Aciclovir 25 Mg/Ml Concentrate For Solution For Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Aciclovir 25 mg/ml Concentrate for solution for infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 25 mg aciclovir as aciclovir sodium
Each vial of 10 ml of solution contains 250 mg aciclovir (sodium salt formed in situ) Each vial of 20 ml of solution contains 500 mg aciclovir (sodium salt formed in situ)
Excipient(s) with known effect:
Each ml of solution contains 2.67 mg of sodium
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Concentrate for solution for infusion A clear, colourless solution, free from visible particles
pH of the solution is between 10.70 and 11.70 and osmolarity of the solution is 353.01 mosmol/kg
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Aciclovir is indicated for the treatment of severe initial genital herpes in the
immunocompromised and the non-immunocompromised.
Aciclovir is indicated for the prophylaxis and treatment of Herpes simplex infections in immunocompromised patients.
Aciclovir is indicated for the treatment of shingles (Varicella zoster virus) in immunocompetent patients in whom a serious course of the illness can be anticipated.
Aciclovir is indicated for the treatment of initial and recurrent Varicella zoster infections in immunocompromised patients.
Aciclovir is indicated for the treatment of herpes encephalitis.
Aciclovir is indicated for the treatment of Herpes simplex infections in the neonate and infant up to 3 months of age.
4.2 Posology and method of administration
Treatment should be started as early as possible during the course of an active infection.
Route of administration: Slow intravenous infusion over 1 hour.
A course of treatment with Aciclovir 25 mg/ml Concentrate for solution for 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 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 Aciclovir 25 mg/ml Concentrate for solution for infusion is determined by the duration of the period of risk.
Dosage in adults: Patients with Herpes simplex (except herpes encephalitis) or Varicella zoster infections should be given Aciclovir 25 mg/ml Concentrate for solution for infusion in doses of 5 mg/kg bodyweight 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 Aciclovir 25 mg/ml Concentrate for solution for infusion in doses of 10 mg/kg bodyweight every 8 hours provided renal function is not impaired (see dosage in renal impairment).
In obese patients dosed with intravenous 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 Aciclovir 25 mg/ml Concentrate for solution for infusion for children aged between 3 months and 12 years is calculated on the basis of body surface area.
Children 3 months of age or older with Herpes simplex (except herpes encephalitis) or Varicella zoster infections should be given Aciclovir 25 mg/ml Concentrate for solution for infusion in doses of 250 mg 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, Aciclovir 25 mg/ml Concentrate for solution for infusion should be given in doses of 500 mg per square metre body surface area every 8 hours if renal function is not impaired.
The dosage of Aciclovir 25 mg/ml Concentrate for solution for infusion 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 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 Aciclovir 25 mg/ml Concentrate for solution for infusion to patients with impaired renal function since the drug is excreted through the kidneys. 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/1.73m2 for infants and children less than 13 years of age. The following adjustments in dosage are suggested:
Dosage adjustments in adults and adolescents:
|
Creatinine Clearance |
Dosage |
|
25 to 50 |
The dose recommended above (5 or 10 mg/kg body weight) |
|
ml/min |
should be given every 12 hours. |
|
10 to 25 |
The dose recommended above (5 or 10 mg/kg body weight) |
|
ml/min |
should be given every 24 hours. |
|
0 (anuric) |
In patients receiving continuous ambulatory peritoneal dialysis |
|
to 10 |
(CAPD) the dose recommended above (5 or 10 mg/kg body |
|
ml/min |
weight) should be halved and administered every 24 hours. |
|
In patients receiving haemodialysis the dose recommended above (5 or 10 mg/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 area or 20 mg/kg body weight) should be given every 12 hours. |
|
10 to 25 ml/min/1. 73 m2 |
The dose recommended above (250 or 500 mg/m2 body surface area or 20 mg/kg body weight) should be given every 24 hours. |
|
0 (anuric) to 10 ml/min/1. 73 m2 |
In patients receiving continuous ambulatory peritoneal dialysis (CAPD) the dose recommended above (250 or 500 mg/m2 body surface area or 20 mg/kg body weight) should be halved and administered every 24 hours. In patients receiving haemodialysis the dose recommended above (250 or 500 mg/m2 body surface area or 20 mg/kg body weight) should be halved and administered every 24 hours and after dialysis. |
Method of Administration
The required dose of Aciclovir 25 mg/ml Concentrate for solution for infusion should be administered by slow intravenous infusion over a one-hour period and adequate hydration should be established.
Aciclovir 25 mg/ml Concentrate for solution for infusion may be administered by a controlled-rate infusion pump.
Refer to Section 6.6 for instructions on use, preparation and handling.
4.3
Contraindications
Hypersensitivity to aciclovir and valaciclovir or any of the excipients listed in section
6.1.
4.4 Special warnings and precautions for use
Solutions of aciclovir are alkaline (pH of approximately 11) and intended for intravenous infusion only and should not be used by any other route.
The dose of Aciclovir 25 mg/ml Concentrate for solution for infusion must be adjusted in patients with impaired renal function in order to avoid accumulation of aciclovir in the body. Infusions of aciclovir must be given over a period of at least one hour in order to avoid renal tubular damage (see dosage in renal impairment in section 4.2).
Dosage in the 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. It is recommended that the state of hydration and the creatinine clearance should be evaluated before the administration of high dosages of aciclovir, especially in elderly patients, who may have reduced renal function despite a normal serum creatinine concentration.
Prolonged or repeated administration of aciclovir in severely immuno compromised individuals can lead to the selection of virus strains with reduced susceptibility, which may not react to continued aciclovir treatment. Caution is advised when administering acyclovir in patients with neurological reactions to cytotoxic drugs observed or concomitantly with interferon are
treated or intrathecally administered methotrexate. Caution should be exercised when administering acyclovir in patients significantly to hypoxia or severe liver disease or electrolyte abnormalities.
Although the aqueous solubility of aciclovir exceeds 100 mg/ml, precipitation of aciclovir crystals in renal tubules and the consequent renal tubular damage can occur if the maximum solubility of free aciclovir (2.5 mg/ml at 37°C in water) is exceeded. Aciclovir infusions must be accompanied by adequate hydration. Since maximum urine concentration occurs within the first few hours following infusion particular attention should be given to establish sufficient urine flow during that period. Concomitant use of other nephrotoxic drugs, pre-existing renal disease and dehydration increase the risk of further renal impairment by aciclovir.
In patients receiving Aciclovir 25 mg/ml Concentrate for solution for infusion 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.
Contact with eyes or unprotected skin should be avoided.
This medicinal product contains 0.116 mmol (or 2.67 mg) sodium per ml, 1.16 mmol (or 26.7 mg) sodium per 10 ml vial & 2.32 mmol (or 53.4 mg) sodium per 20 ml vial. This has to be taken into consideration for patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
There have been rare reports of Probenecid, cimetidine, theophylline and mycophenolate mofetil linked to increases in the aciclovir mean half-life and area under the plasma concentration-time curve. In these cases an adjustment of the aciclovir dosage is not thought to be necessary given the large therapeutic range of aciclovir.
According to one case report, co-administration of intravenous aciclovir and lithium caused a four-fold increase in lithium serum concentrations. Lithium concentrations should be closely monitored and a reduced lithium dose may be needed.
When aciclovir is administered concomitantly with theophylline, close monitoring of theophylline concentrations and possible theophylline dose reduction is recommended. A study has shown that when theophylline was given as single 320 mg doses before and with the sixth dose of aciclovir 800 mg five times daily for 2 days, the AUC of the theophylline was increased by 45% (from 189.9 to 274.9 micrograms.h/ml) and the total body clearance was reduced by 30%.
Care is also required (with monitoring changes in renal function) if administering Aciclovir 25 mg/ml Concentrate for solution for infusion with drugs that affect other aspects or renal physiology (e,g, cyclosporine, tacrolimus) as they may influence the nephrotoxic effect of aciclovir.
4.6 Fertility, pregnancy and lactation
Pregnancy:
A post-marketing aciclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of Aciclovir 25 mg/ml Concentrate for solution for infusion. The birth defects described amongst Aciclovir 25 mg/ml Concentrate for solution for infusion exposed subjects have not shown any uniqueness or consistent pattern to suggest a common cause. Studies in animals have shown reproductive toxicity (see Section 5.3). Caution should therefore be exercised by balancing the potential benefits of treatment against any possible hazard.
Lactation:
Following oral administration of 200 mg five times a day, aciclovir has been detected in human 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 0.3 mg/kg body weight/day. Aciclovir should only be administered to nursing mothers if the benefits to the mother outweigh the potential risks to the child.
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 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.
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 adverse reactions are described according to the MedDRA system organ class in the table below.
Frequencies are defined using the following convention:
Very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Blood and lymphatic system disorders
Uncommon: decrease in haematological values (anemia, thrombocytopenia, leukopenia)
Immune system disorders Common: anaphylaxis
Psychiatric and nervous system disorders
Very rare: headache, dizziness, agitation, confusion, tremor, dysarthria, hallucinations, psychotic symptoms, convulsions, drowsiness, coma.
Aciclovir 25 mg/ml Concentrate for solution for infusion should be used with caution in patients with underlying neurological abnormalities. It should also be used with caution in patients who have manifested neurological reactions to cytotoxic drugs or are receiving concomitant interferon or intrathecal methotrexate.
Vascular disorders Common: phlebitis
Respiratory, thoracic and mediastinal disorders Common: shortness of breath
Gastrointestinal Disorders Common: nausea, vomiting Very rare: diarrhea, abdominal pain
Hepatobiliary
Common: reversible increases in liver-related enzymes Very rare: reversible increases in bilirubin, jaundice, hepatitis
Skin and subcutaneous tissue disorders
Common: pruritus, urticaria, skin rashes (including photosensitivity)
Very rare: angioedema
Renal and urinary disorders
Common: Increased urea and creatinine in blood. Rapid increases in blood urea and creatinine levels may occasionally occur in patients given Aciclovir 25 mg/ml Concentrate for solution for infusion. These are usually reversible but progression to acute renal failure can occur in rare cases. The rapid increases in blood urea and creatinine levels are believed to be related to peak plasma levels 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. Adequate hydration of the patient should be maintained.
Very rare: renal dysfunction, acute renal failure, kidney pain
Adequate hydration should be maintained. Renal impairment usually responds quickly to the rehydrate of the patient and / or reduction of a dose / stop with the drug. Exacerbation to acute renal failure may in exceptional circumstances.
General disorders and administration site conditions Very rare: fatigue, fever, local inflammatory reactions
Severe local inflammatory reactions, which sometimes lead to skin breakdown could have occurred when Aciclovir 25 mg/ml Concentrate for solution for infusion has been accidentally administered in extra cellular 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 (see details below).
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4.9 Overdose
Toxicity and treatment of overdosage
There is little experience concerning overdosage with aciclovir however single doses of Aciclovir 25 mg/ml Concentrate for solution for infusion up to 80 mg/kg bodyweight have been inadvertently administered without adverse effects. Effects of overdosage may be expected to be similar in nature to those described under adverse reactions. Symptoms of overdose may include agitation, seizures, extreme tiredness, loss of consciousness, swelling of the hands, feet, ankles, or lower legs, decrease in urination. Adequate hydration is essential to reduce the possibility of crystal formation in the urine. Aciclovir can be removed from the circulation by haemodialysis.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic groups: Antiviral for systemic use, nucleosides and nucleotides excluding reverse transcriptase inhibitors
ATC Code: J05A B01
Mechanism of action:
Aciclovir is a synthetic acyclic purine nucleoside analogue (ATC J05A B01) 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 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 needs to be phosphorylated to the active compound aciclovir triphosphate, in order to become active against the virus. Aciclovir triphosphate acts as an inhibitor of, and a substrate for, the herpes specified DNA polymerase preventing further viral DNA synthesis.
Mechanism of Resistance:
Resistance to aciclovir is rare, but is more common in patients on chronic antiviral prophylaxis (transplant recipients, people with acquired immunodeficiency syndrome due to HIV infection). Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity. Acyclovir has also shown cross-resistance with valacyclovir and famcyclovir.
5.2 Pharmacokinetic properties
Pharmacokinetics: In adults, the terminal plasma half-life of aciclovir after the administration of Aciclovir 25 mg/ml Concentrate for solution for infusion is about 3 hours.
Absorption:
In adults, mean steady state peak (Cssmax) plasma concentrations following a one-hour infusion were;
|
2.5 mg/kg |
5 mg/kg |
10 mg/kg |
15 mg/kg | |
|
Css max |
22.7 |
43.6 |
92 |
105 |
|
in pmol or in (..g/ml) |
(5.1) |
(9.8) |
(20.7) |
(23.6) |
|
Css min, after 7 hours, _:.......-1_ |
2.2 (0.5) |
3.1 (0.7) _1 1 ffl H\ |
10.2 (2.3) |
8.8 (2.0) |
In children over 1 year of age 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. 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 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).
Distribution:
Aciclovir is widely distributed in tissues and body fluids. Plasma protein binding is relatively low (9 to 33%) and drug interactions involving binding site displacement are not anticipated.
Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels.
Metabolism:
The terminal plasma half-life in neonates was approximately 4 hours. In the elderly, total body clearance falls with increasing age and is associated with decreases in creatinine clearance although there is little change in the terminal plasma half-life.
Excretion:
Approximately 75-80% 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 major significant metabolite of aciclovir and accounts for 10 to 15% of the dose excreted in the urine.
Subjects with renal failure:
In patients with end stage renal failure the plasma half-life is increased, extending to a mean terminal half-life of approximately 20 hours. The mean aciclovir half-life during haemodialysis was 5.7 hours. Plasma aciclovir levels dropped approximately 60% during dialysis.
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. Animal studies indicate that at high dose aciclovir is cytotoxic.
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 Aciclovir on human fertility. Aciclovir tablets have been shown to have no definitive effect upon sperm count, morphology or motility in man.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Water for injections
Sodium hydroxide (for pH adjustment)
Hydrochloric acid (for pH adjustment)
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Aciclovir is reported to be incompatible with solutions of amifostine, amsacrine, aztreonam, diltiazem hydrochloride, dobutamine hydrochloride, dopamine hydrochloride, fludarabine phosphate, foscarnet sodium, idarubicin hydrochloride, meropenem, morphine sulphate, ondansetron hydrochloride, pethidine hydrochloride, piperacillin sodium - tazobactam sodium, sargramostim and vinorelbine tartrate.
Do not use bacteriostatic water for injection containing parabens or benzyl alcohol. Biologic or colloidal fluids (e.g. blood products, protein containing solutions) are incompatible with aciclovir.
6.3 Shelf life
Unopened: 24 months.
After dilution: Chemical and physical in-use stability has been demonstrated for 12 hours at 25 oC. From a microbiological point of view the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
6.4 Special precautions for storage
Keep this medicine out of the sight and reach of children
Do not store this medicine above 25°C. Do not refrigerate.
Store in the original carton in order to protect from light.
6.5 Nature and contents of container
Glass vials with Teflon coated rubber stopper and flip-off seal.
5, 10 and 20 x 10ml 5, 10 and 20 x 20ml
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Aciclovir 25 mg/ml Concentrate for solution for infusion contains no preservative. Dilution should therefore be carried out immediately before use under full aseptic conditions and any unused solution should be discarded.
Refrigeration is not recommended as precipitation may occur.
For adults, it is recommended that infusion bags containing 100 ml of infusion fluid are used, even when this would give an aciclovir concentration substantially below 0.5% w/v. Thus one 100 ml infusion bag may be used for any dose between 250 mg and 500 mg aciclovir but a second bag must be used for doses between 500 and 1000 mg. Aciclovir 25 mg/ml Concentrate for solution for infusion should not be diluted to a concentration greater than 5 mg/ml (0.5%w/v) for administration by infusion. After addition of Aciclovir 25 mg/ml Concentrate for solution for infusion to an infusion solution, the mixture should be shaken to ensure thorough mixing.
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 of solution (100 mg aciclovir) added to 20 ml of infusion fluid.
When diluted in accordance with the recommended schedules, Aciclovir 25 mg/ml Concentrate for solution for infusion is known to be compatible with the infusion fluids listed below:
Sodium Chloride Intravenous Infusion 0.9% w/v;
Sodium Chloride (0.18% w/v) and Glucose (4% w/v) Intravenous Infusion;
Sodium Chloride (0.9% w/v) and Glucose (5% w/v) Intravenous Infusion;
Sodium Chloride (0.45% w/v) and Glucose (2.5% w/v) Intravenous Infusion; Compound Sodium Lactate Intravenous Infusion (Hartmann's Solution).
Dilutions of Aciclovir in the above mentioned diluents have been demonstrated to be stable in Non polyvinyl chloride (Non-PVC) infusion bags
Aciclovir 25 mg/ml Concentrate for solution for infusion when diluted in accordance with the above schedule will give an aciclovir concentration not greater than 0.5% w/v.
Aciclovir 25 mg/ml Concentrate for solution for infusion contains no preservative.
Should any visible turbidity or crystallisation appear in the solution before or during infusion, the preparation should be discarded.
7 MARKETING AUTHORISATION HOLDER
CLARIS LIFESCIENCES UK LIMITED
CREWE HALL
CREWE
CHESHIRE
CW1 6UL
UNITED KINGDOM
8 MARKETING AUTHORISATION NUMBER(S)
PL 20568/0029
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
25/01/2013
10 DATE OF REVISION OF THE TEXT
25/01/2013