Approved on.
Date of revision.
Acyclovir Tablets InstructionsPlease read the instructions carefully and use under the guidance of a physician =”font-size:22pt”>
[Drug Name].
Generic Name: Aciclovir Tablets
English Name: Aciclovir Tablets
Hanyu Pinyin: Axiluowei Pian
[Ingredients].
The main ingredient of this product is acyclovir.
The chemical name is 9-(2-hydroxyethoxymethyl)guanine.
Chemical structure formula.
Molecular formula: C8H11N5O3
Molecular weight: 225.21
[Properties] This product is a white or off-white tablet.
[Indications
This product is indicated for the treatment of the following diseases.
1. Acute herpes zoster: for the treatment of acute herpes zoster.
2. Genital herpes: for the treatment of incipient and recurrent genital herpes.
3. Chickenpox: for the treatment of chickenpox.
[Specifications].
0.1g
[dosage].
Orally, the dose is as follows.
(a) Commonly used dose
1. Acute herpes zoster: 0.2g~0.8g per time for adults, once every 4 hours, 5 times a day, for 7-10 days.
2. Genital herpes.
Incipient genital herpes: 0.2g for adults every 4 hours, 5 times a day for 10 days.
Chronic suppressive therapy for recurrent genital herpes: adults 0.2 g to 0.4 g per dose twice daily for 4 to 6 months or 12 months of continuous treatment for re-evaluation. Based on the results of re-evaluation, a treatment regimen of 0.2g per dose, 3 times daily, or 0.2g per dose, 5 times daily will be selected. The frequency and severity of episodes of untreated genital herpes may change over time. After 1 year of treatment, the frequency and severity of episodes in people with genital herpes infection are re-evaluated to determine whether to continue treatment with this product.
Intermittent treatment: If a recurrence of genital herpes is detected, patients are advised to start treatment at the first sign or symptom detected. Adults take 0.2 g every 4 hours, 5 times a day for 5 days.
3. Chickenpox.
Children (2 years and older): 20 mg/kg each time, 4 times daily, for a total of 80 mg/kg/day for 5 days. children over 40 kg should receive the adult dose for varicella.
Adults and children over 40 kg: 0.8 g per dose, 4 times daily for 5 days.
(ii) Dose adjustment
1. Patients with acute or chronic renal impairment: see the table below for dosage for such patients.
Dose adjustment for patients with renal impairmentCommon dosageCreatinine clearance
(ml/min/1.73m2)Dose adjustment schemeDose (g)Dosing interval0.2g every 4 hours>10
0-100.2
0.2every 4 hours. 5 times a day
every 12 hours, twice a day0.4g per session, every 12 hours>10
0-100.4
0.2every 12 hours. 2 times daily
every 12 hours, twice a day0.8g per session, every 4 hours>25
10-25
0-100.8
0.8
0.8every 4 hours 5 times a day
every 8 hours, 3 times a day
every 12 hours, twice daily2. Hemodialysis: For patients requiring hemodialysis The average half-life of acyclovir in plasma during hemodialysis is approximately 5 h. Six hours of hemodialysis decreases the blood concentration by 60%, so the patient’s dose should be adjusted additionally after each dialysis session.
3. Peritoneal dialysis: no dose adjustment during dosing is required.
[Adverse Reactions
The frequency divisions associated with the following adverse events are estimates. For most events, there are no appropriate data to estimate the incidence. In addition, the incidence of adverse events may vary by indication.
The frequency of occurrence is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), rare (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), and very rare (<1/10,000).
Hematologic and lymphatic system disorders.
Very rare: anemia, leukopenia, thrombocytopenia
Immune system disorders.
Rare: allergic reactions
Psychiatric and neurological disorders.
Common: headache, dizziness
Very rare: agitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, convulsions, somnolence, encephalopathy, coma.
The above events are usually reversible and are usually reported in patients with renal insufficiency or in the presence of other predisposing factors (see [Precautions]).
Respiratory, thoracic, and mediastinal disease.
Rare: dyspnea
Gastrointestinal disorders.
Common: nausea, vomiting, diarrhea, abdominal pain
Diseases of the hepatobiliary system.
Rare: reversible elevation of bilirubin and liver enzymes
Very rare: hepatitis, jaundice
Dermal and subcutaneous tissue disorders.
Common: pruritus, rash (including photosensitivity)
Rare: urticaria, accelerated diffuse alopecia. Accelerated diffuse alopecia is associated with multiple disease processes and medications, and the relationship to acyclovir treatment is uncertain.
Rare: angioedema
Renal and urologic disorders.
Rare: elevated blood urea and creatinine
Very rare: acute renal failure, nephrosis
Renalgia may be associated with renal failure and crystalluria.
Systemic and site of administration diseases.
Common: fatigue, fever
[Contraindicated].
Contraindicated in patients with hypersensitivity to acyclovir or valacyclovir.
[Precautions
1. Warning.
Patients treated with acyclovir are at risk for renal failure, which can lead to death in some cases (see [Adverse Reactions]).
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) has occurred in immunocompromised patients treated with acyclovir and has resulted in death.
2. Dose adjustment is recommended when acyclovir is administered to patients with renal impairment. Older patients may have decreased renal function, and again the need for dose adjustment must be considered. Both elderly patients and patients with renal impairment are at increased risk for neurologic side effects and should be monitored closely. In reported cases, these reactions are usually reversible after discontinuation of therapy (see [Adverse Reactions]). Caution should also be exercised when administering acyclovir to patients who are receiving a potentially nephrotoxic drug, as this may increase the risk of renal dysfunction and/or increase the risk of reversible CNS symptoms (such as those already reported in patients receiving intravenous acyclovir). Adequate hydration should be maintained.
3. In patients with severely compromised immune function, prolonged or repeated treatment with acyclovir may lead to viral strain resistance, and continued treatment with acyclovir may be ineffective.
4. There are no data on treatment initiation after more than 72 hours of shingles flare-ups. Patients are advised to treat shingles as early as possible after the diagnosis is made.
5. This product does not cure genital herpes. There are no data to prove whether this product prevents transmission of the infection. Genital herpes is a sexually transmitted disease, so patients should avoid contact with the affected area or sexual intercourse when lesions and/or symptoms are present to avoid infecting their partners. Genital herpes can also be transmitted without symptoms through asymptomatic shedding of the virus. If a recurrence of genital herpes is detected, patients are advised to start treatment at the first sign or symptom detection.
6. In healthy children, chickenpox presents as a self-limiting mild to moderate disease, whereas it is more severe in adolescents and adults. In controlled studies, treatment was administered within 24 hours of the appearance of a typical varicella rash, and there is no information on the effectiveness of starting treatment late in the onset of the disease. The data available from clinical studies are not sufficient to determine that treatment with acyclovir reduces the incidence of varicella-related complications in immunocompetent patients.
7. Effects on driving ability and ability to operate machinery: The effects of acyclovir on the ability to drive or operate machinery have not been studied. However, this product may cause adverse effects such as impaired consciousness, so caution should be exercised when taking this product in situations such as driving a car or operating dangerous machinery.
8. Patients who feel they have had a serious or bothersome adverse reaction, are pregnant or planning to become pregnant, are planning to breastfeed, or have other problems should consult their doctor and use the drug appropriately under medical supervision.
[For pregnant and lactating women
Pregnancy.
Acyclovir 450 mg/kg/day (oral), 50 mg/kg/day (subcutaneous or intravenous), and 50 mg/kg/day (subcutaneous) given to mice, rabbits, and rats during organogenesis have not been shown to be teratogenic, with plasma exposures 9 to 18, 16 to 106, and 11 to 22 times higher than those in humans, respectively.
Adequate and well-controlled studies have not been performed in women during pregnancy. A prospective epidemiologic record of acyclovir use in pregnant women was established from 1984 to April 1994. Seven hundred and fifty-six outcomes were derived from 749 pregnant women in whom systemic exposure to acyclovir occurred early in pregnancy. The incidence of birth defects was close to that of the general population. However, small records are insufficient to evaluate the less common defects and to draw reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and fetal development. Acyclovir should be considered for use during pregnancy only if the potential benefits of acyclovir outweigh the potential harms to the fetus.
Lactating women.
Acyclovir has been detected in the breast milk of 2 women following oral acyclovir at concentrations ranging from 0.6 to 4.1 times the corresponding plasma concentration. Such concentrations may result in an acyclovir exposure dose of 0.3 mg/kg/day for the nursing infant. Acyclovir should be used with caution during lactation and only when indicated for dosing.
[Pediatric Dosage].
The safety and efficacy of oral formulations of acyclovir in pediatric patients less than 2 years of age have not been established.
[Geriatric Use
In a clinical study of herpes zoster treatment, 376 immunocompetent subjects aged ≥50 years were treated with acyclovir, 244 were aged 65 years and older, and 111 were aged 75 years and older. No overall differences in effectiveness in terms of time to cessation of new lesion formation or time to healing were reported between older subjects and younger adult subjects. the duration of pain after healing was longer in subjects 65 years of age and older. Nausea, vomiting and dizziness were reported more frequently in older subjects. Older patients were more likely to have reduced renal function and required dose reduction. Elderly patients are also more likely to experience renal or central nervous system adverse events. CNS adverse events observed in clinical practice, drowsiness, hallucinations, confusion, and coma were reported more frequently in elderly patients (see [ADVERSE REACTIONS]).
[Drug Interactions
Medication nameClinical symptoms and measuresMechanisms and risk factorsProbenecidInhibition of the excretion of this product. An 18% prolongation of the mean half-life and a 40% increase in the mean area under the plasma concentration curve have been reported for this product in plasma. Probenecid inhibits renal tubular secretion of OAT1 and MATE1, thereby inhibiting renal excretion of the drug (see “Pharmacokinetics”). CimetidineInhibition of acyclovir excretion. A 27% increase in the area under the mean plasma concentration curve was reported (data for valacyclovir hydrochloride). Inhibition of renal tubular secretion of OAT1, MATE1, and MATE2-K. Cimetidine inhibits renal excretion of acyclovir (see “Pharmacokinetics”). MycophenolateThe excretion of this product and mycophenolate metabolites are mutually inhibited. An increase in the mean area under the curve has been reported for both. The product competes with mycophenolate metabolites for excretion via renal tubular secretion. TheophyllineCo-administration with this product may cause symptoms of theophylline toxicity. Although the mechanism is unknown, it is predicted that this product inhibits the metabolism of theophylline, thereby increasing the blood levels of theophylline. ZidovdinCo-administration with this product can cause nephrotoxicity, manifested by profound drowsiness and fatigue. Interferon or methotrexate (intrathecal)Co-administration with this product may cause psychiatric abnormalities. Note: Particularly in patients with decreased renal function (elderly, etc.) should be administered with caution.
[Drug overdose
Overdoses of up to 100 capsules (20 g) have been reported. Adverse events associated with overdose have been reported including agitation, coma, seizures, and drowsiness. Acyclovir may precipitate in the renal tubules when fluid solubility in the renal tubules exceeds 2.5 mg/ml. Drug overdose has been reported when administered by intravenous push or at inappropriately high doses and when fluid and electrolyte balance are not properly monitored. This can lead to elevated urea nitrogen and serum creatinine, followed by renal failure. If acute renal failure and anuria occur, the patient is placed on hemodialysis until renal function is restored (see [DOSAGE]).
[Pharmacology and Toxicology].
Pharmacology
Mechanism: Acyclovir is a synthetic nucleoside antiviral that inhibits herpes simplex virus type I (HSV-1), type II (HSV-2), and varicella-zoster virus (VZV) in vivo and in vitro.
The affinity of acyclovir for the thymidine kinase (TK) encoded by HSV and VZV makes it a highly selective inhibitor. Such viral enzymes convert acyclovir to acyclovir monophosphates, the nucleoside analogs. The monophosphate is further converted to diphosphate by guanylate kinase in the cell, and then to triphosphate by a variety of enzymes in the cell. In vitro, abrogation of herpesvirus DNA replication by acyclovir triphosphate is accomplished in three ways: 1) competitive inhibition of viral DNA polymerase; 2) entry and termination of the extended viral DNA strand; and 3) inactivation of viral DNA polymerase. The antiviral activity of acyclovir against HSV is more potent than that against VZV because of the stronger phosphorylation of HSV TK by acyclovir.
Antiviral activity: The quantitative relationship between in vitro susceptibility of herpesviruses to antivirals and clinical response to treatment has not been established in humans, and viral susceptibility testing has not been standardized. Susceptibility test results (expressed as IC50) can vary considerably depending on a number of factors. In the phagocytosis reduction assay, the IC50 of herpes simplex virus isolates ranged from 0.02 to 13.5 µg/ml for HSV-1 and from 0.01 to 9.9 µg/ml for HSV-2. The IC50 of acyclovir against most laboratory strains and clinical isolates of VZV ranged from 0.12 to 10.8 µg /ml. Acyclovir also showed activity against the Oka vaccine strain of VZV, with an average IC50 of 1.35 µg/ mL.
Resistance: Qualitative and quantitative changes in viral TK and/or DNA polymerase can lead to resistance of HSV and VZV to acyclovir. In immunocompromised individuals, particularly those with advanced HIV infection, clinical isolates of HSV and VZV have been found to have reduced susceptibility to acyclovir. Although most of the acyclovir-resistant mutants isolated to date in these patients have been TK-deficient mutants, other mutants involving the viral TK gene (TK incomplete and TK altered) and DNA polymerase have been isolated. In infants and immunocompromised adults, TK-negative mutants may lead to severe disease. The possibility of viral resistance to acyclovir should be considered in patients who have had a poor clinical response during treatment.
Toxicology studies
The following data describe steady-state peak plasma acyclovir concentrations measured in reference humans at 800 mg orally five times daily (for herpes zoster) and 200 mg orally five times daily (for genital herpes), expressed as multiples of acyclovir exposure in animal studies under human high-dose and low-dose dosing regimens.
Genotoxicity: Acyclovir was tested in 16 genotoxicity tests, 5 of which were positive.
Reproductive toxicity: No impairment of fertility or reproductive function was seen with acyclovir in mice (450 mg/kg/day, administered orally) and rats (25 mg/kg/day, administered subcutaneously). Blood levels in mice and rats were 9 to 18 and 8 to 15 times higher than in humans, respectively. Higher doses in rats and rabbits (50 mg/kg/day, subcutaneously, blood concentrations 11-22 and 16-31 times those in humans, respectively) reduced the fecundity rate, but did not affect litter size. In rats, a statistically significant decrease in mean number of corpus luteum, total number of loci, and surviving litters was seen when acyclovir 50 mg/kg/day was administered subcutaneously during the perinatal period.
No testicular abnormalities were seen in dogs given intravenous acyclovir 50 mg/kg/day for 1 month (blood levels 21 to 41 times that of humans) or orally for 1 year (blood levels 6 to 12 times that of humans). Testicular atrophy and sperm reduction were seen in rats and dogs at higher doses.
Acyclovir 450 mg/kg/day (oral), 50 mg/kg/day (subcutaneous or intravenous), and 50 mg/kg/day (subcutaneous) were not teratogenic in mice, rabbits, and rats given during the organogenesis phase, with plasma exposures 9 to 18, 16 to 106, and 11 to 22 times those of humans, respectively.
Carcinogenicity: No statistical difference was seen in the incidence of tumors between the administered and control animals in a once-daily tube-fed administration of acyclovir up to a maximum dose of 450 mg/kg in a lifetime test in rats and mice, and no shortening of the latency period for tumor development was seen. The maximum plasma concentrations in mice and rats were 3 to 6 times and 1 to 2 times higher than in humans, respectively.
[Pharmacokinetics
Absorption
A single oral dose of 0.2 g and 0.8 g of acyclovir in healthy adults reached maximum plasma concentrations of 0.63 μg/ml and 0.94 μg/ml, respectively, 1.3 hours after dosing, with a half-life of approximately 2.5 hours for plasma concentrations. The mean peak concentrations after 3 days were 0.77-0.85 μg/ml and mean trough concentrations were 0.41-0.45 μg/ml for 0.2 g/4h, 5 times a day, administered orally continuously to healthy adults; mean peak concentrations were 2.02-2.31 μg/ml and mean trough concentrations were 1.18-1.36 μg/mL for 0.8 g administered orally continuously in the same manner.
Metabolism, excretion
A single oral dose of acyclovir 0.2 g and 0.8 g was administered to healthy adults, and 25.0% and 12.0% of the administered dose was excreted in the urine in its original form within 48 hours. When administered orally, the urinary metabolite 9-carboxymethoxymethylguanine accounted for approximately 7.5% of the administered dose.
Distribution (data from abroad)
(1) Concentration of acyclovir in blisters and transfer in vaginal secretions
Acyclovir concentrations in blisters were essentially the same as those in plasma when acyclovir was administered orally at 0.2 g per day/4h continuously. When acyclovir was given orally continuously for 10 days at 0.2g/dose,5 times a day, the drug was transferred to vaginal secretions (0.5-1 h after dosing: approximately 0.43 μg/g).
(2) Breast milk transfer
Acyclovir 0.2 g/dose, after 5 doses in 1 day, the concentration of acyclovir in breast milk was 0.6 to 4.1 times higher than that in plasma, up to about 1.31 μg/mL (3 hours after 0.2 g dosing).
Pharmacokinetics in patients with renal insufficiency (data from abroad)
Prolonged half-life and decreased systemic clearance of acyclovir in vivo with intravenous infusion in patients with renal insufficiency. Based on these results, dose adjustment is recommended for patients with renal insufficiency (see “Dosage”).
In patients with severe renal dysfunction, acyclovir 2.5 mg/kg was administered intravenously for 1 hour, and plasma concentrations were reduced by approximately 60% after 6 hours of hemodialysis.
Pharmacokinetics of pediatric dosing
The pharmacokinetics of acyclovir 0.2 g in a single oral dose in children 6 years of age and older are similar to those in adults. Absorption is the same in children with bone marrow transplantation as in other patients, with creatinine clearance values of 40 to 60 ml/min/1.48 m2 in some children with serum concentrations of 2.25 μg/mL or more.
[Storage]Seal and store.
[Packaging】 Polyvinyl chloride/polyvinylidene chloride solid pharmaceutical laminated rigid tablets/aluminum foil for pharmaceutical packaging, 24 tablets/plate x 1 plate/box, 24 tablets/plate x 2 plates/box. .
[Expiration date] 12 months
[Executive Standard]
[Approval Number】 State Drug Administration H10983103
[Manufacturer]
Company name: Sichuan Keren Pharmaceutical Co.
Production Address: Ziyang Economic and Technological Development Zone Anyue Industrial Park (Shiqiaopu Town, Anyue County)
Postal code: 642350
Phone number: 028-86130259
Fax number: 028-86139152
Website: http://www.kelun.com