Progesterone

Registered South African indications:

• Infertility

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Hepatic impairment (vag)
• Porphyria
• Undiagnosed vaginal/uterine bleeding 
• Known or suspected malignancy of the breast or genital organs (vag)
• Thromboembolic disorders, thrombophlebitis or a history thereof
• Cerebral apoplexy or a history thereof (vag)
• Missed abortion (pvc)

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Severe hepatic impairment (pvc)
• Porphyria
• Undiagnosed vaginal bleeding
• Known of suspected progesterone sensitive malignant tumours
• Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events (pvc)
• Thromboembolic disorder, cerebral apoplexy or a history thereof (vag)
• Known missed abortion
• Known ectopic pregnancy (pvc)

Cautions

South African manufacturer recommendations

• Pregnancy (pvc)
• Pregnancy (>1 month) (vag)
• Breastfeeding
• Renal impairment
• Hepatic impairment (pvc) 
• Elderly
• Epilepsy
• Migraine
• History of mental depression (pvc)
• Asthma
• Cardiovascular impairment
• Diabetes mellitus (pvc)
• Irregular vaginal bleeding (vag)
• Conditions which may be aggravated by fluid retention
• Early manifestations or risk factors of thrombotic disorders (vag)
  - Thrombophelibitis
  - Cerebrovascular disorders
  - Pulmonary embolism
  - Retinal thrombosis
• Hormone sensitive conditions (pvc)
• May impair ability to drive and operate machinery (vag)

International manufacturer recommendations

• Pregnancy (pvc)
• Pregnancy (>1 month) (vag)
• Breastfeeding
• Renal impairment
• Mild to moderate hepatic impairment (pvc)
• Hepatic impairment (vag)
• Threatened miscarriage (pvc)
• Threatened abortion (vag)
• Irregular vaginal bleeding (vag)
• Risk factors for thrombotic disorders
  - Personal or family history
• Early manifestations of thrombotic disorders (vag)
  - Thrombophlebitis
  - Cerebrovascular disorders
  - Pulmonary embolism
  - Retinal thrombosis
• Suspected conditions (pvc)
  - Myocardial infarction
  - Cerebrovascular disorders
  - Arterial or venous thromboembolism
  - Thrombophlebitis
  - Retinal thrombosis
• Conditions influenced by fluid retention
  - Epilepsy
  - Migraine
  - Asthma
  - Cardiac impairment
• History of depression
• Diabetes mellitus
• Hormone sensitive conditions (pvc)
• Abrupt discontinuation (pvc)
• Barrier contraception (pvc)
• Vaginal infection (especially moniliasis) (pvc)
• Recurrent cystitis (pvc)
• Recent delivery (pvc)
• Rectal use in the presence of colitis or faecal incontinence (pvc)
  (See additional prescribing points)

Forms avail. in SA and covered in this monograph: pvc, vag 

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Infertility
- Supplementation of insufficient secretion of progesterone in women participating in fertilisation programmes

• Intravaginal (pvc): 200-400mg, 12-24hrly
• Intravaginal (vag): Insert 1.45g applicator charge, dly; Commencing from after documented ovulation or day 18-21 of the cycle

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When used during in-vitro fertilisation, daily application of progesterone vaginal gel should be continued for 30 days if there is laboratory evidence of  pregnancy

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See additional prescribing points for administration directions

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International manufacturer recommendations

Infertility
- Due to inadequate luteal phase
- During in-vitro fertilisation, where infertility is mainly due to tubal, idiopathic or endometriosis linked sterility associated with normal ovulatory cycles

• Intravaginal (vag): Insert 1 applicator charge, dly; Commencing from after documented ovulation or day 18-21 of the cycle

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When used during in-vitro fertilisation, daily application of progesterone vaginal gel should be continued for 30 days if there is laboratory evidence of  pregnancy

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Premenstrual syndrome
- Premenstrual tension and depression

• Intravaginal/ rectal (pvc): 200-400mg, 12-24hrly; Commencing on day 14 of menstrual cycle (commence on day 12 if symptoms are present at ovulation); Continuing until onset of menstruation

Puerperal depression

• Intravaginal/ rectal (pvc): 200-400mg, 12-24hrly

Not indicated for use in children

Pregnancy

South African manufacturer recommendations

• Caution; no information available (pvc)
• ≤1 month: Safe; no evidence of risk in studies (vag)
• >1 month: Caution; no information available (vag)
• Progesterone is a natural hormone and is not expected to have adverse effects, but no evidence is available to this effect (pvc)
• In case of corpus luteum deficiency, progesterone vaginal gel can be used during the first month of pregnancy (vag)

International manufacturer recommendations

• Caution; not recommended (pvc)
• ≤1 month: Safe (vag)
• >1 month: Caution; no information available (vag)
• Progesterone pessaries should not be used during pregnancy. There is limited and inconclusive data on the risk of congenital anomalies, including genital abnormalities in male or female infants, following intrauterine exposure during pregnancy. The rates of congenital anomalies, spontaneous abortion and ectopic pregnancies observed during the clinical trial were comparable with the event rate described in the general population although the total exposure is too low to allow conclusions to be drawn (pvc)
• In case of corpus luteum deficiency, progesterone vaginal gel can be used during the first month of pregnancy (vag)

Breastfeeding

South African manufacturer recommendations

• Caution; no information available (pvc)  
• Caution; not recommended (vag) 
• Progesterone is a natural hormone and is not expected to have adverse effects, but no evidence is available to this effect (pvc)
• Progesterone gel should not be used during breastfeeding (vag)

International manufacturer recommendations

• Caution; not recommended 
• Progesterone is excreted in human milk and should not be used during breastfeeding (pvc) 
• Do not use during breastfeeding (vag)

Fertility

South African manufacturer recommendations

• No information available

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 dose adjustment recommended

Hepatic Impairment

South African manufacturer recommendations

• Caution; no dose adjustment recommended (pvc) 
• Contraindicated (vag) 

International manufacturer recommendations

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Caution; no dose adjustment recommended (vag)
• Severe: Contraindicated (pvc) 

Elderly

South African manufacturer recommendations

• Caution; no information available 

International manufacturer recommendations

• Not indicated for use in geriatric patients  
  No clinical data have been collected in patients >65 years (pvc)
  Not applicable for use (vag)

Porphyria Information

• Probably porphyrinogenic (PRP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Somnolence

Gastrointestinal Disorders

• Abdominal pain
• Abdominal discomfort
• Diarrhoea
• Flatulence

Genitourinary Disorders

• Breast tenderness
• Breast pain
• Irregular menstrual cycle
• Genital pain
• Intermenstrual bleeding
  - Spotting
• Vaginal irritation

Skin and Subcutaneous Tissue Disorders

• Itching
• Burning
• Urticaria
• Pruritis

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
  - Rash
  - Pruritis

• CYP3A4 inducers (pvc)
• Rifampicin (pvc)
• Carbamazepine (pvc)
• Phenytoin (pvc)
• Other vaginal preparations

• Blood pressure
• Gynaecological examination
• Breast examination
  - Mammogram
• Papanicolaou smear

Specific cases may require

• Endometrial sampling
• Serum progesterone
• Serum triglycerides
• Thyroid stimulating hormone levels

Additional observations

• Vaginal bleeding

Vaginal gel administration directions

1. The applicator should be gripped firmly by the thick end. It should be shaken down like a thermometer to ensure that the contents are at the thin end
2. The tab should be twisted off and discarded
3. The applicator may be inserted while patient is in a sitting position or when lying on her back with the knees bent. The thin end of applicator should be gently inserted well into the vagina
4. The thick end of the applicator should be pressed firmly to deposit gel. The applicator should be removed and discarded in a waste container

Pessary rectal use considerations

• Use rectally if barrier methods of contraception are used
• Use rectally if patients suffer from vaginal infection (especially moniliasis) or recurrent cystitis or have recently given birth
• Use vaginally if patients suffer from colitis or faecal incontinence
• Some leakage of the pessary base may occur

Interactions with CYP3A4 inducers

• Although there is evidence of interaction between oral progestogens and CYP3A4 inducers, resulting in a decrease of serum progestogen levels, no significant consequences on progesterone levels is expected from concurrent administration of progesterone vaginal gel with CYP3A inducers

Progesterone, a natural progestogen, released during the luteal phase of the menstrual cycle leads to the development of a secretory endometrium. Abrupt decline in the release of progesterone from the corpus luteum at the end of the cycle is the main determinant of the onset of menstruation. If the duration of the luteal phase is artificially lengthened, either by sustaining luteal function or by treatment with progesterone, decidual changes in the endometrial stroma similar to those seen in early pregnancy can be induced. The eostrogen-induced maturation of the human vaginal epithelium is modified towards the condition of pregnancy by the action of progesterone. Progesterone is important for the maintenance of pregnancy as it suppresses menstruation and uterine contractility.

Vaginal capsule (pessaries) 200mg

• Cyclogest (Teva Pharmaceuticals) 

Vaginal gel (per dose) 90mg

• Crinone (Merck) originator