Valtrex - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Valaciclovir

Valtrex 250 mg film-coated tablets
Valtrex 500 mg film-coated tablets
Valtrex 1000 mg film-coated tablets

Why is Valtrex used? What is it for?

Valtrex belongs to a group of medicines called antivirals. It works by killing or stopping the growth of viruses called herpes simplex (HSV), varicella zoster (VZV), and cytomegalovirus (CMV).

Valtrex can be used for:

  • treat shingles (in adults)
  • treat HSV infections of the skin and genital herpes (in adults and adolescents over 12 years of age). It is also used to help prevent these infections from returning.
  • treat cold sores (in adults and adolescents over 12 years of age)
  • prevent CMV infections after organ transplantation (in adults and adolescents over 12 years of age)
  • treat and prevent HSV infections of the eye that keep coming back (in adults and adolescents over 12 years of age).

Contraindications When Valtrex should not be used

Do not take Valtrex

  • If you are allergic to valaciclovir or aciclovir or any of the other ingredients of this medicine (listed in section 6).
  • Do not take Valtrex if the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking Valtrex.

Precautions for use What you need to know before taking Valtrex

Talk to your doctor or pharmacist before taking Valtrex if:

  • have kidney problems
  • have liver problems
  • is over 65 years of age
  • his immune system is weak

If you are not sure if the above apply to you, talk to your doctor or pharmacist before taking Valtrex.

To prevent the transmission of genital herpes to other people

If you are taking Valtrex to treat or prevent genital herpes or if you have had genital herpes in the past, you must have protected sex including the use of condoms. This is important to prevent transmission of the infection to other people. . You should not have sex if you have pain or blisters in your genitals.

Interactions Which drugs or foods may change the effect of Valtrex

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription and herbal medicines.

Tell your doctor or pharmacist if you are taking any other medicines that affect the kidneys. These include: aminoglycosides, platinum-based compounds, iodinated contrast media, methotrexate, pentamidine, foscarnet, cyclosporine, tacrolimus, cimetidine and probenecid.

Always tell your doctor or pharmacist about any other medicines while you are taking Valtrex to treat shingles or after an organ transplant.

Warnings It is important to know that:

Pregnancy and breastfeeding

The use of Valtrex is generally not recommended during pregnancy. If you are pregnant, or think you may be or are planning to become pregnant, do not take Valtrex without checking with your doctor. Your doctor will make an assessment of the benefit for you and the risk to your baby of taking Valtrex while pregnant or breastfeeding.

Driving and using machines

Valtrex can cause side effects that affect the ability to drive. Do not drive or operate machinery unless you are sure you will not be affected.

Dose, Method and Time of Administration How to use Valtrex: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

The dose you need to take will depend on why your doctor has prescribed Valtrex for you. Your doctor will discuss this with you.

Treatment of "herpes zoster (St. Anthony's fire)"

  • The usual dose is 1000 mg (one 1000 mg tablet or two 500 mg tablets) three times a day.
  • You must take Valtrex for seven days.

Treatment of cold sores

  • The recommended dose is 2000 mg (two 1000 mg tablets or four 500 mg tablets) twice a day.
  • The second dose should be taken 12 hours (not earlier than 6 hours) after the first dose
  • You must take Valtrex for one day only (two doses).

Treatment of HSV infections of the skin and genital herpes

  • The recommended dose is 500 mg (one 500 mg tablet or two 250 mg tablets) twice a day.
  • For the first infection you should take Valtrex for five days or up to ten days if your doctor recommends it. For recurrent infections the duration of treatment is usually 3 to 5 days.

To help prevent HSV infections from coming back after you have them

  • The recommended dose is one 500 mg tablet once a day.
  • Some people with frequent recurring infections find it beneficial to take one 250 mg tablet twice a day.
  • You must take Valtrex until your doctor tells you to stop.

To prevent getting CMV (Cytomegalovirus) infection

  • The recommended dose is 2000 mg (two 1000 mg tablets or four 500 mg tablets) four times a day.
  • You should take each dose approximately 6 hours apart.
  • Normally you will start taking Valtrex as soon as possible after your surgery.
  • You will need to take Valtrex for about 90 days after your surgery until your doctor tells you to stop.

Your doctor may change the dose of Valtrex if:

  • is over 65 years of age
  • has a weak immune system
  • have kidney problems.

Tell your doctor before taking Valtrex if any of the situations listed above apply to you.

Taking the medicine

  • Take this medicine by mouth.
  • Swallow the tablets whole with a sip of water.
  • Take Valtrex at the same time each day.
  • Take Valtrex as directed by your doctor or pharmacist.

People over 65 years of age or with kidney problems

It is very important while you are taking Valtrex that you drink water regularly throughout the day. This will help reduce unwanted effects that may affect the kidneys or nervous system. Your doctor will monitor you carefully for signs of these effects. Nervous system side effects could include feeling confused or agitated, unusual feeling of sleepiness or numbness.

Overdose What to do if you have taken too much Valtrex

If you take more Valtrex than you should

Valtrex is normally not harmful unless you take too much and for several days. If you take too many tablets you may feel nauseous, vomit, have kidney problems, be confused, agitated or feel less aware, see things that are not there, or lose consciousness. Tell your doctor or pharmacist if you have taken too much Valtrex. Take the medicine pack with you.

If you forget to take Valtrex

  • If you forget to take Valtrex, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose.
  • Do not take a double dose to make up for a forgotten dose.

Side Effects What are the side effects of Valtrex

Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects may occur with this medicine:

Conditions to which you must pay attention

  • severe allergic reactions (anaphylaxis). These are rare in people taking Valtrex. Rapid development of symptoms which include:
  • redness, itchy rash
  • swelling of the lips, face, neck and throat causing difficulty in breathing (angioedema)
  • abrupt drop in blood pressure leading to collapse.

If you have an allergic reaction stop taking Valtrex and contact your doctor immediately.

Very common (may affect more than 1 in 10 people):

  • headache

Common (may affect up to 1 in 10 people):

  • nausea
  • dizziness
  • He retched
  • diarrhea
  • skin reaction after exposure to sunlight (photosensitivity)
  • rash
  • itch

Uncommon (may affect up to 1 in 100 people):

  • state of confusion
  • seeing or hearing things that are not there (hallucinations)
  • state of severe numbness
  • tremors
  • state of agitation

These nervous system side effects generally occur in people with kidney problems, the elderly or organ transplant patients taking high doses, 8 grams or more, of Valtrex per day. These effects usually improve when Valtrex is stopped or taken. dose is reduced.

Other uncommon side effects:

  • shortness of breath (dyspnoea)
  • stomach upset
  • rash, sometimes itching, hives
  • pain in the lower back (kidney pain)
  • blood in the urine (haematuria)

Uncommon side effects that may show up in blood tests:

  • reduced number of white blood cells (leukopenia)
  • reduction in the number of blood platelets which are the cells needed for clotting (thrombocytopenia)
  • increase in substances produced by the liver.

Rare (may affect up to 1 in 1000 people):

  • unsteadiness in walking and lack of coordination (ataxia)
  • words spoken in a slow and defective way (dysarthria)
  • convulsions
  • impaired brain function (encephalopathy)
  • loss of consciousness (coma)
  • confused or disturbed thinking (delirium)

These nervous system side effects generally occur in people with kidney problems, the elderly or organ transplant patients taking high doses, 8 grams or more, of Valtrex per day. These effects usually improve when Valtrex is stopped or taken. dose is reduced.

Other rare side effects

  • kidney problems with little or no urine passing.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

  • Keep this medicine out of the sight and reach of children.
  • Do not use this medicine after the expiry date which is stated on the carton. The expiration date (EXP) refers to the last day of that month.
  • Store at a temperature below 30 ° C.
  • Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What Valtrex contains

  • The active ingredient is valaciclovir. Each tablet contains 250 mg, 500 mg or 1000 mg of valaciclovir (as valaciclovir hydrochloride).

The other ingredients are:

Core of the tablet

Microcrystalline cellulose

Crospovidone

Povidone

Magnesium stearate

Anhydrous colloidal silica

Coating

Hypromellose

Titanium dioxide

Macrogol 400

Polysorbate 80 (for 500 mg and 1000 mg tablets only)

Carnauba wax

What Valtrex looks like and contents of the pack

Valtrex tablets are contained in polyvinyl chloride / aluminum blister packs.

Valtrex 250 mg tablets are supplied in packs containing 20 or 60 film-coated tablets. They are white in color and marked with "GX CE7" on one side.

Valtrex 500 mg tablets are supplied in packs containing 10, 24, 30, 42, 90 or 112 film-coated tablets. They are white in color and marked with "GX CF1" on one side.

Valtrex 1000 mg tablets are supplied in packs containing 21 film-coated tablets. They are white in color and marked with "GX CF2" on one side.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Valtrex is available in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER 09 .0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

ZELITREX TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains valaciclovir hydrochloride equivalent to 250 mg of valaciclovir.

Each tablet contains valaciclovir hydrochloride equivalent to 500 mg of valaciclovir.

Each tablet contains valaciclovir hydrochloride equivalent to 1000 mg of valaciclovir.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet

250 mg tablet

White oblong biconvex tablet with a white to dark white core debossed with "GX CE7" on one side.

500 mg tablet

White oblong biconvex tablet with a white to dark white core debossed with "GX CF 1" on one side.

1000 mg tablet

White oblong biconvex tablet with a white to dark white core with partial score line on both sides and debossed with "GX CF2" on one side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Varicella zoster virus (VZV) infections - herpes zoster

Valtrex is indicated for the treatment of herpes zoster 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 which include

- treatment of the first episode of genital herpes in immunocompetent adults and adolescents and in immunocompromised adults

- treatment of recurrent genital herpes infections in immunocompetent adults and adolescents and immunocompromised adults

- suppression of recurrent genital herpes in immunocompetent adults and adolescents and immunocompromised adults

• for the treatment and suppression of recurrent HSV ocular infections (see section 4.4).

No clinical studies have been conducted in HSV-infected patients who are immunocompromised for causes other than HIV infection (see section 5.1).

Cytomegalovirus infections (CMV)

Valtrex is indicated for the prophylaxis of CMV infection and disease following solid organ transplantation in adults and adolescents (see section 4.4).


04.2 Posology and method of administration

Varicella zoster virus (VZV) infections - herpes zoster and ophthalmic zoster

Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster. There are no data on treatment initiated more than 72 hours after the onset of zoster rash.

Immunocompetent adults

The dose in immunocompetent patients is 1000 mg three times a day for seven days (total daily dose 3000 mg). This dose should be reduced based on creatinine clearance (see Renal impairment below).

Immunocompromised adults

The dose in immunocompromised patients is 1000 mg three times a day for at least seven days (total daily dose 3000 mg) and for 2 days after crusting of the lesions.

This dose should be reduced based on creatinine clearance (see Renal impairment below).

In immunocompromised patients, antiviral treatment is recommended for patients presenting within one week of blistering or at any time prior to 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 based on creatinine clearance (see Renal impairment below).

In recurrent episodes, treatment should be three to four days. For initial episodes, which may be more severe, treatment may need to be extended to ten days. Therapy should begin as soon as possible. In recurrent episodes of herpes simplex, treatment should preferably occur during the prodromal phase or immediately upon the appearance of the first signs or symptoms. Valtrex can prevent the development of lesions when taken at the first signs and symptoms of a recurrent HSV infection.

Cold sores

For cold sores, valaciclovir 2000 mg twice daily for one day is an effective treatment in adults and adolescents. The second dose should be taken approximately 12 hours (not earlier than 6 hours) after the first dose. should be reduced based on creatinine clearance (see Renal impairment below).

When using this dosing regimen, treatment should not exceed one day as this has not been shown to provide "additional clinical benefit. Therapy should begin at the first symptom of cold sores (eg 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 patient's clinical condition and immunological status. For initial episodes, which may be more treatment may need to be extended to ten days. Dosing should begin as soon as possible. This dose should be reduced based on creatinine clearance (see Renal impairment below). For maximum clinical benefit, treatment should be be started within 48 hours. Close monitoring of lesion evolution is recommended.

Suppression of recurrent herpes simplex virus (HSI) infections in adults and adolescents (≥ 12 years)

Immunocompetent adults and adolescents (≥ 12 years)

The dose is 500 mg of Valtrex to be taken once a day. Some patients with very frequent relapse episodes (≥ 10 / year in the absence of therapy) may benefit more from taking a daily dose of 500 mg divided into two doses (250 mg twice daily). This dose should be reduced. based on creatinine clearance (see Renal impairment below) Treatment should be re-evaluated after 6-12 months of therapy.

Immunocompromised adults

The dose is 500 mg of Valtrex twice a day. This dose should be reduced based on creatinine clearance (see Renal impairment below). Treatment should be re-evaluated after 6-12 months of therapy.

Prophylaxis of cytomegalovirus (CMI) infection and disease in adults and adolescents (≥ 12 years)

The dosage of Valtrex is 2000 mg four times a day, to be started as soon as possible after the transplant. This dose should be reduced based on creatinine clearance (see Renal impairment below).

The duration of treatment is typically 90 days but may need to be prolonged in high-risk patients.

Special populations

Children

The efficacy of Valtrex in children under 12 years of age has not been evaluated.

Senior citizens

In the elderly, the possibility of renal insufficiency must be taken into account and the dose adjusted accordingly (see Renal insufficiency below). Adequate hydration must be maintained.

Kidney failure

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 hemodialysis, the dose of Valtrex should be administered after hemodialysis has been performed. Creatinine clearance should be monitored frequently, especially during periods when renal function changes rapidly, such as immediately after kidney transplantation or its taking root.Valtrex dosage should be adjusted accordingly.

Hepatic insufficiency

Studies performed with a 1000 mg dose of valaciclovir in adult patients show that no dose modification is required in patients with mild or moderate cirrhosis (hepatic synthesis function maintained). Pharmacokinetic data in adult patients with advanced cirrhosis (impaired hepatic synthesis function and evidence

portosystemic shunt) do not indicate the need for a dose modification; however clinical experience is limited. For higher doses (4000 mg or more per day) see section 4.4.

Table 1: DOSAGE ADJUSTMENTS IN "KIDNEY INSUFFICIENCY

Therapeutic indications Creatinine clearance (ml / min) Valaciclovir Dosagea Varicella-Zoster Virus (VZV) Infections Treatment of herpes zoster in immunocompetent and immunocompromised adults ≥ 50 1000 mg three times a day 30 to 49 1000 mg twice a day 10 to 29 1000 mg once daily 10 500 mg once a day Herpes Simplex Virus (HSV) Infections Treatment of HSV infections - immunocompetent adults and adolescents ≥ 30 500 mg twice a day 500 mg once a day - immunocompromised adults ≥ 30 1000 mg twice a day 1000 mg once daily Treatment of cold sores in immunocompetent adults and adolescents (1 day alternative regimen) ≥ 50 2000 mg twice in one day 30 to 49 1000 mg twice in one day 10 to 29 500 mg twice in one day 500 mg single dose Suppression of HSV infections - immunocompetent adults and adolescents ≥ 30 500 mg once daily b 250 mg once a day - immunocompromised adults ≥ 30 500 mg twice a day 500 mg once a day Cytomegalovirus (CMV) infections CMV prophylaxis in adults and adolescents with solid organ transplantation ≥ 75 2000 mg four times a day from 50 to 1500 mg four times a day from 25 to 1500 mg three times a day from 10 to 1500 mg twice a day dialysis 1500 mg once a day

a For patients on intermittent hemodialysis, the dose should be administered after dialysis on dialysis days.

bFor HSV suppression in immunocompetent individuals with a history of relapses per year ≥10, better results may be obtained with 250 mg twice daily.


04.3 Contraindications

Hypersensitivity to valaciclovir or aciclovir or to any of the excipients (see section 6.1).


04.4 Special warnings and appropriate precautions for use

State of hydration

Care should be taken to ensure that patients at risk of dehydration, particularly the elderly, get an adequate amount of fluids.

Use in patients with renal insufficiency and elderly patients

Aciclovir is eliminated by renal clearance, therefore the dose of valaciclovir should be reduced in patients with renal insufficiency (see section 4.2). Elderly patients are likely to have impaired renal function and therefore the need for dose reduction should be considered in this patient group. Both elderly patients and patients with renal insufficiency are at increased risk of developing neurological side effects and should be carefully monitored for these effects. In reported reports, these reactions were generally reversible upon discontinuation of treatment (see section 4.8).

Use of higher doses of valaciclovir in liver failure and liver transplantation

There are no data on the use of higher doses of valaciclovir (4000 mg or more per day) in patients with liver disease. No specific studies have been conducted with valaciclovir in liver transplantation and therefore caution should be used when administering daily doses. greater than 4000 mg to these patients.

Use for the treatment of shingles

The clinical response should be closely monitored especially in immunocompromised patients. IV antiviral therapy should be considered if the response to oral therapy is considered insufficient.

Patients with complicated herpes zoster e.g. those with visceral involvement, disseminated zoster, motor neuropathy, encephalitis and cerebrovascular complications should be treated with intravenous antiviral therapy.

In addition, immunocompromised patients with ophthalmic zoster or those at high risk of 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 an antiviral agent, the frequency of viral shedding is significantly reduced. However, the risk of transmission is still possible. Therefore, in addition to valaciclovir therapy, it is recommended that patients have protected sexual intercourse.

Use in HSV ocular infections

The clinical response must be closely monitored in these patients. IV antiviral therapy should be considered if the response to oral therapy is considered insufficient.

Use in CMV infections

Data on the efficacy of valaciclovir in transplant patients (≥ 200) at high risk of CMV disease (e.g. CMV-positive donor / CMV-negative recipient or use of inductive therapy with anti-thymocyte globulin) indicate that valaciclovir should be used only in these patients when tolerability problems preclude the use of valganciclovir or ganciclovir.

The high dose of valaciclovir required for CMV prophylaxis may result in a higher frequency of undesirable effects including central nervous system abnormalities than that seen with lower doses administered for other indications (see section 4.8). Patients should be closely monitored. monitored for changes in renal function and dose adjusted appropriately (see section 4.2).


04.5 Interactions with other medicinal products and other forms of interaction

Concomitant administration of valaciclovir with nephrotoxic medicinal products should be done with caution, especially in subjects with impaired renal function and requires regular monitoring of renal function. This concerns the concomitant administration of aminoglycosides, platinum-based compounds, iodinated contrast media, methotrexate, pentamidine, foscarnet, cyclosporine and tracolimus.

Aciclovir is eliminated unchanged primarily in the urine via active renal tubular secretion. After administration of 1000 mg of valaciclovir, cimetidine and probenecid reduce the renal clearance of aciclovir and increase the aciclovir AUC by approximately 25% and 45%, respectively, by inhibiting the active renal secretion of aciclovir. Cimetidine and probenecid taken together with valaciclovir increase aciclovir AUC by approximately 65%. Other drugs (including eg tenofovir) administered concomitantly, which compete with or inhibit active tubular secretion, may increase aciclovir concentrations by this mechanism. Similarly, administration of valaciclovir may increase the plasma concentrations of other concomitantly administered substances.

In patients exposed to higher dosages of aciclovir from valaciclovir (e.g. at dosages for zoster treatment or CMV prophylaxis) caution is required during concomitant administration with drugs that inhibit active renal tubular secretion.

An increase in the plasma AUC of aciclovir and the inactive metabolite of mycophenolate mofetil, an immunosuppressive agent used in transplant patients, have been observed when the medicinal products are administered concomitantly. No change in peak concentrations or AUC was observed with concomitant administration of valaciclovir and mycophenolate mofetil in healthy volunteers. There is limited clinical experience of the use of this combination.


04.6 Pregnancy and breastfeeding

Pregnancy

There are limited data on the use of valaciclovir and moderate data on the use of aciclovir in pregnancy from the pregnancy use registries (which have documented pregnancy outcomes in women exposed to valaciclovir or aciclovir by the oral or oral route. intravenous - the active metabolite of valaciclovir); 111 and 1246 outcomes (29 and 756 exposed during the first trimester of pregnancy respectively) and "post-marketing experience" did not indicate any malformation or fetal / neonatal toxicity. animals show no reproductive toxicity for valaciclovir (see section 5.3). Valaciclovir should only be used in pregnancy if the potential benefit of treatment outweighs the potential risk.

Feeding time

Aciclovir, the major metabolite of valaciclovir, is excreted in breast milk. However, no effect on breastfed newborns / infants is expected at therapeutic doses of valaciclovir since the dose ingested by the infant is less than 2% of the therapeutic dose of intravenous aciclovir for the treatment of neonatal herpes (see section 5.2) Valaciclovir should be used with caution during breastfeeding and only if clinically indicated.

Fertility

Valaciclovir has no effect on fertility in orally treated rats. Testicular atrophy and aspermatogenesis were observed in rats and dogs at high doses of parenteral aciclovir. No human fertility studies have been performed with valaciclovir but no changes in sperm count, motility and morphology have been reported in 20 patients after 6 months of daily treatment with 400 mg to 1000 mg aciclovir.


04.7 Effects on ability to drive and use machines

No studies on the ability to drive and use machines have been performed.

The clinical condition of the patient and the adverse reaction profile of Valtrex should be taken into account when considering the patient's ability to drive and use machines. Further harmful effects on these activities cannot be predicted from the pharmacology of the active ingredient.


04.8 Undesirable effects

The most common adverse reactions reported in at least one indication by patients treated with Valtrex in clinical trials were headache and nausea. More serious adverse reactions such as thrombotic thrombocytopenic purpura / haemolytic uremic syndrome, acute renal failure and neurological disorders are described in more detail. in other sections of the Summary of Product Characteristics.

Side effects are listed below by system organ and by frequency. The following frequency categories are used to classify undesirable effects:

Very common ≥ 1/10 common ≥ 1/100 in Uncommon ≥ 1 / 1,000 in Rare ≥ 1 / 10,000 a Very rare

Data from clinical trials were used to assign frequency categories to adverse reactions if there was evidence of an association with valaciclovir in the studies.

For adverse reactions identified from post-marketing experience but not observed in clinical trials, the more conservative value of the estimate point ("rule of three") was used to assign frequency categories of adverse reactions. For adverse reactions identified as associated with valaciclovir from post-marketing experience and observed in clinical trials, the incidence reported in the study was used to assign frequency categories of adverse reactions. A clinical trial pharmacovigilance database is based on 5855 subjects exposed to valaciclovir in clinical trials covering multiple indications (treatment of herpes zoster, treatment / suppression of genital herpes and treatment of cold sores).

Data from clinical studies

Nervous system disorders

Very common: headache

Gastrointestinal disorders

Common: nausea

Post marketing data

Disorders of the blood and lymphatic system

Uncommon: leukopenia, thrombocytopenia

Leukopenia is reported for the majority of cases in immunocompromised patients.

Disorders of the immune system

Rare: anaphylaxis

Psychiatric disorders and pathologies of the nervous system

Common: dizziness

Uncommon: confusional state, hallucinations, depressed state of consciousness, tremors,

agitation

Rare: ataxia, dysarthria, convulsions, encephalopathy, coma, psychotic symptoms, delirium.

Neurological disorders, sometimes severe, may be associated with encephalopathy and include confusion, agitation, convulsions, hallucinations, coma. These events are usually reversible and are generally observed in patients with renal insufficiency or other predisposing factors (see section 4.4). In organ transplant patients receiving high doses of Valtrex (8000 mg per day) for CMV prophylaxis, neurological reactions occurred more frequently when compared with the lower doses used for other indications.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnoea

Gastrointestinal disorders

Common: vomiting, diarrhea

Uncommon: abdominal discomfort

Hepatobiliary disorders

Uncommon: reversible changes in liver function tests (e.g. bilirubin, enzymes

liver disease)

Skin and subcutaneous tissue disorders

Common: skin rash including photosensitization, 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 insufficiency who receive higher than recommended doses).

Kidney pain can be associated with kidney failure.

Intratubular precipitation of acyclovir crystals in the kidney has also been reported. Adequate fluid intake should be ensured during treatment (see section 4.4).

Learn more about special patient populations

In severely immunocompromised adult patients, particularly those with advanced HIV disease, receiving high doses (8000 mg per day) of valaciclovir for prolonged periods in clinical trials, there have been reports of renal failure, microangiopathic haemolytic anemia and thrombocytopenia (sometimes associated). These findings have also been observed in patients not treated with valaciclovir with the same underlying or concomitant conditions.


04.9 Overdose

Symptoms and signs

Acute renal failure and neurological symptoms including confusion, hallucinations, agitation, decreased consciousness and coma have been reported in patients who received an overdose of valaciclovir. Nausea and vomiting have also been reported. Caution is required to prevent accidental overdose. Many of these reported cases involved elderly patients and patients with impaired renal function who had received repeated overdoses due to lack of appropriate dose reduction.

Treatment

Patients should be carefully observed for signs of toxicity. Hemodialysis significantly contributes to the removal of acyclovir from the blood and may, therefore, be considered an option in the event of symptomatic overdose.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Nucleosides and nucleotides excluding reverse transcriptase inhibitors. ATC code: J05AB 11.

Mechanism of action

Valaciclovir, an antiviral, is the ester of aciclovir with L-valine. Aciclovir is a purine (guanine) nucleoside analogue.

Valaciclovir is rapidly and almost totally converted in humans to aciclovir and valine probably by the enzyme known as valaciclovir hydrolase.

Acyclovir is a specific inhibitor of herpes viruses with activity, in vitro, against Herpes simplex viruses (HSV) type 1 and 2, Varicella zoster virus (VZV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpetic virus class 6 (HHV-6) ). Acyclovir, once phosphorylated in its active triphosphate form, inhibits the DNA synthesis of herpetic viruses.

The first stage of phosphorylation requires the activity of a specific viral enzyme. In the case of HSV, VZV and EBV viruses this enzyme is the viral thymidine kinase (TK) which is present only in virus-infected cells. In the case of CMV, selectivity it is maintained by at least partly mediated phosphorylation of the phosphotransferase gene UL97. The need for acyclovir to be activated by a specific viral enzyme largely explains its selectivity of action.

The phosphorylation process (from acyclovir-monophosphate to triphosphate) is completed by cellular kinases. Acyclovir-triphosphate competitively inhibits viral DNA polymerase and the incorporation of this nucleoside analog into the viral DNA causes the interruption of the process of elongation of the latter's chain with consequent blocking of DNA synthesis and viral replication.

Pharmacodynamic effects

Resistance to acyclovir is normally due to a phenotypic deficiency of thymidine kinase resulting in a virus that is disadvantaged in the natural host. Reduced susceptibility to aciclovir has been described as the result of minimal changes in viral thymidine kinase or viral DNA polymerase. The virulence of these variant phenotypes is similar to that of wild virus.

A monitoring of the clinical isolates of HSV and VZV of patients undergoing therapy or prophylaxis with aciclovir revealed that the reduction of viral sensitivity to aciclovir is extremely rare in immunocompetent hosts and is observed only infrequently in severely immunocompromised patients such as, for for example, patients undergoing organ or bone marrow transplantation, patients undergoing chemotherapy for malignant neoplasms and patients infected with human immunodeficiency virus (HIV).

Clinical Studies

Varicella Zoster Virus Infection

Valtrex accelerates pain resolution: reduces the duration of zoster-associated pain and the number of patients with zoster-associated pain including acute neuralgia and, in patients over the age of 50, post-herpetic neuralgia. Valtrex reduces the risk of ocular complications of ophthalmic zoster.

Intravenous therapy is generally considered the standard for the treatment of zoster in immunocompromised patients. However, limited data indicate a clinical benefit of valaciclovir in the treatment of VZV infection (herpes zoster) in some immunocompromised patients including those with solid organ cancer, HIV, autoimmune diseases, lymphoma, leukemia and stem cell transplants.

Herpes Simplex Virus Infection

Valaciclovir for HSV ocular infections should be administered in accordance with applicable treatment guidelines.

Studies have been conducted with valaciclovir for the treatment and suppression of genital herpes in patients with concomitant HIV / HSV infection with a median CD4 count greater than 100 cells / mm3. Valaciclovir 500 mg twice daily was higher than the dose of 1000 mg once daily in the suppression of symptomatic relapses Valaciclovir 1000 mg twice daily for the treatment of relapses, on the duration of a herpes episode, was comparable to 200 mg of oral aciclovir five times a day. it has not been studied in patients with severe immunodeficiency.

The efficacy of valaciclovir for the treatment of other HSV skin infections has been documented. Valaciclovir has been shown to be effective in the treatment of cold sores, mucositis due to chemotherapy or radiotherapy, reactivation of HSV from resurfacing on the face, of herpes gladiatorum. Based on the historical experience of aciclovir, it appears that valaciclovir is as effective as aciclovir in the treatment of erythema multiforme, eczema herpeticum and herpetic paronychia.

Valaciclovir has been shown to reduce the risk of transmission of genital herpes in immunocompetent adults when taken as suppressive therapy and combined with protected sexual intercourse. A double-blind, placebo-controlled study was conducted in 1484 immunocompetent, heterosexual, discordant adult couples. whether or not HSV-2 infection is present. The results showed a significant reduction in the risk of transmission: 75% (symptomatic HSV-2 acquisition), 50% (HSV-2 seroconversion) and 48% (complete 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 further information on reduction in transmission).

Cytomegalovirus infection (see section 4.4)

CMV prophylaxis with valaciclovir in subjects receiving a solid organ transplant (kidney, heart) reduces the occurrence of acute transplant rejection, opportunistic infections and other herpetic infections (HSV, VZV). There is no direct study of comparison with valganciclovir to define the optimal therapeutic management in patients with solid organ transplantation.


05.2 "Pharmacokinetic properties

Absorption

Valaciclovir is a prodrug of aciclovir. The bioavailability of aciclovir from valaciclovir is approximately 3.3-5.5 times greater than that observed historically for oral aciclovir. After oral administration, valaciclovir is well and rapidly absorbed and is almost totally converted to aciclovir and valine. This conversion is likely mediated by an enzyme isolated from the human liver known as valaciclovir hydrolase. The bioavailability of aciclovir from a 1000 mg dose of valaciclovir is 54% and is not reduced by food. The pharmacokinetics of valaciclovir are not dose proportional. The rate and extent of absorption decrease with increasing dose, resulting in a less than proportional increase in Cmax beyond the therapeutic dose range and reduced bioavailability at doses above 500 mg. The predictions of the pharmacokinetic parameters (PK) of aciclovir following single doses of 250-2000 mg of valaciclovir in healthy volunteers with normal renal function are shown below.

Aciclovir PK Parameter 250 mg 500 mg 1000 mg 2000 mg (N = 15) (N = 15) (N = 15) (N = 8) Cmax mcg / 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.mcg / 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 time-concentration curve. Values ​​for Cmax and AUC indicate the mean ± standard deviation. The values ​​of Tmax indicate the median and the interval.

Peak plasma concentrations of unchanged valaciclovir are only 4% of peak aciclovir levels, are achieved after a median time of 30-100 minutes after dose administration and are at or below the limit of quantification 3 hours after dose. The pharmacokinetic profiles of valaciclovir and aciclovir are similar after both single and repeated doses. Herpes zoster and herpes simplex and HIV infection do not significantly alter the pharmacokinetics of valaciclovir and aciclovir after oral administration of valaciclovir compared to healthy adults. In transplant subjects receiving valaciclovir 2000 mg 4 times a day, peak concentrations of aciclovir are similar to or greater than those present in healthy volunteers receiving the same dosage.The presumed daily AUCs are significantly higher.

Distribution

Plasma protein binding of valaciclovir is very low (15%).

The cerebrospinal fluid (CSF) penetration determined by the plasma CSF / AUC ratio is independent of renal function and was approximately 25% for aciclovir and the 8-OH-ACV metabolite and approximately 2.5% for the metabolite CMMG.

Biotransformation

After oral administration, valaciclovir is converted to aciclovir e L-valin from a first intestinal passage and / or from hepatic metabolism. Aciclovir is converted to a small amount of metabolites in

9 (carboxymethoxy) methylguanine (CMMG) from alcohol and aldehyde dehydrogenase, in 8-hydroxy-aciclovir (8- OH-ACV) from aldehyde oxidase. Approximately 88% of the combined total plasma exposure is attributable to aciclovir , 11% to CMMG and 1% to 8-OH-ACV. Neither valaciclovir nor aciclovir are metabolised by cytochrome P450.

Elimination

Valaciclovir is primarily eliminated in the urine as aciclovir (more than 80% of the recovered dose) and as a metabolite of aciclovir CMMG (approximately 14% of the recovered dose). The metabolite 8-OH-ACV is only detectable in small amounts in the urine (plasma elimination half-life of aciclovir after both single and multiple doses of valaciclovir is approximately 3 hours.

Special populations

Kidney failure

Elimination of aciclovir is related to renal function and aciclovir exposure will increase

with the increase of renal insufficiency. In patients with end-stage renal disease, the mean elimination half-life of aciclovir after administration of valaciclovir is approximately 14 hours, compared with approximately 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 assessed at steady-state following multiple dose administration of valaciclovir in 6 subjects with normal renal function (mean creatinine clearance 111 ml / min, range 91-144 ml / min) treated with 2000 mg every 6 hours and in 3 subjects with severe renal impairment (clearance mean creatinine 26 ml / min, range 17-31 ml / min) treated with 1500 mg every 12 hours. In plasma, as well as cerebrospinal fluid, concentrations of aciclovir and the metabolites CMMG and 8-OH-ACV were on average 2, 4 and 5-6 times higher, respectively, in severe renal insufficiency compared to normal renal function.

Hepatic insufficiency

Pharmacokinetic data indicate that hepatic insufficiency decreases the transformation rate of valaciclovir to aciclovir but not total transformation. The half-life of aciclovir is not affected.

Pregnant women

A pharmacokinetic study of valaciclovir and aciclovir conducted during late pregnancy indicates that pregnancy has no effect on the pharmacokinetics of valaciclovir.

Transfer into breast milk

After administration of a 500 mg oral dose of valaciclovir the peak aciclovir concentrations Cmax achieved in breast milk ranged from 0.5 to 2.3 times the corresponding maternal serum aciclovir concentrations. The mean concentration of aciclovir in breast milk was 2.24 mcg / ml (9.95 micromol / l). With a maternal dosage of valaciclovir 500 mg twice daily, this level could expose a breastfed infant to a daily oral aciclovir dosage of approximately 0.6 1 mg / kg / day. The elimination half-life of aciclovir from breast milk was similar to that from serum. Unchanged valaciclovir was not found in maternal serum, breast milk or infant urine.


05.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Valaciclovir has no effect on fertility in orally treated male or female rats.

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 and rabbits. In further studies in rats, fetal abnormalities and maternal toxicity were observed at subcutaneous doses resulting in plasma aciclovir levels of 100 μg / ml (more than 10 times higher than the single 2000 mg dose of valaciclovir in humans with normal renal function).

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Core of the tablet

Microcrystalline cellulose

Crospovidone

Povidone

Magnesium stearate

Colloidal silica dioxide

Coating

Hypromellose

Titanium dioxide

Macrogol

Polysorbate 80 (for 500 mg and 1000 mg tablets only)

Carnauba wax


06.2 Incompatibility

Not relevant.


06.3 Period of validity

250 mg tablets, 1000 mg tablets

Two years

500 mg tablets

Three years


06.4 Special precautions for storage

Store at a temperature below 30 ° C


06.5 Nature of the immediate packaging and contents of the package

Polyvinyl chloride / aluminum blister packs.

250 mg tablets

Pack of 20 or 60 tablets

500 mg tablets

Packs of 10, 24, 30, 42, 90 or 112 tablets

Not all pack sizes may be marketed.

1000 mg tablets

Pack of 21 tablets


06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

GlaxoSmithKline S.p.A. - Via A. Fleming, 2 - Verona.

08.0 MARKETING AUTHORIZATION NUMBER

ZELITREX 250 mg Film-coated tablets - 60 tablets A.I.C .: 029503048

ZELITREX 500 mg Film-coated tablets - 42 tablets A.I.C .: 029503012

ZELITREX 500 mg Film-coated tablets - 10 tablets A.I.C .: 029503036

ZELITREX 1000 mg Film-coated tablets - 21 tablets A.I.C .: 029503024

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

42 tablets of 500 mg - 21 tablets of 1000 mg: 19 January 1998 / November 2002

60 tablets of 250 mg -10 tablets of 500 mg: May 9, 2002 / November 2002

10.0 DATE OF REVISION OF THE TEXT

23 September 2011

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

none:  heart-health feeding time supplements