Section 2 – added/amended
Excipient: lactose 46mg
For a full list of excipients, see section 6.1
Section 4.2
Route of administration: oral use (added)
Under How to start Yasmin:
Changing from a progestogen only method….
Deleted: minipill and added: (progestogen-only pill, injection, implant) or from a progestogen-releasing intrauterine system (IUS).
Amended/added: The woman may switch any day from the progestogen-only pill (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due) but should in all of these cases be advised to additionally use a barrier method for the first 7 days of tablet taking.
Amended: Advice in case of gastro-intestinal disturbances
In case of severe gastro-intestinal disturbances (e.g. vomiting or diarrhoea), absorption may not be complete and additional contraceptive measures should be taken.
If vomiting occurs within 3-4 hours after tablet taking, a new (replacement) tablet should be taken as soon as possible. The new tablet should be taken within 12 hours of the usual time of tablet-taking if possible.
Section 4.3
Amended: Arterial thrombosis presence or in history (e.g. myocardial infarction) or prodromal conditions…. [cerebrovascular accident removed from within the e.g. bracket and inserted as a separate contraindication “Cerebrovascular accident presence or in history”]
Amended: Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts)
Added: Pancreatitis, or a history thereof, if associated with severe hypertriglyceridaemia
Section 4.4
Amended: heading Vascular Disorders to Circulatory Disorders
Amended: The incidence of VTE associated with pregnancy is estimated as 60 cases per 100,000 pregnancies. VTE is fatal in 1-2% of cases.
Added: ‘cerebral’ into the list of blood vessels in which thrombosis has been reported to occur
Amended: Symptoms of venous or arterial thrombosis – amended to – Symptoms of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident can include:
Amended/added: “The risk of arterial thrombo-embolic complications” – changed to “The risk of arterial thrombo-embolic complications or of a cerebrovascular accident”
- and migraine, obesity, a positive family history added into the list
Added: Sickle cell disease added to the list of other medical conditions associated with adverse vascular events.
Under the heading Tumours:
Added: “>5 years” has been added into the paragraph - An increased risk of cervical cancer in long-term users of COCs (> 5 years) has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behavior and other factors such as human papilloma virus (HPV).
Under the heading Other Conditions:
Amended:
The progestogen component in Yasmin is an aldosterone antagonist with potassium sparing properties. In most cases, no increase of potassium levels is to be expected. In a clinical study, however, in some patients with mild or moderate renal impairment and concomitant use of potassium-sparing medicinal products, serum potassium levels slightly, but not significantly, increased during drospirenone intake. Therefore, it is recommended to check serum potassium during the first treatment cycle in patients presenting with renal insufficiency and a pretreatment serum potassium in the upper reference range, and particularly during concomitant use of potassium sparing medicinal products. See also section 4.5.
Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. Only in these rare cases an immediate discontinuation of COC use is justified. [Deleted – A systematic relationship between COC use and clinical hypertension has not been established].
Added: In women with hereditary angioedema exogenous oestrogens may induce or exacerbate symptoms of angioedema.
Under the heading Reduced efficacy:
Amended: The efficacy of COCs may be reduced in the event of e.g. missed tablets (see section 4.2), gastrointestinal disturbances (see section 4.2) or concomitant medication (see section 4.5). [“gastrointestinal disturbances” used in place of vomiting or severe diarrhoea]
Section 4.5
Added: Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
· Influence of other medicinal products on Yasmin
Amended: Interactions between oral contraceptives and other medicinal products may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature.
Added: In women on chronic treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal, method of contraception is recommended. [in place of advice to increase the contraceptive steroid dose]
· Influence of Yasmin on other medicinal products
Added: Oral contraceptives may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).
Added: Based on in vitro inhibition studies and in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrate, an interaction of drospirenone at doses of 3 mg with the metabolism of other active substances is unlikely.
· Other interactions
Added: In patients without renal insufficiency, the concomitant use of drospirenone and ACE-inhibitors or NSAIDs did not show a significant effect on serum potassium. Nevertheless, concomitant use of Yasmin with aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, serum potassium should be tested during the first treatment cycle. See also section 4.4.
Section 4.6
Amended: If pregnancy occurs during use of Yasmin, the preparation should be withdrawn immediately. Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during pregnancy. [Slight reword plus deletion of “No such studies have been carried out with Yasmin”]
Amended: Animal studies have shown undesirable effects during pregnancy and lactation (see Section 5.3). Based on these animal data, undesirable effects due to hormonal action of the active compounds cannot be excluded. However, general experience with COCs during pregnancy did not provide evidence for an actual undesirable effect in humans. [Use of “undesirable effects” in place of “adverse events”]
Section 4.7
Amended:
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.
Section 4.8
For serious undesirable effects in COC users see section 4.4. [amended from ‘adverse events’]
Added: In women with hereditary angioedema exogenous oestrogens may induce or exacerbate symptoms.
Section 5.1 – ATC Code amended from G03AA to G03AA12
Section 5.2
Amended:
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 %.
Distribution
After oral administration, serum drospirenone levels decrease with a terminal half-life of 31h. 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.
Metabolism
Drospirenone is metabolised to a minor extent by cytochrome P450 3A4 … following text added…..and has demonstrated a capacity to inhibit this enzyme and cytochrome P450 1A1, cytochrome P450 2C9 and cytochrome P450 2C19 in vitro.
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.
Added: 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, 30-50mL/min) compared to those in women with normal renal function. Drospirenone treatment was also well tolerated by women with mild to moderate renal impairment. Drospirenone treatment did not show any clinically significant effect on serum potassium concentration.
Effect on 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.
Section 6.1
Amended: excipients list split into ‘tablet core’ and ‘tablet coating’
Section 10
Amended: Date of revision from 7 March 2005 to 31 August 2006
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