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ALESSE (levonorgestrel, ethinyl estradiol) Adverse Reactions

Adverse Reactions

Adverse Drug Reaction Overview

An increased risk of the following serious adverse reactions has been associated with the use of Combined Oral Contraceptives:

  • Arterial thromboembolism
  • Being diagnosed with breast cancer
  • Benign hepatic tumours (e.g. focal nodular hyperplasia, hepatic adenomas)
  • Cerebral hemorrhage
  • Cerebral thrombosis
  • Cervical cancer
  • Cervical intraepithelial neoplasia
  • Gallbladder disease, including gallstones*
  • Hepatocellular carcinomas
  • Hypertension
  • Inflammatory bowel disease (Crohn’s Disease, ulcerative colitis)
  • Mesenteric thrombosis
  • Myocardial infarction
  • Neuro-ocular lesions (e.g. retinal thrombosis)
  • Pulmonary embolism
  • Stroke
  • Transient ischemic attach
  • Thrombophlebitis
  • Venous thrombosis

* COCs may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women.

The following adverse reactions also have been reported in patients receiving COCs:
Nausea and vomiting, usually the most common adverse reaction, occurs in approximately 10 percent or fewer of patients during the first cycle. Other reactions, as a general rule, are seen less frequently or only occasionally.

The following adverse reactions have been reported in patients receiving COC and are believed to be drug related:

  • Amenorrhea
  • Breakthrough bleeding
  • Breast changes: pain, tenderness, enlargement, and secretion
  • Change in cervical ectropion and secretion
  • Change in corneal curvature (steepening)
  • Change in menstrual flow
  • Change in weight (increase or decrease)
  • Chloasma (melasma) which may persist
  • Cholestatic jaundice
  • Diminution in lactation when given immediately postpartum
  • Dysmenorrhea
  • Fluid retention/Edema
  • Gastrointestinal symptoms (such as abdominal pain, cramps and bloating)
  • Headache, including migraines
  • Hepatocellular injury (e.g., hepatitis, hepatic function abnormal)
  • Intolerance to contact lenses
  • Mood changes, including depression
  • Rash (allergic)
  • Reduced tolerance to carbohydrates
  • Retinal vascular thrombosis
  • Spotting
  • Temporary infertility after discontinuance of treatment
  • Vaginitis including candidiasis

The following adverse reactions have been reported in users of COCs and the association has been neither confirmed nor refuted:

  • Acne
  • Aggravation of varicose veins
  • Anaphylactic (anaphylactoid reactions, including very rare cases of urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms)
  • Budd-Chiari syndrome
  • Cataracts
  • Cerebrovascular disease with mitral valve prolapse
  • Changes in appetite (increase or decrease)
  • Changes in libido
  • Changes in Serum Lipid levels, including hypertriglyceridemia
  • Colitis
  • Congenital anomalies
  • Cystitis-like syndrome
  • Decrease in serum folate levels**
  • Dizziness
  • Erythema multiforme
  • Erythema nodosum
  • Exacerbation of chorea
  • Exacerbation of porphyria
  • Exacerbation of systemic lupus erythematosus
  • Hemolytic uremic syndrome
  • Hemorrhagic eruption
  • Hepatic adenomas
  • Hepatocellular Carcinomas
  • Hirsutism
  • Impaired renal function
  • Ischemic colitis
  • Loss of scalp hair
  • Lupus-like syndrome
  • Nervousness
  • Optic neuritis***
  • Pancreatitis
  • Premenstrual syndrome
  • Sickle-cell disease
  • Vaginitis

**Serum folate levels may be depressed by COC therapy.
***Optic neuritis may lead to partial or complete loss of vision.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Oral Contraception

Treatment-emergent adverse events were analyzed for 1,477 subjects exposed to the study drug for 7,870 cycles. One or more treatment emergent adverse events were reported for 1,106 (75%) subjects. Table-1 lists the frequency of treatment emergent adverse events that were reported by > 2% of subjects.

Table - 1 FREQUENCY OF TREATMENT EMERGENT ADVERSE EVENTS THAT OCCURRED
IN > 2% OF SUBJECTS
EventNumber (%) of Subjects
(n=1,477)
Headache400 (27%)
Dysmenorrhea210 (14%)
Infection200 (14%)
Pharyngitis146 (10%)
Abdominal pain134 (9%)
Nausea134 (9%)
Metrorrhagia123 (8%)
Sinusitis90 (6%)
Flu syndrome84 (6%)
Vaginal moniliasis71 (5%)
Pain71 (5%)
Back pain66 (4%)
Breast pain65 (4%)
Accidental injury64 (4%)
Acne62 (4%)
Rhinitis54 (4%)
Emotional lability50 (3%)
Vaginitis48 (3%)
Urinary tract infection41 (3%)
Dizziness40 (3%)
Diarrhea40 (3%)
Bronchitis37 (3%)
Depression36 (2%)
Asthenia35 (2%)
Vomiting34 (2%)
Allergic reaction other than to study drug33 (2%)
Amenorrhea30 (2%)

A total of 133 (9%) subjects stopped taking the study medication because of adverse events. Some of the study events that led to subject discontinuation were considered by the medical monitor to be potentially serious: headache (21), hypertension (7), migraine (3), phlebitis (1), palpitations (1), varicose veins (1), vascular disorder (1), hypercholesterolemia/hyperlipidemia(6), depression/emotional lability (16), hypesthesia (1), abnormal vision (2), visual field defect (1), amenorrhea (8), dysmenorrhea (4), menorrhagia (6), irregular bleeding (1), menstrual bloating (1), metrorrhagia (1), fibroid growth (1). No deaths occurred during the multicentre study.

Acne

In the two acne studies (see CLINICAL TRIALS), the safety profile of ALESSE was compared with that of placebo. Treatment-emergent adverse events that were reported by ³ 2% of patients in either treatment group are presented in Table 2.

Table 2. Percentage of Patients (> 2%) Reporting Treatment- Emergent Adverse Events in Either Treatment Group in Studies 0858A1-900, 901
Adverse eventNumber (%) of Subjects
ALESSE
(n=349)
Placebo
(n=355)
Headache110 (31.5)107 (30.1)
Metrorrhagia*77 (21.8)14 (3.9)
Nausea49 (14.0)40 (11.3)
Infection48 (13.8)49 (13.8)
Pharyngitis46 (13.2)58 (16.3)
Pain31 (8.9)36 (10.1)
Abdominal pain27 (7.7)24 (6.8)
Dysmenorrhea27 (7.7)39 (11.0)
Accidental injury21 (6.0)16 (4.5)
Menstrual disorder*21 (6.0)8 (2.3)
Flu syndrome19 (5.4)20 (5.6)
Allergic reaction*16 (4.6)6 (1.7)
Breast pain16 (4.6)11 (3.1)
Rhinitis15 (4.0)13 (3.7)
Sinusitis14 (4.0)2.0 (8)
Asthenia13 (3.7)5 (1.4)
Back pain12 (3.4)12 (3.4)
Dyspepsia12 (3.4)2.3 (8)
Weight gain17 (3.4)12 (2.3)
Emotional lability*12 (3.4)4 (1.1)
Acne13 (3.4)6 (1.4)
Migraine11 (3.2)8 (2.3)
Dizziness11 (3.2)10 (2.8)
Cough increased10 (2.9)8 (2.3)
Vomiting10 (2.6)6 (1.7)
Depression9 (2.6)11 (2.5)
Moniliasis7 (2.0)8 (2.3)
Myalgia7 (2.0)5 (1.4)
Bronchitis7 (2.0)7 (2.0)
Rash7 (2.0)7 (2.0)
Urticaria*7 (2.0)0
Allergic reaction other than drug7 (2.0)7 (2.0)
Diarrhea6 (1.7)10 (2.8)
Unintended pregnancy*2 (0.6)12 (3.1)
* Statistically significantly different between treatment groups (p<0.05).

As expected, menstrual-related events were more frequent in women treated with ALESSE than with placebo. However, other adverse events often associated with oral contraceptive use, including nausea, vomiting, breast pain, headache, migraine, and weight gain, occurred at similar rates in women treated with placebo or ALESSE.

Abnormal Hematologic and Clinical Chemistry Findings

See CLINICAL TRIALS

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