CYCLOVIRAN - PACKAGE LEAFLET - LEAFLETS

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Cycloviran - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Aciclovir

CYCLOVIRAN 200 mg tablets
CYCLOVIRAN 400 mg tablets
CYCLOVIRAN 800 mg tablets
CYCLOVIRAN 400 mg / 5 ml oral suspension

Cycloviran package inserts are available for pack sizes:

CYCLOVIRAN 200 mg tablets, CYCLOVIRAN 400 mg tablets, CYCLOVIRAN 800 mg tablets, CYCLOVIRAN 400 mg / 5 ml oral suspension
CYCLOVIRAN 5% cream
CYCLOVIRAN 3% ophthalmic ointment

Why is Cycloviran used? What is it for?

Cycloviran contains an active substance called aciclovir, which belongs to a group of medicines called antivirals.

Cycloviran is indicated for:

treat Herpes simplex infections of the skin and mucous membranes, including primary (presenting for the first time) or relapsing (which keeps coming back) genital herpes with the exclusion of Herpes simplex infections in immunocompromised infants and children (with a less well-functioning immune system so their bodies are less able to fight infections)
suppress Herpes simplex infections that keep coming back in immunocompetent patients (with a normally functioning immune system)
to prevent Herpes simplex infections in immunocompromised patients (with a less well-functioning immune system)
treat chickenpox and "Herpes zoster (St. Anthony's fire)"

Contraindications When Cycloviran should not be used

Do not take Cycloviran

if you are allergic to aciclovir or valaciclovir to any of the other ingredients of this medicine;
if you are pregnant or breast-feeding (see "Pregnancy and breast-feeding").

Precautions for use What you need to know before taking Cycloviran

Talk to your doctor or pharmacist before taking Cycloviran.

Contact your doctor if:

have kidney problems
is over 65 years of age
if you have a very weakened immune system

Talk to your doctor if you think any of these apply to you. Your doctor may reduce the dose of Cycloviran.

Make sure you drink plenty of fluids such as water while you are taking Cycloviran.

Interactions Which drugs or foods can modify the effect of Cycloviran

Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines.

In particular, tell your doctor or pharmacist if you are taking any of the following medicines: •

probenecid, used to treat gout
cimetidine used to treat stomach ailments
mycophenolate mofetil used to avoid rejection of transplanted organs
theophylline used for breathing problems

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice.

You should not take Cycloviran without first consulting your doctor who will make an assessment of the benefit to you and the risk to your baby of taking Cycloviran while you are pregnant.

Aciclovir can pass into breast milk. If you are breast-feeding, or plan to breast-feed: Talk to your doctor before taking Cycloviran.

Driving and using machines

No studies have been performed to investigate the effects of aciclovir on the ability to drive and operate machinery. Evaluate the possible occurrence of undesirable effects that can alter the level of attention.

Cycloviran 200 mg tablets contain lactose. If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.

Cycloviran 400 mg / 5 ml oral suspension contains parahydroxybenzoates which may cause allergic reactions (including delayed).

Cycloviran 400 mg / 5 ml oral suspension contains sorbitol. If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.

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

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

Take Cycloviran as soon as possible after the infection appears (at the first symptoms or when the first lesions appear).

The dose you need to take will depend on why you have been prescribed Cycloviran. Your doctor will discuss this with you.

Treatment of Herpes simplex infections including genital herpes

Adults and children 2 years of age and older: The recommended dose is 200 mg 5 times a day.
Children under 2 years of age: the recommended dose is half the adult dose. Intravenous administration of Cycloviran is recommended for the treatment of neonatal herpes virus infections.

Take the dose at intervals of about 4 hours, skipping the night dose.

Take Cycloviran for 5 days or longer if your doctor recommends it.

In adult patients with a very weakened immune system (for example after a bone marrow transplant) or with decreased absorption from the gut, the doctor may decide to double the dose to 400 mg (or 5 ml of the suspension) or consider giving Cycloviran to intravenously.

In children with a weakened immune system with severe Herpes simplex infections Cycloviran is not indicated.

Suppression of recurrence of Herpes simplex infections (which keep coming back) in immunocompetent patients (with a normally functioning immune system)

The recommended dose in adults is 200 mg 4 times a day.

Take the dose at approximately 6 hour intervals. Your doctor may change the dose and also the interval between doses. You should always take Cycloviran as directed by your doctor.

Take Cycloviran until your doctor tells you to stop.

Prophylaxis of Herpes simplex infections in immunocompromised patients (with a less well-functioning immune system)

Adults and children 2 years of age and older: The recommended dose is 200 mg 4 times a day.
Children under 2 years of age: the recommended dose is half the adult dose.

Take the dose at approximately 6 hour intervals.

Take Cycloviran until your doctor tells you to stop.

Treatment of chickenpox and "Herpes zoster (St. Anthony's fire)"

Adults

The recommended dose is 800 mg (or 10 ml of oral suspension) 5 times a day.
Take the dose at intervals of about 4 hours, skipping the night dose.
Take Cycloviran for 7 days.

In patients with a very weakened immune system (for example after a bone marrow transplant) or with decreased absorption from the gut, the doctor may consider giving Cycloviran intravenously.

Children - Treatment of chickenpox

Children 6 years of age and older: The recommended dose is 800 mg (or 10 ml suspension), 4 times a day.
Children aged 2 years and less than 6 years: the recommended dose is 400 mg (or 5 ml suspension), 4 times a day.
Children less than 2 years of age: the recommended dose is 200 mg (or 2.5 ml suspension), 4 times a day.
Take Cycloviran for 5 days.

The administration of 20 mg / kg of body weight (not exceeding 800 mg) 4 times a day, allows a more precise dose adjustment.

There are no data available for the treatment of Herpes zoster in children with normally functioning immune systems.

For the treatment of Herpes zoster infections in children with weakened immune systems, the doctor will consider administering Cycloviran intravenously.

Your doctor may also change your Cycloviran dose if:

is over 65 years of age
have kidney problems. If you have kidney problems, it is important that you drink plenty of fluids while taking Cycloviran

Talk to your doctor before taking Cycloviran if the above apply to you.

If you forget to take Cycloviran

If you forget to take Cycloviran, 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.

Overdose What to do if you have taken too much Cycloviran

If you accidentally take too much Cycloviran, contact your doctor or pharmacist for advice.

If you take too much Cycloviran you can:

having nausea, headache or vomiting
feeling confused or agitated
seeing or hearing things that are not there (hallucinations)
having seizures
losing consciousness (coma)

Tell your doctor or pharmacist if you have taken too much Cycloviran and show them the medicine pack.

Side Effects What are the side effects of Cycloviran

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Common side effects

These may affect up to 1 in 10 patients:

headache (headache)
dizziness
nausea
He retched
diarrhea
abdominal pain
itch
skin rash (rash), including skin reaction after exposure to sunlight (photosensitivity)
fatigue

fever

Uncommon side effects

These may affect up to 1 in 100 patients:

skin reaction (hives)
rapid and widespread hair loss

Rare side effects

These may affect up to 1 in 1000 patients

difficult breathing (dyspnoea)
swelling of the lips, face, neck and throat (angioedema)
severe allergic reaction (anaphylaxis)
changes in some laboratory tests (increased blood urea nitrogen, creatinine, bilirubin and enzymes produced by the liver)

Very rare side effects

These may affect up to 1 in 10,000 patients

feeling confused and agitated
tremor
lack of muscle coordination (ataxia)
words spoken in a slow and defective way (dysarthria)
seeing or hearing things that are not there (hallucinations)
changes of opinion and second thoughts (psychotic symptoms)
convulsions
drowsiness
brain damage (encephalopathy)
loss of consciousness (coma)
yellowing of the whites of the eyes or skin (jaundice)
inflammation of the liver (hepatitis)
kidney problems (acute kidney failure)
pain in the kidney area (kidney pain)
reduced number of red blood cells (anemia)
reduced number of white blood cells (leukopenia)
reduction in the number of blood platelets c (thrombocytopenia).

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 www.agenziafarmaco.it/it/responsabili. 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.

Tablets: store in a dry place.

Suspension: Do not store above 30 ° C.

Do not use this medicine after the expiry date which is stated on the carton after (EXP). The expiry date refers to the last day of that month.

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.

Other information

What Cycloviran contains

Tablets

The active ingredient is aciclovir. Each tablet contains 200 mg, 400 mg or 800 mg of aciclovir.
The other ingredients are: lactose (only in the 200 mg tablet), microcrystalline cellulose, sodium starch glycolate, povidone, magnesium stearate.

Oral suspension

The active ingredient is aciclovir. 5 ml of oral suspension contains 400 mg of aciclovir.
The other ingredients are: 70% sorbitol (not crystallizable), glycerol, dispersible cellulose, methyl parahydroxybenzoate, propyl parahydroxybenzoate, orange flavor, purified water.

What Cycloviran looks like and contents of the pack

Cycloviran 200 mg and 400 mg tablets are supplied in blister packs of 25 tablets.

Cycloviran 800 mg tablets are supplied in blister packs of 35 tablets.

Cycloviran 400 mg / 5 ml is supplied in a pack containing a 100 ml bottle of oral suspension with a measuring spoon.

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 Cycloviran can be found 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 interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 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 HOLDER08 .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 RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

CYCLOVIRAN TABLETS / ORAL SUSPENSION

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

CYCLOVIRAN 200 mg Tablets

One tablet contains:

Active ingredient: aciclovir 200.0 mg.

Excipient with known effects:

One tablet contains:

lactose 213 mg

CYCLOVIRAN 400 mg Tablets

One tablet contains:

Active ingredient: aciclovir 400.0 mg.

CYCLOVIRAN 800 mg Tablets

One tablet contains:

Active ingredient: aciclovir 800.0 mg.

CYCLOVIRAN 400 mg / 5 ml Oral suspension

5 ml of suspension contain:

Active ingredient: aciclovir 400.0 mg.

Excipients with known effects:

methyl parahydroxybenzoate 5 mg

propyl parahydroxybenzoate 1 mg

sorbitol 2.25 g

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablets, oral suspension.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

CYCLOVIRAN is indicated:

for the treatment of virus infections herpes simplex (HSV) of the skin and mucous membranes, including herpes genitalis primary and relapsing (excluding neonatal HSV and severe HSV infections in immunocompromised children);

for the suppression of relapses from herpes simplex in immunocompetent patients;

for the prophylaxis of infections herpes simplex in immunocompromised patients;

for the treatment of chickenpox and herpes zoster.

04.2 Posology and method of administration

Adults

Treatment of herpes simplex infections

One tablet of 200 mg 5 times a day at intervals of approximately 4 hours, omitting the night dose.

Treatment should be continued for 5 days but prolongation may be necessary in cases of severe primary infections.

In severely immunocompromised patients (eg after bone marrow transplantation) or in patients with impaired absorption from the gut, the dosage can be doubled to 400 mg in tablets (or 5 ml of the suspension) or, alternatively, the appropriateness can be considered. intravenous administration of aciclovir.

Therapy should be started as early as possible from the first signs of an infection and in the case of recurrent infections this should preferably occur during the prodromal phase or when the first lesions appear.

Suppressive therapy of relapses of herpes simplex infections in immunocompetent patients

One 200 mg tablet 4 times a day at 6 hour intervals.

Many patients can be successfully treated with the administration of 400 mg (or 5 ml of the suspension) twice daily at 12 hour intervals.

Dosages of 200 mg 3 times a day at 8-hour intervals or 2 times a day at 12-hour intervals may also be effective.

Relapses of infection may occur in some patients with a total daily dose of 800 mg of CYCLOVIRAN.

Therapy should be interrupted periodically at intervals of 6 or 12 months, in order to observe any changes in the natural history of the disease.

Prophylaxis of herpes simplex infections in immunocompromised patients

One 200 mg tablet 4 times a day at 6 hour intervals. In severely immunocompromised patients (eg after bone marrow transplantation) or in patients with impaired absorption from the gut the dosage can be doubled to 400 mg in tablets or 5 ml of the suspension or, alternatively, the appropriateness of administration can be considered. of intravenous acyclovir.

The duration of prophylaxis must be considered in relation to that of the risk period.

Treatment of shingles and chickenpox

800 mg (or 10 ml of suspension) 5 times a day at intervals of approximately 4 hours, omitting the night dose. Treatment should be continued for 7 days.

In severely immunocompromised patients (eg after a bone marrow transplant) or in patients with impaired intestinal absorption, intravenous administration of aciclovir may be considered.

The therapy must be started immediately after the onset of the infection, in fact the treatment obtains better results if established when the first lesions appear.

Children

For the treatment of infections with herpes simplex and for the prophylaxis of the same in immunocompromised children aged two years and over, the same dosage as for adults should be administered; in children under two years of age half the adult dose should be administered. Serious HSV infections in the immunocompromised, for which CYCLOVIRAN is not indicated is an exception (see section 4.1).

For the treatment of neonatal herpes virus infections, administration of aciclovir solution for infusion is recommended.

Chickenpox Treatment

- children aged 6 years and over: 800 mg of aciclovir (or 10 ml of suspension) 4 times a day;

- children aged 2 years and less than 6 years: 400 mg of aciclovir (or 5 ml of suspension) 4 times a day;

- children under 2 years of age: 200 mg of aciclovir (or 2.5 ml of suspension) 4 times a day.

The administration of 20 mg / kg of body weight (not exceeding 800 mg) 4 times a day, allows a more precise dosage adjustment. Treatment should be continued for 5 days.

No specific data are available on the suppression of infections with herpes simplex or the treatment of herpes zoster in immunocompetent children.

Intravenous administration of aciclovir should be considered for the treatment of herpes zoster in immunocompromised children.

Elderly patients

In the elderly, the possibility of renal impairment should be taken into account and the dosage should be adjusted accordingly (see Dosage in patients with renal impairment).

Adequate hydration should be maintained in patients taking high doses of oral aciclovir.

Patients with renal impairment

Caution is advised when administering aciclovir to patients with impaired renal function. Adequate hydration must be maintained.

In the treatment and prophylaxis of herpes simplex, in patients with impaired renal function the recommended oral posology should not cause accumulation of aciclovir above the levels deemed acceptable for intravenous administration of the drug.

In the management of herpes simplex in patients with severe renal impairment (creatinine clearance less than 10 ml / min), it is recommended to adjust the dose of aciclovir 200 mg administered twice daily at approximately 12 hour intervals.

In the treatment of varicella and herpes zoster infections it is recommended that the dosage be changed to 800 mg aciclovir tablets or 10 ml suspension administered twice daily at approximately 12 hour intervals in patients with severe renal impairment (creatinine clearance less than 10 ml / min) and 800 mg of aciclovir in tablets or 10 ml suspension 3 times a day, administered at intervals of approximately 8 hours, in patients with moderate renal impairment (creatinine clearance between 10 and 25 ml / min).

04.3 Contraindications

Hypersensitivity to the active substance, to valaciclovir or to any of the excipients listed in section 6.1.

Pregnancy and lactation (see section 4.6).

04.4 Special warnings and appropriate precautions for use

Adequate hydration should be maintained in patients administered intravenous aciclovir or high doses of oral aciclovir.

The risk of renal failure is increased with the use of other nephrotoxic medicinal products.

Use in patients with renal insufficiency and elderly patients

Aciclovir is eliminated by renal clearance, therefore the dose 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).

Prolonged or repeated courses of aciclovir in severely immunocompromised subjects may result in the selection of resistant viral strains with reduced sensitivity that may not respond to continued aciclovir treatment (see section 5.1).

Important information about some of the excipients

CYCLOVIRAN 200 mg tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

CYCLOVIRAN 400 mg / 5 ml Oral suspension contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

CYCLOVIRAN 400 mg / 5 ml Oral suspension contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (including delayed).

Shake the suspension before use.

04.5 Interactions with other medicinal products and other forms of interaction

Aciclovir is primarily eliminated unchanged in the urine via active renal tubular secretion. Any concomitantly administered drug that competes with this mechanism may increase aciclovir plasma concentrations. Probenecid and cimetidine through this mechanism cause an increase in the area under the curve of plasma aciclovir concentrations and therefore decrease its renal clearance. Similarly, the concomitant administration of aciclovir and mycophenolate mofetil, an immunosuppressive agent used in transplant patients, causes an increase in the area under the plasma concentration curve of both aciclovir and the inactive metabolite of mycophenolate mofetil. However, no dosage adjustment is necessary in view of the broad therapeutic index of aciclovir.

An experimental study on 5 male subjects indicates that concomitant therapy of aciclovir with theophylline increases the AUC of totally administered theophylline by 50%. It is recommended that plasma concentrations be measured during therapy with aciclovir.

04.6 Pregnancy and breastfeeding

Fertility

See Clinical Studies section 5.2 and section 5.3.

Pregnancy

A registry on the use of aciclovir in pregnancy provided data on pregnancy outcomes in women exposed to the various formulations of aciclovir after marketing. These observations did not show an increase in the number of birth abnormalities among subjects exposed to aciclovir in comparison. to the general population and all the birth defects found showed no particularity or common characteristics that would suggest a single cause.

Systemic administration of aciclovir using internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rabbits, rats or mice.

In an experimental test not included in the standard tests, conducted on rats, fetal abnormalities were observed, but only after subcutaneous doses of aciclovir so high as to produce toxic effects on the mother. The clinical relevance of these findings is uncertain.

The use of aciclovir should only be considered when the potential benefits of treatment outweigh any possible unknown risks.

Feeding time

Following oral administration of aciclovir 200 mg, 5 times / day, the presence of aciclovir in breast milk was observed at concentrations equal to 0.6-4.1 times the corresponding plasma levels. Such levels would potentially expose infants to doses of acyclovir up to 0.3 mg / kg / day. Therefore, caution is advised in the use of aciclovir during lactation.

04.7 Effects on ability to drive and use machines

The clinical condition of the patient and the adverse event profile of aciclovir should be taken into account with regard to the patient's ability to drive and use machines. No studies have been performed to investigate the effects of aciclovir on the ability to drive and operate machinery. Further harmful effects on these activities cannot be predicted from the pharmacology of the active ingredient.

04.8 Undesirable effects

The frequency categories associated with the adverse events listed below are estimates. Adequate incidence assessment data are not available for most events. In addition, the incidence of adverse events may vary by indication.

The following convention has been used for the classification of undesirable effects in terms of frequency: Very common (≥1 / 10), Common (≥1 / 100,

Disorders of the blood and lymphatic system

Very rare: anemia, leukopenia, thrombocytopenia

Disorders of the immune system

Rare: anaphylaxis

Psychiatric disorders and pathologies of the nervous system

Common headache, dizziness

Very rare: agitation, confusional state, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, convulsions, somnolence, encephalopathy, coma

The above events are usually reversible and generally occur in patients with renal insufficiency or other predisposing factors (see section 4.4).

Respiratory, thoracic and mediastinal disorders

Rare: dyspnoea

Gastrointestinal disorders

Common: nausea, vomiting, diarrhea, abdominal pain

Hepatobiliary disorders

Rare: reversible increases in bilirubin and liver enzymes

Very rare: hepatitis, jaundice

Skin and subcutaneous tissue disorders

Common: pruritus, rash (including photosensitivity)

Uncommon: urticaria. Rapid and widespread hair loss

Rapid and widespread hair loss has been associated with a "wide range of conditions and drug use," so the relationship of this occurrence to acyclovir therapy is uncertain.

Rare: angioedema

Renal and urinary disorders

Rare: increases in blood urea nitrogen and creatinine

Very rare: acute renal failure, renal pain

Kidney pain can be associated with kidney failure.

General disorders and administration site conditions

Common: fatigue, fever

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose

Symptoms and signs: aciclovir is only partially absorbed from the intestine.

Patients who have occasionally ingested an overdose of up to 20 g of aciclovir in a single dose have generally not experienced unexpected effects.

Accidental and repeated overdoses of oral aciclovir over several days have been associated with gastrointestinal effects (such as nausea and vomiting) and neurological effects (headache and confusion).

Overdoses of intravenous aciclovir have resulted in increases in serum creatinine levels, blood urea nitrogen resulting in renal failure. Neurological effects including confusion, hallucinations, agitation, convulsions and coma, associated with intravenous overdose have been described.

Treatment: patients should be carefully observed for any signs of toxicity. Hemodialysis significantly contributes to the elimination of aciclovir from the blood and may, therefore, be considered an option for symptomatic overdose.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Direct acting antivirals for systemic use - nucleosides and nucleotides excluding reverse transcriptase inhibitors.

ATC code: J05AB01.

Mechanism of action

Aciclovir is a synthetic purine nucleoside analog with inhibitory activity, in vitro and in vivo, against human herpes viruses, including the virus herpes simplex (HSV) types 1 and 2, Varicella zoster virus (VZV), Epstein Barr virus (EBV) and cytomegalovirus (CMV).

In cell cultures, aciclovir exhibited the greatest antiviral activity against HSV-1, followed (in order of decreasing potency) by HSV-2, VZV, EBV and CMV.

The inhibitory activity of aciclovir against HSV-1 and HSV-2, VZV, EBV and CMV is highly selective.

The thymidine kinase (TK) enzyme of normal, uninfected cells does not effectively use aciclovir as a substrate; therefore, toxicity to mammalian host cells is poor; on the contrary, the viral thymidine kinase encoded by HSV, VZV and EBV converts aciclovir in acyclovir monophosphate, a nucleoside analogue, which is further converted into di-phosphate and tri-phosphate by cellular enzymes. Aciclovir tri-phosphate interferes with viral DNA polymerase and inhibits viral DNA replication; its incorporation into viral DNA it causes the interruption of the stretching process of the DNA chain.

Pharmacodynamic effects

Prolonged or repeated courses of aciclovir in severely immunocompromised patients may be associated with the selection of viral strains with reduced sensitivity, which may not respond to prolonged aciclovir treatment.

Most of the isolated viral strains, with reduced sensitivity, showed a relative deficiency of viral thymidine kinase; however, strains with altered viral thymidine kinase or DNA polymerase have also been observed. Even the exhibition, in vitro, to aciclovir, of isolated HSV strains, may be associated with the appearance of less sensitive strains. The relationship between sensitivity, determined in vitro, of the isolated HSV strains and the clinical response to aciclovir therapy is unclear.

All patients should be advised to try to avoid any possible transmission of the virus, particularly when active lesions are present.

05.2 Pharmacokinetic properties

Absorption

Aciclovir is only partially absorbed from the intestine.

Peak steady state plasma concentrations (Cssmax) after doses of 200 mg every 4 hours is 3.1 micromolar (0.7 mcg / ml) and the trough concentration (Cssmin) is 1.8 micromolar (0.4 mcg / ml).

After doses of 400 mg and 800 mg every 4 hours the Cssmax, respectively, is 5.3 micromolar (1.2 mcg / ml) and 8 micromolar (1.8 mcg / ml) and the (Cssmin) is 2.7 micromolar (0.6 mcg / ml) and 4 micromolar (0.9 mcg / ml) in adults, respectively.

In adults, the mean Cssmax after a one-hour infusion of 2.5 mg / kg, 5 mg / kg and 10 mg / kg is 22.7 micromolar (5.1 mcg / ml), 43.6 micromolar, respectively. (9.8 mcg / ml) and 92 micromolar (20.7 mcg / ml). The corresponding Cssmin levels after 7 hours are, respectively, 2.2 micromolar (0.5 mcg / ml), 3.1 micromolar ( 0.7 mcg / mL) and 10.2 micromolar (2.3 mcg / mL).

In children over one year of age, similar mean levels of Cssmax and Cssmin were observed when a dose of 5 mg / kg was administered instead of the 250 mg / m2 dose and a dose of 500 mg / m2 dose of 10 mg / kg. In infants up to 3 months of age, treatment with a dose of 10 mg / kg administered as a one-hour infusion at 8-hour intervals, the Cssmax was 61.2 micromolar (13.8 mcg / ml) and Cssmin was 10.1 micromolar (2.3 mcg / mL). A separate group of infants treated with 15 mg / kg every 8 hours showed approximately dose proportional increases, with a Cmax 83.5 micromolar ( 18.8 mcg / mL) and a Cmin of 14.1 micromolar (3.2 mcg / mL).

Distribution

The drug levels in the CSF are approximately 50% of the plasma levels. Plasma protein binding is relatively poor (9 to 33%) and drug interactions due to binding site displacement are not expected.

Elimination

In adults aciclovir administered intravenously, the terminal half-life of the drug is approximately 2.9 hours. Most of the drug is excreted unchanged via the kidney. The renal clearance of aciclovir is considerably greater than that of creatinine, indicating that In addition to glomerular filtration, tubular secretion contributes to the renal elimination of the drug. The only important metabolite is 9-carboxymethoxymethylguanine corresponding to about 10-15% of the administered dose recovered in the urine.

When aciclovir is administered one hour after administration of 1 g probenecid, the terminal half-life and area under the plasma concentration versus time curve extends by 18% and 40%, respectively.

In infants up to 3 months of age treated with a dose of 10 mg / kg administered as a one-hour infusion at 8-hour intervals, the terminal plasma half-life is 3.8 hours.

Special populations

In patients with chronic renal failure, the mean half-life is 19.5 hours while during hemodialysis the mean half-life of aciclovir is 5.7 hours and levels are reduced by an average of about 60% during dialysis.

In the elderly, total clearance decreases with increasing age along with a decrease in creatinine clearance, although there is a slight modification of the terminal plasma half-life.

Studies have shown that there are no obvious changes in the pharmacokinetics of aciclovir or zidovudine when both are administered concurrently in HIV-infected patients.

Clinical Studies

There is no information on the effects of aciclovir oral formulations or solution for infusion on female fertility. In a study of 20 male patients with normal sperm counts, oral administration of aciclovir at doses up to 1 g per day for up to six months was shown to have no clinically significant effect on number, motility or the morphology of spermatozoa.

05.3 Preclinical safety data

Mutagenesis

The results of a large number of in vitro and in vivo mutagenicity tests indicate that aciclovir poses no genetic risk for humans.

Carcinogenesis

In long-term rat and mouse studies, acyclovir was not carcinogenic.

Fertility

In rats and dogs, largely reversible toxic effects on spermatogenesis have been reported only at doses significantly higher than therapeutic ones. Two-generation studies in mice revealed no effects of aciclovir, administered orally, on fertility.

Teratogenesis

Systemic administration of aciclovir using internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rabbits, mice or rats.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

CYCLOVIRAN 200 mg Tablets

Lactose, Microcrystalline cellulose, Sodium starch glycolate, Povidone, Magnesium stearate.

CYCLOVIRAN 400 mg Tablets

Microcrystalline cellulose, Sodium starch glycolate, Povidone, Magnesium stearate.

CYCLOVIRAN 800 mg Tablets

Microcrystalline cellulose, Sodium starch glycolate, Povidone, Magnesium stearate.

CYCLOVIRAN 400 mg / 5 ml Oral suspension

Sorbitol 70% (not crystallizable), Glycerol, Dispersible cellulose, Methyl parahydroxybenzoate, Propyl parahydroxybenzoate, Orange flavor, Purified water.