Zovirax IV

Zovirax IV

aciclovir

Manufacturer:

GlaxoSmithKline Indonesia
Full Prescribing Info
Contents
Aciclovir.
Description
The sodium ion content is approximately 26 mg/vial.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including herpes simplex virus (HSV) types 1 and 2, varicella zoster virus (VZV), Epstein-Barr Virus (EBV) and cytomegaloviruses (CMV). In cell culture, aciclovir has the greatest antiviral activity against HSV-1, followed (in decreasing order of potency) by HSV-2, VZV, EBV and CMV.
The inhibitory activity of aciclovir for HSV-1, HSV-2, VZV, EBV and CMV is highly selective. The enzyme thymidine kinase (TK) of normal, noninfected cells does not use aciclovir effectively as substrate, hence toxicity to mammalian host cells is low; however, TK encoded by HSV, VZV and EBV converts aciclovir to aciclovir monophosphate, a nucleoside analogue, which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes.
Aciclovir triphosphate interferes with the viral DNA polymerase and inhibits viral DNA replication with resultant chain termination following its incorporation into the viral DNA.
Pharmacodynamic Effects: Prolonged or repeated courses of aciclovir in severely immunocompromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued aciclovir treatment.
Most of the clinical isolates with reduced sensitivity have been relatively deficient in viral TK; however, strains with altered viral TK or DNA polymerase have also been reported. In vitro exposure of HSV isolates to aciclovir can also lead to the emergence of less sensitive strains.
The relationship between the in vitro determined sensitivity of HSV isolates and clinical response therapy is not clear. All patients should be cautioned to ensure they avoid the potential of virus transmission, particularly when active lesion are present.
Clinical Studies: There is no information on the effect of Zovirax IV for infusion on human female fertility. In a study of 20 male patients with normal sperm count, oral aciclovir administered at doses of up to 1 g/day for up to 6 months has been shown to have no clinically significant effect on sperm count, motility or morphology.
Pharmacokinetics: Absorption: In adults, mean steady state peak plasma concentrations (Cssmax) following a 1-hr infusion of 2.5 mg/kg, 5 mg/kg, 10 mg/kg and 15 mg/kg were 22.7 micromoles (5.1 mcg/mL), 43.6 micromoles (9.8 mcg/mL), 92 micromoles (20.7 mcg/mL) and 105 micromoles (23.6 mcg/mL), respectively. The corresponding trough levels (Cssmin) 7 hrs later were 2.2 micromoles (0.5 mcg/mL), 3.1 micromoles (0.7 mcg/mL), 10.2 micromoles (2.3 mcg/mL) and 8.8 micromoles (2 mcg/mL), respectively. In children >1 year similar mean peak (Cssmax) and trough (Cssmin) levels were observed when a dose of 250 mg/m2 was substituted for 5 mg/kg and a dose of 500 mg/m2 was substituted for 10 mg/kg.
Distribution: Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels. Plasma protein binding is relatively low (9-33%) and drug interactions involving binding site displacement are not anticipated.
Elimination: In adults the terminal plasma half-life (t½) of aciclovir after administration of aciclovir IV for infusion is about 2.9 hrs. Most of the drug is excreted unchanged by the kidney. Renal clearance of aciclovir is substantially greater than creatinine clearance indicating that tubular secretion in addition to glomerular filtration contributes to the renal elimination of the drug. 9-carboxymethoxy-methylguanine is the only significant metabolite of aciclovir and accounts for approximately 10-15% of the dose excreted in the urine. When aciclovir is given 1 hr after 1 g of probenecid the terminal t½ and the area under the plasma concentration time curve is extended by 18% and 40%, respectively.
Special Patient Populations: In patients with chronic renal failure the mean terminal t½ was found to be 19.5 hrs. The mean aciclovir t½ during haemodialysis was 5.7 hrs. Plasma aciclovir levels dropped approximately 60% during dialysis.
In the elderly total body clearance falls with increasing age, associated with decreases in creatinine clearance, although there is little change in the terminal plasma t½.
Toxicology: Preclinical Safety Data: The results of a wide range of mutagenicity tests in vitro and in vivo indicate that aciclovir is unlikely to pose a genetic risk to man.
Aciclovir was not found to be carcinogenic in long-term studies in the rat and the mouse.
Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses of aciclovir greatly in excess of those employed therapeutically. Two-generation studies in mice did not reveal any effect of (orally administered) aciclovir on fertility.
Systemic administration of aciclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rabbits, rats or mice. In a non-standard test in rats, foetal abnormalities were observed but only following such high SC doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.
Indications/Uses
Treatment for herpes simplex infections in immunocompromised patients; prophylaxis of herpes simplex infections in severely immunocompromised patients; treatment of severe initial genital herpes; primary and recurrent varicella zoster infections in immunocompromised patients; recurrent varicella zoster infection (shingles) in patients with normal immune responses; herpes simplex encephalitis in patient >6 months.
Dosage/Direction for Use
Adults: Patients with Herpes Simplex (except herpes encephalitis) Infections: 5 mg/kg body weight IV infusion infused at a constant rate over a 1 hr period every 8 hrs (15 mg/kg/day) for 7 days in patients with normal renal function. Severe Initial Episodes of Herpes Simplex Genitalis: The same dosages as previously mentioned are administered for 5 days.
Immunocompromised Patients with Varicella Zoster Infection: 10 mg/kg body weight over 1 hr period every 8 hrs for 7 days, with provided renal function is not impaired.
Herpes Simplex Encephalitis and Has No Renal Impairment: 10 mg/kg body weight infused at a constant rate over 1 hr period every 8 hrs for 10 days, with provided renal function is not impaired.
Children: The dose of Zovirax IV for infusion for children 3 months to 12 years is calculated on the basis of body surface area.
Herpes Simplex Infection: 250 mg/m2 infused at a constant rate over a 1 hr period every 8 hrs (750 mg/m2) for 7 days.
In Immunocompromised Children with Varicella Zoster Infection: 500 mg/m2 over a 1 hr period every 8 hrs for 7 days.
Children in 6 months to 12 years With Herpes Simplex Encephalitis: More accurate dosing is achieved by infusing 500 mg/m2 at a constant rate over at least 1 hr every 8 hrs for 10 days.
Children with impaired renal function require an appropriately modified dose, according to the degree of impairment.
Elderly: In the elderly, total aciclovir body clearance declines in parallel with creatinine clearance. Special attention should be given to dosage reduction in elderly patients with impaired creatinine clearance.
Renal Impairment: Caution is advised when administering Zovirax IV for infusion to patients with impaired renal function. The following adjustments in dosage are suggested as follows:
Creatinine clearance (CrCl) >50 mL/min: 5 or 10 mg/kg body weight should be given every 8 hrs.
CrCl 25-50 mL/min: 5 or 10 mg/kg body weight every 12 hrs.
CrCl 10-25 mL/min: 5 or 10 mg/kg body weight every 24 hrs.
0 (anuric)-10 mL/min: In Patients Receiving Continous Ambulatory Peritoneal Dialysis (CAPD): 5 or 10 mg/kg body weight should be halved and administered every 24 hrs. In patients receiving haemodialysis 5 or 10 mg/kg body weight should be halved and administered every 24 hrs and after dialysis.
Overdosage
Symptoms: Overdosage of intravenous aciclovir has resulted in elevations of serum creatinine, blood urea nitrogen and subsequent renal failure. Neurological effects including confusion, hallucinations, agitation, seizures and coma have been described in association with overdosage.
Treatment: Patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.
Contraindications
Patients known to be hypersensitive to aciclovir or valaciclovir.
Special Precautions
In patients receiving Zovirax IV for infusion at higher doses (eg, herpes encephalitis), specific care regarding renal function should be taken, particularly when patients are dehydrated or have any renal impairment.
Reconstituted Zovirax IV for infusion has a pH approximately 11 and should not be administered by mouth.
Patients with Renal Impairment and in Elderly Patients: Aciclovir is eliminated by renal clearance, therefore the dose must be reduced in patients with renal impairment (see Dosage & Administration). Elderly patients are likely to have reduced renal function and therefore the need for dose reduction must be considered in this group of patients. Both elderly patients and patients with renal impairment are at increased risk of developing neurological side effects and should be closely monitored for evidence of these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment (see Adverse Reactions).
Effects on the Ability to Drive or Operate Machinery: Zovirax IV for infusion is generally used in an in-patient hospital population and information on ability to drive and operate machinery is not usually relevant. There have been no studies to investigate the effect of aciclovir on driving performance or the ability to operate machinery.
Use in pregnancy: A post-marketing Zovirax pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of Zovirax. The birth defects described amongst Zovirax exposed subjects have not shown any uniqueness or consistent pattern to suggest a common cause.
The use of Zovirax should be considered only when the potential benefits outweigh the possibility of unknown risks.
Use in lactation: Following oral administration of Zovirax 200 mg 5 times a day, aciclovir has been detected in breast milk at concentrations ranging from 0.6-4.1 times the corresponding plasma levels. These levels would potentially expose nursing infants to aciclovir dosages of up to 0.3 mg/kg/day. Caution is therefore advised if Zovirax is to be administered to a nursing woman.
Use In Pregnancy & Lactation
Use in pregnancy: A post-marketing Zovirax pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of Zovirax. The birth defects described amongst Zovirax exposed subjects have not shown any uniqueness or consistent pattern to suggest a common cause.
The use of Zovirax should be considered only when the potential benefits outweigh the possibility of unknown risks.
Use in lactation: Following oral administration of Zovirax 200 mg 5 times a day, aciclovir has been detected in breast milk at concentrations ranging from 0.6-4.1 times the corresponding plasma levels. These levels would potentially expose nursing infants to aciclovir dosages of up to 0.3 mg/kg/day. Caution is therefore advised if Zovirax is to be administered to a nursing woman.
Adverse Reactions
The frequency categories associated with the adverse events as follows are estimates. For most events, suitable data for estimating incidence were not available. In addition, adverse events may vary in their incidence depending on the indication.
The following convention has been used for the classification of adverse effects in terms of 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.
Blood and Lymphatic System Disorders: Uncommon: Decreases in haematological indices (anaemia, thrombocytopenia, leukopenia).
Immune System Disorders: Very Rare: Anaphylaxis.
Psychiatric and Nervous System Disorders: Very Rare: Headache, dizziness, agitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, convulsions, somnolence, encephalopathy, coma.
The previously mentioned events are generally reversible and usually reported in patients with renal impairment or with other predisposing factors (see Precautions).
Vascular Disorders: Common: Phlebitis.
Respiratory, Thoracic and Mediastinal Disorders: Very Rare: Dyspnoea.
Gastrointestinal Disorders: Common: Nausea, vomiting. Very Rare: Diarrhoea, abdominal pain.
Hepatobiliary Disorders: Common: Reversible increases in liver-related enzymes. Very Rare: Reversible increases in bilirubin, jaundice, hepatitis.
Skin and Subcutaneous Tissue Disorders: Common: Pruritus, urticaria, rashes (including photosensitivity). Very Rare: Angioedema.
Renal and Urinary Disorders: Common: Increases in blood urea and creatinine. Rapid increases in blood urea and creatinine levels are believed to be related to the peak plasma levels and the state of hydration of the patient. To avoid this effect the drug should not be given as an IV bolus injection but by slow infusion over a 1-hr period. Very Rare: Renal impairment, acute renal failure, renal pain.
Adequate hydration should be maintained. Renal impairment usually responds rapidly to rehydration of the patient and/or dosage reduction or withdrawal of the drug. Progression to acute renal failure, however, can occur in exceptional cases. 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 breakdown of the skin have occurred when Zovirax IV for infusion has been inadvertantly infused into extracellular tissues.
Drug Interactions
No clinically significant interactions have been identified.
Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase aciclovir plasma concentrations. Probenecid and cimetidine increase the AUC of aciclovir by this mechanism, and reduce aciclovir renal clearance. However no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.
In patients receiving Zovirax IV, caution is required during concurrent administration with drugs which compete with aciclovir for elimination, because of the potential for increased plasma levels of 1 or both drugs or their metabolites. Increases in plasma AUCs of aciclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant agent used in transplant patients, have been shown when the drugs are co-administered.
Care is also required (with monitoring for changes in renal function) if administering Zovirax IV with drugs which affect other aspects of renal physiology (eg, cyclosporin, tacrolimus).
Caution For Usage
Instructions for Use and Handling: Reconstitution: The required dose of Zovirax IV for infusion should be administered by slow IV infusion over a 1-hr period.
Zovirax IV for infusion should be reconstituted using the following volumes of either water for injections BP or sodium chloride IV injection BP (0.9% w/v) to provide a solution containing Zovirax 25 mg/ mL (Formulation: 250 mg vial; Volume of fluid for reconstitution: 10 mL).
From the calculated dose, determine the appropriate number and strength of vials to be used. To reconstitute each vial, add the recommended volume of infusion fluid and shake gently until the contents of the vial have dissolved completely.
Alternatively, the reconstituted solution may be further diluted to give an Zovirax concentration of not greater than 5 mg/mL (0.5% w/v) for administration by infusion. Add the required volume of reconstituted solution to the chosen infusion solution, as recommended as follows and shake well to ensure adequate mixing occurs.
For children, where it is advisable to keep the volume of infusion fluid to a minimum, it is recommended that dilution is on the basis of 4 mL reconstituted solution (Zovirax 100 mg) added to 20 mL of infusion fluid.
For adults, it is recommended that infusion bags containing 100 mL of infusion fluid are used, even when this would give an Zovirax concentration substantially, below 0.5% w/v.
Thus, one 100-mL infusion bag may be used for any dose between Zovirax 250 and 500 mg (10 and 20 mL of reconstituted solution) but a 2nd bag must be used for doses between 500 and 1000 mg.
When diluted in accordance with the recommended schedules, Zovirax IV for infusion is known to be compatible with the following infusion fluids and stable for up to 12 hrs at room temperature (15°-25°C): Sodium chloride IV infusion (0.45% and 0.9% w/v). Sodium chloride (0.18% w/v) and glucose (4% w/v) IV infusion. Sodium chloride (0.45% w/v) and glucose (2.5% w/v) IV infusion. Compound sodium lactate IV infusion (Hartmann's solution).
Zovirax IV for infusion when diluted in accordance with the above schedule will give an Zovirax concentration not greater than 0.5% w/v.
When reconstituted as directed, Zovirax IV for infusion has a pH of approximately 11.
Since no antimicrobial preservative is included, reconstitution and dilution must be carried out under full aseptic conditions, immediately before use and any unused solution discarded.
Reconstituted or diluted solutions should not be refrigerated.
Should any visible turbidity or crystallisation appear in the solution before or during infusion, the preparation should be discarded.
Storage
Store at temperature not exceeding 25°C.
MIMS Class
ATC Classification
J05AB01 - aciclovir ; Belongs to the class of nucleosides and nucleotides excluding reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.
Presentation/Packing
Infusion 250 mg (sterile, white to off-white, freeze dried powd) x 5's.
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