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

Levonorgestrel (LNG)

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.

Dosage

One white tablet is taken daily for the first 16 days, followed by one pink tablet daily for 12 days.

Administration

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

Carcinogenicity

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.

Mutagenicity

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.

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.

   Inhouse Drugstore (UK)