Approval date: February 20, 2007
Revision date: February 20, 2008
June 17, 2013
Instructions for Vaciclovir Hydrochloride Tablets
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic Name.
Valaciclovir Hydrochloride Tablets
Trade Name.
VadexÒ; ValtrexÒ
English Name.
Valaciclovir Hydrochloride Tablets
Hanyu Pinyin：Yansuan Faxiluowei Pian
Ingredients
The main ingredient of this product is Valaciclovir Hydrochloride, the chemical name of which is L-valine-2-[(6-oxo-2-amino-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl ester hydrochloride.
Chemical structure formula.
.HCl
Molecular formula: C13H20N6O4-HCl
Molecular weight: 360.8
Properties
This product is a film-coated tablet, which appears white to off-white after removing the film coating.
Indications
This product is suitable for the treatment of herpes zoster.
This product is suitable for the treatment of herpes simplex virus infection.
This product is indicated for the prevention (inhibition) of recurrence of herpes simplex virus infection.
Specification
0.5g (as valacyclovir).
Dosage]
Adults
Herpes zoster treatment: take 500mg of this product orally, 2 tablets, 3 times daily for 7 days.
Treatment of herpes simplex: 500 mg orally twice daily. The course of treatment may need to be extended to 10 days for first-episode cases, which may be more severe. For recurrent infections, the course of treatment should be 5 days. It is recommended that treatment be initiated during the prodromal phase or at the first signs and symptoms.
Treatment of herpes simplex virus infection (suppression).
For immunocompetent patients, administer this product orally 500 mg once daily.
For patients with frequent recurrences (≥10 per year), a 250 mg twice-daily dosing regimen is more effective.
For immunodeficient patients, the dosing regimen is 500 mg twice daily.
Renal impairment
In patients with significantly impaired renal function, the dose of this product should be adjusted as follows.
Indications Creatinine clearance mL/min Dose of this product Immunocompetent and immunodeficient adults with herpes zoster treatment
Herpes simplex (treatment)
Immunocompetent adults and adolescents
Herpes simplex prophylaxis (suppression)
Immunocompetent adults and adolescents
Immunodeficient adults at least 50
30-49
10-29
Less than 10
At least 30
Less than 30
At least 30
Less than 30
At least 30
Less than 301g, 3 times a day
1g, 2 times a day
1g, 1 time daily
500mg, 1 time daily
500mg, 2 times daily
500mg, 1 time daily
500mg, 1 time daily
250mg, 1 time daily
500mg, 2 times daily
500mg, 1 time daily
In patients on intermittent hemodialysis, this product should be administered after completion of hemodialysis.
Hepatic impairment
Patients with mild to moderate cirrhosis (hepatic synthesis can be maintained) do not need to adjust the dose of this product.
Pharmacokinetic data in patients with advanced cirrhosis (impaired hepatic synthetic function with portal system shunts) suggest that no dose adjustment is required, but clinical experience in this area is limited.
[Adverse Reactions].
Adverse reactions were classified according to MedDRA human organ classification and frequency of occurrence as follows. The frequency classification criteria are.
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.
Adverse reactions from the clinical trial data were classified according to the above frequency criteria, and the trial data demonstrated that the adverse reactions were associated with this product (i.e., the incidence of adverse reactions in patients treated with this product and placebo was statistically significantly different). The frequencies of all other adverse events were assigned based on spontaneously reported post-marketing data.
Clinical Trial Data
Neurological
Common: Headache.
Gastrointestinal
Common: nausea.
Post-marketing data
Hematologic and lymphatic system
Very rare: leukopenia, thrombocytopenia.
Leukopenia is mainly seen in patients with immune deficiency.
Immune system
Very rare: allergic reactions.
Mental and nervous system
Rare: vertigo, blurred consciousness, hallucinations, loss of consciousness.
Very rare: excitement, tremor, ataxia, dysarthria, psychotic symptoms, convulsions, encephalopathy, coma.
The above adverse reactions are generally reversible and are usually seen in patients with renal impairment or other predisposing factors. The incidence of neurological reactions was higher in organ transplant patients treated with high-dose valacyclovir hydrochloride for prevention of cytomegalovirus infection (CMV) than in patients in the low-dose group.
Respiratory
Unusual: dyspnea.
Gastrointestinal
Rare: abdominal discomfort, vomiting, diarrhea.
Liver
Very rare: reversible elevation of liver function tests.
Hepatitis is occasionally described.
Skin and connective tissue
Unusual: rash including photosensitivity reactions.
Rare: pruritus.
Very rare: urticaria, angioedema.
Kidney and urinary system
Rare: renal impairment.
Very rare: acute renal failure, renal pain.
Renal pain may be associated with renal failure.
Other: renal insufficiency, capillary hemolytic anemia, and thrombocytopenia (sometimes both) have been reported in extended clinical trials in severely immunosuppressed patients, especially those with advanced human immunodeficiency virus (HIV) infection, taking high doses (8 g daily) of valacyclovir. These conditions have also been seen in patients with the same underlying disease or comorbidities who have not been treated with valacyclovir.
Contraindications]
This product is contraindicated in patients who are hypersensitive to valacyclovir, acyclovir, or any component of this formulation.
Precautions]
Body fluid status
Special care should be taken to ensure that patients (especially elderly patients) consume adequate amounts of fluids to prevent dehydration in patients.
Patients with renal impairment and elderly patients.
Acyclovir is excreted by renal metabolism; therefore, the dose of valacyclovir must be reduced in patients with renal impairment (see [DOSAGE AND ADMINISTRATION]). Geriatric patients may have reduced renal function; therefore, dose reductions in the geriatric population should be considered. Elderly patients and patients with renal impairment are at increased risk for neurologic adverse reactions and should be closely monitored for signs of these effects. In reported cases, these reactions are usually reversible after discontinuation of the drug (see [ADVERSE REACTIONS]).
Effects on driving and mechanical handling ability
No special precautions.
[For pregnant and lactating women].
Use in Pregnant Women
There is limited information on the use of this product in pregnant patients. It should be used in women during pregnancy only if the expected efficacy of the treatment received significantly outweighs the risk.
Pregnancy records report the results of the use of valacyclovir or any acyclovir formulation (the active metabolite of valacyclovir) in pregnant women; 111 and 1246 cases were reported in registered pregnant women (including 29 and 756 cases in the first trimester of pregnancy, respectively). Results from the Acyclovir Pregnancy Documentation Project showed that birth defect rates were not increased in acyclovir-exposed patients compared with the overall population, and that none of the birth defects showed uniqueness or consistency to suggest a common etiology. Given the small number of female patients enrolled in the vaxilovir pregnancy registry, no reliable and definitive conclusions can be drawn regarding the safety of vaxilovir use during pregnancy (see [Pharmacokinetics]).
Use in Lactating Women
The major metabolite of vaxilovir secreted in breast milk is acyclovir. Following oral administration of a 500 mg dose of famciclovir, the peak concentration (Cmax) of acyclovir in breast milk is 0.5 – 2.3 (median 1.4) times the corresponding maternal acyclovir serum concentration. The area under the breast milk blood concentration-time curve (AUC) of acyclovir ranged from 1.4 to 2.6 (median 2.2) to the maternal serum AUC ratio. The median acyclovir concentration in breast milk was 2.24 μg/mL (9.95 mmol/L). If the maternal vaxilovir dose is 500 mg twice daily, then this level would expose the nursing infant to a daily oral acyclovir dose of approximately 0.61 mg/kg/day. The elimination half-life of acyclovir from breast milk is similar to that of serum.
No prodromal form of famciclovir was detected in maternal serum, breast milk, or infant urine.
Caution is advised for the use of valaciclovir in breastfeeding women.
Pediatric Dosage]
There is no information available on the treatment of pediatric patients.
Geriatric Use]
No dose adjustment is required, except for those with significantly impaired renal function. Adequate hydration should be maintained.
Drug Interactions
No significant drug interactions have been identified.
Cimetidine and probenecid can increase the area under the blood concentration-time curve (AUC) of acyclovir by decreasing renal clearance, but no dose adjustment is required because of the large therapeutic index of acyclovir. Other drugs that affect renal physiology may also affect plasma levels of acyclovir.
[Drug Overdose].
Data on overdose of this product are limited. However, patients have been treated with single doses of acyclovir up to 20 g, which were partially absorbed through the gastrointestinal tract, without the common toxic effects.
Unexpected gastrointestinal (e.g., nausea, vomiting) and neurologic (headache and confusion) reactions associated with repeated oral overdoses of acyclovir over several days have been observed.
Intravenous overdose of acyclovir has been associated with elevated plasma creatinine anhydride, which can lead to renal failure. There are also neurologic reactions associated with intravenous acyclovir overdose, including confusion, hallucinations, euphoria, convulsions, and coma.
Patients should be closely monitored for signs of toxicity. Hemodialysis can significantly improve the clearance of acyclovir from the blood and may therefore be an option for management after an overdose.
Pharmacology and Toxicology
Pharmacological effects
Pharmacotherapeutic grouping.
Vaciclovir is an antiviral agent and is the L-valine ester of acyclovir. Acyclovir is a purine (guanine) nucleoside analogue.
Vaxilovir is converted almost entirely and rapidly in the body to acyclovir and valine by the action of the enzyme vaxilovir hydrolase.
Acyclovir is a specific inhibitor of herpes viruses and has the ability to inhibit herpes simplex virus (HSV) types 1 and 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6) in vitro.
Acyclovir is converted to the active triphosphate form by phosphorylation to act as an inhibitor of viral DNA synthesis.
The first step of phosphorylation requires the activity of virus-specific enzymes. For HSV, VZV and EBV, the enzyme is viral thymidine kinase (TK), which is present only in virus-infected cells. This selectivity persists in phosphorylated CMV and is mediated, at least in part, by the gene product of UL97 phosphotransferase. Acyclovir activation requires virus-specific enzymes, a condition that explains the selectivity of its action.
The phosphorylation process is accomplished by the action of a cellular kinase (conversion from monophosphate to triphosphate). Acyclovir triphosphate competitively inhibits viral DNA polymerase, and binding to this nucleoside analogue leads to termination of the specialized strand, interrupting viral DNA synthesis and thus blocking viral replication.
In clinical trials for the treatment of herpes zoster, this product reduced the pain associated with herpes zoster, including acute pain and postherpetic neuralgia, and also reduced the time to formation of new lesions.
Extensive clinical monitoring of patients receiving acyclovir treatment or prophylaxis has shown that reduced sensitivity to acyclovir is rare in immunocompetent patients and occasionally seen in patients with severe immunodeficiency, such as patients with solid organ or bone marrow transplants, patients with malignancies receiving chemotherapy, and those with human immunodeficiency virus (HIV) infection.
Resistance is generally caused by a thymidine kinase defective phenotype that places the virus at a significant disadvantage in the natural host. In a few cases, reduced susceptibility to acyclovir may be caused by mutations in the viral thymidine kinase or DNA polymerase. The virulence of these mutated strains is similar to that of wild-type viral strains.
Toxicity studies
Mutagenicity: Results of in vivo and in vitro mutagenicity tests indicate that vaxilovir is not genetically dangerous to humans.
Carcinogenicity: Bioassays in mice and rats have shown that valacyclovir is not carcinogenic.
Teratogenicity: Valacyclovir was not teratogenic in rats and rabbits and was almost completely metabolized to acyclovir.
In internationally recognized experiments, subcutaneous administration of acyclovir to rats and rabbits showed no teratogenic effects. In separate rat studies, subcutaneous administration of plasma concentrations up to 100 mg/ml was found to be abnormal in fetal rats and to cause toxicity in mothers.
Fertility.
Oral administration of vaxilovir did not affect the fertility of male and female rats. Testicular atrophy and absence of sperm production were observed in rats and dogs at high parenteral doses of acyclovir.
[Pharmacokinetics].
General characteristics.
Vaxilovir is completely and rapidly absorbed orally and is converted almost entirely to acyclovir and valine. This conversion process is probably accomplished by the enzyme vaxilovir hydrolase in the human liver.
The bioavailability of acyclovir in 1000 mg of vaxilovir was 54% and was not affected by food. 500 mg of vaxilovir, administered twice daily, was 2.6 times more bioavailable than acyclovir 200 mg, administered five times daily.
The daily AUC (area under the blood concentration-time curve) of acyclovir after vaxilovir 1000 mg , administered orally 3 times daily, was 2-fold higher than that of acyclovir 800 mg , administered orally 5 times daily.
The Cmax and daily AUC of acyclovir were more than 4-fold and 1.8-fold higher, respectively, than those predicted with acyclovir 200 mg administered 5 times daily after 2 doses of vaxilovir 500 mg daily.
The mean peak concentration of acyclovir after a single dose of vaxilovir 250 -1000 mg was 10-25 mM (2.2-5.7 mg/ml), with a mean time to peak of 1.5 hours after dosing.
The peak plasma concentration of vaxilovir was only 4% of that of acyclovir, with a mean time to peak of 30-60 minutes after dosing and a decrease in blood levels below detectable levels after 3 hours of dosing. The pharmacokinetic profiles of vaxilovir and acyclovir were similar after single and multiple doses. Binding of acyclovir to plasma proteins was low (15%).
The plasma clearance half-reduction period of acyclovir after single and multiple doses of vaxilovir was approximately 3 hours. The amount of vaxilovir in its original form in the urine is less than 1% of the ingested amount. Vaciclovir is cleared in the urine primarily as acyclovir and the known acyclovir metabolite 9-carboxymethoxymethylguanine (CMMG).
Pharmacokinetics in patients
Herpes zoster and herpes simplex have no significant effect on the pharmacokinetic profile of vaxilovir and acyclovir following oral administration of this product.
The distribution and pharmacokinetic profile of acyclovir did not change significantly in HIV-infected patients following single or multiple oral doses of vaxilovir 1000 mg or 2000 mg compared to healthy subjects.
Storage
Store below 30°C.
Package
Aluminum-plastic package. 10 tablets, 42 tablets/box.
Expiration date】 36 months.
Executive Standard
Imported drug registration standards: JX20130085
Approval number】 Imported drug registration certificate number: HXXXXXXXX
【Manufacturer】
Manufacturer: GLAXO WELLCOME ,S.A.
Production Address: Avda, Extremadura, 3, 09400 Aranda de Duero, Burgos, Spain (Spain)
Domestic contact address.
6F, Metropolitan Headquarters Building, No. 168, Xizang Middle Road, Shanghai, China
Postal Code: 200001
Telephone number: (86-21) 23019800
Fax Number: (86-21) 23019801
GSK Hotline: 800-820-3383/400-183-3383
Version number: GDS22/IPI04