Acyclovir

DESCRIPTION

Capsules, Tablets, Suspension

Zovirax Capsules, Tablets, and Suspension are formulations for oral administration. Each capsule contains 200 mg of acyclovir and the inactive ingredients corn starch, lactose, magnesium stearate, and sodium lauryl sulfate. The capsule shell consists of gelatin, FD&C Blue No.2, and titanium dioxide. May contain one or more parabens. Printed with edible black ink.

Each 800 mg tablet of Zovirax contains 800 mg of acyclovir and the inactive ingredients FD&C Blue No.2, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.

Each 400 mg tablet of Zovirax contains 400 mg of acyclovir and the inactive ingredients magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.

Each teaspoonful (5 ml) of Zovirax Suspension contains 200 mg of acyclovir and the inactive ingredients methylparaben 0.1% and propylparaben 0.02% (added as a preservative), carbomethylcellulose sodium, flavor, glycerin, microcrystalline cellulose, and sorbitol.

The chemical name of acyclovir sodium is 9-[(2- hydroxyethoxy)methyl]guanine.

CLINICAL PHARMACOLOGY

Mechanism of Antiviral Effects

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses including herpes simplex types 1 (HSV-1) and 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV). In cell cultures, acyclovir has the highest antiviral activity against HSV-1, followed in decreasing order of potency against HSV-2, VZV, EBV and CMV.¹

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 effectively use acyclovir as a substrate. However, TK encoded by HSV, VZV and EBV² 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.³ Acyclovir triphosphate interferes with Herpes simplex virus DNA polymerase and inhibits viral DNA replication. Acyclovir triphosphate also inhibits cellular alpha-DNA polymerase but to a lesser degree. In vitro, acyclovir triphosphate can be incorporated into growing chains of DNA by viral DNA polymerase and to a much smaller extent by cellular alpha-DNA polymerase.⁴When incorporation occurs, the DNA chain is terminated.^5,6Acyclovir is preferentially taken up and selectively converted to the active triphosphate form by herpesvirus-infected cells. Thus, acyclovir is much less toxic in vitro for normal uninfected cells because: 1) less is taken up; 2) less is converted to the active form 3) cellular alpha-DNA polymerase is less sensitive to effects to the active form. The mode of acyclovir phosphorylation in cytomegalovirus-infected cells is not clearly established but may involve virally induced cell kinases or an unidentified viral enzyme. Acyclovir is not efficiently activated in cytomegalovirus infected cells, which may account for the reduced susceptibility of cytomegalovirus to acyclovir in vitro.

Microbiology

The quantitative relationship between the in vitro susceptibility of herpes simplex virus to acyclovir and the clinical response to therapy has not been established in man, 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 (ID₅₀), vary greatly depending upon the particular assay used,⁷the cell type employed,⁸ and the laboratory performing the test.¹ The ID₅₀ of acyclovir against HSV-1 isolates may range from 0.02 mcg/ml (plaque reduction in Vero cells) to 5.9-13.5 mcg/ml (plaque reduction in green monkey kidney (GMK) cells).¹ The ID₅₀against HSV-2 ranges from 0.01 mcg/ml to 9.9 mcg/ml (plaque reduction in Vero and GMK cells, respectively).¹

Using a dye-uptake method in Vero cells,⁹which gives ID₅₀ values approximately 5- to 10-fold higher than plaque reduction assays, 1417 isolates (553 HSV-1 AND 864 HSV-2) from approximately 500 patients were examined over a 5-year period.¹⁰. These assays found that 90% of HSV-1 isolates were sensitive to £0.9 mcg/ml acyclovir and 50% of all isolates were sensitive ot £0.2 mcg/ml acyclovir. For HSV-2 isolates, 90% were sensitive to £2.2 mcg/ml and 50% of all isolates were sensitive to £0.7 mcg/ml of acyclovir. Isolates with significantly diminished sensitivity were found in 44 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 TK.^11-19 Strains with alterations in viral TK²⁰ or viral DNA polymerase²¹ have also been reported. Prolonged exposure to low concentrations (0.1 mcg/ml) of acyclovir in cell culture has resulted in the emergence of a variety of acyclovir-resistant strains.²²

The ID₅₀ against VZV ranges from 0.17-1.53 mcg/ml (yield reduction, human foreskin fibroblasts) to 1.85-3.98 mcg/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 mcg/ml acyclovir. CMV is relatively resistant to acyclovir with ID₅₀values ranging from 2.3-17.6 mcg/ml (plaque reduction, HEF cells) to 1.82-56.8 mcg/ml (DNA hybridization, HEF cells). The latent state of the genome of any of the human herpesviruses is not known to be sensitive to acyclovir.¹

Pharmacokinetics

The pharmacokinetics of acyclovir after oral administration have been evaluated in 6 clinical studies involving 110 adult patients. In one uncontrolled study of 35 immunosuppressed patients with herpes simplex or varicella-zoster infection, acyclovir capsules were administered in doses of 200 to 1000 mg every 4 hours, 6 times daily for 5 days, and steady-state plasma levels were reached by the second day of dosing. Mean steady-state peak and trough concentrations following the final 200 mg dose were 0.49 mcg/ml (0.47 to 0.54 mcg/ml) and 0.31 mcg/ml (0.18 to 0.41 mcg/ml) respectively, and following the final 800 mg dose were 2.8 mcg/ml (2.3 to 3.1 mcg/ml) and 1.8 mcg/ml (1.3 to 2.5 mcg/ml), respectively. In another uncontrolled study of 20 younger immunocompetent patients with recurring genital herpes simplex infections, acyclovir capsules were administered in doses of 800 mg every 6 hours, 4 times daily for 5 days; the mean steady-state peak and trough complications were 1.4 mcg/ml (0.66 to 1.8 mcg/ml) and 0.55 mcg/ml (0.14 to 1.1 mcg/ml), respectively.

In general, the pharmacokinetics of acyclovir in children is similar to adults. Mean half-life after oral doses of 300 mg/m² and 600 mg/m², in children ages 7 months to 7 years, was 2.6 hours. (range 1.59 to 3.74 hours).

A single oral dose bioavailability study in 23 normal volunteers showed that acyclovir capsules 200 mg are bioequivalent to 200 mg acyclovir in aqueous solution; and in a separate study in 20 volunteers, it was shown that acyclovir suspension is bioequivalent to acyclovir capsules. In a different single-dose bioavailability/bioequivalence study in 24 volunteers, one acyclovir 800 mg tablet was demonstrated to be bioequivalent to four Zovirax 200 mg capsules.

In a multiple-dose crossover study where 23 volunteers received acyclovir as one 200 mg capsule, one 400 mg tablet, and one 800 mg tablet 6 times daily, absorption decreased with increasing dose and the estimated bioavailabilities of acyclovir were 20%, 15%, and 10%, respectively. The decrease in bioavailability is believed to be a function of the dose and not the dosage farm. It was demonstrated that acyclovir is not proportional over the dosing range 200 mg to 800 mg. In this study, steady-state peak and trough concentrations of acyclovir were 0.83 and 0.46 mcg/ml, 1.21 and 0.63 mcg/ml, and 1.61 and 0.83 mcg/ml for the 200, 400, and 800 mg dosing regimens, respectively. In another study in 6 volunteers, the influence of food on the absorption of acyclovir was not apparent.

Following oral administration, the mean plasma half-life of acyclovir in volunteers and patients with normal renal function ranged from 2.5 to 3.3 hours. The mean renal excretion of unchanged drug accounts for 14.4% (8.6% to 19.8%) of the orally administered dose. The only urinary metabolite (identified by high performance liquid chromatography) is 9- [(carboxymethoxy)methyl]guanine. The half-life and total body clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function (see DOSAGE AND ADMINISTRATION.)

Orally administered acyclovir in children less than 2 years of age has not yet been fully studied. Animal PHARMACOLOGY

Topical treatment of guinea pigs with 10% acyclovir in polyethylene glycol ointment for three weeks did not result in cutaneous irritation or systemic toxicity. Also, a wide variety of animal tests by parenteral routes demonstrated that acyclovir has a low order of toxicity.

INDICATIONS

Acyclovir capsules and suspension are indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes in certain patients.

Acyclovir capsules, tablets, and suspension are indicated for the acute treatment of herpes zoster (shingles) and chickenpox (varicella). Genital Herpes Infections

The severity of disease is variable depending upon the immune status of the patient, the frequency and duration of episodes, and the degree of cutaneous or systemic involvement. These factors should determine patient management, which may include symptomatic support and counseling only, or the institution of specific therapy. The physical, emotional and psycho-social difficulties posed by herpes infections as well as the degree of debilitation, particularly in immunocompromised patients, are unique for each patient, and the physician should determine therapeutic alternatives based on his or her understanding of the individuals patient's needs. Thus orally administered acyclovir is not appropriate in treating all genital herpes infections. The following guidelines may be useful in weighing the benefit/risk considerations in specific disease categories:

Double-blind, placebo-controlled studies have demonstrated that orally administered acyclovir significantly reduced the duration of acute infection (detection of virus in lesions by tissue culture) and lesion healing. The duration of pain and new lesion formation was decreased in some patient groups. The promptness of initiation of therapy and/or the patient's prior exposure to herpes simplex virus may influence the degree of benefit from therapy. Patients with mild disease may derive less benefit than those with more severe episodes. In patients with extremely severe episodes, in which prostration, central nervous system involvement, urinary retention or inability to take oral medication require hospitalization and more aggressive management, therapy may be best initiated with intravenous acyclovir. Recurrent Episodes

Double-blind, placebo-controlled studies in patients with frequent recurrences (6 or more episodes per year) have shown that orally administered acyclovir given daily for 4 months to 3 years prevented or reduced the frequency and/or severity of recurrences in greater than 95% of patients.

In a study of 283 patients who received 400 mg (two 200mg capsules) twice daily for three years, 45%, 52% and 63% of patients remained free of recurrences in the first, second and third years, respectively. Serial analyses of the 3 month recurrence rates for the 283 patients showed that 71% to 87% were recurrence-free in each quarter, indicating that the effects are constant over time.

The frequency and severity of episodes of untreated genital herpes may change over time. After 1 year of therapy, the frequency and severity of the patient's genital herpes infection should be re-evaluated to assess the need for continuation of acyclovir therapy. Re-evaluation will usually require a trial off acyclovir to assess the need for reinstitution of suppressive therapy. Some patients, such as those with very frequent or severe episodes before treatment, may warrant uninterrupted suppression for more than a year.

Chronic suppressive therapy is most appropriate when, in the judgment of the physician, the benefits of such a regimen outweigh known or potential adverse effects. In general, orally administered acyclovir should not be used for the suppression of recurrent disease in mildly affected patients. Unanswered questions concerning the relevance to humans of in vitro mutagenicity studies and reproductive toxicity studies and reproductive toxicity studies in animals given high parenteral doses of acyclovir for short periods (See PRECAUTIONS, Carcinogenesis, Mutagenesis, and Impairment of Fertility) should be borne in mind when designing long-term management for individual patients. Discussion of these issues with patients will provide them the opportunity to weigh the potential for toxicity against the severity of their disease. Thus, this regimen should be considered only for appropriate patients with annual re-evaluation.

Limited studies have shown that there are certain patients for whom intermittent short-term treatment of recurrent episodes is effective. This approach may be more appropriate than a suppressive regimen in patients with infrequent recurrences.

Immunocompromised patients with recurrent herpes infection can be treated with either intermittent or chronic suppressive therapy. Clinically significant resistance, although rare, is more likely to be seen with prolonged or repeated therapy in severely immunocompromised patients with active lesions. Herpes Zoster Infections

In a double-blind, placebo-controlled study of 187 normal patients with localized cutaneous zoster infection (93 randomized to acyclovir and 94 to placebo), acyclovir (800 mg 5 times daily for 10 days) shortened the times to lesion scabbing, healing and complete cessation of pain, and reduced the duration or viral shedding and the duration of new lesion formation.

In a similar double-blind, placebo-controlled study in 83 normal patients with herpes zoster (40 randomized to acyclovir and 43 to placebo), acyclovir (800 mg 5 times daily for 7 days) shortened the times to complete lesion scabbing, healing and cessation of pain, reduced the duration of new lesion formulation, and reduced the prevalence of localized zoster-associated neurologic symptoms (paresthesia, dysesthesia, or hyperesthesia). Chickenpox

In a double blind-placebo-controlled efficacy study in 110 normal patients, ages 5 to 16 years, who presented within 24 hoursof the onset of a typical chickenpox rash, acyclovir was administered orally 4 times daily for 5 to 7 days at doses of 10, 15, or 20 mg/kg depending on the age group. Acyclovir treatment reduced the maximum number of lesions (336 vs. greater than 500; lesions beyond 500 were not counted). Acyclovir treatment also shortened the mean time to 50% healing (7.1 days vs. 8.7 days), reduced the number of vesicular lesions by the second day of treatment (49 vs. 113), and decreased the proportion of patients with fever (temperature greater than 100°F) by the second day (19% vs. 57%). Acyclovir treatment did not effect the antibody response to varicella-zoster virus measured one month and one year following treatment.

In two concurrent double-blind, placebo-controlled studies, a total of 883 normal patients, ages 2 to 18 years were enrolled within 24 hours of the onset of a typical chickenpox rash, and acyclovir was administered at 20 mg/kg orally up to 800 mg 4 times daily for 5 days. In the larger study of 815 children ages 2 to 12 years, acyclovir treatment reduced the median maximum number of lesions (277 vs. 386), reduced the median number of vesicular lesions by the second day of treatment (26 vs. 40), and reduced the proportion of patients with moderate to severe itching by the third day of treatment (15% vs. 34%). In addition, in both studies (883 patients ages 2 to 18 years), acyclovir treatment also decreased the proportion of patients with fever (temperature greater than 100°F), anorexia, and lethargy by the second day of treatment, and decreased the mean number of residual lesions on Day 28. There were no substantial differences in VZV-specific humoral or cellular immune responses measured at one month following treatment in patients receiving acyclovir compared to patients receiving placebo.

Diagnosis

Diagnosis is confirmed by virus isolation. Accelerated viral culture assays or immunocytology allow more rapid diagnosis than standard viral culture. For patients with initial episodes of genital herpes, appropriate examinations should be performed to rule-out other sexually transmitted diseases. While cutaneous lesions associated with herpes simplex and varicella-zoster infections are often characteristic, the finding of multinucleated giant cells in smears prepared from lesion exudate or scrapings may provide additional support to the clinical diagnosis.

Multinucleated giant cells in smears do not distinguish varicella-zoster from herpes simplex infections.

DOSAGE AND ADMINISTRATION

Treatment of Initial Genital Herpes: 200 mg (one 200 mg capsules or one teaspoonful [5 ml] suspension) every 4 hours, 5 times daily for 10 days. Chronic Suppressive Therapy for Recurrent Disease

400 mg (two 200 mg capsules, one 400 mg tablet, or two teaspoonfuls [10 ml] suspension) 2 times daily for up to 12 months, followed by re-evaluation. See

INDICATIONS

Intermittent Therapy: 200 mg (one 200 mg capsule or one teaspoonful [5 ml] suspension) every 4 hours, 5 times daily for 5 days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence.

Acute Treatment of Herpes Zoster: 800 mg (four 200 mg capsules, two 400 mg tablets, one 800 mg tablet, or four teaspoonfuls [20 ml] suspension) every 4 hours orally 5 times daily for 7 to 10 days.

Treatment of Chickenpox: Children (2 years of age and older): 20 mg/kg per dose orally four times daily (80 mg/kg/day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox.

Adults and Children over 40 kg: 800 mg four times daily for 5 days.

Intravenous acyclovir is indicated for the treatment of varicella-zoster infections in immunocompromised patients.

When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox. There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs and symptoms.

Patients with Acute or Chronic Renal Impairment: Comprehensive pharmacokinetic studies have been completed following IV acyclovir infusions in patients with renal impairment. Based on these studies, dosage adjustments are recommended in the following chart (TABLE 4), for genital herpes and herpes zoster indications:

TABLE 4

Hemodialysis: For Patients who require hemodialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations following a 6-hour dialysis period. Therefore, the patient's dosing schedule should be adjusted so that an additional dose is administered after each dialysis.

Peritoneal Dialysis: No Supplemental dose appears to be necessary after adjustment of the dosing interval.

1. O'Brien JJ, Campoli-Richards DM. Acyclovir -- an updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1989;37:233-309.

2. Littler E, Zeuthen J, McBride AA, et al. Identification of an Epstein-Barr virus- coded thymidine kinase. The EMBO Journal.1986;5(8):1959-1966.

3. Miller WH, Miller RL. Phosphorylation of acyclovir (acycloguanosine) monophosphate by GMP kinase. J Biol Chem.1980;255:7204-7207.

4. Furman PA, St Clair MH, Fyfe JA, et al. Inhibition of herpes simplex virus-induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl)guanine and its triphosphate. J Virol. 1979;32:72-77.

5. Derse D, Cheng YC, Furman PA, et al. Inhibition of purified human and herpes simplex virus-induced DNA polymerases by 9-(2- hydroxyethoxymethyl)guanine triphosphate: Effects on primer-template function. J Biol Chem.1981;256:11447-11451.

6. McGuirt PV, Shaw JE, Elion GB, et al. Identification of small DNA fragments synthesized in herpes simplex virus-infected cells in the presence of acyclovir. Antimicrob Agents Chemother.1984;25:507-509.

7. Barry DW, Blum MR. Antiviral drugs: acyclovir In: Turner P, Shand DG eds. Recent Advances in Clinical Pharmacology. ed 3. New York: Churchill Livingstone, 1983: chap 4.

8. DeClercq E. Comparative efficacy of antiherpes drugs in different cell lines. Antimicrob Agents Chemother.1982;21:661-663.

9. McLaren C, Ellis MN, Hunter GA. A colorimetric assay for the measurement of the sensitivity of herpes simplex viruses to antiviral agents. Antiviral Res. 1983;3:223- 234.

10. Barry DW, Nusinoff-Lehrman S. Viral resistance in clinical practice: summary of five years experience with acyclovir. In: Kono R, Nakajima A eds. Herpes Viruses and Virus Chemotherapy (Ex Med IntCongr Ser 667). New York: Excerpta Medica,1985:269-270.

11. Dekker C, Ellis MN, McLaren C, et al. Virus resistance in clinical practice. J Antimicrob Chemother.1983;12(suppl B):137-152

12. Sibrack CD, Gutman LT, Wilfert CM, et al. Pathogenicity of acyclovir-resistant herpes simplex virus type 1 from an immunodeficient child. J Infect Dis. 1982;146:673-682.

13. Crumpacker CS, Schnipper LE, Marlowe SI, et al. Resistance to antiviral drugs of herpes simplex virus isolated from a patient treated with acyclovir. N Engl J Med.1982;306:343-346.

14. Wade JC, Newton B, McLaren C, et al. Intravenous acyclovir to treat mucocutaneous herpes simplex virus infection after marrow transplantation: a double-blind trial. Ann Intern Med.1982;96:265-269.

15. Burns WH, Saral R, Santos GW, et al. Isolation and characterization of resistant herpes simplex virus after acyclovir therapy. Lancet. 1982;1:421-423.

16. Straus SE, Takiff HE, Seidlin M. et al. Suppression of frequently recurring genital herpes: a placebo-controlled double-blind trial of oral acyclovir. N Engl J Med 1984;310:1545-1550.

17. Collins P. Viral sensitivity following the introduction of acyclovir. Am J Med.1988;85(2A):129-134.

18. Erlich KS, Mills J, Chatis P, et al. Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med.1989;320(5):293-296.

19. Hill EL, Ellis MN, Barry DW. In: 28thIntersci Conf on Antimicrob Agents Chemother. Los Angeles,1988, Abst. No 0840:260.

20. Ellis MN, Keller PM, Fyfe JA, et al. Clinical isolates of herpes simplex virus type 2 that induces a thymidine kinase with altered substrate specificity.Antimicrob Agents Chemother.1987;31(7): 1117-1125.

21. Collins P, Larder BA, Oliver NM, et al. Characterization of a DNA polymerase mutant of herpes simplex virus from a severely immunocompromised patient receiving acyclovir. J gen Virol.1989;(70):375-382.

22. Field HJ, Darby G, Wildy P. Isolation and characterization of acyclovir-resistant mutants of herpes simplex virus.J gen Virol.1980;49:115-124.

23. Blum MR, Liao SH, deMiranda P. Overview of acyclovir pharmacokinetic disposition in adults and children. Am J Med.1982;73:186-192.

24. Laskin OL, Longstreth JA, Whelton A, et al. Effect of renal failure on the pharmacokinetics of acyclovir. Am J Med.1982;73:197-201.

25. Krasny HC, Liao SH, deMiranda P, et al. Influence of hemodialysis on acyclovir pharmacokinetic in patients with chronic renal failure Am. J Med. 1982;73:202-204.

26. Mitchell CD, Bean B, Gentry SR, et al. Acyclovir therapy for mucocutaneous herpes simplex infections in immunocompromised patients. Lancet.1981;1:1389-1392.

27. Meyers JD, Wade JC, Mitchell CD, et al. Multicenter collaborative trial of intravenous acyclovir for treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host. Am J Med. 1982;73:229-235.

28. Data on file, Burroughs Wellcome Co.

29. Corey L, Fife KH, Benedetti JK, et al. Intravenous acyclovir for the treatment of primary genital herpes.Ann Intern Med. 1983;98(6):914- 921.

30. Mindel A, Adler MW, Sutherland S, et al. Intravenous acyclovir treatment for primary genital herpes. Lancet.1982;1:697-700.

31. Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med. 1986;314(3):144-149.

32. Skoldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus vidarabine in herpes simplex encephalitis: randomized multicenter study in consecutive Swedish patients. Lancet. 1984;2(8405):707-711.

33. Balfour HH Jr, Bean B, Laskin OL, et al. Acyclovir halts progression of herpes zoster in immunocompromised patients. N Engl J Med. 1983;308(24):1448-1453.

34. Shepp DH, Danliker PS, Meyers JD. Treatment of varicella-zoster virus infection in severely immunocompromised patients. N Engl J Med. 1986;314:208- 212.

35. Naib ZM, Nahmias AJ, Josey WE, et al. Relation of cytohistopathology of genital herpesvirus infection to cervical anaplasia. Cancer Res. 1973;33:1452-1463.

36. Laskin OL, deMiranda P, King DH, et al. Effects of probenecid on the pharmacokinetics and elimination of acyclovir in humans.Antimicrob Agents Chemother. 1982;21:804-807.

37. Stahlmann R, Klug S, Lewandowski C, et al. Teratogenicity of acyclovir in rats. Infection.1987; 15:261-262.

38. Lau RJ, Emery MG, Galinsky RE, et al. Unexpected accumulation of acyclovir in breast milk with estimate of infant exposure. ObstetGynecol.1987;69(3):468-471.

39. Meyer LJ, deMiranda P, Sheth N, et al. Acyclovir in human breast milk. Am J Obstet Gynecol.1988;158(3):586-588.

40. Boelart J, Schurgers M, Daneels R, et al. Multiple dose pharmacokinetics of intravenous acyclovir in patients on continuous ambulatory peritoneal dialysis. J Antimicrob Chemother. 1987;20:69- 76.

41. Shah GM, Winer RL, Krasny HC. Acyclovir pharmacokinetics in a patient on continuous ambulatory peritoneal dialysis. Am J Kidney Dis. 1986;507-510.

SIDE EFFECTS

Herpes Simplex

Short-Term Administration: The most frequent adverse events reported during clinical trials of treatment of genital herpes with orally administered acyclovir were nausea and/or vomiting in 8 of 298 patient treatments (2.7%) and headache in 2 of 298 (0.6%). Nausea and/or vomiting occurred in 2 of 287 (0.7%) of patients who received placebo.

Less frequent adverse events, each of which occurred in 1 of 298 patient treatments with orally administered acyclovir (0.3%), included diarrhea, dizziness, anorexia, fatigue, edema, skin rash, leg pain, inguinal adenopathy, medication taste, and sore throat.

Long-Term Administration: The most frequent adverse events reported in a clinical trial for the prevention of recurrences with continuous administration of 400 mg (two 200 mg capsules) 2 times daily for 1 year in 586 patients treated with acyclovir were: nausea (4.8%), diarrhea (2.4%), headache (1.9%), and rash (1.7%). The 589 control patients receiving intermittent treatment of recurrences with acyclovir for 1 year reported diarrhea (2.7%), nausea (2.4%), headache (2.2%), and rash (1.5%).

The most frequent adverse effects reported during the second year by 390 patients who elected to continue daily administration of 400 mg (two 200 mg capsules) 2 times daily for 2 years were headache (1.5%), rash (1.3%), and paresthesia (0.8%). Adverse events reported by 329 patients during the third year include asthenia (1.2%), paresthesia (1.2%), and headache (0.9%).

Herpes Zoster

The most frequent adverse effects reported during three clinical trials of treatment of herpes zoster (shingles) with 800 mg of acyclovir 5 times daily for 7 to 10 days in 323 patients were: malaise (11.5%), nausea (8.0%), headache (5.9%), vomiting (2.5%), diarrhea (1.5%), and constipation (0.9%). The 323 placebo recipients reported malaise (11.1%), nausea (11.5%), headache (11.1%), vomiting (2.5%), diarrhea (0.3%), and constipation (2.4%).

Chickenpox

The most frequent adverse events reported during three clinical trials of treatment with chickenpox with oral acyclovir in 495 patients were: diarrhea (3.2%), abdominal pain (0.6%), rash (0.6%), vomiting (0.6%), and flatulence (0.4%). The 498 patients receiving placebo reported: diarrhea (2.2%), flatulence (0.8%), and insomnia (0.4%).

Observed During Clinical Practice

Based on clinical practice experience in patients treated with oral acyclovir in the U.S., spontaneously reported adverse events are uncommon. Data are insufficient to support an estimate of their incidence or to establish causation. These events may also occur as proof of the underlying disease process. Voluntary reports of adverse events which have been received since market introduction include:

General: fever, headache, pain, peripheral edema, and rarely, anaphylaxis

Nervous: confusion, dizziness, hallucinations, paresthesia, somnolence (These symptoms may be marked, especially in older adults.)

Digestive: diarrhea, elevated liver function tests, gastrointestinal distress, nausea

Hemic and Lymphatic: leukopenia, lymphadenopathy

Musculoskeletal: myalgia

Skin: alopecia, pruritus, rash, urticaria

Special Senses: visual abnormalities

Urogenital: elevated creatinine

DRUG INTERACTIONS

Co-administration of probenecid with acyclovir has been shown to increase the mean half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced.³⁶ The clinical effects of this combination have not been studied.

WARNINGS

Acyclovir capsules, tablets, and suspension are for oral ingestion only.

PRECAUTIONS

General

Acyclovir has caused decreased spermatogenesis at high parenteral doses in some animals and mutagenesis in some acute studies of this drug at high concentrations of drug (see Carcinogenesis, Mutagenesis, and Impairment of Fertility below.) The recommended dosage should not be exceeded (see DOSAGE AND ADMINISTRATION) .

Exposure of herpes simplex and varicella-zoster isolates to acyclovir in vitro can lead to the emergence of less sensitive viruses. The possibility of the appearance of less sensitive viruses in humans must be borne in mind when treating patients. The relationship between the in vitro sensitivity of herpes simplex or varicella-zoster virus to acyclovir clinical response to therapy has yet to be established (see CLINICAL PHARMACOLOGY, Microbiology.)

Because of the possibility that less sensitive virus may be selected in patients who are receiving acyclovir, all patients should be advised to take particular care to avoid potential transmission virus if active lesions are present while they are on therapy. In severely immunocompromised patients, the physician should be aware that prolonged or repeated courses of acyclovir may result in selection of resistant viruses which may not fully respond to continued acyclovir therapy.

Caution should be exercised when administering acyclovir to patients receiving potentially nephrotoxic agents since this may increase the risk of renal dysfunction.

Information for the Patient

Patients are instructed to consult with their physician if they experience severe or troublesome adverse reactions, they become pregnant or intend to become pregnant, they intend to breast feed while taking orally administered acyclovir, or they have any other questions.

Genital Herpes Infections

Genital herpes is a sexually transmitted disease and patients should avoid intercourse when visible lesions are present because of the risk of infecting intimate partners. Acyclovir capsules, tablets and suspension are for oral ingestion only. Medication should not be shared with others. The prescribed dosage should not be exceeded. Acyclovir does not eliminate latent viruses. Patients are instructed to consult with their physician if they do not receive sufficient relief in the frequency and severity of their genital herpes recurrences.

There are still unanswered questions concerning reproductive/gonadal toxicity and mutagenesis; long term studies are continuing. decreased sperm production has been seen at high doses in some animals; a placebo-controlled clinical study using 400 mg or 1000 mg of acyclovir per day for 6 months in humans did not show similar findings. Chromosomal breaks were seen in vitro after brief exposure to high concentrations. Some other currently marketed medications also cause chromosomal breaks, and the significance of this finding is unknown. A placebo-controlled clinical study using 800 mg of acyclovir per day for 1 year in humans did not show any abnormalities in structure or number of chromosomes.

Herpes Zoster Infections

Adults age 50 or older tend to have more severe shingles, and treatment with acyclovir showed more significant benefit for older patients. Treatment was begun within 72 hours of rash onset in these studies, and was more useful if started within the first 48 hours.

Chickenpox

Although chickenpox in otherwise healthy children is usually a self-limited disease of mild to moderate severity, adolescents and adults tend to have more severe disease. Treatment was initiated within 24 hours of the typical chickenpox rash in the controlled studies, and there is no information regarding the effects of treatment begun later in the disease course. It is unknown whether the treatment of chickenpox in childhood has any effect on long-term immunity. However, there is no evidence to indicate that acyclovir treatment on chickenpox would have any effect on either decreasing or increasing the incidence or severity of subsequent recurrences of herpes zoster (shingles) later in life. Intravenous acyclovir is indicated for the treatment of varicella-zoster infections in immunocompromised patients.

Pediatric Use

Safety and effectiveness in children less than 2 years of age have not been established.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The data presented below include references to peak steady state plasma acyclovir concentrations observed in humans treated with 800 mg given orally 6 times a day (dosing appropriate for treatment of herpes zoster or herpes encephalitis), or 200 mg given orally 6 times a day (dosing appropriate for treatment of primary genital herpes or herpes simplex infections in immunocompromised patients). Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir at the higher and lower dosing schedules (see CLINICAL PHARMACOLOGY, Pharmacokinetics.)

Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of up to 450 mg/kg administered by gavage. There was no statistically significant difference in the incidence of tumors between treated and control animals, nor did acyclovir shorten the latency of tumors. At 450 mg/kg/day, plasma concentrations in both the mouse and rat bioassay were lower than concentrations in humans.

Acyclovir was tested in two in vitro cell transformation assays. Positive results were observed at the highest concentration tested (31 to 63 times human levels) in one system and the resulting morphologically transformed cells formed tumors when inoculated into immunosuppressed, syngeneic, weanling mice. Acyclovir was negative (40 to 80 times human levels) in the other, possibly less sensitive, transformation assay.

In acute cytogenetic studies, there was an increase, though not statistically significant, in the incidence of chromosomal damage of maximum tolerated parenteral doses of acyclovir (100 mg/kg) in rats (62 to 125 times human levels) but not in Chinese hamster; higher doses of 500 and 1000 mg/kg were clastogenic in Chinese hamsters (380 to 760 times human levels). In addition, to activity was found after 5 days dosing in a dominant lethal study in mice (36 to 73 times human levels). In all 4 microbial assays, no evidence of mutagenicity was observed. Positive results were obtained in 2 of 7 genetic toxicity assays using mammalian cells in vitro. In human lymphocytes, a positive response for chromosomal damage was seen at concentrations 150 to 300 times the acyclovir plasma levels achieved in man. At one locus in mouse lymphoma cells, mutagenicity was observed at concentrations 250 to 500 times human plasma levels. Results in the other five mammalian cell loci follow: at 3 loci in a Chinese hamster ovary cell line, the results were inconclusive at concentrations at least 1850 times human levels; at 2 other loci in mouse lymphoma cells, no evidence of mutagenicity was observed at concentrations at least 1500 times human levels.

Acyclovir has not been shown to impair fertility or reproduction in mice (450 mg/kg/day, p.o.) or in rats (25 mg/kg/day, SC). In the mouse study plasma levels were 9 to 18 times human levels, while in the rat study they were 8 to 15 times human levels. At 50 mg/kg/day, SC in the rat (1 to 2 times human levels), there was a statistically significant increase in post-implantation loss, but no concomitant decrease in littler size. 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 (1 to 3 times human levels). No effect upon implantation efficiency was observed when the same dose was administered intravenously (4 to 9 times human levels). In a rat peri- and postnatal study at 50 mg/kg/day, SC (1 to 2 times human levels), there was a statistically significant decrease in the group mean numbers of corpora lutea, total implantation sites and live fetuses in the F¹ generation. Although not statistically significant, there was also a dose-related decrease in group mean numbers of live fetuses and implantation sites at 12.5 mg/kg/day and 25 mg/kg/day, SC. 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 (plasma levels were not measured). However, at a maximum tolerated intravenous dose of 50 mg/kg/day in rabbits (4 to 9 times human levels), no drug-related reproductive effects were observed.

Intraperitoneal doses of 80 or 320 mg/kg/day acyclovir given to rats for 6 and 1 months, respectively, caused testicular atrophy. Plasma levels were not measured in the one-month study and were 2 to 4 times human levels in the six-month study. Testicular atrophy was persistent through the 4-week postdose recovery phase after 320 mg/kg/day; some evidence of recovery of sperm production was evident 30 days postdose. Intravenous dose of 100 and 200 mg/kg/day acyclovir given to dogs for 31 days caused aspermatogenesis. At 100 mg/kg/day plasma levels were 4 to 8 times human levels, while at 200 mg/kg/day they were 13 to 25 times human levels. No testicular abnormalities were seen in dogs given 50 mg/kg/day IV for one month (2 to 3 times human levels) and in dogs given 60 mg/kg/day orally for one year (the same as human levels).

Pregnancy

Teratogenic Effects: Pregnancy Category C. Acyclovir was not teratogenic in the mouse (450 mg/kg/day, p.o.), rabbit (50 mg/kg/day, SC and IV) or in standard tests in the rat (50 mg/kg/day, SC). These exposures resulted in plasma levels the same as, 4 and 9, and 1 and 2 times, respectively, human levels. In a non-standard test in rats there were fetal abnormalities, such as head and tail anomalies, and maternal toxicity.³⁷ In this test, rats were given 3 SC doses of 100 mg/kg acyclovir on gestation day 10, resulting in plasma levels 5 and 10 times human levels. There are no adequate and well-controlled studies in pregnant women. Acyclovir should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Although acyclovir was not teratogenic in standard animal studies, the drug's potential for causing chromosome breaks at high concentration should be taken into consideration in making this determination.

Pregnancy Exposure Registry: To monitor maternal fetal outcomes of pregnant women exposed to systemic acyclovir, Glaxo Wellcome Co. maintains an Acyclovir Pregnancy Registry. Physicians are encouraged to register patients by calling (800) 722-9292 ext. 8465.

Nursing Mothers

Acyclovir concentrations have been documented in breast milk in two women following oral administration of acyclovir and ranged from 0.6 to 4.1 times corresponding plasma levels.^38,39 These concentrations would potentially expose the nursing infant to a dose acyclovir up to 0.3 mg/kg/day. Caution should be exercised when acyclovir is administered to a nursing woman.