Zovirax

Acyclovir may decrease levels of phenytoin (Dilantin) or valproic acid (Depakote, Depakote ER). Probenecid (Benemid) may increase acyclovir serum levels by decreasing renal excretion of acyclovir. Acyclovir may increase serum levels of theophylline (Theo-Dur, Respbid, Slo-Bid, Theo-24, Theolair, Uniphyl, Slo-Phyllin).

Combining acyclovir with cidofovir (Vistide), amphotericin B (Fungizone) or other drugs that reduce kidney function may increase harmful effects on the kidney.

Before taking acyclovir, tell your doctor or pharmacist if you are allergic to it; or to valacyclovir; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney problems, conditions related to a weakened immune system (such as HIV disease, bone marrow transplant, kidney transplant).This drug may rarely make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).Do not have certain immunizations/vaccinations (such as vaccines against the varicella virus) without the consent of your doctor.Older adults may be more sensitive to the side effects of the drug, especially kidney problems (change in the amount of urine, back/side pain), dizziness, drowsiness, and mental/mood changes (such as confusion, hallucinations, loss of consciousness).Acyclovir does not protect against the spread of genital herpes. To lower the chance of giving herpes to your partner, do not have sexual contact during an outbreak or if you have symptoms. You can spread genital herpes even if you do not have symptoms. Therefore, always use an effective barrier method (latex or polyurethane condoms/dental dams) during all sexual activity. Consult your doctor or pharmacist for more details.During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.This medication passes into breast milk. However, this drug is unlikely to harm a nursing infant. Consult your doctor before breast-feeding.

Dosage Forms & Strengths

injectable solution

• 50mg/mL

oral suspension

• 200mg/5mL

powder for injection

• 500mg/vial
• 1g/vial

tablet

• 400mg
• 800mg

capsule

• 200mg

Genital Herpes

Initial treatment: 200 mg PO q4hr while awake (5 times daily) for 10 days or 400 mg PO q8hr for 7-10 days

Intermittent treatment for recurrence: 200 mg PO q4hr while awake (5 times daily) for 5 days; initiate at earliest sign or symptom of recurrence

Chronic suppression for recurrence: 400 mg PO q12hr for up to 12 months; alternatively, 200 mg 3-5 times daily

Herpes Simplex Virus Encephalitis

10-15 mg/kg IV q8hr for 10 days; up to 14-21 days reported 

In obese patients, use IBW

Mucocutaneous Herpes Simplex Virus Infection

Treatment in immunocompromised patients

IV: 5 mg/kg q8hr for 7 days; dosing up to 14 days reported 

In obese patients, use IBW

PO (off-label): 400 mg q4hr while awake (5 times daily) for 7 days

Herpes Zoster (Shingles)

Acute treatment: 800 mg PO q4hr while awake (5 times daily) for 7-10 days

Immunocompromised patients

• 10 mg/kg IV q8hr for 7 days 
• In obese patients, use IBW
• CrCl 25-50 mL/min: Full recommended IV dose q12hr
• CrCl 10-25 mL/min: Full recommended IV dose once daily
• CrCl 0-10 mL/min: 50% of recommended IV dose once daily

Varicella Zoster (Chickenpox)

>40 kg (immunocompetent): 800 mg PO q6hr for 5 days

Immunocompromised patients: 10-15 mg/kg IV q8hr for 7-10 days 

In obese patients, use IBW

Dosing Modifications

Dose adjustment based on renal clearance and normal dosage regimen

200 mg every 4 hr

• 0-10 mL/min/1.73 m²: 200 mg q12hr
• >10 mL/min/1.73 m²: 200 mg q4hr (five times daily)

400 mg every 12 hr

• 0-10 mL/min/1.73 m²: 200 mg q12hr
• >10 mL/min/1.73 m²: 400 mg q12hr

800 mg every 4 hr

• 0-10 mL/min/1.73 m²: 800 mg q12hr
• 10-25 mL/min/1.73 m²: 800 mg q8hr
• >25 mL/min/1.73 m²: 800 mg q4hr (five times daily)

Dose adjustment based on dosage form

Renal impairment (IV)

• CrCl 25-50 mL/min/1.73 m²: Give recommended dose q12hr
• CrCl 10-25 mL/min/1.73 m²: Give recommended dose q24hr
• CrCl <10 mL/min/1.73 m²: Give 50% of recommended dose q24hr

Renal impairment (PO)

• Normal dosage 200 mg q4hr or 400 mg q12hr and CrCl <10 mL/min/1.73 m²: Decrease to 200 mg q12hr
• Normal dosage 800 mg q4hr and CrCl 10-25 mL/min/1.73 m²: Decrease to 800 mg q8hr
• Normal dosage 800 mg q4hr and CrCl <10 mL/min/1.73 m²: Decrease to 800 mg q12hr

Herpetic Keratitis (Orphan)

Orphan designation for treatment of herpetic keratitis

Sponsor

• Cumulus Pharmaceuticals LLC; 1712 Pioneer Avenue, Suite 1377; Cheyenne, Wyoming 82001

Dosage Forms & Strengths

injectable solution

• 50mg/mL

oral suspension

• 200mg/5mL

powder for injection

• 500mg/vial
• 1g/vial

tablet

• 400mg
• 800mg

capsule

• 200mg

Neonatal Herpes Simplex Virus Infection

30 mg/kg/day IV divided q8hr for 14-21 days; alternatively, 20 mg/kg IV q8hr for 14-21 days  

In obese patients, use IBW

Herpes Simplex Virus Encephalitis

3 months-12 years: 20 mg/kg IV q8hr for 10 days; up to 14-21 days reported  

In obese patients, use IBW

>12 years: 10-15 mg/kg IV q8hr for 14-21 days

Mucocutaneous Herpes Simplex Virus Infection

Treatment in immunocompromised patients

<12 years: 10 mg/kg IV q8hr for 7 days 

In obese patients, use IBW

>12 years: 5-10 mg/kg/day IV divided q8hr for 5-7 days; up to 14 days reported

Herpes Zoster (Shingles)

<12 years (immunocompromised): 20 mg/kg IV q8hr for 7 days  

In obese patients, use IBW

>12 years (immunocompetent): 800 mg PO q4hr while awake (5 times daily) for 7-10 days

>12 years (immunocompromised): 30 mg/kg/day IV divided q8hr for 7-10 days

Varicella Zoster (Chickenpox)

≥2 years and <40 kg: 20 mg/kg/dose PO q6hr for 5 days; not to exceed 800 mg/dose 

In obese patients, use IBW

>40 kg: 800 mg PO q6hr for 5 days

Immunocompromised patients

• <12 years: 20 mg/kg/dose IV q8hr for 7 days
• >12 years: 10 mg/kg/dose IV q8hr for 7 days

>10%

Oral

• Malaise (≤12%)

1-10%

Parenteral

• Inflammation or phlebitis at injection site (9%)
• Nausea (7%)
• Vomiting (7%)
• Rash or hives (2%)
• Elevated transaminase levels (1-2%)

Oral

• Nausea (2-5%)
• Vomiting (≤3%)
• Diarrhea (2-3%)
• Headache (2%)

<1%

Abdominal pain

Aggression/confusion

Agitation

Alopecia

Anaphylaxis

Anemia

Angioedema

Anorexia

Ataxia

Coma

Disseminated intravascular coagulation (DIC)

Dizziness

Fatigue

Adverse Drug Reaction Overview

The most frequent adverse reactions associated with the use of ZOVIRAX® (acyclovir) are headache and nausea.

Neurological side effects have also been reported in rare instances. Elderly patients and patients with a history of renal impairment are at increased risk of developing these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Treatment of Herpes Simplex

Short-term administration (5-10 days): The most frequent adverse reactions reported during clinical trials of treatment of genital herpes with oral ZOVIRAX® in 298 patients are listed in Table 1.

Table 1 : Adverse Reactions Reported in Clinical Trials of Treatment of Genital Herpes with Acyclovir

Adverse Reactions	Total	%
Nausea and/or Vomiting	8	2.7

Suppression of Herpes Simplex

Long-term administration: 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 are listed in Table 2.

Table 2 : Adverse Reactions Reported in a Clinical Trial for the Prevention of Recurrences of Genital Herpes with Acyclovir

Adverse Reactions	1st Year (n=586) %	2nd Year (n=390) %	3rd Year (n=329) %
Nausea	4.8
Diarrhea	2.4
Headache	1.9	1.5	0.9
Rash	1.7	1.3
Paresthesia		0.8	1.2
Asthenia			1.2

Evidence so far from clinical trials suggests that the severity and frequency of adverse events is unlikely to necessitate discontinuation of therapy.

Herpes Zoster

The most frequent adverse reactions reported during three clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral ZOVIRAX® 5 times daily for 7 or 10 days or placebo are listed in Table 3.

Table 3 : Adverse Reactions Reported in Clinical Trials of Treatment of Herpes Zoster

Adverse Reactions	ZOVIRAX® (n=323) %	Placebo (n=323) %
Malaise	11.5	11.1
Nausea	8.0	11.5
Headache	5.9	11.1
Vomiting	2.5	2.5
Diarrhea	1.5	0.3

Chickenpox

The most frequent adverse events reported during three clinical trials of treatment of chickenpox with oral ZOVIRAX® or placebo are listed in Table 4.

Table 4 : Adverse Reactions Reported in Clinical Trials of Treatment of Chickenpox

Adverse Reactions	ZOVIRAX® (n=495)%	Placebo (n=498)%
Diarrhea	3.2	2.2

Less Common Clinical Trial Adverse Drug Reactions ( < 1%)

Other adverse reactions reported in less than 1% of patients receiving ZOVIRAX® in any clinical trial included: abdominal pain, anorexia, constipation, dizziness, edema, fatigue, flatulence, inguinal adenopathy, insomnia, leg pain, medication taste, skin rash, sore throat, spasmodic hand movement and urticaria.

Abnormal Hematologic And Clinical Chemistry Findings

No clinically significant changes in laboratory values have been observed in clinical trials for the treatment of chickenpox and zoster, and for the treatment and suppression of genital herpes with ZOVIRAX®.

Post-Market Adverse Drug Reactions

The following events have been reported voluntarily during post-market use of ZOVIRAX® in clinical practice. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to ZOVIRAX® or a combination of these factors. Post-market adverse events are reported spontaneously from a population of unknown size, thus estimates of frequency cannot be made.

General: Fever, headache, pain and peripheral edema.

Nervous: Dizziness, paresthesia, agitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, convulsions, somnolence, encephalopathy and coma have been reported. These events are generally reversible and usually reported in patients with renal impairment, or with other predisposing factors (see WARNINGS AND PRECAUTIONS). These symptoms may be marked, particularly in older adults.

Digestive: Diarrhea, gastrointestinal distress and nausea.

Hematogical and Lymphatic: Anaemia, leukopenia, lymphadenopathy and thrombocytopenia.

Hypersensitivity and Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, rashes including photosensitivity, pruritus, urticaria, dyspnoea, angioedema and anaphylaxis.

Hepatobiliary Tract and Pancreas: Reports of reversible hyperbilirubinemia and elevated liver related enzymes. Hepatitis and jaundice.

Musculoskeletal: Myalgia.

Special Senses: Visual abnormalities.

Urogenital: Elevated blood creatinine and blood urea nitrogen (BUN). Acute renal failure, renal pain and hematuria have been reported. Renal pain may be associated with renal failure (see WARNINGS AND PRECAUTIONS).

Oral/Injectable:

• Zovirax capsule, tablet, oral suspension, and injectable are prescription medications used to treat infections caused by the varicella-zoster and herpes viruses. Infections include chickenpox, genital herpes, and cold sores.

Topical:

• Zovirax ointment is a prescription medication used to treat genital herpes and in certain herpes simplex virus infections in patients with lowered immunity (immunocompromised).
• Zovirax cream is a prescription medication used to treat herpes labialis (cold sores) in those 12 years of age and older.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

If you take too much Zovirax, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Zovirax is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Antiviral; purine nucleoside analog derived from guanine.403 409

Nephrotoxic Agents

Potential pharmacodynamic interaction (increased risk of renal dysfunction and/or reversible CNS manifestations); use concomitantly with caution.403 409

Specific Drugs

Drug	Interaction	Comments
Interferon	Additive or synergistic antiviral effect against HSV-1 in vitroa	Clinical importance unknown;a use with caution409
Methotrexate		Manufacturer states that IV acyclovir should be used with caution in patients receiving intrathecal methotrexate409
Probenecid	Decreased renal clearance of acyclovir403 409
Zidovudine	Neurotoxicity (profound drowsiness, lethargy) reported in at least 1 patient298	Monitor patients closely during concomitant therapy298

Zovirax is the brand name for acyclovir, a synthetic nucleoside analogue active against herpesviruses. Zovirax Capsules, Tablets, and Suspension are formulations for oral administration. Each capsule of Zovirax contains 200 mg of acyclovir and the inactive ingredients corn starch, lactose, magnesium stearate, and sodium lauryl sulfate. The capsule shell consists of gelatin, FD&C Blue No. 2, and titanium dioxide. May contain one or more parabens. Printed with edible black ink.

Each 800-mg tablet of Zovirax contains 800 mg of acyclovir and the inactive ingredients FD&C Blue No. 2, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.

Each 400-mg tablet of Zovirax contains 400 mg of acyclovir and the inactive ingredients magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.

Each teaspoonful (5 mL) of Zovirax Suspension contains 200 mg of acyclovir and the inactive ingredients methylparaben 0.1% and propylparaben 0.02% (added as preservatives), carboxymethylcellulose sodium, flavor, glycerin, microcrystalline cellulose, and sorbitol.

Acyclovir is a white, crystalline powder with the molecular formula C8H11N5O3 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:

Herpes Zoster Infections:

Zovirax is indicated for the acute treatment of herpes zoster (shingles).

Genital Herpes:

Zovirax is indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes.

Chickenpox:

Zovirax is indicated for the treatment of chickenpox (varicella).

Herpes Simplex:

Short-Term Administration: The most frequent adverse events reported during clinical trials of treatment of genital herpes with Zovirax 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.

Long-Term Administration: 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 Zovirax were nausea (4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with Zovirax for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%).

Herpes Zoster:

The most frequent adverse event reported during 3 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 was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%).

Chickenpox:

The most frequent adverse event reported during 3 clinical trials of treatment of chickenpox with oral Zovirax 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%).

Observed During Clinical Practice:

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of Zovirax. 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 Zovirax, 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).

Overdoses involving ingestion of up to 100 capsules (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 DOSAGE AND ADMINISTRATION).

Herpes infections are contagious and you can infect other people, even while you are being treated with Zovirax. Avoid letting infected areas come into contact with other people. Avoid touching an infected area and then touching your eyes. Wash your hands frequently to prevent passing the infection to others.

Taking this medicine will not prevent you from passing genital herpes to your sexual partner. Avoid sexual intercourse while you have active lesions or the first symptoms of an outbreak. Genital herpes may still be contagious through "viral shedding" from your skin, even if you have no symptoms.