Civral

CIVRAL 400 mg tablets
CIVRAL 8 g/100 ml oral suspension
A
M E
THERAPEUTIC PHARMACOLOGICAL CATEGORY
Antivirals for systemic use with direct action – Nucleosides and nucleotides excluding reverse transcriptase inhibitors.
THERAPEUTIC INDICATIONS
CIVRAL is indicated:

• for the treatment of herpes simplex virus (HSV) infections of the skin and mucous membranes, including primary and recurrent genital herpes (excluding neonatal HSV and severe HSV infections in immunocompromised children).
• for the suppression of recurrent herpes simplex infections in immunocompetent patients,
• for the prophylaxis of herpes simplex infections in immunocompromised patients,
• for the treatment of herpes zoster infections.

CONTRAINDICATIONS
Hypersensitivity to aciclovir, valaciclovir, or any of the excipients.
Generally contraindicated during pregnancy and breastfeeding.
PRECAUTIONS FOR USE
Adequate hydration must be maintained in patients taking high oral doses of CIVRAL.
The risk of renal impairment increases with the use of other nephrotoxic drugs.
Use in elderly patients and patients with renal impairment
Aciclovir is eliminated via renal clearance; therefore, the dose should be reduced in patients with renal impairment. Elderly patients are likely to have reduced renal function, and thus dose reduction should be considered in this patient group. Both elderly patients and those with renal impairment are at increased risk of developing neurological adverse effects and should be closely monitored for such effects. In reported cases, these reactions were generally reversible upon discontinuation of treatment.
Repeated or prolonged courses of aciclovir treatment in severely immunocompromised patients may lead to selection of less sensitive viral strains, which may not respond to continued aciclovir therapy.
Oral suspension: shake the suspension well before use.
CIVRAL oral suspension contains methyl parahydroxybenzoate and propyl parahydroxybenzoate, which may cause allergic reactions (including delayed-type reactions).
CIVRAL oral suspension contains sorbitol; patients with rare hereditary fructose intolerance should not take this medicine.
Sorbitol may have a mild laxative effect, and its caloric value is 2.6 kcal/g.
INTERACTIONS
Aciclovir is primarily excreted unchanged in urine via active tubular secretion. Any concomitantly administered drug capable of competing with this mechanism may increase plasma concentrations of aciclovir. Probenecid and cimetidine, through this mechanism, increase the area under the plasma concentration-time curve (AUC) of aciclovir and thus reduce its renal clearance. Similarly, concomitant administration of aciclovir and mycophenolate mofetil, an immunosuppressive agent used in transplant patients, results in increased AUCs for both aciclovir and the inactive metabolite of mycophenolate mofetil. Nevertheless, no dosage adjustment is required due to the wide therapeutic index of aciclovir.
An experimental study conducted in five male subjects indicates that concomitant therapy with aciclovir increases the AUC of total theophylline by approximately 50%. Plasma theophylline concentrations should be monitored during concomitant therapy with aciclovir.
Inform your doctor or pharmacist if you have recently taken any other medicines,
including those without a prescription.
SPECIAL WARNINGS
Fertility
No data are available regarding fertility in women. CIVRAL has not shown any effect on sperm count, morphology, or mortality in men.
Pregnancy
Because clinical data on administration during pregnancy are limited, the drug should be administered only when absolutely necessary under direct medical supervision and only when the potential benefits of treatment outweigh any unknown risks.
A registry on the use of aciclovir during pregnancy has provided data on pregnancy outcomes in women exposed to various formulations of CIVRAL after marketing authorization. These observations have not shown an increased number of birth defects among subjects exposed to CIVRAL compared to the general population, and all birth defects observed did not show any particular pattern or common characteristics suggesting a single cause.
Systemic administration of aciclovir using internationally accepted standard tests has not produced embryotoxic or teratogenic effects in rabbits, mice, or rats.
In an experimental study in rats not included in classical teratogenicity tests, fetal abnormalities were observed only after subcutaneous doses of aciclovir so high as to produce toxic effects in the mother. The clinical relevance of these findings is uncertain.
Breastfeeding
Limited clinical data show that after administration of CIVRAL during breastfeeding, aciclovir is excreted in breast milk; therefore, use of the product should be avoided during breastfeeding.
Following oral administration of 200 mg aciclovir five times daily, aciclovir has been detected in breast milk at concentrations of 0.6–4.1 times the corresponding plasma levels. These levels could potentially expose infants to aciclovir doses up to 0.3 mg/kg/day. Therefore, caution is advised when using CIVRAL during breastfeeding.
Effects on the ability to drive and use machines
No negative effects of CIVRAL on the ability to drive or operate machinery are known.
DOSAGE, ADMINISTRATION, AND DURATION
Adults
Treatment of herpes simplex infections in adults: half a 400 mg tablet or 2.5 ml of suspension five times daily at approximately 4-hour intervals, omitting the nighttime dose. Treatment should continue for 5 days but may need to be prolonged in cases of severe primary infections.
In severely immunocompromised patients (e.g., after bone marrow transplantation) or patients with reduced intestinal absorption, the dose may be doubled to 400 mg in tablets or 5 ml of suspension, or alternatively, intravenous administration may be considered.
Treatment should be initiated as early as possible upon first signs of infection, and in recurrent infections, preferably during the prodromal phase or at the appearance of the first lesions.
Suppressive therapy of recurrent herpes simplex infections in immunocompetent patients: half a 400 mg tablet or 2.5 ml of suspension four times daily at 6-hour intervals.
Many patients may be successfully treated with 400 mg in tablets or 5 ml of suspension twice daily at 12-hour intervals. Doses of 200 mg three times daily at 8-hour intervals or twice daily at 12-hour intervals may also be effective.
In some patients, recurrences may occur despite a total daily dose of 800 mg of CIVRAL.
Therapy should be periodically interrupted at intervals of 6 to 12 months to assess any changes in the natural course of the disease.
Prophylaxis of herpes simplex infections in immunocompromised patients: half a 400 mg tablet or 2.5 ml of suspension four times daily at 6-hour intervals.
In severely immunocompromised patients (e.g., after bone marrow transplantation) or patients with reduced intestinal absorption, the dose may be doubled to 400 mg in tablets or 5 ml of suspension, or alternatively, intravenous administration may be considered.
The duration of prophylaxis should be considered in relation to the period of risk.
Treatment of herpes zoster and varicella: 800 mg in tablets (2 tablets of 400 mg) or 10 ml of suspension five times daily at approximately 4-hour intervals, omitting the nighttime dose.
Treatment should continue for 7 days.
In severely immunocompromised patients (e.g., after bone marrow transplantation) or patients with reduced intestinal absorption, intravenous administration may be considered.
Treatment should be initiated promptly after onset of infection, as treatment is most effective when started at the appearance of the first lesions.
Children
For treatment and prophylaxis of herpes simplex infections in children over 2 years of age with compromised immune function, the dosage is similar to that in adults. For children under 2 years, the dose should be halved. Exceptions are severe HSV infections in immunocompromised patients, for which CIVRAL is not indicated (see section "Therapeutic indications").
Elderly
In elderly patients, the possibility of renal impairment should be considered, and dosage should be adjusted accordingly (see below "Renal impairment").
In the elderly, total clearance decreases as creatinine clearance declines with age. Adequate hydration should be maintained in patients taking high oral doses of CIVRAL.
Renal impairment: Caution is advised when administering aciclovir to patients with impaired renal function. Adequate hydration should be maintained.
For treatment and prophylaxis of herpes simplex infections in patients with severe renal impairment (creatinine clearance <10 ml/min), the dose should be adjusted to 200 mg of aciclovir administered twice daily at approximately 12-hour intervals.
For treatment of herpes zoster infections, dosage adjustment is recommended as follows:

• In patients with severe renal impairment (creatinine clearance <10 ml/min): 800 mg of aciclovir in tablets (2 tablets of 400 mg) or 10 ml of suspension twice daily at approximately 12-hour intervals.
• In patients with moderate renal impairment (creatinine clearance 10–25 ml/min): 800 mg of aciclovir in tablets (2 tablets of 400 mg) or 10 ml of suspension three times daily at approximately 8-hour intervals.
  METHOD OF ADMINISTRATION
  For oral use only.
  Tablets: Swallow the tablet (or half tablet for the 200 mg dose) whole with water.
  Oral suspension: Shake the bottle vigorously before use. Using the dosing syringe provided, the amount of aciclovir can be measured according to the desired dose:
  1.25 ml: 100 mg
  2.50 ml: 200 mg
  5.00 ml: 400 mg
  10.0 ml: 800 mg
  OVERDOSE
  Symptoms and signs: Aciclovir is only partially absorbed in the intestine.
  Patients who have occasionally ingested overdoses up to 20 g of aciclovir in a single dose have generally not shown unexpected effects.
  Accidental and repeated oral overdoses of aciclovir over several days have been associated with gastrointestinal effects (such as nausea and vomiting) and neurological effects (headache and confusion).
  Intravenous overdoses of aciclovir have resulted in increased serum creatinine and blood urea nitrogen levels, leading to renal failure. Neurological effects including confusion, hallucinations, agitation, seizures, and coma have been reported with intravenous overdose.
  Treatment: Patients should be closely observed for signs of toxicity. Hemodialysis significantly contributes to the removal of aciclovir from the blood and may therefore be considered as a treatment option in symptomatic overdose.
  ADVERSE EFFECTS
  The frequency categories associated with the adverse events listed below are estimates. For most events, adequate data on incidence are not available. Furthermore, the incidence of adverse events may vary depending on the indication.
  The following convention has been used to classify adverse effects by frequency: very common ≥1/10, common ≥1/100 and <1/10, uncommon ≥1/1000 and <1/100, rare ≥1/10,000 and <1/1000, very rare <1/10,000.
  Disorders of the hematopoietic and lymphatic system
  Very rare: anemia, leukopenia, thrombocytopenia
  Immune system disorders
  Rare: anaphylaxis
  Psychiatric and nervous system disorders
  Common: headache, dizziness
  Very rare: agitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, seizures, somnolence, encephalopathy, coma
  The above events are usually reversible and generally occur in patients with renal failure or other predisposing factors.
  Respiratory, thoracic and mediastinal disorders
  Rare: dyspnea
  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; therefore, the relationship of this event to aciclovir therapy is uncertain.
  Rare: angioedema
  Renal and urinary disorders
  Rare: increased blood urea nitrogen and creatinine
  Very rare: acute renal failure, renal pain
  Renal pain may be associated with renal failure.
  Systemic disorders and administration site conditions
  Common: fatigue, fever
  Reporting of adverse effects
  If you experience any adverse effects, including those not listed in this leaflet, consult your doctor or pharmacist. You may also report adverse effects directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili.
  By reporting adverse effects, you can help provide more information on the safety of this medicine.
  EXPIRY DATE AND STORAGE:
  Do not use the medicine after the expiry date stated on the packaging.
  CIVRAL tablets: Store at a temperature not exceeding 25°C.
  KEEP OUT OF REACH AND SIGHT OF CHILDREN.
  COMPOSITION
  CIVRAL tablets
  Each tablet contains:
  Active substance: Aciclovir 400 mg
  Excipients: microcrystalline cellulose; sodium starch glycolate; polyvinylpyrrolidone; red iron oxide (E172); magnesium stearate.
  CIVRAL oral suspension
  100 ml of oral suspension contains:
  Active substance: Aciclovir 8 g
  Excipients: sorbitol (70% non-crystallizable); glycerol; dispersible cellulose; methyl p-hydroxybenzoate; propyl p-hydroxybenzoate; orange flavor; purified water.
  PHARMACEUTICAL FORM AND CONTENT
  CIVRAL 400 mg tablets: 25 tablets in blister
  CIVRAL 8 g/100 ml oral suspension: 1 bottle of 100 ml with a white-milky polyethylene dosing syringe
  MARKETING AUTHORIZATION HOLDER
  PHARMABER S.r.l., Corso Magenta, 32 – 20123 Milan
  MANUFACTURER AND FINAL CONTROLLER
  SPECIAL PRODUCT’S LINE S.p.A.
  Via Campobello, 15 - 00040 Pomezia (Rome)
  CIVRAL 250 mg powder for solution for infusion
  A
  M
  THERAPEUTIC PHARMACOLOGICAL CATEGORY
  Antivirals for systemic use with direct action – Nucleosides and nucleotides excluding reverse transcriptase inhibitors.
  THERAPEUTIC INDICATIONS
  CIVRAL is indicated for:
  Herpes simplex and varicella zoster infections in immunocompromised patients.
  Prophylaxis of herpes simplex infections in severely immunocompromised patients.
  Recurrent varicella zoster virus infections and severe primary genital herpes in patients with normal immune function. Herpes simplex encephalitis, with restricted use to hospitals and clinics.
  Treatment of herpes simplex infections in neonates.
  CONTRAINDICATIONS
  CIVRAL infusion solution is contraindicated in patients with known hypersensitivity to aciclovir, valaciclovir, or any of the excipients.
  Generally contraindicated during pregnancy and breastfeeding (see "Special Warnings").
  PRECAUTIONS FOR USE
  Adequate hydration must be maintained in patients receiving CIVRAL injection solution.
  Intravenous administration must be performed by slow infusion over at least one hour to prevent renal precipitation of aciclovir; rapid injection or bolus administration must be avoided.
  The risk of renal impairment is increased by the use of other nephrotoxic drugs. Caution is required when administering CIVRAL injection solution with other nephrotoxic drugs.
  Use in elderly patients and patients with renal impairment
  Aciclovir is eliminated via renal clearance; therefore, the dose must be reduced in patients with renal impairment. Elderly patients are likely to have reduced renal function, and thus dose reduction should be considered in this group. Both elderly and renally impaired patients are at increased risk of developing neurological adverse effects and must be closely monitored for such effects. In reported cases, these reactions were generally reversible upon discontinuation of treatment.
  Repeated or prolonged courses of aciclovir treatment in severely immunocompromised patients may lead to selection of less sensitive viral strains, which may not respond to continued aciclovir therapy.
  In patients receiving CIVRAL infusion solution at higher doses (e.g., for the treatment of herpes encephalitis), particular attention must be paid to renal function, especially in patients with poor hydration or impaired renal function.
  Reconstituted aciclovir infusion solution has a pH of approximately 11.0 and therefore must not be administered orally.
  INTERACTIONS
  Aciclovir is primarily excreted unchanged in urine via active tubular secretion. Any concomitantly administered drug capable of competing with this mechanism may increase plasma concentrations of aciclovir. Probenecid and cimetidine, through this mechanism, increase the area under the plasma concentration-time curve (AUC) of aciclovir and thus reduce its renal clearance.
  Nevertheless, no dosage adjustment is required due to the wide therapeutic index of aciclovir.
  In patients receiving CIVRAL intravenously, caution is required when co-administering drugs that compete with aciclovir for elimination due to the potential increase in plasma levels of one or both drugs or their metabolites. Increases in AUCs of both aciclovir and the inactive metabolite of mycophenolate mofetil, an immunosuppressive agent used in transplant patients, have been observed when administered together.
  If lithium is administered concomitantly with high intravenous doses of aciclovir, serum lithium concentrations must be closely monitored due to the risk of lithium toxicity.
  Caution (with monitoring of changes in renal function) is required when CIVRAL is administered intravenously with drugs affecting other aspects of renal physiology (e.g., cyclosporine, tacrolimus).
  An experimental study conducted in five male subjects indicates that concomitant therapy with aciclovir increases the AUC of total theophylline by approximately 50%. Plasma theophylline concentrations should be monitored during concomitant therapy with aciclovir.
  Inform your doctor or pharmacist if you have recently taken any other medicines,
  including those without a prescription.
  SPECIAL WARNINGS
  Fertility
  No data are available regarding fertility in women. CIVRAL has not shown any effect on sperm count, morphology, or mortality in men.
  Pregnancy
  Because clinical data on administration during pregnancy are limited, the drug should be administered only when absolutely necessary under direct medical supervision and only when the potential benefits of treatment outweigh any unknown risks.
  A registry on the use of aciclovir during pregnancy has provided data on pregnancy outcomes in women exposed to various formulations of CIVRAL after marketing authorization. These observations have not shown an increased number of birth defects among subjects exposed to CIVRAL compared to the general population, and all birth defects observed did not show any particular pattern or common characteristics suggesting a single cause.
  In conventional, internationally accepted tests, systemic administration of aciclovir did not produce embryotoxic or teratogenic effects in rabbits, rats, or mice.
  In an experimental study in rats not included in classical teratogenicity tests, fetal abnormalities were observed only after subcutaneous doses of aciclovir so high as to produce toxic effects in the mother. The clinical relevance of these findings is uncertain.
  Breastfeeding
  Limited clinical data show that after administration of CIVRAL during breastfeeding, aciclovir is excreted in breast milk; therefore, use of the product should be avoided during breastfeeding.
  Following oral administration of 200 mg aciclovir five times daily, aciclovir has been detected in breast milk at concentrations of 0.6–4.1 times the corresponding plasma levels. These levels could potentially expose infants to aciclovir doses up to 0.3 mg/kg/day. Therefore, caution is advised when using CIVRAL during breastfeeding.
  This medicine contains sodium (26 mg, approximately 1.13 mmol). This should be taken into consideration in patients with reduced renal function or those on a low-sodium diet.
  Effects on the ability to drive and use machines
  CIVRAL infusion solution is primarily used in hospitalized patients, and information on the ability to drive or operate machinery is generally not relevant.
  No studies have been conducted to evaluate the effects of CIVRAL on the ability to drive or operate machinery.
  DOSAGE, ADMINISTRATION, AND DURATION
  Route of administration: slow infusion over at least 1 hour.
  Adults
  For herpes simplex infections (excluding herpes encephalitis) and recurrent varicella-zoster virus infections (in patients with normal immune function), the dosage is 5 mg/kg every 8 hours, provided renal function is not impaired (see Patients with impaired renal function).
  In immunocompromised patients with varicella-zoster virus infections and in those with herpes simplex encephalitis, the dosage is 10 mg/kg every 8 hours, provided renal function is not impaired (see Patients with impaired renal function).
  Obese patients should receive the recommended adult dose based on ideal body weight rather than actual body weight.
  Children
  The dose of CIVRAL infusion solution in children aged 3 months to 12 years is calculated based on body surface area.
  In children aged 3 months or older with herpes simplex infections (excluding herpes encephalitis) and in those with recurrent varicella-zoster virus infections (in patients with normal immune function), the dosage is 250 mg/m² body surface area every 8 hours, provided renal function is not impaired.
  In immunocompromised children with varicella-zoster virus infections and in those with herpes simplex encephalitis, the dosage is 500 mg/m² every 8 hours, provided renal function is not impaired.
  Neonates and children up to 3 months of age
  The dose of CIVRAL infusion solution in neonates and children up to 3 months of age should be calculated based on body weight.
  The recommended dose for treatment of neonates with known or suspected neonatal herpes infection is 20 mg/kg body weight of aciclovir injection solution every 8 hours for 21 days in cases of disseminated disease or central nervous system involvement, or for 14 days in cases of disease limited to skin and mucous membranes.
  Neonates and children with impaired renal function require appropriate dose adjustment based on the degree of renal impairment (see Patients with impaired renal function).
  Elderly
  The possibility of renal impairment should be considered, and dosage should be adjusted accordingly (see also below Patients with impaired renal function). Adequate hydration should be maintained.
  Patients with impaired renal function
  Caution is advised when administering aciclovir infusion solution to patients with impaired renal function.
  Adequate hydration should be maintained.
  Dosage adjustment for patients with renal impairment is based on creatinine clearance in ml/min for adults and adolescents, and in ml/min/1.73m² for neonates and children under 13 years of age.
  Dose adjustments in adults and adolescents

Dosing adjustments in neonates and children

Duration
Treatment should be continued for 5 days; however, the duration may be modified according to the patient's condition and therapeutic response. In the treatment of herpes encephalitis, treatment should be continued for 10 days. In the treatment of neonatal herpes, treatment should be continued for 14 days for mucocutaneous infections (skin-eye-mouth) and for 21 days for disseminated disease and disease involving the central nervous system.
The duration of prophylactic administration of CIVRAL injectable solution is determined by the period of risk.

Reconstitution
The contents of each vial of CIVRAL must be dissolved in 10 ml of water for injections or physiological saline solution, gently shaken until completely dissolved. This results in a solution containing 25 mg/ml of aciclovir.

Administration
The required dose of CIVRAL must be administered by slow intravenous infusion over a period of 1 hour.
After reconstitution, CIVRAL may be administered using an infusion pump at a controlled rate.
Alternatively, the reconstituted solution may be further diluted to achieve a concentration of aciclovir not exceeding 5 mg/ml (0.5% w/v), and administered by intravenous infusion:
add the required volume of reconstituted solution to the chosen infusion fluid, as specified below, and mix well to ensure adequate homogeneity;
in children and neonates, where it is desirable to keep the volume of infusion fluid to a minimum, it is recommended that dilution be performed by adding 4 ml of reconstituted solution (100 mg of aciclovir) to 20 ml of infusion solution;
in adults, infusion bags containing 100 ml of infusion solution are recommended, even when this results in an aciclovir concentration substantially below 0.5% w/v. Thus, a 100 ml infusion bag may be used for any aciclovir dose between 250 mg and 500 mg (10 and 20 ml of reconstituted solution, respectively), but a second bag must be used for doses between 500 mg and 1000 mg.
After dilution as specified above, CIVRAL is compatible with the following infusion fluids and remains stable for up to 12 hours at room temperature (15–25 °C):
Sodium chloride (0.9% w/v)
Glucose with sodium chloride I (4.7% w/v and 0.18% w/v, respectively)
Glucose with sodium chloride III (2.75% w/v and 0.45% w/v, respectively)
Ringer's lactate.
If cloudiness or crystals appear in the solution before or during administration, the solution must be discarded.
Since no antimicrobial preservative is present, reconstitution and dilution must be performed aseptically immediately before use, and any unused residue must be discarded. The reconstituted or diluted solution must not be frozen.

METHOD OF ADMINISTRATION
Administration
For intravenous use only, administered slowly.

OVERDOSE
Symptoms and signs: intravenous overdose of aciclovir has led to increased serum creatinine, increased blood urea nitrogen (BUN), and consequent renal failure. Neurological effects including confusion, hallucinations, agitation, dizziness, and coma have been reported in association with overdose.
Treatment: patients should be closely monitored for signs of toxicity. Hemodialysis significantly increases the elimination of aciclovir from the blood and may therefore be considered as a management option in cases of drug overdose.

ADVERSE EFFECTS
The frequency categories associated with the adverse events listed below are estimates. For most events, reliable data to calculate exact incidence are not available. Furthermore, the incidence of adverse events may vary depending on the indication.
The following convention has been used to classify adverse effects by frequency: very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1,000 and < 1/100; rare ≥ 1/10,000 and < 1/1,000; very rare < 1/10,000.

Hematopoietic and lymphatic system disorders
Uncommon: decreased hematological parameters (anemia, thrombocytopenia, and leucopenia)

Immune system disorders
Very rare: anaphylaxis

Psychiatric and nervous system disorders
Very rare: headache, dizziness, agitation, confusion, tremors, ataxia, dysarthria, hallucinations, psychotic symptoms, seizures, somnolence, encephalopathy, coma
These events are usually reversible and generally occur in patients with renal impairment or other predisposing factors.

Vascular disorders
Common: phlebitis

Respiratory, thoracic and mediastinal disorders
Very rare: dyspnea

Gastrointestinal disorders
Common: nausea, vomiting
Very rare: diarrhea, abdominal pain

Hepatobiliary disorders
Common: reversible elevations in liver enzymes
Very rare: reversible elevations in bilirubin, jaundice, hepatitis

Skin and subcutaneous tissue disorders
Common: pruritus, urticaria, rash (including photosensitivity)
Very rare: angioedema

Renal and urinary disorders
Common: increases in blood urea nitrogen (BUN) and creatinine
Rapid increases in BUN and creatinine levels are believed to be related to peak plasma levels and the patient's hydration status. To avoid this effect, the drug must not be administered as an intravenous bolus injection but by slow infusion over at least one hour.
Very rare: renal impairment, acute renal failure, renal pain.
Adequate hydration of patients must be maintained. Renal impairment generally responds rapidly to rehydration and/or dose reduction or discontinuation of the drug. However, progression to acute renal failure may exceptionally occur.
Renal pain may be associated with renal failure.

General disorders and administration site conditions
Very rare: fatigue, fever, local inflammatory reactions
Severe local inflammatory reactions, sometimes leading to skin lesions, have occurred when aciclovir infusion solution was inadvertently injected into extravascular tissues.

Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, consult your doctor or pharmacist. You may also report adverse reactions directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili.
By reporting adverse reactions, you can help provide more information on the safety of this medicine.

EXPIRY AND STORAGE:
Do not use this medicine after the expiry date stated on the packaging.
Store at a temperature not exceeding 25°C.
Does not contain preservatives. Reconstitution and dilution must therefore be performed immediately before use, and any unused residue must be discarded. The reconstituted or diluted solution must not be frozen.
The reconstituted or diluted solution must not be frozen (see section 4.2).
After dilution, CIVRAL is compatible with the specified infusion fluids and remains stable for up to 12 hours at room temperature (15–25°C).
KEEP OUT OF REACH AND SIGHT OF CHILDREN.

COMPOSITION
Each vial contains:
Active substance: aciclovir 250 mg
Excipients: sodium hydroxide

PHARMACEUTICAL FORM AND CONTENT
3 vials for intravenous use containing 250 mg of aciclovir.

MARKETING AUTHORISATION HOLDER
PHARMABER S.r.l., Corso Magenta, 32 – 20123 Milan

MANUFACTURER AND FINAL CONTROLLER
BIOLOGICI ITALIA LABORATORIES S.R.L.
Via F. Serpero, 2 - 20060 Masate (Milan)

PACKAGE LEAFLET DERMATOLOGICAL CREAM

CIVRAL 5% cream

Aciclovir
Generic Medicine
THERAPEUTIC PHARMACOLOGICAL CATEGORY
Topical antivirals.
THERAPEUTIC INDICATIONS
CIVRAL cream is indicated for the treatment of cutaneous infections caused by Herpes Simplex, such as:
primary or recurrent genital herpes and herpes labialis.
CONTRAINDICATIONS
CIVRAL cream is contraindicated in patients with known hypersensitivity to aciclovir, valaciclovir,
propylene glycol, or any of the excipients in CIVRAL cream.
SUITABLE PRECAUTIONS FOR USE
No phenomena of habituation or dependence have been reported with this drug.
CIVRAL cream is not recommended for application on mucous membranes such as those of the
mouth, eyes, or vagina, as it may be irritating. Particular care should be taken to avoid accidental
application into the eyes.
Animal studies indicate that vaginal application of CIVRAL cream may cause reversible irritation.
In severely immunocompromised patients (e.g., patients with AIDS or bone marrow transplant
recipients), administration of aciclovir in oral formulations should be considered. Such patients should
be encouraged to consult their physician regarding treatment of any infection.
The excipient propylene glycol may cause skin irritation, and the excipient cetyl stearyl alcohol may
cause local skin reactions (e.g., contact dermatitis).
Prolonged use of the product, especially if prolonged, may lead to sensitization; if this occurs, treatment
should be discontinued and a physician consulted.
Keep out of sight and reach of children.
INTERACTIONS WITH OTHER MEDICINES
Probenecid increases the mean half-life and the area under the plasma concentration-time curve of
systemically administered aciclovir. No clinically significant interactions have been identified.
However, systematically inform your physician of any other concomitant therapies.
SPECIAL WARNINGS
CIVRAL does not affect alertness; therefore, it has no effect on the ability to drive or operate machinery.
DOSAGE AND ADMINISTRATION
CIVRAL cream should be applied 5 times daily at intervals of approximately 4 hours.
CIVRAL cream should be applied to lesions or areas where lesions are developing as early as possible
after the onset of infection.
It is particularly important to initiate treatment of recurrent episodes during the prodromal phase or at
the first appearance of lesions.
Treatment should continue for at least 5 days and up to a maximum of 10 days if healing has not occurred.
Administration
For topical use only.
OVERDOSE (UNINTENTIONAL INGESTION)
Even if the entire contents of the tube containing 150 mg of aciclovir were ingested, adverse effects
are not expected, since single oral doses of 600 mg and daily doses up to 3600 mg have been
administered orally without observed side effects. Accidental intravenous doses up to 80 mg/kg have
been administered without adverse effects.
Emergency interventions
Treatment: patients who have ingested aciclovir doses exceeding 5 g should be closely monitored.
Aciclovir is dialyzable.
USE IN PREGNANCY AND DURING BREASTFEEDING
Pregnancy
Since there are no clinical data on the effects of CIVRAL cream during pregnancy, the drug should be
used during this period only if absolutely necessary, under direct medical supervision, and only when
the potential benefits of treatment outweigh any unknown risks. However, systemic exposure to aciclovir
following topical application of CIVRAL cream is very low.
A post-marketing registry on the use of aciclovir during pregnancy has provided data on pregnancy
outcomes in women exposed to various aciclovir formulations. These observations have not shown an
increase in the number of birth defects among aciclovir-exposed subjects compared to the general
population, and all birth defects observed lacked any particular pattern or common characteristics
suggesting a single cause.
Systemic administration of aciclovir in internationally accepted standard tests has not produced
embryotoxic or teratogenic effects in rabbits, rats, or mice.
In an experimental study in rats not included in standard teratogenicity tests, fetal abnormalities were
observed only after subcutaneous doses of aciclovir so high as to produce toxic effects in the mother.
The clinical relevance of these findings is uncertain.
Breastfeeding
Limited human data show that the drug passes into breast milk following systemic administration.
However, the dose received by an infant as a result of aciclovir cream use in the mother should be
insignificant.
UNDESIRABLE EFFECTS
The following convention has been used to classify undesirable effects by frequency: very common ≥ 1/10, common ≥ 1/100 and < 1/10, uncommon ≥ 1/1,000 and < 1/100,
rare ≥ 1/10,000 and < 1/1,000, very rare < 1/10,000.
Data from clinical studies on the use of Aciclovir 3% ophthalmic ointment were used to assign
frequency categories to adverse reactions observed during clinical trials. Due to the nature of the
adverse events observed, it is not possible to definitively determine which events are related to drug
administration and which are related to the disease itself. Spontaneous reporting data were used as
the basis to determine the frequency of events detected after marketing authorization.
Skin and subcutaneous tissue disorders
Uncommon: Transient burning or pain after application of aciclovir cream.
Moderate dryness or desquamation of the skin.
Pruritus.
Rare: Erythema. Contact dermatitis after application. Where sensitivity
testing has been performed, substances causing reactivity were found
to be components of the cream base rather than aciclovir itself.
Immune system disorders
Very rare: Immediate hypersensitivity reactions including angioedema and urticaria.
Reporting of undesirable effects
If any undesirable effect occurs, including those not listed in this leaflet, consult your doctor or
pharmacist. You may also report adverse effects directly via the national reporting system at
www.agenziafarmaco.gov.it/it/responsabili.
By reporting adverse effects, you can help provide more information on the safety of this medicine.
Expiry date: Do not use the medicine after the expiry date stated on the packaging.
Store below 25°C
COMPOSITION
100 g of cream contains:
Active substance: Aciclovir 5 g
Excipients: poloxamer 407; cetyl stearyl alcohol; sodium lauryl sulfate; white soft paraffin; liquid paraffin; propylene glycol; purified water.
PHARMACEUTICAL FORM AND PACKAGING
5% aciclovir dermatological cream; 3 g tube
MARKETING AUTHORIZATION HOLDER
PHARMABER S.r.l., Corso Magenta, 32 – 20133 Milan
MANUFACTURING SITE
FARMIGEA S.p.A.
Via G. B. Oliva, 8 – 56121 Ospedaletto (Pisa)
and also at:
SPECIAL PRODUCT’S LINE S.p.A.
Via Campobello, 15 - 00040 Pomezia (Rome)