Zevin

Aciclovir.

ZEVIN 200 mg: Round, flat, blue tablet, impressed "BIOLAB" on one face and bisect on the obverse.
Each tablet contains aciclovir 200 mg.
ZEVIN 400 mg: Oblong, biconvex, blue tablet, impressed "400" on one face and "BIOLAB" on the obverse.
Each tablet contains aciclovir 400 mg.
ZEVIN 800 mg: Oblong, biconvex, white tablet, impressed "BIOLAB" on one face and "800" on the obverse.
Each tablet contains aciclovir 800 mg.

Pharmacology: Pharmacodynamics: Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus type 1 (HSV-1), 2 (HSV-2) and varicella zoster virus (VZV). In cell culture, aciclovir's highest antiviral activity is against HSV-1, followed in decreasing order of potency against HSV-2 and VZV.
The inhibitory activity of aciclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts aciclovir into aciclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. The formation of aciclovir monophosphate appears to be the rate-limiting step in the formation of aciclovir triphosphate.
Aciclovir also is apparently converted to aciclovir triphosphate by other mechanisms since the drug has some activity against several viruses that apparently do not code for viral TK.
In vitro, aciclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: competitive inhibition of viral DNA polymerase; incorporation into and termination of the growing viral DNA chain; and inactivation of the viral DNA polymerase.
Pharmacokinetics: Absorption: Aciclovir is only partially absorbed from the gut. The average oral bioavailability varies between 10% and 20% (bioavailability decrease with increased dose). Mean peak plasma concentration shown as follows: Css_max: at 200 mg is 0.83 mcg/ml; at 400 mg is 1.21 mcg/ml; at 800 mg is 1.61 mcg/ml.
Css_trough: at 200 mg is 0.46 mcg/ml; at 400 mg is 0.63 mcg/ml; at 800 mg is 0.83 mcg/ml.
Poorly absorbed, absorption improves with multiple small doses compared to one large daily dose.
Distribution: Plasma protein binding of aciclovir is relatively low between 9% to 33%. Cerebrospinal fluid concentration is approximately 50% of corresponding plasma concentration at steady-state.
V_dss: Neonates to 3 months of age: 28.8 L/1.73 m².
Children 1 to 2 years: 31.6 L/1.73 m².
Children 2 to 7 years: 42 L/1.73 m².
Adult: 0.8 L/kg.
Metabolism: Aciclovir is converted by viral enzymes to aciclovir monophosphate, and further converted to diphosphate then triphosphate (active form) by cellular enzymes. The only significant urinary metabolite is 9-[(carboxymethoxy)methylguanine].
Excretion: Excrete as unchanged and metabolite form in urine between 62% to 91%. Plasma elimination half-life is 2.5 to 3.3 hours.
Special patient populations: Renal function impairment: The half-life and total body clearance of aciclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function.
Elderly: Aciclovir plasma concentrations are higher in elderly patients compared with younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in elderly patients with underlying renal impairment.

Treatment of herpes simplex virus infections of the skin and mucous membranes including initial and recurrent genital herpes.
Prophylaxis of herpes simplex infections in immunocompromised patients.
Treatment of varicella (chickenpox) infection.
Treatment of Herpes zoster: Acute treatment of herpes zoster (shingles).

Recommended Dose: Adult: Genital Herpes simplex: Immunocompetent patients: Treatment, initial episode: Oral 400 mg 3 times daily or 200 mg 5 times daily for 7 to 10 days, extend duration if lesions have not healed completely after 10 days.
Recurrent episode: Oral 400 mg 3 times daily for 5 days or 800 mg twice daily for 5 days or 800 mg 3 times daily for 2 days.
Immunocompromised patients (including HIV-infected): Treatment initial or recurrent episode: Oral 400 mg 3 times daily for 5 to 10 days; extend treatment duration if lesions have not healed completely after 10 days.
Herpes simplex, prophylaxis in the immunocompromised: Oral 200-400 mg 4 times a day.
Oralabial Herpes simplex: Initiate therapy at earliest symptom. Immunocompetent and immunocompromised patients (including HIV-infected): Treatment, initial or recurrent episode: Oral 400 mg 3 times daily for 5 to 10 days and until complete lesion resolution.
Herpes zoster: Immunocompetent patients: Oral 800 mg 5 times daily for 7 days. Initiate at earliest sign or symptom; treatment is most effective when initiated ≤72 hours after rash onset.
Immunocompromised patients: Oral 800 mg 5 times daily for 7 to 10 days; consider longer duration if lesions resolve slowly.
Varicella (chickenpox): Ideally initiate therapy within 24 hours of symptom onset: Immunocompetent patients: Oral 800 mg 5 times daily for ≥5 to 7 days and until all lesions have crusted.
Uncomplicated infection: Oral 800 mg 5 times daily for 5 to 7 days, extending the course until all lesions have crusted.
Paediatric: Oralabial Herpes simplex: A dosage of 15 mg/kg (up to 200 mg) 5 times daily for 7 days in immunocompetent children age 1-6 years of age.
Genital Herpes simplex: In immunocompetent, 12 years and older recommended dose is 1000 to 1200 mg/day in 3 to 5 divided doses for 7 to 10 days.
Younger than 12 years recommended dose is 40 to 80 mg/kg/day divided into 3 to 4 doses for 5 to 10 days.
Herpes Zoster: In immunocompetent children 12 years of age or older, the recommended oral dosage of aciclovir is 800 mg every 4 hours 5 times daily for 5-10 days. Initiated within 48 hours of rash onset.
Varicella-Zoster: Children weigh more than 40 kg receive 800 mg orally 4 times daily for 5 days, 2 years of age and older weighing 40 kg or less receive 20 mg/kg 4 times daily (maximum daily dosage 80 mg/kg) for 5 days.
Elderly: Refer to adult dosing; use with caution.
Renal impairment: See table.

Click on icon to see table/diagram/image

Mode of Administration: Aciclovir is an oral administration.
Food does not appear to affect oral absorption of aciclovir, and the drug may be administered without regard to meals.

Symptoms and signs: Aciclovir has been reported following administration inappropriately high doses and in patients with fluid and electrolyte imbalance, resulting in elevations in BUN and serum creatinine concentration and subsequent renal failure. Other adverse effects reported with aciclovir overdosage include agitation, coma, lethargy, and seizures. At renal concentration exceeding 2.5 mg/ml, aciclovir crystals may precipitate in the renal tubules, possibly causing renal dysfunction and eventual renal failure and anuria.
Treatment: Use of hemodialysis should be considered until renal function is restored. A 6-hour period of hemodialysis may result in a 60% decrease in plasma aciclovir concentrations. Patients should be observed closely for signs of toxicity.

Hypersensitivity to the aciclovir, valaciclovir or to any of the excipients.

Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, which has resulted in death, has occurred in immunocompromised patients receiving aciclovir therapy.
Renal effect: Renal failure, in some cases resulting in death, has been observed with aciclovir therapy.
Herpes zoster: There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Advise patients to initiate treatment as soon as possible after a diagnosis of herpes zoster.
Genital herpes infection: Inform patients that aciclovir is not a cure for genital herpes. There are no data evaluating whether aciclovir will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease, advise patients to 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, advise patients to initiate therapy at the first sign or symptom of an episode.
Chickenpox: Chickenpox in otherwise healthy children is usually a self-limited disease of mild to moderate severity. Adolescents and adult tend to have more severe disease. Treatment was initiated within 24 hours of typical chickenpox rash in the controlled studies, and there is no information regarding the effects of treatment begun later in the disease course.
Renal function impairment: Dosage adjustment is recommended when administering aciclovir to patients with renal impairment. Caution should also be exercised when administering aciclovir to patients receiving potentially nephrotoxicity agents because this may increase the risk of renal dysfunction.
Neurotoxicity: Neurotoxicity (eg, tremor/myoclonus, confusion, agitation, lethargy, hallucination and impaired consciousness) may be increased with higher doses and in patients with renal failure. Monitor patients for signs/symptoms of neurotoxicity; ensure appropriate dosage reductions in patients with renal impairment.
Varicella: For maximum benefit, treatment should begin within 24 hours of appearance of rash; oral route not recommended for routine use in otherwise healthy children with varicella but may be effective in patients at increased risk of moderate to severe infection (>12 years of age, chronic cutaneous or pulmonary disorders, long-term salicylate therapy, corticosteroid therapy).
Potentially significant drug-drug interaction may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy.
Use in the Elderly: The duration of pain after healing was longer in patients 65 years and older. 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.

Pregnancy: There are no adequate and controlled studies to date using aciclovir in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.
Aciclovir is pregnancy category B. Aciclovir has been shown to cross the human placenta. Results from a pregnancy registry, established in 1984 and closed in 1999, did not find an increase in the number of birth defects with exposure to aciclovir when compared to those expected in the general population.
Lactation: Limited data indicate that aciclovir is distributed into milk, generally in concentration greater than concurrent maternal plasma concentrations, and can be absorbed by nursing infants. Aciclovir should be administered to nursing women with caution and only when indicated.

Central nervous system: Headache, malaise.
Dermatologic: Pruritus, skin rash, urticaria.
Gastrointestinal: Diarrhea, nausea, vomiting.
Hematologic: Decrease in absolute neutrophil count, decrease hemoglobin, thrombocytopenia.
Hepatic: Increased serum bilirubin, increased serum transaminases.
Renal: Increased blood urea nitrogen, increased serum creatinine.
Rare but important or life-threatening: Abdominal pain, aggressive behavior, agitation, alopecia, anaphylaxis, anemia, angioedema, anorexia, ataxia, coma, confusion, delirium, disseminated intravascular coagulation, dizziness, drowsiness, dysarthria, encephalopathy, erythema multiforme, fatigue, fever, gastrointestinal distress, hallucination, hematuria, hemolysis, hepatitis, hyperbilirubinemia, hypersensitivity angiitis, hypotension, impaired consciousness, increased liver enzymes, jaundice, leukocytosis, leukopenia, lymphadenopathy, myalgia, neutropenia, neutrophilia, obtundation, pain, paresthesia, peripheral edema, psychosis, renal failure syndrome, seizure, skin photosensitivity, Stevens-Johnson syndrome, thrombocythemia, toxic epidermal necrolysis, tremor, visual disturbance.

Aciclovir may interact with the following as follows: Foscarnet: May enhance the nephrotoxic effect of aciclovir.
Mycophenolate: Aciclovir may increase the serum concentration of mycophenolate.
Mycophenolate may increase the serum concentration of aciclovir.
Talimogene laherparepvec: Antiherpetic antivirals may diminish the therapeutic effect of talomogene laherparepvec.
Tenofovir Products: Aciclovir may increase the serum concentration of tenofovir products. Tenofovir products may increase the serum concentration of aciclovir.
Varicella Virus Vaccine: Aciclovir may diminish the therapeutic effect of varicella virus vaccine.
Zoster Vaccine: Aciclovir may diminish the therapeutic effect of zoster vaccine.
Antifungal Agents: Amphotericin B has been shown to potentiate the antiviral effect of aciclovir against pseudorabies virus in vitro when both drugs are added to the culture medium. Ketoconazole and aciclovir have shown dose-dependent, synergistic, antiviral activity against herpes simplex virus type 1 and 2 (HSV-1 and 2) in in vitro replication studies. The clinical importance of these interactions has not been established, and additional study is necessary to determine potential antiviral synergy between these antifungal agents and aciclovir.
Probenecid: Concomitant administration of probenecid and aciclovir has reportedly increased the mean plasma half-life and area under the plasma concentration-time curve (AUC) and decreased urinary excretion and renal clearance of aciclovir. In one study following oral administration of a 1 g dose of probenecid 1 hour prior to a 1 hour IV infusion of aciclovir 5 mg/kg, the half-life and AUC for aciclovir increased by 18% and 40%, respectively, and urinary excretion and renal clearance of aciclovir decrease by 13% and 32%, respectively. This interaction may result from competitive inhibition of the renal secretion of aciclovir by probenecid.
Interferon: IV aciclovir should be used with caution in patients receiving interferon. In vitro, when aciclovir and interferon are both added cultures of herpes simplex virus type 1 (HSV-1), the drugs have an additive or synergistic antiviral effect; however, the clinical importance of this interaction is not known.
Methotrexate: IV aciclovir should be used with caution in patients receiving intrathecal methotrexate.
Zidovudine: Aciclovir has been used concomitantly with zidovudine in some patients with human immunodeficiency virus (HIV) infections without evidence of increased toxicity; however, neurotoxicity (profound drowsiness and lethargy), which recurred on rechallenge, has been reported in at least one patient with acquired immunodeficiency syndrome (AIDS) during concomitant therapy with the drugs. Neurotoxicity was evident within 30-60 days after initiation of IV aciclovir therapy, persisted with some improvement when aciclovir was administered orally, and resolved following discontinuance of aciclovir in this patient.

Store at temperature not exceeding 30°C.

Antivirals

J05AB01 - aciclovir ; Belongs to the class of nucleosides and nucleotides excluding reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.

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