Progesterone

Registered South African indications:

Oral

• Luteal phase insufficiency associated with progesterone deficiency
  - Premenstrual syndrome
  - Mastopathy
  - Irregular menstruation
  - Perimenopause
• Hormone replacement therapy for menopause 

Intravaginal

• Ovarian insufficiency or complete ovarian failure
• Luteal phase insufficiency
  - In-vitro fertilisation (IVF) cycles
  - Spontaneous or induced cycles, in cases of subfertility or primary or secondary infertility, particularly due to dysovulation
• Threatened miscarriage or prevention of recurrent miscarriage

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
  (See additional prescribing points)
• Breastfeeding
• Severe hepatic impairment
  - Cholestatic jaundice
  - Hepatitis
  - History of severe hepatic disease
  - Hepatic cell tumours
  - Rotor syndrome
  - Dubin-Johnson syndrome
• Porphyria
• Undiagnosed vaginal bleeding
• Conditions of rare occurrence known to be affected by sex steroids
  - Herpes gestationis
  - Jaundice of pregnancy
  - Otosclerosis
  - Severe pruritus
• Previous or current thromboembolism disorders
  - Deep venous thrombosis
  - Pulmonary embolism
• Thrombophlebitis 
• Known thrombophilic disorders
• Cerebral haemorrhage

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
  (See additional prescribing points)
• Breastfeeding (oral)
• Hepatic impairment (oral)
  - Acute hepatic disease, or a history of hepatic disease as long as hepatic function tests have failed to return to normal
• Severe hepatic impairment (intravaginal)
• Porphyria
• Known, past or suspected breast cancer (oral)
• Known or suspected oestrogen-dependent malignant tumours
  - Mammary or genital tract carcinoma
• Undiagnosed genital bleeding
• Previous or current thromboembolism disorders
  - Deep venous thrombosis
  - Pulmonary embolism
• Thrombophlebitis
• Known thrombophilic disorders (oral)
• Cerebral haemorrhage
• Missed abortion (intravaginal) 

Cautions

South African manufacturer recommendations

• Pregnancy
• Renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Missed abortion
• Early miscarriages
• Postmenopausal women with a uterus
• Prolonged use
• Women taking combined oestrogen-progestogen therapy for more than 5 years
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy (second and third trimester) (intravaginal)
• Breastfeeding (intravaginal)
• Renal impairment
• Mild to moderate hepatic impairment (intravaginal)
• Hepatic disorders (e.g. hepatic adenoma) (oral)
• Cholelithiasis (oral)
• Premature menopause (oral)
• Leiomyoma (uterine fibroids) (oral)
• Endometriosis (oral)
• History of endometrial hyperplasia (oral)
• Risk factors for thromboembolic disorders (oral)
• Premature labour (oral)
• Use as a contraceptive 
• Women taking combined oestrogen-progestogen therapy for more than 5 years (oral)
• Risk factors for oestrogen dependent tumours (oral)
  - First-degree heredity for breast cancer
• Risk factors for venous thromboembolism (oral)
  - Use of oestrogens
  - Older age
  - Major surgery
  - Prolonged immobilisation
  - Obesity (BMI >30kg/m²)
  - Postpartum period
  - Systemic lupus erythematosus (SLE)
  - Cancer
• First degree relative with a history of thrombosis at a young age (oral)
• Hypertension (oral)
• Diabetes mellitus with or without vascular involvement (oral)
• Migraine or (severe) headache (oral)
• Depression (oral)
• Photosensitivity (oral)
• Systemic lupus erythematosus (oral)
• Epilepsy (oral)
• Asthma (oral)
• Otosclerosis (oral)
• Fluid retention (oral)
• Coadministration with chronic anticoagulant treatment (oral)
• May impair ability to drive and operate machinery (oral) 

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

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Luteal phase insufficiency associated with progesterone deficiency
- Premenstrual syndrome
- Mastopathy
- Irregular menstruation
- Perimenopause

• Oral (cap): Day 17-26: 200mg, dly at bedtime OR 300mg/day, in 2 divided doses; Treatment duration: 10 days per cycle

Hormone replacement therapy (HRT) for menopause (Additional agent required)

• Oral (cap): 200mg, dly at bedtime OR 200mg/day, in 2 divided doses; From either day 12-14 of the month or during the last 2 weeks of each treatment course; Followed by: 1 week treatment suspension

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Oestrogen therapy alone is not advised (due to the risk of endometrial hyperplasia)

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During the 1 week suspension of all replacement therapies, it is normal to observe withdrawal bleeding

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Oral: It is recommended to take progesterone sometime after eating, preferably in the evenings upon going to bed

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For indications of luteal phase insufficiency and HRT for menopause, the vaginal route should be used, at the same dosage as for the oral route, in the event of side effects caused by progesterone (drowsiness following oral absorption)

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Progesterone replacement therapy in cases of ovarian insufficiency or complete ovarian failure in women lacking ovaries (oocyte donation) (Additional agent required)

• Intravaginal (cap): Day 13 and 14: 100mg, dly of the transfer cycle; Day 15 and 25: 200mg, dly of the transfer cycle OR 200mg/day in 2 divided doses; Maintenance: Day 26 onward, and in cases of an incipient pregnancy: Up to 600mg/day in 3 divided doses; Treatment duration: Until day 60 OR until week 12 of pregnancy; Max: 600mg/24hrs

Supplementation of the luteal phase during IVF cycles

• Intravaginal (cap): 400-600mg/day in 2-3 divided doses; Treatment duration: Until week 12 of pregnancy

Supplementation of the luteal phase in cases of spontaneous or induced cycles
- In subjects with sub-fertility or primary or secondary sterility, particularly due to dysovulation

• Intravaginal (cap): Day 17-26: 200-300mg/day in 2 divided doses; Treatment duration: 10 days per cycle

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If menstruation does not resume and pregnancy is diagnosed, treatment should be quickly resumed until week 12 of pregnancy

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Threatened early miscarriage or repeated miscarriage due to luteal phase insufficiency

• Intravaginal (cap): 200-400mg/day in 2 divided doses; Treatment duration: Until week 12 of pregnancy

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Intravaginal: Each capsule should be inserted deep into the vagina

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The dosage must not exceed 200mg per dose, regardless of the indication and route of administration (oral or vaginal)

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International manufacturer recommendations

Hormone replacement therapy (HRT)
- Adjunctive use with estrogen in post-menopausal women with an intact uterus

• Oral (cap): Day 15-26: 200mg, dly at bedtime OR Day 1-25: 100mg, dly at bedtime

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Withdrawal bleeding may occur in the following week of each therapeutic cycle, however, occurs less with the 100mg, dly treatment schedule

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Progesterone 100mg should not be taken with food and should be taken at bedtime. Concomitant food ingestion increases the bioavailability of micronized progesterone

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Supplementation of the luteal phase during Assisted Reproductive Technology (ART) cycles

• Intravaginal (cap): 600mg/day in 2-3 divided doses; Treatment duration: From day 1 of embryo transfer, until 7-12 weeks of pregnancy

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Vaginal route: Each capsule should be inserted deep into the vagina

Not indicated for use in children

Pregnancy

South African manufacturer recommendations

• Oral: Not indicated for use in pregnant women
• First trimester: Intravaginal: Caution; no evidence of risk in studies
• Second and third trimester: Intravaginal: Caution; positive evidence of risk
• Safety in pregnancy has not been established
• The use of progesterone during pregnancy is restricted to the first trimester via the vaginal route
• Cases of hepatic cytolysis and cases of cholestasis of pregnancy have been reported during administration of micronised progesterone during the second and third trimesters of pregnancy
• Progesterone is not a treatment for the threat of preterm birth
• The use of progesterone must be reserved for cases with insufficient secretion of the corpus luteum
• Treatment should be discontinued upon diagnosis of a missed abortion

International manufacturer recommendations

• Oral: Not indicated for use in pregnant women
• First trimester: Intravaginal: Safe; no evidence of risk in studies
• Second and third trimester: Intravaginal: Caution; positive evidence of risk
• If pregnancy occurs during oral treatment, progesterone capsules should be withdrawn immediately
• Clinically, data on a large number of exposed pregnancies indicate no adverse effects of progesterone on the foetus. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of estrogens + progesterone indicate no teratogenic or foetotoxic effect
• No association has been found between the maternal use of natural progesterone in early pregnancy and foetal malformations, with regard to progesterone vaginal 200mg capsules
• Progesterone vaginal 200mg capsules should only be used during the first three months of pregnancy and must only be administrated by vaginal route. Prescription of progesterone beyond the first trimester of pregnancy may reveal gravidic cholestasis
• Vaginal treatment should be discontinued upon diagnosis of a missed abortion

Breastfeeding

South African manufacturer recommendations

• Contraindicated 
• The use of progesterone during breastfeeding is not recommended

International manufacturer recommendations

• Oral: Contraindicated
• Intravaginal: Caution; not recommended 
  Progesterone capsules are not indicated during breastfeeding. Detectable amounts of progesterone enter the breast milk

Fertility

South African manufacturer recommendations

• Progesterone is indicated to support luteal deficiency in subfertile or infertile women

International manufacturer recommendations

• As this medicinal product is indicated to support luteal deficiency in subfertile or infertile women, there is no deleterious known effect on fertility

Renal Impairment

• Caution; no information available 

Hepatic Impairment

South African manufacturer recommendations

• Mild to moderate: Caution; no information available 
• Severe: Contraindicated 
  Severe hepatic disease such as cholestatic jaundice, or hepatitis, or a history of severe hepatic disease, hepatic cell tumours, Rotor syndrome, or Dubin-Johnson syndrome

International manufacturer recommendations

• Oral: Contraindicated
  Acute hepatic disease, or a history of hepatic disease as long as hepatic function tests have failed to return to normal
• Intravaginal: Mild to moderate: Caution; no information available 
• Intravaginal: Severe: Contraindicated 

Elderly

South African manufacturer recommendations

• Caution; no information available 

International manufacturer recommendations

• Oral: No dose adjustment recommended
• Intravaginal: Not indicated for use in geriatric patients 

Porphyria Information

• Probably porphyrinogenic (PRP) 

Drugs in Sport

• Permitted - No warnings

Oral route
Central Nervous System Disorders

• Depression
• Drowsiness
• Headache
• Dizziness
• Fatigue
• Somnolence
• Insomnia
• Probable dementia >65 years

Gastrointestinal Disorders

• Nausea
• Abdominal bloating
• Abdominal pain

Hepatobiliary Disorders

• Gravidic cholestasis
• Gall bladder disease

Genitourinary Disorders

• Amenorrhoea
• Mastodynia
• Hot flushes
• Vaginal discharge
• Urinary problems
• Vaginal haemorrhage
• Irregular menstruation
• Changes in libido

Endocrine and Metabolic Disorders

• Weight changes

Musculoskeletal Disorders

• Joint pain

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Rash
• Urticaria
• Chloasma
• Melasma
• Alopecia
• Erythema multiforme
• Erythema nodosum
• Vascular purpura

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
  - Urticarial and anaphylactic shock
• Pyrexia
• Oedema

Intravaginal
Hepatobiliary Disorders

• Gravidic cholestasis

Genitourinary Disorders

• Vaginal discharge
• Vaginal haemorrhage

Skin and Subcutaneous Tissue Disorders

• Pruritus

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
  - Urticarial and anaphylactic shock

Oral

• CYP450-3A4  inducers
• Barbiturates
• Antiepileptic agents
• Phenytoin
• Carbamazepine
• Rifampicin
• Phenylbutazone
• Bromcriptine
• Spironolactone
• Griseofulvin
• Ampicillins
• Tetracyclines
• CYP450-3A4  inhibitors
• Ketoconazole
• Ritonavir
• Nelfinavir
• Ciclosporin
• Antisteroidal agents
• Aminoglutethimide
• Anticoagulants
• Coumarins
• Phenindione
• Antidiabetic agents
• Emergency contraceptives
• Ulipristal acetate
• Diazepam
• Tizanidine
• Terbinafine

Other interactions

• St. John's wort
• Results of hepatic and endocrine function tests

Intravaginal

• Bromocriptine
• Ciclosporin
• Rifamycins
• Rifampicin
• Antibacterial agents
• CYP450-3A4  inhibitors
• Ketoconazole

Other interactions

• Results of hepatic and endocrine function tests

• Blood pressure
• Pelvic examination
• Breast examination
  - Mammography

Specific cases may require

• Hepatic function
• Endocrine function
• Cardiovascular function
• Serum progesterone
• Serum triglycerides
• Thyroid stimulating hormone level

Additional observations

• Vaginal bleeding

The following risks apply in relation to systemic oestrogen/progestogen treatment:

• Breast cancer
• Endometrial cancer
• Ovarian cancer
• Venous thromboembolism
• Coronary artery disease
• Ischaemic stroke

Special warnings

• Progesterone capsules contains soybean lecithin and may cause hypersensitivity reactions (urticarial and anaphylactic shock in hypersensitive patients). As there is a possible relationship between allergy to soya and allergy to peanut, patients with peanut allergy should avoid using progesterone capsules

Reasons for immediate withdrawal of therapy (oral)

- Therapy should be discontinued in case a contraindication is discovered and in the following situations:

• Jaundice or deterioration in hepatic function
• Significant increase in blood pressure
• New onset of migraine-type headache
• Pregnancy
• Sudden or gradual, partial or complete loss of vision
• Proptosis or diplopia
• Papilloedema
• Retinal vascular lesions

Progesterone is a natural progestogen, the main hormone of the corpus luteum and the placenta. It acts on the endometrium by converting the proliferating phase to the secretory phase, and has all the properties of endogenous progesterone, in particular gestagenic, antioestrogenic, slightly antiandrogenic and antialdosterone effects. 

Capsule 100mg

• Lutiges 100mg (Ferring)
• Utrogestan (Medi Challenge) originator

Capsule 200mg

• Utrogestan (Medi Challenge) originator

Also available in the following forms: Pessary and gel.