Treatment of symptoms of PMDD (Premenstrual Dysphoric Disorder).

How to Start Yaz Tablets:

No preceding hormonal contraceptive use (in the past month): Tablet-taking has to start on the day 1 of the woman’s natural cycle (ie, the 1st day of her menstrual bleeding). Starting on days 2-5 is allowed, but during the 1st cycle a barrier method is recommended in addition for the 1st 7 days of tablet-taking.

Changing from a combined hormonal contraceptive (combined oral contraceptive/COC), vaginal ring or transdermal patch: The woman should start with Yaz preferably on the day after the last active tablet (the last tablet containing the active substances) of her previous COC, but at the latest on the day following the usual tablet-free or placebo tablet interval of he previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Yaz preferably on the day of removal, but at the latest when the next application would have been due.

Changing from a progestogen-only-method (minipill, injection, implant) or from a progestogen-releasing intrauterine system (IUS): The woman may switch any day from minipill (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 1st 7 days of tablet-taking.

Following 1st trimester abortion: The woman may start immediately. When doing so, there is no need to take additional contraceptive measures.

Following delivery or 2nd trimester abortion: For breastfeeding women, see Use in pregnancy & lactation under Precautions.

Women should be advised to start at day 21-28 after delivery or 2nd trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the 1st 7 days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait for her 1st menstrual period.

Management of Missed Tablets: Missed inert tablets can be disregarded. However, they should be discarded to avoid unintentionally prolonging the inert tablet phase: If the user is <12 hrs late in taking any tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.

If she is >12 hrs late in taking any tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following 2 basic rules: (1) Tablet-taking must never be discontinued for >4 days; (2) 7 days of uninterrupted tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.

Accordingly the following advice can be given in daily practice:

Day 1-7: The user should take the last missed tablet as soon as she remembers, even if this means taking 2 tabs at the same time. She then continues to take tablets at her usual time. In addition, a barrier method eg, condom should be used for the next 7 days. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered. The more tablets are missed and the closer they are to the inert tablet phase, the higher the risk of a pregnancy.

Day 8-14: The user should take the last missed tablet as soon as she remembers, even if this means taking 2 tabs at the same time. She then continues to take tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the 1st missed tablet, there is no need to use extra contraceptive precautions. However, if this is not the case, or if she missed >1 tab, the woman should be advised to use extra precautions for 7 days.

Day 15-24: The risk of reduced reliability is imminent because of the forthcoming inert tablet phase. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following 2 options, therefore, there is no need to use extra contraceptive precautions, provided that in the 7 days preceding the 1st missed tablet, the woman has taken all tablets correctly. If this is not the case, the woman should be advised to follow the first of these 2 options and to use extra precautions for the next 7 days as well:

(1) The user should take the last missed tablet as soon as she remembers, even if this means taking 2 tabs at the same time. She then continues to take tablets at her usual time until the active tablets are used up. The 4 inert tabs must be discarded. The next pack must be started right away. The user is unlikely to have a withdrawal bleed until the end of the active tablets section of the 2nd pack, but she may experience spotting or breakthrough bleeding tablet-taking days.

(2) The woman may also be advised to discontinue tablet-taking from the current pack. She should than have a tablet-free interval of up to 4 days, including the days missed tablets, and subsequently continue with the next pack.

If the woman missed tablets and subsequently has no withdrawal bleed in the inert tablet phase, the possibility of a pregnancy should be considered.

Advice in Case of Gastrointestinal Disturbances: In case of severe gastrointestinal disturbances, absorption may not be complete and additional contraceptive measures should be taken.

If vomiting occurs within 3-4 hrs after active tablet-taking, the advice concerning missed tablets, as given previously, is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) needed from another pack.

How to Shift Periods or How to Delay a Period: To delay a period, the woman should continue with another pack of Yaz tablets without taking the inert tablets from her current pack. The extension can be carried on for as long as necessary, until the end of active tablets in the 2nd pack. During the extension, the woman may experience breakthrough bleeding or spotting. Regular intake of Yaz tablets is then resumed after the inert tablet phase.

To shift her periods to another day of the week other than the woman is used to with her current scheme, she can be advised to shorten her forthcoming inert tablet phase by as many days as she likes. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough bleeding and spotting during the 2nd pack (just as when delaying a period).

Presence or history of prodromi of a thrombosis (eg, transient ischemic attack, angina pectoris).

History of migraine with focal neurological symptoms.

Diabetes mellitus with vascular involvement.

The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contraindication (see Precautions).

Pancreatitis or a history thereof if associated with hypertriglyceridemia.

Presence or history of severe hepatic disease as long as liver function values have not returned to normal.

Severe renal insufficiency or acute renal failure.

Presence or history of liver tumors (benign or malignant).

Known or suspected sex-steroid influenced malignancies (eg, of the genital breasts).

Undiagnosed vaginal bleeding. Known or suspected pregnancy.

Hypersensitivity to the active substances or to any excipients of Yaz.

Venous thromboembolism (VTE), manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all COCs. The risk for venous thromboembolism is highest during the first year a woman ever uses a COC. The approximate incidence of VTE in users of low estrogen dose (<0.05 mg ethinylestradiol) OCs is up to 4 per 10,000 woman-years compared to 0.5-3 per 10,000 woman-years in non-OC users. The incidence of VTE associated with pregnancy is 6 per 10,000 pregnant woman-years.

Extremely rarely, thrombosis has been reported to occur in other blood vessels, eg hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.

Symptoms of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident can include: Unilateral leg pain and/or swelling; sudden sever pain in the chest, whether or not it radiates to the left arm; sudden breathlessness; sudden onset of coughing; any unusual, severe, prolonged headache; sudden partial or complete loss of vision; diplopia; slurred speech or aphasia; vertigo; collapse with or without focal seizure; weakness or very marked numbness suddenly affecting one side or one part of the body; motor disturbances; “acute” abdomen.

The risk of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular increases with: Age; smoking (with heavier smoking and increasing age, the risk further increases, especially in women >35 years); positive family history (eg, venous or arterial thromboembolism ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any COC use; obesity (body mass index >30 kg/m2); dyslipoproteinemia; hypertension; migraine; valvular heart disease; atrial fibrillation; prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations, it is advisable to discontinue COC use (in the case of elective surgery at least 4 weeks in advance) and not to resume until 2 weeks after complete remobilization.

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.

The increased risk of thromboembolism in the puerperium must be considered (see Use in pregnancy & lactation).

Other medical conditions, which have been associated with adverse circulatory events, include diabetes mellitus, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease.

An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with low-dose COCs (<0.05 mg ethinylestradiol).

Tumors: The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, eg cervical screening and sexual behaviour including use of barrier contraceptives.

A meta-analysis from 54 epidemiological studies reported that there is slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the ten years after the cessation of COC use. Because breast cancer is rare in women <40 years, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

In rare cases, benign liver tumors, and even more rarely, malignant liver tumors have been reported in users of COCs. In isolated cases, these tumors have led to life- threatening intra-abdominal hemorrhages. A hepatic tumor should be considered in the differential diagnosis when severe, abdominal pain, liver enlargement or signs of intra-abdominal hemorrhage occur in women taking COCs.

Other Conditions: Potassium excretion capacity may be limited in patients with renal insufficiency. In a clinical study, drospirenone intake did not show an effect on the serum potassium concentration in patients with mild or moderate renal impairment. A theoretical risk for hyperkalemia can be assumed only for patients with renal impairment whose pre-treatment serum potassium is in the upper reference range, and who are additionally using potassium-sparing drugs. Women with high hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. The antimineralocorticoid effect of drospirenone may counteract ethinylestradiol-induced increases in blood pressure observed in normotensive women using other COCs. However, if a sustained clinically significant hypertension develops during the use of COC, then it is prudent for the physician to withdraw the COC and treat the hypertension. When considered appropriate, COC may be resumed if normotensive values can be achieved with antihypertensive therapy.

The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: Jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham’s chorea; herpes gestations; otosclerosis-related hearing loss.

In women with hereditary angioedema exogenous estrogens may include or exacerbate symptoms of angioedema.

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice, which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.

Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs (containing <0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking COCs.

Crohn’s disease and ulcerative colitis have been associated with COC use.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.

Medical Examination/Consultation: A complete medical history and physical examination should be taken prior to the initiation or reinstitution of COC use, guided by the Contraindications and Precautions, and should be repeated periodically. Periodic medical assessment is also of importance because contraindications (eg, transient ischemic attack, etc.) or risk factors (eg, family history of venous or arterial thrombosis) may appear for the first time during the use of a COC. The frequency and nature of these assessments should be based on established practice guidelines and be adapted to the individual woman, but should generally include reference to blood pressure, breasts, abdomen, pelvic organs, including cervical cytology.

Women should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Reduced Efficacy: The efficacy of COCs may be reduced in the event of eg, missed tablets, gastrointestinal disturbances during active tablet taking (see Dosage & Administration) or concomitant medication (see Interactions).

Reduced Cycle Control: With all the COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.

If bleeding irregularities persists or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.

In some women, withdrawal bleeding may not occur during the inert tablet phase. If the COC has been taken according to the directions described in Dosage & Administration, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if 2 withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.

Effects on the Ability to Drive or Operate Machinery: No observed effects.

Use in pregnancy & lactation: Yaz is not indicated during pregnancy. If pregnancy occurs during treatment with Yaz, further intake should be stopped. However, extensive epidemiological studies have revealed neither an increased risk or birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs where taken inadvertently during early pregnancy.

The available data regarding the use of Yaz during pregnancy are too limited to permit conclusions concerning negative effects of Yaz on pregnancy, health of the fetus or neonate. No relevant epidemiological data are available yet.

Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should generally not be recommended until the nursing mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk.

Eye Disorders: Rare: Contact lens intolerance.

GI Disorders: Common: Nausea, abdominal pain; Uncommon: Vomiting, diarrhea.

Immune System Disorders: Rare: Hypersensitivity.

Investigations: Common: Weight increased; Uncommon: Weight decreased.

Metabolism and Nutrition Disorders: None.

Nervous System Disorders: Common: Headache; Uncommon: Migraine.

Psychiatric Disorders: Common: Depressed mood, mood altered; Uncommon: Libido decreased; Rare: Libido increased.

Reproductive System and Breast Disorders: Common: Breast pain, breast tenderness; Uncommon: Breast hypertrophy; Rare: Vaginal discharge, breast discharge.

Skin and Subcutaneous Tissue Disorders: Uncommon: Rash, urticaria; Rare: Erythema nodosum, erythema multiforme.

In women with hereditary angioedema exogenous estrogens may include or exacerbate symptoms of angioedema.

Also HIV protease (eg, ritonavir) and non-nucleoside reverse transcriptase inhibitors (eg, nevirapine), and combinations of them, have been reported to potentially affect hepatic metabolism.

Interference with Enterohepatic Circulation: Some clinical reports suggest that enterohepatic circulation of estrogens may decrease when certain antibiotic agents are given, which may reduce ethinylestradiol concentrations (eg, penicillins, tetracyclines).

Women on treatment with any of these drugs should temporarily use a barrier method in addition to the COC or choose another method of contraception. With microsomal enzyme-inducing drugs, the barrier method should be used during the time of concomitant drug administration and 28 days after their discontinuation. Women on treatment with antibiotics (except rifampicin and griseofulvin) should use the barrier method until 7 days of discontinuation. If the period during which the barrier method used runs beyond the end of the active tablets in the COC pack, the inert tablets should be omitted and the next COC pack be started.

The main metabolites of drospirenone in human plasma are generated without involvement of cytochrome P450 system. Inhibitors of this enzyme are therefore unlikely to influence the metabolism of drospirenone.

Oral contraceptives may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may either increase (eg, cyclosporin) or decrease (eg, lamotrigine).

Based on in vitro inhibition studies and in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrates, an interaction of drospirenone at doses of 3 mg with the metabolism of other drugs is unlikely.

Other Interactions: There is a theoretical potential for an increase in serum potassium in women taking Yaz with other drugs that may increase serum potassium levels. Such drugs include angiotensin II receptor antagonists, potassium-sparing diuretics, and aldosterone antagonists. However, in studies evaluating the interaction of drospirenone (combined with estradiol) with an ACE inhibitor or indomethacin, no clinically or statistically significant differences in serum potassium concentrations were observed.

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

Laboratory Tests: The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, eg corticosteroid-binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range. Drospirenone causes an increase in plasma rennin activity and plasma aldosterone induced by its mild antimineralocorticoid activity.

In 2 multicenter, double-blinded, randomized, placebo-controlled studies on the efficacy and safety of Yaz as an acne therapy in women with moderate acne vulgaris, Yaz produced clinically and statistically significant anti-acne effects on all the primary efficacy variables [inflammatory lesion, non-inflammatory lesion, total lesion counts, and the number and percentage of subjects with a 'clear' or 'almost clear' rating on the Investigator's Stated Global Assessment (ISGA) scale] and on the majority of secondary efficacy variables.

Drospirenone is devoid of any androgenic, estrogenic, glucocorticoid, and antiglucococrticoid activity. This, in combination with the antimineralocorticoid and antiandrogenic properties, gives drospirenone a biochemical and pharmacological profile closely resembling the natural hormone progesterone. Apart from this, there is evidence of a reduced risk of endometrial and ovarian cancer. Furthermore, the higher-dosed COCs (0.05 mg ethinylestradiol) have been shown to reduce the incidence of ovarian cysts, pelvic inflammatory disease, benign breast disease and ectopic pregnancy. Whether this also applies to lower-dosed COCs remains to be confirmed.

Pharmacokinetics: Drospirenone: Absorption: Orally administered drospirenone is rapidly and almost completely absorbed. Maximum concentrations of the drug in serum of about 35 ng/mL are reached at about 1-2 hr after single ingestion. Bioavailability is between 76% and 85%. The intake of food had no influence on the bioavailability of drospirenone as compared to drug intake on an empty stomach.

Distribution: After oral administration, serum drospirenone levels decrease in 2 phases which are characterized by half-lives of 1.6 ± 0.7 hr and 27 ± 7.5 hr, respectively. 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 drug concentrations 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 extensively metabolized after oral administration. The major metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, both of which are formed without involvement of the P450 system. Drospirenone is metabolized to a minor extent by cytochrome P450 1A1, cytochrome P450 3A4 and has demonstrated a capacity to inhibit this enzyme and cytochrome P450 1A1, cytochrome P450 2C9 and cytochrome 2C19 in vitro.

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 feces and urine at an excretion ratio of about 1.2 to 1.4. The half-life of metabolite excretion with the urine and feces is about 40 hrs.

Steady-State Conditions: During a treatment cycle, maximum steady-state concentrations of drospirenone in serum of about 60 ng/mL are reached between day 7 and day 14 of treatment. Serum drospirenone levels accumulated by a factor of about 2-3 as a consequence of the ratio of terminal half-life and dosing interval. Further accumulation of drospirenone levels beyond treatment cycles was observed between cycles 1 and 6 but thereafter, no further accumulation was observed.

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 (CLcr, >80 mL/min). The serum drospirenone levels were on average 37% higher in women with normal renal function. Drospirenone treatment was well tolerated by all groups. Drospirenone treatment did not show any clinically significant effect on serum potassium concentration.

Effect of Hepatic Impairment: in women with moderate hepatic function, (Child-Pugh B) mean serum drospirenone concentration-time profiles were comparable to those of women with normal hepatic function during the absorption/distribution phases with similar Cmax values. The decline in serum drospirenone concentrations during the terminal disposition phase was about 1.8 times greater for the volunteers with moderate hepatic impairment than for volunteers with normal hepatic function. An about 50% decrease in apparent oral clearance (CL/f) was seen 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 compared to normal volunteers did not translate into any apparent difference in terms of serum potassium concentrations between the 2 groups of volunteers. Even in the presence of diabetes and concomitant treatment with spironolactone (2 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: The impact of ethnic factors on the pharmacokinetics of drospirenone and ethinylestradiol was studied after single and repeated daily oral administration to young, healthy Caucasian and Japanese women. The results showed that ethnic differences between Japanese and Caucasian women had no clinically relevant influence on the pharmacokinetics of drospirenone and ethinylestradiol.

Ethinylestradiol: Absorption: Orally administered ethinylestradiol is absorbed rapidly and completely. Peak serum concentrations of about 88-100 pg/mL are reached within 1-2 hr after single oral administration. Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is approximately 60%. Concomitant intake of food reduced the bioavailability of ethinylestradiol in about 25% of the investigated subjects while no change was observed in the others.

Distribution: Serum ethinylestradiol levels decrease in 2 phases, the terminal disposition phase is characterized by a half-life of approximately 24 hrs. Ethinylestradiol is highly but nonspecifically bound to serum albumin (approximately 98.5%), and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 5 L/kg was determined.

Metabolism: Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. 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 metabolic clearance rate of ethinylestradiol is about 5 mL/min/kg.

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.

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.

Toxicology: Preclinical Safety Data: Preclinical data reveal no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.