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Acyclovir
Overview
What is Acyclovir?
Acyclovir is a synthetic nucleoside analogue active against
herpesviruses.
Each teaspoonful (5 mL) of acyclovir oral suspension, USP, for oral
administration, contains 200 mg of acyclovir and the inactive ingredients
artificial banana flavor, carboxymethylcellulose sodium, glycerin, methylparaben
0.1% (added as a preservative), microcrystalline cellulose, propylparaben 0.02%
(added as a preservative), purified water, and sorbitol.
Acyclovir is a white, crystalline powder with the molecular formula CHNO and a molecular weight of 225. The maximum solubility in
water at 37°C is 2.5 mg/mL. The pka’s of acyclovir are 2.27 and 9.25.
The chemical name of acyclovir is
2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]- 6H-purin-6-one; it has the
following structural formula:
Acyclovir is a synthetic purine nucleoside analogue with and inhibitory
activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and
varicella-zoster virus (VZV).
The inhibitory activity of acyclovir is highly selective due to its affinity
for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme
converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The
monophosphate is further converted into diphosphate by cellular guanylate kinase
and into triphosphate by a number of cellular enzymes. , acyclovir triphosphate stops replication of herpes viral DNA. This
is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2)
incorporation into and termination of the growing viral DNA chain, and 3)
inactivation of the viral DNA polymerase. The greater antiviral activity of
acyclovir against HSV compared with VZV is due to its more efficient
phosphorylation by the viral TK.
The quantitative relationship between the susceptibility of herpes viruses to antivirals and the clinical
response to therapy has not been established in humans, and virus sensitivity
testing has not been standardized. Sensitivity testing results, expressed as the
concentration of drug required to inhibit by 50% the growth of virus in cell
culture (IC), vary greatly depending upon a number of
factors. Using plaque-reduction assays, the IC against
herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from
0.01 to 9.9 mcg/mL for HSV-2. The IC for acyclovir
against most laboratory strains and clinical isolates of VZV ranges from 0.12 to
10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain
of VZV with a mean IC of 1.35 mcg/mL.
Resistance of HSV and VZV to acyclovir can result from
qualitative and quantitative changes in the viral TK and/or DNA polymerase.
Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have
been recovered from immunocompromised patients, especially with advanced HIV
infection. While most of the acyclovir-resistant mutants isolated thus far from
immunocompromised patients have been found to be TK-deficient mutants, other
mutants involving the viral TK gene (TK partial and TK altered) and DNA
polymerase have been isolated. TK-negative mutants may cause severe disease in
infants and immunocompromised adults. The possibility of viral resistance to
acyclovir should be considered in patients who show poor clinical response
during therapy.
What does Acyclovir look like?
What are the available doses of Acyclovir?
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What should I talk to my health care provider before I take Acyclovir?
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How should I use Acyclovir?
Acyclovir oral suspension, USP is indicated for the acute
treatment of herpes zoster (shingles).
Acyclovir oral suspension, USP is indicated for the treatment of
initial episodes and the management of recurrent episodes of genital
herpes.
Acyclovir oral suspension, USP is indicated for the treatment of
chickenpox (varicella).
800 mg every 4 hours orally, 5 times daily for 7 to 10
days.
200 mg every 4 hours, 5 times daily for 10 days.
400 mg 2 times daily for up to 12 months, followed by
re-evaluation. Alternative regimens have included doses ranging from 200 mg 3
times daily to 200 mg 5 times daily.
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 therapy with acyclovir oral suspension.
200 mg every 4 hours, 5 times daily for 5 days. Therapy should be
initiated at the earliest sign or symptom (prodrome) of recurrence.
20 mg/kg orally 4 times daily
(80 mg/kg per day) for 5 days. Children over 40 kg should receive the adult dose
for chickenpox.
800 mg 4 times daily for 5 days.
Intravenous acyclovir oral suspension is indicated for the treatment of
varicellazoster 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.
In patients with renal impairment, the dose of acyclovir oral
suspension should be modified as shown in Table 3:
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.
No supplemental dose appears to be necessary after adjustment of
the dosing interval.
What interacts with Acyclovir?
Acyclovir is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir.
What are the warnings of Acyclovir?
As with any other non-deformable material, caution should be used when
administering glipizide extended-release tablets in patients with pre-existing
severe gastrointestinal narrowing (pathologic or iatrogenic). There have been
rare reports of obstructive symptoms in patients with known strictures in
association with the ingestion of another drug in this non-deformable sustained
release formulation.
Acyclovir is intended for oral ingestion only. Renal failure, in
some cases resulting in death, has been observed with acyclovir therapy (see : Observed During Clinical Practice and ).
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS),
which has resulted in death, has occurred in immunocompromised patients
receiving acyclovir therapy.
What are the precautions of Acyclovir?
Dosage adjustment is recommended when administering acyclovir to
patients with renal impairment (see ). Caution should also be exercised when administering
acyclovir 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 intravenous acyclovir. Adequate hydration should be
maintained.
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 acyclovir, or they have any other questions.
Patients should be advised to maintain adequate hydration.
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.
Patients should be informed that acyclovir is not a cure for
genital herpes. There are no data evaluating whether acyclovir 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 genital herpes recurrence is indicated,
patients should be advised to initiate therapy at the first sign or symptom of
an episode.
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.
See : Pharmacokinetics.
The data presented below include references to peak steady-state
plasma acyclovir concentrations observed in humans treated with 800 mg given
orally 5 times a day (dosing appropriate for treatment of herpes zoster) or 200
mg given orally 5 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 : 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. Maximum 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 16 and genetic toxicity assays. Acyclovir was positive in
5 of the assays.
Acyclovir did not impair fertility or reproduction in mice (450 mg/kg per
day, PO) or in rats (25 mg/kg per 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 higher doses (50 mg/kg per day, SC) in rats and rabbits (11 to
22 and 16 to 31 times human levels, respectively) implantation efficacy, but not
litter size, was decreased. In a rat peri- and post-natal study at 50 mg/kg per
day, SC, there was a statistically significant decrease in group mean numbers of
corpora lutea, total implantation sites, and live fetuses.
No testicular abnormalities were seen in dogs given 50 mg/kg per day, IV for
1 month (21 to 41 times human levels) or in dogs given 60 mg/kg per day orally
for 1 year (6 to 12 times human levels). Testicular atrophy and aspermatogenesis
were observed in rats and dogs at higher dose levels.
Pregnancy Category B. Acyclovir administered during organogenesis
was not teratogenic in the mouse (450 mg/kg per day, PO), rabbit (50 mg/kg per
day, SC and IV), or rat (50 mg/kg per day, SC). These exposures resulted in
plasma levels 9 and 18, 16 and 106, and 11 and 22 times, respectively, human
levels.
There are no adequate and well-controlled studies in pregnant women. A
prospective epidemiologic registry of acyclovir use during pregnancy was
established in 1984 and completed in April 1999. There were 749 pregnancies
followed in women exposed to systemic acyclovir during the first trimester of
pregnancy resulting in 756 outcomes. The occurrence rate of birth defects
approximates that found in the general population. However, the small size of
the registry is insufficient to evaluate the risk for less common defects or to
permit reliable or definitive conclusions regarding the safety of acyclovir in
pregnant women and their developing fetuses. Acyclovir should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Acyclovir concentrations have been documented in breast milk in 2
women following oral administration of acyclovir and ranged from 0.6 to 4.1
times corresponding plasma levels. These concentrations would potentially expose
the nursing infant to a dose of acyclovir up to 0.3 mg/kg per day. Acyclovir
should be administered to a nursing mother with caution and only when
indicated.
Safety and effectiveness of oral formulations of acyclovir in
pediatric patients younger than 2 years of age have not been established.
Of 376 subjects who received acyclovir in a clinical study of
herpes zoster treatment in immunocompetent subjects greater than or equal to 50
years of age, 244 were 65 and over while 111 were 75 and over. No overall
differences in effectiveness for time to cessation of new lesion formation or
time to healing were reported between geriatric subjects and younger adult
subjects. The duration of pain after healing was longer in patients 65 and over.
Nausea, vomiting, and dizziness were reported more frequently in elderly
subjects. Elderly patients are more likely to have reduced renal function and
require dose reduction. Elderly patients are also more likely to have renal or
CNS adverse events. With respect to CNS adverse events observed during clinical
practice, somnolence, hallucinations, confusion, and coma were reported more
frequently in elderly patients (see , : Observed During Clinical Practice, and ).
What are the side effects of Acyclovir?
The most frequent adverse events reported during clinical trials
of treatment of genital herpes with acyclovir 200 mg administered orally 5 times
daily every 4 hours for 10 days were nausea and/or vomiting in 8 of 298 patient
treatments (2.7%). Nausea and/or vomiting occurred in 2 of 287 (0.7%) patients
who received placebo.
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%) and diarrhea (2.4%). The 589 control patients receiving
intermittent treatment of recurrences with acyclovir for 1 year reported
diarrhea (2.7%), nausea (2.4%), and headache (2.2%).
The most frequent adverse event reported during 3 clinical trials
of treatment of herpes zoster (shingles) with 800 mg of oral acyclovir 5 times
daily for 7 to 10 days in 323 patients was malaise (11.5%). The 323 placebo
recipients reported malaise (11.1%).
The most frequent adverse event reported during 3 clinical trials
of treatment of chickenpox with oral acyclovir at doses of 10 to 20 mg/kg 4
times daily for 5 to 7 days or 800 mg 4 times daily for 5 days in 495 patients
was diarrhea (3.2%). The 498 patients receiving placebo reported diarrhea
(2.2%).
In addition to adverse events reported from clinical trials, the
following events have been identified during post-approval use of acyclovir.
Because they are reported voluntarily from a population of unknown size,
estimates of frequency cannot be made. These events have been chosen for
inclusion due to either their seriousness, frequency of reporting, potential
causal connection to acyclovir, or a combination of these factors.
Anaphylaxis, angioedema, fever, headache, pain, peripheral
edema.
Aggressive behavior, agitation, ataxia, coma, confusion,
decreased consciousness, delirium, dizziness, dysarthria, encephalopathy,
hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These
symptoms may be marked, particularly in older adults or in patients with renal
impairment (see ).
Diarrhea, gastrointestinal distress, nausea.
Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy,
thrombocytopenia.
Elevated liver function tests, hepatitis, hyperbilirubinemia,
jaundice.
Myalgia.
Alopecia, erythema multiforme, photosensitive rash, pruritus,
rash, Stevens- Johnson syndrome, toxic epidermal necrolysis, urticaria.
Visual abnormalities.
Renal failure, renal pain (may be associated with renal failure),
elevated blood urea nitrogen, elevated creatinine, hematuria (see ).
What should I look out for while using Acyclovir?
Acyclovir is contraindicated for patients who develop hypersensitivity to
acyclovir or valacyclovir.
Acyclovir is intended for oral ingestion only. Renal failure, in
some cases resulting in death, has been observed with acyclovir therapy (see : Observed During Clinical Practice and ).
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS),
which has resulted in death, has occurred in immunocompromised patients
receiving acyclovir therapy.
What might happen if I take too much Acyclovir?
Overdoses involving ingestion of up to 20 g have been reported. Adverse events
that have been reported in association with overdosage include agitation, coma,
seizures, and lethargy. Precipitation of acyclovir in renal tubules may occur
when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid.
Overdosage has been reported following bolus injections or inappropriately high
doses and in patients whose fluid and electrolyte balance were not properly
monitored. This has resulted in elevated BUN and serum creatinine and subsequent
renal failure. In the event of acute renal failure and anuria, the patient may
benefit from hemodialysis until renal function is restored (see ).
How should I store and handle Acyclovir?
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Acyclovir oral suspension, USP (off-white, artificial banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL) – Bottle of 1 pint (473 mL)NDC 54868-5687-0Store at 20° - 25°C (68° to 77°F) [see USP Controlled Room Temperature].Manufactured by:Hi-Tech Pharmacal Co., Inc.Amityville, NY 11701MG #19296Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 Acyclovir oral suspension, USP (off-white, artificial banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL) – Bottle of 1 pint (473 mL)NDC 54868-5687-0Store at 20° - 25°C (68° to 77°F) [see USP Controlled Room Temperature].Manufactured by:Hi-Tech Pharmacal Co., Inc.Amityville, NY 11701MG #19296Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 Acyclovir oral suspension, USP (off-white, artificial banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL) – Bottle of 1 pint (473 mL)NDC 54868-5687-0Store at 20° - 25°C (68° to 77°F) [see USP Controlled Room Temperature].Manufactured by:Hi-Tech Pharmacal Co., Inc.Amityville, NY 11701MG #19296Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 Acyclovir oral suspension, USP (off-white, artificial banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL) – Bottle of 1 pint (473 mL)NDC 54868-5687-0Store at 20° - 25°C (68° to 77°F) [see USP Controlled Room Temperature].Manufactured by:Hi-Tech Pharmacal Co., Inc.Amityville, NY 11701MG #19296Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 Acyclovir oral suspension, USP (off-white, artificial banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL) – Bottle of 1 pint (473 mL)NDC 54868-5687-0Store at 20° - 25°C (68° to 77°F) [see USP Controlled Room Temperature].Manufactured by:Hi-Tech Pharmacal Co., Inc.Amityville, NY 11701MG #19296Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 Acyclovir oral suspension, USP (off-white, artificial banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL) – Bottle of 1 pint (473 mL)NDC 54868-5687-0Store at 20° - 25°C (68° to 77°F) [see USP Controlled Room Temperature].Manufactured by:Hi-Tech Pharmacal Co., Inc.Amityville, NY 11701MG #19296Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 Acyclovir oral suspension, USP (off-white, artificial banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL) – Bottle of 1 pint (473 mL)NDC 54868-5687-0Store at 20° - 25°C (68° to 77°F) [see USP Controlled Room Temperature].Manufactured by:Hi-Tech Pharmacal Co., Inc.Amityville, NY 11701MG #19296Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 Acyclovir oral suspension, USP (off-white, artificial banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL) – Bottle of 1 pint (473 mL)NDC 54868-5687-0Store at 20° - 25°C (68° to 77°F) [see USP Controlled Room Temperature].Manufactured by:Hi-Tech Pharmacal Co., Inc.Amityville, NY 11701MG #19296Relabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
The pharmacokinetics of acyclovir after oral administration have
been evaluated in healthy volunteers and in immunocompromised patients with
herpes simplex or varicella-zoster virus infection. Acyclovir pharmacokinetic
parameters are summarized in Table 1.
*Bioavailability decreases with increasing dose.
In one multiple-dose, cross-over study in healthy subjects (n = 23), it was
shown that increases in plasma acyclovir concentrations were less than dose
proportional with increasing dose, as shown in Table 2. The decrease in
bioavailability is a function of the dose and not the dosage form.
There was no effect of food on the absorption of acyclovir (n=6); therefore,
acyclovir oral suspension, USP may be administered with or without food.
The only known urinary metabolite 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 ).
Acyclovir plasma concentrations are higher in geriatric patients
compared with younger adults, in part due to age-related changes in renal
function. Dosage reduction may be required in geriatric patients with underlying
renal impairment (see :
Geriatric Use).
In general, the pharmacokinetics of acyclovir in pediatric
patients is similar to that of adults. Mean half-life after oral doses of 300
mg/m and 600 mg/m in pediatric
patients aged 7 months to 7 years was 2.6 hours (range 1.59 to 3.74
hours).
Coadministration of probenecid with intravenous acyclovir has
been shown to increase the mean acyclovir half-life and the area under the
concentration-time curve. Urinary excretion and renal clearance were
correspondingly reduced.
Double-blind, placebo-controlled studies have demonstrated that
orally administered acyclovir significantly reduced the duration of acute
infection and duration of lesion healing. The duration of pain and new lesion
formation was decreased in some patient groups.
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 10 years prevented or reduced
the frequency and/or severity of recurrences in greater than 95% of
patients.
In a study of patients who received orally administered acyclovir 400 mg
twice daily for 3 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 patients showed that 71% to 87% were
recurrence free in each quarter.
In a double-blind, placebo-controlled study of immunocompetent
patients with localized cutaneous zoster infection, 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 of viral shedding and the duration
of new lesion formation.
In a similar double-blind, placebo-controlled study, 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 formation;
and reduced the prevalence of localized zoster-associated neurologic symptoms
(paresthesia, dysesthesia, or hyperesthesia).
Treatment was begun within 72 hours of rash onset and was most effective if
started within the first 48 hours.
Adults greater than 50 years of age showed greater benefit.
Three randomized, double-blind, placebo-controlled trials were
conducted in 993 pediatric patients aged 2 to 18 years with chickenpox. All
patients were treated within 24 hours after the onset of rash. In 2 trials,
acyclovir was administrated at 20 mg/kg 4 times daily (up to 3,200 mg per day)
for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were administered 4
times daily for 5 to 7 days. Treatment with acyclovir shortened the time to 50%
healing; reduced the maximum number of lesions; reduced the median number of
vesicles; decreased the median number of residual lesions on day 28; and
decreased the proportion of patients with fever, anorexia, and lethargy by day
2. Treatment with acyclovir did not affect varicella-zoster virus-specific
humoral or cellular immune responses at 1 month or 1 year following treatment.
Non-Clinical Toxicology
Acyclovir is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir.Acyclovir is intended for oral ingestion only. Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see : Observed During Clinical Practice and ).
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy.
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving glipizide, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for loss of controlbinding studies with human serum proteins indicate that glipizide binds differently than tolbutamide and does not interact with salicylate or dicumarol. However, caution must be exercised in extrapolating these findings to the clinical situation and in the use of glipizide with these drugs.
Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glipizide, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for hypoglycemia.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known. The effect of concomitant administration of fluconazole and glipizide has been demonstrated in a placebo-controlled crossover study in normal volunteers. All subjects received glipizide alone and following treatment with 100 mg of fluconazole as a single daily oral dose for 7 days. The mean percentage increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35 to 81%).
Dosage adjustment is recommended when administering acyclovir to patients with renal impairment (see ). Caution should also be exercised when administering acyclovir 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 intravenous acyclovir. Adequate hydration should be maintained.
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 acyclovir, or they have any other questions.
Patients should be advised to maintain adequate hydration.
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.
Patients should be informed that acyclovir is not a cure for genital herpes. There are no data evaluating whether acyclovir 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 genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.
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.
See : Pharmacokinetics.
The data presented below include references to peak steady-state plasma acyclovir concentrations observed in humans treated with 800 mg given orally 5 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally 5 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 : 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. Maximum 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 16 and genetic toxicity assays. Acyclovir was positive in 5 of the assays.
Acyclovir did not impair fertility or reproduction in mice (450 mg/kg per day, PO) or in rats (25 mg/kg per 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 higher doses (50 mg/kg per day, SC) in rats and rabbits (11 to 22 and 16 to 31 times human levels, respectively) implantation efficacy, but not litter size, was decreased. In a rat peri- and post-natal study at 50 mg/kg per day, SC, there was a statistically significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses.
No testicular abnormalities were seen in dogs given 50 mg/kg per day, IV for 1 month (21 to 41 times human levels) or in dogs given 60 mg/kg per day orally for 1 year (6 to 12 times human levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.
Pregnancy Category B. Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg per day, PO), rabbit (50 mg/kg per day, SC and IV), or rat (50 mg/kg per day, SC). These exposures resulted in plasma levels 9 and 18, 16 and 106, and 11 and 22 times, respectively, human levels.
There are no adequate and well-controlled studies in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Acyclovir concentrations have been documented in breast milk in 2 women following oral administration of acyclovir and ranged from 0.6 to 4.1 times corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg per day. Acyclovir should be administered to a nursing mother with caution and only when indicated.
Safety and effectiveness of oral formulations of acyclovir in pediatric patients younger than 2 years of age have not been established.
Of 376 subjects who received acyclovir in a clinical study of herpes zoster treatment in immunocompetent subjects greater than or equal to 50 years of age, 244 were 65 and over while 111 were 75 and over. No overall differences in effectiveness for time to cessation of new lesion formation or time to healing were reported between geriatric subjects and younger adult subjects. The duration of pain after healing was longer in patients 65 and over. Nausea, vomiting, and dizziness were reported more frequently in elderly subjects. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events. With respect to CNS adverse events observed during clinical practice, somnolence, hallucinations, confusion, and coma were reported more frequently in elderly patients (see , : Observed During Clinical Practice, and ).
The most frequent adverse events reported during clinical trials of treatment of genital herpes with acyclovir 200 mg administered orally 5 times daily every 4 hours for 10 days were nausea and/or vomiting in 8 of 298 patient treatments (2.7%). Nausea and/or vomiting occurred in 2 of 287 (0.7%) patients who received placebo.
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%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with acyclovir for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%).
The most frequent adverse event reported during 3 clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral acyclovir 5 times daily for 7 to 10 days in 323 patients was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%).
The most frequent adverse event reported during 3 clinical trials of treatment of chickenpox with oral acyclovir at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days or 800 mg 4 times daily for 5 days in 495 patients was diarrhea (3.2%). The 498 patients receiving placebo reported diarrhea (2.2%).
In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of acyclovir. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to acyclovir, or a combination of these factors.
Anaphylaxis, angioedema, fever, headache, pain, peripheral edema.
Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with renal impairment (see ).
Diarrhea, gastrointestinal distress, nausea.
Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia.
Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice.
Myalgia.
Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens- Johnson syndrome, toxic epidermal necrolysis, urticaria.
Visual abnormalities.
Renal failure, renal pain (may be associated with renal failure), elevated blood urea nitrogen, elevated creatinine, hematuria (see ).
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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