Acyclovir Sodium for Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Acyclovir Sodium for Injection - Scientific Information

Manufacture: Abbott Laboratories
Country: Canada
Condition: Herpes Simplex, Herpes Simplex Encephalitis, Herpes Simplex, Mucocutaneous/Immunocompromised Host, Herpes Zoster
Class: Purine nucleosides
Form: Intravenous (IV), Powder
Ingredients: Acyclovir sodium

Pharmaceutical Information

Drug Substance

Common Name: Acyclovir USP
Chemical Name: (1) 6H-Purin-6-one,2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]
or
(2) 9-[(2-Hydroxyethoxy)methyl]guanine
Structural Formula:
Molecular Formula: C8H11N5O3
Molecular Weight: 225.21
Description: Acyclovir is a white crystalline powder which is freely soluble in dimethylsulfoxide, slightly soluble in dimethylformamide, very slightly soluble in methanol and water, and insoluble in acetone, acetonitrile, dichloroethane ethenol, toluene and chloroform. The pKa is 10.5 (0.3 g in 30 mL dimethylsulfoxide and 25 mL water) and the melting point is 256.5 to 257°C.
Common Name: Acyclovir Sodium USP*
Chemical Name 9-[(2-Hydroxyethoxy)methyl]guanine sodium
Structural Formula:
Molecular Formula: C8H10N5NaO3
Molecular Weight: 247.19
Description: Acyclovir sodium is a white crystalline powder with solubility exceeding 100 mg/mL in water at 25°C, but at pH 7.4 and 37°C, the maximum solubility is 2.5 mg/mL.
*Acyclovir sodium is prepared in situ with the aid of sodium hydroxide
Composition:Vials contain acyclovir sodium equivalent to 500 mg or 1 g of acyclovir, and sodium hydroxide as pH adjuster. The pH of freshly reconstituted solution (50 mg/mL) is approximately 11.

Instructions for Use

Reconstituted Solutions

Solutions for Reconstitution

Sterile Water for Injection. Do not use Bacteriostatic Water for Injection which contains benzyl alcohol or parabens. The reconstitution table is (see Table 1).

Table 1 Reconstitution Table
Vial Size Volume to be Added to Vial Approximate Average Concentration
500 mg 10 mL 50 mg/mL
1 g 20 mL 50 mg/mL

SHAKE WELL UNTIL DISSOLVED. ASSURE COMPLETE DISSOLUTION BEFORE MEASURING AND TRANSFERRING EACH INDIVIDUAL DOSE. UNUSED PORTIONS OF THE RECONSTITUTED SOLUTION SHOULD BE DISCARDED.

Diluted Solutions for Intravenous Infusion

The calculated dose of the reconstituted solution should be removed and added to an appropriate i.v. solution listed below at a volume selected for administration during each 1-hour infusion. Infusion concentrations exceeding 10 mg/mL are not recommended. Since the vials do not contain any preservatives, any unused portion of the reconstituted solution should be discarded.

  • ACYCLOVIR SODIUM FOR INJECTION has been shown to be compatible when administered with the following intravenous fluids:

5% Dextrose Injection
5% Dextrose and 0.9% Sodium Chloride Injection
5% Dextrose and 0.2% Sodium Chloride Injection
Ringer's Injection
Normal Saline Injection
Lactated Ringer's Injection

Reconstituted solutions at a concentration of 50 mg/mL should be used within 12 hours if kept at room temperature. Refrigeration may result in the formation of a precipitate which will redissolve at room temperature. Once diluted, the admixtures are to be administered within 24 hours of the initial preparation. The admixtures are not to be refrigerated. Unused portions of the diluted solution should be discarded.

General

The reconstituted and diluted solutions should be inspected visually for discoloration, haziness, particulate matter and leakage prior to administration whenever solution and container permit. Discard unused portion.

Incompatibility

ACYCLOVIR SODIUM FOR INJECTION should not be added to biologic or colloidal fluids (e.g. blood products, protein hydrolysates or amino acids, fat emulsions).

Stability and Storage Recommendations

ACYCLOVIR SODIUM FOR INJECTION should be stored between 15 and 25°C.

Availability of Dosage Forms

ACYCLOVIR SODIUM FOR INJECTION is supplied in single dose vials as follows:

  • 10 mL vial containing acyclovir sodium equivalent to 500 mg acyclovir, cartons of 5 vials
  • 25 mL vial containing the equivalent of 1 g of acyclovir, cartons of 5 vials

Virology

Spectrum of Activity In Vitro

The quantitative relationship between the in vitro susceptibility of herpes simplex and varicella-zoster viruses to acyclovir and the clinical response to therapy has not been established in man, and virus sensitivity has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (ID50), vary greatly depending upon the particular assay used, the cell type employed, and the laboratory performing the test. The ID50 of acyclovir against HSV-1 isolates may range from 0.02 :g/mL (plaque reduction in Vero cells) to 5.9 to 13.5 :g/mL (plaque reduction in green monkey kidney in Vero and GMK cells) . The ID50 against HSV-2 ranges from 0.01 :g/mL to 9.9 :g/mL (plaque reduction in Vero and GMK cells, respectively).

Using a dye- uptake method in Vero cells, which gives ID50 values approximately 5- to 10-fold higher than plaque reduction assays, HSV-1 and HSV-2 isolates from several patients were examined. These assays found that 50% of all isolates were sensitive to #0.2 µg/mL acyclovir. For HSV-2 isolates, 50% of all isolates were sensitive to #0.7 : g/mL of acyclovir. Isolates with significantly diminished sensitivity were found in some patients. It must be emphasized that neither the patients nor the isolates were randomly selected and, therefore, do not represent the general population. Most of the less sensitive HSV clinical isolates have been relatively deficient in the viral thymidine kinase (TK). Strains with alterations in viral TK or viral DNA polymerase have also been reported. Prolonged exposure to low concentrations (0.1 :g/mL) of acyclovir in cell culture has resulted in the emergence of a variety of acyclovir-resistant strains.

The ID50 against VZV ranges from 0.17 to 1.53 :g/mL (yield reduction, human foreskin fibroblasts) to 1.85 to 3.98 :g/mL (foci reduction, human embryo fibroblasts [HEF]). Reproduction of EBV genome is suppressed by 50% in superinfected Raji cells or P3HR-1 lymphoblastoid cells by 1.5 :g/mL acyclovir. CMV is relatively resistant to acyclovir with ID50 values ranging from 2.3 to 17.6 :g/mL (plaque reduction, HEF cells) to 1.82 to 56.8 :g/mL (DNA hybridization, HEF cells). The latent state of the human herpes viruses is not known to be sensitive to acyclovir.

Resistance

Prolonged exposure of herpes simplex virus (HSV) to subinhibitory concentrations (0.1 :g/mL) of acyclovir in cell structure has resulted in the emergence of a variety of acyclovir -resistant strains. The emergence of resistant strains is believed to occur by "selection" of naturally occurring viruses with relatively low susceptibility to acyclovir. Such strains have been reported in pre-therapy isolates from several clinical studies.

Two resistance mechanisms involving viral thymidine kinase (required for acyclovir activation) have been described. These are: (a) selection of thymidine- kinase-deficient mutants that induce little or no enzyme activity after infection, and (b) selection of mutants possessing a thymidine kinase of altered substrate specificity that is able to phosphorylate the natural nucleoside thymidine but not the acyclovir. The majority of less susceptible viruses arising in vitro are of the thymidine-kinase-deficient type which have reduced infectivity and pathogenicity and less likelihood of inducing latency in animals.

However, an acyclovir-resistant HSV infection in an immunosuppressed bone marrow transplant recipient on extended acyclovir therapy was found to be due to a clinical isolate which had a normal thymidine kinase but an altered DNA polymerase. This third mechanism of resistance involving herpes simplex virus DNA polymerase is due to the selection of mutants encoding an altered enzyme, which is resistant to inactivation by acyclovir triphosphate.

Varicella-zoster virus appears to manifest resistance to acyclovir via mechanisms similar to those seen in herpes simplex virus.

However, limited clinical investigation has revealed no evidence of a significant change in in vitro susceptibility of varicella- zoster virus with acyclovir therapy, although resistant mutants of this virus can be isolated in vitro in a manner analogous to herpes simplex virus. Analysis of a small number of clinical isolates from patients who received oral acyclovir or placebo for acute herpes zoster suggests that in vivo emergence of resistant varicella-zoster virus may occur infrequently. Prolonged acyclovir treatment of highly immunocompromised patients with acquired immunodeficiency syndrome and severe varicella-zoster virus may lead to the appearance of resistant virus.

Cross-resistance to other antivirals occurs in vitro in acyclovir- resistant mutants. Herpes simplex virus mutants which are resistant to acyclovir due to an absence of viral thymidine kinase are cross-resistant to other agents which are phosphorylated by herpesvirus thymidine kinase, such as bromovinyldeoxyuridine, ganciclovir and the 2’-fluoropyrimidine nucleosides, such as 2'-fluoro-5-iodoarabinosyl-cytosine (FIAC).

The clinical response to acyclovir treatment has usually been good for patients with normal immunity from whom herpesvirus, having reduced susceptibility to acyclovir, has been recovered either before, during or after therapy. However, certain patient groups, such as the severely immunocompromised (especially bone marrow transplant recipients) and those undergoing chronic suppressive regimens have been identified as being most frequently associated with the emergence of resistant herpes simplex strains, which may or may not accompany a poor response to the drug. The possibility of the appearance of less sensitive viruses must be recognised when treating such patients, and susceptibility monitoring of clinical isolates from these patients should be encouraged.

In summary, the quantitative relationship between the in vitro susceptibility of herpes simplex and varicella-zoster viruses to acyclovir and the clinical response to therapy has not been clearly established in man. Standardised methods of virus sensitivity testing are required to allow more precise correlations between in vitro virus sensitivity and clinical response to acyclovir therapy.

Pharmacology

Intravenous administration of acyclovir to adults at 5 mg/kg (approximately 250 mg/m2 body surface area [BSA]) by 1-hour intravenous infusions every 8 hours produces mean steady-state peak and trough concentrations of 9.8 :g/mL and 0.7 :g/mL, respectively. Similar concentrations are achieved in pediatric patients over 1 year of age when doses of 250 mg/m2 BSA are given intravenously every 8 hours.

Concentrations achieved in the cerebrospinal fluid are approximately 50% of plasma values. Plasma protein binding is relatively low (9 to 33%) and drug interactions involving binding site displacement are not anticipated.

Renal excretion of unchanged drug by glomerular filtration and tubular secretion is the major route of acyclovir elimination accounting for 62 to 91% of the dose of intravenously administered 14 C-labelled drug in man . The only significant urinary metabolite is 9-carboxymethoxy-methylguanine. An insignificant amount of drug is recovered in feces and expired CO2 and there is no evidence to suggest tissue retention.

The t½ and total body clearance of intravenous acyclovir is dependent on renal function as shown in Table 2 below.

Table 2 Half-life and Total Body Clearance of i.v. Acyclovir
Creatinine Clearance (mL/min/1.73 m2 BSA*) t½ (hr) Total Body Clearance (mL/min/1.73m2 BSA)
> 80 2.4 332
50-80 2.9 251
15-50 3.7 185
0 (Anuric) 18 26

* Body Surface Area

The t½ and total body clearance of intravenous acyclovir in pediatric patients over 1 year of age is similar to adults with normal renal function. Additional data are needed to fully define the pharmacokinetics of i.v. acyclovir in premature infants.

The plasma concentrations of acyclovir in neonates after i.v. infusion of 5, 10 or 15 mg/kg every 8 hours are presented in Table 3 below.

Table 3 Plasma Concentrations of Acyclovir in Neonates
Dose 5 mg/kg q8h 10 mg/kg q8h 15 mg/kg q8h
Mean peak conc. 30 :M ±9.9quivalent to 6.75 :g/mL 61.2 :M ±18.3quivalent to 13.8 :g/mL 86.1 :M ±23.5quivalent to 19.4 :g/mL
Mean trough conc. 5.3 :M ±3.4quivalent to 1.19 :g/mL 10.1 :M ±8.4quivalent to 2.27 :g/mL 13.8 :M ±11.1quivalent to 3.1 :g/mL

The principal pharmacokinetic parameters in neonate are presented in Table 4 below.

Table 4 Principal Pharmacokinetic Parameters in Neonates
Cltot (mL/min/1.73 m2) 105 ± 42
t1/2 (h) 4.05 ± 1.22
Vdss (L/1.73 m2) 28.8 ± 9.3

Pharmacokinetic parameters in patients with end-stage renal disease are presented in Table 5 below.

Table 5 Pharmacokinetic Parameters in Patients with End-Stage Renal Disease
Terminal t1/2 (h) 19.5 ± 5.9
V1 (L/1.73 m2) 15.3 ± 8.1
Vdss (L/1.73 m2) 41.2 ± 2.3
V1/Vdss x 100(%) 37 ± 19.9
Cltot (mL/min/1.73 m2) 28.6 ± 9.5
Kel (L/h) 0.15 ± 0.09
Terminal dialysis t1/2 (h) 5.73 ± 0.85
Coefficient of dialysis extraction 0.45 ± 0.12

Acyclovir dosing in patients with end-stage renal disease is presented in Table 6 below.

Table 6 Acyclovir Dosing in Patients with End-Stage Renal Disease
  Changing Dosage Changing Interval
Loading dose 37% of the standard dosage*93-185 mg/m2) Full standard dose250-500 mg/m2)
Maintenance dose 14% of the standard dosagevery 8 hours (35-70 mg/m2) Full standard dose every8 hours (250-500 mg/m2)
Post-dialysis 60-100% loading dose 60-100% standard dose
Potential advantages Minimises fluctuations betweeneaks and troughs Less frequent administration

* Standard acyclovir dosage (patients with normal renal function) = 250 to 500 mg/m2 initially and every 8 hours.

Toxicology

Acute Toxicity

The acute toxicity of acyclovir in adult mice and rats is summarized in Table 7 below.

Table 7 Acute Toxicity in Adult Animals
Species Sex Route LD50 95% Conf. Level Signs
Mouse M Oral >10,000 - None
Rat M Oral >20,000 - None
Mouse M i.v. 405 - Ataxia/Depression
Rat M i.v. >600 - None
Mouse M i.p. 1,454 1,323-1,662 Sedation
Mouse F i.p. 999 670-1,364 Sedation
Rat M i.p. 1,305 512-1,733 Sedation
Rat F i.p. 1,210 504-1,580 Sedation

Subchronic Toxicity

In a 31 -day study in Beagle dogs, acyclovir was administered as a bolus intravenous injection to groups of 8 dogs (4 males and 4 females) at dosage levels of 0, 25, 50 and 100 mg/kg, b.i.d.

Intravenous bolus doses of 50 or 100 mg/kg, produced very high drug plasma levels [range: 45 to 254 :g/mL (200 to 1127 :m)] which were highly toxic. Drug-related effects included infrequent retching and/or emesis, occasional tachycardia and "loud" heartbeat, increased urine output, hyaline droplets in the cytoplasm of the liver parenchymal cells, mild cytologic changes in the colon mucosa and kidney toxicity.

In addition, serious drug- related effects including tremors, cyanosis, prostration and early death, were observed within the first 8 days of the study.

In a second intravenous study, two groups of 8 Beagle dogs (4 males and 4 females) were given acyclovir by bolus injection at dose levels of either 10 or 20 mg/kg, b.i.d. for 31 or 32 consecutive days.

Signs of toxicity were limited to increased water intake and urine output volumes that occurred at the end of the dosing period in dogs given 20 mg/kg. The increased urine output volumes were accompanied by reduction in urine specific gravity and osmolality.

Chronic Toxicity

In Charles River CD- 1 (ICR) mice (115/sex/dose group) given acyclovir by oral gavage in a lifetime oral carcinogenicity study, there were no drug-related toxicological effects. Similarly, no treatment-related toxicological effects were observed in Sprague-Dawley rats (100/sex/dose group) given 50, 150 or 450 mg/kg/day acyclovir by oral gavage on a lifetime study.

In a 12-month chronic toxicity study in Beagle dogs, oral acyclovir given at 45 or 50 mg/kg/day was associated with acute toxicity consisting of severe emesis, diarrhea, decreased food consumption, and weight loss during the first two weeks of the study. The dosages were lowered to 10 or 20 mg/kg/day given t.i.d. during the remaining 50 weeks of treatment. With the exception of residual alterations in old keratin at the tips of the claws, there were no signs of treatment-related effects in any of the tissues examined by light microscopy. Nor were there significant alterations in values for the organs weighed at necropsy. Thus, dose levels up to 60 mg/kg/day were well tolerated for one year. The "no dose effect" dose level of acyclovir was 15 mg/kg/day (5 mg/kg t.i.d.); however, the only adverse effects at 30 or 60 mg/kg/day were changes in nails and footpads (30 and 60 mg/kg/day) and mild gastrointestinal signs (60 mg/kg/day).

Reproductive Studies

Acyclovir was administered to pregnant Sprague -Dawley rats by subcutaneous injection during the period of organogenesis (day 6 through day 15 of gestation) at dose levels of 0.0, 6.0, 12.5 and 25.0 mg/kg body weight, b.i.d.

No drug -related effects were noted in maternal body weight values, appearance and behaviour, survival rates, pregnancy rates, or implantation efficiencies. In addition, no drug-related differences were noted in evaluations of fetal size, sex, and development. Therefore acyclovir was not considered to be teratogenic or embryotoxic when administered to rats at levels up to 50.0 mg/kg of body weight per day during organogenesis.

In a second study, female Wistar rats (35/group) were given acyclovir at 0, 6.25, 12.5, or 25 mg/kg b.i.d. subcutaneously from days 7 to 17 of pregnancy, with two- thirds of dams terminated on day 20 of the pregnancy and the remainder allowed to deliver and rear their young. There was no maternal toxicity during the treatment period or subsequently that could be attributed to treatment.

In summary, the results of the two studies indicate that the subcutaneous administration of acyclovir was not associated with any drug-related effects on pregnancy, embryonic or fetal development.

In a third study, groups of 25 pregnant Sprague-Dawley rats were given subcutaneous doses of acyclovir at 6.25, 12.5 or 25 mg/kg b.i.d. on the 6th through the 15th days of gestation. Their fetuses were taken by cesarean section on the 20th day of gestation and examined for gross, visceral and skeletal abnormalities.

There were no signs of teratogenesis or other fetal toxicity. Clinical signs in the dams consisted of marginally decreased body weights at all dose levels and cutaneous scabs and alopecia (dose-related incidence, size and duration of the scabs).

Acyclovir did not impair fertility or reproduction in mice receiving 450 mg/kg/day, p.o. or in rats (25 mg/kg/day, s.c.). In female rabbits treated subcutaneously with acyclovir subsequent to mating, there was a statistically significant decrease in implantation efficiency but no concomitant decrease in litter size at a dose of 50 mg/kg/day. No effect upon implantation efficiency was observed when the same dose was administered intravenously. The intravenous administration of 100 mg/kg/day, a dose known to cause obstructive nephropathy in rabbits, caused a significant increase in fetal resorptions and a corresponding decrease in litter size. However, at a maximum tolerated intravenous dose of 50 mg/kg/day in rabbits, there were no drug- related reproductive effects. Acyclovir caused testicular atrophy in rats receiving intraperitoneal doses of 320 mg/kg/day for 1 month or 80 mg/kg/day for 6 months. Testicular atrophy persisted through the 4-week postdose recovery phase in rats dosed at 320 mg/kg/day; some evidence of recovery of sperm production was evident 30 days postdose.

A teratology study was done in New Zealand White rabbits using essentially the same experimental design as in the rat, except that dosing was from day 6 through day 18 of gestation. No signs of maternal toxicity were observed at any dose, but there was a statistically significant (p<0.05) lower implantation efficiency in the high-dose group. While there were a few terata (teratogenic events) observed in the study (in both control and treated animals) there was no apparent association with drug treatment. There was, however, an apparent dose-related response in the number of fetuses having supernumerary ribs. No similar effect was noted in the rat teratology study or in a reproduction-fertility experiment in mice.

Mutagenicity

Acyclovir has been tested for mutagenic potential in a number of in vitro and in vivo systems:

Microbial

Acyclovir was tested for mutagenic activity in the Ames Salmonella plate assay; in a preincubation modification of the Ames assay; in the Rosenkrantz E. Coli polA+/polA- DNA repair assay; and in the eukaryote S. cerevisiae, D-4. All studies were performed both in the presence and absence of exogenous mammalian metabolic activation.

No positive effects were observed either in the presence or absence of exogenous mammalian metabolic activation, at concentrations of acyclovir up to 300 mg/plate (80 mg/mL).

Mammalian Systems

Acyclovir was tested for mutagenic activity in cultured L5178Y mouse lymphoma cells, heterozygous at the thymidine kinase (TK) locus, by measuring the forward mutation rate to TK-deficiency (TK+/- 6 TK-/- ; additional studies were performed at the HGPRT locus and at the Ouabain-resistance marker in these same cells). All studies were performed in the presence and in the absence of exogenous mammalian metabolic activation.

Acyclovir, at a concentration of 50 :g/mL (222 : m) for a 72-hour exposure, has been shown to cause a statistically significant increase in the incidence of morphologically-transformed foci resulting from treating BALB/C-3T3 cells in vitro in the absence of exogenous metabolic activation.

Acyclovir, at concentrations of 62.5 and 125 :g/mL for a 48-hour exposure, did not induce any chromosome aberrations in cultured human lymphocytes in the absence of exogenous metabolic activation. At higher and toxic concentrations - 250 and 500 :g/mL for 48 hours exposure- acyclovir caused a significant increase in the incidence of chromosome breakage. There was also a significant dose-related decrease in mitotic index with exposure to acyclovir.

Acyclovir, at single intravenous doses of 25, 50 and 100 mg/kg, failed to induce chromosome aberrations in bone marrow cells of male and female rats when examined at 6, 24 and 48 hours after treatment.

In summary, the results of these mutagenicity studies showed that acyclovir does not cause single-gene mutations but is capable of breaking chromosomes.

Immunotoxicology Studies

Acyclovir was subjected to a number of in vitro and in vivo immunological tests.

In two in vitro tests, lymphocyte-mediated cytotoxicity and neutrophil chemotaxis, acyclovir showed no inhibitory effects at concentrations as high as 135 :g/mL (600 :m). The compound inhibited rosette formation approximately 50% at 0.9 :g/mL (4 :m).

In four in vivo tests in mice which measured cell-mediated immunity (complement-dependent cellular cytotoxicity, complement-independent cellular cytotoxicity, delayed hypersensitivity and graft vs. host reaction) acyclovir showed no inhibitory effects at single doses up to 200 mg/kg given on day 2 after antigenic stimulation.

Studies were carried out to evaluate the influence of acyclovir in vitro on human lymphocyte function. Inhibitory effects on blastogenesis were seen only in assays examining peak concentrations of potent mitogens, phytohemagglutinin (PHA) and concanavaline (Con A), and only at concentrations of drug above 50 :g/mL (222 :m) and were much less with monilia and tetanus toxoid antigens, where the blastogenic response is characteristically less vigorous. There was very little effect on cytotoxicity or LIF production except at concentrations of 200 :g/mL (890 :m) where there has already been demonstrated to be a direct cytotoxic effect.

Drug Interactions

Co-administration of probenecid with acyclovir has been shown to increase the mean t½ and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced. Although Acyclovir has been used concomitantly with zidovudine in some patients with human immunodeficiency virus (HIV) infections without evidence of increased toxicity, such patients should be monitored closely for signs of neurotoxicity during combined therapy. Anti fungal agents (i.e. Amphotericin B and Ketoconazole) have been reported to potentiate the antiviral effect of acyclovir in vitro; the clinical significance of these interactions has not been established.

Acyclovir should be used with caution in patients who have exhibited prior neurologic reactions to interferon since the two drugs have demonstrated an additive or synergistic antiviral effect in vitro. Caution is also advised in patients who have exhibited prior neurologic reactions to intrathecal methotrexate.