Loette

Oral contraception and the recognised gynaecological indications for such oestrogen-progestogen combinations.

The decision to prescribe Loette 30 ED should take into consideration the individual woman's current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Loette 30 ED compares with other combined hormonal contraceptives (CHCs).

Tablets must be taken orally in the order directed on the blister package at about the same time every day, with some liquid if necessary.

First treatment cycle: 1 tablet daily for 28 days, starting on the first day of the menstrual cycle. 21 (small) active tablets are taken followed by 7 (larger) placebo tablets. Contraceptive protection begins immediately.

Subsequent cycles: Tablet-taking is continuous, which means that the next pack of Loette 30 ED follows immediately without a break. A withdrawal bleed usually occurs when the placebo tablets are being taken.

Changing from 21-day combined oral contraceptives: The first tablet of Loette 30 ED should be taken on the first day immediately after the end of the previous oral contraceptive course. Additional contraceptive precautions are not required.

Changing from a combined Every Day pill (28 -day pill): Loette 30 ED should be started after taking the last active tablet from the previous Every Day pill pack. The first Loette 30 ED tablet is taken the next day. Additional contraceptive precautions are not then required.

Changing from a progestogen-only pill (POP):

The first tablet of Loette 30 ED should be taken on the first day of bleeding, even if a POP has already been taken on that day. Additional contraceptive precautions are not then required. The remaining progestogen-only pills should be discarded.

Post-partum and post-abortum use: After pregnancy, oral contraception can be started 21 days after a vaginal delivery, provided that the patient is fully ambulant and there are no puerperal complications. Additional contraceptive precautions will be required for the first 7 days of tablet taking to ensure adequate contraceptive cover if early ovulation has occurred. Since the first post-partum ovulation may precede the first bleeding, another method of contraception should be used in the interval between childbirth and the first course of tablets. After a first-trimester abortion, oral contraception may be started immediately in which case no additional contraceptive precautions are required.

Special circumstances requiring additional contraception

Incorrect administration: Errors in taking the 7 placebo tablets (i.e. the larger white tablets in the last row) can be ignored.

A single delayed active (small) tablet should be taken as soon as possible, and if this can be done within 12 hours of the correct time, contraceptive protection is maintained.

With longer delays in taking active tablets, additional contraception is needed. Only the most recently delayed tablet should be taken, earlier missed tablets being omitted, and additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used for the next 7 days, while the next 7 active (small) tablets are being taken. Therefore, if the 7 days additional contraception extend beyond the last active (small) tablet, the user should finish taking all the active tablets, discard the placebo tablets and start a new pack of Loette 30 ED the next day with an appropriate active (small) tablet. Thus, active tablet follows active tablet with no 7 day break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. Some breakthrough bleeding may occur on tablet taking days but this is not clinically significant. If the patient does not have a withdrawal bleed following the end of the second pack, the possibility of pregnancy must be ruled out before starting the next pack.

Gastro-intestinal upset: Vomiting or diarrhoea may reduce the efficacy of oral contraceptives by preventing full absorption. If vomiting or diarrhoea occurs within 4 hours of tablet-taking from the current pack should be continued. Additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used during the gastro-intestinal upset and for 7 days following the upset. If these 7 days extend beyond the last active (small) tablet the user should finish taking all the active tablets, discard the placebo tablets and start a new pack of Loette 30 ED the next day with an appropriate active (small) tablet. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed at the end of the second pack, the possibility of pregnancy must be ruled out before starting the next pack. Other methods of contraception should be considered if the gastro-intestinal disorder is likely to be prolonged.

Children: Not applicable

Elderly: Not applicable

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.

- Presence or risk of venous thromboembolism (VTE)

o Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE])

o Known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance, (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency

o Major surgery with prolonged immobilisation

o A high risk of venous thromboembolism due to the presence of multiple risk factors

- Presence or risk of arterial thromboembolism (ATE)

o Arterial thromboembolism - current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)

o Cerebrovascular disease - current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA)

o Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and anti-phospholipid antibodies (anticardiolipin-antibodies, lupus anticoagulant)

o History of migraine with focal neurological symptoms

o A high risk of arterial thromboembolism due to multiple risk factors or to the presence of one serious risk factor such as:

- diabetes mellitus with vascular symptoms

- severe hypertension

- severe dyslipoproteinaemia

- Presence or history of severe hepatic disease, e.g. active viral hepatitis and severe cirrhosis, as long as liver function values have not returned to normal.

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

- Current or history of breast cancer.

- Hypersensitivity to the active substance(s) or to any of the excipients.

Relevant UK clinical guidance should also be consulted.

Loette 30 ED is contraindicated for concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir.

Warnings

- If any of the conditions or risk factors mentioned below is present, the suitability of Loette 30 ED 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 Loette 30 ED should be discontinued.

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, such as Loette 30 ED, norgestimate or norethisterone are associated with the lowest risk of VTE. The decision to use Loette 30 ED should be taken after a discussion with the woman to ensure she understands the risk of VTE with Loette 30 ED, 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 estimated that out of 10,000 women who use a CHC that contains levonorgestrel, about 6¹ will develop a VTE in a year.

This number of VTEs per year is fewer than the number expected in women 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, cerebral 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).

Loette 30 ED is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis. 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.

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.

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). Loette 30 ED is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis. 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.

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.

Medical Examination/Consultation

Prior to the initiation or reinstitution of Loette 30 ED 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 and warnings. It is important to draw a woman's attention to the information on venous and arterial thrombosis, including the risk of Loette 30 ED 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.

Undiagnosed vaginal bleeding that is suspicious for underlying conditions should be investigated.

Conditions which require strict medical supervision

The decision to prescribe the COC must be made using clinical judgement and in consultation with the woman. Exacerbation or first appearance of any of these conditions or risk factors may indicate that use of the oral contraceptive should be discontinued. The woman should contact her physician, who should then decide on whether COC use should be discontinued:

- Diabetes mellitus with mild vascular disease or mild nephropathy, retinopathy or neuropathy

- 'Reasons for stopping oral contraception immediately')

- porphyria

- obesity

- migraine

- cardiovascular diseases

Reasons for stopping oral contraception immediately:

When stopping oral contraception non-hormonal contraception should be used to ensure contraceptive protection is maintained.

1. Occurrence for the first time, or exacerbation, of migrainous headaches or unusually frequent or unusually severe headaches

2. Sudden disturbances of vision, of hearing or other perceptual disorders

3. First signs of thrombosis or blood clots (e.g. unusual pains in or swelling of the leg(s), stabbing pains on breathing or coughing for no apparent reason). Feeling of pain and tightness in the chest

4. Six weeks before an elective major operation (e.g. abdominal, orthopaedic), any surgery to the legs, medical treatment for varicose veins or prolonged immobilisation, e.g. after accidents or surgery. Do not restart until 2 weeks after full ambulation. In case of emergency surgery, thrombotic prophylaxis is usually indicated e.g. subcutaneous heparin

5. Onset of jaundice, hepatitis, itching of the whole body

6. Significant rise in blood pressure

7. Severe upper abdominal pain or liver enlargement

8.'Conditions which deteriorate in pregnancy or during previous COC use' under 'Other conditions')

Tumours

Numerous epidemiological studies have been reported on the risks of ovarian, endometrial, cervical and breast cancer in women using combined oral contraceptives. The evidence is clear that high dose combined oral contraceptives offer substantial protection against both ovarian and endometrial cancer. However, it is not clear whether low dose COCs confer protective effects to the same level.

- Breast cancer

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 cancers 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

- Cervical Cancer

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, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.

- Liver Cancer

In rare cases benign and, in even rarer cases, malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as those contained in Loette 30 ED. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, the possibility of a liver tumour should be included in the differential diagnosis.

Other conditions

The possibility cannot be ruled out that certain chronic diseases may occasionally deteriorate during the use of combined oral contraceptives.

- Known hyperlipidaemias

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

- Blood pressure

- Conditions which deteriorate in pregnancy or during previous COC use

The following conditions have been reported to occur or deteriorate with both pregnancy and COC use. Consideration should be given to stopping Loette 30 ED if any of the following occur during use:

- jaundice and/or pruritus related to cholestasis

- COCs may increase the risk of gallstone formation and may worsen existing disease.

- systemic lupus erythematosus

- herpes gestationis

- otosclerosis-related hearing loss

- sickle cell anaemia

- renal dysfunction

- hereditary angioedema

- any other condition an individual woman has experienced worsening of during pregnancy or previous use of COCs.

- Disturbances of liver function

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 and/or cholestasis-related pruritus which occurred during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.

- Diabetes (without vascular involvement)

Insulin-dependent diabetics without vascular disease can use COCs. However it should be remembered that all diabetics are at an increased risk of arterial disease and this should be considered when prescribing COCs. Diabetics with existing vascular disease are contraindicated from using 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.

- Chloasma

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.

- Menstrual Changes

Reduction of menstrual flow: This is not abnormal and it is to be expected in some patients. Indeed, it may be beneficial where heavy periods were previously experienced.

Missed menstruation: Occasionally, withdrawal bleeding may not occur at all. If the tablets have been taken correctly, pregnancy is very unlikely. If withdrawal bleeding fails to occur at the end of a second pack, the possibility of pregnancy must be ruled out before resuming with the next pack.

Intermenstrual bleeding: 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 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. This may include curettage.

Some women may experience amenorrhoea or oligomenorrhoea after discontinuation of oral contraceptives, especially when these conditions existed prior to use. Women should be informed of this possibility.

- Lactose and Sucrose Intolerance

Each tablet of this medicinal product contains 32.97 mg lactose and 19.371 mg sucrose per tablet. Each placebo tablet contains 48.25 mg lactose and 33.98 mg sucrose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, fructose intolerance or glucose-galactose malabsorption or sucrase-isomaltase should not take this medicine.

- Reduced efficacy

The efficacy of COCs may be reduced, in the event of missed tablets, vomiting or diarhhoea, or concomitant medication.

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 frequent in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs).

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.

Ethinylestradiol / levonorgestrel has no effects or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most commonly reported adverse reactions with Loette 30 ED are nausea, abdominal pain, increased weight, headache, depressed mood, altered mood, breast pain, breast tenderness. They occur in >1% of users.

Serious adverse reactions are arterial and venous thromboembolism.

The following adverse events have been reported during use of ethinylestradiol / levonorgestrel:

Description of selected adverse reactions

- Venous thromboembolic disorders

- Arterial thromboembolic disorders

- Strokes (e.g. transient ischemic attack, ischemic stroke, haemorrhagic stroke)

- Hypertension

- Liver tumours (benign and malignant)

The frequency of diagnosis of breast cancer is very slightly increased among COC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer.'Contraindications' and 4.4 'Special warnings and precautions for use'.

Conditions reported to deteriorate with pregnancy or previous COC use

Jaundice and/or pruritus related to cholestasis; gallstone formation; systemic lupus erythematosus; herpes gestationis; otosclerosis-related hearing loss; sickle cell anaemia; renal dysfunction; hereditary angioedema; porphyria; cervical cancer.

Changes in glucose tolerance or effect on peripheral insulin resistance have been reported in women using COCs.

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.

There have been no reports of serious effects from overdose. Overdosage may cause nausea, vomiting and, in females, withdrawal bleeding. Withdrawal bleeding may even occur in girls before their menarche, if they accidentally take the medicinal product.

There are no specific antidotes and treatment should be symptomatic.

Loette 30 ED is an oestrogen-progestogen combination which acts by inhibiting ovulation by suppression of the mid-cycle surge of luteinizing hormone, the inspissation of cervical mucus so as to constitute a barrier to sperm, and the rendering of the endometrium unreceptive to implantation.

Levonorgestrel

Levonorgestrel is absorbed quickly and completely. Maximum active substance levels of approx. 3 ng/ml were reached in serum just one hour after ingestion of Loette 30 ED. The serum concentrations subsequently fell in 2 phases with half-lives of around 0.5 hours and 20 hours. The metabolic clearance rate from plasma is approx. 1.5 ml/min/kg.

Levonorgestrel is eliminated not in unchanged form, but in the form of metabolites with a half-life of around one day and in almost equal proportions via the kidney and bile. Levonorgestrel is extensively metabolised. The major metabolites in plasma are the unconjugated and conjugated forms of 3α, 5β-tetrahydrolevonorgestrel. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of levonorgestrel.

Levonorgestrel is bound to serum albumin and SHBG. Only around 1.5% of the respective total concentration is present in unbound form, while approx. 65% is bound to SHBG. The relative proportions (free, albumin-bound, SHBG-bound) depend on the concentration of SHBG. After induction of the binding protein, the portion bound to SHBG increases, while the free portion and that bound to albumin decreases.

After daily repeated ingestion, levonorgestrel accumulates by about the factor 2. A steady state is reached during the second half of the treatment cycle. The pharmacokinetics of levonorgestrel are dependent on the concentration of SHBG in plasma. Under treatment with Loette 30 ED, an increase in the serum levels of SHBG effect a concomitant increase in the specific binding capacity and therefore also an increase in levonorgestrel serum levels.

The levonorgestrel serum levels do not change any further after 1 - 3 cycles of use owing to the fact that SHBG induction is concluded. Compared to a single administration, 3 - 4 fold higher levonorgestrel serum levels are reached in the steady state.

The absolute bioavailability of levonorgestrel amounts to almost 100%.

Approx. 0.1% of the maternal dose can be passed on to a baby with the breast milk.

Ethinylestradiol

Orally administered ethinylestradiol is absorbed quickly and completely. Ingestion of Loette 30 ED leads to maximum plasma levels of approx. 100 pg/ml after 1 - 2 hours. The substance concentration then falls in 2 phases for which half-lives of around 1 - 2 hours and about 20 hours have been determined. For technical reasons, these data can only be calculated at higher dosages.

An imaginary distribution volume of around 5 l/kg and a metabolic clearance rate from plasma of approx. 5 ml/min/kg have been determined for ethinylestradiol. Ethinylestradiol is bound non-specifically to serum albumin to the extent of 98%.

Ethinylestradiol is metabolised even during its absorption phase and during its first liver transit, leading to reduced and individually varying oral bioavailability. Ethinylestradiol is eliminated not in unchanged form, but in the form of metabolites with a half-life of around one day. The excretion ratio is 40 (urine) : 60 (bile).

Because of the half-life of the terminal elimination phase from plasma, a steady state characterised by a 30 - 40% higher plasma substance level becomes established after approx. 5 - 6 daily administrations.

The absolute bioavailability of ethinylestradiol is subject to considerable interindividual variations. After oral ingestion, it amounts to around 40 - 60% of the dose.

In women with fully established lactation, around 0.02% of the maternal dose can be passed on to the baby with the breast milk.

Other drugs can have a negative or positive effect on the systemic availability of ethinylestradiol. No interaction with vitamin C takes place. On continuous use, ethinylestradiol induces the hepatic synthesis of CBG and SHBG, the extent of SHBG induction being dependent on the type and dose of the simultaneously administered progestogen.

There is no preclinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.

None known.

No special requirements.