PanretinĀ®
(alitretinoin) Gel 0.1%
(For topical use only)
DRUG DESCRIPTION
PanretinĀ® gel 0.1% contains alitretinoin and is intended for topical application only. The chemical name is 9-cis-retinoic acid and the structural formula is as follows:
Chemically, alitretinoin is related to vitamin A. It is a yellow powder with a molecular weight of 300.44 and a molecular formula of C20H28O2. It is slightly soluble in ethanol (7.01 mg/g at 25oC) and insoluble in water. Panretin (alitretinoin) Ā® gel is a clear, yellow gel containing 0.1% (w/w) alitretinoin in a base of dehydrated alcohol USP, polyethylene glycol 400 NF, hydroxypropyl cellulose NF, and butylated hydroxytoluene NF.
For patients:
WHAT ARE THE POSSIBLE SIDE EFFECTS OF ALITRETINOIN TOPICAL (PANRETIN)?
Serious side effects are not likely to occur. Stop using alitretinoin topical and seek emergency medical attention if you experience an allergic reaction (shortness of breath; closing of your throat; swelling of your lips, face, or tongue; or hives).
If you experience any of the following less serious side effects at the application site(s), continue to use alitretinoin topical and notify your doctor
" redness;
" itching;
" irritation;
" warmth;
" burning, stinging, or...
Read All Potential Side Effects and See Pictures of Panretin "
WHAT ARE THE PRECAUTIONS WHEN TAKING ALITRETINOIN (PANRETIN)?
Before using alitretinoin, tell your doctor or pharmacist if you are allergic to it; or to other retinoids (e.g., tretinoin); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.
Before using this medication, tell your doctor or pharmacist your medical history, especially of: a certain type of cancer (skin T-cell lymphoma).
This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.
This medication is not recommended for use during pregnancy. Discuss the risks and benefits with your doctor.
It is not known whether this...
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INDICATIONS
PanretinĀ® (alitretinoin) gel is indicated for topical treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma. PanretinĀ® (alitretinoin) gel is not indicated when systemic anti-KS therapy is required (e.g., more than 10 new KS lesions in the prior month, symptomatic lymphedema, symptomatic pulmonary KS, or symptomatic visceral involvement). There is no experience to date using PanretinĀ® (alitretinoin) gel with systemic anti-KS treatment.
DOSAGE AND ADMINISTRATION
PanretinĀ® (alitretinoin) gel should initially be applied two (2) times a day to cutaneous KS lesions. The application frequency can be gradually increased to three (3) or four (4) times a day according to individual lesion tolerance. If application site toxicity occurs, the application frequency can be reduced. Should severe irritation occur, application of drug can be temporarily discontinued for a few days until the symptoms subside.
Sufficient gel should be applied to cover the lesion with a generous coating. The gel should be allowed to dry for three to five minutes before covering with clothing. Because unaffected skin may become irritated, application of the gel to normal skin surrounding the lesions should be avoided. In addition, do not apply the gel on or near mucosal surfaces of the body.
A response of KS lesions may be seen as soon as two weeks after initiation of therapy but most patients require longer application. With continued application, further benefit may be attained. Some patients have required over 14 weeks to respond. In clinical trials, PanretinĀ® (alitretinoin) gel was applied for up to 96 weeks. PanretinĀ® (alitretinoin) gel should be continued as long as the patient is deriving benefit.
Occlusive dressings should not be used with PanretinĀ® (alitretinoin) gel.
HOW SUPPLIED
PanretinĀ® (alitretinoin) gel is available in tubes containing 60 grams. Store at 25Ā°C (77Ā°F); excursions permitted to 15-30Ā°C (59-86Ā°F) [see USP Controlled Room Temperature].
SIDE EFFECTS
The safety of PanretinĀ® (alitretinoin) gel has been assessed in clinical studies of 385 patients with AIDS-related KS. Adverse events associated with the use of PanretinĀ® (alitretinoin) gel in patients with AIDS-related KS occurred almost exclusively at the site of application. The dermal toxicity begins as erythema; with continued application of PanretinĀ® (alitretinoin) gel, erythema may increase and edema may develop. Dermal toxicity may become treatment-limiting, with intense erythema, edema, and vesiculation. Usually, however, adverse events are mild to moderate in severity; they led to withdrawal from the study in only 7% of the patients. Severe local (application site) skin adverse events occurred in about 10% of patients in the U.S. study (versus 0% in the vehicle control). Table 2 lists the adverse events that occurred at the application site with an incidence of at least 5% during the double-blind phase in the PanretinĀ® (alitretinoin) gel-treated group and in the vehicle control group in either of the two controlled studies. Adverse events were reported at other sites but generally were similar in the two groups.
TABLE 2: Adverse Events with an Incidence of at Least 5% at the Application Site in Either Controlled Study in Patients Receiving PanretinĀ® (alitretinoin) Gel or Vehicle Control
Adverse Event Term Study 1 Study 2
PanretinĀ® (alitretinoin) Gel
N=134 Pts
.% Vehicle Gel
N=134 Pts.
% PanretinĀ® (alitretinoin) Gel
N=36 Pts.
% Vehicle Gel
N=46 Pts.
%
Rash1 77 11 25 4
Pain2 34 7 0 4
Pruritus3 11 4 8 4
Exfoliative dermatitis4 9 2 3 0
Skin disorder5 8 1 0 0
Paresthesia6 3 0 22 7
Edema7 8 3 3 0
Includes Investigator terms:
1Erythema, scaling, irritation, redness, rash, dermatitis
2Burning, pain
3Itching, pruritis
4Flaking, peeling, desquamation, exfoliation
5Excoriation, cracking, scab, crusting, drainage, eschar, fissure or oozing
6Stinging, tingling
7Edema, swelling, inflammation
DRUG INTERACTIONS
Patients who are applying PanretinĀ® (alitretinoin) gel should not concurrently use products that contain DEET (N,N-diethyl-m-toluamide), a common component of insect repellent products. Animal toxicology studies showed increased DEET toxicity when DEET was included as part of the formulation.
Although there was no clinical evidence in the vehicle-controlled studies of drug interactions with systemic antiretroviral agents, including protease inhibitors, macrolide antibiotics, and azole antifungals, the effect of PanretinĀ® (alitretinoin) gel on the steady-state concentrations of these drugs is not known. No drug interaction data are available on concomitant administration of PanretinĀ® (alitretinoin) gel and systemic anti-KS agents.
Drug/Laboratory Test Interactions
No interference with laboratory tests has been observed.
WARNINGS
Pregnancy
PanretinĀ® (alitretinoin) gel could cause fetal harm if significant absorption were to occur in a pregnant woman. 9-cis-Retinoic acid has been shown to be teratogenic in rabbits and mice. An increased incidence of fused sternebrae and limb and craniofacial defects occurred in rabbits given oral doses of 0.5 mg/kg/day (about five times the estimated daily human topical dose on a mg/mĀ² basis, assuming complete systemic absorption of 9-cis-retinoic acid, when PanretinĀ® (alitretinoin) gel is administered as a 60 g tube over 1 month in a 60 kg human) during the period of organogenesis. Limb and craniofacial defects also occurred in mice given a single oral dose of 50 mg/kg on day eleven of gestation (about 127 times the estimated daily human topical dose on a mg/mĀ² basis). Oral 9-cis-retinoic acid was also embryocidal, as indicated by early resorptions and post-implantation loss when it was given during the period of organogenesis to rabbits at doses of 1.5 mg/kg/day (about 15 times the estimated daily human topical dose on a mg/mĀ² basis) and to rats at doses of 5 mg/kg/day (about 25 times the estimated daily human topical dose on a mg/mĀ²basis). Animal reproduction studies with topical 9-cis-retinoic acid have not been conducted. It is not known whether topical PanretinĀ® (alitretinoin) gel can modulate endogenous 9-cis-retinoic acid levels in a pregnant woman nor whether systemic exposure is increased by application to ulcerated lesions or by duration of treatment. There are no adequate and well-controlled studies in pregnant women. If PanretinĀ® (alitretinoin) gel is used during pregnancy, or if the patient becomes pregnant while taking it, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant.
PRECAUTIONS
PanretinĀ® (alitretinoin) gel is indicated for topical treatment of Kaposi's sarcoma. Patients with cutaneous T-cell lymphoma were less tolerant of topical PanretinĀ® (alitretinoin) gel; five of seven patients had 6 episodes of treatment-limiting toxicities-grade 3 dermal irritation-with PanretinĀ® (alitretinoin) gel (0.01% or 0.05%).
Photosensitivity
Retinoids as a class have been associated with photosensitivity. There were no reports of photosensitivity associated with the use of PanretinĀ® (alitretinoin) gel in the clinical studies. Nonetheless, because in vitro data indicate that 9-cis-retinoic acid may have a weak photosensitizing effect, patients should be advised to minimize exposure of treated areas to sunlight and sunlamps during the use of PanretinĀ® (alitretinoin) gel.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to assess the carcinogenic potential of 9-cis-retinoic acid have not been conducted. 9-cis-Retinoic acid was not mutagenic in vitro (bacterial assays, Chinese hamster ovary cell HGPRT mutation assay) and was not clastogenic in vitro (chromosome aberration test in human lymphocytes) nor in vivo (mouse micronucleus test).
Pregnancy Category D
(see "WARNINGS" section)
Nursing Mothers
It is not known whether alitretinoin or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions from PanretinĀ® (alitretinoin) gel in nursing infants, mothers should discontinue nursing prior to using the drug.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Inadequate information is available to assess safety and efficacy in patients age 65 years or older.
OVERDOSE
There has been no experience with acute overdose of PanretinĀ® (alitretinoin) gel in humans. Systemic toxicity following acute overdosage with topical application of PanretinĀ® (alitretinoin) gel is unlikely because of limited systemic plasma levels observed with normal therapeutic doses. There is no specific antidote for overdosage.
CONTRAINDICATIONS
PanretinĀ® (alitretinoin) gel is contraindicated in patients with a known hypersensitivity to retinoids or to any of the ingredients of the product.
CLINICAL PHARMACOLOGY
Mechanism of Action
Alitretinoin (9-cis-retinoic acid) is a naturally-occurring endogenous retinoid that binds to and activates all known intracellular retinoid receptor subtypes (RAR?, RAR?, RAR?, RXR?, RXR? and RXR?). Once activated these receptors function as transcription factors that regulate the expression of genes that control the process of cellular differentiation and proliferation in both normal and neoplastic cells. Alitretinoin inhibits the growth of Kaposi's sarcoma (KS) cells in vitro.
Pharmacokinetics
No studies have examined plasma 9-cis-retinoic acid concentrations before and after treatment with PanretinĀ® (alitretinoin) gel. There is, however, indirect evidence that absorption is not extensive. Plasma concentrations of 9-cis-retinoic acid were evaluated during clinical studies in patients with cutaneous lesions of AIDS-related KS after repeated multiple-daily dose application of PanretinĀ® (alitretinoin) gel for up to 60 weeks. The range of 9-cis-retinoic acid plasma concentrations in these patients was similar to the range of circulating, naturally-occurring 9-cis-retinoic acid plasma concentrations in untreated healthy volunteers.
Although there are no detectable plasma concentrations of 9-cis-retinoic acid metabolites after topical application of PanretinĀ® (alitretinoin) gel, in vitro studies indicate that the drug is metabolized to 4-hydroxy-9-cis-retinoic acid and 4-oxo-9-cis-retinoic acid by CYP 2C9, 3A4, 1A1, and 1A2 enzymes. In vivo, 4-oxo-9-cis-retinoic acid is the major circulating metabolite following oral administration of 9-cis-retinoic acid.
No formal pharmacokinetic drug interaction studies between PanretinĀ® (alitretinoin) gel and antiretroviral agents have been conducted.
Clinical Studies
PanretinĀ® (alitretinoin) gel is not a systemic therapy; it therefore cannot treat visceral Kaposi's sarcoma (KS) nor prevent the development of new KS lesions where it has not been applied. Visceral KS disease was not monitored in these trials, and the appearance of new KS lesions was not considered part of the response assessment in clinical trials.
PanretinĀ® (alitretinoin) gel was evaluated in two multicenter, prospective, randomized, double-blind, vehicle-controlled studies in patients with cutaneous lesions of AIDS-related KS. In both studies the primary efficacy endpoint was the patients' cutaneous KS tumor response rate through 12 weeks of study drug treatment which was assessed by evaluating from 3 to 8 KS index lesions according to the modified AIDS Clinical Trials Group (ACTG) response criteria as applied to topical therapy (i.e., evaluation of height and area reductions of the index lesions only; progressive disease in non-index lesions and new lesions were not considered progressive disease; progressive disease was scored only in the treated index lesions). A global evaluation by physicians was also carried out. It considered all of the patient's treated lesions (index and other) compared to baseline. In this evaluation, patients with at least a 50% improvement in the KS lesions were considered responders. In addition, photographs of lesions in patients considered responders by the modified ACTG criteria were examined by the FDA for a cosmetically beneficial response, defined as at least a 50% improvement in appearance compared to baseline, considering both the KS lesions and dermal toxicity at the lesion site, in at least 50% of the index lesions and maintained for at least 3 weeks. Patients were also asked about their satisfaction with the treatment.
In Study 1, a total of 268 patients were entered from centers in the U.S. and Canada. Patients were treated topically three to four times a day with either PanretinĀ® (alitretinoin) gel or a matching vehicle gel for a minimum of 12 weeks, followed by an open-label phase in patients who had not yet progressed on PanretinĀ® (alitretinoin) gel. Responses during the double-blind phase are shown in Table 1. Responses to PanretinĀ® (alitretinoin) gel were seen in both previously untreated patients and in patients with prior systemic and/or topical KS treatment. A total of 72 patients responded to PanretinĀ® (alitretinoin) gel during the randomized or crossover portions of the study. At a median duration of monitoring of 16 weeks, only 15% of the 72 patients had relapsed. PanretinĀ® (alitretinoin) gel would not be expected to affect development of new lesions in untreated areas and these were seen in about 50% of patients, at similar rates in treated and untreated patients, responders and non-responders. The patients' assessment of their overall satisfaction with the drug effect on all treated lesions significantly favored PanretinĀ® (alitretinoin) gel.
Study 2 was an international study with a planned enrollment of 270 patients. Patients were treated topically twice a day with PanretinĀ® (alitretinoin) gel or a matching vehicle for 12 weeks. The study was stopped early because of positive interim results in the initial 82 patient data set. Results of the study are shown in Table 1. Responses to PanretinĀ® (alitretinoin) gel were seen both in previously untreated patients and in patients with prior systemic and/or topical KS treatment.
TABLE 1: Summary of Tumor Responses
STUDY 1 STUDY 2
PanretinĀ® Gel
N=134 Vehicle Gel
N=134 PanretinĀ® Gel
N=36 Vehicle Gel
N=46
Modified ACTG Response
(index lesions) 34% PR
1% CR 16% PR
p=0.0012 36% PR 7% PR
Physician's Global/ Subjective Assessment
(all treated lesions) 19% PR 4% PR
p=0.00014 47% PR 11% PR
Beneficial Response Photographs
(index lesions only) 15% 4%
p=0.0026 19% 2%
In the clinical trials, responses were seen as early as two (2) weeks; most patients, however, required four (4) to eight (8) weeks of treatment, and some patients did not experience significant improvement until 14 or more weeks of treatment. The cumulative percentage of patients who achieved a response was less than 1% at 2 weeks, 10% at 4 weeks, and 28% at 8 weeks.
In both studies, responses occurred in patients with a wide range of baseline CD4+ lymphocyte counts, including patients with CD4+ lymphocyte counts less than 50 cells/mmĀ³. Nearly all patients received concomitant combination antiretroviral therapy.
Photographs of patients revealed a substantial erythematous and edematous response in some cases, leading to a cosmetically mixed outcome even in apparent responders. Nonetheless, in Study 1 it appeared that a cosmetically satisfactory result occurred at about the same rate as the Physician's Global response rate and in both studies such a response was more frequent than in the vehicle control.
PANRETIN CONSUMER
IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.
ALITRETINOIN GEL - TOPICAL
(AL-i-TRET-i-noyn)
COMMON BRAND NAME(S): Panretin
USES: This medication is used to treat skin sores in patients with a certain type of AIDS-related cancer (Kaposi's sarcoma). Alitretinoin belongs to a class of medications called retinoids. It works by affecting the growth of skin cells.
This medication should not be used when medications taken by mouth are needed to treat the Kaposi's sarcoma (e.g., more than 10 new skin sores in the previous month, disease affects the lungs or other organs).
HOW TO USE: Use this medication on the skin only. Wait at least 20 minutes after bathing or showering before applying the medication. Apply enough medication to cover the skin sore(s) well, usually 2 to 4 times daily or as directed by your doctor. It is not necessary to rub the medication into the sore. Allow 3 to 5 minutes for the medication to dry before covering the affected area with clothing.
Do not apply the medication on unaffected skin because doing so may cause increased irritation. Do not apply the medication in or around the eyes, nose, mouth, anus, vagina, or tip of the penis. If you do get the medication in those areas, flush with plenty of water.
Wash your hands after using, unless you are using this medication to treat the hands. Do not bathe, shower, or swim for at least 3 hours after using the medication.
Do not wrap, cover, or bandage the affected area unless directed to do so by your doctor.
Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same times each day.
Do not apply other skin products, except mineral oil, on the treated sores. You may apply mineral oil at least 2 hours before or after applying this medication to help prevent skin dryness/itching.
Tell your doctor if your condition does not improve or if it worsens. You should start to see an improvement in your skin condition in as little as 2 weeks of treatment, but it may take up to 14 weeks of treatment to see the benefit.