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PROGESTERONE 400MG PESSARIES

Active substance(s): PROGESTERONE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Progesterone 400mg Pessaries

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each pessary contains 400mg Progesterone
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Off-white pessaries

4.1

Therapeutic indications
Progesterone is indicated for the
1) Treatment of premenstrual syndrome, including premenstrual tension and
depression.
2) Treatment of puerperal depression.
3) Luteal phase support as part of an Assisted Reproductive Technology
(ART) treatment for women.

4.2

Posology and method of administration
For the treatment of premenstrual syndrome and puerperal depression:
200mg daily to 400mg twice a day, by vaginal or rectal insertion. For
premenstrual syndrome commence treatment on day 14 of menstrual cycle and
continue treatment until onset of menstruation. If symptoms are present at
ovulation commence treatment on day 12.
For luteal phase support as part of an ART treatment:
400 mg administered vaginally twice a day starting at oocyte retrieval. The
administration of Progesterone should be continued for 38 days, if pregnancy
has been confirmed.
Use in special populations: There is no experience with use of Progesterone in
patients with impaired liver or renal function.
Paediatric population:There is no relevant use of Progesterone in the
paediatric population.
Elderly: No clinical data have been collected in patients over age 65.

4.3

Contraindications
-

4.4

Hypersensitivity to the active substance or to any of the excipients listed
in section 6.1.
Undiagnosed vaginal bleeding.
Known or suspected progesterone sensitive malignant tumours.
Porphyria.
Severe hepatic dysfunction or disease
Known missed abortion or ectopic pregnancy.
Active arterial or venous thromboembolism or severe thrombophlebitis, or
a history of these events.

Special warnings and precautions for use
Progesterone is not indicated in threatened miscarriage. Treatment should be
discontinued in the event of a missed miscarriage.
Progesterone should be discontinued if any of the following conditions are
suspected:
myocardial infarction, cerebrovascular disorders, arterial or venous
thromboembolism (venous thromboembolism or pulmonary embolism),
thrombophlebitis or retinal thrombosis.
Although risk of thromboembolism has been associated with estrogens, a link
with progestins remains questionable. Therefore, in women with generally
recognised risk factors for thromboembolic events, such as personal or family
history, treatment with Progesterone may further increase the risk. In these
women, the benefits of Progesterone administration need to be weighed
against the risks. It should be noted however, that pregnancy itself carries an
increased risk of thrombo-embolic events.
Patients with a history of depression need to be closely observed. Consider
discontinuation if symptoms worsen.
Because progesterone may cause some degree of fluid retention, conditions
that might be influenced by this factor (e.g. epilepsy, migraine, asthma, cardiac
or renal dysfunction) require careful observation.
A decrease in glucose tolerance has been observed in a small number of
patients on estrogen-progestin combination drugs. The mechanism of this
decrease is not known. For this reason, diabetic patients should be carefully
observed while receiving progestin therapy.
Progesterone is metabolised in the liver and should be used with caution in
patients with hepatic dysfunction.

Progesterone contains the hormone progesterone which is present in
significant concentrations in women during the second half of the menstrual
cycle and during pregnancy. This should be borne in mind when treating
patients with conditions that may be hormone-sensitive.
Abrupt discontinuation of progesterone dosing may cause increased anxiety,
moodiness, and increased sensibility to seizures.
Treatment of premenstrual syndrome and puerperal depression:
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.

4.5

Interactions with other medicinal products and other forms of
interaction
Drugs known to induce the hepatic cytochrome-P450-3A4 system (e.g.
rifampicin, carbamazepine or phenytoin) may increase the elimination rate and
thereby decrease the bioavailability of progesterone.
The effect of concomitant vaginal products on the exposure of progesterone
from Progesterone has not been assessed and is therefore not recommended.

4.6

Pregnancy and lactation
Pregnancy
Progesterone should not be used during pregnancy except as indicated during
the first trimester of pregnancy for use as part of an assisted reproduction
(ART) treatment treatment (see section 4.1 for full details. 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.
Lactation
Progesterone is excreted in human milk and progesterone should not be used
during breast-feeding

4.7

Effects on ability to drive and use machines
None known

4.8

Undesirable effects
Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000
to < 1/100), Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000), Not
known (cannot be estimated from the available data)

SYSTEM
ORGAN
CLASS
Nervous system
disorder
Gastrointestinal
disorders

Reproductive
system and
breast disorders

Common

Uncommon

Not known

Somnolence
Abdominal
pain,
Abdominal
discomfort
Breast pain

Diarrhoea and flatulence
may occur with rectal
administration.
Menstruation may occur
earlier than expected, or,
more rarely, menstruation
may be delayed.
Hypersensitivity
reactions (e.g.
rash, pruritus)

Skin and
subcutaneous
tissue disorders
General
disorders and
administration
site conditions

Soreness, some leakage of
the pessary base

Adverse reactions in patients undergoing luteal support as a part of ART
treatment is presented in the table below:
SYSTEM ORGAN CLASS

Common

Uncommon
Rectal neoplasm

Neoplasms benign,
malignant and unspecified
(incl cysts and polyps)
Psychiatric disorders

Mood altered

Nervous system disorder

Somnolence

Headache, dizziness, dysgeusia

Vascular disorders

Hot flush

Haemorrhage

Gastrointestinal disorders

Abdominal distension,
abdominal pain,
constipation

Diarrhoea, vomiting, flatulence,
gastric dilatation

Skin and subcutaneous tissue
disorders
Musculoskeletal and
connective tissue disorders

Rash, pruritus, night sweats
Arthralgia

Pollakiuria, incontinence

Renal and urinary disorders
Reproductive system and
breast disorders

Breast pain

Vaginal haemorrhage, pelvic
pain, metrorrhagia, ovarian
enlargement, vulvovaginal
pruritus

General disorders and
administration site
conditions

Fatigue

Feeling cold, feeling of body
temperature change, application
site pruritus, discomfort

Investigations

Weight increased

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; website:
www.mhra.gov.uk/yellowcard

4.9

Overdose
There is a wide margin of safety with Progesterone pessaries, but overdosage may
produce euphoria or dysmenorrhoea.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Sex hormones and modulators of the genital
system; Progestogens; Pregnen-(4) derivatives. ATC code: G03DA04.
Progesterone is a naturally occurring steroid that is secreted by the ovary,
placenta, and adrenal gland. In the presence of adequate estrogen,
progesterone transforms a proliferative endometrium into a secretory
endometrium. Progesterone is necessary to increase endometrial receptivity for
implantation of an embryo. Once an embryo is implanted, progesterone acts to
maintain the pregnancy.
Clinical efficacy and safety
In a Phase III clinical trial in pre-menopausal women subjected to ART and
IVF the pregnancy rates after vaginally applied Progesterone pessary (400 mg
twice daily) was found to be 38.3% (FAS) and 38.1% (PP) after 38 days of
luteal phase support. The clinical pregnancy rate was 34.5% after 70 days of
luteal phase support.

5.2

Pharmacokinetic properties
Absorption
Vaginal administration of Progesterone 400 mg every 12 h in healthy women
has been shown effective in rapidly achieving and maintaining serum
progesterone concentrations at physiological levels appropriate to the
midluteal phase of the ovarian cycle and early pregnancy.
The mean Cmax after 10 days of multiple dosing was 18.4 [ng/mL] and
Ctrough was 10.5 [ng/mL].
Distribution
Progesterone is approximately 96 % to 99 % bound to serum proteins,
primarily to serum albumin and corticosteroid binding globulin.
Biotransformation
Progesterone is metabolized primarily by the liver largely to pregnanediols and
pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to
glucuronide and sulfate metabolites. Progesterone metabolites that are
excreted in the bile may be deconjugated and may be further metabolized in
the gut via reduction, dehydroxylation, and epimerization.
Elimination
Progesterone undergoes renal and biliary elimination.

5.3

Preclinical safety data
There are no preclinical data of relevance to the prescriber which are
additional to those already included in other sections of the SmPC.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Also contains: vegetable fat.

6.2

Incompatibilities
None known

6.3

Shelf life
Shelf-life
Three years from the date of manufacture.
Shelf-life after dilution/reconstitution

Not applicable.
Shelf-life after first opening
Not applicable.

6.4

Special precautions for storage
Store below 25°C in a dry place

6.5

Nature and contents of container
The product may be supplied in strip packs contained in cartons:
Carton: White backed folding box board printed on white.
Strip pack: Aluminium foil lacquer-laminated to 20µm polypropylene foil and coated
on the reverse with polythene (20mg/m²). The alternative is thermoplastic film and
laminated PVC to 95µm and polyethylene to 27-30µm.
Pack sizes: 5s, 12s, 15s

6.6

Special precautions for disposal and handling
Not applicable.

7

MARKETING AUTHORISATION HOLDER
Actavis Group PTC ehf
Reykjavikurvegur 76-78,
220 Hafnarfjordur
Iceland

8

MARKETING AUTHORISATION NUMBER(S)
PL 30306/0323

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
10/03/2011

10

DATE OF REVISION OF THE TEXT
12/09/2016

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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