NUVELLE
®
Two-phase hormonal preparation containing
oestradiol valerate and levonorgestrel tablets
Presentation
The memo pack contains 16 white, sugar-coated
tablets, each containing oestradiol valerate 2.0 mg and 12 pink, sugar-coated
tablets, each containing oestradiol valerate 2.0 mg and levonorgestrel 0.075
mg.
Uses
Actions
NUVELLE contains oestradiol valerate (the valeric
acid ester of the endogenous female estrogen, oestradiol) and the synthetic
progestogen, levonorgestrel. Oestradiol valerate provides hormone replacement
during and after the climacteric. The addition of levonorgestrel in the second
half of each course of tablets helps to provide good cycle control and opposes
the development of endometrial hyperplasia.
NUVELLE eliminates the typical subjective
complaints associated with oestrogen deficiency which frequently occur in the
climacteric. These complaints include hot flushes, tendency towards outbreaks of
sweating, sleep disturbances, depressive moods, irritability, headaches and
dizziness. NUVELLE also has a favourable influence on the irritable bladder (a
not infrequent occurrence in the climacteric), signs of cutaneous and mucosal
involution (particularly in the genital region) which normally occur with
advancing age, and during the osteoporotic process.
Epidemiological studies suggest a number of risk
factors may contribute to postmenopausal osteoporosis including early menopause
(either natural or surgically induced), family history of osteoporosis, recent
corticosteroid therapy, a small frame, thin, cigarette consumption.
Most studies show that oral administration of
oestradiol valerate to post-menopausal women increases serum high-density
lipoprotein cholesterol (HDL-C) and decreases low density lipoprotein
cholesterol (LDL-C). Although epidemiological data are limited such alterations
are recognised as potentially protective against the development of arterial
disease. A possible attenuation of these effects may occur with the addition of
a progestogen. However, at the doses used in NUVELLE, the 12 days of combined
therapy with oestradiol valerate and levonorgestrel have not been observed to be
associated with any unwanted lipid effects.
NUVELLE does not consistently inhibit ovulation and
is therefore unsuitable for contraception.
Pharmacokinetics
Orally administered LNG is rapidly and completely
absorbed. Following ingestion of one tablet of NUVELLE maximum drug serum levels
of 1.9 ng/ml were found at 1.3 hours. Thereafter, LNG serum levels decrease in
two phases. The first phase is described by a half-life of 0.5-1.5 hours and the
terminal phase by a half-life of 20-27 hours.
For LNG, a metabolic clearance rate from serum of
about 1.5 ml/min/kg was determined. LNG is not excreted in unchanged form but as
metabolites. LNG metabolites are excreted at about equal proportions with urine
and faeces.
The biotransformation follows the known pathways of
steroid metabolism. No pharmacologically active metabolites are
known.
LNG is bound to serum albumin and SHBG (sex hormone
binding globulin). Only about 1.5 % of the total serum drug levels are present
as free steroid, but 65 % are specifically bound to SHBG. The relative
distribution (free, albumin-bound, SHBG-bound) depends on the SHBG
concentrations in the serum. Following induction of the binding protein, the
SHBG bound fraction increases while the unbound and the albumin-bound fraction
decrease.
Following daily repeated administration, LNG
concentrations in the serum increase by a factor of about 2. Steady-state
conditions are reached within a few days. The pharmacokinetics of LNG is
influenced by SHBG serum levels. Under treatment with NUVELLE SHBG levels will
rise by about 40 % during the estrogen phase and remain constant or slightly
decrease thereafter.
The absolute bioavailability of LNG was determined
to be almost 100 % of the dose administered. The relative bioavailability was
tested against an aqueous microcrystalline suspension and was found to be
complete (108%).
About 0.1 % of the maternal dose can be transferred
via milk to the nursed infant.
- Oestradiol valerate (E 2 val)
E 2 val is completely absorbed from the
NUVELLE tablet. During absorption and the first passage through the liver, the
steroid ester is cleaved into oestradiol (E2) and valeric acid. At
the same time, E 2 undergoes extensive further metabolism yielding E
2 conjugates, estrone (E1) and E 1 conjugates.
The pharmacologically most active metabolites of E
2 val are E 2 and E1. Maximum serum levels of
25 pg E 2 /ml and 180 pg E 1 /ml are reached 5-7 hours
after the administration of one NUVELLE tablet. Mean E 1 serum levels
are 10-12 fold higher than mean E 2 serum concentrations. Serum
levels of E 1 conjugates are about 25 fold higher than the
E1 serum levels.
E 2 is rapidly metabolised and the
metabolic clearance rate has been determined to 30 ml/min/kg. After oral intake
of E 2 the half-life of the terminal disposition phase was about 13
hours for E2. The respective half-life for E 1 serum level
decline was about 20 hours.
The daily use of NUVELLE will lead to an about 50 %
increase in E 2 serum levels and to twofold E 1 levels at
steady state.
Oestradiol is bound to about 97 % to serum
proteins, about 35 % are specifically bound to SHBG.
E 2 val is not excreted in unchanged
form. The metabolites of oestradiol are excreted via urine and bile with a
half-life of about 1 day at a ratio of 9:1.
The absolute bioavailability of E 2 from
E 2 val is about 3 % of oral dose and thus in the same range like
oral E 2 (5 % of dose).
The relative bioavailability of E 2 val
(reference: aqueous microcrystalline suspension) from NUVELLE tablets was
complete (111-112 %).
Oestradiol and its metabolites are excreted into
milk only to a minor extent.
Indications
Hormone replacement therapy for the treatment of
the climacteric syndrome.
Prevention of postmenopausal osteoporosis in women
considered at risk of developing fractures. Bone mineral density measurements
may help to confirm the presence of low bone mass. Studies of bone mineral
content have shown NUVELLE to be effective in the prevention of progressive bone
loss following the menopause.
NUVELLE is unsuitable for contraception.
Dosage and Administration
If the patient is still menstruating, treatment
should begin in the course of the first five days of menstruation. Patients
whose periods are very infrequent or who are postmenopausal may start at any
time, provided pregnancy has been excluded.
One white tablet is taken daily for the first 16
days, followed by one pink tablet daily for 12 days.
Each pack covers 28 days of treatment. Treatment is
continuous, which means that the next pack follows immediately without a break.
The tablets are to be swallowed whole with some liquid.
It does not matter at what time of the day the
patient takes her tablet, but once she has selected a particular time, she
should keep to it every day. If she forgets to take a tablet at the usual time,
she may take it within the following 12 to 24 hours. If the treatment is
discontinued for longer, irregular bleeding may occur. Bleeding usually occurs
within the last few days of one pack and/or the first week of the
next.
Contraindications
Pregnancy, severe disturbances of liver function,
previous or existing liver tumours, jaundice or general pruritus during a
previous pregnancy, Dubin-Johnson syndrome, Rotor syndrome, active deep venous
thrombosis, thromboembolic disorders, or a documented history of these
conditions, sickle-cell anaemia, suspected or existing hormone-dependent
disorders or tumours of the uterus and breast, undiagnosed irregular vaginal
bleeding, congenital disturbances of lipid metabolism, a history of herpes
gestationis (also known as pemphigoid gestationis), otosclerosis with
deterioration in previous pregnancies, endometriosis, severe diabetes with
vascular changes, mastopathy.
Warnings and Precautions
Before starting treatment, pregnancy must be
excluded. If the expected bleeding fails to occur at about 28-day intervals,
treatment should be stopped until pregnancy has been ruled out.
Before starting NUVELLE, patients should have a
thorough general medical and gynaecological examination with special emphasis on
the body weight, blood pressure, heart, breasts, and pelvic organs with an
endometrial assessment if indicated and observation of the legs and skin.
Follow-up examinations are recommended at least six-monthly during
treatment.
Epidemiological studies have suggested that hormone
replacement therapy (HRT) may be associated with an increased relative risk of
developing venous thromboembolism (VTE), i.e. deep venous thrombosis or
pulmonary embolism. Risk/benefit should therefore be carefully weighed in
consultation with the patient when prescribing HRT to women with a risk factor
for VTE.
Generally recognised risk factors for VTE include a
personal history, a family history (the occurrence of VTE in a direct relative
at a relatively early age may indicate genetic disposition) and severe obesity.
The risk of VTE also increases with age. There is no consensus about the
possible role of varicose veins in VTE.
The risk of VTE may be temporarily increased with
prolonged immobilisation, major elective or post-traumatic surgery, or major
trauma. Depending on the nature of the event and the duration of the
immobilisation, consideration should be given to a temporary discontinuation of
HRT.
Treatment should be stopped at once if migrainous
or frequent and unusually severe headaches occur for the first time, or if there
are other symptoms that are possible prodromata of vascular
occlusion.
Treatment should be stopped at once if jaundice or
pregnancy occurs, or if there is a significant rise in blood pressure, the
occurrence of thromboembolic disease, or an increase in epileptic
seizures.
Pre-existing fibroids may increase in size under
the influence of oestrogens. If this is observed treatment should be
discontinued.
In patients with mild chronic liver disease, liver
function should be checked every 8 - 12 weeks.
Persistent breakthrough bleeding during treatment
is an indication for endometrial assessment, which may include
biopsy.
Some women are predisposed to cholestasis during
steroid therapy. Diseases that are known to be subject of deterioration during
pregnancy (e. g. multiple sclerosis, epilepsy, diabetes, benign breast disease,
hypertension, cardiac or renal dysfunction, asthma, porphyria, tetany and
otosclerosis) should be carefully observed during treatment.
Prolonged exposure to unopposed estrogens increases
the risk of development of endometrial carcinoma. The general consensus of
opinion is that the addition of 12 days progestogen towards the end of the
cycle, as in NUVELLE, diminishes the possibility of such a risk, and some
investigators consider that it might be protective.
A meta-analysis from 51 epidemiological studies
reported that there is a modest increase in the risk of having breast cancer
diagnosed in women who have used HRT for more than five years. The findings may
be due to an earlier diagnosis, the biological effects of HRT, or a combination
of both. The relative risk increases with duration of treatment (by 2.3 % per
year of use). This is comparable to the increased risk of breast cancer observed
in women with every year of delay of natural menopause. The increased risk
gradually disappears during the course of the first five years after cessation
of HRT. Breast cancers found in women using HRT are more likely to be localised
to the breast than those found in non-users.
Regular breast examinations and, where appropriate,
mammography should be carried out in women on HRT. Breast status should also be
closely monitored in women with a history of, or known breast nodules or
fibrocystic breast disease.
In rare cases benign and in even rarer cases
malignant liver tumours leading in isolated cases to life-threatening
intraabdominal haemorrhage have been observed after the use of hormonal
substances such as those contained in NUVELLE. A hepatic tumour should be
considered in the differential diagnosis if upper abdominal pain, enlarged
liver, or signs of intraabdominal haemorrhage occur.
Preclinical safety data
The results from toxicity studies with repeated
administration including tumorigenicity studies with the two active ingredients
are not suggestive of a particular risk related to use in humans. However, it
has to be born in mind that sex steroids can promote the growth of certain
hormone-dependent tissues and tumours.
- Embryotoxicity/teratogenicity
Reproductive toxicity studies with levonorgestrel
(LNG) did not indicate a teratogenic potential nor a risk of a virilisation of
female foetuses related to the androgenic partial effect of LNG at therapeutic
dose levels. However, pregnancy is a contraindication for the use of
NUVELLE.
As no non-physiological
oestradiol-plasma-concentrations are produced by administration of oestradiol
valerate, there is no evidence of a risk to the foetuses due to this component
of the preparation.
In vitro and in vivo studies with 17ß-oestradiol or
with LNG gave no indications of a mutagenic potential.
Pregnancy and lactation
Contra-indicated.
Adverse Effects
During the first few months of treatment,
breakthrough bleeding, spotting and breast tenderness or enlargement can occur.
These are usually temporary and normally disappear after continued treatment.
Other symptoms known to occur are: anxiety, increased appetite, bloating,
palpitations, depressive symptoms, headache, dizziness, dyspepsia, leg pains,
oedema, altered libido, nausea, rashes, vomiting, altered weight.
Interactions
Hormonal contraception should be stopped when
treatment with NUVELLE is started and the patient should be advised to take
non-hormonal contraceptive precautions.
Drugs which induce hepatic microsomal enzyme
systems, e. g. barbiturates, phenytoin, rifampicin, accelerate the metabolism of
estrogen/progestogen combinations such as NUVELLE and may reduce their
efficacy.
The requirement for oral antidiabetics or insulin
can change as a result of the effect on glucose tolerance.
Overdosage
Acute toxicity studies did not indicate a risk of
acute adverse effects in case of inadvertent intake of a multiple of the daily
therapeutic dose.
Pharmaceutical Precautions
Shelf life: 5 years.
Special precautions for storage
: None.
Medicine Classification
Prescription Medicine
Package Quantities
Three calendar packs containing 28
tablets.
Further Information
List of excipients: lactose monohydrate, maize
starch, povidone 25000 povidone 700000, talc, magnesium stearate, sucrose,
macrogol 6000, calcium carbonate, glycerol 85%, montanglycol wax, ferric oxide
pigment (E172), titanium dioxide (E171).
Nature and contents of container
NUVELLE tablets are contained in blister packs
consisting of transparent films made of polyvinyl chloride and metallic foils
made of aluminium (mat side hot sealable).
Instructions for use/handling
Store all drugs properly and keep them out of reach
of children.
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