Acyclovir JPI is indicated for the treatment of Herpes simplex infections in immunocompromised patients and severe initial genital herpes in the non-immunocompromised.

Acyclovir JPI is indicated for the prophylaxis of Herpes simplex infections in immunocompromised patients.

Acyclovir JPI is indicated for the treatment of Varicella zoster infections.

Acyclovir JPI is indicated for the treatment of herpes encephalitis.

Acyclovir JPI is indicated for the treatment of Herpes simplex infections in the neonate and infant up to 3 months of age.

Route of administration: 

Slow intravenous infusion over 1 hour.

A course of treatment with Acyclovir JPI usually lasts 5 days, but this may be adjusted according to the patient's condition and response to therapy. Treatment for herpes encephalitis usually lasts 10 days. Treatment for neonatal herpes infections usually lasts 14 days for mucocutaneous (skin-eye-mouth) infections and 21 days for disseminated or central nervous system disease.

The duration of prophylactic administration of Acyclovir JPI is determined by the duration of the period at risk.

Dosage in adults:

Patients with Herpes simplex (except herpes encephalitis) or Varicella zoster infections should be given Acyclovir JPI in doses of 5 mg/kg body weight every 8 hours provided renal function is not impaired (see Dosage in renal impairment).

Immunocompromised patients with Varicella zoster infections or patients with herpes encephalitis should be given Acyclovir JPI in doses of 10 mg/kg body weight every 8 hours provided renal function is not impaired (see Dosage in renal impairment).

In obese patients dosed with intravenous acyclovir based on using ideal body weight, rather than actual body weight, higher plasma concentrations may be obtained (see 5.2 Pharmacokinetic properties). Consideration should therefore be given to dosage reduction in obese patients and especially in those with renal impairment or the elderly.

Dosage in infants and children: 

The dose of Acyclovir JPI for infants and children aged between 3 months and 12 years is calculated on the basis of body weight.

Infants and children 3 months of age or older with herpes simplex infections should be given acyclovir 20 mg / kg body weight IV every eight hours for 21 days for herpes encephalitis, or for 14 days for disease limited to skin and mucous membrane if renal function is not impaired. Infants and children with varicella zoster infections should be given acyclovir 20mg/kg body weight IV every eight hours if renal function is not impaired.

In immunocompromised children with Varicella zoster infections or children with herpes encephalitis, Acyclovir JPI should be given in doses of 500 mg per square metre body surface area every 8 hours, if renal function is not impaired.

The recommended regimen for infants treated for known or suspected neonatal herpes is acyclovir 20 mg/kg body weight IV every 8 hours for 21 days for disseminated and CNS disease, or for 14 days for disease limited to the skin and mucous membranes.

Infants and children with impaired renal function require an appropriately modified dose, according to the degree of impairment (see Dosage in renal impairment).

Dosage in the elderly:

The possibility of renal impairment in the elderly must be considered and dosage should be adjusted accordingly (see Dosage in renal impairment below).

Adequate hydration should be maintained.

Dosage in renal impairment:

Caution is advised when administering Acyclovir JPI to patients with impaired renal function. Adequate hydration should be maintained.

Dosage adjustment for patients with renal impairment is based on creatinine clearance, in units of ml/min for adults and adolescents and in units of ml/min/1.73 m² for infants and children less than 13 years of age. The following adjustments in dosage are suggested: 

Recommended dosage adjustments in adults and adolescents:

Recommended dosage adjustments in infants and children:

Adequate hydration should be maintained in patients given IV or high oral doses of acyclovir.

Intravenous doses should be given by infusion over one hour to avoid precipitation of acyclovir in the kidney; rapid or bolus injection should be avoided.

The risk of renal impairment is increased by use with other nephrotoxic drugs. Care is required if administering IV acyclovir with other nephrotoxic drugs.

Use in patients with renal impairment and in elderly patients:

Acyclovir is eliminated by renal clearance, therefore the dose must be adjusted in patients with renal impairment (see section 4.2 Posology and method of administration). Elderly patients are likely to have reduced renal function and therefore the need for dose adjustment 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 section 4.8 Undesirable effects). Prolonged or repeated courses of acyclovir in severely immune-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued acyclovir treatment (see section 5.1).

In patients receiving Acyclovir JPI at higher doses (e.g. for herpes encephalitis) specific care regarding renal function should be taken, particularly when patients are dehydrated or have any renal impairment.

Reconstituted Acyclovir JPI has a pH of approximately 11 and should not be administered by mouth. Each vial contains 42.6 mg sodium. To be taken into consideration by patients on a controlled sodium diet.

Acyclovir JPI contains no antimicrobial preservative. Reconstitution and dilution should therefore be carried out under full aseptic conditions immediately before use and any unused solution discarded. The reconstituted or diluted solutions should not be refrigerated.

Other warnings and precautions

The labels shall contain the following statements:

For intravenous use.

Keep out of the sight and reach of children.

Do not store above 30°C.

Prepare immediately before use.

Discard unused solution.

Acyclovir JPI contains sodium

Acyclovir JPI contains sodium. Each vial contains 42.6 mg sodium. This is equivalent to 2.13% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Acyclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase acyclovir plasma concentrations. Probenecid and cimetidine increase the AUC of acyclovir by this mechanism and reduce acyclovir renal clearance. However, no dosage adjustment is necessary because of the wide therapeutic index of acyclovir.

In patients receiving intravenous acyclovir caution is required during concurrent administration with drugs which compete with acyclovir for elimination, because of the potential for increased plasma concentrations of one or both drugs or their metabolites. Increases in plasma AUCs of acyclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant agent used in transplant patients, have been shown when the drugs are coadministered.

If lithium is administered concurrently with high dose acyclovir IV, the lithium serum concentration should be closely monitored because of the risk of lithium toxicity.

Care is also required (with monitoring for changes in renal function) if administering intravenous acyclovir with drugs which affect other aspects of renal physiology (e.g. cyclosporin, tacrolimus).

An experimental study on five male subjects indicates that concomitant therapy with acyclovir increases AUC of totally administered theophylline with approximately 50%. It is recommended to measure plasma concentrations during concomitant therapy with acyclovir.

Fertility:

There is no information on the effect of acyclovir on human female fertility.

In a study of 20 male patients with normal sperm count, oral acyclovir administered at doses of up to 1g per day for up to six months has been shown to have no clinically significant effect on sperm count, motility or morphology.

See clinical studies in section 5.2.

Pregnancy:

A post-marketing acyclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of acyclovir. The registry findings have not shown an increase in the number of birth defects amongst acyclovir exposed subjects compared to with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause. Systemic administration of acyclovir 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 subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.

Caution should therefore be exercised by balancing the potential benefits of treatment against any possible hazard. Findings from reproduction toxicology studies are included in Section 5.3.

Breast-feeding:

Following oral administration of 200 mg five times a day, acyclovir has been detected in human breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding plasma concentrations. These concentrations would potentially expose nursing infants to acyclovir dosages of up to 0.3 mg/kg body weight/day. Caution is therefore advised if acyclovir is to be administered to a nursing woman.

Acyclovir 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 acyclovir on driving performance or the ability to operate machinery.

The frequency categories associated with the adverse events below 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 undesirable effects in terms of 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.

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 above events are generally reversible and usually reported in patients with renal impairment or with other predisposing factors (see 4.4 Special Warnings and Precautions for Use).

Vascular disorders:

Common: phlebitis.

Respiratory, thoracic and mediastinal disorders:

Very rare: dyspnoea.

Gastrointestinal disorders:

Common: nausea, vomiting.

Very rare: diarrhoea, abdominal pain.

Hepato-biliary 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 concentrations are believed to be related to the peak plasma concentrations and the state of hydration of the patient. To avoid this effect the drug should not be given as an intravenous bolus injection but by slow infusion over a one-hour period.

Very rare: renal impairment, acute renal failure and 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 and crystalluria.

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 acyclovir IV has been inadvertently infused into extracellular tissues.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

•  Saudi Arabia

The National Pharmacovigilance Centre (NPC)

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

• Other GCC States

Please contact the relevant competent authority.

Overdosage of intravenenous acyclovir 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.

Patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of acyclovir from the blood and may, therefore, be considered an option in the management of overdose of this drug.

Pharmacotherapeutic group: Direct acting antivirals, Nucleosides and nucleotides excl. reverse transcriptase inhibitors

ATC code: J05AB01.

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including Herpes simplex virus types 1 and 2 and Varicella zoster virus (VZV), Epstein Barr virus (EBV) and Cytomegalovirus (CMV). In cell culture acyclovir 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 acyclovir for HSV-1, HSV-2, VZV and EBV is highly selective. The enzyme thymidine kinase (TK) of normal, uninfected cells does not use acyclovir effectively as a substrate, hence toxicity to mammalian host cells is low; however, TK encoded by HSV, VZV and EBV converts acyclovir to acyclovir monophosphate, a nucleoside analogue, which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes. Acyclovir triphosphate interferes with the viral DNA polymerase and inhibits viral DNA replication with resultant chain termination following its incorporation into the viral DNA.

Absorption

Acyclovir is only partially absorbed from the gut. The average oral bioavailability varies between 10 and 20%. Under fasting conditions, mean peak concentrations (C_max) of 0.4 microgram/ml are achieved at approximately 1.6 hours after a 200 mg dose administered as oral suspension or capsule. Mean peak plasma concentrations (C^ss_max) increase to 0.7 microgram/ml (3.1 micromoles) at steady state following doses of 200 mg administered every four hours. A less than proportional increase is observed for C^ss_max concentrations following doses of 400 mg and 800 mg administered four-hourly, with values reaching 1.2 and 1.8 microgram/ml (5.3 and 8 micromoles), respectively.

Distribution

The mean volume of distribution of 26 L indicates that acyclovir is distributed within total body water. Apparent values after oral administration (Vd/F) ranged from 2.3 to 17.8 L/kg. As plasma protein binding is relatively low (9 to 33%), drug interactions involving binding site displacement are not anticipated. Cerebrospinal fluid concentrations are approximately 50% of corresponding plasma concentrations at steady-state.

Metabolism

Acyclovir is predominantly excreted unchanged by the kidney. The only significant urinary metabolite is 9-[(carboxymethoxy) methyl]guanine, and accounts for 10-15% of the dose excreted in the urine.

Elimination

In adults mean systemic exposure (AUC0-∞) to acyclovir ranges between 1.9 and 2.2 microgram*h/ml after a 200 mg dose. At this dose, the mean terminal plasma half-life after oral administration has been shown to vary between 2.8 and 4.1 hours.

In adults, the terminal plasma half-life of acyclovir after administration of acyclovir IV is about 2.9 hours. Renal clearance of acyclovir (CLr= 14.3 L/h) is substantially greater than creatinine clearance, indicating that tubular secretion, in addition to glomerular filtration, contributes to the renal elimination of the drug. The half-life and total clearance of acyclovir are dependent on renal function. Therefore, dosage adjustment is recommended for renally impaired patients.

In adults, mean steady state peak plasma concentrations (C^ss_max) following a one-hour infusion of 2.5 mg/kg, 5 mg/kg and 10 mg/kg were 22.7 micromolar (5.1 microgram/ml), 43.6 micromolar (9.8 microgram/ml) and 92 micromolar (20.7 microgram/ml) respectively. The corresponding trough concentrations (C^ss_min) 7 hours later were 2.2 micromolar (0.5 microgram/ml), 3.1 micromolar (0.7 microgram/ml) and 10.2 micromolar (2.3 microgram/ml) respectively. In children over 1 year of age similar mean peak (C^ss_max) and trough (C^ss_min) concentrations 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.

In neonates (0 to 3 months of age) treated with doses of 10 mg/kg administered by infusion over a one-hour period every 8 hours the C^ss_max was found to be 61.2 micromolar (13.8 microgram/ml) and the C^ss_min to be 10.1 micromolar (2.3 microgram/ml). A separate group of neonates treated with 15 mg/kg every 8 hours showed approximate dose proportional increases, with a C_max of 83.5 micromolar (18.8 microgram/ml) and C_min of 14.1 micromolar (3.2 microgram/ml). The terminal plasma half-life in these patients was 3.8 hours.

Special Patient Populations

Elderly

In the elderly patients with normal renal function total clearance falls with increasing age due to decreases in creatinine clearance. However, the possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly.

Renal impairment

In patients with chronic renal failure the mean terminal half-life was found to be 19.5 hours. The mean acyclovir half-life during haemodialysis was 5.7 hours. Plasma acyclovir concentrations dropped approximately 60% during dialysis.

Weight

In a clinical study in which morbidly obese female patients (n=7) were dosed with intravenous acyclovir based on their actual body weight, plasma concentrations were found to be approximately twice that of normal weight patients (n=5), consistent with the difference in body weight between the two groups.

Mutagenicity:

The results of a wide range of mutagenicity tests in vitro and in vivo indicate that acyclovir is unlikely to pose a genetic risk to man.

Carcinogenicity:

Acyclovir was not found to be carcinogenic in long-term studies in the rat and the mouse.

Teratogenicity:

Systemic administration of acyclovir 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 subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.

Fertility:

Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses of acyclovir greatly in excess of those employed therapeutically. Two-generation studies in mice did not reveal any effect of (orally administered) acyclovir on fertility.

-    Sodium hydroxide.

The reconstituted concentrate and diluted solution for infusion must not be mixed with other medicinal products except those mentioned in Section 6.6.

Do not store above 30°C.

Store in the original package.

Prepare immediately before use.

When reconstituted and/or diluted, the solutions are stable for up to 12 hours at room temperature (15 to 25°C).

Discard unused solution.

10 ml type I clear tubular glass vials with grey lyo-rubber stoppers and aluminum caps.

Pack size: 5 Vials

Reconstitution:

Acyclovir JPI should be reconstituted using the following volumes of either water for injection or 0.9% sodium chloride intravenous injection to provide a solution containing 25 mg acyclovir per 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.

Administration:

The required dose of Acyclovir JPI should be administered by slow intravenous infusion over a one-hour period.

After reconstitution Acyclovir JPI may be administered by a controlled-rate infusion pump.

Alternatively, the reconstituted solution may be further diluted to give an acyclovir 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 below, and shake well to ensure adequate mixing occurs.

For children and neonates, 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 (100 mg acyclovir) added to 20 ml of infusion fluid reaching a concentration of 4.2 mg/ml.

For adults, it is recommended that infusion bags containing 100 ml of infusion fluid are used, even when this would give an acyclovir concentration substantially below 0.5% w/v (reaching a concentration of 2.3 mg/ml for 250 mg vial and 4.2 mg/ml for 500 mg vial). Thus one 100 ml infusion bag may be used for any dose between 250 mg and 500 mg acyclovir (10 and 20 ml of reconstituted solution) but a second bag must be used for doses between 500 mg and 1000 mg.

When diluted in accordance with the recommended schedules, Acyclovir JPI is known to be compatible with the following infusion fluids and stable for up to 12 hours at room temperature (15 to 25°C):

• (0.45% and 0.9% w/v) Sodium chloride intravenous infusion
• (0.18% w/v) Sodium chloride and (4% w/v) dextrose intravenous infusion
• (0.45% w/v) Sodium chloride and (2.5% w/v) dextrose intravenous infusion
• (0.45% w/v) Sodium chloride and (5% w/v) dextrose intravenous infusion
• Compound sodium lactate intravenous infusion (Hartmann's solution).

Acyclovir JPI when diluted in accordance with the above schedule will give an acyclovir concentration not greater than 0.5% w/v.

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.

Should any visible turbidity or crystallisation appear in the solution before or during infusion, the preparation should be discarded.