Estriol/ Lactobacillus Acidophilus

Registered South African indications:

• Atrophic vaginitis and symptomatic vaginal atrophy due to oestrogen deficiency during menopause and post-menopause

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Existing or suspected breast cancer or a history of breast cancer
• Known or suspected oestrogen-dependent malignant tumours (especially endometrial carcinoma)
• Known or suspected endometriosis
• Untreated endometrial hyperplasia
• Unexplained bleeding in the genital area
• Vaginitis with severe inflammation and purulent infiltrates
• Previous idiopathic or existing venous thromboembolic disease (especially deep vein thrombosis, pulmonary embolism)
• Known thrombophilia (e.g. protein C, protein S, or antithrombin deficiency)
• Existing or recent arterial embolic disease (especially angina pectoris, myocardial infarction)
• Acute liver disease or a history of liver disease if the relevant liver enzyme values have not returned to normal
• Porphyria
• Should not be used in girls before puberty

South African recommendations

Caution in the following patient groups

• Pregnancy
• Renal impairment

Risk considerations with short-term use

• Estriol/ lactobacillus acidophilus contains a small amount of estriol, with minimal systemic absorption
• Short-term use (6-12 days) poses slight risks in patients with severe hepatic, renal, or cardiac impairment, epilepsy, migraine (or history thereof), hypertension, diabetes mellitus, porphyria, or hyperlipidaemia
• Caution is also advised in patients with severe pruritus, gestational herpes, exacerbation of otosclerosis during early pregnancy, or a history of thrombophlebitis or thromboembolic events
• Treatment should be discontinued if these conditions worsen or if abnormal vaginal bleeding occurs

Risk-benefit assessment for long-term use

• Topical oestrogen therapy should be initiated only to treat postmenopausal symptoms that negatively affect quality of life
• A thorough risk-benefit assessment should be conducted at least once a year
• Treatment should continue only while the benefits outweigh the risks

Medical and follow-up examinations

• A complete personal and family history must be obtained before starting or resuming treatment
• Regular physical and gynaecological examinations should be performed throughout treatment
• The frequency and nature of examinations should be based on individual patient risk
• Patients should be advised to report any unusual symptoms, such as unexpected genital bleeding or breast changes, to their doctor
• Screening, including imaging procedures like mammography, should be conducted in accordance with standard clinical guidelines

Situations requiring special medical surveillance

• Postmenopausal patients receiving maintenance therapy with estriol/ lactobacillus acidophilus should be closely monitored for conditions covered in the Monitoring section, which are worsened during pregnancy or previous hormone therapy, or deteriorate during current treatment

Reasons for immediate withdrawal of maintenance therapy

• Treatment should be discontinued if a contraindication is present
• Therapy should also be stopped in the following situations:
  • Jaundice or deterioration in liver function
  • Significant increase in blood pressure
  • First-time occurrence of migraine-like headaches or more frequent severe headaches

Endometrial hyperplasia

• The risk of endometrial hyperplasia and carcinoma increases with oral oestrogen monotherapy, depending on dose and duration of treatment
• No increased risk has been established for vaginal estriol monotherapy
• If long-term treatment is required, regular examinations are recommended, focusing on symptoms suggestive of endometrial hyperplasia or malignancy
• Any breakthrough bleeding should be investigated, and an endometrial biopsy may be necessary to rule out malignancy
• Unhindered oestrogen stimulation may cause premalignant transformation of residual endometrial lesions
• Caution is advised in women with a history of hysterectomy for endometriosis, particularly if residual endometriosis is present

Breast, uterine, and ovarian cancer

• Systemic oestrogen therapy may increase the risk of certain cancers, including uterine, ovarian, and breast cancer
• Estriol/ lactobacillus acidophilus vaginal tablets contain a low dose of estriol, with minimal and transient systemic absorption
• The risk of cancer is not expected to increase with estriol/ lactobacillus acidophilus therapy

Venous thromboembolic disease, stroke, and coronary artery disease

• Systemic hormone replacement therapy is associated with increased risks of VTE, stroke, and coronary artery disease
• Estriol/ lactobacillus acidophilus, given its low dose of estriol and topical administration, is not expected to increase these risks
• Established risk factors for VTE include:
  • Personal or family history of VTE
  • BMI >30kg/m²
  • Systemic lupus erythematosus (SLE)
• The role of varicose veins in VTE remains unclear, but close monitoring is advised for at-risk patients

Other disease states

• Systemic oestrogens may cause fluid retention or increase plasma triglyceride levels
• Patients with heart disease, renal impairment, or pre-existing hypertriglyceridaemia should be closely monitored during the first weeks of treatment
• Given its topical application, estriol/ lactobacillus acidophilus is not expected to cause systemic effects
• Patients with severe renal insufficiency should be monitored, as estriol levels in the blood may increase

Additional interaction considerations

• No studies are available on possible interactions between estriol/ lactobacillus acidophilus vaginal tablets and latex products (e.g. condoms, diaphragms, etc.)
• As a precaution, other methods of contraception should be used during estriol/ lactobacillus acidophilus use and for the first few days after discontinuation of treatment

Ability to drive and use machines

• No studies have been conducted on the effect of estriol/ lactobacillus acidophilus on the ability to drive and use machines

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

South African registered indications and dosages

Atrophic vaginitis and symptomatic vaginal atrophy due to oestrogen deficiency during menopause and post-menopause

Estriol/ Lactobacillus Acidophilus
0.03mg/1x10⁸ cfu* (900mg)

• Intravaginal (vat): 1 vaginal tab, daily; Treatment duration: ≥12 days; Maintenance: 1 vaginal tab, 2-3 days per week

---

*cfu - colony forming units

---

For the initiation and continuation of treatment of postmenopausal symptoms, the smallest effective dose should be used for the shortest period of time

---

The vaginal tablets should be inserted deeply (about the depth of one finger) into the vagina in the evening before retiring. This is best performed in a reclining position with the knees slightly bent towards the chest

Paed forms avail. in SA and covered in this monograph: vat

South African registered indications and dosages

Atrophic vaginitis and symptomatic vaginal atrophy due to oestrogen deficiency during menopause and post-menopause

Estriol/ Lactobacillus Acidophilus
0.03mg/1x10⁸ cfu* (900mg)

Girls before menarche

• Contraindicated

Adolescent girls after their first period

• See adult dosage

---

*cfu - colony forming units

Pregnancy

South African recommendations

• Caution
• There are limited data from studies on the use of estriol/ lactobacillus acidophilus in pregnancy. They provide no evidence of negative effects on the pregnancy or the health of the foetus/newborn child
• Endogenous production by the placenta itself results in a significant increase in estriol levels during pregnancy, about 1 000 times as compared to non-pregnant women. Because estriol is present in a very low dose in estriol/ lactobacillus acidophilus and undergoes only limited absorption, adverse effects on the foetus/newborn are unlikely following use of this medicine during pregnancy
• Pharmacovigilance data compiled over many years also fail to show any increased risk. Animal studies show adverse effects on the foetus after oral administration of estriol. However, these can be extrapolated to humans only to a limited extent
• Estriol/ lactobacillus acidophilus may be used during pregnancy after careful assessment of the risks and benefits by a medical practitioner

Breastfeeding

South African recommendations

• Safe
• Estriol is secreted in breast milk. Because of the small quantity and the low vaginal absorption rate of estriol in estriol/ lactobacillus acidophilus the combination product may be used during lactation

Fertility

South African recommendations

• No studies on effects on fertility have been conducted in animals

South African recommendations

• Caution; no information available
  Estriol/ lactobacillus acidophilus has not been studied in patients with renal insufficiency, however it is probably not necessary to adjust the dose
  Patients with severe renal insufficiency should be monitored closely because this may result in increased levels of estriol in the blood

South African recommendations

• Acute liver disease or a history of liver disease if the relevant liver enzyme values have not returned to normal (including severe insufficiency): Contraindicated
  Estriol/ lactobacillus acidophilus has not been studied in patients with hepatic insufficiency
  As with all sex hormones, estriol/ lactobacillus acidophilus is also contraindicated in the presence of severe hepatic insufficiency

South African recommendations

• No dose adjustment recommended

Infections and Infestations

Uncommon

• Vaginitis

Immune System Disorders

Rare

• Allergic reaction with redness and pruritus

Reproductive System and Breast Disorders

Uncommon

• Vulvovaginal pruritus
• Vaginal discharge
• Vulvovaginal burning sensation (especially at the start of treatment)

• Anti-infective medicines (local or systemic)

• Medical and follow-up examinations (frequency and nature of examinations should be based on individual patient risk)
  • A complete personal and family history must be obtained before starting or resuming treatment
  • Regular physical and gynaecological examinations should be performed throughout treatment

Specific cases may require

• Screening, including imaging procedures like mammography, should be conducted in accordance with standard clinical guidelines and the clinical needs of the individual patient
• Any breakthrough bleeding should be investigated, and an endometrial biopsy may be necessary to rule out malignancy

Additional observations

• Postmenopausal patients receiving maintenance therapy with estriol/ lactobacillus acidophilus should be closely monitored if any of the following conditions are present, worsened during pregnancy or previous hormone therapy, or deteriorate during current treatment:
  • Risk factors for oestrogen-dependent tumours, e.g. occurrence of breast cancer in a first degree relative
  • History of endometrial hyperplasia
  • Leiomyoma (fibroids) or endometriosis
  • Risk factors for venous thromboembolism (VTE)
    - A personal or family history of VTE
    - Being significantly overweight (BMI > 30kg/m²)
    - Systemic lupus erythematosus (SLE)
  • Migraine or severe headaches
  • Systemic lupus erythematosus
  • Liver disease, including hepatic adenoma
  • Diabetes mellitus, with or without vascular involvement
  • Cholelithiasis
  • Hypertension
  • Epilepsy
  • Asthma
  • Otosclerosis
• Patients with heart disease, renal impairment or pre-existing hypertriglyceridaemia should be monitored closely during the first few weeks of treatment
• Severe renal impairment
• Patients should be advised to report any unusual symptoms, such as unexpected genital bleeding or breast changes, to their doctor
• Regular examinations are recommended, focusing on symptoms suggestive of endometrial hyperplasia or malignancy

Estriol/ lactobacillus acidophilus has a unique dual mechanism of action. Estriol as contained in estriol/ lactobacillus acidophilus stimulates the proliferation and maturation of the vaginal epithelium, which result in an increase in the amount of glycogen and glycogen by-products in vaginal secretions. Glycogen and by-products are a nourishment source for lactobacilli bacteria and estriol promotes Lactobacillus adhesion to vaginal epithelium. Lactobacillus acidophilus metabolises the glycogen and by-products to lactic acid, helping to maintain the local vaginal pH in the normal range (below 4.5) and create a healthy vaginal ecosystem.

Estriol
Estriol is an endogenous oestrogenic hormone, naturally found in humans, and the major metabolite of estradiol and estrone. Estriol cannot be transformed into estradiol and estrone. Estriol has been defined as a short-acting oestrogen, having the shortest receptor occupancy (about 10 times lower than for estradiol) of all natural oestrogens. Oestrogens act through binding to nuclear oestrogen receptors, DNA-binding proteins which are found in oestrogen-responsive tissues and by regulating the transcription of a limited number of genes. Some oestrogenic effects, so-called early effects, can be observed after a single administration of estriol, whereas others, the late effects, are seen only with estradiol – which has a longer retention time in the target organ – but not with estriol.

Lactobacillus Acidophilus
Lactobacillus is a species of bacteria that naturally inhabits a healthy vagina. Lactobacilli are non-pathogenic bacteria which inhibit the colonisation and growth of pathogenic microorganisms in the vagina. They ferment glycogen stored in the vaginal epithelium to lactic acid. The resulting acidic environment (pH 3.8-4.5) provides unfavourable conditions for the colonisation and growth of pathogenic microorganisms and provides an optimal medium for the proliferation of the lactobacilli. In addition to lactic acid, lactobacilli produce hydrogen peroxide and bacteriocins, which also inhibit the growth of pathogenic microorganisms. The strain of Lactobacillus acidophilus contained in estriol/ lactobacillus acidophilus is sensitive to beta-lactam antibiotics, as well as to aminoglycosides, tetracyclines and macrolides. It is resistant to metronidazole, cotrimoxazole, as well as some quinolones (e.g. nalidixic acid and ofloxacin).