Adverse reactions : תופעות לוואי

4.8 Undesirable effects
 a)      General Description:
External genital warts:
In the pivotal trials with 3 times a week dosing, the most frequently reported adverse drug reactions judged to be probably or possibly related to imiquimod cream treatment were application site reactions at the wart treatment site (33.7% of imiquimod treated patients). Some systemic adverse reactions, including headache (3.7%), influenza-like symptoms (1.1%), and myalgia (1.5%) were also reported.

Patient reported adverse reactions from 2292 patients treated with imiquimod cream in placebo controlled and open clinical studies are presented below. These adverse events are considered at least possibly causally related to treatment with imiquimod.

Superficial basal cell carcinoma:
In trials with 5 times per week dosing 58% of patients experienced at least one adverse event. The most frequently reported adverse events from the trials judged probably or possibly related to imiquimod cream are application site disorders, with a frequency of 28.1%. Some systemic adverse reactions, including back pain (1.1%) and influenza-like symptoms (0.5%) were reported by imiquimod cream patients.

Patient reported adverse reactions from 185 patients treated with imiquimod cream in placebo controlled phase III clinical studies for superficial basal cell carcinoma are presented below.
These adverse events are considered at least possibly causally related to treatment with imiquimod.

Actinic keratosis
In the pivotal trials with 3 times per week dosing for up to 2 courses each of 4 weeks, 56% of imiquimod patients reported at least one adverse event. The most frequently reported adverse event from these trials judged probably or possibly related to imiquimod cream was application site reactions (22% of imiquimod treated patients). Some systemic adverse reactions, including myalgia (2%) were reported by imiquimod treated patients.

Patient reported adverse reactions from 252 patients treated with imiquimod cream in vehicle controlled phase III clinical studies for actinic keratosis are presented below. These adverse events are considered at least possibly causally related to treatment with imiquimod.
 b)      Tabular Listing of adverse events:
Frequencies are defined as Very common (1/10), Common (1/100 to <1/10) and Uncommon (1/1,000 to <1/100). Lower frequencies from clinical trials are not reported here.

External genital    Superficial basal    Actinic keratosis warts               cell carcinoma
(3x/ wk,16wks)      (5x/wk, 6 wks)       (3x/wk, 4 or 8 wks)
N = 2292            N = 185              N = 252
Infections and infestations:
Infection                             Common              Common               Uncommon Pustules                                                  Common               Uncommon Herpes simplex                        Uncommon
Genital candidiasis                   Uncommon
Vaginitis                             Uncommon
Bacterial infection                   Uncommon
Fungal infection                      Uncommon
Upper respiratory tract infection     Uncommon
Vulvitis                              Uncommon
Rhinitis                                                                       Uncommon Influenza                                                                      Uncommon Blood and lymphatic system disorders:
Lymphadenopathy                       Uncommon            Common               Uncommon Metabolism and nutrition disorders:
Anorexia                              Uncommon                                 Common Psychiatric disorders:
Insomnia                              Uncommon
Depression                            Uncommon                                 Uncommon Irritability                                              Uncommon
Nervous system disorders:
Headache                         Common                Common
Paraesthesia                     Uncommon
Dizziness                        Uncommon
Migraine                         Uncommon
Somnolence                       Uncommon
Eye disorders
Conjunctival irritation                                Uncommon
Eyelid oedema                                          Uncommon
Ear and labyrinth disorders:
Tinnitus                         Uncommon
Vascular disorders:
Flushing                         Uncommon
Respiratory, thoracic and mediastinal disorders:
Pharyngitis                      Uncommon
Rhinitis                         Uncommon
Nasal congestion                                                Uncommon Pharyngo laryngeal pain                                         Uncommon Gastrointestinal disorders:
Nausea                           Common     Uncommon              Common Abdominal pain                   Uncommon
Diarrhoea                        Uncommon                       Uncommon Vomiting                         Uncommon
Rectal disorder                  Uncommon
Rectal tenesmus                  Uncommon
Dry mouth                                   Uncommon
Skin and subcutaneous tissue
Pruritus                         Uncommon
Dermatitis                       Uncommon   Uncommon
Folliculitis                     Uncommon
Rash erythematous                Uncommon
Eczema                           Uncommon
Rash                             Uncommon

Sweating increased               Uncommon
Urticaria                        Uncommon
Actinic keratosis                                               Uncommon Erythema                                                        Uncommon Face oedema                                                     Uncommon Skin ulcer                                                      Uncommon Musculoskeletal and connective
Tissue disorders:
Myalgia                          Common                           Common Arthralgia                       Uncommon                         Common Back pain                        Uncommon    Common
Pain in extremity                                               Uncommon Renal and urinary disorders:
Dysuria                          Uncommon
Reproductive system and breast disorders:
Genital pain male                 Uncommon
Penile disorder                   Uncommon
Dyspareunia                       Uncommon
Erectile dysfunction              Uncommon
Uterovaginal prolapse             Uncommon
Vaginal pain                      Uncommon
Vaginitis atrophic                Uncommon
Vulval disorder                   Uncommon
General disorders and administration site conditions:
Application site pruritus         Very common   Very common   Very common Application site pain             Very common       Common        Common Application site burning          Common            Common        Common Application site irritation       Common            Common        Common Application site erythema                           Common        Common Application site reaction                                         Common Application site bleeding                          Common       Uncommon Application site papules                           Common       Uncommon Application site paraesthesia                      Common       Uncommon Application site rash                              Common
Fatigue                           Common                         Common Pyrexia                           Uncommon                     Uncommon Influenza-like illness            Uncommon       Uncommon
Pain                              Uncommon
Asthenia                          Uncommon                     Uncommon Malaise                           Uncommon
Rigors                            Uncommon                     Uncommon Application site dermatitis                                    Uncommon Application site discharge                       Uncommon      Uncommon Application site hyperaesthesia                                Uncommon Application site inflammation                    Uncommon

Application site oedema                          Uncommon      Uncommon Application site scabbing                        Uncommon      Uncommon Application site scar                                          Uncommon Application site skin breakdown                  Uncommon
Application site swelling                        Uncommon      Uncommon Application site ulcer                                         Uncommon Application site vesicles                        Uncommon      Uncommon Application site warmth                                        Uncommon Lethargy                                         Uncommon
Discomfort                                                     Uncommon Inflammation                                                   Uncommon c)      Frequently occurring adverse events:

External genital warts:
Investigators of placebo controlled trials were required to evaluate protocol mandated clinical signs (skin reactions). These protocol mandated clinical sign assessments indicate that local skin reactions including erythema (61%), erosion (30%), excoriation/flaking/scaling (23%) and oedema (14%) were common in these placebo controlled clinical trials with imiquimod cream applied three times weekly (see section 4.4). Local skin reactions, such as erythema, are probably an extension of the pharmacologic effects of imiquimod cream.

Remote site skin reactions, mainly erythema (44%), were also reported in the placebo controlled trials. These reactions were at non-wart sites which may have been in contact with imiquimod cream. Most skin reactions were mild to moderate in severity and resolved within 2 weeks of treatment discontinuation. However, in some cases these reactions have been severe, requiring treatment and/or causing incapacitation. In very rare cases, severe reactions at the urethral meatus have resulted in dysuria in women (see section 4.4).

Superficial basal cell carcinoma:
Investigators of the placebo controlled clinical trials were required to evaluate protocol mandated clinical signs (skin reactions). These protocol mandated clinical sign assessments indicate that severe erythema (31%) severe erosions (13%) and severe scabbing and crusting (19%) were very common in these trials with imiquimod cream applied 5 times weekly. Local skin reactions, such as erythema, are probably an extension of the pharmacologic effect of imiquimod cream.

Skin infections during treatment with imiquimod have been observed. While serious sequelae have not resulted, the possibility of infection in broken skin should always be considered.

Actinic keratosis
In clinical trials of imiquimod cream 3 times weekly for 4 or 8 weeks the most frequently occurring application site reactions were itching at the target site (14%) and burning at the target site (5%). Severe erythema (24%) and severe scabbing and crusting (20%) were very common.
Local skin reactions, such as erythema, are probably an extension of the pharmacologic effect of imiquimod cream. See 4.2 and 4.4 for information on rest periods.

Skin infections during treatment with imiquimod have been observed. While serious sequelae have not resulted, the possibility of infection in broken skin should always be considered.
 d)      Adverse events applicable to all indications:
Reports have been received of localised hypopigmentation and hyperpigmentation following imiquimod cream use. Follow-up information suggests that these skin colour changes may be permanent in some patients. In a follow-up of 162 patients five years after treatment for sBCC a mild hypopigmentation was observed in 37% of the patients and a moderate hypopigmentation was observed in 6% of the patients. 56% of the patients have been free of hypopigmentation; hyperpigmentation has not been reported.

Clinical studies investigating the use of imiquimod for the treatment of actinic keratosis have detected a 0.4% (5/1214) frequency of alopecia at the treatment site or surrounding area.
Postmarketing reports of suspected alopecia occurring during the treatment of sBCC and EGW have been received.

Reductions in haemoglobin, white blood cell count, absolute neutrophils and platelets have been observed in clinical trials. These reductions are not considered to be clinically significant in patients with normal haematologic reserve. Patients with reduced haematologic reserve have not been studied in clinical trials. Reductions in haematological parameters requiring clinical intervention have been reported from postmarketing experience. There have been postmarketing reports of elevated liver enzymes.

Rare reports have been received of exacerbation of autoimmune conditions.

Rare cases of remote site dermatologic drug reactions, including erythema multiforme, have been reported from clinical trials. Serious skin reactions reported from postmarketing experience include erythema multiforme, Stevens Johnson syndrome and cutaneous lupus erythematosus.
 e)      Paediatric patients:
Imiquimod was investigated in controlled clinical studies with paediatric patients (see sections 4.2 and 5.1). There was no evidence for systemic reactions. Application site reactions occurred more frequently after imiquimod than after vehicle, however, incidence and intensity of these reactions were not different from that seen in the licensed indications in adults. There was no evidence for serious adverse reaction caused by imiquimod in paediatric patients.