrombocytopenia.
Leucopenia is mainly reported in immunocompromised patients.
Immune system disorders
Rare:
 Anaphylaxis.
Psychiatric and nervous system disorders
Common:
 Dizziness
Uncommon:
 confusion, hallucinations, decreased consciousness, tremor, agitation.
Rare:
 ataxia, dysarthria, convulsions, encephalopathy, coma, psychotic symptoms, delirium.
Neurological disorders, sometimes severe, may be linked to encephalopathy and include confusion, agitation, convulsions, hallucinations, coma. These events are generally reversible and usually seen in patients with renal impairment or with other predisposing factors (see section 4.4). In organ transplant patients receiving high doses (8000 mg daily) of Valtrex for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses used for other indications.
Respiratory, thoracic and mediastinal disorders
Uncommon:
 Dyspnoea.
Gastrointestinal disorders
Common:
 Vomiting, diarrhoea.

Uncommon:
 Abdominal discomfort.
Hepato-biliary disorders
Uncommon:
 Reversible increases in liver function tests (e.g. bilirubin, liver enzymes).
Skin and subcutaneous tissue disorders

Common:
 Rashes including photosensitivity, pruritus.
Uncommon:
 Urticaria
Rare:
 angioedema.
Renal and urinary disorders
Uncommon:
Renal pain, haematuria (often associated with other renal events).
Rare:
Renal impairment acute renal failure (especially in elderly patients or in patients with renal impairment receiving higher than the recommended doses).
Renal pain may be associated with renal failure.
Intratubular precipitation of aciclovir crystals in the kidney has also been reported. Adequate fluid intake should be ensured during treatment (see section 4.4).
Additional information on special populations
There have been reports of renal insufficiency, microangiopathic haemolytic anaemia and thrombocytopenia (sometimes in combination) in severely immunocompromised adult patients, particularly those with advanced HIV disease, receiving high doses (8000 mg daily) of valaciclovir for prolonged periods in clinical trials. These findings have been observed in patients not treated with valaciclovir who have the same underlying or concurrent conditions.
4.9 Overdose
Symptoms and signs:
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. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Nucleotides and nucleotides excluding reverse transcriptase inhibitors, ATC code: J05AB11
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) type 1 and type 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), and human herpes virus 6 (HHV-6). Aciclovir inhibits herpes virus DNA synthesis once it has been phosphorylated to the active triphosphate form.
The first 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 results in obligate chain termination, halting virus DNA synthesis and thus blocking virus replication.
Pharmacodynamic effects
Resistance to aciclovir is normally due to a thymidine kinase deficient phenotype which results in a virus which is disadvantaged in the natural host. 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.
Monitoring of clinical HSV and VZV isolates from patients receiving aciclovir therapy or prophylaxis has revealed that virus with reduced sensitivity to aciclovir is extremely rare in the immunocompetent host and is found infrequently in severely immunocompromised individuals e.g. organ or bone marrow transplant recipients, patients receiving chemotherapy for malignant disease and people infected with the human immunodeficiency virus (HIV).
Clinical studies
Varicella Zoster Virus Infection
Valtrex accelerates the resolution of pain: it reduces the duration of and the proportion of patients with zoster-associated pain, which includes acute and, in patients older than 50 years, also post-herpetic neuralgia. Valtrex reduces the risk of ocular complications of ophthalmic zoster.
Intravenous therapy generally is considered standard for zoster treatment in immunocompromised patients; however, limited data indicate a clinical benefit of valacivlovir in the treatment of VZV infection (herpes zoster) in certain immunocompromised patients, including those with solid organ cancer. HIV, autoimmune diseases, lymphoma, leukaemia and stem cell transplants.
Herpes Simplex Virus Infection
Valaciclovir for ocular HSV infections should be given according to applicable treatment guideline.
Studies - of valaciclovir treatment and suppression for genital herpes were performed in HIV/HSV coinfected patients – with a median CD4 count of > 100 cells/mm3. Valaciclovir 500 mg twice daily was superior to 1000 mg once daily for suppression of symptomatic recurrences. Valaciclovir 1000 mg twice daily for treatment of recurrences was comparable to oral aciclovir 200 mg five times daily on herpes episode duration. Valaciclovir has not been studied in patients with severe immune deficiency.
The efficacy of valaciclovir for the treatment of other HSV skin infections has been documented. Valaciclovir has shown efficacy in the treatment of herpes labialis (cold sores), mucositis due to chemotherapy or radiotherapy, HSV reactivation from facial resurfacing, and herpes gladiatorum. Based on historical aciclovir experience, valaciclovir appears to be as effective as aciclovir for the treatment of erythema multiforme, eczema herpeticum and herpetic whitlow.
Valaciclovir has been proven to reduce the risk of transmission of genital herpes in immunocompetent adults when taken as suppressive therapy and combined with safer sex practices. A double blind, placebo controlled study was conducted in 1,484 heterosexual, immunocompetent adult couples discordant for HSV-2 infection. Results showed significant reductions in risk of transmission: 75% (symptomatic HSV-2 acquisition), 50% (HSV-2 seroconversion) and 48% (overall HSV-2 acquisition) for valaciclovir compared to placebo. Among subjects participating in a viral shedding sub-study, valaciclovir significantly reduced shedding by 73% compared to placebo (see section 4.4 for additional information on transmission reduction).
Cytomegalovirus Infection (see section 4.4)
CMV prophylaxis with valaciclovir in subjects receiving solid organ transplantation (kidney, heart) reduces the occurrence of acute graft rejection, opportunistic infections and other herpes virus infections (HSV, VZV). There is no direct comparative study versus valganciclovir to define the optimal therapeutic management of solid organ transplant patients.
5.2 Pharmacokinetic properties
Absorption
Valaciclovir is a prodrug of aciclovir. The bioavailability of aciclovir from valaciclovir is about 3.3 to 5.5-fold greater than that historically observed for oral aciclovir. After oral administration valaciclovir is well absorbed and rapidly and 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 1000 mg valaciclovir is 54%, and is not reduced by food.
Valaciclovir pharmacokinetics is not dose-proportional. The rate and extent of absorption decreases with increasing dose, resulting in a less than proportional increase in Cmax over the therapeutic dose range and a reduced bioavailability at doses above 500 mg. Aciclovir pharmacokinetic (PK) parameter estimates following single doses of 250 to 2000 mg valaciclovir to healthy subjects with normal renal function are shown below.

 

Aciclovir PK Parameter		250 mg (N=15)	500 mg (N=15)	1000 mg (N=15)	2000 mg (N=8)
Cmax	micrograms/mL	2.20 ± 0.38	3.37 ± 0.95	5.20 ± 1.92	8.30 ± 1.43
Tmax	hours (h)	0.75 (0.75-1.5)	1.0 (0.75-2.5)	2.0 (0.75-3.0)	2.0 (1.5-3.0)
AUC	h.micrograms/mL	5.50 ± 0.82	11.1 ± 1.75	18.9 ±4.51	29.5 ± 6.36

Cmax = peak concentration; Tmax = time to peak concentration; AUC = area under the concentration-time curve. Values for Cmax and AUC denote mean ± standard deviation. Values for Tmax denote median and range.
Peak plasma concentrations of unchanged valaciclovir are only about 4% of peak aciclovir levels, occur at a median time of 30 to 100 minutes post dose, and are at or below the limit of quantification 3 hours after dosing. The valaciclovir and aciclovir pharmacokinetic profiles are similar after single and repeat dosing. . Herpes zoster, herpes simplex and HIV infection do not significantly alter the pharmacokinetics of valaciclovir and aciclovir after oral administration of valaciclovir compared with healthy adults. 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.
Distribution
Binding of valaciclovir to plasma proteins is very low (15%). CSF penetration, determined by CSF/plasma AUC ratio, is independent of renal function and was about 25% for aciclovir and the metabolite 8-OH-ACV, and about 2.5% for the metabolite CMMG.
Biotransformation
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(carboxymethoxy)methylguanine (CMMG) by alcohol and aldehyde dehydrogenase and to 8-hydroxy-aciclovir (80OH-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 metabolised by cytochrome P450 enzymes.
Elimination
Valaciclovir is eliminated in the urine principally as aciclovir (greater than 80% of the recovered dose) and the aciclovir metabolite CMMG (about 14% of the recovered dose). The metabolite 8-OH-ACV is detected only in small amounts in urine (<2% of the recovered dose). Less than 1% of the administered dose of valaciclovir is recovered in the urine as unchanged drug. In patients with normal renal function the plasma elimination half-life of aciclovir after both single and multiple dosing with valaciclovir is approximately 3 h.
Special 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 half-life of aciclovir after valaciclovir administration is approximately 14 hours, compared with about 3 hours for normal renal function (see section 4.2).
Exposure to aciclovir and its metabolites CMMG and 8-OH-ACV in plasma and cerebrospinal fluid (CSF) was eva luated at steady-state after multiple-dose valaciclovir administration in 6 subjects with normal renal function (mean creatinine clearance 111 mL/min, range 91-144 mL/min) receiving 2000 mg every 6 hours and 3 subjects with severe renal impairment (mean CLcr 26 mL/min, range 17-31 mL/min) receiving 1500 mg every 12 hours. In plasma as well as CSF, concentrations as aciclovir, CMMG and 8-OH-ACV were on average 2, 4 and 5-6 times higher, respectively, at severe renal impairment compared with normal renal function.
Hepatic impairment
Pharmacokinetic data indicate that hepatic impairment decreases the rate of conversion of valaciclovir to aciclovir but not the extent of conversion. Aciclovir half-life is not affected.
Pregnant women
A study of the pharmacokinetics of valaciclovir and aciclovir during late pregnancy indicates that pregnancy does not affect the pharmacokinetics of valaciclovir.
Transfer into breast milk
Following oral administration of a 500 mg dose of valaciclovir, peak aciclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 times the corresponding maternal aciclovir serum concentrations. The median aciclovir concentration in breast milk was 2.24 micrograms/ml (9.95 micromoles/L). With a maternal valaciclovir 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 half-life of aciclovir from breast milk was similar to that from serum. Unchanged valaciclovir was not detected in maternal serum, breast milk, or infant urine.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenicity potential.
Valaciclovir did not affect fertility in male or female rats dosed by the oral route.
Valaciclovir was not teratogenic in rats or rabbits. Valaciclovir is almost completely metabolised to aciclovir. Subcutaneous administration of aciclovir in internationally accepted tests did not produce teratogenic effects in rats or rabbits. In additional studies in rats, foetal abnormalities and maternal toxicity were observed at subcutaneous doses that produced plasma aciclovir levels of 100 micorgrams/mL (>10-fold higher than 2000 mg single dose valaciclovir in humans with normal renal function).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core
Microcrystalline cellulose
Crospovidone
Povidone
Magnesium stearate
Colloidal silicon dioxide
Film coat
Hypromellose
Titanium dioxide
Macrogol
Polysorbate 80
Carnauba wax
6.2 Incompatibilities
Not applicable
6.3 Shelf life
Three years
6.4 Special precautions for storage
Store below 30°C.
6.5 Nature and contents of container
Polyvinyl chloride / aluminium foil blister packs.
Packs of 10, 30, 42, 90 or 112 tablets.
Not all pack sizes may be marketed
6.6 Special precautions for disposal and other handling
No special requirements
7. MARKETING AUTHORISATION HOLDER
GlaxoSmithKline (Ireland) Limited
Stonemasons Way
Rathfarnham
Dublin 16
8. MARKETING AUTHORISATION NUMBER(S)
 PA 1077/082/002
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
 Date of first authorisation:
 20 December 1994
Date of last renewal:
 09 September 2009
10. DATE OF REVISION OF THE TEXT
August 2011