Xerese

XERESE- acyclovir and hydrocortisone cream
Bausch Health US LLC

1 INDICATIONS AND USAGE

XERESE, a combination of acyclovir, a herpes simplex virus deoxynucleoside analog DNA polymerase inhibitor, and hydrocortisone, a corticosteroid, is indicated for the early treatment of recurrent herpes labialis (cold sores) to reduce the likelihood of ulcerative cold sores and to shorten the lesion healing time in adults and children (6 years of age and older).

2 DOSAGE AND ADMINISTRATION

Topically apply XERESE 5 times per day for 5 days. Therapy should be initiated as early as possible after the first signs and symptoms (i.e., during the prodrome or when lesions appear).

For each dose, topically apply a quantity of XERESE sufficient to cover the affected area, including the outer margin. Avoid unnecessary rubbing of the affected area to avoid aggravating or transferring the infection. For children 6 years of age and older, the dosage is the same as in adults.

3 DOSAGE FORMS AND STRENGTHS

Each gram of XERESE contains 50 mg (equivalent to 5%, w/w) acyclovir and 10 mg (equivalent to 1%, w/w) hydrocortisone in an aqueous cream base.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 General

XERESE is intended for cutaneous use only for herpes labialis of the lips and around the mouth. XERESE should not be used in the eye, inside the mouth or nose, or on the genitals.

There are other orofacial lesions, including bacterial and fungal infections, which may be difficult to distinguish from a cold sore. Patients should be encouraged to seek medical advice when a cold sore fails to heal within 2 weeks.

XERESE has a potential for irritation and contact sensitization [see Adverse Reactions (6.1)].

6 ADVERSE REACTIONS

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

The safety data derived from XERESE clinical trials reflect exposure to XERESE in 1,056 subjects with recurrent herpes labialis treated 5 times daily for 5 days.

The most common adverse reactions (<1%) were local skin reactions, and occurred in the area of the application site, including:

Drying or flaking of the skin; burning or tingling following application; erythema; pigmentation changes; application site reaction including signs and symptoms of inflammation.

Contact dermatitis following application has been observed when applied under occlusion in dermal safety trials. Where contact sensitivity tests have been conducted, the reactive substances were hydrocortisone or a component of the cream base.

A trial enrolling 225 healthy adults was conducted to evaluate the contact sensitization potential of XERESE using repeat insult patch testing methodology. Of 205 evaluable subjects, one confirmed case (0.5%) of sensitization to hydrocortisone and 2 additional cases (1.0%) of possible sensitization to the XERESE base were identified. Additionally, one subject developed a contact allergy in the photosafety study to propylene glycol, one of the inactive ingredients of the cream base.

Dermal tolerance was assessed in a 21-day cumulative irritation trial in 36 healthy subjects. XERESE, its cream base and Zovirax® (acyclovir) Cream 5% all showed a high and cumulative irritation potential under occlusive and semi-occlusive conditions.

Photoallergic potential and phototoxicity were assessed in two trials in 50 and 30 healthy volunteers, respectively. No photoallergic or phototoxicity potential was identified for XERESE.

7 DRUG INTERACTIONS

No drug interaction studies have been performed with XERESE.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on XERESE use in pregnant women. However, published observational studies over decades of use of topical acyclovir and low and medium potency topical corticosteroids during pregnancy have not established any association between use of these products and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).

Animal reproduction studies have not been conducted with XERESE. Systemic exposure of acyclovir and hydrocortisone following topical administration of XERESE is expected to be minimal. Animal reproduction studies with systemic exposure of acyclovir and hydrocortisone have been conducted. Refer to acyclovir and hydrocortisone prescribing information for additional details.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

While available studies cannot definitively establish the absence of risk, published data from multiple large observational studies have not established an association with the use of topical acyclovir or low and medium potency topical corticosteroids (including hydrocortisone) during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available studies have methodological limitations including whether women who filled a prescription actually took the medication, non-randomized design, retrospective data collection, and the inability to control for confounders such as underlying maternal disease and use of concomitant medications.

8.2 Lactation

Risk Summary
There are no data on the presence of acyclovir or hydrocortisone in human milk following topical administration. There are no data on the effects of acyclovir or hydrocortisone on the breastfed infant or on milk production. Systemic exposure following topical administration of either drug is expected to be minimal. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XERESE and any potential adverse effects on the breastfed child from XERESE or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric subjects less than 6 years of age have not been established.

8.5 Geriatric Use

In clinical studies, there were insufficient subjects above 65 years of age to reach a firm conclusion regarding safety and efficacy of XERESE in this group, although the available results were similar to lower age subjects.

8.6 Immunocompromised Subjects

Even though the safety of XERESE has been studied in immunocompromised subjects, data are insufficient to support use in this population. Immunocompromised subjects should be encouraged to consult a physician concerning the treatment of any infection.

Benefit has not been adequately assessed in immunocompromised patients. A randomized, double-blind trial was conducted in 107 immunocompromised subjects with stable HIV infection and recurrent herpes labialis. Subjects had on average 3.7 episodes of herpes labialis in the previous 12 months. The median age was 30 years (range 19 to 64 years), 46% were female, and all Caucasian. Median CD4+ T-cell count at screening was 344/mm3 (range 100-500/mm3). Subjects were treated with XERESE or 5% acyclovir in XERESE vehicle. The primary objective was to exclude a doubling of the healing time in either treatment arm. The mean healing time for cold sores was similar between the two treatment groups: 6.6 days for XERESE and 6.9 days for 5% acyclovir in XERESE vehicle.

10 OVERDOSAGE

Overdosage by topical application of XERESE is unlikely because of minimal systemic exposure [see Clinical Pharmacology (12.3)].

11 DESCRIPTION

XERESE contains acyclovir, a synthetic nucleoside analogue active against herpes viruses, and hydrocortisone, an anti-inflammatory corticosteroid, combined in a cream for topical administration. Each gram of XERESE contains 50 mg (equivalent to 5%, w/w) of acyclovir, 10 mg (equivalent to 1%, w/w) of hydrocortisone and the following inactive ingredients: cetostearyl alcohol, citric acid monohydrate, isopropyl myristate, mineral oil, Poloxamer 188, propylene glycol, purified water, USP, sodium hydroxide, sodium lauryl sulfate, and white petrolatum. Sodium hydroxide or hydrochloric acid may have been added to adjust the pH to approximately pH 5.

Acyclovir, 2-Amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one, is a synthetic nucleoside analogue active against herpes viruses. The maximum solubility of acyclovir in water at 37°C is 2.5 mg/mL. The pKa’s of acyclovir are 2.27 and 9.25. Its empirical formula is C8 H11 N5 O3 . The structural formula is provided in Figure 1:

Figure 1: Structural Formula of Acyclovir

Structural Formula of Acyclovir

Hydrocortisone, pregn-4-ene-3,20-dione, 11,17,21-trihydroxy- (11β), is an anti-inflammatory corticosteroid. Its empirical formula is C21 H30 O5 . The structural formula is provided in Figure 2:

Figure 2: Structural Formula of Hydrocortisone

Structural Formula of HydrocortisoneStructural Formula of AcyclovirStructural Formula of Hydrocortisone
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