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Aminolevulinic Acid (Topical)


VA CLASSIFICATION
Primary: DE900

Commonly used brand name(s): Levulan® Kerastick™.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Photosensitizer—

Photodynamic therapy—

Indications

General considerations
This product is intended to be applied by qualified medical personnel only.{01}

Accepted

Actinic keratoses, non–hyperkeratotic (treatment) —Aminolevulinic acid (ALA) with a blue light photodynamic therapy (PDT) illuminator is indicated for the treatment of non–hyperkeratotic actinic keratoses of the face or scalp.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    167.59{01}

Solubility:
     Very soluble in water, slightly soluble in methanol and ethanol, and practically insoluble in chloroform, hexane and mineral oil.{01}


Mechanism of action/Effect:

Aminolevulinic acid (ALA) is a metabolic prodrug of the photosensitizer, protoporphyrin IX (PpIX). PpIX accumulates intracellularly in the skin to which ALA has been applied. Light of appropriate wavelength and energy is directed and then absorbed by the affected skin. A cytotoxic process occurs through a photodynamic reaction when accumulated PpIX is exposed to light of appropriate wavelength and energy in the presence of oxygen. The absorption of light results in an excited state of the porphyrin molecule, and subsequent spin transfer from PpIX to molecular oxygen generates singlet oxygen, which can further react to form superoxide and hydroxyl radicals. The formation of the oxygens and radicals induces local cytotoxic effects.{01}

Absorption:

Oral bioavailability is 50%–60%.{01}


Biotransformation:

Aminolevulinic acid: After topical administration, synthesis into protoporphyrin IX takes place in situ in the skin.{01}


Half-life:

Aminolevulinic acid: 0.7 hours and 0.83 hours after oral and intravenous dose, respectively.{01}

Protoporphyrin IX: 30 hours and 28 hours for lesions and perilesional skin, respectively, after topical administration.{01}Plasma half–life is 8 hours after oral administration.{02}

Peak serum concentration:

Oral: 4.65 mcg/mL, aminolevulinic acid.{01}


Precautions to Consider

Cross-sensitivity and/or related problems

Allergies to porphyrins.

Carcinogenicity

Carcinogenicity studies have not been performed with aminolevulinic acid.{01}

Mutagenicity

Four studies; Ames mutagenicity assay with and without light, L5178Y TK +/- mouse lymphoma forward mutation assay, and in vivo mouse micronucleus assay, demonstrated no evidence of mutagenic effects. However, published studies demonstrate genotoxic effects in cultured rat hepatocytes after ALA exposure with PpIX formation.{01}Oxidative DNA damage in vivo and in vitro as a result of ALA exposure is also documented.{01}

Pregnancy/Reproduction
Fertility—
Assessment of fertility with aminolevulinic acid have not been performed.{01}

Pregnancy—
Studies in humans and animals have not been done.{01}

FDA Pregnancy Category C{01}

Breast-feeding

It is not known whether aminolevulinic acid is distributed in breast milk.{01} However, problems in humans have not been documented.{01}

Pediatrics

No information is available on the relationship of age to the effects of aminolevulinic acid in pediatric patients. Safety and efficacy have not been established.{01}


Geriatrics


No information is available on the relationship of age to the effects of aminolevulinic acid in geriatric patients.{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Any photosensitizing agent such as
Diuretics, thiazide
Griseofulvin
Phenothiazines
Sulfonamides
Sulfonylureas
Tetracyclines    (concomitant use may increase the photosensitivity reaction of actinic keratoses treated with aminolevulinic acid {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


The medication should not be used when the following medical problems exist:
» Allergy to porphyrins{01}
» Cutaneous photosensitivity to wavelengths of 400 to 450 nanometers (nm){01}
» Porphyria{01}
Risk–benefit should be considered when the following medical problems exist (reason given where appropriate; » = major clinical significance)
Coagulation defects, inherited or acquired    (Safety and efficacy have not been studied{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Bleeding or hemorrhage

{01}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Dysesthesia{01} (burning, crawling, itching, numbness, prickling, "pins and needles," stinging, or tingling feelings)
    
edema{01} (swelling of skin )
    
erosion{01} (skin sore)
    
hypopigmentation{01} (lightening of treated skin)
    
hyperpigmentation{01} (darkening of treated skin)
    
scaling or crusting{01}
    
wheal/flare{01} (small red raised itchy bumps)

{01}
Note: For dysesthesia, severe effects were reported by at least 50% of patients at some time during treatment. Sensation peaks 6 minutes into treatment and subsides between 1 minute and 24 hours after phototherapy is turned off; qualitatively similar to erythropoietic protoporphyria upon exposure to sunlight.{01}

Incidence less frequent
    
Excoriation{01} (raw skin)
    
oozing{01}
    
pain{01}
    
pustules{01} (pus filled blister; pimple)
    
scabbing{01}
    
tenderness{01}
    
ulceration{01} (open sore on skin)
    
vesiculation{01} (blister)

{01}

Note:  Following photodynamic light therapy treatment, the actinic keratoses and, to some degree, the surrounding skin, will redden, and swelling and scaling may also occur.{01} However, these lesion changes are temporary and should completely resolve by 4 weeks after treatment.{01}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Treatment of overdose
In the event that the drug is ingested, monitoring and supportive care are recommended.{01}Incidental exposure to intense light sources for at least 40 hours should be avoided.{01}

The consequences of exceeding the recommended topical dosage are unknown.{01}


Patient Consultation
The consequences of exceeding the recommended topical dosage are unknown.{01}
As an aid to patient consultation, refer to Advice for the Patient, Aminolevulinic acid in Volume II.

Consider advising the patient on the following (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergies to porphyrins

Pregnancy—Not recommended unless clearly needed.{01}





Breast-feeding—It is unknown if aminolevulinic acid is excreted into breast milk.{01}
Other photosensitizing medications, especially griseofulvin, phenothiazines, sulfonamides, sulfonylureas, thiazide diuretics, tetracyclines.{01}
Other medical problems, especially cutaneous photosensitivity to wavelengths of 400 to 450 nanometers (nm), porphyria.{01}

Proper use of this medication
» If the patient cannot return for the photodynamic therapy within the specified time period after aminolevulinic acid application, the doctor should be notified and the patient should protect the treated skin from sunlight or prolonged or intense light for at least 40 hours.

Precautions while using this medication
» Returning to the doctor's office to receive photodynamic therapy (blue light treatment) 14 to 18 hours after application of aminolevulinic acid.{01}

» Keeping the treated actinic keratoses areas out of bright light until the blue light photodynamic treatment. Importance of wearing light-protective clothing, such as a wide-brimmed hat, when exposed to sunlight or sources of light

» Keeping the treated actinic keratoses dry, not washing the area before the blue light photodynamic treatment

» Not depending on sunscreen to protect against photosensitivity reactions

» Reducing exposure to light if stinging and/or burning is felt on the actinic keratoses prior to blue light treatment

» Wearing eye protection during blue light photodynamic treatment

» Expecting reddening, swelling, and/or scaling of actinic keratoses and the surrounding skin to occur following blue light treatment; changes that usually resolve by 4 weeks after treatment


Side/adverse effects
Signs of potential side effects, especially bleeding and/or hemorrhage{01}


General Dosing Information
Do not apply to the eyes, around the eyes, or to mucous membranes.{01}

Application involves either the face or scalp but not both simultaneously.{01}

After aminolevulinic acid application, patients treated site will become photosensitive. Exposure to light may result in stinging and/or burning sensation and may cause erythema and/or edema of the treated area. Therefore, the patient should avoid exposure to sunlight or bright light (e.g., examination lamps, operating room lamps, tanning beds, or lights of close proximity) up until the time of phototherapy. Light-protective clothing, such as a wide–brimmed hat, will protect against photosensitivity reactions caused by visible light.{01} Sunscreens will not protect the patient against photosensitivity reactions.{01}

Patient and medical personnel should wear blue blocking protective eyewear during photodynamic therapy (blue light treatment).{01}

Rinse and thoroughly dry the actinic keratoses prior to blue light treatment.{01}


Topical Dosage Forms

AMINOLEVULINIC ACID HYDROCHLORIDE SOLUTION

Usual Adult Dose
Actinic keratoses
Topical, 2-step process
1. Application of aminolevulinic acid solution: Apply to individual lesions of actinic keratoses and not to perilesional skin. Apply the solution directly to the target lesions by dabbing gently with the wet applicator tip. Enough solution should be applied to uniformly wet the lesion surface, including the edges, without excess running or dripping.{01} Once the initial application has dried, apply again in the same manner.{01}
2. Blue light illumination: Illumination with blue light follows the application 14 to 18 hours later. Photoactivation is accomplished with blue light photodynamic illumination from the BLU–U Blue Light Photodynamic Therapy Illuminator.{01} The dose for illumination is a 1000 second (16 minutes 40 seconds) exposure that is required to provide 10 Joules/cm2.{01}

Note: Transient stinging or burning at the target lesion sites occurs during the period of light exposure.
If blue light illumination is interrupted or stopped for any reason, it should not be restarted and the patient should be advised to protect the treated lesions from exposure to sunlight or prolonged or intense light for at least 40 hours after application of the aminolevulinic acid from the first visit.{01}
Treated lesions that have not completely resolved after 8 weeks may be treated a second time with aminolevulinic acid and blue light illumination.{01}



Usual Pediatric Dose
Actinic keratoses
Safety and efficacy have not been established.{01}


Usual Geriatric Dose
See Usual adult dose.

Strength(s) usually available
U.S.—


354 mg (as the hydrochloride) dry powder (Rx) [Levulan® Kerastick™ ( 20% solution after mixing with vehicle) (ethanol alcohol) ( water) (laureth–4) ( isopropyl alcohol) (polyethylene glycol)]

Packaging and storage:
Store at 25° C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).{01}

Preparation of dosage form:
Prepare immediately prior to application.   • Hold the applicator stick so the cap is pointing up.
   • Crush the bottom vehicle solution ampule by applying finger pressure to Position A on the cardboard sleeve.
   • Crush the top ampule containing aminolevulinic acid powder by applying finger pressure to Position B on the cardboard sleeve.
   • Continue crushing the applicator downward and applying finger pressure to Position A.
   • Holding the applicator stick between the thumb and forefinger, point the applicator cap away from the face, then shake the applicator stick gently for at least 3 minutes to dissolve the drug powder in the solution vehicle.{01}
   • Remove the cap from the applicator stick. The dry applicator tip should be dabbed on a gauze pad until the tip is uniformly wet with solution.


Stability:
Aminolevulinic acid topical solution should be prepared immediately prior to use. Unused solution must be discarded 2 hours after preparation.{01}

Additional information:
Aminolevulinic topical solution available as Levulan® Kerastick™ is intended for the BLU–U Blue Light Photodynamic Illuminator only. Use of aminolevulinic acid solution without subsequent BLU–U illumination is not recommended.{01}.



Revised: 04/07/2000



References
  1. Product Information: Levulan® Keratick™, aminolevulinic acid HCL for topical solution, 20%. DUSA Pharmaceuticals, Inc., Wilmington, MA, (PI revised 12/3/99) reviewed 2/2000.
  1. Peng Q, Warloe T, Berg K eta L : 5–Aminolevulinic acid–based photodynamic therapy. Clinical research and future challenges. Cancer 1997; 79: 2282–2308 .
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