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The safety of famciclovir in patients with herpes zoster
CURRENT THERAPEUTIC RESEARCH@ VOL. 56, NO. 3, MARCH 1995
THE SAFETY OF FAMCICLOVIR IN PATIENTS WITH HERPES ZOSTER ROBIN SALTZMAN’
AND RON BOON’
lSmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania, and %mithKline Beecham Pharmaceuticals, Brenybrd, Middlesex, United Kingdam
ABSTRACT Famciclovir is the well-absorbed oral form of the antiherpes agent penciclovir. Safety reports from clinical studies of more than 6500 patients and from spontaneous reports indicate that famciclovir is well tolerated. Safety data have been compiled for 808 patients with herpes zoster from three randomized, double-blind, clinical trials. Overall, 51.6% of the famciclovir-treated patient population were women and 48.4% were men. The patient population ranged in age from 15 to 102 years (mean, 51.8 years), with 55.7% aged 50 years or older. The mean duration of exposure to famciclovir was 6.7 days. Total daily doses ranged from 750mg to 2250mg. The most common adverse experiences reported were headache, nausea, and diarrhea. The frequency of adverse experiences and laboratory abnormalities (hematologic, clinical chemistry, and urinalysis variables) was similar in both famciclovir and placebo recipients. Safety data from these three clinical studies demonstrate that famciclovir is well tolerated by patients with herpes zoster and has a safety profile comparable to that of placebo. INTRODUCTION
Famciclovir* is the well-absorbed (77% bioavailable) oral form of penciclovir, a novel, selective antiviral agent with activity against varicellazoster virus.1*2Since licensure in the United States and the United Kingdom, more than 100,000 patients have received famciclovir.3 Both the relative and absolute potency of penciclovir and acyclovirt depend on the host cell and assay methods used, and inhibitory concentrations are generally comparable in vitro.2*4*5However, the active triphosphate form of penciclovir has a prolonged intracellular half-life in vitro of 7 hours in cells infected with varicella-zoster virus6 The most common adverse reactions reported in clinical studies with acyclovir in patients with herpes zoster include malaise, nausea, headache, vomiting, diarrhea, and constipation. 7*8Famciclovir has been well tolerAddress correspondence to: Robin Saltsman, SmithKline Beecham Pharmaceuticals, Four Falls Corporate Center, Boute 23 and Woodmont Avenue, P.O. Box 1610, King of Prussia, PA 19406. Received for publication on January 17,1995. Printed in the U.S.A. Reproduction in whole or part is not permitted. * Trademark: Fanwir” (SmithKline Bee&am Pharmaceuticals, Philadelphia, Pennsylvania). t Trademark: Zovirax@ (Burroughs Wellcome Co., Research Triangle Park, North Carolina). 219
00113931096/$3.50
SAFETY
OF FAMCICLOVIR
ated by more than 6500 patients in clinical trials, and since its clearance for the treatment of herpes zoster, spontaneous reports of adverse events have been infrequent. This report presents safety data for 273 patients who received famciclovir in a placebo-controlled trial and an integrated analysis of 535 patients who received famciclovir in two randomized, doubleblind, acyclovir-controlled trials. PATIENTS
AND METHODS
safety of famciclovir was assessed in studies of immunocompetent patients with herpes zoster by recording adverse experiences and monitoring laboratory variables. The patients were primarily adults with very few individuals in the 15- to M-year age range; no pediatric patients were studied. Adverse experiences were either identified by the investigator or elicited from the patient in response to the question, “Have you felt different in any way since starting the new treatment/the last assessment?” Details of each adverse experience (eg, time of onset, duration, intensity, and relationship to study medication) were recorded. Adverse experiences were classified according to the World Health Organization coding system. Adverse experiences that were fatal, life-threatening, disabling, or incapacitating; that resulted in a new or prolonged hospitalization, a congenital anomaly, or a carcinoma; or that resulted from an overdose were classified as serious and are discussed separately, as are events that led to withdrawal from the studies. The investigator assigned the causality of the adverse event to the study medication. Hematologic, clinical chemistry, and urinalysis studies were performed periodically in accordance with the protocol for each study (eg, at baseline and during or on completion of treatment). Any laboratory value considered clinically significant by the investigator was reported as an adverse event. In addition, values that changed from baseline by more than a specified amount and that were outside the sponsor-defined extended normal range were defined as values of potential clinical concern for the purpose of this safety evaluation. To detect overall changes, laboratory data were also examined by calculating the mean difference between values when receiving treatment, or within 7 days following completion of treatment, and values at baseline (mean change from baseline). Proportions of patients experiencing adverse events were analyzed, in a pair-wise fashion, by Fisher’s exact test. For each comparison, a twotailed test of the null hypothesis of no difference between treatment groups was conducted. The
RESULTS
Similar distribution of demographic characteristics was noted across all three studies. Therefore, demographic data for all 808 patients treated with famciclovir in these three trials were combined and are described.
R. SALTZMAN
AND R. BOON
The mean age of famciclovir-treated patients was 51.8 years (range, 15 to 102 years), with 55.7% aged 50 years or more; 51.6% were women and 48.4% were men. Overall, 89.6% of participants were white, 5.0% were black, and 5.4% were of other ethnic origin. All patients provided informed consent to participate in the trials. Mean duration of exposure to famciclovir was 6.7 days, and the total daily dose ranged from 750 mg to 2250 mg. Distribution of patients grouped according to total daily dose is presented in Table I. The mean cumulative dose of famciclovir was approximately 10 g (range, 750 mg to 15.8 g).
Adverse Experiences Table II summarizes the incidence of adverse experiences, regardless of causality, reported by 32% of patients in the placebo-controlled trial. There were no statistically significant differences in adverse experience reporting rates between patients treated with famciclovir or placebo. Headache, nausea, and diarrhea were the most common events reported by both groups. As anticipated, the incidence of adverse experiences reported as “related” (includes the categories of related, probably related, possibly related, and causalities that were unassessable or not indicated) to study medication was lower than the overall incidence of adverse experiences. In addition, the incidence and severity of adverse experiences reported as “related” to study medication administration were comparable between the famciclovir and placebo groups. Headache, nausea, and diarrhea were again the most common adverse experiences reported. In the famciclovir group, headache was reported by 8.1% of patients, nausea was reported by 4.0% of patients, and diarrhea was reported by 2.6% of patients. In the placebo group, nausea was the most common event, reported by 8.2% of patients; headache was reported in 6.8% of patients, and diarrhea was reported in 2.1% of patients. Somnolence was reported in 1.5% of famciclovir patients and 2.1% of placebo patients. All other adverse experiences occurred in ~2% of the patient population. Table III summarizes the incidence of drug-related adverse experiences occurring in 21% of patients in the placebo-controlled trial. There were no statistically significant differ-
Table I. Distribution of patients grouped according to total daily dose of famciclovir. No. of Patients’
Total Dally Dose of Femciclovir 3750 mg ~1500 mg 2250 mg l
E! 272
Data presented for 806 of 808 patients; data were incomplete for 2 patients. 221
SAFETY
OF FAMCICLOVIR
Table II. Adverse experiences, regardless of causality, reported by 32% of patients in a placebocontrolled famciclovir trial.
Famciclovlr (n = 273) %
Placebo (n = 146) %
pJS
ii
5;
Dizziness Zoster-related signs/symptoms/complications Pharynpitis
i::
4.1 3.4 4.8 4.1
Adverse Experience ;;;-W&he Diarrhea Vomiting Constipation
2.9
EYc Somnolence Sinusitis Injury Paresthesia Rigor Back pain Arthralgia Abdommal pain
Z 1.4 :::
ences in adverse-experience reporting rates between famciclovir-treated patients and patients who received placebo. Serious adverse experiences were seen in 1.1% of patients who received famciclovir and 1.4% of patients who received placebo. None of the Table III. Adverse experiences related to study medication occurring in 3 1% of patients in a placebo-controlled famciclovir trial.*
Famciclovir (n = 273) %
Adveme Experience
Placebo (n = 146) %
~e,a,~F” Diarrhea Somnolence Fatigue
!znus Anorexia Rigor Vomiting Dizziness Depression Hyperesthesia Fever Zoster-related signs/symptoms/complications * Includes categories of related, probably related, possibly related, and adverse experiences where the relationship was unassessable or not indicated. Causality was assessed by the investigator. 222
Ft. SALTZMAN
AND R. BOON
headache, nausea, or diarrhea episodes noted previously were classified as serious. All of the serious events reported in the placebo-controlled trial (either in the famciclovir or placebo group) were considered by the investigators to be unrelated to the study medication. Each of the serious adverse experiences reported in the placebo-controlled trial was unique (ie, reported by only one patient). The overall incidence of withdrawals due to adverse experiences was 0.7% and 3.4% for the famciclovir and placebo groups, respectively. Two patients who received famciclovir were withdrawn due to adverse experiences (one patient each for constipation and nausea). For the placebo recipients, five patients were withdrawn due to adverse experiences: two patients withdrew because of worsening of herpes zoster (1.4%) and one patient each withdrew for thrombocytopenia, rash, and leukopenia. Adverse experiences leading to withdrawal that were considered to be related, probably related, or possibly related to study medication or where the relationship was unassessable or not indicated occurred in 0.4% of the patients who received famciclovir and 1.4% of patients who received placebo. No deaths were attributed to treatment with famciclovir. For two of the three studies of patients with herpes zoster, acyclovir was used as the control. Table IV summarizes the incidence of adverse experiences related to study medication that occurred in ~1% of patients, in these two studies. As with the placebo-controlled trial, headache (6.0%) and nausea (3.7%) were the most frequently reported adverse experiences for famciclovir-treated patients. The most common adverse experiences reported for acyclovir-treated patients were headache (4.6%), nausea (2.7%), abdominal pain (2.3%), and fatigue (2.3%). Anorexia was the only drug-related adverse experience that was statistically different for famciclovir (0.2%) versus acyclovir (1.9%).
Table IV. Adverse experiences related to study medication occurring in 31% of patients in two acvclovir-controlled famciclovir trial.*
Adverse Experience
Famclclovlr (n = 555)%
;;;i;;he Abdominal pain Diarrhea Vomiting Dizziness Constipation Fatigue Anorexia Includes categories of related, probably related, possibly related, and adverse experiences where the relationship was unassessable or not indicated. Causality was assessed by the investigator. l
223
SAFETY
OF FAMCICLOVIR
Laboratory Assessments There was no consistent association between treatment with or duration of exposure to famciclovir and the incidence of laboratory abnormalities. In the placebo-controlled trial, ~1% of patients treated with famciclovir had values of potential clinical concern, with the exception of increases in alanine transaminase (2.4%) and serum phosphate (1.6%) levels. Similarly, 2.3% of patients in the placebo group had increased alanine transaminase values; a slightly lower incidence of increased serum phosphate values (0.7%) was noted in the placebo group. Laboratory variables related to hematology, hepatic function, renal function, serum electrolytes, muscle metabolism, bone metabolism, and serum glucose were examined for mean changes from baseline. No clinically significant differences between the famciclovir and placebo groups were observed. Similarly, famciclovir administration did not lead to any clinically relevant changes in urinalysis values. DISCUSSION AND CONCLUSION
Biochemical studies on the mode of action of penciclovir have shown that the preferential phosphorylation in herpesvirus-infected cells is more marked for penciclovir than for acyclovir.g The minimal phosphorylation of penciclovir in uninfected cells, together with the low activity of penciclovir-triphosphate against cellular DNA polymerases, provides a rationale for the lack of toxicity of penciclovir in cell culture. This hypothesis has been tested in a wide range of human cell lines of differing tissue origin.2 These tests showed that penciclovir is like acyclovir in that it is exceptionally nontoxic to replicating cells in culture. Furthermore, evaluation of famciclovir and penciclovir in toxicologic tests have shown that these compounds have a good safety profile, similar to that of acyclovir. The favorable safety profile of famciclovir demonstrated by this safety summary is particularly noteworthy when viewed in relation to the current therapies available for the treatment of herpesviruses. Famciclovir is the only antiherpes agent other than acyclovir that exhibits a safety profile comparable to placebo. Ganciclovir, a nucleoside analog with a broad spectrum of activity against herpesviruses (herpes simplex virus 1 and 2, varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus), is considerably more toxic than either famciclovir or acyclovir, and therefore is indicated primarily for the treatment of life- or sight-threatening cytomegalovirus-caused disease in immunocompromised patients.” Similarly, foscamet, a non-nucleoside analog with an in vitro spectrum of activity similar to ganciclovir, is limited in indication to the treatment of cytomegalovirus-caused retinitis in immunocompromised patients because of its potential for renal impairment. l1 The biochemical properties and safety profile of famciclovir favor its 224
R.SALTZMANANDR.BOON
use for the treatment of herpes zoster, a disease in which treatment alternatives with acceptable safety profiles are limited. This safety summary of 808 patients who received famciclovir in three clinical studies of herpes zoster demonstrates that this agent is well tolerated and exhibits a safety profile comparable to that of placebo. References: 1. Pue MA, Benet LZ. Pharmacokinetics of famciclovir in man. Antiviral Chem Chemother. 1993;4(Suppl 1):47-55. 2. Boyd MR, Safrin S, Kern ER. Penciclovir: A review of spectrum of activity, selectivity, and cross-resistance pattern. Antiviral Chem Chemother. 1993;4(Suppl 1):3-11. 3. Data on file, SmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania, 1995. 4. Bacon TH, Schinaxi RF. An overview of the further evaluation of penciclovir against herpes simplex virus and varicella-zoster virus in cell culture highlighting contrasts with acyclovir. Antiviml Chem Chemother. 1993;4(Suppl 1):25-36. 5. DeClerq E. Comparative efficacy of antiherpes drugs in different cell lines. Antimicrob Agents Chemother. 1982;21:661-663. 6. Standring-Cox R, Bacon TH, Howard B, et al. Prolonged activity of penciclovir against varicella-zoster virus in cell culture. Presented at the Seventh International Conference on Antiviral Research; February 27-March 4,1994; Charleston, SC. Poster 114. 7. Huff JC, Bean B, Balfour HH, et al. Therapy of herpes zoster with oral acyclovir. Am J Med. 1988;85(Suppl 2A):84-89. 8. Morton P, Thompson AN. Oral acyclovir in the treatment of herpes zoster in general practice. New Zealand Med J. 1989;102:93-95. 9. Earnshaw DL, Vere Hodge RA. Effective inhibition of herpesvirus DNA synthesis by Wpenciclovir-triphosphate. Presented at the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy; October ll-14,1992; Anaheim, Calif. Abstract 1707. 10. Faulds D, Heel RC. Ganciclovir: A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs. 1990;39:597-638. 11. Physicians' Desk Reference”. 47th ed. Montvale, NJ: Medical Economics Data Production Company; 1993:643-646.
225
THE SAFETY OF FAMCICLOVIR IN PATIENTS WITH HERPES ZOSTER ROBIN SALTZMAN’
AND RON BOON’
lSmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania, and %mithKline Beecham Pharmaceuticals, Brenybrd, Middlesex, United Kingdam
ABSTRACT Famciclovir is the well-absorbed oral form of the antiherpes agent penciclovir. Safety reports from clinical studies of more than 6500 patients and from spontaneous reports indicate that famciclovir is well tolerated. Safety data have been compiled for 808 patients with herpes zoster from three randomized, double-blind, clinical trials. Overall, 51.6% of the famciclovir-treated patient population were women and 48.4% were men. The patient population ranged in age from 15 to 102 years (mean, 51.8 years), with 55.7% aged 50 years or older. The mean duration of exposure to famciclovir was 6.7 days. Total daily doses ranged from 750mg to 2250mg. The most common adverse experiences reported were headache, nausea, and diarrhea. The frequency of adverse experiences and laboratory abnormalities (hematologic, clinical chemistry, and urinalysis variables) was similar in both famciclovir and placebo recipients. Safety data from these three clinical studies demonstrate that famciclovir is well tolerated by patients with herpes zoster and has a safety profile comparable to that of placebo. INTRODUCTION
Famciclovir* is the well-absorbed (77% bioavailable) oral form of penciclovir, a novel, selective antiviral agent with activity against varicellazoster virus.1*2Since licensure in the United States and the United Kingdom, more than 100,000 patients have received famciclovir.3 Both the relative and absolute potency of penciclovir and acyclovirt depend on the host cell and assay methods used, and inhibitory concentrations are generally comparable in vitro.2*4*5However, the active triphosphate form of penciclovir has a prolonged intracellular half-life in vitro of 7 hours in cells infected with varicella-zoster virus6 The most common adverse reactions reported in clinical studies with acyclovir in patients with herpes zoster include malaise, nausea, headache, vomiting, diarrhea, and constipation. 7*8Famciclovir has been well tolerAddress correspondence to: Robin Saltsman, SmithKline Beecham Pharmaceuticals, Four Falls Corporate Center, Boute 23 and Woodmont Avenue, P.O. Box 1610, King of Prussia, PA 19406. Received for publication on January 17,1995. Printed in the U.S.A. Reproduction in whole or part is not permitted. * Trademark: Fanwir” (SmithKline Bee&am Pharmaceuticals, Philadelphia, Pennsylvania). t Trademark: Zovirax@ (Burroughs Wellcome Co., Research Triangle Park, North Carolina). 219
00113931096/$3.50
SAFETY
OF FAMCICLOVIR
ated by more than 6500 patients in clinical trials, and since its clearance for the treatment of herpes zoster, spontaneous reports of adverse events have been infrequent. This report presents safety data for 273 patients who received famciclovir in a placebo-controlled trial and an integrated analysis of 535 patients who received famciclovir in two randomized, doubleblind, acyclovir-controlled trials. PATIENTS
AND METHODS
safety of famciclovir was assessed in studies of immunocompetent patients with herpes zoster by recording adverse experiences and monitoring laboratory variables. The patients were primarily adults with very few individuals in the 15- to M-year age range; no pediatric patients were studied. Adverse experiences were either identified by the investigator or elicited from the patient in response to the question, “Have you felt different in any way since starting the new treatment/the last assessment?” Details of each adverse experience (eg, time of onset, duration, intensity, and relationship to study medication) were recorded. Adverse experiences were classified according to the World Health Organization coding system. Adverse experiences that were fatal, life-threatening, disabling, or incapacitating; that resulted in a new or prolonged hospitalization, a congenital anomaly, or a carcinoma; or that resulted from an overdose were classified as serious and are discussed separately, as are events that led to withdrawal from the studies. The investigator assigned the causality of the adverse event to the study medication. Hematologic, clinical chemistry, and urinalysis studies were performed periodically in accordance with the protocol for each study (eg, at baseline and during or on completion of treatment). Any laboratory value considered clinically significant by the investigator was reported as an adverse event. In addition, values that changed from baseline by more than a specified amount and that were outside the sponsor-defined extended normal range were defined as values of potential clinical concern for the purpose of this safety evaluation. To detect overall changes, laboratory data were also examined by calculating the mean difference between values when receiving treatment, or within 7 days following completion of treatment, and values at baseline (mean change from baseline). Proportions of patients experiencing adverse events were analyzed, in a pair-wise fashion, by Fisher’s exact test. For each comparison, a twotailed test of the null hypothesis of no difference between treatment groups was conducted. The
RESULTS
Similar distribution of demographic characteristics was noted across all three studies. Therefore, demographic data for all 808 patients treated with famciclovir in these three trials were combined and are described.
R. SALTZMAN
AND R. BOON
The mean age of famciclovir-treated patients was 51.8 years (range, 15 to 102 years), with 55.7% aged 50 years or more; 51.6% were women and 48.4% were men. Overall, 89.6% of participants were white, 5.0% were black, and 5.4% were of other ethnic origin. All patients provided informed consent to participate in the trials. Mean duration of exposure to famciclovir was 6.7 days, and the total daily dose ranged from 750 mg to 2250 mg. Distribution of patients grouped according to total daily dose is presented in Table I. The mean cumulative dose of famciclovir was approximately 10 g (range, 750 mg to 15.8 g).
Adverse Experiences Table II summarizes the incidence of adverse experiences, regardless of causality, reported by 32% of patients in the placebo-controlled trial. There were no statistically significant differences in adverse experience reporting rates between patients treated with famciclovir or placebo. Headache, nausea, and diarrhea were the most common events reported by both groups. As anticipated, the incidence of adverse experiences reported as “related” (includes the categories of related, probably related, possibly related, and causalities that were unassessable or not indicated) to study medication was lower than the overall incidence of adverse experiences. In addition, the incidence and severity of adverse experiences reported as “related” to study medication administration were comparable between the famciclovir and placebo groups. Headache, nausea, and diarrhea were again the most common adverse experiences reported. In the famciclovir group, headache was reported by 8.1% of patients, nausea was reported by 4.0% of patients, and diarrhea was reported by 2.6% of patients. In the placebo group, nausea was the most common event, reported by 8.2% of patients; headache was reported in 6.8% of patients, and diarrhea was reported in 2.1% of patients. Somnolence was reported in 1.5% of famciclovir patients and 2.1% of placebo patients. All other adverse experiences occurred in ~2% of the patient population. Table III summarizes the incidence of drug-related adverse experiences occurring in 21% of patients in the placebo-controlled trial. There were no statistically significant differ-
Table I. Distribution of patients grouped according to total daily dose of famciclovir. No. of Patients’
Total Dally Dose of Femciclovir 3750 mg ~1500 mg 2250 mg l
E! 272
Data presented for 806 of 808 patients; data were incomplete for 2 patients. 221
SAFETY
OF FAMCICLOVIR
Table II. Adverse experiences, regardless of causality, reported by 32% of patients in a placebocontrolled famciclovir trial.
Famciclovlr (n = 273) %
Placebo (n = 146) %
pJS
ii
5;
Dizziness Zoster-related signs/symptoms/complications Pharynpitis
i::
4.1 3.4 4.8 4.1
Adverse Experience ;;;-W&he Diarrhea Vomiting Constipation
2.9
EYc Somnolence Sinusitis Injury Paresthesia Rigor Back pain Arthralgia Abdommal pain
Z 1.4 :::
ences in adverse-experience reporting rates between famciclovir-treated patients and patients who received placebo. Serious adverse experiences were seen in 1.1% of patients who received famciclovir and 1.4% of patients who received placebo. None of the Table III. Adverse experiences related to study medication occurring in 3 1% of patients in a placebo-controlled famciclovir trial.*
Famciclovir (n = 273) %
Adveme Experience
Placebo (n = 146) %
~e,a,~F” Diarrhea Somnolence Fatigue
!znus Anorexia Rigor Vomiting Dizziness Depression Hyperesthesia Fever Zoster-related signs/symptoms/complications * Includes categories of related, probably related, possibly related, and adverse experiences where the relationship was unassessable or not indicated. Causality was assessed by the investigator. 222
Ft. SALTZMAN
AND R. BOON
headache, nausea, or diarrhea episodes noted previously were classified as serious. All of the serious events reported in the placebo-controlled trial (either in the famciclovir or placebo group) were considered by the investigators to be unrelated to the study medication. Each of the serious adverse experiences reported in the placebo-controlled trial was unique (ie, reported by only one patient). The overall incidence of withdrawals due to adverse experiences was 0.7% and 3.4% for the famciclovir and placebo groups, respectively. Two patients who received famciclovir were withdrawn due to adverse experiences (one patient each for constipation and nausea). For the placebo recipients, five patients were withdrawn due to adverse experiences: two patients withdrew because of worsening of herpes zoster (1.4%) and one patient each withdrew for thrombocytopenia, rash, and leukopenia. Adverse experiences leading to withdrawal that were considered to be related, probably related, or possibly related to study medication or where the relationship was unassessable or not indicated occurred in 0.4% of the patients who received famciclovir and 1.4% of patients who received placebo. No deaths were attributed to treatment with famciclovir. For two of the three studies of patients with herpes zoster, acyclovir was used as the control. Table IV summarizes the incidence of adverse experiences related to study medication that occurred in ~1% of patients, in these two studies. As with the placebo-controlled trial, headache (6.0%) and nausea (3.7%) were the most frequently reported adverse experiences for famciclovir-treated patients. The most common adverse experiences reported for acyclovir-treated patients were headache (4.6%), nausea (2.7%), abdominal pain (2.3%), and fatigue (2.3%). Anorexia was the only drug-related adverse experience that was statistically different for famciclovir (0.2%) versus acyclovir (1.9%).
Table IV. Adverse experiences related to study medication occurring in 31% of patients in two acvclovir-controlled famciclovir trial.*
Adverse Experience
Famclclovlr (n = 555)%
;;;i;;he Abdominal pain Diarrhea Vomiting Dizziness Constipation Fatigue Anorexia Includes categories of related, probably related, possibly related, and adverse experiences where the relationship was unassessable or not indicated. Causality was assessed by the investigator. l
223
SAFETY
OF FAMCICLOVIR
Laboratory Assessments There was no consistent association between treatment with or duration of exposure to famciclovir and the incidence of laboratory abnormalities. In the placebo-controlled trial, ~1% of patients treated with famciclovir had values of potential clinical concern, with the exception of increases in alanine transaminase (2.4%) and serum phosphate (1.6%) levels. Similarly, 2.3% of patients in the placebo group had increased alanine transaminase values; a slightly lower incidence of increased serum phosphate values (0.7%) was noted in the placebo group. Laboratory variables related to hematology, hepatic function, renal function, serum electrolytes, muscle metabolism, bone metabolism, and serum glucose were examined for mean changes from baseline. No clinically significant differences between the famciclovir and placebo groups were observed. Similarly, famciclovir administration did not lead to any clinically relevant changes in urinalysis values. DISCUSSION AND CONCLUSION
Biochemical studies on the mode of action of penciclovir have shown that the preferential phosphorylation in herpesvirus-infected cells is more marked for penciclovir than for acyclovir.g The minimal phosphorylation of penciclovir in uninfected cells, together with the low activity of penciclovir-triphosphate against cellular DNA polymerases, provides a rationale for the lack of toxicity of penciclovir in cell culture. This hypothesis has been tested in a wide range of human cell lines of differing tissue origin.2 These tests showed that penciclovir is like acyclovir in that it is exceptionally nontoxic to replicating cells in culture. Furthermore, evaluation of famciclovir and penciclovir in toxicologic tests have shown that these compounds have a good safety profile, similar to that of acyclovir. The favorable safety profile of famciclovir demonstrated by this safety summary is particularly noteworthy when viewed in relation to the current therapies available for the treatment of herpesviruses. Famciclovir is the only antiherpes agent other than acyclovir that exhibits a safety profile comparable to placebo. Ganciclovir, a nucleoside analog with a broad spectrum of activity against herpesviruses (herpes simplex virus 1 and 2, varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus), is considerably more toxic than either famciclovir or acyclovir, and therefore is indicated primarily for the treatment of life- or sight-threatening cytomegalovirus-caused disease in immunocompromised patients.” Similarly, foscamet, a non-nucleoside analog with an in vitro spectrum of activity similar to ganciclovir, is limited in indication to the treatment of cytomegalovirus-caused retinitis in immunocompromised patients because of its potential for renal impairment. l1 The biochemical properties and safety profile of famciclovir favor its 224
R.SALTZMANANDR.BOON
use for the treatment of herpes zoster, a disease in which treatment alternatives with acceptable safety profiles are limited. This safety summary of 808 patients who received famciclovir in three clinical studies of herpes zoster demonstrates that this agent is well tolerated and exhibits a safety profile comparable to that of placebo. References: 1. Pue MA, Benet LZ. Pharmacokinetics of famciclovir in man. Antiviral Chem Chemother. 1993;4(Suppl 1):47-55. 2. Boyd MR, Safrin S, Kern ER. Penciclovir: A review of spectrum of activity, selectivity, and cross-resistance pattern. Antiviral Chem Chemother. 1993;4(Suppl 1):3-11. 3. Data on file, SmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania, 1995. 4. Bacon TH, Schinaxi RF. An overview of the further evaluation of penciclovir against herpes simplex virus and varicella-zoster virus in cell culture highlighting contrasts with acyclovir. Antiviml Chem Chemother. 1993;4(Suppl 1):25-36. 5. DeClerq E. Comparative efficacy of antiherpes drugs in different cell lines. Antimicrob Agents Chemother. 1982;21:661-663. 6. Standring-Cox R, Bacon TH, Howard B, et al. Prolonged activity of penciclovir against varicella-zoster virus in cell culture. Presented at the Seventh International Conference on Antiviral Research; February 27-March 4,1994; Charleston, SC. Poster 114. 7. Huff JC, Bean B, Balfour HH, et al. Therapy of herpes zoster with oral acyclovir. Am J Med. 1988;85(Suppl 2A):84-89. 8. Morton P, Thompson AN. Oral acyclovir in the treatment of herpes zoster in general practice. New Zealand Med J. 1989;102:93-95. 9. Earnshaw DL, Vere Hodge RA. Effective inhibition of herpesvirus DNA synthesis by Wpenciclovir-triphosphate. Presented at the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy; October ll-14,1992; Anaheim, Calif. Abstract 1707. 10. Faulds D, Heel RC. Ganciclovir: A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs. 1990;39:597-638. 11. Physicians' Desk Reference”. 47th ed. Montvale, NJ: Medical Economics Data Production Company; 1993:643-646.
225