Валтрекс
Producer: Glaxo Operetaions UK Limited (Glakso Opereyshns YuK Limited) Great Britain
Code of automatic telephone exchange: J05AB11
Release form: Firm dosage forms. Tablets.
General characteristics. Structure:
Tablets, film coated white color, oblong, biconvex, without risks, on one party the text "GX CF1" is engraved; a tablet kernel from white till almost white color.
Active ingredient: a valatsiklovira a hydrochloride of 556 mg that corresponds to the maintenance of a valatsiklovir of 500 mg.
Excipients: cellulose microcrystallic - 70 mg, кросповидон - 28 mg, K90 povidone - 22 mg, magnesium stearate - 4 mg, silicon dioxide colloid - 2 mg.
Structure of a film cover: опадрай white ~ 14 mg (a gipromelloza - 9.48 mg, titanium dioxide - 3.26 mg, a macrogoal of 400 - 1.12 mg, polysorbate of 80 - 0.14 mg); polish (wax of karnaubskiya ~ 0.016 mg).
Pharmacological properties:
Valatsiklovir is antiviral means, acyclovir ester represents L-valinovy. The acyclovir is an analog of a purine nucleoside (guanine).
In a human body валацикловир quickly and completely turns into an acyclovir and valine under the influence of valatsiklovirgidrolaza enzyme. The acyclovir possesses in vitro the specific inhibiting activity against the herpes simplex viruses (HSV) of the 1st and 2nd types, a virus of chicken pox and the surrounding herpes (VZV - a varitsella-zoster a virus, Varicella zoster virus), a cytomegalovirus (TsMV), the Epstein-Barre's virus (EBV) and a virus of herpes of the person of the 6th type. The acyclovir inhibits synthesis of virus DNA right after phosphorylation and transformation into an active form ацикловиртрифосфат.
The first stage of phosphorylation demands activity of virus-specific enzymes. For VPG, VZV, and VEB such enzyme is a virus thymidinekinase which is present at the cells affected with a virus. Partial selectivity of phosphorylation remains at a cytomegalovirus and is mediated through an UL97 phosphotransferase gene product. Activation of an acyclovir specific virus enzyme substantially explains its selectivity.
Process of phosphorylation of an acyclovir (transformation from mono - in triphosphate) comes to the end with cellular kinases. Atsiklovirtrifosfat competitively inhibits a virus DNA polymerase and, being a nucleoside analog, is built in virus DNA that leads to an obligate rupture of a chain, the termination of synthesis of DNA and, therefore, to blocking of replication of a virus.
With the kept immunity of VPG and VZV with a hyposensitivity to a valatsiklovir occur at patients extremely seldom, but can be sometimes found in patients with heavy disturbance of immunity, for example, with a marrow transplant, at receiving chemotherapy concerning malignant new growths and at HIV-positive people.
Resistance is usually caused by deficit of a thymidinekinase that leads to excessive spread of a virus in the owner's organism. Sometimes decrease in sensitivity to an acyclovir is caused by emergence of virus strains with disturbance of structure of a virus thymidinekinase or DNA polymerase. Virulence of these kinds of a virus reminds that at its wild strain.
Pharmacokinetics. Absorption
After intake валацикловир it is well soaked up from a GIT, quickly and almost completely turning into an acyclovir and valine. This transformation is catalyzed by enzyme of a liver valatsiklovirgidralazy. After a single dose of a valatsiklovir in a dose of 250-2000 mg average Cmax of an acyclovir in plasma at healthy volunteers with normal function of kidneys makes 10-37 µmol/l (2.2-8.3 mkg/ml), and the average time of achievement of Cmax of 1-2 h. At reception of a valatsiklovir from 1000 mg bioavailability of an acyclovir is equal in a dose to 54% and does not depend on meal. Cmax of a valatsiklovir in plasma makes only 4% of concentration of an acyclovir, the average time of achievement of Cmax of a valatsiklovir in plasma – 30-100 min. after reception of a dose, the limit of quantitative definition of a valatsiklovir in plasma is reached in 3 h or earlier. Valatsiklovir and an acyclovir have similar pharmacokinetic parameters after intake.
Distribution
Extent of linkng of a valatsiklovir with proteins of plasma is very low (only 15%).
Removal
At patients with normal function of kidneys T1/2 of an acyclovir after reception of a valatsiklovir makes about 3 h of plasma, and at patients with a final stage of a renal failure an average elimination half-life about 14 h Valatsiklovir is brought from an organism by kidneys preferential in the form of an acyclovir (more than 80% of a dose) and a metabolite of an acyclovir of a 9-karboksimetoksimetilguanin, in not changed look less than 1% of a valatsiklovir eliminirutsya.
Special groups of patients
The pharmacokinetics of a valatsiklovir and acyclovir substantially does not change at the patients infected with VPG and VZV.
On late durations of gestation the daily indicator of AUC in an equilibrium state after reception of 1000 mg of a valatsiklovir was approximately twice more, than that at reception of an acyclovir in a dose of 1200 mg /
HIV-positive patients have pharmacokinetic parameters of an acyclovir after intake of a valatsiklovir in a dose of 1000 mg or 2000 mg are comparable to the parameters observed at healthy volunteers.
At recipients of the transplants which received валацикловир in a dose of 2000 mg 4, Cmax of an acyclovir was comparable or exceeded the concentration observed at healthy volunteers after reception of the same doses, at the same time daily indicators of the area under a pharmacokinetic curve were significantly higher.
Indications to use:
Adults
— treatment of shingles (Herpes zoster) (drug promotes stopping of a pain syndrome, reduces its duration and percent of patients with the pains caused by shingles including acute and post-herpetic neuralgia);
— treatment of infections of skin and the mucous membranes caused by VPG, including for the first time the revealed and recurrent genital herpes (Herpes genitalis), and also labial herpes (Herpes labialis);
— prevention (suppression) of a recurrence of infections of skin and the mucous membranes caused by VPG including genital herpes;
— prevention of transfer of genital herpes to the healthy partner at reception as suppressive therapy in combination with safe sex.
Adults and teenagers aged from 12 years are also more senior
— prevention of a Cytomegaloviral (TsMV) infection, and also reaction of acute graft rejection (at patients with transplants of kidneys), opportunistic infections and other herpesviridae infections (VPG, VZV) after organ transplantation.
Route of administration and doses:
The drug Valtreks® is accepted regardless of meal, tablets should be washed down with water.
Treatment of shingles (Herpes zoster)
Adults
The recommended dose makes 1 g 3 within 7 days.
Treatment of the infections caused by VPG
Adults
The recommended dose for therapy of an episode makes 500 mg 2 within 5 days.
In more hard cases of the beginning of a disease treatment should be begun as soon as possible, and its duration can be increased from 5 to 10 days. In case of a recurrence treatment has to continue 3 or 5 days. At VPG recurrence purpose of the drug Valtreks® in a prodromal stage or at once after emergence of the first symptoms of a disease is considered ideal.
As an alternative for treatment of labial herpes purpose of the drug Valtreks® in a dose of 2 g is effective 2 Second dose have to be is accepted approximately in 12 h (but not earlier, than in 6 h) after reception of the first dose. When using such mode of dosing duration of treatment makes one days. Therapy has to be begun at emergence of the earliest symptoms of labial herpes (i.e. tingling, an itch, burning).
Prevention (suppression) of a recurrence of the infections caused by VPG
Adults
At patients with the kept immunity the recommended dose makes 500 mg of 1 times /
At patients with an immunodeficiency the recommended dose makes 500 mg 2
Prevention of transfer of genital herpes to the healthy partner
To the infected immunocompetent persons with a recurrence no more than 9 times a year, the recommended dose of the drug Valtreks® makes 500 mg of 1 times / within a year and more than an every day.
Data on prevention of infection in other populations of patients are absent.
Prevention of a Cytomegaloviral (TsMV) infection after transplantation
Adults and teenagers aged from 12 years are also more senior
The recommended dose makes 2 g 4, is appointed as soon as possible, after transplantation.
The dose should be reduced depending on clearance of creatinine.
Duration of treatment makes 90 days, but at patients with high risk the course of treatment can be prolonged.
Special groups of patients
Patients with a renal failure
Treatment of shingles and the infections caused by VPG, prevention (suppression) of a recurrence of the infection caused by VPG, prevention of transfer of genital herpes to the healthy partner
The dose of the drug Valtreks® is recommended to be reduced at patients with considerable depression of function of kidneys (see the dosing mode in Table 1). At such patients it is necessary to support adequate hydration.
There is no experience of use of the drug Valtreks® for children with values of clearance of creatinine less than 50 ml/min. / 1.73 sq.m.
Table 1.
Indications Clearance of creatinine, drug Valtreks® Dose
ml/min.
Shingles
(Herpes zoster) 15-30 1 of 2
less than 15 1 g of 1 times /
Treatment of an infection,
the caused VPG
(according to the scheme of 500 mg 2) less than 15 500 mg of 1 times /
Treatment of labial 31-49 1 g twice within one day
herpes (according to the scheme of 2 g
2 times a day in 15-30 500 mg twice within one day
current of one days) less than 15 500 mg once
Prevention (suppression) of a recurrence of the infections caused by VPG:
— patients with normal immunity less than 15 250 mg once a day
— patients with reduced immunity less than 15 500 mg once a day
— decrease in risk of transfer of genital herpes less than 15 250 mg once a day
The patients who are on a hemodialysis are recommended to apply Valtreks® right after the end of a session of a hemodialysis in the same dose as to patients with clearance of creatinine less than 15 ml/min.
Prevention of a Cytomegaloviral (TsMV) infection after transplantation
The mode of purpose of the drug Valtreks® at patients with a renal failure has to be set according to Table 2 given below.
Table 2.
Clearance of creatinine, ml/min. drug Valtreks® Dose
75 and more than 2 g 4 razanut
from 50 to less than 75 1.5 g 4
from 25 to less than 50 1.5 g 3
from 10 to less than 25 1.5 g 2
less than 10 or dialysis * 1.5 g of 1 times /
* At the patients who are on a hemodialysis, it is necessary to appoint the drug Valtreks® after the end of a session of a hemodialysis.
It is necessary to define often clearance of creatinine, especially when function of kidneys quickly changes, for example, right after transplantation or engraftment of a transplant, at the same time the dose of the drug Valtreks® is adjusted according to indicators of clearance of creatinine.
Patients with an abnormal liver function
With an abnormal liver function of easy or moderate severity at safe synthetic function dose adjustment of the drug Valtreks® is not required from adult patients. Pharmacokinetic data at adult patients with heavy abnormal liver functions (dekompensirovanny cirrhosis), with disturbance of synthetic function of a liver and existence of a porto-caval anastomosis also do not confirm need to adjust a drug Valtreks® dose, however, clinical experience at this pathology is limited.
Children aged up to 12 years
There are no data on use of the drug Valtreks® for children.
Patients of advanced age
Dose adjustment is not required, except for a considerable renal failure. It is necessary to support adequate water and electrolytic balance.
Features of use:
Patients with risk have dehydrations, especially at patients of advanced age, it is necessary to provide adequate completion of liquid.
As the acyclovir is removed by kidneys, the dose of the drug Valtreks® has to be adjusted depending on extent of disturbance of renal function. At patients with a renal failure the increased risk of development of neurologic complications is noted, such patients need to provide careful observation. As a rule, these reactions, generally have reversible character after drug withdrawal.
There are no data on use of the drug Valtreks® in high doses (4 g higher) at patients with a liver disease therefore high doses of the drug Valtreks® to them have to be appointed with care. Special researches on studying of effect of the drug Valtreks® at liver transplantation were not conducted. However it was shown that preventive intravenous purpose of an acyclovir in high doses reduces displays of the TsMV-infection.
Suppressive therapy by the drug Valtreks® reduces risk of transfer of genital herpes, but completely does not exclude risk of infection and does not lead to full treatment. Therapy by the drug Valtreks® is recommended in combination with safe sex.
Influence on ability to driving of motor transport and to control of mechanisms
It is necessary to consider a clinical condition of the patient and a profile of side reactions of a valatsiklovir at assessment of ability of the patient to drive the car or moving mechanisms.
Side effects:
Undesirable reactions are listed below according to classification by the main systems and bodies and by emergence frequency: very often (≥1/10), it is frequent (≥1/100, <1/10), infrequently (≥1/1000, <1/100), is rare (≥1/10 000, <1/1000), is very rare (<10 000).
Data of clinical trials
From a nervous system: often - a headache.
From a GIT: often - nausea.
Data of post-market researches
From system of blood and bodies of a hemopoiesis: very seldom - a leukopenia, thrombocytopenia. Generally the leukopenia was observed at patients with reduced immunity.
From immune system: very seldom - an anaphylaxis.
From a nervous system and mentality: seldom - dizziness, confusion of consciousness, a hallucination, consciousness oppression; very seldom - agitation, a tremor, an ataxy, a dysarthtia, psychotic symptoms, spasms, encephalopathy, a coma. The listed above symptoms, are generally reversible and are usually observed at patients with a renal failure or against the background of other contributing states. At the adult patients with a transplanted organ receiving high doses (8 g/) the drug Valtreks® for prevention of the TsMV-infection, neurologic reactions develop more often than at reception of lower doses.
From respiratory system and bodies of a mediastinum: infrequently - an asthma.
From a GIT: seldom - discomfort in a stomach, vomiting, diarrhea.
From a liver and biliary tract: very seldom - reversible disturbances of functional hepatic trials which sometimes regard as displays of hepatitis.
From skin and a hypodermic fatty tissue: infrequently - rashes, including photosensitivity manifestations; seldom - an itch; very seldom - a small tortoiseshell, a Quincke's disease.
From an urinary system: seldom - a renal failure; very seldom - an acute renal failure, renal colic. Renal colic can be connected with a renal failure.
Others: at patients with heavy disturbances of immunity, especially at the adult patients with far come stage of HIV infection receiving high doses of a valatsiklovir (8 g/) during a long span, cases of a renal failure, mikroangiopatichesky hemolitic anemia and thrombocytopenia were observed (sometimes in a combination). Similar complications were noted at patients with the same the basic and/or associated diseases, but not receiving валацикловир.
Interaction with other medicines:
Clinically significant interactions are not established.
The acyclovir is removed by kidneys, generally in not changed look by means of active renal secretion. The combined use of medicines with this mechanism of removal can lead to increase in concentration of an acyclovir in plasma.
After purpose of the drug Valtreks® in a dose of 1 g, Cimetidinum and пробенецид which are removed in the same way as the drug Valtreks®, is raised by AUC of an acyclovir and, thus, reduce its renal clearance. However, in view of a wide therapeutic index of an acyclovir, drug Valtreks® dose adjustment in this case it is not required.
It is necessary to be careful in case of simultaneous use of the drug Valtreks® in higher doses (4 g higher) and medicines which compete with an acyclovir for a way of removal as there is a potential threat of increase in plasma of concentration of one or both drugs or their metabolites. Increase in AUC of an acyclovir and inactive metabolite of a mikofenolat of a mofetil, the immunodepressive drug used at transplantation, at simultaneous use of these drugs was noted.
It is also necessary to be careful (monitoring of function of kidneys) at a drug Valtreks® combination in higher doses (4 g higher) with drugs which exert impact on other functions of kidneys (for example, cyclosporine, такролимус).
Contraindications:
— children's age up to 12 years at prevention of a Cytomegaloviral (TsMV) infection after transplantation;
— children's age up to 18 years for all other indications (in connection with the insufficient number of data on clinical trials for the specified age group);
— hypersensitivity to the valatsiklovir, an acyclovir and any other component which is a part of drug.
With care
— at patients with a renal failure;
— patients with clinically expressed HIV infection forms;
— at a concomitant use of nefrotoksichny medicines;
— at clinically expressed HIV infection forms.
Use of the drug VALTREKS® at pregnancy and feeding by a breast
Data on use of the drug Valtreks® at pregnancy are not enough. Drug should be used at pregnancy only if the potential advantage for mother surpasses potential risk for a fruit.
Data of registration records about the result of pregnancy at the women accepting Valtreks® or other drugs containing an acyclovir (the acyclovir is an active metabolite of the drug Valtreks®), did not reveal increase in number of inborn defects at their children in comparison with the general population. As the register included a small amount of the women accepting валацикловир during pregnancy, the authentic and certain conclusions about safety of a valatsiklovir at pregnancy cannot be made.
The acyclovir, the main metabolite of a valatsiklovir, is excreted by breast milk. After purpose of a valatsiklovir in a dose of 500 mg in Cmax of an acyclovir in breast milk at 0.5-2.3 time (on average in the 14th time) exceeded the corresponding concentration of an acyclovir in a blood plasma of mother. Average value of concentration of an acyclovir in breast milk made 2.24 mkg/ml (9.95 µmol/l). At reception by mother of a valatsiklovir in a dose of 500 mg the 2nd child is exposed to the same influence of an acyclovir, as at its reception inside in a dose about 0.61 mg/kg / acyclovir T1/2 from breast milk same, as from a blood plasma.
Valatsiklovir in not changed look was not defined in mother's plasma, breast milk or the child's urine.
The feeding women should appoint the drug Valtreks® with care.
Use at abnormal liver functions
At abnormal liver functions with poorly or moderately expressed cirrhosis (synthetic function of a liver is kept) dose adjustment of Valtreks is not required from patients. At a pharmacokinetics research at patients with heavy cirrhosis (with disturbance of synthetic function of a liver and existence of shunts between portal system and the general vascular bed) the data testimonial of need of correction of the mode of dosing are also not obtained; however clinical experience of use of drug of Valtreks for this category of patients is organic.
There are no data on Valtreks's use in high doses (4 g any more) at patients with liver diseases therefore it is necessary to appoint with care drug in high doses of this category of patients.
Use at renal failures
At a renal failure the mode of dosing is set depending on clearance of creatinine and indications.
Indications Clearance of creatinine Valtreks's Dose
The surrounding herpes of 15-30 ml/min. 1 g 2
less than 15 ml/min. 1 g of 1 times /
Treatment of infections,
the caused Herpes
simplex less than 15 ml/min. 500 mg of 1 times /
Treatment of labial 31-49 ml/min. on 1 g 2 times within 1 day
herpes of 15-30 ml/min. on 500 mg 2 within 1 day
less than 15 ml/min. 500 mg once
at a normality
immuniteta:250 mg of 1 times /
Prevention (suppression) less than 15 ml/min. at an immunodeficiency: 500 mg of 1 times /
the infections caused
Herpes simplex
For decrease in infection
genital herpes less than 15 ml/min. 250 mg of 1 times /
The patients who are on a hemodialysis are recommended to appoint Valtreks right after the end of a session of a hemodialysis in the dose intended for patients with KK less than 15 ml/min. Drug should be used after the end of a session of a hemodialysis.
For prevention of Cytomegaloviral infections of Valtreks it is recommended to appoint in the following doses.
Clearance of creatinine (ml/min.) Valtreks's Dose
75 or more 2 g 4 times /
50 - less than 75 1.5 g 4
25 - less than 50 1.5 g 3
10 - less than 25 1.5 g 2
less than 10 or dialysis of 1.5 g of 1 times /
To the patients who are on a hemodialysis, it is necessary to appoint Valtreks after the end of a session of a hemodialysis.
Frequent control of KK, especially is necessary when function of kidneys quickly changes (including right after transplantation or engraftment of a transplant); Valtreks's dose should be adjusted according to KK.
Use for elderly patients
It is not required to patients of advanced age of dose adjustment, except for cases of a considerable renal failure. It is necessary to support adequate water and electrolytic balance.
Use for children
Experience of a clinical use of drug at children is absent.
Overdose:
Symptoms: the acute renal failure and neurologic disturbances, including confusion of consciousness, hallucinations, agitation, oppression of consciousness and a coma, and also nausea and vomiting, were observed at the patients who received the doses of a valatsiklovir exceeding recommended. Similar states were more often noted at patients with a renal failure and the patients of advanced age who received repeated the exceeding recommended doses of a valatsiklovir, owing to non-compliance with the mode of dosing.
Treatment: patients have to be under careful medical observation. The hemodialysis substantially promotes removal of an acyclovir from blood and can reckon as a choice method when maintaining patients with drug Valtreks® overdose.
Storage conditions:
Drug should be stored at a temperature not above 30 °C in the place, unavailable to children. A period of validity - 3 years.
Issue conditions:
According to the recipe
Packaging:
• tablets, film cover, 500 mg: 10 or 42-P N015441/01, 27.04.09. Validity period рег. уд. it is not limited.
