Stezza

Stezza contains 24 white active film-coated tablet, each containing Nomegestrol (Stezza) acetate 2.5 mg and Estradiol (Stezza) hemihydrate 1.5 mg; 4 yellow, round and coded 'p' on both sides, placebo film-coated tablet.

Each white active and yellow placebo film-coated tablet also contains lactose monohydrate 57.71 mg and 61.76 mg, respectively.

It also contains the following excipients: Tablet Core (White Active and Yellow Placebo Film-Coated Tablets): Lactose monohydrate, microcrystalline cellulose (E460), crospovidone (E1201), talc (E553b), magnesium stearate (E572) and anhydrous colloidal silica. Tablet Coating (White Active Film-Coated Tablets): Polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol 3350 and talc (E553b). Yellow Active Film-Coated Tablets: Polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol 3350, talc (E553b), yellow ferric oxide (E172) and black ferric oxide (E172).

Hormone replacement therapy (HRT) of estrogen deficiency symptoms in postmenopausal women.

- The experience of this treatment is limited in women aged over 65 years.

One tablet is to be taken daily for 28 consecutive days. Each pack starts with 24 white active tablets, followed by 4 yellow placebo tablets. A subsequent pack is started immediately after finishing the previous pack, without a break in daily tablet intake and irrespective of presence or absence of withdrawal bleeding. Withdrawal bleeding usually starts on day 2-3 after intake of the last white tablet and may not have finished before the next pack is started.

Special Populations: Renal Impairment: Although data in renal impaired patients are not available, renal impairment is unlikely to affect the elimination of Nomegestrol (Stezza) acetate and Estradiol (Stezza).

Hepatic Impairment: No clinical studies have been performed in patients with hepatic insufficiency. Since the metabolism of steroid hormones might be impaired in patients with severe hepatic disease, the use of Stezza in these women is not indicated as long as liver function values have not returned to normal.

Administration:

Oral use.

Tablets must be taken every day at about the same time without regard to meals. Tablets should be taken with some liquid as needed, and in the order as directed on the blister. Stickers marked with the 7 days of the week are provided. The woman should choose the sticker that starts with the day she begins taking the tablets and stick it on the blister.

Starting on Stezza: No Preceding Hormonal Contraceptive Use (In the Past Month): Tablet-taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding). When doing so, no additional contraceptive measures are necessary. Starting on days 2-5 is allowed, but during the 1st pill pack a barrier method should be used until the woman has completed 7 days of uninterrupted white tablet taking.

Changing from a Combined Hormonal Contraceptive [Combined

Oral Contraceptive (COC), Vaginal Ring or Transdermal Patch]: The woman should start with Stezza 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 her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Stezza 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, Implant, Injectable) or from a Hormone-Medicated Intrauterine System (IUS): The woman may switch any day from the minipill and Stezza should be started on the next day. An implant or IUS may be removed any day and Stezza should be started on the day of its removal. When changing from an injectable, Stezza should be started on the day when the next injection would have been due. In all of these cases, the woman should be advised to additionally use a barrier method until she has completed 7 days of uninterrupted white active tablet-taking.

Following First-Trimester Abortion: The woman may start immediately. When doing so, no additional contraceptive measures are necessary.

Following Delivery or Second-Trimester Abortion: Women should be advised to start between day 21 and 28 after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method until she has completed 7 days of uninterrupted white active 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.

For breastfeeding women see Precautions.

The increased risk of VTE during the postpartum period should be considered when restarting Stezza.

Management of Missed Tablets: The following advice only refers to missed white active tablets: If the woman is less than 24 hours late in taking any active 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 the woman is 24 or more hours late in taking any active tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules: 7 days of uninterrupted 'white active tablet'-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.

The more 'white active tablets' are missed and the closer the missed tablets are to the 4 yellow placebo tablets, the higher the risk of a pregnancy.

Day 1-7: The woman should take the last missed white tablet as soon as remembered even if this means taking two tablets at the same time. Then continue to take tablets at her usual time. In addition, a barrier method such as a condom hould be used until the woman has completed 7 days of uninterrupted white tablet-taking. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered.

Day 8-17: The woman should take the last missed white tablet as soon as remembered, even if this means taking two tablets at the same time. Then continue to take tablets at the usual time. Provided that the woman has taken the tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. However, if the woman missed more than 1 tablet, the woman should be advised to use extra precautions until completed the 7 days of uninterrupted white tablet-taking.

Day 18-24: The risk of reduced reliability is higher because of the forthcoming yellow placebo-tablet phase. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has taken all tablets correctly. If this is not the case, the woman should follow the first of these two options and use extra precautions for the next 7 days as well.

The woman should take the last missed tablet as soon as remembered, even if this means taking two tablets at the same time. Then continue to take tablets at the usual time until the active tablets are used up. The 4 placebo tablets from the last row must be discarded. The next blister pack must be started right away. The woman is unlikely to have a withdrawal bleed until the end of the active tablets section of the second pack, but the woman may experience spotting or breakthrough bleeding on tablet-taking days.

The woman may also be advised to discontinue active tablet-taking from the current blister pack. Then take placebo tablets from the last row for a maximum of 3 days such that the total number of placebo plus missed active white tablets is not more than 4, and subsequently continue with the next blister pack.

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

Note: If the woman is not sure about the number or color of tablets missed and what advice to follow, a barrier method should be used until the woman has completed 7 days of uninterrupted white active tablet-taking.

Yellow Placebo Tablets Missed: Contraceptive protection is not reduced. Yellow tablets from the last (4th) row of the blister can be disregarded. However, the missed tablets should be discarded to avoid unintentionally prolonging the placebo tablet phase.

Advice in Case of Gastrointestinal Disturbances: In case of severe gastrointestinal disturbance (e.g., vomiting or diarrhoea), absorption of the active substances may not be complete and additional contraceptive measures should be taken.

If vomiting occurs within 3-4 hours after white tablet-taking, the tablet should be considered as missed and a new tablet should be taken as soon as possible. The new tablet should be taken within 24 hours of the usual time of tablet-taking if possible. The next tablet should then be taken at the usual time. If 24 or more hours have passed since last tablet intake, the advice concerning missed tablets as given in Management of Missed Tablets, is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra white tablet(s) from another pack.

How to Shift Periods or How to Delay a Period: To delay a period the woman should continue with another blister pack of Stezza without taking the yellow placebo tablets from the current pack. The extension can be carried on for as long as wished until the end of the white active tablets in the second pack. Regular intake of Stezza is then resumed after the yellow placebo tablets have been taken of the second pack. During the extension the woman may experience breakthrough-bleeding or spotting.

To shift periods to another day of the week than the woman is used to with the current scheme, the woman can be advised to shorten the forthcoming yellow placebo tablet phase with a maximum of 4 days. The shorter the interval, the higher the risk that the woman does not have a withdrawal bleed and may experience breakthrough-bleeding and spotting during the subsequent pack (just as when delaying a period).

Hypersensitivity to Nomegestrol (Stezza) acetate and Estradiol (Stezza) or to any of the excipients of Stezza.

Combined hormonal contraceptives (CHCs) should not be used in the presence of any of the conditions listed as follows. As no epidemiological data are yet available with 17β-Estradiol (Stezza)-containing combined oral contraceptives (COCs), the contraindications for ethinylestradiol-containing CHCs are considered applicable to the use of Stezza. Should any of the conditions appear for the first time during Stezza use, the medicinal product should be stopped immediately.

Presence or history of venous thrombosis (deep venous thrombosis, pulmonary embolism).

Presence or history of arterial thrombosis (e.g. myocardial infarction) or prodromal conditions (e.g. transient ischaemic attack, angina pectoris).

Presence or history of cerebrovascular accident.

History of migraine with focal neurological symptoms.

The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis such as: Diabetes mellitus with vascular symptoms; severe hypertension; severe dyslipoproteinemia.

Major surgery with prolonged immobilisation.

Hereditary or acquired predisposition for venous or arterial thrombosis, such as activated protein C (APC) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

Pancreatitis or a history thereof if associated with severe hypertriglyceridaemia.

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

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

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

Known or suspected pregnancy.

Influence of Other Medicinal Products on Stezza: Interactions between oral contraceptives and enzyme-inducing medicinal products may lead to breakthrough bleeding and even contraceptive failure.

Examples of active substances that induce hepatic enzymes and thus result in increased clearance of sex hormones: Phenytoin, phenobarbital, primidone, bosentan, carbamazepine, rifampicin and medicinal products or herbal preparations containing St. John’s wort, and to a lesser extent, oxcarbazepine, topiramate, felbamate, and griseofulvin. Also HIV protease inhibitors with an inducing potential (e.g. ritonavir and nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine and efavirenz), may affect hepatic metabolism.

With hepatic enzyme-inducing substances, a barrier method should be used during the time of concomitant medicinal product administration and for 28 days after their discontinuation. In case of long-term treatment with hepatic enzyme-inducing substances another method of contraception should be considered.

Medicinal product interaction studies were not performed with Stezza, but two studies with rifampicin and ketoconazole, respectively, were performed with a higher dosed Nomegestrol (Stezza) acetate-Estradiol (Stezza) combination (Nomegestrol (Stezza) acetate 3.75 mg + Estradiol (Stezza) 1.5 mg) in post-menopausal women. Concomitant use of rifampicin decreases the AUC_0-∞ of Nomegestrol (Stezza) acetate by 95% and increases the AUC_0-tlast of Estradiol (Stezza) by 25%. Concomitant use of ketoconazole (200 mg single dose) does not modify Estradiol (Stezza) metabolism whereas increases in the peak concentration (85%) and AUC_0-∞ (115%) of Nomegestrol (Stezza) acetate were observed, which were of no clinical relevance. Similar conclusions are expected in women of childbearing potential.

Influence of Stezza on Other Medicinal Products:

Oral contraceptives may affect the metabolism of other medicinal products. Special attention should be paid to the interaction with lamotrigine.

Laboratory Tests: The use of COCs may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g., 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.

Summary of the Safety Profile: Six (6) multicenter clinical trials of up to 1 year duration were used to evaluate safety of Stezza. In total 3434 women, 18-50, were enrolled and completed 33,828 cycles.

Summary of Adverse Reactions: Possibly related adverse reactions that have been reported in users of Stezza are listed as follows.

All adverse reactions are listed by system organ class and frequency: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100) and rare (≥1/10,000 to <1/1000).

Adverse Reaction in MedDRA Term¹: Metabolism and Nutrition Disorders: Uncommon: Increased appetite, fluid retention. Rare: Decreased appetite.

Psychiatric Disorders: Common: Decreased libido, depression/depressed mood, altered mood. Rare: Increased libido.

Nervous System Disorders: Common: Headache, migraine. Rare: Disturbance in attention.

Eye Disorders: Rare: Contact lens intolerance/dry eyes.

Vascular Disorders: Uncommon: Hot flush.

Gastrointestinal Disorders: Common: Nausea. Uncommon: Abdominal distension. Rare: Dry mouth.

Hepatobiliary Disorders: Rare: Cholelithiasis, cholecystitis.

Skin and Subcutaneous Tissue Disorders: Very Common: Acne. Uncommon: Hyperhydrosis, alopecia, pruritus, dry skin, seborrhea. Rare: Chloasma, hypertrichosis.

Musculoskeletal and Connective Tissue Disorders: Uncommon: Sensation of heaviness.

Reproductive System and Breast Disorders: Very Common: Abnormal withdrawal bleeding. Common: Metrorrhagia, menorrhagia, breast pain, pelvic pain. Uncommon: Hypomenorrhoea, breast swelling, galactorrhoea, uterine spasm, premenstrual syndrome, breast mass, dyspareunia, vulvovaginal dryness. Rare: Vaginal odour, vulvovaginal discomfort.

General Disorders and Administration Site Conditions: Uncommon: Irritability, oedema. Rare: Hunger.

Investigations: Common: Increased weight. Uncommon: Increased hepatic enzyme.

¹The most appropriate MedDRA term to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

Description of Selected Adverse Reactions: A number of adverse reactions have been reported in women using combined oral contraceptives containing ethinylestradiol, which are discussed in more detail in Precautions.