Drospirenone/ Ethinylestradiol Betadex/ Levomefolate Calcium

Registered South African indications:

• Contraception
• Improvement in folate status in women who elect to use oral contraception
• Moderate acne vulgaris in women seeking oral contraception 
• Symptoms of premenstrual dysphoric disorder (PMDD) in women who have chosen oral contraception as their method of birth control

Contraindications

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients in this combination product
• Presence or a history of venous or arterial thrombotic/thromboembolic events (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction) or of a cerebrovascular accident
• Presence or history of prodromata of a thrombosis (e.g. transient ischaemic attack, angina pectoris)
• A high risk of venous or arterial thrombosis
• History of migraine with focal neurological symptoms
• Diabetes mellitus with vascular involvement
• Severe hepatic disease as long as liver function values have not returned to normal
• Severe renal insufficiency or acute renal failure with a creatinine clearance of ˂30ml/min
• 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)
• Undiagnosed vaginal bleeding
• Known or suspected pregnancy
• Coadministration with direct-acting antiviral (DAA) medicines containing ombitasvir, paritaprevir, or dasabuvir, and combinations of these

Drospirenone/ethinylestradiol betadex/levomefolate calcium should not be used in the presence of any of the conditions listed above. Should any of the conditions appear for the first time during treatment, the product should be stopped immediately

Cautions

• Breastfeeding
• Renal impairment (CrC≥30-50ml/min)
• Mild to moderate hepatic impairment
• Porphyria
• Malignancy
• Haemolytic uraemic syndrome
• Chronic inflammatory bowel disease
• Sickle cell disease
• Age above 35 years
• Smoking
• Hypertension
• Obesity
• Family history of arterial thromboembolism
• Family history of venous thromboembolism
• Symptoms of deep vein thrombosis
• Symptoms of pulmonary embolism
• Migraine
• Diabetes mellitus
• Hyperhomocysteinaemia
• Valvular heart disease
• Atrial fibrillation
• Dyslipoproteinaemia  
• Systemic lupus erythematosus
• Hypertriglyceridemia
• Risk factors for breast cancer
• Risk factors for oestrogen-dependent tumours
• Any other condition that is known to worsen during pregnancy or with previous use of combined oral contraceptives
• Hereditary angioedema
• History of chloasma
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Contraception
Improvement in folate status in women who elect to use oral contraception

Drospirenone 3mg / Ethinyloestradiol 0.03mg / Levomefolate Calcium 0.451mg (21 tab), Levomefolate Calcium 0.451mg (non-hormonal tablets) (7 tab)

• Oral (fct): 1 tab, dly at the same time of day, for 28 days in the order directed on the package. Start with the specified section on the pack, on the first day of the menstrual cycle (1st day of the menstrual period), using the day label (e.g., “MO” for Monday)

Each subsequent pack is started the day after the last intake of the previous pack. A withdrawal bleed typically starts on days 2-3 after starting the hormone-free film-coated tablets (last row) and may continue into the start of the next pack

Missed dose 
Advise patient to disregard missed hormone-free tablets but to discard them to avoid extending the hormone-free phase. Instructions below are for missed hormone-containing tablets
Under 12 hours late: No reduced contraceptive protection. The missed tablet should be taken immediately and the regular schedule should be continued
Over 12 hours late: Contraceptive protection might be reduced
Day 1-7: Missed tablet should be taken immediately (even if this means taking two tablets at the same time). Barrier protection should be used for 7 days. Consider pregnancy risk if intercourse happened in the past week
Day 8-14: Missed tablet should be taken immediately (even if this means taking two tablets at the same time). No extra precautions needed if prior 7 days had correct tablet intake. If not, or multiple tablets missed, a barrier method should be used for 7 days
Day 15-21: Two options to prevent reduced contraceptive protection. Missed tablet should be taken (even if this means taking two tablets at the same time), with the regular schedule continued, discarding the 7 hormone-free tablets, starting a new pack immediately. Alternatively the current pack should be stopped by having a tablet-free interval of up to 7 days, including the days tablets were missed, and subsequently continuing with the next pack, commencing with the hormone-containing tablets on the appropriate day of the week

See additional prescribing points

Contraception
Improvement in folate status in women who elect to use oral contraception
Moderate acne vulgaris in women seeking oral contraception 
Symptoms of premenstrual dysphoric disorder (PMDD) in women who have chosen oral contraception as their method of birth control

Drospirenone 3mg / Ethinyloestradiol 0.02mg / Levomefolate Calcium 0.451mg (24 tab), Levomefolate Calcium 0.451mg (non-hormonal tablets) (4 tab)

• Oral (fct): 1 tab, dly at the same time of day, for 28 days in the order directed on the package. Start with the specified section on the pack, on the first day of the menstrual cycle (1st day of the menstrual period), using the day label (e.g., “MO” for Monday)

Each subsequent pack is started the day after the last intake of the previous pack. A withdrawal bleed usually starts on day 2 to 3 after starting the hormone-free film-coated tablets and may not have finished before the next pack is started

The efficacy of drospirenone/ethinylestradiol betadex/levomefolate calcium for PMDD was not assessed beyond 3 cycles. It has not been evaluated for the treatment of premenstrual syndrome (PMS)

Missed dose
Advise patient to disregard missed hormone-free tablets but to discard them to avoid extending the hormone-free phase. Instructions below are for missed hormone-containing tablets
Under 24 hours late: No reduction in contraceptive protection. The missed tablet should be taken immediately as soon as patient remembers and the regular schedule should be continued
Over 24 hours late: Risk of reduced contraceptive protection
Day 1-7: Missed tablet should be taken as soon as patient remembers (even if this means taking two tablets at the same time) and the regular schedule should be continued. Barrier methods should be used for 7 days. Consider pregnancy risk if there was intercourse in the past week
Day 8-14: Missed tablet should be taken as soon as patient remembers (even if this means taking two tablets at the same time) and the regular schedule should be continued. If the prior 7 days had correct tablet intake, no extra precautions are needed. If not, or if multiple tablets were missed, barrier methods should be used for 7 days
Day 15-24: Two options to ensure contraceptive protection. Take last missed hormone-containing tablet as soon as patient remembers (even if this means taking two tablets at the same time) and the regular schedule should be continued by taking the hormone-containing tablet until these are used up. The 4 hormone-free tablets should be discarded, and the new pack commenced immediately on the appropriate day of the week. Alternatively, the current pack should be stopped, taking up to 4 tablet-free days (including the missed days), then starting a new pack with hormone-containing tablets on the appropriate day of the week

See additional prescribing points

Not indicated for use in premenarchal children

Pregnancy

South African recommendations

• Contraindicated
• Drospirenone/ethinylestradiol betadex/levomefolate calcium is contraindicated in known or suspected pregnancy
• As drospirenone/ethinylestradiol betadex/levomefolate calcium is not indicated during pregnancy, if pregnancy occurs during treatment, further intake must be stopped
• Women stopping drospirenone/ethinylestradiol betadex/levomefolate should consider continuation of folate supplementations

Breastfeeding

South African recommendations

• Caution; not recommended
• Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk

South African recommendations

• CrC≥50-80ml/min: No dose adjustment recommended
• CrC≥30-50ml/min: Caution; no dose adjustment recommended
• CrCl˂30ml/min: Contraindicated

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated 
  Drospirenone/ethinylestradiol betadex/levomefolate calcium is contraindicated in severe hepatic disease as long as liver function values have not returned to normal

• Not indicated for use in geriatric patients

Central Nervous System Disorders

• Depressed mood
• Decreased libido
• Increased libido
• Headache
• Migraine

Cardiovascular Disorders

• Hypertension
• Hypotension
• Venous thromboembolism
• Arterial thromboembolism

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea

Genitourinary Disorders

• Menstrual disorders
• Intermenstrual bleeding
• Vaginal discharge
• Vulvovaginal candidiasis
• Vaginal infection

Endocrine and Metabolic Disorders

• Breast pain
• Breast tenderness
• Breast enlargement
• Breast discharge
• Increased weight
• Decreased weight

Skin and Subcutaneous Tissue Disorders

• Acne
• Eczema
• Pruritis
• Alopecia
• Erythema nodosum
• Erythema multiforme
• Fluid retention

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
• Asthma

Sensory Disorders

• Hypoacusis

• Phenytoin
• Barbiturates
• Phenobarbital
• Primidone
• Carbamazepine
• Rifampicin
• Oxcarbazepine
• Topiramate
• Felbamate
• Griseofulvin
• HIV/HCV protease inhibitors
• Non-nucleoside reverse transcriptase inhibitors
• Methotrexate
• Trimethoprim
• Sulphasalazine
• Triamterene
• Cholestyramine
• Valproic acid
• Strong and moderate CYP3A4 inhibitors
• Azole antifungals
• Itraconazole
• Voriconazole
• Fluconazole
• Macrolides
• Verapamil
• Clarithromycin
• Erythromycin
• Diltiazem
• Etoricoxib
• Ketoconazole
• Cyclosporin
• Lamotrigine
• Direct-acting antiviral (DAA) medicines and combinations of these
• Ombitasvir
• Paritaprevir
• Dasabuvir
• Angiotensin-II-receptor antagonists
• Potassium-sparing diuretics
• Aldosterone antagonists

Other interactions

• Products containing St John’s wort
• Grapefruit juice

• Pregnancy status
• Physical examination
• Blood pressure

Specific cases may require

• Serum potassium
• Blood glucose
• Endometrial cytology
• Lipid profile

Initiating treatment for both 3/0.03/0.451 (mg) and 3/0.02/0.451 (mg)

• No preceding hormonal contraceptive use (in the past month): Begin on day 1 of the natural cycle (1st day of menstrual bleeding). Starting on days 2 to 5 is allowed, but a barrier method should be used in addition for the first 7 days
• Switching from a combined hormonal contraceptive: Begin treatment preferably the day after the last hormone-containing tablet of the previous contraceptive, or latest by the day after the usual tablet-free interval. If switching from a vaginal ring or patch, start treatment preferably on the removal day of the last ring/patch, or at most by the day the next application is due
• Switching from a progestogen-only method: Begin any day from the minipill, on the removal day of an implant or intrauterine system, or when the next injection is due. Use an additional barrier method for the first 7 days
• After a first-trimester abortion: Can start immediately without the need for additional contraceptive measures
• After delivery or a second-trimester abortion: Begin between days 21 to 28 post-delivery/abortion. If starting later, use a barrier method for the first 7 days. If intercourse has occurred, confirm no pregnancy before starting treatment or wait for the first menstrual period

Gastrointestinal issues

• If severe, take additional contraceptive measures. If vomiting occurs within 3-4 hours after tablet, follow the missed tablet advice. If the woman does not want to change her normal tablettaking schedule, she must take the extra tablet(s) needed from another pack

Delaying a period

• To delay a period using drospirenone/ethinylestradiol betadex/levomefolate calcium, the patient should be advised to skip the hormone-free tablets from the current pack and continue with a new pack up to the end of the pack. Breakthrough bleeding or spotting may occur during this time. After the second pack's hormone-free phase, resume regular intake
• To adjust the start day of the period, reduce the number of upcoming hormone-free tablets. However, shorter intervals increase the risk of missing a withdrawal bleed and experiencing spotting or breakthrough bleeding, similar to when delaying a period
• Use a new pack without hormone-free tablets. Spotting or breakthrough bleeding might occur

Laboratory tests

• Contraceptive steroids can impact results of some laboratory tests
• They affect biochemical markers of liver, thyroid, adrenal, and kidney functions
• They influence plasma levels of certain proteins, including corticosteroid-binding globulin
• They can alter lipid and lipoprotein fractions
• They may affect carbohydrate metabolism markers
• They can change parameters of coagulation and fibrinolysis
• Changes usually stay within normal lab ranges
• Drospirenone increases plasma renin activity and plasma aldosterone due to its antimineralocorticoid activity

Drospirenone/ Ethinyloestradiol
The oestrogen-progestogen combination acts by inhibiting ovulation by suppression of the mid-cycle surge of luteinising hormone, the inspissation of cervical mucus so as to constitute a barrier to sperm and the rendering of the endometrium unreceptive to implantation. At therapeutic dosages, drospirenone also possesses antiandrogenic and mild antimineralocorticoid properties.

Levomefolate Calcium
Levomefolate is the primary biologically active isomer of folate. It is the form of folate in circulation and also the form which is transported across membranes into peripheral tissues, particularly across the blood-brain barrier. Levomefolate calcium is the predominant folate found in food and offers an improvement in folate status before the onset of pregnancy.

COMBINATION PREPARATIONS

Drospirenone/ Ethinylestradiol Betadex/ Levomefolate Calcium; Levomefolate Calcium

Tablet 3mg/ 0.03mg/ 0.451mg; 0.451mg

• Yasmin Plus (Bayer) originator

Tablet 3mg/ 0.02mg/ 0.451mg; 0.451mg

• Yaz Plus (Bayer) originator