¹Department of Medicine, University of Western Ontario, London, ON, Canada
²Windsor Clinical Research Inc., Windsor, ON, Canada

Introduction

Acne vulgaris is a multifactorial disease characterized by different types of lesions at various stages of development. Treatment options must address a spectrum of disease from mild to severe; and encompasses topical to systemic agents, respectively. For all acne therapy however, adherence remains an issue. Advances in delivery mechanisms have been developed to improve patient compliance with both topical and systemic modalities. Most recently, the novel lipid technology (Lidose®) has been utilized in the administration of oral isotretinoin. CIP-Isotretinoin (Epuris™), approved by Health Canada in November 2012 and released commercially in June 2013, enhances drug absorption during fasted states and lessens the need for administration with a high-fat meal, thereby potentially improving bioavailability and patient adherence.

UVA and UVB Light-Induced Skin Reactions

• Acne treatment selection is generally based on the severity and type of lesions, with the goal of treatment being to reduce sebum production, infundibular occlusion, inflammation and Propionibacterium acnes proliferation.
• Conventional topical therapies were originally composed of single agent preparations.
• Improved knowledge of acne pathogenesis and topical formulation chemistry led to development and clinical application of combination products (Table 1).
• Recent studies have demonstrated greater efficacy and tolerability with combination therapy compared to monotherapy.
• As a result, current consensus guidelines recommend the use of combination treatment as first-line therapy for most patients with mild to moderate acne.
• Notwithstanding efficacy, issues such as irritation and the emergence of bacterial resistance to both topical and oral antibiotics remain significant barriers to improved treatment outcomes.
• It is estimated that 30-40% of patients using topical formulations do not adhere to their prescribed regimen.¹

Improving Patient Adherence to Topical Therapy

• Treatment efficacy, local tolerance and adherence have all been improved through recent advances in vehicle technology.²
• Additionally, delivery mechanisms such as pumps which provide convenience, are preferred by patients and may improve adherence.³
• In a Patient Preferences in Acne: A Point-of-Care Educational Initiative, a national survey of 1709 Canadian patients showed that pump delivery systems are the preferred format (42% of patients).³
• However, patient preferences have been shown to extend beyond treatment side-effects: variables such as vehicle composition, messiness, texture, aroma, difficulty of use, lack of early improvement, and staining, can all decrease compliance.⁴
• Many new topical acne formulations have aqueous-based gel vehicle delivery systems that do not contain alcohol and are suitable for use in all skin types as they are less drying.
• Topical acne agents can cause cutaneous irritation related in part to impaired epidermal barrier function.⁵ Therefore:
  • the use of gentle cleansers and moisturizers has been shown to reduce this cutaneous irritation;⁶
  • moisturizers containing ceramides can improve skin barrier function.
• Additionally, vehicle advances, such as microsphere technology and solubilized crystalline formulations, reduce the potential of irritation from tretinoin.
• Photodegradation is not increased with microsphere tretinoin, tazarotene and adapalene, allowing for morning application.
• Clindamycin/BPO formulations with humectants and emollients may reduce the dry skin associated with BPO use.
• Clindamycin/BPO formulations without preservatives may reduce the irritation associated with these agents.⁷
• The addition of BPO to topical antibiotic agents and the use of BPO with long-term oral antibiotics can reduce the risk of cutaneous bacterial resistance.

Systemic Treatment for Severe Acne

Oral Isotretinoin

• Since US FDA approval of the oral isotretinoin agent Accutane™ in 1982, and its subsequent approval by Health Canada in 1983, it has remained the standard of treatment for severe nodular acne in Canada.
• Oral isotretinoin is a synthetic derivative of vitamin A, and is similar to the parent compound in being highly fat-soluble.
• As a result, ingestion of oral isotretinoin with food increases its bioavailability.⁸
  • In the fasted state, ingestion of standard oral isotretinoin formulations leads to plasma levels that are approximately 60% lower compared to the fed state.⁸
  • Accordingly, standard practice recommendations promote ingestion with food, particularly a high-fat meal, to enhance absorption.
• However, patient adherence and reliability in taking isotretinoin with high-fat meals may be inconsistent.^9-11
• Irregular eating habits may result in irregular dosing and therefore variable drug absorption.

CIP-Isotretinoin (Epuris™)

• CIP-Isotretinoin (Epuris™) was approved by Health Canada in November 2012 and launched in June of 2013.
  • It utilizes Lidose® technology to imbed isotretinoin in a lipid matrix, thereby increasing drug absorption during fasted state.¹²
  • CIP-Isotretinoin may lead to more consistent plasma levels of isotretinoin during variable dietary conditions, providing the potential for enhanced patient outcomes.
• Particularly for those with irregular eating times, treatment adherence may be improved as the absorption of the drug is better than the standard formulation in the absence of a high fat meal.
• This technology has already been successfully combined with a fenofibrate formulation (Lipofen™) to create a novel capsule used for treatment of hyperlipidemia.
• An application of this delivery platform encompassing oral CIP-Isotretinoin was approved by the US FDA in May 2012 (Absorica™) with indications for treatment of severe nodular and or inflammatory acne, acne conglobate, and recalcitrant acne.

Efficacy & Safety

• An open label, single dose randomized crossover study demonstrated pharmacokinetic bioequivalence of CIPIsotretinoin to standard isotretinoin formulations during high fat fed states, with significantly greater absorption during fasting.¹³
  • In the fasted state, the absorption of CIP-Isotretinoin, was approximately 83% greater than that of conventional isotretinoin.
  • The products were bioequivalent when taken with a high fat meal.¹³
• In a double-blind, randomized, controlled trial comparing CIP-Isotretinoin under high fat fed conditions to a currently marketed formulation of oral isotretinoin (Accutane™), 925 subjects with severe recalcitrant nodular acne aged 12-54 years were recruited.⁸ Subjects had to have at least 10 acne nodules on the face and/or trunk.
  • The number of responders, defined as those with ≥90% reduction in nodules at end of study compared to baseline, was similar in both treatment groups with overlapping 95% confidence intervals in per protocol (79% CIPIsotretinoin versus 81% Accutane™) and intent-to-treat (70% versus 75%) analyses.
  • Furthermore, the mean reduction in nodules in both groups was similar for both analyses (-17 versus -16, -16 versus -16, respectively), demonstrating clinical noninferiority.
  • Almost all patients experienced at least one adverse event in both groups at a similar rate (92% with CIP-Isotretinoin to 90% with Accutane™).¹⁴
  • Reported adverse events were typical for oral isotretinoin use, with the majority related to dry skin and cheilitis.¹⁴
  • Rates of serious adverse events occurring with the use of both CIP-Isotretinoin and standard oral isotretinoin were low (5/464 or 1.1% and 7/464 or 1.5%, respectively).¹⁴
  • Adverse events leading to discontinuation of participation occurred in 4.1% (19/464) of patients with CIPIsotretinoin, compared to 3.3% (15/460) of patients with standard oral isotretinoin.

Dosage & Administration

• Capsules of CIP-Isotretinoin are available in 10 mg (yellow), 20 mg (red), 30 mg (brown), and 40 mg (brown and red) doses in packages of 30 capsules (3 x 10 blister cards), which provides for flexible, individualized dosing according to the patient’s weight and disease severity.
• Inactive ingredients in this formulation include: stearoyl macrogolglycerides, soybean oil, sorbitan monooleate, and propyl gallate.
• Accutane™ is currently available in Canada in 10 mg (pink), and 40 mg (orange) doses in blister packages of 30 capsules. Ingredients include beeswax, black iron oxide, gelatin, glycerol, soybean and peanut oils, parabens, shellac, and titanium dioxide.
• To prevent potential allergic reactions, Accutane™ should particularly be avoided in patients with sensitivities to peanut oil and parabens, in addition to the aforementioned contents.
• As with standard isotretinoin formulations, the starting dose of CIP-Isotretinoin should be administered according to the patient’s weight and severity of the disease.
• In general, patients should initially receive CIP-Isotretinoin 0.5 mg/kg body weight daily for 2-4 weeks while monitoring their responsiveness to the drug.¹⁴
• Maintenance dose should be adjusted between 0.1 mg and 1 mg/kg body weight daily, depending on response and tolerance.
• A complete course of therapy consists of 12-16 weeks of CIP-Isotretinoin administration.¹⁴
• In view of differences in bioavailability, CIP-Isotretinoin is not interchangeable with standard oral isotretinoin formulations.
• As with any oral retinoid treatment, the need for ongoing pregnancy prevention and safety monitoring is of paramount concern.
• Generally, the side effects of oral isotretinoin have been well characterized, with the most common ones being mucocutaneous and mild.
• It is recommended to initiate CIP-Isotretinoin treatment at a low dose of 0.5 mg/kg/day for 2-4 weeks to assess drug tolerance.

Conclusion

Advances in delivery technologies for mild, moderate and severe acne are improving treatment adherence. Additionally, in mild to moderate acne, a greater understanding of acne pathogenesis has led to the development of effective combination treatments. In severe nodular acne, the novel CIPIsotretinoin formulation has been designed to reduce variation in bioavailability during fed and fasted states. In the context of clinical use, where patients may be unable to consistently take oral isotretinoin with a high-fat meal, this product enhances bioavailability and has the potential of improving clinical outcomes.

References

1. Finlay AY. J Eur Acad Dermatol Venereol. 1999;12(Suppl 2):S77.
2. Koo J. Skinmed. 2003;2(4):229-33.
3. Vender R, et al. Patient preferences in acne: a point-of-care educational initiative. Poster presentation.
4. Kircik LH, et al. Practical Dermatol. 2010;7(6 Suppl):1-16.
5. Del Rosso JQ, et al. J Drugs Dermatol. 2006;5(2):160-4.
6. Gollnick H, et al. J Am Acad Dermatol. 2003;49(1 Suppl):S1-37.
7. Zeichner JA. J Drugs Dermatol. 2012;11(3):313-7.
8. Colburn WA, et al. J Clin Pharmacol. 1983;23(11-12):534-9.
9. Hogan DJ, et al. CMAJ. 1988;138(1):47-50.
10. Cohen B, et al. Can J Public Health. 2003;94(1):41-4.
11. Rampersaud GC, et al. J Am Diet Assoc. 2005;105(5):743-60.
12. Laboratories S.M.B., Brussels, Belgium. Web site. Lidose. Accessed July 29, 2013.
13. Webster GF, et al. J Am Acad Dermatol. 2013 Aug 13. [Epub ahead of print]
14. Epuris™ [Product monograph]. March 14, 2013. Cipher Pharmaceuticals Inc., Mississauga, ON.

¹Department of Medicine, University of Western Ontario, London, ON, Canada
²Windsor Clinical Research Inc., Windsor, ON, Canada

ABSTRACT

Current practice guidelines recommend administration of oral isotretinoin with high-fat meals, which may pose issues with patient compliance. Isotretinoin-Lidose (Epuris™), approved by Health Canada in November 2012 and scheduled for commercial release June 2013, is based on novel lipid encapsulation technology (Lidose®) to enclose isotretinoin, thereby increasing drug absorption during fasted states. An open label, single dose randomized crossover study demonstrated pharmacokinetic bioequivalence of isotretinoin-Lidose to standard isotretinoin formulations during fed states, with significantly greater absorption during fasting. Isotretinoin-Lidose, may lead to more consistent plasma levels of isotretinoin during variable dietary conditions, providing the potential for enhanced patient outcomes.

Key Words:
acne vulgaris, bioavailability, drug delivery, isotretinoin

Introduction

Since US FDA approval of the oral isotretinoin agent Accutane™ in 1982, and its subsequent approval by Health Canada in 1983, it has been and continues to be the standard of treatment for severe nodular acne in the US and Canada. As this agent is a synthetic derivative of vitamin A, it is similar to the parent compound in being fat-soluble. As a result, ingestion of oral isotretinoin with food increases bioavailability.¹ In the fasted state, ingestion of standard oral isotretinoin formulations leads to plasma levels that are approximately 60% lower compared to the fed state.¹ Accordingly, standard practice recommendations promote ingestion with food, particularly a high-fat meal, to enhance absorption.

However, patient adherence and reliability in taking isotretinoin with high-fat meals may be problematic.^2-4 Inconsistent eating habits during drug administration may result in irregular dosing and considerable variation in plasma levels of isotretinoin, within and between patients. Thus, a previous unmet need with oral isotretinoin has been a formulation less dependent on the fed state to reduce this potential for suboptimal absorption and subtherapeutic plasma levels. Hoffman-La Roche Pharmaceuticals Inc., the manufacturer of Accutane™ the incumbent branded oral isotretinoin formulation, addressed this issue through the development of Accutane-NF (new formulation). This microionized version of Accutane™ was developed to reduce particle size, thereby increasing bioavailability.⁵ Accutane-NF was projected to result in therapeutic levels of isotretinoin with once-daily dosing and without the need for administration with food.⁵ A randomized, double-blind clinical trial comparing these two formulations in 600 patients with severe recalcitrant nodular acne showed that the overall efficacy of Accutane-NF was statistically similar to standard Accutane™. However, the new formulation trended towards lower efficacy as demonstrated in the proportion of subjects achieving >90% reduction in nodule counts, including percentage changes with respect to nodule counts, papules/pustules, and total inflammatory lesion counts, as well as global evaluations of excellent response/clearance. At the dosages tested, a lower risk of mucocutaneous adverse event and hypertriglyceridemia were noted.⁵ However, in the absence of clear advantages of the new formulation compared to standard Accutane™, when considering the balance of efficacy to adverse events (benefit:risk), there was no apparent public health benefit to marketing both formulations.⁵

Recently, this ongoing inadequacy was addressed with an innovative technology that encapsulates lipophilic drugs, such as isotretinoin, with lipid agents – thereby providing a more optimal environment for absorption within the formulation. Originally developed by SMB Laboratories, the Lidose® drug delivery system consists of a hard gelatin capsule containing liquid or semi-liquid contents composed of an active drug melted together with lipid excipients, then cooled under specific conditions.⁶ This technology has already been successfully combined with a fenofibrate formulation (Lipofen™, Cipher Pharmaceuticals Inc.) to create a novel capsule used for treatment of hyperlipidemia.

Potential advantages of Lidose® over conventional capsule technology include greater tolerability with less gastric irritation, rapid absorption, and protection of drug against oxidation.⁶ An application of this delivery platform encompassing oral isotretinoin-Lidose was approved by the US FDA in May 2012 (Absorica™, Cipher Pharmaceuticals Inc.) with indications for treatment of severe nodular and or inflammatory acne, acne conglobate, and recalcitrant acne. Health Canada approved isotretinoin-Lidose for the same indication in November 2012 (Epuris™, Cipher Pharmaceuticals Inc.).

Pharmacokinetic Studies

In an open label, single dose, randomized, crossover study involving 60 healthy subjects comparing isotretinoin-Lidose against standard oral isotretinoin, these preparations were shown to be pharmacokinetically bioequivalent under fed conditions (modified high-fat, high-calorie breakfast with reduced vitamin A content). However, administration of isotretinoin- Lidose resulted in significantly better absorption of isotretinoin and its metabolites under fasted conditions than did the standard isotretinoin formulation (Accutane™). Plasma levels of isotretinoin using the Lidose® formulation attained 67% of that achieved with a fatty meal compared to 40% using standard Accutane™.⁷ Furthermore, while more than 75% of subjects absorbed less than 50% isotretinoin with Accutane™ during the fasting state compared to fed state, 75% of patients prescribed isotretinoin-Lidose formulation absorbed at least 60%.⁷ A total of 55 adverse effects were reported, with the most common being headache. No significant difference in adverse event frequency between treatments was observed and no serious adverse events were reported.⁷

Clinical Trials

In a double-blind, randomized, controlled trial comparing isotretinoin-Lidose to a currently marketed formulation of oral isotretinoin (Accutane™), 925 subjects with severe recalcitrant nodular acne aged 12-54 years were recruited. Subjects had to have at least 10 acne nodules on the face and/or trunk. Active treatment under fed conditions with isotretinoin-Lidose or the reference marketed formulation was initiated at a dose of 0.5 mg/kg/day for the first 4 weeks, followed thereafter by 1 mg/kg/day for the subsequent 16 weeks. All participants were instructed to take the assigned isotretinoin formulation twicedaily with meals at breakfast and dinner for the full 20 weeks of treatment.⁸ The number of responders, defined as those with ≥90% reduction in nodules at end of study compared to baseline, was similar in both treatment groups with overlapping 95% confidence intervals in per protocol (79% isotretinoin- Lidose versus 81% Accutane™) and intent to treat (70% versus 75%) analyses. Furthermore, the mean reduction in nodules in both groups was similar for both analyses (-17 versus -16, -16 versus -16, respectively), demonstrating clinical noninferiority. Almost all patients experienced at least one adverse event in both groups at a similar rate (92% with isotretinoin- Lidose to 90% with Accutane™). Reported adverse events were typical for oral isotretinoin use, with the majority related to dry skin and cheilitis. No significant differences were observed in frequency of adverse events between treatment groups for psychiatric, ocular, auditory, musculoskeletal, cardiovascular, or gastrointestinal systems.⁸ Rates of serious adverse events occurring with the use of both isotretinoin-Lidose and standard oral isotretinoin were low (5/464 or 1.1% and 7/464 or 1.5%, respectively). Three serious side effects possibly related to isotretinoin-Lidose were severe abdominal pain, severe upper abdominal pain, and moderate migraine, all of which resolved completely. Serious adverse events related to standard oral isotretinoin were not included in this publication. Adverse events leading to discontinuation of participation were reported in 4.1% (19/464) of patients with isotretinoin-Lidose, compared to 3.3% (15/460) of patients with standard oral isotretinoin. These were classified as psychiatric and gastrointestinal events in the isotretinoin-Lidose group, and as psychiatric and musculoskeletal/connective tissue events in the reference group.

Dosage Forms and Administration

Capsules of isotretinoin-Lidose are available in 10 mg (yellow), 20 mg (red), 30 mg (brown), and 40 mg (brown and red) doses in packages of 30 capsules (3 x 10 blister cards). Inactive ingredients in this formulation include: stearoyl macrogolglycerides, soybean oil, sorbitan monooleate, and propyl gallate. Accutane™ is currently available in 10 mg (pink), 20 mg (red; not available in Canada) and 40 mg (orange) doses in blister packages of 30 capsules, and ingredients include beeswax, black iron oxide, gelatin, glycerol, soybean and peanut oils, parabens, shellac, and titanium dioxide. To prevent potential allergic reactions, Accutane™ should particularly be avoided in patients with sensitivities to peanut oil and parabens, in addition to the aforementioned contents. Isotretinoin-Lidose dye systems vary with the dose forms: 10 mg – iron oxide (yellow) and titanium dioxide; 20 mg – iron oxide (red) and titanium dioxide; 30 mg – iron oxide (yellow, red, and black) and titanium dioxide; and 40 mg – iron oxide (yellow, red, and black) and titanium dioxide.

As with standard isotretinoin formulations, the starting dose of isotretinoin-Lidose should be administered according to the patient’s weight and severity of the disease. In general, patients should initially receive isotretinoin-Lidose 0.5 mg/kg body weight daily for 2-4 weeks while monitoring their responsiveness to the drug.⁸ Maintenance dose should be adjusted between 0.1 mg and 1 mg/kg body weight daily, depending on the response and tolerance. A complete course of therapy consists of 12-16 weeks of isotretinoin-Lidose administration.⁸ In view of differences in bioavailability, the use of isotretinoin-Lidose is not considered interchangeable with standard oral isotretinoin formulations.

As with any oral retinoid treatment, the need for on-going pregnancy prevention and safety monitoring is of paramount concern. Generally, the side effects of oral isotretinoin have been well characterized, with the most common ones being mucocutaneous and mild. As isotretinoin-Lidose is formulated to be a more bioavailable form of oral isotretinoin under fasted conditions, rates of adverse events should not be appreciably different between the two therapies – as demonstrated by the clinical trial.⁸ However, due to the specific parameters and controlled conditions of the study, this data may not directly generalize to overall rates observed in clinical practice. Therefore, it is recommended to initiate isotretinoin-Lidose treatment at a low dose of 0.5 mg/kg/day for 2-4 weeks to assess drug tolerance.

Discussion: Epuris™ and Other Recent Isotretinoin Advancements

Several current guidelines for the treatment of severe nodulocystic and conglobate acne indicate the use of isotretinoin as a monotherapy in doses ranging from 0.5-2.0 mg/kg/day over 4-6 months^9-11 to achieve a final cumulative dose of 120-150 mg/kg.^9,11 This cumulative dose has been considered to be optimal to minimize relapse requiring retreatment. Preventing the need for retreatment is a desirable prospect, as it would reduce the likelihood of fetal exposure to teratogens in women of child-bearing age with additional treatment courses, decrease the overall occurrence of adverse events, and lessen the development of permanent acne scarring resulting from incomplete resolution of acne lesions. As the isotretinoin-Lidose formulation increases isotretinoin bioavailability during fasted states, it may mitigate the obstacle of variable patient compliance, thereby increasing the probability of efficiently attaining the recommended cumulative dose. However, the evidence basis for current cumulative dose thresholds is tenuous. Recent evidence suggests that there may be less of a role for cumulative dose in the treatment of acne than previously thought, and prevention of relapse may be more directly attributable to prolonged sebosuppresion.¹² In particular, it is unclear whether prolonged remission is best achieved through prolonged sebosuppression achievable by long-term, low-dose administration, or through apoptosis and sebaceous gland atrophy requiring higher doses. Nevertheless, though it currently serves as an acceptable approximation of appropriate treatment duration, further investigation is required to provide high-level evidence for remissions with varying dosing regimens.

The reassessment of isotretinoin dosing regimens has increased in recent years, with the aim of determining the most efficient and scientifically credible means of oral isotretinoin administration. Recognition of the efficacious role of low-dose isotretinoin therapy in severe acne is compelling and emerging evidence suggests that current practice guidelines may be recommending unnecessary high doses of isotretinoin, resulting in preventable side effects. Several studies have suggested that continuous, low-dose regimens may be as effective for treatment of acne and prevention of relapse as those using higher, classic doses.^13-16 A recent randomized, double-blind, placebo-controlled trial demonstrated that doses as low as 5 mg/day isotretinoin independent of body weight, significantly reduced acne lesion count and improved Dermatology Life Quality Index (DQLI) scores after 16 weeks of treatment.¹⁴ Patients continued to improve 10 weeks after treatment discontinuation and relapses were not observed during this post-treatment follow-up. Furthermore, in one of the largest studies evaluating low-dose isotretinoin treatment, 638 patients were successfully treated with 0.3-0.4 mg/kg/day over 6 months, with none relapsing at the 24-week follow-up.¹⁶ Although these studies may not have had adequate follow-up durations to sufficiently assess relapse, their findings present considerable potential in improving patient satisfaction, as lower-dose regimens have been associated with fewer overall adverse events and increased cost effectiveness.¹⁷ A prospective, randomized, controlled study investigating the clinical efficacy and tolerance of low-dose regimens reported that patient satisfaction was significantly higher in the low-dose treatment group (0.25-0.4 mg/kg/day) compared to higher dose group (0.5-0.7 mg/kg/day).¹³ A major limitation of evidence for low-dose regimens is that they have not been directly compared to full-dosing (1.0 mg/kg/day). The combination of low-dose strategies with increased bioavailability formulations such as isotretinoin-Lidose could optimize the benefits of treatment with less medication.

Conclusion

The novel isotretinoin-Lidose formulation was designed to reduce variation in bioavailability during fed and fasted states compared to standard isotretinoin. In the context of clinical use, where patients may be unable to consistently take oral isotretinoin with a high-fat meal, this product enhances bioavailability and has the potential of improving clinical outcomes.

References

1. Colburn WA, Gibson DM, Wiens RE, et al. Food increases the bioavailability of isotretinoin. J Clin Pharmacol. 1983 Nov-Dec;23(11-12):534-9.
2. Hogan DJ, Strand LM, Lane PR. Isotretinoin therapy for acne: a populationbased study. CMAJ. 1988 Jan 1;138(1):47-50.
3. Cohen B, Evers S, Manske S, et al. Smoking, physical activity and breakfast consumption among secondary school students in a southwestern Ontario community. Can J Public Health. 2003 Jan-Feb;94(1):41-4.
4. Rampersaud GC, Pereira MA, Girard BL, et al. Breakfast habits, nutritional status, body weight, and academic performance in children and adolescents. J Am Diet Assoc. 2005 May;105(5):743-60.
5. HLR Technology Corporation (Hoffman-La Roche), Nutley, NJ. NDA 21-177: New formulation isotretinoin [Executive Summary]. Summary date: August 9, 2000. Available at: www.fda.gov/ohrms/dockets/ac/00/backgrd/3639b1d_01. doc. Accessed July 29, 2013.
6. Laboratories S.M.B., Brussels, Belgium. Web site. Lidose.
7. Webster GF, Leyden JJ, Gross JA. Comparative pharmacokinetic profiles of a novel isotretinoin formulation (isotretinoin-Lidose) and the innovator isotretinoin formulation: a randomized, 4-treatment, crossover study. J Am Acad Dermatol. 2013 Aug 13. [Epub ahead of print]
8. Epuris™ [Product monograph]. March 14, 2013. Cipher Pharmaceuticals Inc., Mississauga, ON.
9. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol. 2007 Apr;56(4):651-63.
10. Nast A, Dreno B, Bettoli V, et al. European evidence-based (S3) guidelines for the treatment of acne. J Eur Acad Dermatol Venereol. 2012 Feb;26 Suppl 1:1-29.
11. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003 Jul;49(1 Suppl):S1-37.
12. Rademaker M. Isotretinoin: dose, duration and relapse. What does 30 years of usage tell us? Australas J Dermatol. 2012 Sep 26.
13. Lee JW, Yoo KH, Park KY, et al. Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative study. Br J Dermatol. 2011 Jun;164(6):1369-75.
14. Rademaker M, Wishart JM, Birchall NM. Isotretinoin 5 mg daily for low-grade adult acne vulgaris – a placebo-controlled, randomized double-blind study. J Eur Acad Dermatol Venereol. 2013 Apr 27. [Epub ahead of print]
15. Boyraz N, Mustak PK. Comparison of the efficacies of intermittent and continuous low-dose isotretinoin regimens in the treatment of moderate acne vulgaris. Int J Dermatol. 2013 May 17. [Epub ahead of print]
16. Agarwal US, Besarwal RK, Bhola K. Oral isotretinoin in different dose regimens for acne vulgaris: a randomized comparative trial. Indian J Dermatol Venereol Leprol. 2011 Nov-Dec;77(6):688-94.
17. Amichai B, Shemer A, Grunwald MH. Low-dose isotretinoin in the treatment of acne vulgaris. J Am Acad Dermatol. 2006 Apr;54(4):644-6.