Aminolevulinic acid

Pharmacology: The metabolism of aminolevulinic acid (ALA) is the first step in the biochemical pathway resulting in heme synthesis. Aminolevulinic acid is not a photosensitizer, but rather a metabolic precursor of protoporphyrin IX (PpIX), which is a photosensitizer. The synthesis of ALA is normally tightly controlled by feedback inhibition of the enzyme, ALA synthetase, presumably by intracellular heme levels. ALA, when provided to the cell, bypasses this control point and results in the accumulation of PpIX, which is converted into heme by ferrochelatase through the addition of iron to the PpIX nucleus.

According to the presumed mechanism of action, photosensitization following application of LEVULAN KERASTICK (aminolevulinic acid) Topical Solution occurs through the metabolic conversion of ALA to PpIX, which accumulates in the skin to which LEVULAN Topical Solution has been applied. When exposed to light of appropriate wavelength and energy, the accumulated PpIX produces a photodynamic reaction, a cytotoxic process dependent upon the simultaneous presence of light and 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. Photosensitization of actinic (solar) keratosis lesions using the LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution, plus illumination with the BLU-U® Blue Light Photodynamic Therapy Illuminator (BLU-U), is the basis for LEVULAN photodynamic therapy (PDT).

Pharmacokinetics: In a human pharmacokinetic study (N=6) using a 128 mg dose of sterile intravenous ALA HCl and oral ALA HCl (equivalent to 100 mg ALA) in which plasma ALA and PpIX were measured, the mean half-life of ALA was 0.70 ± 0.18 h after the oral dose and 0.83 ± 0.05 h after the intravenous dose. The oral bioavailability of ALA was 50-60% with a mean Cmax of 4.65 ± 0.94 μg/mL. PpIX concentrations were low and were detectable only in 42% of the plasma samples. PpIX concentrations in plasma were quite low relative to ALA plasma concentrations, and were below the level of detection (10 ng/mL) after 10 to 12 hours.

ALA does not exhibit fluorescence, while PpIX has ahigh fluorescence yield.

Time-dependent changes in surface fluorescence have been used to determine PpIX accumulation and clearance in actinic keratosis lesions and perilesional skin after application of LEVULAN KERASTICK (aminolevulinic acid) Topical Solution in 12 patients. Peak fluorescence intensity was reached in 11 ± 1 h in actinic keratoses and 12 ± 1 h in perilesional skin. The mean clearance half-life of fluorescence for lesions was 30 ± 10 h and 28 ± 6 h for perilesional skin. The fluorescence in perilesional skin was similar to that in actinic keratoses. Therefore, LEVULAN KERASTICK (aminolevulinic acid) Topical Solution should only be applied to the affected skin.

Clinical Studies: LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution, 20%, plus blue light at 6-10.9 J/cm², has been used to treat actinic keratoses in 232 patients in six clinical trials. Phase 3 studies were two, identically designed, multicenter, two-arm studies using LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution applicators plus illumination from the BLU-U for 1000 seconds (16 min 40 sec) for a nominal exposure of 10 J/cm². Patients were excluded from these studies who had a history of cutaneous photosensitization, porphyria, hypersensitivity to porphyrins, photodermatosis, or inherited or acquired coagulation defects. A minimum of 4 and a maximum of 15 clinically typical, discrete, (Grade 1 or 2, see table 2 for definition), target actinic keratosis lesions were identified. Target lesions on the face or on the scalp, but not in both locations in the same patient, received treatment. The patients were randomized to receive treatment either with the LEVULAN KERASTICK (aminolevulinic acid) Topical Solution plus BLU-U or vehicle plus BLU-U. Patients were randomized at a 3 to 1 LEVULAN to vehicle ratio. A total of 243 patients were enrolled in two Phase 3 studies (ALA-018, ALA-019). Lesions were designated as cleared (complete response) if the lesion had completely cleared and adherent scaling plaques of actinic keratoses were no longer evident on the surface of the treated skin when palpated. The percentage of patients in whom 75% or more of treated lesions were cleared, and the percentage of patients in whom 100% of treated lesions were cleared (Complete Responders), for each study at 8 weeks after treatment are shown in Table 1.

TABLE 1 - Patient Responses at Week 8

Because clinical studies ALA-018 and ALA-019 had identical protocols, the combined results from the two trials are shown in the following tables. For actinic keratoses with a variety of thicknesses (excluding very thick, Grade 3 actinic keratoses which were not studied in the phase 3 trials), LEVULAN KERASTICK (aminolevulinic acid) Topical Solution plus BLU-U is more effective than vehicle plus BLU-U, but as shown in Table 2, the percentage of lesions with complete responses at 8 weeks after treatment with LEVULAN KERASTICK (aminolevulinic acid) Topical Solution plus blue light illumination was lower for those lesions that were thicker at baseline. Efficacy of LEVULAN KERASTICK (aminolevulinic acid) Topical Solution plus BLU-U on higher grade lesions was not studied in the Phase 3 clinical efficacy trials.

TABLE 2 - Lesions Complete Responses at Week 8 for Different Lesion Grades

Those patients who were not Complete Responders at week 8 had retreatment of the persistent target lesions at week 8. Among the patients undergoing retreatment, efficacy results seen at 12 weeks after the initial treatment, i.e., at 4 weeks after the second treatment, are shown in Table 3.

TABLE 3 - Complete Responders at Week 12, among Patients Receiving Two Treatments

The efficacy results seen at 12 weeks after treatment, which include the results at 12 weeks for those patients who received a single treatment as well as the results at 12 weeks for those patients who received a second treatment at week 8, are shown in Table 4.

TABLE 4 - Patient Responses at Week 12, among Patients who Received One or Two Treatments

Among Complete Responders at week 8, 93%(in study ALA-018) and 83% (in study ALA-019) maintained complete response at week 12. Among patients with scalp lesions, the percentage of patients with 100% of AK lesions having complete response declined from week 8 (55%) to week 12 (50%), because there were more patients with scalp lesions with 100% of AK lesions cleared at week 8 who had a recurrence of a lesion by week 12 than there were patients with scalp lesions who had retreatment of persistent lesions at week 8 and who then achieved 100% of AK lesions cleared by week 12. Patients did not receive follow-up past 12 weeks after the initial treatment.

Patient outcomes recorded in the two Phase 3 trials are depicted in the following flowchart, in which Complete Responders are designated clear. Seven patients in the active treatment arm and three patients in the vehicle treatment arm withdrew or were lost to follow-up, and their outcomes are not included in the flowchart. Three patients in the active treatment arm were treated at baseline but did not return for evaluation until week 12. One patient in the active treatment arm and two in the vehicle treatment arm who were not clear at week 8 did not receive retreatment.

LEVULAN Photodynamic Therapy for Actinic Keratoses.

The first step in LEVULAN KERASTICK (aminolevulinic acid) photodynamic therapy (PDT) for actinic keratoses is application of the LEVULAN KERASTICK (aminolevulinic acid) Topical Solution to actinic keratoses located on the patient's face or scalp. After LEVULAN KERASTICK (aminolevulinic acid) Topical Solution is applied to the actinic keratoses in the doctor's office, the patient will be told to return the next day. During this time the actinic keratoses will become sensitive to light (photosensitive). Care should be taken to keep the treated actinic keratoses dry and out of bright light. After LEVULAN KERASTICK (aminolevulinic acid) Topical Solution is applied, it is important for the patient to wear lightprotective clothing, such as a wide-brimmed hat, when exposed to sunlight or sources of light. Fourteen to eighteen hours after application of LEVULAN KERASTICK (aminolevulinic acid) Topical Solution the patient will return to the doctor's office to receive blue light treatment, which is the second and final step in the treatment. Prior to blue light treatment, the actinic keratoses will be rinsed with tap water. The patient will be given goggles to wear as eye protection during the blue light treatment. The blue light is of low intensity and will not heat the skin. However, during the light treatment, which lasts for approximately 17 minutes, the patient will experience sensations of tingling, stinging, prickling or burning of the treated lesions. These feelings of discomfort should improve at the end of the light treatment. Following treatment, the actinic keratoses and, to some degree, the surrounding skin, will redden, and swelling and scaling may also occur. However, these lesion changes are temporary and should completely resolve by 4 weeks after treatment.

Photosensitivity

After LEVULAN KERASTICK (aminolevulinic acid) Topical Solution is applied to the actinic keratoses in the doctor's office, the patient should avoid exposure of the photosensitive actinic keratoses to sunlight or bright indoor light (e.g., from examination lamps, operating room lamps, tanning beds, or lights at close proximity) during the period prior to blue light treatment. If the patient feels stinging and/or burning on the actinic keratoses, exposure to light should be reduced. Before going into sunlight, the patient should protect treated lesions from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material. Sunscreens will not protect the patient against photosensitivity reactions.

If for any reason the patient cannot return for blue light treatment during the prescribed period after application of LEVULAN KERASTICK (aminolevulinic acid) Topical Solution (14 to 18 hours), the patient should call the doctor. The patient should also continue to avoid exposure of the photosensitized lesions to sunlight or prolonged or intense light for at least 40 hours. If stinging and/or burning is noted, exposure to light should be reduced.

Aminolevulinic acid is a prescription medication used to treat to actinic keratoses of the face or scalp. This is a condition of small crusty or scaly bumps or horns on or under the skin that result from exposure to sunlight and can develop into skin cancer.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.
 

Aminolevulinic Acid is part of the drug class:

• Sensitizers used in photodynamic/radiation therapy

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• antihistamines
• diuretics ('water pills')
• griseofulvin (Fulvicin-U/F, Grifulvin V, Gris-PEG)
• medications for diabetes
• medications for mental illness
• medications for nausea
• sulfa antibiotics
• tetracycline antibiotics such as demeclocycline (Declomycin), doxycycline (Doryx, Vibramycin), minocycline (Dynacin, Minocin), and tetracycline (Sumycin)

This is not a complete list of aminolevulinic acid drug interactions. Ask your doctor or pharmacist for more information.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• an antibiotic or sulfa drug;

• a diuretic or "water pill";

• medicine to treat nausea or vomiting;

• antipsychotic medication; or

• an oral diabetes medicine.

This list is not complete. Other drugs may interact with aminolevulinic acid, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

In the U.S.

• Gleolan

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Photosensitizing Agent

In deciding to use a diagnostic test, any risks of the test must be weighed against the good it will do. This is a decision you and your doctor will make. Also, other things may affect test results. For this test, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to aminolevulinic acid or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of aminolevulinic acid in children. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of aminolevulinic acid in the elderly. However, some elderly patients are more sensitive to the effects of aminolevulinic acid than younger adults.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this diagnostic test, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Receiving this diagnostic test with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acetazolamide
• Acetohexamide
• Balofloxacin
• Bendroflumethiazide
• Benzthiazide
• Besifloxacin
• Chlorothiazide
• Chlorpromazine
• Chlorpropamide
• Chlortetracycline
• Chlorthalidone
• Cinoxacin
• Ciprofloxacin
• Clopamide
• Demeclocycline
• Diazoxide
• Dixyrazine
• Doxycycline
• Enoxacin
• Flumequine
• Fluphenazine
• Gatifloxacin
• Gemifloxacin
• Gliclazide
• Glimepiride
• Glipizide
• Gliquidone
• Glyburide
• Griseofulvin
• Hydrochlorothiazide
• Hydroflumethiazide
• Indapamide
• Levofloxacin
• Lomefloxacin
• Lymecycline
• Mafenide
• Meclocycline
• Methacycline
• Methdilazine
• Methotrimeprazine
• Methyclothiazide
• Metolazone
• Metopimazine
• Minocycline
• Moxifloxacin
• Nadifloxacin
• Nalidixic Acid
• Norfloxacin
• Ofloxacin
• Oxolinic Acid
• Oxytetracycline
• Pazufloxacin
• Pefloxacin
• Perazine
• Periciazine
• Perphenazine
• Pipemidic Acid
• Pipotiazine
• Polythiazide
• Prochlorperazine
• Promazine
• Promethazine
• Propiomazine
• Prulifloxacin
• Rolitetracycline
• Rosoxacin
• Rufloxacin
• Silver Sulfadiazine
• Sparfloxacin
• St John's Wort
• Sulfacetamide
• Sulfacytine
• Sulfadiazine
• Sulfadoxine
• Sulfamethizole
• Sulfamethoxazole
• Sulfapyridine
• Sulfasalazine
• Sulfisoxazole
• Tetracycline
• Thiethylperazine
• Thioproperazine
• Thioridazine
• Tolazamide
• Tolbutamide
• Trichlormethiazide
• Trifluoperazine
• Triflupromazine
• Xipamide
• Zonisamide

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this diagnostic test. Make sure you tell your doctor if you have any other medical problems, especially:

• Allergy to porphyrins or
• Porphyria, acute or chronic—Should not be used in patients with these conditions.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Applies to aminolevulinic acid topical: topical gel/jelly, topical kit, topical solution, topical stick

Along with its needed effects, aminolevulinic acid topical may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking aminolevulinic acid topical:

• Pain, burning, itching, redness, or swelling at the application site

• Bleeding during lesion preparation

• difficulty seeing at night
• double vision
• increased sensitivity of the eyes to sunlight
• red, sore eyes
• seeing double
• swelling of the eyelids

Some side effects of aminolevulinic acid topical may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Burning, crawling, itching, numbness, prickling, “pins and needles,” stinging, or tingling feelings
• darkening of the treated skin
• lightening of the treated skin
• scaling or crusting
• skin sore
• small red raised itchy bumps
• swelling of the skin

• Blister
• oozing
• open sore on the skin
• pain
• pus filled blister or pimple
• raw skin
• scabbing
• tenderness

Data not available