Treating cold sores & fever blisters with prescription antiviral medications -

Denavir® (penciclovir) / Zovirax® (acyclovir) / Xerese® (acyclovir, hydrocortisone) / Valtrex® (valacyclovir) / Famvir® (famciclovir)  |  How they work.  |  Which works best?

FDA approved antivirals.

This page discusses prescription antiviral medications that have been approved by the FDA for the treatment of colds sores (fever blisters). They include:

  • Denavir® 1% (penciclovir) - Topical cream.
  • Zovirax® 5% (acyclovir) - Topical cream.
  • Xerese® (acyclovir 5% and hydrocortisone 1%) - Topical cream.
  • Valtrex® (valacyclovir) - Taken orally.
  • Famvir® (famciclovir) - Taken orally.

How antiviral cold sore medicines work.

The mode of action associated with prescription antiviral medications is one where they are used to interfere with herpes virus replication (the production of more virus particles, called virions).

These medicines don't stop cold sores from forming. But by reducing the total number of virions that are involved, they limit the lesion's extent and severity.

Sideshow of pictures of herpes simplex virions.

The herpes simplex virus.

a) Early use/application is key.

The only way an antiviral medication can be effective is if its use is begun at the very earliest sign that a cold sore is forming (i.e., the Tingle stage, a point where the developing lesion can typically only be felt, not seen). That's because at this point the rate of viral replication has not yet reached its peak and can still be stifled.

In comparison, once a lesion has reached the Blister stage (the point of maximum viral presence) or beyond, an antiviral will have no practical effect because the stages involving the bulk of virus production have already passed.

b) These are treatments, not a preventive or cure.

This page describes the use of antiviral medications as a treatment for cold sores. And as such, the following needs to be understood:

  • These medicines are not a cure for cold sores/fever blisters. They only inhibit the replication of the virus, they do not eradicate it. The virus will still reside in your body and your risk for continued outbreaks will remain the same.
  • When used as a treatment, antiviral medications will not have an affect/prevent future cold sore outbreaks. The person's risk of recurrence remains the same whether the medication was used or not.
  • Even when a lesion is being treated with an antiviral, the risk of transmission of the herpes virus to others, or to other parts of your own body, remains and therefore precautions should still be taken.

FDA approved topical antiviral medications.

Topical medicines for cold sores are those that are applied as an ointment or cream directly to the surface of the lesion. The FDA has given approval for 3 topical products for the treatment of cold sores:  1) Denavir® 1% (penciclovir).  2) Zovirax® 5% (acyclovir)  and  3) Xerese® (acyclovir 5% and hydrocortisone 1%).

a) Denavir® cream 1% (penciclovir)

Denavir® cream was the first antiviral medication to be granted FDA approval for use in the treatment of cold sores. Approval was given in 1996.

Its instructions state that it should be applied repeatedly throughout the day every 2 waking hours (roughly 9 times a day) for 4 days on those external areas of the lips or face where the cold sore is forming. (Denavir® cream is not intended for internal use.)

Application of the cream should be started as soon as it's sensed that a cold sore has begun to form (i.e., the Tingle stage).

b) Zovirax® cream 5% (acyclovir)

Zovirax® cream received FDA approval for use in the treatment of cold sores in late 2002, although other formulations of this medication have been used in treating herpes for many years (including an "off-label" use in the treatment of cold sores in the years prior to 2002).

It's used in a similar fashion as with Denavir® cream. However, the dosing schedule is slightly more convenient (less applications per day).

The instructions for Zovirax® state that treatment should be started as soon it is sensed that a cold sore has begun to form (i.e., the Tingle stage). The cream is applied to those external areas of the lips or face where the cold sore is developing, 5 times a day for 4 days. (Zovirax® cream is not intended for internal use.)

c) Xerese® - (acyclovir [5%] and hydrocortisone [1%])

Xerese® cream is a combination product. It contains both an antiviral (acyclovir) and a steroid (hydrocortisone). It received FDA approval in 2009.

The cream is applied to the area where the cold sore is forming 5 times per day, for 5 days. (Xerese® cream is not intended for internal use.) As with other antiviral medications, early application is the key and is preferably started during the Tingle stage.

The idea with this product is that the steroid component helps to stifle the extent of the inflammation reaction that takes place in response to the presence of the virus particles and the destruction they have caused. By limiting this response, the size and severity of the lesion that forms is reduced.

Which is best? - Denavir® and Zovirax® vs. Xerese®

We think that the answer to this question is best answered by your health care professional. Having said that, research seems to suggest that the combination medication Xerese® (antiviral plus steroid) is more effective than just-antiviral medications.

  • A study by Hull (2014) evaluated the use of an acyclovir (5%) and hydrocortisone (1%) cream (Xerese®). It found that the total area of the cold sore lesions that formed were 50% smaller than when no treatment was used. And 25% smaller than when just an antiviral cream (Zovirax®) was applied.
  • Arain (2015) reviewed four studies that had evaluated the approach of combining topical antivirals and steroids in the treatment of cold sores (the approach used by Xerese®) and determined that this method was both as safe and more effective than treatment involving an antiviral cream alone (such as the use of Denavir® or Zovirax®).

    Overall, healing times were the same for both treatment approaches. But combination treatment was less likely to result in cold sore ulcerative lesions (sores that advanced to the Weeping/Ulcer stage and beyond).

[page references]

Which is best? - Denavir® vs. Zovirax®

In regard to cases where the use of Xerese® isn't applicable (i.e., patients with whom a steroid should not be used), we found several studies that evaluated the effectiveness of just antiviral treatment alone.


Opstelten (2008) reviewed 10 studies that had evaluated the use of acyclovir cream (found in Zovirax®). Application was begun at the first sign of symptoms (the Tingle stage).

  • All of the studies found that the time needed for cold sore healing was shortened (varying from 0.5 days up to 2.5 days reduction).
  • None of the studies reported a decrease in the severity or duration of pain.

This same literature review stated that two penciclovir studies (the compound found in Denavir®) reported findings that were similar as those for acyclovir. However, one of these studies also reported a reduction in the duration of pain, by 0.5 days.

An edge for Denavir®.

We found three studies (Femiano 2001, Lin 2002, McKeough 2001) that each studied the head-to-head effectiveness of acyclovir cream (the compound found in Zovirax®) and penciclovir cream (the compound found in Denavir®) in the treatment of cold sores. The conclusions drawn by all three of these studies seem to suggest that penciclovir cream is the more effective of the two.

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FDA approved oral antiviral medicines.

Historically, oral antiviral medications have not routinely been used in the treatment of cold sores. However, short-course regimens of valacyclovir (Valtrex®) and famciclovir (Famvir®) now do have FDA approval for this use and have been shown to accelerate lesion healing and decrease pain. (Cunningham 2012)

Depending on the practitioner, it may be that these medicines are more likely prescribed in situations where there's a history of especially severe or disfiguring lesions, cases involving newborn babies or immunocompromised patients.

As with all other antiviral approaches, starting the medication as early as possible (during the Tingle stage) is key for effectiveness.

Hand washing graphic.

Always wash your hands after treating a cold sore.

Always keep in mind ...

All prescription medications should only be used under the direction and supervision of a health care professional.

All stages of cold sore formation should be considered to be contagious. So to avoid spreading the herpes virus (either to other people or other parts of your own body), after applying any medication or treatment to cold sores you should always wash your hands.



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