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Panretin (alitretinoin) – Summary of product characteristics - L01XX22

Updated on site: 09-Oct-2017

Medication namePanretin
ATC CodeL01XX22
Substancealitretinoin
ManufacturerEisai Ltd

1.NAME OF THE MEDICINAL PRODUCT

Panretin 0.1 % gel

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

1 g of gel contains 1 mg alitretinoin (0.1%).

For a full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Gel.

Clear yellow gel.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Panretin gel is indicated for the topical treatment of cutaneous lesions in patients with AIDS-related Kaposi’s sarcoma (KS) when:

-lesions are not ulcerated or lymphoedematous, and

-treatment of visceral KS is not required, and

-lesions are not responding to systemic antiretroviral therapy, and

-radiotherapy or chemotherapy are not appropriate

4.2Posology and method of administration

Posology

Panretin therapy should only be initiated and maintained by specialist physicians experienced in the treatment of patients with KS.

Men

Patients should apply Panretin to cutaneous KS lesions using sufficient gel so as to cover each lesion with a generous coating.

Frequency of application

Patients should initially apply Panretin twice a day to cutaneous KS lesions. The application frequency can be increased stepwise to three or four times a day according to individual lesion tolerance, allowing no less than two weeks between dose increases. The frequency of application should be adjusted for each lesion independently. If application site toxicity occurs, the application frequency can be reduced as described below. There are no data on the efficacy of Panretin applied less frequently than twice daily.

Local dermal irritation may be graded according to the five-point scale shown in Table 1. Guidelines for treatment adjustments necessitated by local dermal treatment-related toxicity are specified in

Table 2.

Table 1: Grading of local dermal irritation

GRADE

DEFINING CLINICAL SIGNS

= No reaction

None

=

Mild

Definite pink to red coloration

=

Moderate

Increased redness, possible oedema

=

Severe

Very red, with oedema, with or without vesiculation

=

Very severe

Deep red, swelling and oedema with or without signs of bullae formation

 

 

 

and necrosis

Table 2: Adjustment guidelines for treatment-limiting toxicity

LOCAL DERMAL IRRITATION

 

(Graded per Table 1)

TREATMENT ADJUSTMENTS

Grade 0, 1 or 2

No action required except continued monitoring.

Grade 3

Treatment frequency for that lesion should be reduced or

 

suspended. When dermal irritation improves to Grade 0 or 1,

 

treatment may be restarted at twice daily, increasing every two

 

weeks as tolerated.

Grade 4

As for Grade 3 irritation. However, treatment should not be

 

restarted if Grade 4 toxicity occurred at an application

 

frequency of less than twice a day.

Duration of application

It is recommended that Panretin should be applied to lesions for an initial period of up to 12 weeks. Treatment of lesions that have not shown a decrease in area and/or height by week 12 should be discontinued.

For those lesions that have shown a decrease in height and/or area by week 12, applications may be continued providing that there is continued improvement or at least maintenance of the response and that the product continues to be tolerated.

Treatment of any lesion that has fully resolved on clinical assessment should be discontinued.

Precautions to be taken before handling or administering the medicinal product

Patients should wash their hands before and after applications; it is not necessary to wear gloves. The gel must be allowed to dry for three to five minutes before covering with clothing. Occlusive dressings should be avoided.

Care must be taken to avoid application of the gel to normal skin surrounding the lesions.

Gel should not be applied on or near eyes or mucosal surfaces of the body. Showering, bathing, or swimming for at least three hours after any application should be avoided.

Women

Safety and effectiveness in women have not been established because of the paucity of clinical data. AIDS-related Kaposi’s sarcoma is infrequent in women.

Paediatric population

The safety and efficacy of Panretin gel in children under 18 years has not been established. No data are available.

Panretin is not approved for use in children and adolescents under 18 years of age.

Elderly men

There are no specific recommendations for use in elderly men (above 65 years of age). AIDS-related Kaposi’s sarcoma is infrequent in this population.

Renal or hepatic impairment

There are no data regarding the use of Panretin gel in patients with renal insufficiency or liver disease. Pharmacokinetic studies indicate that the range and frequency of detection of quantifiable 9-cis- retinoic acid plasma concentrations in patients with KS after application of the medicinal product were comparable to the range and frequency of detection of quantifiable plasma concentrations of circulating, naturally-occurring 9-cis-retinoic acid in untreated individuals (see section 5.2). On a theoretical basis, no dose adjustment is necessary in patients with renal insufficiency or liver disease, but these patients should be closely monitored and treatment frequency reduced, or withdrawn, if they experience adverse effects.

4.3 Contraindications

Hypersensitivity to retinoids in general, to alitretinoin or to any of the excipients.Pregnancy and breast-feeding (see section 4.6).

Treatment of KS lesions in close proximity to other skin disorders.

4.4 Special warnings and precautions for use

Retinoids as a class have been associated with photosensitivity. There were no reports of photosensitivity associated with the use of Panretin gel in the clinical studies. However, patients must be cautioned to minimise exposure of treated areas to sunlight or other ultraviolet (UV) light. (see section 5.3).

It is recommended that daily dietary intake of vitamin A should not exceed the Recommended Dietary Intake value.

Alitretinoin may cause harm to the foetus. Women of child-bearing potential must use a reliable form of contraception during treatment with Panretin gel (see section 4.6) and until one month after cessation of treatment.

4.5Interaction with other medicinal products and other forms of interaction

The use of other topical products on Panretin treated KS lesions should be avoided. Mineral oil may be used between Panretin applications in order to help prevent excessive dryness or itching. However, mineral oil should not be applied for at least two hours before or after the application of Panretin.

It is not recommended for patients to apply Panretin gel concurrently with products that contain N,N- diethyl-m-toluamide (DEET ), a common component of insect repellent products. Animal toxicology studies showed increased DEET toxicity when DEET was included as part of the formulation.

The range and frequency of detection of quantifiable plasma 9-cis-retinoic acid concentrations in patients with KS applying the medicinal product to up to 64 lesions were comparable to respective values in untreated patients. Therefore, there is a low potential for interactions with systemic medicinal products.

There was no clinical evidence in the vehicle-controlled studies of interactions with systemic antiretroviral agents, including protease inhibitors; macrolide antibiotics and azole antifungals. While no data are available, it is possible that co-administration of medicinal products which induce CYP isozymes may reduce circulating levels of alitretinoin, with a possible negative effect on the efficacy of Panretin gel.

4.6Fertility, pregnancy and lactation

Women of child-bearing potential

Women of child-bearing potential must use effective contraception during, and up to one month after cessation of treatment.

Men using Panretin should take precautions to ensure that their female partners do not become pregnant.

Pregnancy

Panretin is contraindicated (see section 4.3) in pregnancy, as alitretinoin may cause foetal harm when administered systemically to a pregnant woman. In rabbits, alitretinoin was shown to be teratogenic at a dose which resulted in plasma concentrations about 60 times the highest observed plasma concentration in male patients with KS following topical application of the gel. However, it is not currently certain to what extent topical treatment with Panretin gel would increase 9-cis-retinoic acid plasma concentrations, in women with KS above naturally occurring levels; therefore, alitretinoin should not be used in pregnant women.

Breast-feeding

It is not known whether this medicinal product is excreted in human milk. Based on the plasma concentrations observed in patients, milk concentrations of 9-cis-retinoic acid probably pose a low risk for the infant. However, because of the potential for undesirable effects from Panretin gel in infants being breast-fed, mothers must discontinue breast-feeding prior to using the medicinal product and not initiate breast-feeding while using the medicinal product.

Care should be taken not to bring the neonate into skin contact with areas to which Panretin has been recently applied. It is recommended that HIV-infected mothers do not breast-feed their children to exclude the risk of transmission of the virus.

Fertility

No specific studies on fertility have been conducted in men or women. However, alitretinoin is teratogenic so both men and women should take adequate precautions to avoid female partners becoming pregnant.

4.7Effects on ability to drive and use machines

Panretin gel is for cutaneous use and is unlikely to have an effect on one’s ability to drive or operate machines.

4.8Undesirable effects

Adverse events associated with the use of Panretin gel in AIDS-related KS occurred almost exclusively at the site of application. The dermal toxicity typically begins as erythema; with continued application of Panretin gel erythema may increase and oedema may develop. Dermal toxicity may become treatment-limiting, with intense erythema, oedema, and vesiculation. When applying Panretin gel, 69.1% of patients experienced adverse drug reactions at the application site.

The following application-site drug-related adverse reactions were reported during clinical studies in patients with KS. The frequency of adverse events are classified as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), and very rare (<1/10,000). Adverse events include verbatim terms in parentheses.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic system disorders

Uncommon: Lymphadenopathy

Nervous system disorders

Common:

Paraesthesia (stinging, tingling)

Vascular disorders

Common:

Haemorrhage (bleeding at or around lesions), Oedema (oedema, swelling,

 

inflammation), Peripheral oedema

Uncommon:

Phlebitis, Vascular disorder

Skin and subcutaneous tissue disorders

Very common:

Skin disorder (cracking, scab, crusting, excoriation, drainage, oozing), Rash

 

(erythema, redness, scaling, irritation, dermatitis), Pruritus (itching, pruritus)

Common:

Skin ulcer, Serous drainage, Exfoliative dermatitis (flaking, peeling, desquamation,

 

exfoliation), Skin discoloration (brown discoloration, surrounding

 

hyperpigmentation, paler), Dry skin

Uncommon:

Cellulitis, Vesiculobullous rash, Maculopapular rash, Allergic reaction

General disorders and administration site conditions

Very common:

Pain (burning, pain, soreness)

Uncommon:

Infection, including bacterial infection

The safety of Panretin gel has been assessed in clinical studies of more than 469 patients with AIDS- related KS, 439 of whom were treated with an alitretinoin concentration of 0.1%.

The incidence of drug-related skin disorder, skin ulcer, pain and rash appeared to be greater in patients applying Panretin gel four times daily than in those applying it less frequently. However, the incidence of other equally common drug-related adverse events such as pruritus, oedema, exfoliative dermatitis and dry skin did not appear to increase as a function of the frequency of application.

The incidence of mild/moderate rash (all events regardless of causality) was less in patients treated for less than 16 weeks than in those treated for 16 weeks or more (mild, 33% v 63%; moderate, 29% v 43%). The incidence of severe skin rash was independent of the duration of treatment (10% in both cases).

Local dermal toxicity associated with Panretin gel therapy generally resolved with treatment adjustment or discontinuation (see section 4.2).

Only two serious adverse reactions were reported (sepsis and cellulitis in the same patient).

The adverse events seen with Panretin gel are similar to those seen with other topical retinoids. It is unlikely that the undesirable systemic side effects associated with oral retinoids will be observed with the use of Panretin gel because the range and frequency of quantifiable 9-cis-retinoic acid plasma levels concentrations after application of the medicinal product were comparable to the range and frequency of quantifiable plasma concentrations of circulating, naturally occurring 9-cis-retinoic acid in untreated individuals.

4.9Overdose

No case of overdose has been reported.

Systemic toxicity following acute overdose with topical application of Panretin gel is unlikely.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: other antineoplastic agents, ATC code: LO1XX22

Although the molecular action of alitretinoin is thought to be mediated through interaction with the retinoid receptors, the exact mechanism of action of this medicinal product in the topical treatment of cutaneous lesions of AIDS-related KS is unknown. Alitretinoin (9-cis-retinoic acid), a naturally- occurring endogenous hormone related to vitamin A, binds to and activates all known intracellular retinoid receptor subtypes (RAR , RAR , RAR , RXR , RXR , RXR ). Once activated, these receptors function as ligand dependent transcription factors that regulate the expression of specific genes. The regulation of gene expression by alitretinoin controls the process of cellular differentiation and proliferation in both normal and neoplastic cells. The efficacy of Panretin gel in treating KS lesions may be related to the demonstrated ability of alitretinoin to inhibit the in vitro growth of KS cells.

Panretin gel can be expected to have local therapeutic effects only and it has no role in the prevention or treatment of visceral KS.

Two controlled, multicentre, randomised, double blind parallel group, Phase III studies provided the data for Panretin gel in the treatment of index cutaneous lesions of KS (Table 3). The patient response rate was evaluated using the AIDS Clinical Trials Group (ACTG) criteria for lesion response in KS. Study 1 included an open-label phase, in which patients themselves elected to enrol. Study 2 was followed by an open label study (Study 2a), which included only patients electing to continue from Study 2.

Table 3: Best response according to ACTG criteria for vehicle controlled phase

 

Study 1 (TID, QID)1

Study 2 (BD)2

 

 

 

 

 

 

Panretin

Vehicle

Panretin

Vehicle

 

N= 134

N=134

N=62

N=72

 

 

 

 

 

Clinical Complete

0.7

0.0

1.6

0.0

Response (CCR) %

 

 

 

 

 

 

 

 

 

Partial Response (PR) %

34.3

17.9

35.5

6.9

 

 

 

 

 

Stable Disease %

50.0

59.0

43.5

58.3

 

 

 

 

 

Progressive Disease %

14.9

23.1

19.4

34.7

 

 

 

 

 

Overall Response %

35.1

17.9

37.1

6.9

 

 

p=0.002

 

p= 0.00003

1.Protocol-specified dose regimen was application three times a day (TID) escalating to four times a day (QID) after two weeks, with downward adjustments for toxicity

2.Protocol-specified dose regimen was application twice a day (BD) only, with downward adjustments for toxicity

In the open label phase of Study 1 (N = 184), the overall response rate increased to 66.7%. In Study 2a (N = 99), the overall response rate increased to 56.1%.

In study 1, of 110 responding patients, 36 (33%) relapsed, while all but four still being on active treatment.

Response rates were analysed both by the patient as the unit of analysis and by the lesion. Table 4 provides the individual lesion response rates for patients being treated with Panretin gel in the Phase III studies.

Table 4: Index/indicator lesion1 responses within patients during the first 12 weeks on study in initial blinded phase

 

Patients with given number of index/indicator lesion responses (CCR or PR)

 

 

Study 1

 

 

Study 2

 

Number of

Panretin

 

Vehicle (N=134)

Panretin

 

Vehicle (N=72)

Responding

(N=134)

 

 

 

(N=62)

 

 

 

Lesions2,3

N %4

 

N %4

N %4

 

N %4

At Least One

73 (54.5%)

 

(31.3%)

33 (53.2%)

 

(29.2%)

At Least Four

27 (20.1%)

 

(6.0%)

8 (12.9%)

 

(2.8%)

1.Study 1, 6 index lesions; Study 2, up to 8 index lesions

2.Each index lesion assessed individually for response.

3.Lesions responding during the first 12 weeks on study, initial blinded phase, confirmed over at least four study weeks (confirmation of response may have occurred after 12 weeks for some lesions in Study 1).

4.Percentages calculated as number of patients with responding lesions divided by total number of patients in the initial blinded phase.

In one trial, 29% of the lesions that had reached a partial response (PR) but had not attained clinical complete response (CCR) within the first 12 weeks of treatment developed a CCR during continuing treatment beyond 12 weeks. The projected time for lesions that were in partial response (PR) to later attain clinical complete response (CCR) was 168 days. It is recommended that Panretin gel should be applied for an initial treatment period of up to 12 weeks. In lesions that have responded to treatment during this time, application may be continued provided that the response improves or is maintained and the product continues to be tolerated. If a complete response of a lesion occurs, no further application of Panretin gel should be made to the responding lesion.

There are no data regarding the efficacy of Panretin gel when applied to complicated lesions (e.g., when lymphoedema is present).

5.2Pharmacokinetic properties

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 Panretin gel for up to 60 weeks. A subset of these patients were followed during treatment of up to 64 lesions (range 4-64, median 11.5 lesions) for up to 44 weeks (range 2-44, median 15 weeks). In this latter group, the range and frequency of detection of quantifiable 9-cis-retinoic acid plasma concentrations in patients with KS after application of the medicinal product were comparable to the range and frequency of detection of quantifiable plasma concentrations of circulating, naturally-occurring 9-cis- retinoic acid in untreated individuals.

5.3Preclinical safety data

Toxicology

Three doses of alitretinoin (0.01%, 0.05%, or 0.5%) in a topical gel formulation were given to rats in a 28-day dermal toxicology study. Observed effects at the application site included erythema, epidermal thickening, scaling and loosening of the stratum corneum. Clinical pathology evaluations revealed significant increases in absolute polymorphonuclear leukocyte counts, monocyte counts, percentage of monocytes and decreases in percentage of lymphocyte differential white blood cell counts on day 29 of rats treated with alitretinoin 0.5% gel. Clinical chemistry evaluations revealed biologically relevant significant increases in the mean BUN and alkaline phosphatase values in females after the 28-day treatment. Serum LDL was increased in both male and female groups at Day 29. There were no biologically relevant haematology differences or serum chemistry differences after the 14-day period. Observed increases in mean heart-to-final body weight differences were attributed principally to the difference in the terminal body weights. Following treatment with alitretinoin 0.5% gel, mean plasma concentrations in the female rats were generally below the lower limit of quantitation (5 nMol) and

mean plasma concentrations in the male rats were about 200 nMol. In contrast to these findings in rats, plasma concentrations of 9-cis-retinoic acid in patients with KS applying Panretin gel never exceeded 0.638 ng/ml (2.13 nMol). This level is about 1/100 the mean concentration measured in male rats.

Genotoxicity

Alitretinoin was studied for genotoxic potential using the Ames test, the in vivo mouse micronucleus assay, the chromosomal aberration test in human lymphocytes, and the CHO cell mutation test. The medicinal product was not genotoxic.

Carcinogenesis, mutagenesis, impairment of fertility

Studies have not been performed to determine the carcinogenic potential of alitretinoin. However, the mutagenic potential has been evaluated, and alitretinoin has tested negative in the Ames test, the

in vivo mouse micronucleus assay, the chromosomal aberration test in human lymphocytes, and the CHO cell mutation test.

Teratogenicity

In an oral dose-ranging study in rabbits, alitretinoin induced gross malformations at a dose 35 times the topical human dose. This dose in rabbits resulted in plasma concentrations more than 60 times the highest observed plasma concentration in patients with KS following topical application of Panretin gel. No gross malformations were observed following oral administration to rabbits of doses 12 times the human topical dose (which resulted in plasma concentrations 60 times the highest observed plasma concentration in patients with KS following topical application of the gel). However, an increased rate of fused sternebrae was observed.

Phototoxicity

The phototoxicity potential of alitretinoin was assessed based on its chemical properties and data from a battery of in vitro tests. The results suggest that alitretinoin absorbs light in the UV range and is subject to photodegradation to other isomers (predominantly all-trans-retinoic acid). Alitretinoin was shown to have a weak potential to be a photo-irritant based on histidine and photoprotein binding. In cell-based in vitro assays, alitretinoin showed weak phototoxic potential.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Ethanol

Macrogol 400

Hydroxypropylcellulose

Butylhydroxytoluene

6.2Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. The use of other topical products on treated KS lesions should be avoided. Panretin gel should not be used concurrently with products containing DEET.

6.3Shelf life

Unopened: 3 years.

In-use: Any remaining tube should be discarded 90 days after first opening.

6.4Special precautions for storage

Do not store above 25 C.

Store in the original container in order to protect from light. Keep the container tightly closed.

After opening the tube for application, the tube cap must be replaced and closed tightly to provide an airtight seal. Opened tubes of Panretin gel must not be stored above 25 C, and should be protected from exposure to strong light and heat (e.g., direct sunlight).

6.5Nature and contents of container

Panretin gel is supplied in a multi-use 60 g epoxy-lined aluminium tube.

Each carton contains one tube of gel.

6.6Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

Panretin gel contains alcohol, keep away from naked flame.

7.MARKETING AUTHORISATION HOLDER

Eisai Ltd.

European Knowledge Centre

Mosquito Way

Hatfield

Hertfordshire

AL10 9SN

United Kingdom

8.NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

EU/1/00/149/001

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorization: 11 October 2000

Date of latest renewal:

10.DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

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