Combined hormonal contraceptives (CHCs) should not be used in the following conditions. Should any of the conditions appear for the first time during CHC use, the product should be stopped immediately.
If any of the conditions or risk factors mentioned below is present, the suitability of Qlaira 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 Qlaira should be discontinued.
In case of suspected or confirmed VTE or ATE, CHC use should be discontinued. In case anticoagulant therapy is started, adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).
The following warnings and precautions are mainly derived from clinical and epidemiological data of ethinyl estradiol containing COCs.
• Circulatory Disorders
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. Limited data suggests that Qlaira may have a risk of VTE in the same range. The decision to use any other product (such as Qlaira) than one known to have the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, 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).
Epidemiological studies in women who use low dose (<50 µg ethinylestradiol) combined hormonal contraceptives have found that out of 10,000 women between about 6 and 12 will develop a VTE in one year
It is estimated that out of 10,000 women who use a levonorgestrel-containing CHC about 61 will develop a VTE in one year.
Limited epidemiological evidence suggests that the risk of VTE with the use of Qlaira may be in the same range as the risk with other CHCs, including CHCs containing levonorgestrel.
The number of VTEs per year with low dose CHCs is fewer than the number expected in women during pregnancy or in the postpartum period.
VTE may be fatal in 1-2% of the cases.
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.
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).
Qlaira 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:
| Risk factor | Comment |
|---|---|
| Obesity (body mass index over 30 kg/m²) | Risk increases substantially as BMI rises. Particularly important to consider if other risk factors also present. |
| Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors | In these situations it is advisable to discontinue use of the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Antithrombotic treatment should be considered if Qlaira has not been discontinued in advance. |
| Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age e.g. before 50). | If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use |
| Other medical conditions associated with VTE | Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease |
| Increasing age | Particularly above 35 years |
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).
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:
Symptoms of pulmonary embolism (PE) can include:
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.
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.
The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Qlaira 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:
| isk factor | Comment |
|---|---|
| Increasing age | Particularly above 35 years |
| Smoking | Women should be advised not to smoke if they wish to use a CHC. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception. |
| Hypertension | |
| Obesity (body mass index over 30 kg/m²) | Risk increases substantially as BMI increases. Particularly important in women with additional risk factors |
| Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age e.g. below 50). | If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use |
| Migraine | An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation |
| Other medical conditions associated with adverse vascular events | Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus. |
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:
Temporary symptoms suggest the event is a transient ischaemic attack (TIA).
Symptoms of myocardial infarction (MI) can include:
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 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 COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of 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. 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 tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal hemorrhages. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal hemorrhage occur in women taking COCs.
Women with hypertriglyceridaemia, 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. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC 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 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 gestationis; otosclerosis-related hearing loss.
In women with hereditary angioedema exogenous estrogens may induce 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, particularly in the early stage of COC use.
Worsening of endogenous depression, of epilepsy, of Crohn’s disease and of ulcerative colitis has been reported during COC use.
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.
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 whilst taking COCs.
Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since the level of circulating estrogens may be increased after administration of Qlaira.
This medicinal product contains not more than 50 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this amount into consideration.
Prior to the initiation or reinstitution of Qlaira 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 (see section 4.3) and warnings (see section 4.4). It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of Qlaira 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.
The efficacy of COCs may be reduced for example in the following events: missed active tablets (section 4.2), gastro-intestinal disturbances (section 4.2) during active tablet taking or concomitant medication (section 4.5).
With all 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 3 cycles.
Based on patient diaries from a comparative clinical trial, the percentage of women per cycle experiencing intracyclic bleeding was 10–18% for women using Qlaira.
Users of Qlaira may experience amenorrhea although not being pregnant. Based on patient diaries, amenorrhea occurs in approximately 15% of cycles.
If Qlaira has been taken according to the directions described in Section 4.2, it is unlikely that the woman is pregnant. If Qlaira has not been taken according to these directions prior to the first missed withdrawal bleed or if the withdrawal bleeding is missed in two consecutive cycles, pregnancy must be ruled out before Qlaira use is continued.
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.
1 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.
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Interaction studies have only been performed in adults.
The following interactions have been reported in the literature for COCs in general or were studied in clinical trials with Qlaira.
Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.
Management:
Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.
Short-term treatment:
Women on treatment with enzyme-inducing drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method must be used during the whole time of the concomitant drug therapy and for 28 days after its discontinuation. If the drug therapy runs beyond the end of the active tablets in the COC pack, the placebo tablets must be discarded and the next COC pack should be started right away.
Long-term treatment:
In women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal, method of contraception is recommended.
Substances increasing the clearance of COCs (diminished efficacy of COCs by enzyme-induction), e.g.:
Barbiturates, carbamazepine, phenytoin, primidone, rifampicin, and HIV medication ritonavir, nevirapine and efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John’s Wort (hypericum perforatum).
In a clinical study the strong cytochrome P450 (CYP 3A4) inducer rifampicin led to significant decreases in steady state concentrations and systemic exposures of dienogest and estradiol. The AUC (0-24h) of dienogest and estradiol at steady state, were decreased by 83% and 44%, respectively.
Substances with variable effects on the clearance of COC:
When co-administered with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of estrogen or progestins. The net effect of these changes may be clinically relevant in some cases.
Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.
Substances decreasing the clearance of COCs (enzyme inhibitors):
Dienogest is a substrate of CYP3A4.
The clinical relevance of potential interactions with enzyme inhibitors remains unknown.
Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of the estrogen or the progestin or both.
Coadministration with the strong CYP3A4 enzyme inhibitor ketoconazole resulted in a 2.9-fold and 1.6-fold increase of AUC (0-24h) at steady state for dienogest and estradiol, respectively. Concomitant administration of the moderate inhibitor erythromycin increased the AUC (0-24h) of dienogest and estradiol at steady state by 1.6-fold and 1.3-fold, respectively.
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).
Pharmacokinetics of nifedipine were not affected by concomitant administration of 2 mg dienogest + 0.03 mg ethinyl estradiol thus confirming results of in vitro studies indicating that inhibition of CYP enzymes by Qlaira is unlikely at the therapeutic dose.
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.
Qlaira should not be used during pregnancy.
If pregnancy occurs during use of Qlaira, further intake must be stopped. However, extensive epidemiological studies with ethinylestradiol containing COCs 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. Animal studies do not indicate a risk for reproductive toxicity (see section 5.3).
The increased risk of VTE during the postpartum period should be considered when re-starting Qlaira (see section 4.2 and 4.4).
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. These amounts may affect the child.
Qlaira is indicated for the prevention of pregnancy. For information on return to fertility, see section 5.1.
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.
The most commonly reported adverse reactions with Qlaira when used as an oral contraceptive or in the treatment of heavy menstrual bleeding in women without organic pathology who desire oral contraception are acne, breast discomfort, headache, intracyclic bleeding, nausea and weight increased.
Serious adverse reactions are arterial and venous thromboembolism, which are discussed in section 4.4.
The table below reports adverse reactions (ARs) by MedDRA system organ classes (MedDRA SOCs). The most appropriate MedDRA term (version 12.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well. The frequencies are based on clinical trial data. The adverse reactions were recorded in 5 phase III clinical studies (N=2,266 women at risk for pregnancy, N=264 women suffering from dysfunctional uterine bleeding without organic pathology who desire oral contraception) and considered at least possibly causally related to Qlaira use. All ADRs listed in the category ‘rare’ occurred in 1 to 2 volunteers resulting in <0.1%.
N=2,530women (100.0%)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Uncommon: Fungal infection, Vulvovaginal mycotic infection1, Vaginal infection
Rare: Candidiasis, Oral herpes, Pelvic inflammatory disease, Presumed ocular histoplasmosis syndrome, Tinea versicolor, Urinary tract infection, Vaginitis bacterial
Uncommon: Increased appetite
Rare: Fluid retention, Hypertriglyceridaemia
Uncommon: Depression/depressed mood, Emotional disorder2, Insomnia, Libido decreased3, Mental disorder, Mood change4
Rare: Aggression, Anxiety, Dysphoria, Libido increased, Nervousness, Nightmare, Restlessness, Sleep disorder, Stress
Common: Headache5
Uncommon: Dizziness, Migraine6
Rare: Disturbance in attention, Paraesthesia, Vertigo
Rare: Contact lens intolerance, Dry eye, Eye swelling
Rare: Myocardial infarction, Palpitations
Uncommon: Hot flush, Hypertension
Rare: Bleeding varicose vein, Venous thromboembolism (VTE), Arterial thromboembolism (ATE), Hypotension, Phlebitis superficialis, Vein pain
Common: Abdominal pain7, Nausea
Uncommon: Diarrhoea, Vomiting
Rare: Constipation, Dry mouth, Dyspepsia, Gastrooesophageal reflux disease
Uncommon: Liver enzymes increased8
Rare: Focal nodular hyperplasia of the liver, Cholecystitis chronic
Common: Acne9
Uncommon: Alopecia, Hyperhidrosis, Pruritus10, Rash11
Rare: Allergic skin reaction12, Chloasma, Dermatitis, Hirsutism, Hypertrichosis, Neurodermatitis, Pigmentation disorder, Seborrhoea, Skin disorder13
Uncommon: Muscle spasms
Rare: Back pain, Pain in jaw, Sensation of heaviness
Rare: Urinary tract pain
Common: Amenorrhea, Breast discomfort14, Dysmenorrhoea, Intracyclic bleeding (Metrorrhagia)15
Uncommon: Breast enlargement16, Breast mass, Cervical dysplasia, Dysfunctional uterine bleeding, Dyspareunia, Fibrocystic breast disease, Menorrhagia, Menstrual disorder, Ovarian cyst, Pelvic pain, Premenstrual syndrome, Uterine leiomyoma, Uterine spasm, Uterine/vaginal bleeding incl. spotting17, Vaginal discharge, Vulvovaginal dryness
Rare: Abnormal withdrawal bleeding, Benign breast neoplasm, Breast cancer in situ, Breast cyst, Breast discharge, Cervical polyp, Cervix erythema, Coital bleeding, Galactorrhea, Genital discharge, Hypomenorrhoea, Menstruation delayed, Ovarian cyst ruptured, Vaginal odour, Vulvovaginal burning sensation, Vulvovaginal discomfort
Rare: Lymphadenopathy
Rare: Asthma, Dyspnoea, Epistaxis
Uncommon: Fatigue, Irritability, Oedema18
Rare: Chest pain, Malaise, Pyrexia
Common: Weight increased
Uncommon: Weight decreased, Blood pressure changes19
Rare: Smear cervix abnormal
1 including vulvovaginal candidiasis and fungus cervical specimen identified
2 including crying and affect lability
3 including loss of libido
4 including mood altered and mood swings
5 including tension headache and sinus headache
6 including migraine with aura and migraine without aura
7 including abdominal distension, abdominal pain upper and abdominal pain lower
8 including alanine aminotransferase increased, aspartate aminotransferase increased and gamma- glutamyltransferase increased
9 including acne pustular
10 including pruritus generalized and rash pruritic
11 including rash macular
12 including dermatitis allergic and urticaria
13 including skin tightness
14 including breast pain, breast tenderness, nipple disorder and nipple pain
15 including menstruation irregular
16 including breast swelling
17 including vaginal hemorrhage, genital hemorrhage and uterine hemorrhage
18 including oedema peripheral
19 including blood pressure increased and blood pressure decreased
An increased risk of arterial and venous thrombotic and thrombo-embolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4.
Occurrence of amenorrhea and intracyclic bleeding based on patient diaries is summarized in section 4.4 Cycle control.
The following serious adverse events have been reported in women using COCs, which are discussed in section 4.4 Special warning and precautions for use:
Tumours:
Other conditions:
Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with oral contraceptives (see section 4.5).
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;
United Kingdom: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Malta: ADR Reporting, Website: www.medicinesauthority.gov.mt/adrportal
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
