The following Structured Product Label (SPL) was submitted to the FDA by Padagis Israel Pharmaceuticals Ltd for the product Acyclovir (NDC 45802-044). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2 dosage and administration, 3 dosage forms and strengths, 4 contraindications, 5.1 general, 5.2 contact sensitization, 6.1 clinical trials experience, 6.2 postmarketing experience, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
Acyclovir Cream is a herpes simplex virus (HSV) nucleoside analogue DNA polymerase inhibitor indicated for the treatment of recurrent herpes labialis (cold sores) in immunocompetent adults and adolescents 12 years of age and older.
Acyclovir Cream should be applied five times per day for four days. Therapy should be initiated as early as possible following the onset of signs or symptoms of herpes labialis i.e., during the prodrome or when lesions appear.
For adolescents 12 years of age and older, the dosage is the same as in adults.
Each gram of Acyclovir Cream, 5% contains 50 mg of acyclovir.
Acyclovir Cream is contraindicated in patients with known hypersensitivity to acyclovir, valacyclovir, or any component of the formulation.
Acyclovir Cream should only be applied on the affected external aspects of the lips and face in patients with herpes labialis. Because no data are available, application to human mucous membranes is not recommended. Acyclovir Cream is intended for cutaneous use only and should not be used in the eye or inside the mouth or nose.
Acyclovir Cream has a potential for irritation and contact sensitization [see Adverse Reactions (6.1)].
The effect of Acyclovir Cream has not been established in immunocompromised patients.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice.
In five double-blind, placebo-controlled trials, 1,124 patients were treated with acyclovir cream and 1,161 with placebo (vehicle) cream. Local application site reactions were reported by 5% of patients receiving acyclovir cream and 4% of patients receiving placebo. The most common adverse reactions at the site of topical application were dry lips, desquamation, dryness of skin, cracked lips, burning skin, pruritus, flakiness of skin, and stinging on skin; each adverse reaction occurred in less than 1% of patients receiving acyclovir cream and placebo. Three patients on acyclovir cream and one patient on placebo discontinued treatment due to an adverse event.
An additional study, enrolling 22 healthy adults, was conducted to evaluate the dermal tolerance of acyclovir cream compared with vehicle using single occluded and semi-occluded patch testing methodology. Both acyclovir cream and placebo showed a high and cumulative irritation potential. Another study, enrolling 251 healthy adults, was conducted to evaluate the contact sensitization potential of acyclovir cream using repeat insult patch testing methodology. Of 202 evaluable subjects, possible cutaneous sensitization reactions were observed in the same 4 (2%) subjects with both acyclovir cream and placebo, and these reactions to both acyclovir cream and placebo were confirmed in 3 subjects upon rechallenge. The sensitizing ingredient(s) has not been identified.
The safety profile in patients 12 to 17 years of age was similar to that observed in adults.
In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of acyclovir cream. 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 a combination of their seriousness, frequency of reporting, or potential causal connection to acyclovir cream.
General: Angioedema, anaphylaxis.
Skin: Contact dermatitis, eczema.
Clinical experience has identified no interactions resulting from topical or systemic administration of other drugs concomitantly with acyclovir cream. Due to minimal systemic absorption of acyclovir cream, systemic drug interactions are unlikely.
Pregnancy Category B.
There are no adequate and well-controlled studies of acyclovir cream in pregnant women. Acyclovir cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data
Acyclovir was not teratogenic in the mouse, rabbit, or rat at exposures greatly in excess of human exposure.
It is not known whether topically applied acyclovir is excreted in breast milk. Systemic exposure following topical administration is minimal.
However, after oral administration of acyclovir, acyclovir concentrations have been documented in breast milk in two women and ranged from 0.6 to 4.1 times the corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg/day. Nursing mothers who have active herpetic lesions near or on the breast should avoid nursing.
An open-label, uncontrolled trial with acyclovir cream, 5% was conducted in 113 patients aged 12 to 17 years with recurrent herpes labialis. In this trial, therapy was applied using the same dosing regimen as in adults and subjects were followed for adverse events. The safety profile was similar to that observed in adults. Safety and effectiveness in pediatric patients less than 12 years of age have not been established.
Clinical studies of acyclovir cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Systemic absorption of acyclovir after topical administration is minimal [see Clinical Pharmacology (12.3)].
Overdosage by topical application of Acyclovir Cream is unlikely because of minimal systemic exposure [see Clinical Pharmacology (12.3)]. There is no information available for overdose.
Acyclovir is a synthetic nucleoside analogue active against herpes viruses. Acyclovir Cream, 5% is a formulation for topical administration.
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:
Chemical Structure (Image 01)
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.
Each gram of Acyclovir Cream, 5% contains 50 mg of acyclovir and the following inactive ingredients: cetostearyl alcohol, mineral oil, poloxamer 407, propylene glycol, sodium lauryl sulfate, water, and white petrolatum.
Acyclovir is an antiviral drug active against herpes simplex virus [see Microbiology (12.4)].
A clinical pharmacology study was performed with acyclovir cream in adult volunteers to evaluate the percutaneous absorption of acyclovir. In this study, which included 6 male volunteers, the cream was applied to an area of 710 cm2 on the backs of the volunteers 5 times daily at intervals of 2 hours for a total of 4 days. The weight of cream applied and urinary excretion of acyclovir were measured daily. Plasma concentration of acyclovir was assayed 1 hour after the final application. The average daily urinary excretion of acyclovir was approximately 0.04% of the daily applied dose. Plasma acyclovir concentrations were below the limit of detection (0.01 μM) in 5 subjects and barely detectable (0.014 μM) in 1 subject. Systemic absorption of acyclovir from acyclovir cream is minimal in adults.
The systemic absorption of acyclovir following topical application of cream has not been evaluated in patients <18 years of age.
Mechanism of Action: Acyclovir is a synthetic purine nucleoside analogue with cell culture and in vivo inhibitory activity against HSV types 1 (HSV-1) and 2 (HSV-2).
The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV. 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. In cell culture, acyclovir triphosphate stops replication of herpes viral DNA. This inhibition 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.
Antiviral Activity: The quantitative relationship between the cell culture 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 (EC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the EC50 values against herpes simplex virus isolates range from 0.09 to 59.9 μM (0.02 to 13.5 μg/mL) for HSV-1 and from 0.04 to 44.0 μM (0.01 to 9.9 μg/mL) for HSV-2.
Drug Resistance: Resistance of HSV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV 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.
Systemic exposure following topical administration of acyclovir is minimal. Dermal carcinogenicity studies were not conducted. Results from the studies of carcinogenesis, mutagenesis and fertility are not included in the full prescribing information for acyclovir cream due to the minimal exposures of acyclovir that result from dermal application. Information on these studies is available in the full prescribing information for acyclovir capsules, tablets, and suspension and acyclovir for injection.
Acyclovir cream was evaluated in two double-blind, randomized, placebo (vehicle)- controlled trials for the treatment of recurrent herpes labialis. The average patient had five episodes of herpes labialis in the previous 12 months. In the first trial, the median age of subjects was 37 years (range 18 to 81 years), 74% were female, and 94% were Caucasian. In the second trial, median age of subjects was 38 years (range 18 to 87 years), 73% were female, and 94% were Caucasian. Subjects were instructed to initiate treatment within one hour of noticing signs or symptoms and continue treatment for four days, with application of study medication five times per day. In both studies, the mean duration of the recurrent herpes labialis episode was approximately one-half day shorter in the subjects treated with acyclovir cream (n = 682) compared with subjects treated with placebo (n = 703) for approximately 4.5 days versus 5 days, respectively. No significant difference was observed between subjects receiving acyclovir cream or placebo in the prevention of progression of cold sore lesions.
An open-label, uncontrolled trial with acyclovir cream, 5% was conducted in 113 patients aged 12 to 17 years with recurrent herpes labialis. In this trial, therapy was applied using the same dosing regimen as in adults and subjects were followed for adverse events. The safety profile was similar to that observed in adults.
Acyclovir Cream is a white, odorless, smooth homogeneous cream.
Each gram of Acyclovir Cream 5% contains 50 mg acyclovir in an aqueous cream base. Acyclovir Cream is supplied as follows:
Store at or below 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature).
Advise the patient to read the FDA-approved patient labeling (Patient Information).
General
Patients should be informed that Acyclovir Cream is a prescription topical cream for the treatment of cold sores (recurrent herpes labialis) that occur on the face and lips. Acyclovir Cream is not a cure for cold sores. Patients should be instructed that Acyclovir Cream is intended for cutaneous use only for herpes labialis of the lips and around the mouth. Patients should be advised that Acyclovir Cream should not be used in the eye, inside the mouth or nose, or on the genitals. Patients should be instructed to avoid applying other topical products to the affected area while using Acyclovir Cream.
Do not use if you are allergic to Acyclovir Cream or any of the ingredients in Acyclovir Cream. Before you use Acyclovir Cream, tell your doctor if you are pregnant, planning to become pregnant, or are breast-feeding.
Instructions for Use
Treatment should be initiated at the earliest sign or symptom of recurrence. Patients should be instructed to wash hands prior to application and ensure the face and/or lips are clean and dry. Patients should be advised to apply Acyclovir Cream topically five times per day for four days. Patients should be instructed to topically apply a quantity of Acyclovir Cream sufficient to cover the affected area, including the outer margin. Patients should be advised to avoid unnecessary rubbing of the affected area to avoid aggravating or transferring the infection. Patients should be instructed to wash their hands with soap and water after using Acyclovir Cream. Keep out of reach of children.
Possible Side Effects
Common skin-related side effects that occurred when acyclovir cream was applied include application site reactions. Acyclovir Cream has the potential for irritation and contact sensitization.
Made in Israel
Manufactured By Perrigo
Yeruham 80500, Israel
Distributed By
Perrigo®
Allegan, MI 49010 • www.perrigo.com
Rev 04-16
7G800 RC J1
Acyclovir (ay-SYE-kloe-vir) Cream, 5%
Important information: Acyclovir Cream is for use on cold sores on the lips and around the mouth only.
Acyclovir Cream should not be used in your eyes, mouth, nose, or on your genitals.
What is Acyclovir Cream?
Who should not use Acyclovir Cream?
Do not use Acyclovir Cream if you are:
What should I tell my healthcare provider before using Acyclovir Cream?
Before using Acyclovir Cream, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How should I use Acyclovir Cream?
What are the possible side effects of Acyclovir Cream?
The most common side effects of Acyclovir Cream are skin reactions at the treatment site and may include: dry or cracked lips, peeling, flaking or dryness of the skin, a burning or stinging feeling, and itching.
These are not all the possible side effects of Acyclovir Cream. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Acyclovir Cream?
Keep Acyclovir Cream and all medicines out of the reach of children.
General information about the safe and effective use of Acyclovir Cream
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Acyclovir Cream for a condition for which it was not prescribed.
Do not give Acyclovir Cream to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Acyclovir Cream that is written for health professionals.
What are the ingredients in Acyclovir Cream?
Active ingredient: acyclovir
Inactive ingredients: cetostearyl alcohol, mineral oil, poloxamer 407, propylene glycol, sodium lauryl sulfate, water, and white petrolatum
For more information, call Perrigo at 1-866-634-9120.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Made in Israel
Manufactured By Perrigo
Yeruham 80500, Israel
Distributed By
Perrigo®
Allegan, MI 49010 • www.perrigo.com
Rev 04-16
7G800 RC J1
Rx Only
NDC 45802-044-75
Acyclovir Cream, 5%
Each gram contains 50 mg acyclovir.
5 g
USE ONLY FOR COLD SORES.
* Please review the disclaimer below.
