Aciclovir 250mg For I.V. Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Aciclovir 250mg for I.V. Infusion.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Aciclovir sodium equivalent to 250mg sterile aciclovir per vial.
3. PHARMACEUTICAL FORM
Vials containing the equivalent of 250mg sterile aciclovir as the freeze-dried sodium salt , a white to off-white powder for reconstitution and iv infusion.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Aciclovir for intravenous infusion is indicated for the following:
• the treatment of Herpes simplex infections in immunocompromised patients and severe initial genital herpes in the non-immunocompromised;
• the prophylaxis of Herpes simplex infections in immunocompromised patients;
• the treatment of Varicella zoster infections;
• the treatment of herpes encephalitis;
• the treatment of Herpes simplex infections in the neonate and infant up to 3 months of age.
4.2 Posology and method of administration
Route of administration: Slow intraveneous infusion over 1 hour.
A course of treatment with Aciclovir for intravenous infusion 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 intravenous aciclovir 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 doses of 5mg/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 doses of 10mg/kg every 8 hours provided renal function is not impaired (see Dosage in renal impairment).
In obese patients dosed with intraveneous aciclovir based on their 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 Children: The dose of intravenous aciclovir for children aged between 3 months and 12 years is calculated on the basis of body surface area.
Children 3 months or older with Herpes simplex (except herpes encephalitis) or Varicella zoster infections should be given doses of 250mg per square metre of body surface area every 8 hours if renal function is not impaired.
In immunocompromised children with Varicella zoster infections or children with herpes encephalitis, intravenous aciclovir should be given in doses of 500mg per square metre body surface area every 8 hours if renal function is not impaired.
The dosage of intravenous aciclovir in neonates and infants up to 3 months of age is calculated on the basis of body weight.
The recommended regimen for infants treated for known or suspected neonatal herpes is aciclovir 20mg/kg bodyweight 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).
Dosage in renal impairment:
Caution is advised when administering aciclovir intravenously 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 dosage adjustments are suggested:
|
Creatinine Clearance |
Dosage |
|
25 to 50ml/min 10 to 25ml/min 0(anuric) to 10ml/min |
The dose recommended above (5 or 10mg/kg body weight) should be given every 12 hours. The dose recommended above (5 or 10mg/kg body weight) should be given every 24 hours. In patients receiving continuous ambulatory peritoneal dialysis (CAPD) the dose recommended above (5 or 10mg/kg body weight) should be halved and administered every 24 hours. In patients receiving haemodialysis the dose recommended above (5 or 10mg/kg body weight) should be halved and administered every 24 hours and after dialysis. |
Dosage adjustments in infants and children:
|
Creatinine Clearance |
Dosage |
|
25 to 50 ml/min.1.73 m2 |
The dose recommended above (250 or 500 mg/m2 body surface or 20 mg/kg body weight) should be given every 12 hours. |
|
10 to 25 ml/min/1.73m2 |
The dose recommended above (250 or 500 mg/m2 body surface or 20 mg/kg body weight ) should be given every 24 hours |
|
0 (anuric) to 10ml/min/1.73 m2 |
In patients receiving continuous ambulatory peritoneal dialysis (CAPD) the dose recommended above (250 or 500 mg/m2 body surface or 20 mg/kg body weight ) should be halved and administered every 24 hours. In patients receiving heomodialysis, the dose recommended above (250 or 500 mg/m2 body surface or 20 mg/kg body weight) should be halved and administered every 24 hours and after dialysis |
4.3 Contraindications
Known hypersensitivity to aciclovir or valaciclovir, or to any of the excipients..
4.4 Special warnings and precautions for use
Use in patients with renal impairment and in elderly patients
Aciclovir 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 aciclovir in severely immune-compromised individuals may result on the selection of virus strains with reduced sensitivity, which may not response to continued aciclovir treatment (see section 5.1)
In-patients receiving aciclovir IV 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 aciclovir IV has a pH of approximately 11 and should not be administered by mouth. Product contains sodium (26mg, approx. 1.13mmol)
Aciclovir IV contains no antimicrobial preservative. Reconstitution and dilution should therefore be carried out under full antiseptic conditions immediately before use and any unused solution discarded. The reconstituted or diluted solutions should not be refrigerated.
Other warnings and precaution
The labels shall contain the following statements:
For intraveneous use only
Keep out of reach and sight of children
Store below 25°C
Prepare immediately prior to use
Discard unused solution
4.5 Interaction with other medicinal products and other forms of interaction
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 and reduce aciclovir renal clearance. Probenecid and cimetidine increase the AUC of acyclovir by this mechanism and reduce aciclovir renal clearance. However no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.
Probenecid increases the aciclovir mean half-life and area under the plasma concentration-time curve.
In patients receiving intravenous aciclovir, caution is required during concomitant administration with drugs which compete with acyclovir for elimination, because of the potential for increased plasma levels of one 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 coadministered.
Care is also required (with monitoring for changes in renal function) if administering intravenous aciclovir with drugs which affect other aspects of renal physiology (e.g. ciclosporin, tacrolimus).
Fertility, pregnancy and lactation
4.6
A post-marketing aciclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of aciclovir. The birth defects described amongst aciclovir exposed subjects have not shown any uniqueness or consistent pattern to suggest a common cause. 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.
Following oral administration of 200mg aciclovir five times a day, aciclovir has been detected in breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding plasma levels. These levels would potentially expose nursing infants to aciclovir dosages of up to 0.3mg/kg/day. Caution is therefore advised if aciclovir is to be administered to nursing women.
Fertility
There is no information on the effect of aciclovir on human female fertility.
In a study of 20 male patients with normal sperm count, oral aciclovir administered of doses 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.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable effects
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 > 1/1000, rare >1/10,000, very rare, 1/10,000.
Blood and lymphatic system
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, and 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
Hepatobiliary disorders
Common: reversible increases in liver-related enzyme Very rare: reversible increases in bilirubin, jaundice, hepatitis
Skin and subcutaneous tissue disorders
Common: pruritis, utricaria, 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 intraveneous 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 has been inadvertently infused into extracellular tissues.
4.9. Overdose
Single intravenous doses of up to 80mg/kg have been inadvertently administered without adverse effects.
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.
Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered an option in the management of overdose of this drug.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Mode 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 and Varicella zoster virus (VZV), Epstein Barr virus (EBV) and Cytomegalovirus (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 and EBV is highly selective. The enzyme thymidine kinase (TK) of normal, uninfected cells does not use aciclovir effectively as a 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.
5.2 Pharmacokinetic properties
In adults, the terminal plasma half-life of aciclovir after intravenous administration is about 2.9 hours. 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-carboxymethoxymethylguanine is the only significant metabolite of aciclovir, accounting for 10 to 15% of the dose excreted in the urine.
When aciclovir is given one hour after 1 gram of probenecid the terminal half-life and the area under the plasma concentration time curve is extended by 18% and 40% respectively.
In adults, mean steady state peak plasma concentrations (Cssmax) following a one hour infusion of 2.5mg/kg, 5mg/kg, 10mg/kg and 15mg/kg were 22.7 micromolar (5.1 microgram/ml), 43.6 micromolar (9.8 microgram/ml), 92 micromolar (20.7 microgram/ml) and 105 micromolar (23.6 microgram/ml), respectively. The corresponding trough levels (Cssmin) 7 hours later were 2.2 micromolar (0.5 microgram/ml), 3.1 micromolar (0.7 microgram/ml), 10.2 micromolar (2.3 microgram/ml) and 8.8 micromolar (2.0 microgram/ml), respectively. In children over 1 year of age similar mean peak and trough levels were observed when a dose of 250mg/m2 was substituted for 5mg/kg and a dose of 500mg/m2 was substituted for 10mg/kg. In neonates (0 to 3 months of age) treated with doses of 10mg/kg administered by infusion over a one-hour period every 8 hours the Cssmax was found to be 61.2 micromolar (13.8 microgram/ml) and the Cssmin 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 Cmax of 83.5 micromolar (18.8 microgram/ml) and Cmin of 14.1 micromolar (3.2 microgram/ml)
The terminal plasma half-life in these patients was 3.8 hours. 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 half-life.
In patients with chronic renal failure the mean terminal half-life was found to be 19.5 hours. The mean aciclovir half-life during haemodialysis was 5.7 hours. Plasma aciclovir levels dropped approximately 60% during dialysis.
In a clinical study in which morbidly obese female patients (n=7) were dosed with intraveneous aciclovir based in 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.
Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels.
Plasma protein binding is relatively low (9 to 33%) and drug interactions involving binding site displacement areis not anticipated.
5.3. 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.
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 subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.
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. There is no experience of the effect of intravenous aciclovir on human fertility. Aciclovir tablets have been shown to have no definitive effect upon sperm count, morphology or motility in man.
PHARMACEUTICAL PARTICULARS
6.
6.1. List of excipients
Sodium hydroxide Ph.Eur, Water for Injections Ph.Eur.
6.2. Incompatibilities
None known.
6.3. Shelf life
Unopened: 36 months After reconstitution :24 hours.
6.4. Special precautions for storage
The unopened product should be stored at or below 25 °C. When reconstituted store at 2-8°C for up to 24 hours.
6.5 Nature and contents of container
Colourless glass Type I vial closed with bromobutyl rubber stopper and aluminium seal with light blue polypropylene flip-off part.
6.6 Special precautions for disposal
Reconstitution: Aciclovir for intravenous infusion 250mg or 500mg should be reconstituted using 10ml or 20ml respectively of either Water for Injections B.P. or Sodium Chloride Intravenous Injection B.P. (0.9% w/v) to provide a solution containing 25mg aciclovir per ml. From the calculated dose, determine the appropriate number of vials to be used. Add the recommended volume of infusion fluid and shake gently until the contents of the vial have dissolved completely.
Administration: The required dose of aciclovir should be administered by slow intravenous infusion over a one-hour period. The reconstituted product may be administered by a controlled-rate infusion pump.
Alternatively, the reconstituted solution may be further diluted to give an aciclovir concentration of not greater than 5mg/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, the recommended dilution is 4ml reconstituted solution (100mg aciclovir) in 20ml of infusion fluid.
For adults, it is recommended that infusion bags containing 100ml of infusion fluid are used, even when this would give an aciclovir concentration substantially below 0.5% w/v. Thus one 100ml infusion bag may be used for any dose between 250mg and 500mg aciclovir (10 and 20ml of reconstituted solution) but a second bag must be used for doses between 500 and 1000mg.
When diluted in accordance with the recommended schedules, intravenous aciclovir is known to be compatible with the following infusion fluids and stable for up to 24 hours at 2-8°C. Sodium Chloride Intravenous Infusion B.P. (0.9% w/v); Sodium Chloride (0.18% w/v) and Glucose (4% w/v) Intravenous Infusion; Sodium Chloride (0.45% w/v) and Glucose (2.5% w/v) Intravenous Infusion B.P.; Compound Sodium Lactate Intravenous Infusion B.P. (Hartmann's Solution). When diluted in accordance with the above schedule, an aciclovir concentration not greater than 0.5% w/v will result.
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.
7 MARKETING AUTHORISATION HOLDER
Genus Pharmaceuticals Limited
T/A Genus Pharmaceuticals
Linthwaite
Huddersfield
HD75QH
UK
8. MARKETING AUTHORISATION NUMBER(S)
PL: 06831/0055.
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06/02/2009
10 DATE OF REVISION OF THE TEXT
09/09/2014