Adverse reactions : תופעות לוואי

4.8. Undesirable Effects


4.8.1. Clinical Trial Data

ORTHO-CYCLEN

The safety of ORTHO-CYCLEN was evaluated in 1,891 healthy women of child- bearing potential who participated in 5 clinical trials and received at least 1 dose of ORTHO-CYCLEN for contraception. Two trials were randomized active-controlled trials and 3 were uncontrolled open-label trials. In 3 trials, subjects were followed for up to 24 cycles and in the other 2 trials, subjects were followed for up to 12 cycles.
The most frequent Adverse Drug Reactions (ADRs) reported in >5% of subjects were headache, vaginal infection, genital discharge and breast pain. Adverse Drug Reactions reported by ≥1% of ORTHO-CYCLEN-treated subjects in these trials are shown in Table 1.


Table 1. Adverse Drug Reactions Reported by ≥1% of ORTHO-CYCLEN-treated Subjects in 5 Clinical Trials of ORTHO-CYCLEN
System/Organ Class                                                    % 
Adverse Reaction                                                      (N=1,891) 
Infections and Infestations
Vaginal infection                                                     7.5 Metabolism and Nutrition Disorders
Fluid retention                                                       1.0 Psychiatric Disorders
Depression                                                            3.4 Nervousness                                                           3.2 Mood altered                                                          1.4 Nervous System Disorders
Headache                                                              27.9 Migraine                                                              1.5 Gastrointestinal Disorders
Abdominal pain                                                        4.0 Gastrointestinal pain                                                 3.4 Flatulence                                                            2.8 Skin and Subcutaneous Tissue Disorders
Rash                                                                  2.2 Reproductive System and Breast Disorders
Genital discharge                                                     6.0 Breast pain                                                           5.7 General Disorders and Administration Site Conditions

Oedema                                                                1.6 
Investigations

Weight increased                                                      1.5 
Additional ADRs reported by <1% of ORTHO-CYCLEN-treated subjects (N=1,891) in the above clinical dataset are shown in Table 2.


Table 2. Adverse Drug Reactions Reported by <1% of ORTHO-CYCLEN-treated Subjects in 5 
Clinical Trials of ORTHO-CYCLEN
System/Organ Class
Adverse Reaction
Metabolism and Nutrition Disorders

Increased appetite
Decreased appetite
Weight fluctuation
Appetite disorder
Psychiatric Disorders
Libido disorder
Vascular Disorders
Hypertension
Thrombosis
Skin and Subcutaneous Tissue Disorders
Skin discolouration
Alopecia
Erythema
Reproductive System and Breast Disorders
Breast discharge
Breast enlargement
Vaginal discharge
Investigations
Weight decreased



In the above trials with ORTHO-CYCLEN, details for specific ADRs, namely nausea, vomiting, gastrointestinal disorder (reported as nausea or vomiting), dysmenorrhoea, metrorrhagia, abnormal withdrawal bleeding and amenorrhoea, were solicited or determined from bleeding pattern or cycle characteristics data on a by- treatment cycle (i.e., “by-cycle”) basis, e.g., using menstrual calendars or diary cards.
These ADRs are not included in Tables 1 and 2, as the incidence of each ADR was reported separately by treatment cycle only and no overall subject incidence for the whole trial was reported. In general, solicited events are associated with higher reporting rates than events spontaneously reported by subjects. In addition to the 5 clinical trials whose data were used in Tables 1 and 2, an uncontrolled, 6–cycle trial was included in the by-cycle ADR analysis (Table 3). This trial was not included in Tables 1 and 2, as it did not report overall incidences for ADR data.


By-cycle ADRs reported by ≥1% of ORTHO-CYCLEN-treated subjects in cycle 1 are shown in Table 3. With the exception of vomiting and dysmenorrhoea, the incidence of these ADRs was highest in cycle 1 and decreased over time with further treatment cycles (based on incidence data from cycles 1, 3, 6, 12, and 24). Vomiting increased in some later cycles, whereas dysmenorrhoea remained relatively stable, with a slight decrease over time.


Table 3. Adverse Drug Reactions Reported by ≥1% of ORTHO-CYCLEN-treated Subjects in Cycle 1 in 6 Clinical Trials (Except Where Specified) of ORTHO-CYCLEN
System/Organ Class
1
Adverse Reaction                                Total subjects (N)        Cycle 1(%) Gastrointestinal Disorders
2
Nausea                                          86                        29.1 3,4
Gastrointestinal disorder                       1,639                     24.6 2
Vomiting                                        86                        7.0 
Reproductive System and Breast Disorders
5
Dysmenorrhoea                                   1,729                     40.4 Metrorrhagia                                    10,117                    26.3 5
Abnormal withdrawal bleeding                    1,667                     16.9 6
Amenorrhoea                                     1,783                     1.6 
1
Number of subjects with available data for cycle 1.

2
Based on data from 1 trial.
3
Reported as nausea or vomiting.

4
Based on data from 3 trials.

5
Based on data from 4 trials.
6
Based on data from 5 trials.



4.8.2. Post-Marketing Data

Adverse drug reactions first identified during post-marketing experience with NGM/EE are included in Table 4. The frequencies are provided according to the following convention:


Very common (≥1/10)

Common (≥1/100 and <1/10)

Uncommon (≥1/1,000 and <1/100)


Rare (≥1/10,000 and <1/1,000)

Very rare (<1/10,000, including isolated reports)

Not known (Cannot be estimated from the available data)


In Table 4, ADRs are presented by frequency category based on spontaneous reporting rates. The frequency category “not known” is used for ADRs for which no valid estimate of the incidence rate can be derived from clinical trials.


Table 7 4: Adverse Drug Reactions Identified During Post-Marketing Experience with NGM/EE by Frequency Category Estimated from Spontaneous Reporting Rates
Infections and Infestations
Very
Urinary tract infection rare
Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps) Very     Breast cancer, Cervical dysplasia, Benign breast neoplasm, Hepatic adenoma, Focal nodular rare     hyperplasia, Fibroadenoma of breast, Breast cyst
Immune System Disorders
Very
Hypersensitivity rare
Metabolism and Nutrition Disorders
Very
Dyslipidaemia rare
Psychiatric Disorders

Very
Anxiety, Insomnia rare
Nervous System Disorders
Very
Cerebrovascular accident, Syncope, Convulsion, Paraesthesia, Dizziness rare
Eye Disorders
Very
Retinal vascular thrombosis, Visual impairment, Dry eye, Contact lens intolerance rare
Ear and Labyrinth Disorders
Very
Vertigo rare
Cardiac Disorders
Very
Myocardial infarction, Tachycardia, Palpitations rare
Vascular Disorders
Very
Arterial thromboembolism Deep vein thrombosis, Hot flush rare
Respiratory, Thoracic and Mediastinal Disorders
Very
Pulmonary embolism, Dyspnoea rare
Gastrointestinal Disorders
Very
Pancreatitis, Abdominal distension, Diarrhoea, Constipation rare
Hepatobiliary Disorders
Very
Hepatitis rare
Skin and Subcutaneous Tissue Disorders
Very    Angioedema, Erythema nodosum, Hirsutism, Night sweats, Hyperhidrosis, Photosensitivity rare    reaction, Urticaria, Pruritus, Acne
Musculoskeletal, Connective Tissue, and Bone Disorders
Very
Muscle spasms, Pain in extremity, Myalgia, Back pain rare
Reproductive System and Breast Disorders
Very
Ovarian cyst, Suppressed lactation, Vulvovaginal dryness rare
General Disorders and Administration Site Conditions
Very
Chest pain, Asthenic conditions rare
NGM/EE: norgestimate/ethinyl estradiol


1
Frequency category based on the higher of the 2 incidence values estimated from either clinical trials with ORTHO-CYCLEN or from clinical trials with ORTHO TRI- CYCLEN.

2
Higher Level Term; frequency category based on incidence of most common Preferred Term within the Higher Level Term of Asthenic conditions from pooled clinical trial data, namely fatigue.


NGM/EE: norgestimate/ethinyl estradiol