Active ingredients: Imiquimod
Aldara 5% cream
Why is Aldara used? What is it for?
Aldara cream can be used in three different situations.
Aldara cream can be prescribed by your doctor to treat:
- Condylomas (condylomata acuminata) that appear on the surface of the genitals (sexual organs) and around the anus (perianal area)
- Superficial basal cell carcinoma.
It is a common, slow-growing skin cancer with very little chance of spreading to other parts of the body. It usually occurs in elderly or middle-aged people, particularly with fair skin, and is due to excessive exposure to sunlight. If left untreated, basal cell carcinoma can have disfiguring effects, particularly on the face. It is therefore important to recognize this and intervene early.
- Actinic keratosis.
Actinic keratosis is characterized by rough areas of skin found in people who have been excessively exposed to sunlight during their lifetime. Some of them are colored, others are greyish, pink, red or brown. They can be flat and partially overlapping, or raised, rough, hard and warty. Aldara should only be used for flat actinic keratoses of the face and scalp in patients with a healthy immune system, when your doctor has decided that Aldara is the most appropriate treatment for you.
Aldara cream helps your body's immune system to produce physiological substances that help fight superficial basal cell carcinoma, actinic keratosis or the virus responsible for warts.
Contraindications When Aldara should not be used
Do not use Aldara cream:
- In case of hypersensitivity (allergy) to imiquimod (the active substance) or to any of the ingredients of Aldara cream.
Children and adolescents:
- Use is not recommended in children and adolescents.
Precautions for use What you need to know before taking Aldara
- If you have previously used Aldara cream or another similar medicine, tell your doctor before starting this treatment.
- Tell your doctor if you have immune system diseases.
- Do not use Aldara cream until the area to be treated has healed after previous medical or surgical treatment.
- Avoid contact with the eyes, lips and nostrils. In case of accidental contact, remove the cream by rinsing with water.
- Do not apply the cream in internal areas.
- Do not apply more cream than your doctor prescribes.
- Do not cover warts with bandages or the like after applying Aldara cream.
- If you experience discomfort in the affected area, wash off the cream by washing it with mild soap and water. As soon as the problem is gone, you can resume your applications.
- Tell your doctor if you have abnormal blood counts (blood cell counts).
Due to the way Aldara cream works, there is a possibility that the cream may worsen pre-existing inflammation in the treatment area.
- If you are being treated for genital warts, follow these additional precautions:
Men with warts under the foreskin should retract the foreskin and wash the underside daily. If this wash is not performed daily, it is very likely that symptoms of stiffening edema and loss of skin lining may appear with consequent difficulty in retracting the foreskin. If you experience such symptoms, stop treatment immediately and tell your doctor.
If you have open wounds: do not start treatment with Aldara cream until they have completely healed.
If you have internal warts: Do not use Aldara cream in the urethra (the opening through which urine passes), vagina, cervix or any position inside the anus (rectum). Do not use this drug for more than one course of treatment if your doctor has diagnosed you with severe immune system problems, either due to the disease or due to the medicines you are already using.
If you are HIV-positive, you must inform your doctor, as Aldara cream has been shown to be of limited efficacy in this category of patients.
If you decide to have intercourse while warts are still present, apply Aldara cream after - not before - intercourse. Aldara cream can damage condoms or diaphragms, so it should not be left on the skin during sexual intercourse. Remember that Aldara cream does not protect against the risk of HIV transmission or other sexually transmitted diseases.
- If you are being treated for basal cell carcinoma or actinic keratosis, follow these additional precautions
Do not use lamps or tanning beds and avoid exposure to sunlight as much as possible during treatment with Aldara cream. Wear protective clothing and wide-brimmed hats when you leave the house.
During Aldara cream therapy and until healing, the treatment area will likely look very different from normal skin.
Interactions What medications or foods can change the effect of Aldara
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those obtained without a prescription.
There are no known medicines that are incompatible with Aldara cream.
Warnings It is important to know that:
Pregnancy and breastfeeding:
Ask your doctor or pharmacist for advice before taking any medicine.
You should tell your doctor if you are pregnant or plan to become pregnant. Your doctor will then explain the risks and benefits of using Aldara cream during pregnancy. Animal studies have not indicated any direct or indirect harmful effects in pregnancy.
Do not breastfeed during treatment with Aldara cream, as it is not known whether imiquimod is excreted in human milk.
Important information about some of the ingredients of Aldara cream:
Methyl hydroxybenzoate (E218), and propyl hydroxybenzoate (E216) can cause allergic reactions (possibly delayed). Cetyl and stearyl alcohol can cause local skin reactions (such as contact dermatitis).
Dose, Method and Time of Administration How to use Aldara: Posology
Children and adolescents:
Use is not recommended in children and adolescents.
Adults:
Always use Aldara cream exactly as your doctor has told you. If you are not sure, ask your doctor or pharmacist.
Wash your hands thoroughly before and after applying the cream.
Do not cover the treated area with bandages or patches after applying Aldara cream. Open a new sachet each time you use the cream. Throw away the sachet with the cream left over from use. Do not keep the sachet open for later use.
The frequency and duration of treatment are different depending on whether they refer to genital warts, basal cell carcinoma or actinic keratosis (see specific instructions for each indication).
Aldara Cream Application Instructions
- If you are being treated for genital warts:
Application Instructions - (Monday, Wednesday and Friday)
- Before going to bed, wash your hands and the area to be treated with mild soap and water. Dry well.
- Open a new sachet and squeeze some cream onto your fingertips.
- Apply a thin layer of Aldara cream to the previously washed and dried area of the warts and massage gently until the cream is completely absorbed.
- After applying the cream, throw away the opened sachet and wash your hands with soap and water.
- Leave Aldara cream on the warts for about 6-10 hours. Avoid bathing or showering during this time.
- After approximately 6-10 hours, wash the Aldara cream application area with mild soap and water.
Apply Aldara cream 3 times a week. For example, apply the cream on Mondays, Wednesdays and Fridays. Each sachet contains a quantity of cream sufficient to cover a surface of warts of 20 cm2.
Men with warts located under the foreskin will need to retract it and wash the area daily (see the “Take special care” section).
Continue to use Aldara cream according to the instructions until the warts are completely healed (approximately half of women and men who achieve full recovery have the treatment for 8 and 12 weeks respectively, although, in some cases, the warts may heal. be reached after 4 weeks of treatment).
Do not use Aldara cream for more than 16 weeks to treat each episode of warts.
If you have the feeling that the effect of Aldara cream is too strong or too weak, please tell your doctor or pharmacist.
- If you are undergoing treatment for basal cell carcinoma:
Application Instructions - (Monday, Tuesday, Wednesday, Thursday and Friday) 1
- Before going to bed, wash your hands and the area to be treated with mild soap and water. Dry well.
- Open a new sachet and squeeze some cream onto your fingertips.
- Apply Aldara cream to the affected area and 1 cm (approximately 0.5 inch) of the surrounding area. Massage the area lightly until the cream is completely absorbed.
- After applying the cream, throw away the open sachet. Wash your hands with soap and water.
- Leave Aldara cream on the skin for about 8 hours. Avoid bathing or showering during this time. 6. After approximately 8 hours, wash the Aldara cream application area with mild soap and water.
Apply enough Aldara cream to cover the area to be treated and 1 cm of the surrounding area, every day for 5 consecutive days a week for 6 weeks. For example, apply the cream from Monday to Friday. Do not apply the cream on Saturdays and Sundays.
- If you are being treated for actinic keratosis
Application Instructions - (Monday, Wednesday and Friday)
- Before going to bed, wash your hands and the area to be treated with mild soap and water. Dry well.
- Open a new sachet and squeeze some cream onto your fingertips.
- Apply the cream only to the affected area. Massage the area lightly until the cream is completely absorbed.
- After applying the cream, throw away the open sachet. Wash your hands with soap and water.
- Leave Aldara cream on the skin for about 8 hours. Avoid bathing or showering during this time.
- After about 8 hours, wash the Aldara cream application area with mild soap and water.
Apply Aldara cream 3 times a week. For example, apply the cream on Monday, Wednesday and Friday. Each sachet contains enough cream to cover an area of 25 cm2 (approximately 4 inches2). Continue the treatment for 4 weeks. Four weeks after finishing the first treatment, the doctor will look at the skin. If the lesions have not disappeared, an additional 4 weeks of treatment may be required.
Overdose What to do if you have taken too much Aldara
If you use more Aldara cream than you should:
Eliminate the excess by washing it off with mild soap and water. When any skin reaction has disappeared, treatment can be resumed. In case of accidental ingestion of Aldara cream, contact your doctor.
If you forget to use Aldara cream:
In case you miss a dose, apply the cream as soon as possible and continue according to the pre-established schedule.
Do not apply the cream more than once a day.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
Side Effects What are the side effects of Aldara
The frequency of undesirable effects is defined as follows:
Very common side effects (may affect more than 1 in 10 patients)
Common side effects (may affect less than 1 in 10 patients)
Uncommon side effects (may affect less than 1 in 100 patients).
Rare side effects (may affect less than 1 in 1,000 patients).
Very rare side effects (may affect less than 1 in 10,000 patients).
Like all medicines, Aldara can cause side effects, although not everybody gets them.
If you feel unwell while taking Aldara cream, tell your doctor or pharmacist as soon as possible.
Some patients have observed skin color changes in the area where Aldara cream was applied. While these changes generally tend to improve over time, for some patients they may be permanent in nature.
If your skin reacts badly to the application of Aldara cream, stop the treatment, wash the area with mild soap and water and contact your doctor or pharmacist.
A reduction in the number of blood cells has been shown in some patients. A decrease in the number of blood cells can make you more susceptible to infections, it can make you bruise more easily or cause fatigue.
Serious skin reactions have been reported rarely. If you notice lesions or patches on your skin, which start out as small red areas and grow to look like small target-shaped lesions accompanied by symptoms such as itching, fever, generally feeling unwell, joint problems, visual disturbances, burning, pain or itching eyes and mouth pain, stop using Aldara cream and tell your doctor immediately.
In a small number of patients, hair loss has occurred in the treated area or the surrounding area.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
- If you are being treated for genital warts:
Many of the undesirable effects of Aldara cream are due to its local action on the skin.
Very common effects include redness (in 61% of patients), erosions (in 30% of patients), flaking and swelling. It is also possible that subcutaneous indurations, small ulcerations, crusting during the healing process and small subcutaneous blisters may occur. You may also experience itching (in 32% of patients), burning (in 26% of patients) or pain (in 8% of patients) in the areas where Aldara cream is applied. Most of these reactions are moderate. and the skin returns to normal within 2 weeks of cessation of applications.
Headache, uncommonly fever and flu syndrome, and muscle and joint pains have been reported commonly in some patients (4% or less): uterine prolapse; pain during intercourse in women; erectile difficulties; increased sweating; feeling nauseous; stomach and intestinal symptoms; ringing or ringing in the ears; redness; tiredness; dizziness; migraine; pins and needles; insomnia, depression; lack of appetite; enlarged glands; bacterial, fungal and viral infections (e.g. cold sores); vaginal infections and candidiasis of the oral route; coughs and colds with sore throat.
Serious or painful reactions have occurred very rarely, particularly in cases of excessive use of the product compared to the recommended amount. Painful skin reactions on the vaginal opening have made it difficult for women to urinate. If such situations occur, you should seek medical attention immediately.
- If you are being treated for basal cell carcinoma:
Many of the side effects of Aldara cream are due to its local action on the skin. Local skin reactions may be a sign that the medicine is working properly.
Very commonly, a slight itch may be felt on the treated skin.
Common effects include: tingling, small swelling of the skin, pain, burning, irritation, bleeding, redness or rash.
If a skin reaction becomes excessively bothersome during the course of treatment, please contact your doctor. They may advise you to stop applying Aldara cream for a few days. If you have pus or other signs of infection, talk to your doctor. In addition to skin reactions, other common effects are swollen lymph glands and back pain. .
Uncommonly some patients have reported changes at the application site (discharge, inflammation, swelling, crusting, skin lesions, blisters, dermatitis) or irritability, nausea, dry mouth, flu symptoms and fatigue.
- If you are undergoing treatment for actinic keratosis
Many of the side effects of Aldara cream are due to its local action on the skin. Local skin reactions may be a sign that the drug is working properly.
Very commonly, a slight itch may be felt on the treated skin
Common effects include: pain, burning, irritation or redness. If a skin reaction becomes excessively bothersome during the course of treatment, please contact your doctor. This may advise you to stop applying Aldara cream for a few days (ie to take some rest from treatment).
If you have pus or other signs of infection, talk to your doctor. In addition to skin reactions, other common effects are headache, anorexia, nausea, muscle and joint pain and fatigue.
Uncommonly some patients have observed changes in the application site (bleeding, inflammation, discharge, sensitization, edema, small swelling of the skin, chills, crusting or scarring, ulceration or a sensation of warmth or discomfort), or inflammation of the nasal lining. , stuffy nose, flu or flu symptoms, depression, eye irritation, swollen eyelids, sore throat, diarrhea, actinic keratosis, redness, swelling of the face, ulcers, pain in extremities, fever, weakness or tremors.
Expiry and Retention
Keep out of the reach and sight of children.
Do not store above 25 ° C
Do not use after the expiry date stated on the package.
Once opened, the sachets must not be reused
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Aldara Cream contains
- The active ingredient is Imiquimod. Each sachet contains 250 mg of cream (100 mg of cream contains 5 mg of imiquimod).
- The other ingredients are: isostearic acid, benzyl alcohol, cetyl alcohol, stearyl alcohol, white petroleum jelly, polysorbate 60, sorbitan stearate, glycerol, methyl hydroxybenzoate (E218), propyl hydroxybenzoate (E216), xanthan gum, purified water.
What Aldara Cream looks like and contents of the pack
- Each Aldara 5% cream sachet contains 250 mg of a yellowish-white cream.
- Each pack contains 12 or 24 single-use polyester / aluminum foil sachets. Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ALDARA 5% CREAM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 250 mg sachet of cream contains 12.5 mg of imiquimod (5%).
100 mg of cream contains 5 mg of imiquimod.
Excipients:
methyl hydroxybenzoate (E218)
propyl hydroxybenzoate (E216)
cetyl alcohol
stearyl alcohol
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Cream
Cream of yellowish-white color
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Imiquimod cream is indicated for the topical treatment of:
Genital and perianal external acuminate warts (condylomata acuminata) in adult patients
Small superficial basal cell carcinomas (sBCC) in adult patients
Clinically typical non-hypertrophic, non-hyperkeratotic actinic keratoses (AK) present on the face and skull in immunocompetent adult patients, when the size or number of lesions limit the "efficacy and / or acceptability" of cryotherapy or when other topical treatment options are contraindicated or not appropriate.
04.2 Posology and method of administration
Dosage
The frequency of application and the duration of treatment with imiquimod cream vary according to the different indications.
External genital warts in adult patients:
Imiquimod cream must be applied 3 times a week (example: Monday, Wednesday and Friday, or Tuesday, Thursday and Saturday) before bed and must remain on the skin for a period of 6-10 hours.
Treatment with imiquimod cream should continue until the visible genital or perianal warts disappear or for a maximum of 16 weeks per episode of warts.
For the quantity to be applied, see section 4.2 Method of application.
Superficial basal cell carcinomas in adult patients:
Apply imiquimod cream for 6 weeks, 5 times a week (example: Monday to Friday) before going to bed and leave it to act on the skin for about 8 hours.
For the quantity to be applied, see section 4.2 Method of application.
Actinic keratosis in adult patients
Treatment must be initiated and monitored by a physician. Imiquimod cream should be applied 3 times a week (example: Monday, Wednesday and Friday) for 4 weeks, before going to bed and left to act on the skin for a period of approximately 8 hours. A sufficient dose of cream should be applied to cover the area to be treated. Healing of actinic keratosis should be evaluated after the next 4 weeks of suspension from treatment. If signs of actinic keratosis persist in the treated area, the treatment should be repeated to further 4 weeks.
The maximum recommended dose is one sachet. The maximum recommended duration of treatment is 8 weeks.
An "interruption of treatment should be considered if intense local inflammatory reactions occur (see section 4.4) or if an" infection "is detected in the treated area. In the latter case, appropriate measures should be used. Each treatment period should not exceed 4 weeks even in the case of missed doses or withdrawal periods.
If the treated lesion or lesions show an incomplete response to the examination of follow up at 4-8 weeks after the second treatment period, a different therapy should be used (see section 4.4).
Information applicable to all indications:
If a dose is missed, the patient should apply the cream as soon as possible, continuing according to the established schedule. However, the cream should not be applied more than once a day.
Pediatric patients
The use of imiquimod is not recommended in pediatric patients. There are no data available on the use of imiquimod in children and adolescents in the approved indications.
Aldara should not be used in children with molluscum contagiosum due to lack of efficacy in this indication (see section 5.1).
Application procedure
External genital warts:
Imiquimod cream must be applied to the area affected by warts, previously washed, in a thin layer, massaging until completely absorbed. Apply the product only on the affected areas, carefully avoiding the application on internal surfaces. Imiquimod cream must be applied before bedtime. During the 6 - 10 hours of the treatment, bathing and showering should be avoided. After this period it is essential that imiquimod cream is eliminated. with the use of mild soap and water.
Application of an excessive amount of cream or prolonged contact of the cream on the skin can cause severe reactions in the application area (see sections 4.4, 4.8 and 4.9). One single use sachet is sufficient to cover a 20 cm2 area of warts. Once opened, the sachets must not be reused. Wash your hands thoroughly before and after applying the cream.
Treatment of warts in uncircumcised men should be preceded by retraction of the foreskin and accompanied by daily washing of the area (see section 4.4).
Superficial basal cell carcinomas:
Before applying imiquimod cream, patients should wash the area to be treated with mild soap and water, drying it thoroughly. Apply a dose of cream sufficient to cover the treatment area, extending the application on the skin around the tumor for one centimeter. The cream should be applied by exerting a light massage on the area to be treated until completely absorbed. The cream should be applied before going to bed and left to act on the skin for about 8 hours. Avoid showers or baths during this time. After this period it is essential that imiquimod cream is washed off with mild soap and water.
Once opened, the sachets must not be reused. Wash your hands thoroughly before and after applying the cream.
Response to tumor treatment with imiquimod cream should be assessed 12 weeks after the end of treatment. If the tumor response to treatment is incomplete, a different therapy should be used (see section 4.4).
If the local skin reaction to imiquimod cream causes excessive patient discomfort or infections are observed at the treatment site, applications may be suspended for several days (see section 4.4). In the case of infections, additional appropriate measures should be used.
Actinic keratosis:
Before applying imiquimod cream, patients should wash the area to be treated with mild soap and water, then dry thoroughly. Apply a sufficient dose of cream to cover the treatment area. The cream should be applied by exerting a light massage on the area to be treated until completely absorbed.
The cream should be applied before bedtime and left to act on the skin for about 8 hours. Avoid showers or baths during this time. After this period it is essential that imiquimod cream is eliminated with the use of mild soap and water. Once opened, the sachets must not be reused. Wash hands thoroughly before and after applying the cream.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
04.4 Special warnings and appropriate precautions for use
External genital warts, superficial basal cell carcinoma and actinic keratosis:
Avoid contact with eyes, lips and nostrils.
It is possible that imiquimod cream causes an "exacerbation of inflammatory skin processes.
Imiquimod cream should be used with caution in patients with autoimmune diseases (see section 4.5). A benefit / risk analysis should be done before treating these patients with imiquimod in relation to the possibility of their autoimmune disease worsening. Imiquimod cream should be used with caution in organ transplant patients (see section 4.5). . A risk / benefit analysis for imiquimod treatment of these patients associated with the possibility of organ rejection or graft-versus-host immunological reaction should be performed.
Therapy with imiquimod cream is not recommended until skin, which has previously undergone any other pharmacological or surgical treatment, has achieved complete healing. Application to broken skin may result in systemic absorption of imiquimod, leading to an increased risk of adverse events (see sections 4.8 and 4.9).
The use of occlusive bandages is not recommended during the treatment of genital and perianal warts with imiquimod cream.
The excipients methyl hydroxybenzoate (E218), propyl hydroxybenzoate (E216), cetyl alcohol and stearyl alcohol can cause allergic reactions.
Rarely, intense local inflammatory reactions with exudate or erosion may occur, even after a few applications of imiquimod cream. Local inflammatory reactions could be accompanied or even preceded by systemic flu-like symptoms with malaise, pyrexia, nausea, myalgia and stiffness. In this case, discontinuation of treatment should be considered. Imiquimod should be used with caution in patients with impaired haematological function (see section 4.8 d).
External genital warts:
There are limited data on the use of imiquimod cream in the treatment of men with warts localized under the foreskin. The relative tolerability of uncircumcised men treated with imiquimod cream 3 times a week, following the rules of daily foreskin hygiene, is based on a series of fewer than 100 patients.In other studies, in which daily foreskin hygiene was not followed, there were two severe cases of phimosis and one case of stenosis leading to circumcision. Treatment of this patient population is therefore only recommended for those men who are able or willing to follow daily foreskin hygiene rules. Early symptoms of stricture may include local skin reactions (such as erosion, ulceration, edema and induration) or increasing difficulty in retracting the foreskin. Discontinue treatment immediately if these symptoms appear. Based on currently available knowledge, the treatment of urethral, intra-vaginal, cervical, rectal or intra-anal warts is not recommended. Do not initiate therapy with imiquimod cream on tissues with ulceration or open wounds, until the affected area has completely healed.
Local skin reactions such as erythema, erosions, excoriation / peeling and edema are common. Other local reactions such as indurations, ulcerations, scabs and blisters have also been reported. In the event of an intolerable skin reaction, remove the cream by washing the area with mild soap and water. Treatment with imiquimod cream may be resumed when the skin reaction subsides.
The risk of severe local skin reactions may increase following applications of higher than recommended doses (see section 4.2). However, severe local reactions requiring treatment and / or causing temporary incapacity have rarely been observed in patients who had used imiquimod in accordance with instructions. When these reactions have occurred in the urethral meatus, some women have experienced difficulty in urinating, sometimes with urgent need for catheterization and treatment of the affected area.
There is no clinical experience on the use of imiquimod cream after treatments with other drugs for locally applied genital or perianal warts.
Imiquimod cream should be removed from the skin prior to sexual intercourse. Imiquimod cream could damage condoms or diaphragms, so the simultaneous use of imiquimod cream is not recommended.
It is advisable to consider alternative methods of contraception.
In immunocompromised patients, repeated treatment with imiquimod cream after recurrence of warts is not recommended.
Although the limited data available showed a higher rate of reduction of warts in HIV-positive patients, imiquimod cream did not demonstrate similar efficacy in terms of disappearance of warts in this patient group.
Superficial basal cell carcinomas:
Imiquimod has not been evaluated for the treatment of basal cell carcinoma located within 1 cm of the eyelids, nose, lips and hairline.
During therapy and until healing, the affected skin will likely look very different from normal skin. Local skin reactions are normal, but these reactions generally decrease in intensity during therapy or resolve after discontinuation of imiquimod cream therapy. There is an association between the complete cure rate and the intensity of local skin reactions (eg erythema). Such local skin reactions may be linked to the stimulation of the local immune response. applications can be suspended for several days and treatment with imiquimod cream can be resumed when the skin reaction has subsided.
The result of the therapy can be determined after the regeneration of the treated skin, approximately 12 weeks after the end of the treatment.
There is no clinical experience with the use of imiquimod cream in immunocompromised patients.
Clinical experience is not available in patients with relapsing superficial basal cell carcinomas or previously treated with other therapies, therefore the use of the drug is not recommended in these patients.
Data from an open-label clinical study indicate that large tumors (> 7.25 cm2) are less likely to respond to imiquimod therapy.
The treated superficial skin area must be protected from sun exposure.
Actinic keratosis
Actinic keratosis lesions clinically atypical or suspected to be malignant should be biopsied to determine appropriate treatment.
Imiquimod has not been evaluated for the treatment of actinic keratoses on the eyelids, the inside of the nostrils or ears or the lip area within the pigmented border.
The available data regarding the use of imiquimod for the treatment of actinic keratoses in anatomical sites other than the face and skull are very limited. The use for keratoses on the forearms and hands is not recommended as the available data do not support the efficacy of imiquimod for this indication.
Imiquimod is not recommended for the treatment of actinic keratosis lesions with marked hyperkeratosis or hypertrophy such as for skin indurations.
During therapy and until healing, the affected skin will likely look very different from normal skin. Local skin reactions are normal, but generally decrease in intensity during therapy or resolve after discontinuation of imiquimod cream therapy. There is an association between the index of complete recovery and the intensity of local skin reactions (eg erythema). Such local skin reactions may be linked to the stimulation of the local immune response. local skin reaction should require it, applications can be suspended for several days .. Treatment with imiquimod cream can be resumed when the skin reaction has subsided.
If one or more doses have been forgotten or following a withdrawal period, each treatment period should not extend beyond 4 weeks.
The clinical outcome of therapy can be determined after regeneration of the treated skin, approximately 4-8 weeks after the end of treatment.
There is no clinical experience with the use of imiquimod cream in immunocompromised patients.
Re-treatment of healed actinic keratoses after one or two courses of therapy and relapsing is not recommended, as no data are available on any of these uses.
Data from an open-label clinical study indicate that subjects with more than 8 actinic keratosis lesions show a reduced incidence of complete healing compared to patients with fewer than 8 lesions.
The surface area of the treated skin must be protected from sun exposure.
04.5 Interactions with other medicinal products and other forms of interaction
No interaction studies have been performed, including studies with immunosuppressive drugs. Interactions with systemic drugs would be limited as skin absorption of imiquimod cream is minimal.
Due to its immunostimulating properties, imiquimod cream should be used with caution in patients undergoing immunosuppressive therapy (see section 4.4).
04.6 Pregnancy and lactation
No clinical data are available on the use of imiquimod during pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to gestation, embryo or fetal development, parturition or postnatal development (see paragraph 5.3). Take precautions when prescribed in pregnant women.
There was no quantifiable level of imiquimod (> 5 ng / ml) in serum after single or repeated topical dosing, therefore, it is not possible to give a specific recommendation for use during lactation.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
Based on the undesirable effects reported in section 4.8, it is unlikely that the treatment will have any effect on the ability to drive and use machines.
04.8 Undesirable effects
General description:
External genital warts:
In clinical studies performed at a dosage of three applications per week, the most frequently encountered undesirable drug reactions and probably or likely due to treatment with imiquimod cream were those limited to the area of application at the site of the warts (33.7% of patients treated with imiquimod). Some systemic adverse reactions have also been reported, such as headache (3.7%), flu symptoms (1.1%) and myalgia (1.5%).
The following are adverse reactions reported by 2,292 patients treated with imiquimod cream in open, placebo-controlled clinical trials. Such undesirable events are considered at least in probable cause and effect relationship with imiquimod treatment.
Superficial basal cell carcinoma:
In studies performed with 5 applications per week, 58% of patients reported at least one adverse event. The most frequently reported undesirable reactions and believed to be likely or likely to be related to treatment with imiquimod cream are those limited to the area of application, with a frequency of 28.1%. Some systemic adverse reactions such as back pain (1.1%) and flu symptoms (0.5%) have been reported in patients treated with imiquimod cream.
The following are adverse reactions reported by 185 patients treated with imiquimod cream in placebo-controlled phase III clinical trials in superficial basal cell carcinoma. Such undesirable events are considered at least in probable cause and effect relationship with imiquimod treatment.
Actinic keratosis
In pre-registration studies with 3 times per week dosing for up to two courses of therapy for each of 4 weeks, 56% of patients treated with imiquimod reported at least one adverse event. The most frequently reported undesirable events during these studies and thought to be likely or likely to be related to imiquimod cream treatment are application area disorders (22% of imiquimod treated patients). Patients treated with imiquimod reported some adverse systemic reactions, including myalgia (2%).
Adverse reactions reported by 252 patients treated with imiquimod cream in phase III placebo-controlled clinical trials in actinic keratosis are listed below. Such undesirable events are likely to be considered cause and effect related to imiquimod treatment.
b) Table of adverse events:
Frequencies are defined as Very common (≥1 / 10), Common (≥1 / 100,
c) Adverse events that occur frequently:
External genital warts:
Investigators in placebo-controlled clinical trials with imiquimod cream applied 3 times per week were asked to evaluate protocol-indicated clinical signs (skin reactions). These assessments indicate that the most common local skin reactions were erythema (61%), erosion (30%), excoriation / desquamation (23%) and edema (14%) (see section 4.4). Local skin reactions, such as erythema, are likely to result from the pharmacological effects of imiquimod cream.
Distant skin reactions, mainly erythematous in nature, were also reported in placebo-controlled studies (44%). Such reactions were observed in sites without warts, which probably had come into contact with imiquimod cream. Most skin reactions were mild or moderate in intensity and resolved within 2 weeks of stopping treatment.
However, in some cases these reactions have proved to be severe and required treatment and / or caused disability. In very rare cases, severe reactions in the urethral meatus have resulted in dysuria in women (see section 4.4).
Superficial basal cell carcinoma:
Investigators in placebo-controlled clinical trials with imiquimod cream applied 5 times per week were asked to evaluate protocol-indicated clinical signs (skin reactions). These assessments indicate that the most common local skin reactions were severe erythema (31%), severe erosions (13%), and severe crusting and induration (19%). Local skin reactions, such as erythema, probably result from the pharmacological effects of imiquimod cream.
Skin infections have been observed during treatment with imiquimod cream. Although no serious sequelae have occurred, the possibility of infection of the broken skin should always be considered.
Actinic keratosis
In clinical studies with imiquimod cream applied 3 times a week for 4 or 8 weeks, the side effects at the application site were irritation of the application site (14%) and burning on the wound (5%). Very common severe erythema (24%) and severe crusting and induration (20%). Local skin reactions, such as erythema, are likely an extension of the pharmacological effects of imiquimod cream. See sections 4.2 and 4.4 for information on withdrawal periods. Skin infections have been observed during treatment with imiquimod cream. If severe sequelae occur, the possibility of infection of the broken skin should always be considered.
d) Adverse events applicable to all indications:
Some cases of localized hypopigmentation and hyperpigmentation have been reported following the use of imiquimod cream. These changes in skin color could be permanent for some patients. At follow-up of 162 patients, 5 years after the end of treatment for sBCC, mild hypopigmentation was observed in 37% of patients examined and moderate hypopigmentation in 6%. 56% of these patients revealed no hypopigmentation; no cases of hyperpigmentation were recorded.
Clinical studies conducted on the use of imiquimod for the treatment of actinic keratosis have shown a frequency of 0.4% (5/1214) of alopecia in the treated area or in the surrounding area. Following marketing, we have received reports of suspected alopecia occurring in the course of treatment of superficial basal cell carcinoma and external genital warts.
Reductions in hemoglobin, white blood cell counts, and absolute neutrophils and platelets have been observed in clinical studies. These reductions are not considered clinically significant in patients with normal blood reserves. Patients with reduced blood reserve were not taken into consideration. consideration in clinical trials Reductions in haematological parameters requiring clinical intervention have been reported post-marketing. There have been reports of post-marketing elevations in liver enzymes.
Rare cases of exacerbation of autoimmune diseases have been reported.
Rare cases of dermatological drug reactions distant from the application site, including erythema multiforme, have been reported in clinical trials. post-marketing include erythema multiforme, Steven Johnson syndrome and cutaneous lupus erythematosus.
e) Pediatric patients:
Imiquimod has been evaluated in controlled clinical trials with pediatric patients (see sections 4.2 and 5.1).
No systemic reactions were noted. Administration site reactions occurred more frequently after imiquimod than with placebo, however, the incidence and intensity of these reactions were not different from those seen in adults within the licensed indications. They did not occur in pediatric patients. serious adverse reactions due to imiquimod.
04.9 Overdose
Systemic overdose due to locally applied imiquimod cream is unlikely given the minimal skin absorption. Studies in rabbits have shown that only a cutaneous dose above 5 g / kg is lethal. Prolonged skin overdose of imiquimod cream could result in severe local skin reactions.
Following accidental ingestion, nausea, vomiting, headache, myalgia and fever occur after a single dose of 200 mg imiquimod, corresponding to the content of approximately 16 sachets. The most serious side effect reported following repeated ingestion of doses ≥200 mg is hypotension, which is resolved with oral or intravenous fluid administration.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: topical chemotherapeutic agents, antivirals: ATC code: D06BB10.
Imiquimod is an immune response modifier. Studies on saturation bonds suggest the existence of a membrane receptor for imiquimod on responding immune cells. Imiquimod does not have direct antiviral activity. animals, imiquimod is active on viral infections and acts as an antitumor agent mainly through the induction of interferon alpha and other cytokines. In clinical studies, the induction of interferon alpha and other cytokines following the application of imiquimod cream on the genital wart tissue. A pharmacokinetic study has shown increased systemic levels of interferon alpha and other cytokines following topical application of imiquimod.
External genital warts
Clinical studies
The results of 3 pilot phase III efficacy studies have shown that treatment with imiquimod for 16 weeks is significantly more effective than placebo in inducing complete healing of treated warts.
In 119 women treated with imiquimod the total cure rate was 60% compared to 20% in 105 patients treated with placebo (95% CI: 20% - 61%, p
In 157 men treated with imiquimod the percentage of total healings was 23% compared to 5% found in 161 patients treated with placebo (95% CI: 3% - 36%, p
Superficial basal cell carcinoma:
Clinical Studies:
The efficacy of imiquimod applied 5 times per week for 6 weeks was evaluated in two double-blind placebo-controlled clinical studies. On histological examination, the target tumors were single primary superficial basal cell carcinomas with a minimum size of 0.5 cm2. and a maximum diameter of 2 cm. Tumors located within 1 cm of the eyes, nose, mouth, ears and hairline were excluded.
In a cumulative analysis of the two studies, histological healing was observed in 82% (152/185) of patients. In cases where clinical evaluation was included, healing judged by the composite clinical and histological endpoint was observed in 75% (139/185) of patients. These results are statistically significant (p
Data from a 5-year open-label long-term uncontrolled study indicate that an estimated 77.9% [95% CI (71.9%, 83.8%)] of all subjects initially undergoing treatment are clinically healed and remained so for 60 months.
Actinic keratosis:
Clinical Studies:
The efficacy of imiquimod applied 3 times a week for one or two 4-week cycles separated by a 4-week withdrawal period was evaluated in two double-blind placebo-controlled clinical trials. Patients exhibited keratosis lesions. Clinically typical, visible, discrete, non-hyperkeratotic, non-hypertrophic, within a treatment zone of 25 cm2 on the bald skull or face. 4-8 actinic keratosis lesions were treated. The incidence of complete healing (imiquimod minus placebo) for the pooled clinical trials was 46.1% (CI 39.0%, 53.1%).
Data collected one year apart from two combined observational studies indicate a relapse rate of 27% (35/128 patients) in those patients clinically cured after one or two courses of treatment. The incidence of single lesion relapses was 5.6% (41/737). The corresponding incidence of relapses for placebo was 47% (8/17 patients) and 7.5% (6/80 lesions). The incidence of progression in squamous cell carcinoma (SCC) was reported in 1.6% (2/128 patients).
There are no data on the incidence of relapse and disease progression beyond one year.
Pediatric patients
The approved indications: external genital warts, actinic keratosis and superficial basal cell carcinoma are conditions not generally observed in the pediatric population and therefore have not been studied.
Aldara cream was evaluated in 4 randomized, controlled vs. vehicle, double-blind in children aged 2 to 15 with molluscum contagiosum (imiquimod n = 576, vehicle n = 313). These studies did not demonstrate the efficacy of imiquimod in any of the dosing regimens studied (3 times per week for ≤ 16 weeks and 7 times per week for ≤ 8 weeks).
05.2 Pharmacokinetic properties
External genital warts, superficial basal cell carcinoma and actinic keratosis:
In humans, less than 0.9% of a single dose of locally applied radiolabelled imiquimod was absorbed through the skin. The small absorbed dose of drug was immediately excreted via the urinary and faecal routes in a mean ratio of 3 to 1. single and repeated locales revealed no quantifiable serum drug levels (> 5 ng / mL).
Systemic exposure (percutaneous penetration) was calculated from the recovery of carbon 14 from imiquimod [14C] present in urine and faeces.
A minimal systemic absorption of imiquimod 5% cream through the skin was observed in a study of 58 patients with actinic keratosis treated with 3 applications per week for 16 weeks.
The extent of percutaneous absorption did not change significantly between the first and last application. Peak blood concentrations of the drug at the end of week 16 were observed between 9 and 12 hours and were 0, respectively. 1, 0.2 and 1.6 ng / mL for applications on the face (12.5 mg, one single use sachet), scalp (25 mg, 2 sachets) and hands / arms (75 mg, 6 sachets) . The application area surface was not controlled in the scalp and hand / arm treated groups. Dose proportionality was not observed. An apparent half-life of approximately 10 times the observed half-life of 2 hours was calculated. , in a previous study, following subcutaneous application. This indicates a prolonged stay of the drug in the skin. At week 16, the amount of drug in the urine was less than 0.6% of the applied dose in these patients.
Pediatric patients
The pharmacokinetic properties of imiquimod after single and multiple topical application in pediatric patients with molluscum contagiosum (MC) were investigated. Systemic exposure data demonstrated that the absorption value of imiquimod after topical application to CD skin of patients aged 6-12 years was low and comparable to that observed in healthy adults with actinic keratosis or carcinoma. superficial basal cell. In children 2-5 years of age, absorption, based on Cmax values, was higher than in adults.
05.3 Preclinical safety data
Non-clinical data from conventional studies of pharmacology, safety, mutagenicity and teratogenicity did not reveal any particular risks for humans.
In a dermal toxicity study in rats treated with doses of 0.5 and 2.5 mg / kg for four months, a significant reduction in body weight and an increase in spleen weight were observed, while they were not found. similar effects during a similar study in mice. Local dermal irritation appeared in both species, particularly at high dosages.
In a two-year study on the carcinogenicity of dermal administration in mice three days per week, no tumors were found at the application site. However, the incidence of hepatocellular tumors in treated animals was found to be higher than in control subjects. The mechanism underlying this phenomenon is unknown, but since imiquimod has low systemic absorption through human skin and is not mutagenic, the likelihood of human risk of systemic exposure is believed to be quite low. In addition, no tumors were observed in a two-year oral carcinogenicity study in rats.
The photocarcinogenicity of imiquimod cream was evaluated in a study performed in hairless albino rats exposed to simulated solar ultraviolet radiation (UVR). Imiquimod cream was applied to the animals three times a week, which were then irradiated 5 days a week for 40 weeks. The rats were treated for an additional 12 weeks for a total of 52 weeks. Tumors developed earlier and in greater numbers in the group of rats that received the placebo cream than in the low-intensity UVR-irradiated control group. The relevance of these findings in humans is unknown. Topical administration of imiquimod cream resulted in no tumor development at any dose compared to the placebo cream group.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Isostearic acid
benzyl alcohol
cetyl alcohol
stearyl alcohol
white petroleum jelly
polysorbate 60
sorbitan stearate
glycerol
methyl hydroxybenzoate (E218)
propyl hydroxybenzoate (E216)
xanthan gum
purified water.
06.2 Incompatibility
Not applicable
06.3 Period of validity
2 years
06.4 Special precautions for storage
Store at a temperature not exceeding 25 ° C.
Once opened, the sachets must not be reused.
06.5 Nature of the immediate packaging and contents of the package
Packs of 12 or 24 disposable polyester / aluminum sachets. 250 mg of cream. Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions
07.0 MARKETING AUTHORIZATION HOLDER
Meda AB
Pipers väg 2
170 73 Solna
Sweden
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/98/080 / 001-002
034405011
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 18/09/1998
Date of last renewal: 03/09/2008
