Acyclovir: Package Insert and Label Information

ACYCLOVIR — acyclovir sodium injection, solution
Zydus Pharmaceuticals (USA) Inc.

FOR INTRAVENOUS INFUSION ONLY

DESCRIPTION

Acyclovir Sodium Injection is a synthetic nucleoside analogue, active against herpes viruses. It is a sterile, aqueous solution for intravenous infusion, containing 50 mg acyclovir per mL in Water for Injection, USP. The concentration is equivalent to 54.9 mg of acyclovir sodium per mL in Water for Injection, USP. The sodium content is approximately 5.1 mg/mL. The pH range of the solution is 10.85 to 11.50. Acyclovir Sodium Injection contains Sodium Hydroxide, NF as inactive ingredient. Further dilution of Acyclovir Sodium Injection in an appropriate intravenous solution must be performed before infusion (see DOSAGE AND ADMINISTRATION, Administration).

The chemical name of acyclovir sodium is 9-[(2-Hydroxyethoxy)methyl] guanine, and has the following structural formula:

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(click image for full-size original)

Acyclovir, USP is a white to off-white, crystalline powder. Acyclovir sodium is the sodium salt of acyclovir, which is formed in situ , with the molecular formula C8 H10 N5 NaO3 and a molecular weight of 247.19. The maximum solubility in water at 25°C exceeds 100 mg/mL. At physiologic pH, acyclovir sodium exists as the unionized form with a molecular weight of 225 and a maximum solubility in water at 37°C of 2.5 mg/mL. The pka’s of acyclovir are 2.27 and 9.25.

VIROLOGY

Mechanism of Antiviral Action

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2) and varicella-zoster virus (VZV).

The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro , acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase.

The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activities

The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing 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 (IC50 ), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL.

Drug Resistance

Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from such patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK-negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.

CLINICAL PHARMACOLOGY

Pharmacokinetics

The pharmacokinetics of acyclovir after intravenous administration have been evaluated in adult patients with normal renal function during Phase 1/2 studies after single doses ranging from 0.5 mg/kg to 15 mg/kg and after multiple doses ranging from 2.5 to 15 mg/kg every 8 hours. Proportionality between dose and plasma levels is seen after single doses or at steady state after multiple dosing. Average steady-state peak and trough concentrations from 1-hour infusions administered every 8 hours are given in Table 1.

Table 1 Acyclovir Peak and Trough Concentrations at Steady State
Dosage Regimen CSS max CSS trough
5 mg/kg q 8 h (n=8) 9.8 mcg/mL range: 5.5 to 13.8 0.7 mcg/mL range: 0.2 to 1
10 mg/kg q 8 h (n=7) 22.9 mcg/mL range: 14.1 to 44.1 1.9 mcg/mL range: 0.5 to 2.9

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 is the major route of acyclovir elimination accounting for 62% to 91% of the dose. The only major urinary metabolite detected is 9-carboxymethoxymethylguanine accounting for up to 14.1% of the dose in patients with normal renal function.

The half-life and total body clearance of acyclovir are dependent on renal function as shown in Table 2.

Table 2 Acyclovir Half-life and Total Body Clearance
Total Body Clearance
Creatinine Clearance (mL/min/1.73 m2) Half-Life (h) (mL/min/1.73 m2) (mL/min/kg)
> 80 2.5 327 5.1
50 to 80 3 248 3.9
15 to 50 3.5 190 3.4
0 (Anuric) 19.5 29 0.5

Special Populations

Adults with Impaired Renal Function

Acyclovir was administered at a dose of 2.5 mg/kg to 6 adult patients with severe renal failure. The peak and trough plasma levels during the 47 hours preceding hemodialysis were 8.5 mcg/mL and 0.7 mcg/mL, respectively.

Consult DOSAGE AND ADMINISTRATION section for recommended adjustments in dosing based upon creatinine clearance.

Pediatrics

Acyclovir pharmacokinetics were determined in 16 pediatric patients with normal renal function ranging in age from 3 months to 16 years at doses of approximately 10 mg/kg and 20 mg/kg every 8 hours (Table 3). Concentrations achieved at these regimens are similar to those in adults receiving 5 mg/kg and 10 mg/kg every 8 hours, respectively (Table 1). Acyclovir pharmacokinetics were determined in 12 patients ranging in age from birth to 3 months at doses of 5 mg/kg, 10 mg/kg, and 15 mg/kg every 8 hours (Table 3).

Table 3 Acyclovir Pharmacokinetics in Pediatric Patients (Mean ± SD)
Parameter Aged from Birth to 3 Months (n=12) Aged 3 Months to 12 Years (n=16)
CL (mL/min/kg) 4.46 ± 1.61 8.44 ± 2.92
VDSS (L/kg) 1.08 ± 0.35 1.01 ± 0.28
Elimination half-life (hours) 3.80 ± 1.19 2.36 ± 0.97

Acyclovir pharmacokinetic samples were collected in full-term and pre-term neonates with normal renal function who received varying dosing regimens of acyclovir for the treatment of suspected neonatal HSV infection. Model-predicted pharmacokinetic parameters stratified by post-menstrual age (PMA) are summarized in Table 4.

Table 4 Acyclovir Pharmacokinetics in Neonates Aged from Birth to 3 Months
*
Administered over 1 hour.
Post-Menstrual Age (PMA) n IV Dose * Parameter (Median [Range])
Cminss (mg/L) Cmaxss (mg/L) CL (L/h/kg) V (L/kg)
< 30 Weeks 13 500 mg/m2 every 8 h or 3.92 (2.38 to 39.3) 10.3 (4.59 to 110) 0.21 (0.10 to 0.31) 2.88 (0.65 to 5.30)
10 mg/kg or 20 mg/kg every 12 h
30 to < 36 Weeks 9 500 mg/m2 every 8 h or 5.10 (2.54 to 9.62) 8.83 (5.44 to 29.8) 0.45 (0.30 to 0.81) 4.49 (1.87 to 10.85)
10 mg/kg or 20 mg/kg every 12 h
or
20 mg/kg every 8 h
36 to 41 Weeks 6 500 mg/m2 every 8 h 2.90 (2.19 to 7.46) 12.4 (10.8 to 86.1) 0.59 (0.13 to 0.77) 2.55 (0.29 to 4.09)
Overall 28 4.15 11.1 0.28 3.34
(2.19 to 39.3) (4.59 to 110) (0.10 to 0.81) (0.29 to 10.9)

Geriatrics

Acyclovir plasma concentrations are higher in geriatric patients compared with younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in geriatric patients with underlying renal impairment (see PRECAUTIONS:Geriatric Use).

Drug Interactions

Coadministration of probenecid with acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced.

CLINICAL TRIALS

Herpes Simplex Infections in Immunocompromised Patients

A multicenter trial of acyclovir at a dose of 250 mg/m2 every 8 hours (750 mg/m2 /day) for 7 days was conducted in 98 immunocompromised patients (73 adults and 25 children) with orofacial, esophageal, genital and other localized infections (52 treated with acyclovir and 46 with placebo). Acyclovir decreased virus excretion, reduced pain, and promoted healing of lesions.

Initial Episodes of Herpes Genitalis

In placebo-controlled trials, 58 patients with initial genital herpes were treated with intravenous acyclovir 5 mg/kg or placebo (27 patients treated with acyclovir and 31 treated with placebo) every 8 hours for 5 days. Acyclovir decreased the duration of viral excretion, new lesion formation, duration of vesicles, and promoted healing of lesions.

Herpes Simplex Encephalitis

Sixty-two patients aged 6 months to 79 years with brain biopsy-proven herpes simplex encephalitis were randomized to receive either acyclovir (10 mg/kg every 8 hours) or vidarabine (15 mg/kg/day) for 10 days (28 were treated with acyclovir and 34 with vidarabine). Overall mortality at 12 months for patients treated with acyclovir was 25% compared with 59% for patients treated with vidarabine. The proportion of patients treated with acyclovir functioning normally or with only mild sequelae (e.g., decreased attention span) was 32% compared with 12% of patients treated with vidarabine.

Patients younger than 30 years and those who had the least severe neurologic involvement at time of entry into study had the best outcome with treatment with acyclovir. An additional controlled study performed in Europe demonstrated similar findings.

Neonatal Herpes Simplex Virus Infection

The safety and efficacy of acyclovir was evaluated for the treatment of herpes simplex virus infection in neonates and infants. In one study (Study 1), Acyclovir Sodium Injection 10 mg/kg every 8 hours (30 mg/kg/day) was compared with vidarabine. In a follow-up study, (Study 2), Acyclovir Sodium Injection 20 mg/kg every 8 hours (60 mg/kg/day) was compared with Acyclovir Sodium Injection 15 mg/kg every 8 hours (45 mg/kg/day).

Study 2 was an open-label clinical trial with an objective of establishing the safety and efficacy of Acyclovir Sodium Injection 15 mg/kg every 8 hours (45 mg/kg/day) or 20 mg/kg every 8 hours (60 mg/kg/day) administered to neonates ≤ 28 days old with suspected HSV infection. Neonates aged ≤ 28 days with suspected HSV infection were eligible for enrollment. In total, 88 neonates were enrolled in the trial and received IV acyclovir for 21 days. Of the 88 subjects, 69 had confirmed systemic disease, 10 had confirmed localized disease, and 9 had suspected but unconfirmed infection. Among the 79 subjects with confirmed infection, 13 subjects received 45 mg/kg/day and 66 subjects received 60 mg/kg/day. The mean gestational ages (GA) were 37.5 and 37.9 weeks for the 45 mg/kg/day and 60 mg/kg/day doses, respectively. The number of premature infants (≤ 37 weeks GA) receiving 45 mg/kg/day and 60 mg/kg/day were 7 (54%) and 22 (33%), respectively.

Among 69 patients with proven systemic (disseminated or CNS) herpes infection, 57 were randomized to receive acyclovir (20 mg/kg every 8 hours) while the remaining 12 patients received a lower dose of acyclovir every 8 hours. Overall, the mortality among patients treated with acyclovir 20 mg/kg every 8 hours was lower compared with patients who received a lower dose of acyclovir.

Varicella-Zoster Infections in Immunocompromised Patients

A multicenter trial of acyclovir at a dose of 500 mg/m2 every 8 hours for 7 days was conducted in immunocompromised patients with zoster infections (shingles). Ninety-four (94) patients were evaluated (52 patients were treated with acyclovir and 42 with placebo).

Acyclovir was superior to placebo as measured by reductions in cutaneous dissemination and visceral dissemination.

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