Oregon daily emerald., May 16, 1997, Page 9A, Image 9

VALTREX® BRIEF SUMMARY
(valacyclovir hydrochloride)
Caplets
The tallowing is a brief summaiy only; see full prescribing information
for complete product information.
CONTRAINDICATIONS: VALTREX is contraindicated in patients with a known hypersensitivity or intolerance to
valacyclovir, acyclovir, or any component of the formulation.
WARNINGS: Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), In some cases
resulting in death, has occurred in patients with advanced HIV disease and also In allogeneic bone marrow
transplant and renal transplant recipients participating in clinical trials of VALTREX at doses of 8 grams per day.
PRECAUTIONS: The efficacy of VALTREX has not been established for the treatment of disseminated heipes
zoster, or suppression of recurrent genital herpes, or in immunocompromised patients.
Dosage adjustment is recommended when administering VALTREX to patients with renal impairment (see
DOSAGE AND ADMINISTRATION). Caution should also be exercised when administering VALTREX to patients
receiving potentially nephrotoxic agents since this may increase the risk of renal dysfunction and/or the risk of
reversible central nervous system symptoms such as those that have been reported in patients treated with intra
venous acyclovir.
Information for Patients: Herpes Zoster: There are no data on treatment initiated more than 72 hours after onset of
the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.
Genital Herpes: Patients should be informed that VALTREX is not a cure for genital herpes. There are no data
evaluating whether VALTREX will prevent transmission of infection to others. Because genital herpes is a sexually
transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are
present to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through
asymptomatic viral shedding. If medical management of a genital herpes recurrence is indicated, patients should be
advised to initiate therapy at the first sign or symptom of an episode.
There are no data on the effectiveness of treatment initiated more than 72 hours after the onset of signs and symp
toms of a first episode of genital herpes or more than 24 hours of the onset of signs and symptoms of a recurrent
episode.
Drug Interactions: An additive increase in acyclovir AUC and was observed when VALTREX was administered
to healthy volunteers who were taking cimetidine, probenecid, or a combination of both cimetidine and probenecid
(see CLINICAL PHARMACOLOGY: Pharmacokinetics).
Carcinogenesis, Mutagenesis, Impairment of Fertility: The data presented below include references to the steady
state acyclovir AUC observed in humans treated with 1 gram VALTREX given orally three times a day to treat herpes
, iuoimu u.Uy wuv^iiiiauwiio 111 annual Diuuica aic e*pies>i>«2u as muiupies oi numari expo
sure to acyclovir (see CLINICAL PHARMACOLOGY: Pharmacokinetics section).
Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gav
age) of up to 120 mg/kg/day for mice and 100 mg/kg/day for rats. There was no significant differ
ence in the incidence of tumors between treated and control animals, nor did valacyclovir shorten
the latency of tumors. Plasma concentrations of acyclovir were equivalent to human levels in the
mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay.
Valacyclovir was tested in five genetic toxicity assays. An Ames assay was negative in the absence or presence of
metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and a rat cytogenetic
study at a single oral dose of 3000 mg/kg (8 to 9 times human plasma levels).
In the mouse lymphoma assay, valacyclovir was negative in the absence of metabolic activation. In the presence of
metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was weakly mutagenic.
A mouse micronucleus assay was negative at 250 mg/kg but weakly positive at 500 mg/kg (acyclovir concentra
tions 26 to 51 times human plasma levels).
Valacydovir did not impair fertility or reproduction in rats at 200 mg/k^day (6 times human plasma levels).
Pregnancy: Teratogenic Effects: Pregnancy Category B. Valacydovir was not teratogenic in rats or rabbits given
400 mg/kg (which results in exposures of 10 and 7 times human plasma levels, respectively) during the period of
major organogenesis. There are no adequate and well-controtled studies of VALTREX or ZOVIRAX in pregnant
women. A prospective epidemiologic registry of acyclovir use during pregnancy has been ongoing since 1984. As of
December 1994, outcomes of live births have been documented in 380 women exposed to systemic acyclovir during
the first trimester of pregnancy. The occurrence rate of birth defects approximates that found in the general popula
tion. However, the small size of the registry is insufficient to evaluate the risk for less common defects oAo permit
reliable and definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.
VALTREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Exposure Registry: To monitor maternal-fetal outcomes of pregnant women exposed to VALTREX,
Glaxo Wellcome Inc. maintains a Valacyclovir in Pregnancy Registry. Physicians are encouraged to register their
patients by calling (800) 722-9292, ext. 39437.
Nursing Mothers: There is no experience with VALTREX. However, acyclovir concentrations have been document
ed in breast milk in two women following oral administration of ZOVIRAX and ranged from 0.6 to 4.1 times corre
sponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir as
high as 0.3 mg/kg/day. VALTREX should be administered to a nursing mother with caution and only when indicated.
Pediatric Use: Safety and effectiveness of VALTREX in pediatric patients have not been established.
Geriatric Use: Of the total number of patients included in clinical studies of VALTREX, 810 were age 65 or older, and
339 were age 75 or older. A total of 34 volunteers age 65 or older completed a pharmacokinetic trial of
VALTREX. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of VALTREX in
geriatric volunteers varied with renal function. Dosage reduction may be required in geriatric patients, depending on
the underlying renal status of the patient (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS: The adverse events reported by greater than 2% of a given treatment qroup in clinical
trials of VALTREX are listed in Table 1.
Table 1
Incidence (%) of Adverse Events in Herpes Zoster and Genital Herpes Study Populations
Adverse
Event
Nausea
Headache
Vomiting
Diarrhea
Constipation
Asthenia
Dizziness
Abdominal Pain
Anorexia
Herpes Zoster
VALTREX
1gram
t.i.d.
(n=967)
15
14
6
5
4
4
3
3
2
ZOVIRAX
800 mg
5x daily
(n=376)
19
13
8
7
5
5
6
3
3
Placebo
(n=195)
8
12
3
6
3
4
2
2
2
Genital Herpes
VALTREX
1 gram
b.i.d.
(n=1,194)
6
16
1
4
<1
2
3
2
<1
VALTREX
500 mg
b.i.d.
(n=359)
6
17
1
5
1
1
2
3
<1
ZOVIRAX
200 mg
5x daily
(n=822)
7
12
2
3
1
2
2
2
<1
Placebo
(n=439)
8
14
<1
6
1
4
3
3
<1
OVERDOSAGE: There have been no reports of overdosage from the administration of VALTREX. However, it is
known that precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the
intratubular fluid. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal
function is restored (see DOSAGE AND ADMINISTRATION).
U.S. Patent No. 4,957,924 RL-377 November 1996
© 1997 Glaxo Wellcome Inc. VAL215RO Printed in USA January 1997
ZOVIRAX® (acyclovir) Capsules
ZOVIRAX® (acyclovir) Tablets
ZOVIRAX (acyclovir) Suspension briefsuumary
The following is a brief summary only; see full prescribing information for complete product information, including references.
CONTRAINDICATIONS: ZOVIRAX Capsules, Tablets, and Suspension are contraindicated for patients who develop hypersensitivity or intolerance to
the components of the formulations.
WARNINGS: ZOVIRAX Capsules. Tablets, and Suspension are intended for oral ingestion only.
PRECAUTIONS:
General: ZOVIRAX has caused decreased spermatogenesis at high parenteral doses in some animals and mutagenesis in some acute studies at high
concentrations of drug (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility). The recommended dosage should not be exceed
ed (see DOSAGE AND ADMINISTRATION section of full prescribing information).
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 and clinical response to therapy has yet to be established (see CLINICAL PHARMACOLOGY:
Microbiology section of full prescribing information)
Because of the possibility that less sensitive virus may be selected in patients who are receiving acyclovir, all patients should be advised to take par
ticular care to avoid potential transmission of 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 ZOVIRAX to patients receiving potentially nephrotoxic agents since this may increase the risk of
renal dysfunction.
Information for Patients: 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 breastfeed while taking orally administered ZOVIRAX, 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. ZOVIRAX Capsules, Tablets, and Suspension are for oral ingestion only. Medication should not be
shared with others. The preserved dosage should not be exceeded. ZOVIRAX 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 ZOVIRAX 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 cur
rently marketed medications also cause chromosomal breaks, and the significance of this finding is unknown. A placebo-controlled clinical study using
800 mg of ZOVIRAX 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 ZOVIRAX 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 treatment of chickenpox with ZOVIRAX would have any effect on
either decreasing or increasing the incidence or severity of subsequent recurrences of herpes zoster (shingles) later in life. Intravenous ZOVIRAX is
indicated for the treatment of varicella-zoster infections in immunocompromised patients.
Drug Interactions: Co-administration of probenecid with intravenous acyclovir has been shown to increase the mean half-life and the area under the con
centration-time curve. Urinary excretion and renal clearance were correspondingly reduced. The clinical effects of this combination have not been studied.
Carcinogenesis, Mutagenesis, Impairment of Fertility: The data presented below include references to peak steady-state plasma acyclovir concentra
tions observed in humans treated with 800 mg given orally 6 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given oraly 6 times
a day (dosing appropriate for treatment of genital herpes). 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 section of full prescribing information).
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 statistical
ly 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 were 3 to 6 times human levels in the mouse bioassay and 1 to 2 times human levels in the rat bioassay.
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 at maximum tolerat
ed parenteral doses of acyclovir (100 mg/kg) in rats (62 to 125 times human levels) but not in Chinese hamsters; higher doses of 500 and 1000 mg/kg
were clastogenic in Chinese hamsters (380 to 760 times human levels). In addition, no 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 tor chromosomal damage was seen at concentra
tions 150 to 300 times the acyclovir plasma levels achieved in humans. At one locus in mouse lymphoma ceUs, mutagenicity was observed at concen
trations 250 to 500 times human plasma levels. Results in the other five mammalian cell tod follow: at 3 tod in a Chinese hamster ovary cel line, the
results were inconclusive at concentrations at least 1850 times human levels; at 2 other tod 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, s.c.). In the mouse study, plas
ma levels were 9 to 18 times human levels, while in the rat study they were 8 to 15 times human levels. At a higher dose in the rat (50 mg/kg/day, &&),
there was a statistically significant increase in post-implantation loss, but no concomitant decrease in litter size. In female rabbits treated subcutaneously
with acyclovir subsequent to mating, there was a statistical significant decrease in implantation efficiency but no concomitant decrease in litter size at a
dose of 50 mg/kg/day (16 to 31 times human levels). No effect upon implantation efficiency was observed when the same dose was administered intra
venously (53 to 106 times human levels). In a rat peri- and postnatal study at 50 mg/kg/day s.c. (11 to 22 times human levels), there was a statisticaly
significant decrease in the group mean numbers of corpora lutea, total implantation sites, and live fetuses in the generation. Although not statistical
ly 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 resumptions and a corresponding decrease in litter size (plasma levels were not measured). However, at a maximum tolerated intra
venous dose of 50 mg/kg/day in rabbits (53 to 106 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 1-month study and were 24 to 48 times human levels in the 6-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 postoose. Intravenous doses of
100 and 200 mg/kg/day acyclovir given to dogs for 31 days caused aspermatogenesis. At 100 mg/kg/day plasma levels were 47 to 94 times human
levels, while at 200 mg/kg/day they were 159 to 317 times human levels. No testicular abnormalities were seen in dogs given 50 mg/kg/day i.v. for 1
month (21 to 41 times human levels) and in dogs given 60 mg/kg/day orally for 1 year (6 to 12 times 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, s.c.
and i.v.), or in standard tests in the rat (50 mg/kg/day, s.c.). These exposures resulted in plasma levels 9 and 18.16 and 106, and 11 and 22 times,
respectively, human levels. In a non-standard test in rats, there were fetal abnormalities, such as head and tail anomalies, and maternal toxicity. In this
test, rats were given 3 s.c. doses of 100 mg/kg acyclovir on gestation day 10, resulting in plasma levels 63 and 125 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 poten
tial nsk to the fetus Although acyclovir was not teratogenic in standard animal studies, the drug’s potential for causing chromosome breaks at high con
centration 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 Inc. main
tains an Acyclovir in Pregnancy Registry. Physicians are encouraged to register patients by calling (800) 722-9292. ext. 58465
Nursing Mothers: Acyclovir concentrations have been documented in breast milk in two women following oral administration of ZOVIRAX and ranged
from 0.6 to 4.1 times corresponding plasma levels. These concentrations would potentially expose Ihe nursing infant to a dose of acyclovir up to
0.3 mg/kg/day. Caution should be exercised when ZOVIRAX is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in children less than 2 years of age have not been adequately studied
ADVERSE REACTIONS:
Herpes Simplex: Short-Term Administration: The most frequent adverse events reported during clinical trials of treatment of genital herpes with
orally administered ZOVIRAX 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%) patients who received placebo.
Less frequent adverse events, each of which occurred in 1 of 298 patient treatments with orally administered ZOVIRAX (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 adminis
tration of 400 mg (two 200 mg capsules) 2 times daily for 1 year in 586 patients treated with ZOVIRAX were: nausea (4.8%), diarrhea (2.4%),
headache (1.9%), and rash (1.7%). The 589 control patients receiving intermittent treatment of recurrences with ZOVIRAX for 1 year reported oiarrhea
(2.7%), nausea (2.4%), headache (22%), and rash (1.5%).
The most frequent adverse events 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 included asthenia (12%), paresthesia (1.2%), and headache (0.9%).
Herpes Zoster: The most frequent adverse events reported during three clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral
ZOVIRAX 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%).
Chickmpox: The most frequent adverse events reported during three clinical trials of treatment of chickenpox with oral ZOVIRAX in 495 patients were:
diarrhea (32%), abdominal pain (0.6%), rash (0.6%), vomiting (0.6%), and flatulence (0.4%). The 498 patients receiving placebo reported: diarrhea
(22%), flatulence (0.8%), and insomnia (0.4%).
Observed During Clinical Practice: Based on clinical practice experience m patients treated with oral ZOVIRAX 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 part 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, seizure, somnolence (These symptoms may be marked, particularly 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
OVERDOSAGE: Patients have ingested intentional ovetdoses of up to 100 capsules (20 g) of ZOVIRAX, with no unexpected adverse effects
Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) in me inlratubular fluid is exceeded Renal lesions considered to
be related to obstruction of renal titoules by precipitated drug crystals occurred in the following species: rats treated with i.v. and i.p. doses of
20 mg/kg/day for 21 and 31 days, respectively, and at s.c doses of 100 mg/kg/day for 10 days: rabbits al s.c. and i.v doses of 50 mg/kg/day
tor 13 days; and dogs at i.v. doses of 100 mgflrg/day tor 31 days. A 6-hour hemodialysis results in a 60% decrease in plasma acyclovir concentration.
Data concerning peritoneal dialysis are incomplete but indicate that mis method may be significantly less efficient in removing acyclovir from the blood
tn the event of acute renal failure and anuria, fhe patient may benefit from hemodialysis unS renal function is restored (see DOSAGE AND ADMINIS
TRATION section of ful prescribing information)
U5. Patent No. 4,199,574 RL-316 May 1996
Ot997 Glaxo Welcome Inc PiinledinUSA
VAL215R0 January 1997
GlaxoWellcome
Glaxo Wellcome Inc.
Research Triangle Park. NC 27709