Acyclovir

Acyclovir Sodium Injection is indicated for: • the treatment of initial and recurrent mucosal and cutaneous herpes simplex (HSV-1 and HSV-2) infections and varicella-zoster (shingles) infections in immunocompromised adults and children.

• severe initial episodes of herpes simplex infections in patients who may not be immunocompromised. 1 Pediatrics Pediatrics (1 year to < 18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Acyclovir Sodium Injection in pediatric patients aged 1 year to < 18 years of age has been established.

Therefore, Health Canada has authorized an indication for pediatric use in patients aged 1 year to < 18 years. 2 Geriatrics Geriatrics: Acyclovir plasma concentrations are higher in geriatric patients compared with younger adults, in part due to age-related changes in renal function.

1 Dosing Considerations Caution: Acyclovir Sodium Injection is for slow intravenous infusion only, over a period of at least 1 hour. Healing Process Because complete re-epithelialization of herpes-disrupted integument necessitates recruitment of several complex repair mechanisms, the physician should be aware that the disappearance of visible lesions is somewhat variable and will occur later than the cessation of virus excretion.

Diagnosis Acyclovir Sodium Injection Page 5 of 36 Whereas cutaneous lesions associated with herpes simplex and varicella-zoster infections are often pathognomonic, Tzanck smears prepared from lesion exudate or scrapings may assist in diagnosis.

Positive cultures for herpes simplex virus offer the only absolute means for confirmation of the diagnosis. Appropriate examinations should be performed to rule out other sexually transmitted diseases. The Tzanck smear does not distinguish varicella-zoster from herpes simplex infections.

2 Recommended Dose and Dosage Adjustment Herpes Simplex Infections Mucosal and Cutaneous Herpes Simplex (HSV-1 and HSV-2) in Immunocompromised Patients: Adults: 5 mg/kg infused at a constant rate over at least 1 hour, every 8 hours for 7 days in adult patients with normal renal function.

Pediatric patients aged 1 year to < 18 years: equivalent plasma concentrations are attained by infusing 250 mg/m2 at a constant rate over at least 1 hour, every 8 hours for 7 days.

Severe Initial Clinical Episodes of Herpes Genitalis in Immunocompetent Patients:

The same dose given above, administered for 5 days.

Varicella Zoster Infections Zoster in Immunocompromised Patients:

Adults: 10 mg/kg infused at a constant rate over at least 1 hour, every 8 hours for 7 days in adult patients with normal renal function. Pediatric patients aged 1 year to < 18 years: equivalent plasma concentrations are attained by infusing 500 mg/m2 at a constant rate over at least 1 hour, every 8 hours for 7 days.

Obese patients should be dosed at 10 mg/kg (Ideal Body Weight). A maximum dose equivalent to 500 mg/m2 every 8 hours should not be exceeded for any patient. Patients with Acute or Chronic Renal Impairment Use the recommended doses and method of administration; and adjust the dosing interval as indicated in the following table.

73 m2) Percent of Recommended Dose Dosing Interval (hours) Acyclovir Sodium Injection Page 6 of 36 > 50 100 8 25 to 50 100 12 10 to 25* 100 24 0 to 10* 50 24 to 48 *Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of acyclovir during dialysis is approximately 5 hours, which results in a 60% decrease in plasma concentrations following a 6-hour dialysis period.

Recommended doses should be administered every 24 to 48 hours, and after hemodialysis. 3 Reconstitution Diluted Solutions for Intravenous Infusion The calculated dose of the solution should be removed and added to an appropriate intravenous solution listed below at a volume selected for administration during each 1-hour infusion.

Infusion concentrations exceeding 10 mg/mL are not recommended. Since the solution does not contain any preservatives, any unused portion of the vial should be discarded (see 11 STORAGE, STABILITY AND DISPOSAL). 9% Sodium Chloride Injection Normal Saline Injection Lactated Ringer's Injection Once diluted, the admixtures are to be administered within 24 hours of the initial preparation.

The admixtures are not to be refrigerated. The diluted solution should be inspected visually for discolouration, haziness, particulate matter and leakage prior to administration. Discard unused portion. ,blood products, protein hydrolysates or amino acids, fat emulsions).

, 10 CLINICAL PHARMACOLOGY, and 14 CLINICAL TRIALS). 4 Geriatrics Clinical studies of Acyclovir Sodium Injection did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased renal function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 2 Clinical Trial Adverse Reactions Adult and Pediatric Clinical Trials The adverse reactions listed below have been observed in controlled and uncontrolled clinical trials in approximately 700 patients who received acyclovir at approximately 5 mg/kg (250 mg/m2) and approximately 200 patients who received approximately 10 mg/kg (500 mg/m2).

The most frequent adverse reactions reported during intravenous acyclovir administration were inflammation or phlebitis at the injection site in approximately 9% of the patients, and transient elevations of serum creatinine or BUN in 5% to 10% [the higher incidence occurred usually following rapid (< 10 minutes) intravenous infusion].

Nausea and/or vomiting occurred in approximately 7% of the patients (the majority occurring in non-hospitalized patients who received 10 mg/kg). Itching, rash or hives occurred in approximately 2% of patients. Elevation of transaminases occurred in 1 to 2% of patients.

Approximately 1% of patients receiving intravenous acyclovir have manifested encephalopathic changes characterized by either lethargy, obtundation, tremors, confusion, hallucinations, agitation, seizures or coma (see 7 WARNINGS AND PRECAUTIONS).

3 Less Common Clinical Trial Adverse Reactions Adverse reactions which occurred at a frequency of less than 1% and which were probably or possibly related to intravenous acyclovir administration were: anemia, anuria, hematuria, hypotension, edema, anorexia, light-headedness, thirst, headache, diaphoresis, fever, neutropenia, thrombocytopenia, abnormal urinalysis (characterized by an increase in formed elements in urine sediment) and pain on urination.

Other reactions have been reported with a frequency of less than 1% in patients receiving acyclovir, but a causal relationship between acyclovir and the reaction could not be determined. These include pulmonary edema with cardiac tamponade, abdominal pain, chest pain, thrombocytosis, leukocytosis, neutrophilia, ischemia of digits, hypokalemia, purpura fulminans, pressure on urination, hemoglobinemia and rigors.

5 Post-Market Adverse Reactions Severe local inflammatory reactions, including tissue necrosis, have occurred following inadvertent infusion of acyclovir into extravascular tissues.

Acyclovir Sodium Injection is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

INDICATIONS & USAGE

Herpes Zoster Infections:

Acyclovir tablets, USP are indicated for the acute treatment of herpes zoster (shingles).

Genital Herpes:

Acyclovir tablets, USP are indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes.

Chickenpox:

Acyclovir tablets, USP are indicated for the treatment of chickenpox (varicella).

DOSAGE & ADMINISTRATION

Acute Treatment of Herpes Zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days.

Genital Herpes:

Treatment of Initial Genital Herpes: 200 mg every 4 hours, 5 times daily for 10 days. Chronic Suppressive Therapy for Recurrent Disease: 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 tablets.

Intermittent Therapy: 200 mg every 4 hours, 5 times daily for 5 days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence.

Treatment of Chickenpox:

Children (2 years of age and older): 20 mg/kg per dose orally 4 times daily (80 mg/kg/day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox. Adults and Children over 40 kg: 800 mg 4 times daily for 5 days.

Intravenous acyclovir is indicated for the treatment of varicella-zoster 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.

Patients With Acute or Chronic Renal Impairment:

In patients with renal impairment, the dose of acyclovir tablets should be modified as shown in Table 3. Table 3. 73 m 2) Adjusted Dosage Regimen Dose (mg) Dosing Interval 200 mg every 4 hours > 10 0-10 200 200 every 4 hours, 5x daily every 12 hours 400 mg every 12 hours > 10 0-10 400 200 every 12 hours every 12 hours 800 mg every 4 hours > 25 10-25 0-10 800 800 800 every 4 hours, 5x daily every 8 hours every 12 hours Hemodialysis: 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.

Peritoneal Dialysis:

No supplemental dose appears to be necessary after adjustment of the dosing interval.

ADVERSE REACTIONS

7%). 7%) patients who received placebo. 4%). 2%). 5%). 1%). 2%). 2%). Observed During Clinical Practice In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of acyclovir tablets.

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 tablets or a combination of these factors.

General:

Anaphylaxis, angioedema, fever, headache, pain, peripheral edema.

Nervous:

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 PRECAUTIONS ).

Digestive:

Diarrhea, gastrointestinal distress, nausea.

Hematologic and Lymphatic:

Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia.

Hepatobiliary Tract and Pancreas:

Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice.

Musculoskeletal:

Myalgia.

Skin:

Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.

Special Senses:

Visual abnormalities.

Urogenital:

Renal failure, renal pain (may be associated with renal failure), elevated blood urea nitrogen, elevated creatinine, hematuria (see WARNINGS ).

CONTRAINDICATIONS

Acyclovir tablets are contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir.