CIMIZT Tablet Ref.[10435] Active ingredients: 17 alpha-Ethinylestradiol Desogestrel

4.4.1 Warnings

If any of the conditions or risk factors mentioned below is present, the suitability of Cimizt should be discussed with the woman.

In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of Cimizt should be discontinued.

1. Circulatory Disorders

Risk of venous thromboembolism (VTE):

The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as Cimizt may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with Cimizt, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.

• In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below).

It is estimated¹ that out of 10,000 women who use a CHC containing desogestrel between 9 and 12 women will develop a VTE in one year; this compares with about 6² in women who use a levonorgestrel-containing CHC.

In both cases, the number of VTEs per year is fewer than the number expected during pregnancy or in the postpartum period.

• VTE may be fatal in 1-2% of cases.

Number of VTE events per 10,000 women in one year:

Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries.

Risk factors for VTE:

The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).

Cimizt is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).

Table. Risk factors for VTE:

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.

The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the puerperium, must be considered (for information on “Pregnancy and lactation” see section 4.6). Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of deep vein thrombosis (DVT) can include:

• unilateral swelling of the leg and/or foot or along a vein in the leg;
• pain or tenderness in the leg which may be felt only when standing or walking,
• increased warmth in the affected leg; red or discoloured skin on the leg. Symptoms of pulmonary embolism (PE) can include:
• sudden onset of unexplained shortness of breath or rapid breathing;
• sudden coughing which may be associated with haemoptysis;
• sharp chest pain;
• severe light headedness or dizziness;
• rapid or irregular heartbeat.

Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).

Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.

If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.

Risk of arterial thromboembolism (ATE):

Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.

Risk factors for ATE:

The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Cimizt is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).

Table. Risk factors for ATE:

Symptoms of ATE:

In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of a cerebrovascular accident can include:

• sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
• sudden trouble walking, dizziness, loss of balance or coordination;
• sudden confusion, trouble speaking or understanding;
• sudden trouble seeing in one or both eyes;
• sudden, severe or prolonged headache with no known cause
• loss of consciousness or fainting with or without seizure.

Temporary symptoms suggest the event is a transient ischaemic attack (TIA).

Symptoms of myocardial infarction (MI) can include:

• pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;
• discomfort radiating to the back, jaw, throat, arm, stomach;
• feeling of being full, having indigestion or choking;
• sweating, nausea, vomiting or dizziness;
• extreme weakness, anxiety, or shortness of breath;
• rapid or irregular heartbeats.

2. Tumours:

• An increased risk of cervical cancer in long-term users of combined oral contraceptives has been reported in some studies, but there continues to be controversy about the extent to which this is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV).
• A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives (COCs). 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 additional breast cancers diagnosed in current users of COCs or in women who have used COCs in the last ten years are more likely to be localised to the breast than those in women who never used COCs.
• Breast cancer is rare among women under 40 years of age whether or not they take COCs. Whilst this background risk increases with age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer (see bar chart).The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping COC use such that by 10 years there appears to be no excess.
• The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).

Estimated cumulative numbers of breast cancer per 10,000 women diagnosed in 5 years of use and up to 10 years after stopping COCs, compared with numbers of breast cancers diagnosed in 10,000 women who had never used COCs:

In rare cases, benign liver tumours, and even more rarely malignant liver tumours have been reported in users of CHCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A hepatic tumour should be considered in the differential diagnosis when upper abdominal pain, enlarged liver or signs of intra-abdominal haemorrhage occur in women taking CHCs.

3. ALT elevations:

During clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequently in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.5).

4. Other conditions:

• Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using CHCs.
• Although small increases in blood pressure have been reported in many women taking CHCs, clinically relevant increases are rare. A relationship between CHC use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of a CHC then it is prudent for the physician to withdraw the CHC and treat the hypertension. Where considered appropriate, CHC use 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 CHC use, but the evidence of an association with CHC use is inconclusive: Jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uremic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss; hereditary angioedema.
• Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred previously during pregnancy or use of sex steroids necessitates the discontinuation of CHCs.
• Although CHCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regime in diabetics using CHCs. However, diabetic women should be carefully observed, while taking CHCs. Crohn’s disease and ulcerative colitis have been associated with CHC use.
• Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to sun or ultra-violet radiation whilst taking this preparation.

Cimizt Tablets contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Relative Contraindications:

Severe depression or a history of this condition.

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

4.4.2 Medical examination/consultation

Prior to the initiation or reinstitution of Cimizt a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contra-indications (section 4.3) and warnings (section 4.4). It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of Cimizt compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis. The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman. Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases. If there is risk of STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method.

4.4.3 Reduced efficacy

The efficacy of Cimizt may be reduced in the event of missed tablets (Section 4.2.3), gastrointestinal disturbances (Section 4.2.4) or concomitant medications that decrease the plasma concentration of etonogestrel, the active metabolite of desogestrel (Section 4.5.1).

4.4.4 Reduced cycle control/irregular bleeding

With all CHCs, 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 3 cycles.

If bleeding irregularities persist 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 tablet-free interval. If the CHC has been taken according to the directions described in section 4.2, it is unlikely that the woman is pregnant. However, if the CHC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before CHC use is continued.

¹ These incidences were estimated from the totality of the epidemiological study data, using relative risks for the different products compared with levonorgestrel-containing CHCs.
² Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6

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.:

• Hepatic metabolism: Interactions can occur with medicinal or herbal products that induce microsomal enzymes, specifically cytochrome P450 enzymes (CYP), which can result in increased clearance reducing plasma concentrations of sex hormones and may decrease the effectiveness of combined oral contraceptives, including Cimizt. These products include phenytoin, phenobarbital, primidone, bosentan, carbamazepine, rifampicin, rifabutin and possibly also oxcarbazepine, modafinil, topiramate, felbamate, griseofulvin, some HIV protease inhibitors (e.g., ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz) and products containing the herbal remedy St. John’s wort.Enzyme induction can occur after a few days of treatment. Maximal enzyme induction is generally observed within a few weeks. After drug therapy is discontinued, enzyme induction can last for about 28 days.

Women receiving any of the above mentioned hepatic enzyme-inducing medicinal or herbal products should be advised that the efficacy of Cimizt may be reduced. A barrier contraceptive method should be used in addition to Cimizt during administration of the hepatic enzyme-inducing medicinal product, and for 28 days after discontinuation of the hepatic enzyme-inducing medicinal product. If concomitant drug administration runs beyond the end of the tablets in the current COC pack, the next COC pack should be started right away without the usual tablet-free interval.

For women on long-term therapy with enzyme-inducing medicinal products, an alternative method of contraception unaffected by enzyme-inducing medicinal products should be considered.

• When co-administered with hormonal contraceptives, many combinations of HIV protease inhibitors (e.g., nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine), and/or combinations with Hepatitis C virus (HCV) medicinal products (e.g., boceprevir, telaprevir), can increase or decrease plasma concentrations of progestins, including etonogestrel, the active metabolite of desogestrel, or estrogens. The net effect of these changes may be clinically relevant in some cases.
• Concomitant administration of strong (e.g., ketoconazole, itraconazole, clarithromycin) or moderate (e.g., fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may increase the serum concentrations of estrogens or progestins, including etonogestrel, the active metabolite of desogestrel.
• Oral contraceptives may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may be increased (e.g., ciclosporin) or decreased (e.g., lamotrigine).

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

Pharmacodynamic interactions

Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin may increase the risk of ALT elevations (see sections 4.3 and 4.4).

Therefore, Cimizt users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen. Cimizt can be restarted 2 weeks following completion of treatment with this combination drug regimen.

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, 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.

Cimizt is not indicated for use during pregnancy. If pregnancy occurs during treatment with Cimizt, further intake should be stopped.

However, most epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used CHCs prior to pregnancy, nor a teratogenic effect when CHCs were taken inadvertently during early pregnancy.

The increased risk of VTE during the postpartum period should be considered when re-starting Cimizt (see sections 4.2 and 4.4).

Lactation may be influenced by CHCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of CHCs 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 but there is no evidence that this adversely affects infant health.

No effects on ability to drive and use machines have been observed.

Description of selected adverse reactions

As with all COCs, changes in vaginal bleeding patterns may occur, especially during the first months of use. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration.

An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4.

Possibly related undesirable effects that have been reported in users of Cimizt or CHC users in general are listed in the table below¹. All ADRs are listed by system organ class and frequency; common (≥1/100), uncommon (≥1/1,000 to <1/100) and rare (<1/1,000).

Immune system disorders

Rare: Hypersensitivity

Metabolism and nutrition disorders

Uncommon: Fluid retention

Psychiatric disorders

Common: Depressed mood, mood altered

Uncommon: Libido decreased

Rare: Libido increased

Nervous system disorders

Common: Headache

Uncommon: Migraine

Eye disorders

Rare: Contact lens intolerance

Vascular disorders

Rare:Venous thromboembolism², Arterial thromboembolism²

Gastrointestinal disorders

Common:Nausea, abdominal pain

Uncommon:Vomiting, diarrhoea

Skin and subcutaneous tissue disorders

Uncommon:Rash, urticaria

Rare:Erythema Nodosum, Erythema multiforme

Reproductive system and breast disorders

Common:Breast tenderness, breast pain

Uncommon:Breast enlargement

Rare:Vaginal Discharge, breast discharge

Investigations

Rare:Weight increased

Common:Weight decreased

¹ The most appropriate MedDRA term (version 11) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.
² Incidence in observational cohort studies of ≥1/10000 to 1/1000 women-years.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

Not applicable.