A Novel Combination for Treatment of Acne Vulgaris

Adapalene 0.1% and Benzoyl Peroxide 2.5%: A Novel Combination for Treatment of Acne Vulgaris

Topical products commonly used to treat acne include retinoids and antimicrobials, due to their effects on different components of pathogenesis. Accordingly, a fixed combination of adapalene 0.1% and benzoyl peroxide (BPO) 2.5% was developed (Epiduo™, Galderma) and was approved by the US FDA in December 2008 for the treatment of acne. The superior efficacy of this combination was demonstrated in 2 large randomized controlled trials. This paper reviews the evidence for efficacy and tolerability of the combination of the retinoid adapalene 0.1% and BPO 2.5%, a once-daily gel formulation for the treatment of acne.

Adapalene, a receptor-selective naphthoic acid derivative with retinoid-like properties, has comedolytic, anticomedogenic, and anti-inflammatory effects. Benzoyl peroxide (BPO) is a highly lipophilic oxidizing agent with bacteriocidal and keratolytic effects. The addition of adapalene with BPO does not result in chemical or photo-instability of the combined product. Retinoids are considered first line therapy for mild comedonal and inflammatory acne.¹ In dermatological practice, topical retinoids are the class of agents most commonly used as topical monotherapy for acne. When 2 topical agents are used, the agents most frequently selected are retinoids and BPO, either alone or with antibiotics.² In view of the primary role of these 2 classes of topical agents, a single formulation comprising both is rational and may increase adherence and improve overall efficacy.

Review of Clinical Studies

Dose-ranging Studies

Individually, topical retinoids and BPO are potentially irritating agents and a combination product may increase this potential. In an irritancy study³ comparing adapalene 0.1% gel, tazarotene cream 0.05%, and tretinoin microsphere gel 0.04% used in combination with 2 different clindamycin/BPO products under occlusion, the adapalene 0.1% gel was reported to be the least irritating. This 3-week randomized, controlled intraindividual study involved test site applications at the back under occlusion. The tolerability of 2 different combination clindamycin/BPO topical products followed 8 hrs later by adapalene 0.1% gel, tazarotene cream 0.05%, and tretinoin microsphere gel 0.04% was evaluated. Regardless of the type of clindamycin/BPO combination, the mean cumulative irritancy index and erythema scores were significantly lower for sites involving adapalene gel. The combination of adapalene 0.1% and BPO 2.5% was selected for further development based on a cutaneous tolerability study⁴ evaluating adapalene 0.1% combined with either BPO 2.5% or 5%. In that study, 60 healthy subjects were randomized into a 3 week split-face trial with daily application of adapalene 0.1% + BPO 2.5%, adapalene 0.1% + BPO 5%, BPO 2.5% or 5%. This study showed that irritation scores (total sum score comprising erythema, dryness, pruritus, and stinging/burning) for adapalene 0.1% + BPO 2.5% were lower than for the combination product containing BPO 5%, and similar to BPO 5% alone.

Randomized-Controlled Trials (See Table 1)

A Phase II/III randomized, double-blind, parallel group study5 of adapalene 0.1% + BPO 2.5% gel, adapalene 0.1% gel, BPO 2.5% gel, or vehicle gel used nightly for 12 weeks involved 517 acne patients enrolled in a 2:2:2:1 ratio, respectively. The combination arm was significantly more effective in achieving a facial acne global grade of clear/almost clear (i.e., 28% vs. 16% vs. 15% vs. 10%, respectively). The differences were significant against the BPO (P=0.003) and vehicle (P=0.02) arms, and borderline for adapalene itself (P=0.08). Significant improvements in the lesion counts were observed for the combination compared with monotherapy and vehicle arms. Total acne lesions were reduced by 51% (median 78 at baseline to 40 at end of study), inflammatory lesions by 63% (27 to 17), and noninflammatory lesions by 51% (44 to 22). Overall local tolerability of the combination was similar to that for adapalene alone, with a somewhat higher percentage of subjects in the combination group having erythema, dryness, and/or stinging/burning. Mean tolerability scores, based on erythema, scaling, dryness, and stinging/burning, peaked at the first week and declined thereafter. Mean symptom scores were mild or less for all treatment arms.

A subsequent larger Phase III double-blind, randomized-controlled trial⁶ (RCT) with similar trial design involving 1668 patients randomized into the same 4 treatment arms in a 1:1:1:1 ratio was performed. Results demonstrated that the combination was more effective in achieving clear/almost clear global scores (30% vs. 20% for adapalene 0.1% gel , 22% for BPO 2.5% gel and 10% for vehicle gel), and in reducing acne counts. Total acne counts were reduced by 56% (median 76 at baseline to 35 at end of study), inflammatory lesions by 62% (27 to 11), and noninflammatory lesions by 54% (44 to 20). A significant reduction in all lesion counts were noted within the first week of treatment compared with vehicle. Local intolerability adverse events were mild-to-moderate in all treatment arms and peaked during the first week. However, more patients in the adapalene + BPO combination group experienced signs and symptoms of local intolerability compared with the other treatment groups. The number of patients with adverse events leading to discontinuation was slightly higher with the combination compared with adapalene monotherapy, BPO monotherapy, and vehicle groups: 11 (2.7%) vs. 4 (1.0%), 5 (1.2%), and 2 (0.5%), respectively. The most frequent treatment-related adverse event was dry skin, which was higher in the combination and adapalene groups than in the BPO monotherapy and vehicle groups (i.e., 6.0%, 4.3%, 1.9%, and 2.2% respectively).

Study	Summary	Epiduo™	Adapalene 0.1% in Vehicle Gel	BPO 2.5% in Vehicle Gel	Vehicle Gel
Thiboutot, et al.5	number of patients	149	148	149	71
	success rate (%)	28	16	15	10
	P-value (vs. Epiduo™)		0.008	0.003	0.002
	total lesions (median % change)	-51	-35*	-36*	-31*
	inflammatory lesions	-63	-46*	-44*	-38*
	noninflammatory lesions	-51	-33*	-36*	-38*
Stein-Gold et al.6	number of patients	415	420	415	418
	success rate (%)	30	20	22	11
	P-value (vs. Epiduo™)		<0.001	0.006	<0.001
	total lesions (median % change)	-56	-47**	-48**	-28**
	inflammatory lesions	-62	-50**	-56**	-34**
	noninflammatory lesions	-54	-49**	-44**	-29**
Pooled outcomes	number of patients	564	568	564	489
	success rate (%)	28	18	19	10
Table 1: Efficacy of Epiduo™ and its components on success rate and lesion reduction in acne (success defined as investigator global scores of clear or almost clear). * P <0.001; ** P < 0.017

Long-term Safety and Efficacy

The long-term tolerability and safety of adapalene 0.1% + BPO 2.5% gel was evaluated in 452 acne subjects over 12 months.⁷ Of these, 327 completed the study (72%). No subjects discontinued due to lack of efficacy, while discontinuation due to adverse events was 2%. Overall, treatment was well tolerated with mean scores for local intolerance (comprising erythema, dryness, scaling, and burning/stinging) reported as mild or less in all study visits. The mean worst scores of subjects were consistent with mild irritation. The highest irritation scores were recorded at the first week and subsequently declined thereafter. The most common adverse event was dry skin (17%). Efficacy, based on the intent to treat population with last observation carried forward, was 65% reduction in total, 70% in inflammatory, and 66% in noninflammatory lesion counts.

Conclusion

The combination of adapalene 0.1% + BPO 2.5% gel in a single formulation is a novel topical agent for the treatment of mild-to-moderate inflammatory acne. The clinical efficacy and tolerability of this fixed dose combination over 12 weeks has been shown in 2 large high quality RCTs. Furthermore, long-term tolerability and ongoing efficacy has been demonstrated in a 12-month study.

J. K. L. Tan, MD, FRCPC
Department of Medicine, University of Western Ontario, London, ON, Canada

Oil Production in the skin

The skin has many oil (sebaceous) glands, which secrete oil that contains wax esters, triglycerides, and squalene - a hydrocarbon that is an intermediate in the formation of cholesterol. These fats (or lipids) form a film that helps keep moisture in the skin. While increased sebum production results in oily skin, the opposite is not always the case, as dry skin can also arise from an impaired skin barrier. Oil production can be affected by diet, stress, and hormones-as well as genetics. In a study of twenty pairs each of identical and nonidentical same-sex twins, identical twins had virtually identical amounts of oil production, while the nonidentical twins had significantly different amounts.

No amount of blotting and scrubbing will “remove” the skin’s oil production, and many of us unknowingly destroy the natural beauty of the skin in pursuit of clarity. The skin’s own sebum mechanism is there to regulate own moisture. Drying your skin profusely with oil-stripping, foaming cleansers, detergents and de-greasers like soap and sulfates, or alcohol-based toners that leave the skin feeling tight (always a sign it’s been stripped), will only cause the skin to “rebound” with excess oiliness and destroy its protective and anti-bacterial “matrix,” leaving it sensitized. By stripping the natural acid mantle of the skin, these deep cleaning products actually make skin more vulnerable to bacteria and inflammation. Dabbing benzoyl peroxide often destroys the beauty of the skin by causing flaking, while more aggressive treatments, such as antibiotics or Accutane can cause a cascade of side-effects.

Benzoyl Peroxide and Tretinoin

When applying antiacne drugs to the skin, people should be careful not to get the medicine in the eyes, mouth, or inside the nose. They should not put the medicine on skin that is wind burned, sunburned, or irritated, and not apply it to open wounds.

Because antiacne drugs such as benzoyl peroxide and tretinoin irritate the skin slightly, users should avoid doing anything that might cause further irritation. They should wash the face with mild soap and water only two or three times a day, unless the physician says to wash it more often. They should also avoid using abrasive soaps or cleansers and products that might dry the skin or make it peel, such as medicated cosmetics, cleansers that contain alcohol, or other acne products that contain resorcinol, sulfur, or salicylic acid.

If benzoyl peroxide or tretinoin make the skin too red or too dry or cause too much peeling, the user should check with a physician. Using the medicine less often or using a weaker strength may be necessary. Benzoyl peroxide can irritate the skin of people with skin of color and cause darkened spots called hyperpigmentation on the skin. Benzoyl peroxide may discolor hair or colored fabrics.

ORAL DRUGS. Oral antibiotics are taken daily for two to four months. The drugs used include tetracycline, erythromycin, minocycline (Minocin), doxycycline, clindamycin (Cleocin), and trimethoprim-sulfamethoxazole (Bactrim, Septra). Possible side effects include allergic reactions, stomach upset, vaginal yeast infections, dizziness, and tooth discoloration.

The goal of treating moderate acne is to decrease inflammation and prevent new comedones from forming. One effective treatment is topical tretinoin, used along with a topical or oral antibiotic. A combination of topical benzoyl peroxide and erythromycin is also very effective. Improvement is normally seen within four to six weeks, but treatment is maintained for at least two to four months.

Special Conditions

People who have certain medical conditions or who are taking certain other medicines may have problems if they use antiacne drugs. Before using these products, the physician should be informed about any of the following conditions.

ALLERGIES. Anyone who has had unusual reactions to etretinate, isotretinoin, tretinoin, vitamin A preparations, or benzoyl peroxide in the past should let the physician know before using an antiacne drug. The physician should also be told about any allergies to foods, dyes, preservatives, or other substances.

PREGNANCY. Teens who are pregnant or who may become pregnant should check with a physician before using tretinoin or benzoyl peroxide. Isotretinoin causes birth defects in humans and must not be used during pregnancy.

OTHER MEDICAL CONDITIONS. Before using antiacne drugs applied to the skin, people with any of these medical problems should make sure their physicians are aware of their conditions:
•    Eczema. Antiacne drugs that are applied to the skin may make this condition worse.
•    Sunburn or raw skin. Antiacne drugs that are applied to the skin may increase the pain and irritation of these conditions.

In people with certain medical conditions, isotretinoin may increase the amount of triglyceride (a fatty-substance) in the blood. This may lead to heart or blood vessel problems. Before using isotretinoin, adolescents with any of the following medical problems should make sure their physicians are aware of their conditions:

•    alcoholism or heavy drinking, currently or in the past
•    diabetes or family history of diabetes (Isotretinoin may change blood sugar levels.)
•    family history of high triglyceride levels in the blood
•    severe weight problems

Using antiacne drugs with certain other drugs may affect the way the drugs work or may increase the chance of side effects.

Oil Production in the skin

The skin has many oil (sebaceous) glands, which secrete oil that contains wax esters, triglycerides, and squalene - a hydrocarbon that is an intermediate in the formation of cholesterol. These fats (or lipids) form a film that helps keep moisture in the skin. While increased sebum production results in oily skin, the opposite is not always the case, as dry skin can also arise from an impaired skin barrier. Oil production can be affected by diet, stress, and hormones-as well as genetics. In a study of twenty pairs each of identical and nonidentical same-sex twins, identical twins had virtually identical amounts of oil production, while the nonidentical twins had significantly different amounts.

No amount of blotting and scrubbing will “remove” the skin’s oil production, and many of us unknowingly destroy the natural beauty of the skin in pursuit of clarity. The skin’s own sebum mechanism is there to regulate own moisture. Drying your skin profusely with oil-stripping, foaming cleansers, detergents and de-greasers like soap and sulfates, or alcohol-based toners that leave the skin feeling tight (always a sign it’s been stripped), will only cause the skin to “rebound” with excess oiliness and destroy its protective and anti-bacterial “matrix,” leaving it sensitized. By stripping the natural acid mantle of the skin, these deep cleaning products actually make skin more vulnerable to bacteria and inflammation. Dabbing benzoyl peroxide often destroys the beauty of the skin by causing flaking, while more aggressive treatments, such as antibiotics or Accutane can cause a cascade of side-effects.

Benzoyl peroxide and Isotretinoin

Benzoyl peroxide is found in many over-the-counter acne products that are applied to the skin, such as Benoxyl, Neutrogena Acne, PanOxyl, and some formulations of Clean & Clear, Clearasil, and Oxy. Some benzoyl peroxide products are available without a physician’s prescription; others require a prescription. Acne treatments that can dry the skin should be used with caution by people with skin of color.
Tretinoin (Retin-A) is available only with a physician’s prescription. It comes in liquid, cream, and gel forms, which are applied to the skin. Isotretinoin (Accutane), which is taken by mouth in capsule form, is available only with a physician’s prescription. Only physicians experienced in diagnosing and treating severe acne, such as dermatologists, should prescribe isotretinoin.
Recommended Dosages

The recommended dosage depends on the type of antiacne drug. These drugs usually come with written directions for patients and should be used only as directed by the prescribing physician. Teens who have questions about how to use the medicine should check with their physician or pharmacist.

Patients who use isotretinoin usually take the medicine for a few months, then stop for at least two months. Their acne may continue to improve even after they stop taking the medicine. If the condition is still severe after several months of treatment and a two-month break, the physician may prescribe a second course of treatment.
Precautions

Isotretinoin

Isotretinoin can cause serious birth defects, including mental retardation and physical deformities. This medicine should not be used during pregnancy. Females who are able to bear children should not use isotretinoin unless they have very severe acne that has not cleared up with the use of other antiacne drugs. In that case, a woman who uses this drug must have a pregnancy test two weeks before beginning treatment and each month she is taking the drug. Another pregnancy test must be done one month after treatment ends. The woman must use an effective birth control method for one month before treatment begins and must continue using it throughout treatment and for one month after treatment ends.

Females who are able to bear children and who want to use this medicine should discuss this information with their healthcare providers. Before using the medicine, they will be asked to sign a consent form stating that they understand the danger of taking isotretinoin during pregnancy and that they agree to use effective birth control.
People using this drug should not donate blood to a blood bank while taking isotretinoin or for 30 days after treatment with the drug ends. This will help reduce the chance of a pregnant woman receiving blood containing isotretinoin, which could cause birth defects.
Isotretinoin may cause a sudden decrease in night vision. If this happens, users should not drive or do anything else that could be dangerous until vision returns to normal. They should also let the physician know about the problem.

This medicine may also make the eyes, nose, and mouth dry. Ask the physician about using special eye drops to relieve eye dryness. To temporarily relieve the dry mouth, chew sugarless gum, suck on sugarless candy or ice chips, or use saliva substitutes, which come in liquid and tablet forms and are available without a prescription. If the problem continues for more than two weeks, check with a physician or dentist. Mouth dryness that continues over a long time may contribute to tooth decay and other dental problems.
Isotretinoin may increase sensitivity to sunlight. Patients being treated with this medicine should avoid exposure to the sun and should not use tanning beds, tanning booths, or sunlamps until they know how the drug affects them.

In the early stages of treatment with isotretinoin, some people’s acne seems to get worse before it starts getting better. If the condition becomes much worse or if the skin is very irritated, they should check with the physician who prescribed the medicine.

SKIN HYDRATION: OILY VS. DRY

With oily skin, your face may often look shiny, and you naturally avoid products that feel oily. You’ll be more vulnerable to acne and breakouts than dry skin types. People with dry skin will notice that their skin feels dry and has a dull color and/or rough texture.

Oil Production

The skin has many oil (sebaceous) glands, which secrete oil that contains wax esters, triglycerides, and squalene. These fats (or lipids) form a film that helps keep moisture in the skin. While increased sebum production results in oily skin, the opposite is not always the case, as dry skin can also arise from an impaired skin barrier. Oil production can be affected by diet, stress, and hormones-as well as genetics. In a study of twenty pairs each of identical and nonidentical same-sex twins, identical twins had virtually identical amounts of oil production, while the nonidentical twins had significantly different amounts.

Dryness and oiliness depend primarily on the condition of the skin barrier, the outer layer of skin which helps the skin retain moisture, and the oil (sebum) production itself. The barrier is like a brick wall, with each brick (or cell) held in place by mortar (fats called lipids). Harmful ingredients, cold, and dry weather can wear down these fats, eroding the mortar so that the “bricks” are not secured in their proper place. A variety of outside agents, including detergents, acetone, chlorine and other chemicals, and even prolonged water immersion can harm the barrier, or the barrier may be deficient for genetic reasons.

The barrier’s main components are ceramides, fatty acids, and cholesterol, all different kinds of lipids. These must be present in the right proportion to keep the skin watertight. An impaired barrier will tend toward both dryness and sensitivity. Dryness results when skin moisture evaporates. Sensitivity results when a deficient barrier permits the entry of outside irritants.

Repairing the skin barrier with the right skin care products will help treat a variety of skin conditions. Incorporating key dietary nutrients, such as essential fatty acids and cholesterol, provides the necessary building blocks. Nutrient deficiencies can weaken your skin’s ability to repair and rebuild, which is why people who take cholesterol-lowering drugs often have dry skin.