There has not yet been any experience of overdose with Yasmin. On the basis of general experience with combined oral contraceptives, symptoms that may possibly occur in this case are nausea, vomiting and, withdrawal bleeding. Withdrawal bleeding may even occur in girls before their menarche, if they accidentally take the medicinal product. There are no antidotes and further treatment should be symptomatic.
Not applicable.
The following adverse drug reactions have been reported during use of Yasmin:
| System Organ Class (MedDRA) | Frequency of adverse reactions | ||
| Common > 1/100 to <1/10 | Uncommon > 1/1,000 to < 1/100 | Rare > 1/10,000 to < 1/1000 | |
| Immune system disorders | Hypersensitivity Asthma | ||
| Psychiatric disorders | Depressive mood | Libido increased Libido decreased | |
| Nervous system disorders | Headache | ||
| Ear and labyrinth disorders | Hypoacusis | ||
| Vascular disorders | Migraine | Hypertension, Hypotension | Venous thromboembolism (VTE) Arterial thromboembolism (ATE) |
| Gastrointestinal disorders | Nausea | Vomiting, Diarrhoea | |
| Skin and subcutaneous tissue disorders | Acne, Eczema, Pruritus, Alopecia | Erythema nodosum Erythema multiforme | |
| Reproductive system and breast disorders | Menstrual disorders, Intermenstrual bleeding, Breast pain, Breast tenderness, Vaginal discharge, Vulvovaginal candidiasis | Breast enlargement, Vaginal infection | Breast discharge |
| General disorders and administration site conditions | Fluid retention, Weight increased, Weight decreased | ||
Description of selected adverse reactions
An increased risk of arterial and venous thrombotic and thrombo-embolic events, including myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis and pulmonary embolism has been observed in women using
:
- Venous thromboembolic disorders;
- Arterial thromboembolic disorders;
- Hypertension;
- Liver tumours;
- Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn's disease, ulcerative colitis, epilepsy, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uremic syndrome, cholestatic jaundice;
- Chloasma;
- Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal.
- In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
The frequency of diagnosis of breast cancer is very slightly increased among COC users.4.
Interactions
Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with oral contraceptives.
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, Website: www.mhra.gov.uk/yellowcard.
In laboratory animals, the effects of drospirenone and ethinylestradiol were confined to those associated with the recognised pharmacological action. In particular, reproduction toxicity studies revealed embryotoxic and fetotoxic effects in animals which are considered as species specific. At exposures exceeding those in users of Yasmin, effects on sexual differentiation were observed in rat foetuses but not in monkeys.
Pharmacotherapeutic group (ATC): Progestogens and estrogens, fixed combinations
ATC Code: G03AA 12
Pearl Index for method failure: 0.09 (upper two-sided 95 % confidence limit: 0.32).
Overall Pearl Index (method failure + patient failure): 0.57 (upper two-sided 95 % confidence limit: 0.90).
The contraceptive effect of Yasmin is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the endometrium.
Yasmin is a combined oral contraceptive with ethinylestradiol and the progestogen drospirenone. In a therapeutic dosage, drospirenone also possesses antiandrogenic and mild antimineralocorticoid properties. It has no estrogenic, glucocorticoid and antiglucocorticoid activity. This gives drospirenone a pharmacological profile closely resembling the natural hormone progesterone.
There are indications from clinical studies that the mild antimineralocorticoid properties of Yasmin result in a mild antimineralocorticoid effect.
- Drospirenone
Absorption
Orally administered drospirenone is rapidly and almost completely absorbed. Maximum concentrations of the active substance in serum of about 38 ng/ml are reached at about 1-2 h after single ingestion. Bioavailability is between 76 and 85 %. Concomitant ingestion of food has no influence on the bioavailability of drospirenone.
Distribution
After oral administration, serum drospirenone levels decrease with a terminal half-life of 31 h. Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Only 3 - 5 % of the total serum concentrations of the active substance are present as free steroid. The ethinylestradiol-induced increase in SHBG does not influence the serum protein binding of drospirenone. The mean apparent volume of distribution of drospirenone is 3.7 ± 1.2 l/kg.
Biotransformation
Drospirenone is extensively metabolized after oral administration. The major metabolites in plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, formed by reduction and subsequent sulfatation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4.
In vitro, drospirenone is capable to inhibit weakly to moderately the cytochrome P450 enzymes CYP1A1, CYP2C9, CYP2C19 and CYP3A4.
Elimination
The metabolic clearance rate of drospirenone in serum is 1.5 ± 0.2 ml/min/kg. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine at an excretion ratio of about 1.2 to 1.4. The half-life of metabolite excretion with the urine and faeces is about 40 h.
Steady-State Conditions
During a treatment cycle, maximum steady-state concentrations of drospirenone in serum of about 70 ng/ml are reached after about 8 days of treatment. Serum drospirenone levels accumulated by a factor of about 3 as a consequence of the ratio of terminal half-life and dosing interval.
Special Populations
Effect of renal impairment
Steady-state serum drospirenone levels in women with mild renal impairment (creatinine clearance CLcr, 50-80 mL/min) were comparable to those of women with normal renal function. The serum drospirenone levels were on average 37 % higher in women with moderate renal impairment (CLcr, 30 - 50 mL/min) compared to those in women with normal renal function. Drospirenone treatment was also well tolerated by women with mild and moderate renal impairment. Drospirenone treatment did not show any clinically significant effect on serum potassium concentration.
Effect of hepatic impairment
In a single dose study, oral clearance (CL/F) was decreased approximately 50 % in volunteers with moderate hepatic impairment as compared to those with normal liver function. The observed decline in drospirenone clearance in volunteers with moderate hepatic impairment did not translate into any apparent difference in terms of serum potassium concentrations. Even in the presence of diabetes and concomitant treatment with spironolactone (two factors that can predispose a patient to hyperkalemia) an increase in serum potassium concentrations above the upper limit of the normal range was not observed. It can be concluded that drospirenone is well tolerated in patients with mild or moderate hepatic impairment (Child-Pugh B).
Ethnic groups
No clinically relevant differences in the pharmacokinetics of drospirenone or ethinylestradiol between Japanese and Caucasian women have been observed.
- Ethinylestradiol
Absorption
Ethinylestradiol is rapidly and completely absorbed after ingestion. After administration of 30 µg, peak plasma concentrations of 100 pg/ml are reached 1-2 hours after ingestion. Ethinylestradiol undergoes an extensive first-pass effect, which displays great inter-individual variation. The absolute bioavailability is approx. 45 %.
Distribution
Ethinylestradiol has an apparent volume of distribution of 5 l/kg and binding to plasma proteins is approx. 98 %. Ethinylestradiol induces the hepatic synthesis of SHBG and CBG. During treatment with 30 µg ethinylestradiol the plasma concentration of SHBG increases from 70 to about 350 nmol/l.
Ethinylestradiol passes in small amounts into breast milk (0.02 % of the dose).
Biotransformation
Ethinylestradiol is subject to significant gut and hepatic first-pass metabolism. Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucoronides and sulfate. The metabolite clearance rate of ethinylestradiol is about 5 ml/min/kg.
In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism based inhibitor of CYP3A4/5, CYP2C8 and CYP2J2.
Elimination
Ethinylestradiol is not excreted in unchanged form to any significant extent. The metabolites of ethinylestradiol are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day. The elimination half-life is 20 hours.
Steady-state conditions
Steady-state conditions are reached during the second half of a treatment cycle and serum levels of ethinylestradiol accumulate by a factor of about 1.4 to 2.1.
No studies on the effects on the ability to drive and use machines have been performed. No effects on ability to drive and use machines have been observed in users of COCs.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
