There have been no reports of serious effects from overdose. Overdosage may cause nausea, vomiting and, in females, withdrawal bleeding. Withdrawal bleeding may even occur in girls before their menarche, if they accidentally take the medicinal product.
There are no specific antidotes and treatment should be symptomatic.
None known.
Summary of the safety profile
The most commonly reported adverse reactions with Leeloo 30 ED are nausea, abdominal pain, increased weight, headache, depressed mood, altered mood, breast pain, breast tenderness. They occur in >1% of users.
Serious adverse reactions are arterial and venous thromboembolism.
The following adverse events have been reported during use of ethinylestradiol / levonorgestrel:
| System Organ Class | Adverse events reported in clinical trials | Adverse events reported post marketing | ||
| Common (> 1/100) | Uncommon (> 1/1000, <1/100) | Rare (< 1/1000) | ||
| Eye disorders | contact lens intolerance | |||
| Gastrointestinal disorders | nausea, abdominal pain | vomiting, diarrhea | Crohn's disease, ulcerative colitis | |
| Immune system disorders | hypersensitivity | exacerbation of hereditary angioedema | ||
| Investigations | weight increased | weight decreased | ||
| Metabolism and nutrition disorders | fluid retention | Hypertriglyceridemia | ||
| Nervous system disorders | headache | migraine | exacerbation of chorea | |
| Vascular system disorders | Venous thromboembolism (VTE), Arterial thromboembolism (ATE) | |||
| Hepatobiliary disorders | liver function disturbances | |||
| Psychiatric disorders | depressed mood, mood altered | libido decreased | libido increased | |
| Reproductive system and breast disorders | breast pain, breast tenderness | breast hypertrophy | vaginal discharge, breast discharge | reduced menstrual flow, spotting, breakthrough bleeding and missed withdrawal bleeding, post pill amenorrhoea |
| Skin and subcutaneous tissue disorders | rash, urticaria | erythema nodosum, erythema multiforme | chloasma | |
Description of selected adverse reactions
'Special warnings and precautions for use':- Venous thromboembolic disorders
- Arterial thromboembolic disorders
- Strokes (e.g. transient ischemic attack, ischemic stroke, haemorrhagic stroke)
- Hypertension
- Liver tumours (benign and malignant)
The frequency of diagnosis of breast cancer is very slightly increased among COC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer.'Contraindications' and 4.4 'Special warnings and precautions for use'.
Conditions reported to deteriorate with pregnancy or previous COC use
Jaundice and/or pruritus related to cholestasis; gallstone formation; systemic lupus erythematosus; herpes gestationis; otosclerosis-related hearing loss; sickle cell anaemia; renal dysfunction; hereditary angioedema; porphyria; cervical cancer.
Changes in glucose tolerance or effect on peripheral insulin resistance have been reported in women using COCs.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
There is no preclinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.
Leeloo 30 ED is an oestrogen-progestogen combination which acts by inhibiting ovulation by suppression of the mid-cycle surge of luteinizing hormone, the inspissation of cervical mucus so as to constitute a barrier to sperm, and the rendering of the endometrium unreceptive to implantation.
Levonorgestrel
Levonorgestrel is absorbed quickly and completely. Maximum active substance levels of approx. 3 ng/ml were reached in serum just one hour after ingestion of Leeloo 30 ED. The serum concentrations subsequently fell in 2 phases with half-lives of around 0.5 hours and 20 hours. The metabolic clearance rate from plasma is approx. 1.5 ml/min/kg.
Levonorgestrel is eliminated not in unchanged form, but in the form of metabolites with a half-life of around one day and in almost equal proportions via the kidney and bile. Levonorgestrel is extensively metabolised. The major metabolites in plasma are the unconjugated and conjugated forms of 3α, 5β-tetrahydrolevonorgestrel. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of levonorgestrel.
Levonorgestrel is bound to serum albumin and SHBG. Only around 1.5% of the respective total concentration is present in unbound form, while approx. 65% is bound to SHBG. The relative proportions (free, albumin-bound, SHBG-bound) depend on the concentration of SHBG. After induction of the binding protein, the portion bound to SHBG increases, while the free portion and that bound to albumin decreases.
After daily repeated ingestion, levonorgestrel accumulates by about the factor 2. A steady state is reached during the second half of the treatment cycle. The pharmacokinetics of levonorgestrel are dependent on the concentration of SHBG in plasma. Under treatment with Leeloo 30 ED, an increase in the serum levels of SHBG effect a concomitant increase in the specific binding capacity and therefore also an increase in levonorgestrel serum levels.
The levonorgestrel serum levels do not change any further after 1 - 3 cycles of use owing to the fact that SHBG induction is concluded. Compared to a single administration, 3 - 4 fold higher levonorgestrel serum levels are reached in the steady state.
The absolute bioavailability of levonorgestrel amounts to almost 100%.
Approx. 0.1% of the maternal dose can be passed on to a baby with the breast milk.
Ethinylestradiol
Orally administered ethinylestradiol is absorbed quickly and completely. Ingestion of Leeloo 30 ED leads to maximum plasma levels of approx. 100 pg/ml after 1 - 2 hours. The substance concentration then falls in 2 phases for which half-lives of around 1 - 2 hours and about 20 hours have been determined. For technical reasons, these data can only be calculated at higher dosages.
An imaginary distribution volume of around 5 l/kg and a metabolic clearance rate from plasma of approx. 5 ml/min/kg have been determined for ethinylestradiol. Ethinylestradiol is bound non-specifically to serum albumin to the extent of 98%.
Ethinylestradiol is metabolised even during its absorption phase and during its first liver transit, leading to reduced and individually varying oral bioavailability. Ethinylestradiol is eliminated not in unchanged form, but in the form of metabolites with a half-life of around one day. The excretion ratio is 40 (urine) : 60 (bile).
Because of the half-life of the terminal elimination phase from plasma, a steady state characterised by a 30 - 40% higher plasma substance level becomes established after approx. 5 - 6 daily administrations.
The absolute bioavailability of ethinylestradiol is subject to considerable interindividual variations. After oral ingestion, it amounts to around 40 - 60% of the dose.
In women with fully established lactation, around 0.02% of the maternal dose can be passed on to the baby with the breast milk.
Other drugs can have a negative or positive effect on the systemic availability of ethinylestradiol. No interaction with vitamin C takes place. On continuous use, ethinylestradiol induces the hepatic synthesis of CBG and SHBG, the extent of SHBG induction being dependent on the type and dose of the simultaneously administered progestogen.
No special requirements.
