PRODUCT INFORMATION

LOETTE TABLETS

NAME OF THE MEDICINE

Levonorgestrel and Ethinyloestradiol

Chemically, levonorgestrel is 13-ethyl-17-hydroxy-18, 19-dinor-17-pregn-4-en-20-yn-3-

one and has the following chemical structure:

Chemical Formula: C21H2802

Molecular Weight: 312.45

Melting Point: 232-239C

CAS No: 797-63-7

Chemically, ethinyloestradiol is 19-nor-17-pregna-1,3,5 (10)-trien-20-yne-3,17-diol and has

the following chemical structure:

Chemical Formula: C20H2402

Molecular Weight: 296.41

Melting Point: 181-185C

CAS No: 57-63-6

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DESCRIPTION
LOETTE is a combined oral contraceptive tablet containing the synthetic progestogen,
levonorgestrel, and the synthetic oestrogen, ethinyloestradiol.

Levonorgestrel is a progestogen. Levonorgestrel is a white, odourless crystalline powder. It

is practically insoluble in water, slightly soluble in alcohol, acetone, ether, and soluble in
chloroform.

Ethinyloestradiol is an oestrogen. Ethinyloestradiol is a white to creamy white, odourless,

crystalline powder. It is insoluble in water and soluble in alcohol, chloroform, ether,
vegetable oils, and aqueous solutions of alkali hydroxides.

Each pink active tablet contains 100g levonorgestrel and 20g ethinyloestradiol and the
excipients: cellulose-microcrystalline, lactose, polacrilin potassium, magnesium stearate,
macrogol 1450, glycol montanate, hypromellose, titanium dioxide and the colourant, Iron
Oxide Red CI 77491.

Each white inactive tablet contains cellulose-microcrystalline, lactose, polacrilin potassium,

magnesium stearate, macrogol 1500, glycol montanate, hypromellose and titanium dioxide.

PHARMACOLOGY
Oral Contraception
The contraceptive effects of the hormonal components contained in LOETTE are based on
the inhibition of ovulation (by suppression of gonadotropin release) and are believed to
include changes in the cervical mucus, which increase the difficulty of sperm penetration into
the uterus. Additionally, changes could be expected in the endometrium that may reduce the
likelihood of implantation.

Acne
Acne treatment with LOETTE is based on oestrogen-induced increases in sex hormone
binding globulin (SHBG). Because testosterone binds to SHBG, bioavailable testosterone is
reduced. In addition, LOETTE suppresses gonadotropin production, leading to decreased
ovarian production of androgens, including androstenedione. Serum levels of 3 a-
androstenediol glucuronide (a marker of peripheral 5 a-reductase activity) are also reduced.
These biochemical changes produced by the co-administration of levonorgestrel and ethinyl
oestradiol are associated with improvement of acne in otherwise healthy women.

Pharmacokinetics
Absorption
No specific investigation of the absolute bioavailability of LOETTE in humans has been
conducted. However, literature indicates that levonorgestrel is rapidly and completely
absorbed after oral sugar coated tablet administration (bioavailability about 100%) and is not
subject to first-pass metabolism. Ethinyloestradiol is rapidly and almost completely absorbed
from the gastrointestinal tract but due to first-pass metabolism in gut mucosa and liver, the
bioavailability of ethinyloestradiol is between 38% and 48%, with marked inter-individual
variation.

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After a single dose of LOETTE to 22 women under fasting conditions, maximum serum
concentrations of levonorgestrel are 2.8 ± 0.9 ng/mL (mean ± SD) at 1.6 ± 0.9 hours. At
steady state, attained from day 19 onwards, maximum levonorgestrel concentrations of 6.0 ±
2.7 ng/mL are reached at 1.5 ± 0.5 hours after the daily dose. The minimum serum levels of
levonorgestrel at steady state are 1.9 ± 1.0 ng/mL. Observed levonorgestrel concentrations
increased from day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%,
respectively. Unbound levonorgestrel concentrations increased from day 1 to days 6 and 21
by 25% and 83%, respectively. The kinetics of total levonorgestrel are nonlinear due to an
increase in binding of levonorgestrel to sex hormone binding globulin (SHBG), which is
attributed to increased SHBG levels that are induced by the daily administration of
ethinyloestradiol.

Following a single dose, maximum serum concentrations of ethinyloestradiol of 62 ± 21

pg/mL are reached at 1.5 ± 0.5 hours. At steady state, attained from at least day 6 onwards,
maximum concentrations of ethinyloestradiol were 77 ± 30 pg/mL and were reached at 1.3 ±
0.7 hours after the daily dose. The minimum serum levels of ethinyloestradiol at steady state
are 10.5 ± 5.1 pg/mL. Ethinyloestradiol concentrations did not increase from days 1 to 6, but
did increase by 19% from days 1 to 21.

Distribution
Levonorgestrel in serum is primarily bound to SHBG. Ethinyloestradiol is about 97% bound
to plasma albumin. Ethinyloestradiol does not bind to SHBG, but induces SHBG synthesis.

Metabolism
Levonorgestrel: Extensive reduction of the , -unsaturated ketone in ring A occurs, in
addition to hydroxylation at carbons 2 and 16 to form dihydro and tetrahydro reduced
products. Metabolites may circulate as sulfates or glucuronides; however most of the
metabolites that circulate in the blood are sulfates of 3, 5-tetrahydro-levonorgestrel. There
are also large amounts of unconjugated levonorgestrel in the circulation with small amounts
of unconjugated and /or conjugated forms of 3, 5-tetrahydrolevonorgestrel and 16-
hydroxylevonorgestrel. Excretion occurs predominantly in the form of glucuronides.

Ethinyloestradiol: Cytochrome P450 enzymes (CYP3A4) in the liver are responsible for the
2-hydroxylation that is the major oxidative reaction. The 2-hydroxy metabolite is further
transformed by methylation and glucuronidation prior to urinary and faecal excretion. Levels
of Cytochrome P450 (CYP3A4) vary widely among individuals and may explain the
variation in rates of ethinyloestradiol 2-hydroxylation. Ethinyloestradiol is excreted in the
urine and faeces as glucuronide and sulfate conjugates, and undergoes enterohepatic
circulation.

Excretion
The elimination half-life for levonorgestrel is approximately 36 ± 13 hours at steady state.
Levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and
about 16% to 48% are excreted in faeces. The elimination half-life of ethinyloestradiol is 18
± 4.7 hours at steady state.

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CLINICAL TRIALS
Contraception
An ongoing open-label, non-comparative multi-centre phase III clinical study was conducted
in 1,447 women receiving LOETTE for a planned individual maximum of 36 cycles. Six
cycles were completed by 789 women. Of 7,720 cycles of exposure that were evaluated for
efficacy, a total of 5 pregnancies were reported. This represents an overall user-efficacy
(typical user-efficacy) pregnancy rate of 0.84 per 100 woman-years (over 99% effective at
preventing pregnancy). This rate includes patients who missed up to 5 non-consecutive pills
per cycle or up to 3 consecutive pills per cycle.

The overall user-efficacy pregnancy rates for LOETTE and other forms of contraception from
a number of non-comparative trials based on historical data are given below:

Oral Contraceptive Overall user-efficacy Effectiveness*

(Pearl Index) at Preventing Pregnancy

LOETTE

100 g levonorgestrel 0.84 99.16%

20 g ethinyloestradiol

150 g levonorgestrel 0.30 - 0.35 99.65% -99.7%

30 g ethinyloestradiol

30 g levonorgestrel 0.30 –3.0 97.00% - 99.7%

* 100% - (Pearl Index) = User effectiveness per 100-woman years (e.g. if 100 women took oral contraceptive
tablets for 1 year the chance of an accidental pregnancy would be less than 1%).

Whilst the contraceptive efficacy of LOETTE is 99.16%, compared historically with the
contraceptive efficacy of 99.7% for 150g levonorgestrel/30g ethinyloestradiol tablets, this
represents a 2-fold increase in the risk of pregnancy.

Cycle control was also evaluated by analysing cycle characteristics such as duration and
intensity of withdrawal bleeding and the incidence of breakthrough bleeding and
amenorrhoea. A total of 7,508 cycles were valid for cycle control analysis; the overall
incidence of inter menstrual bleeding was low. Although there was no comparative study of
the cycle control of LOETTE compared with higher dosage oral contraceptives, cycle control
data from historical studies with oral contraceptives containing higher doses of
ethinyloestradiol and levonorgestrel are given in the table below.

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 Dose*/ Number Number Breakthrough Spotting Amenorrhoea Cycle Mean length
Study of of cycles bleeding length of
women (% cycles) (% cycles) menstruation
(% cycles) (days)
(days)

100/20 1447 7508 4.3 12.1 2.6 26 - 30 4.8

Loette

(6 cycle)

150/30 1130 11064 6.0 7.7 1.8 26 – 30 4.3

(mean
28.5)

150/30 325 3445 0.7 2.7 0.6 27-29 -

* Dose levonorgestrel (g)/ ethinyloestradiol (g). Note that the definitions of bleeding in these studies are not
necessarily the same.

The length of withdrawal bleeding was 3 to 7 days in 86% of cycles (mean 4.8 days), and the
mean intensity was light for the most common episode length (4 to 6 days). The mean cycle
length, excluding cycle 1, was 29.1 days, and 90% of the cycles ranged in duration from 26 to
30 days. The cycle control for LOETTE remains consistent with these values over time.

Acne
Two (2) randomised, double blind, placebo-controlled, 6-cycle, multicentre, phase III clinical
studies were done to evaluate the efficacy and safety of levonorgestrel/ethinyloestradiol
(LNG/EE) 100g/20g for the treatment of moderate acne. Study 1 was conducted at 12
sites in the United States and at 1 site each in Canada and Australia, and study 2 was
conducted at 18 sites in the United States. Patients in studies 1 and 2 were randomly assigned
to receive 28-day packs of either LNG/EE or placebo tablets. Those in the LNG/EE group
received active tablets for 21 consecutive days and inert tablets for the subsequent 7 days.
The study medication was taken for up to 6 cycles during the studies. Moderate acne was
defined in the clinical trials as a total facial count of 6-200 non-inflammatory lesions
(comedones), 10-75 inflammatory lesions (papules and pustules) and 0-5 nodules.

In both studies, LNG/EE treatment consistently produced greater mean reductions in lesion
counts than placebo treatment. Generally, the differences between treatment groups became
apparent at cycles 2 or 3 and increased over time, becoming significant at cycles 4, 5 or 6.
The combined clinical global assessment results showed that a significantly greater
percentage of patients in the LNG/EE treatment group than in the placebo group rated clear
or mild at end-of-study (EOS). Mean percentage changes in the total inflammatory, total
non-inflammatory, total lesion counts and clinical global assessment (mild or clear) at EOS
compared with baseline for each individual study, as well as pooled data, are shown in the
table below.

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Analysis of Inflammatory, Non-inflammatory, Total Lesion Counts and Clinical Global
Assessment from Baseline to End-Of-Study (EOS)

Parameter Time LNG/EE Placebo Difference

p-value1

Study 1 n = 174 n = 176

Inflammatory Baseline 2011 2015 0.11

Lesion Count
End-of-study 1210 1524
(EOS)
-33% -25%
Change

Non- Baseline 5167 4342 0.16

inflammatory
Lesion Count End-of-study 3028 3227
Change -21% -13%

Total Lesion Baseline 7170 6352 0.02*

Count
End-of-study 4232 4638
Change -30% -20%

Clinical Baseline 12% 8.3% 0.25

Global
Assessment – End-of-study 47% 42%
mild or clear

Study 2 n = 185 n = 186

Inflammatory Baseline 2212 2211 0.04*

Lesion Count
End-of-study 1412 1614
Change -32% -22%

Non- Baseline 5052 4743 0.05*

inflammatory
Lesion Count End-of-study 4467 4967
Change -13% +4%

Total Lesion Baseline 7256 6947 0.02*

Count
End-of-study 4467 6572

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 Change -23% -9%

Clinical Baseline 11% 12% 0.02*

Global
Assessment – End-of-study 48% 38%
mild or clear

Pooled n = 359 n = 362

Inflammatory Baseline 2111 2113 0.01*

Lesion Count
End-of-study 1311 1520
Change -32% -24%

Non- Baseline 5160 4543 0.02*

inflammatory
Lesion Count End-of-study 3753 4153
Change -17% -4%

Total Lesion Baseline 7263 6650 0.001*

Count
End-of-study 5058 5659
Change -26% -14%

Clinical Baseline 11% 10% 0.01*

Global
Assessment – End-of-study 48% 40%
mild or clear
Change

*significant
1
= Between-group difference based on mean change adjusted for baseline, study centre, antibiotic use and
weight.
*EOS uses the last observation point for each patient. For patients who withdrew from the study before taking
study medication, the baseline value was used in the analysis.

Furthermore, there was no statistically significant difference between measured mean weight
gain from baseline to end of study (up to 6 cycles) in women treated with LNG/EE (0.72 
2.64 kg) and women treated with placebo (0.51  2.77 kg).

INDICATIONS
LOETTE is indicated for:

The prevention of pregnancy.

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The treatment of moderate acne vulgaris not controlled with topical preparations in post-
menarchal, pre-menopausal women who accept contraception.

CONTRAINDICATIONS
LOETTE is contraindicated in patients with:

A history of or current deep vein thrombosis, thrombophlebitis or thromboembolic disorders;

thrombogenic valvulopathies or thrombogenic rhythm disorders.

Hereditary or acquired predisposition for venous or arterial thrombosis.

Cerebrovascular or coronary artery disease.

Idiopathic cholestatic jaundice of pregnancy or jaundice with prior combined oral

contraceptive use; current or previous history of hepatic adenomas or carcinoma; or active
liver disease, as long as liver function has not returned to normal.

Known or suspected carcinoma of the breast.

Known or suspected oestrogen-dependent neoplasias (e.g. endometrial carcinoma).

Disorders of lipid metabolism.

Diabetes with vascular involvement.

Headaches with focal neurological symptoms (such as aura) including hemiplegic migraine.

Uncontrolled hypertension.

Undiagnosed vaginal bleeding.

Pancreatitis associated with severe hypertriglyceridaemia (current or history)

Known or suspected pregnancy.

Hypersensitivity to any of the ingredients contained in LOETTE.

PRECAUTIONS
The information contained in this document is principally based on studies carried out in
women who used oral contraceptives with higher formulations of oestrogens and
progestogens than those in common use today. The effect of long-term use of the oral
contraceptives with lower doses of both oestrogens and progestogens remains to be
determined.

Cigarette Smoking
Cigarette smoking increases the risk of serious cardiovascular side effects (e.g. myocardial
infarction, stroke) from oral contraceptive use. This risk increases with age and with heavy

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smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age.
Women who use oral contraceptives should be strongly advised not to smoke.

Thromboembolic Disorders
Use of combined oral contraceptives is associated with an increased risk of venous and
arterial thrombotic and thromboembolic events.

For any particular oestrogen/progestogen combination, the dosage regimen prescribed should
be one which contains the least amount of oestrogen and progestogen that is compatible with
a low failure rate and the needs of the individual patient.

New acceptors of combined oral contraceptives should be started on preparations containing

less than 50 micrograms of oestrogen.

Arterial Thrombosis and Thromboembolism

The use of combined oral contraceptives increases the risk of arterial thrombotic and
thromboembolic events. Reported events include myocardial infarction and cerebrovascular
events (ischaemic and haemorrhagic stroke, transient ischemic attack). The risk of arterial
thrombotic and thromboembolic events is further increased in women with underlying risk
factors or predisposing conditions such as cigarette smoking, certain inherited or acquired
thrombophilias, hypertension, hyperlipidaemias, obesity, diabetes and increasing age.
Caution must be exercised when prescribing LOETTE for women with risk factors or
predisposing conditions for arterial thrombotic or thromboembolic events.

Venous Thrombosis and Thromboembolism

The use of any combined oral contraceptives increases the risk of venous thrombotic and
thromboembolic events compared to no use. The excess risk is highest during the first year a
woman ever uses a combined oral contraceptive. Venous thromboembolism (VTE)
manifesting as deep venous thrombosis and/or pulmonary embolism may occur during the
use of all combined oral contraceptives. The approximate incidence of VTE in users of low
oestrogen dose (50g ethinyloestradiol) oral contraceptives is up to 4 per 10,000 woman-
years compared to 0.5 - 3 per 10,000 woman-years in non-oral contraceptive users. The
increased risk of venous thrombotic and thromboembolic events during any combined oral
contraceptive use is less than the incidence associated with pregnancy (i.e. 6 per 10,000
pregnant woman-years). Venous thromboembolism is fatal in 1-2% of cases.

The risk of venous thrombotic and thromboembolic events is further increased in women
with conditions predisposing for venous thrombosis and venous thromboembolism. When
prescribing oral contraceptives bear in mind the following predisposing conditions: obesity,
surgery or trauma with increased risk of thrombosis, recent delivery or second trimester
abortion, prolonged immobilisation and increasing age. There is no consensus about the
possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism
in the onset or progression of venous thrombosis.

A two- to four-fold increase in relative risk of postoperative thromboembolic complications

has been reported with the use of combined oral contraceptives. The relative risk of venous
thrombosis in women who have predisposing conditions is twice that of women without such
medical conditions. If feasible, combined oral contraceptives should be discontinued at least

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four weeks prior to and for two weeks after elective surgery with an increased in risk of
thrombosis, and during prolonged immobilisation.

Since the immediate post-partum period is associated with an increased risk of

thromboembolism, combined oral contraceptives should be started no earlier than day 28
after delivery or second-trimester abortion.

Carcinoma of the Reproductive Organs

Cervical Cancer
The most important risk factor for cervical cancer is persistent human papillomavirus
infection.

Several epidemiological studies suggest that oral contraceptive use may be associated with an
increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer. The
studies suggest that there is an “ever used” effect in addition to duration of use. These
findings must be balanced against evidence of effects attributable to sexual behaviour,
smoking and other factors. In cases of undiagnosed abnormal genital bleeding, adequate
diagnostic measures are indicated.

Breast Cancer
A meta-analysis from 54 epidemiological studies showed that there is a slightly increased
relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using
combined oral contraceptives compared to never-users. The increased risk gradually
disappears during the course of the 10 years after cessation of combined oral contraceptive
use. These studies do not provide evidence for causation. The observed pattern of increased
risk may be due to an earlier diagnosis of breast cancer in combined oral contraceptive users
(due to more regular clinical monitoring), the biological effects of combined oral
contraceptives or a combination of both. Because breast cancer is rare in women under 40
years of age, the excess number of breast cancer diagnoses in current and recent combined
oral contraceptive users is small in relation to the lifetime risk of breast cancer. Breast
cancers diagnosed in ever-users tend to be less advanced clinically than the cancers
diagnosed in never-users.

Established risk factors for the development of breast cancer include increasing age, family
history, obesity, nulliparity, and late age for first full-term pregnancy.

Women with a strong family history of breast cancer or who have breast nodules, fibrocystic
breast disease or abnormal mammograms should be monitored with particular care.

Hepatic Neoplasia/Liver Disease

In very rare cases hepatic adenomas, and in extremely rare cases, hepatocellular carcinoma
may be associated with combined oral contraceptives use. The risk appears to increase with
duration of combined oral contraceptive use. Hepatic adenomas may rupture and cause death
through intra-abdominal haemorrhage. Such lesions may present as an abdominal mass or
with the signs and symptoms of an acute abdomen and should be considered if the patient has
abdominal pain and tenderness or evidence of intra-abdominal bleeding.

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Hepatocellular injury has been reported with combined oral contraceptive use. Early
identification of drug-related hepatocellular injury can decrease the severity of hepatotoxicity
when the drug is discontinued. If hepatocellular injury is diagnosed, patients should stop
their combined oral contraceptive use, use a non-hormonal form of contraception and consult
their doctor.

Acute or chronic disturbances of liver function require the discontinuation of combined oral
contraceptive use until liver function has returned to normal (see CONTRAINDICATIONS).

Steroid hormones may be poorly metabolised in patients with impaired liver function.

Ocular Lesions
With the use of combined oral contraceptives, there have been case reports of retinal
thrombosis, which may lead to partial or complete loss of vision. Oral contraceptives should
be discontinued and the cause immediately evaluated if there are signs or symptoms such as
visual changes; onset of proptosis or diplopia; papilloedema, or retinal vascular lesions.

Gallbladder Disease
Combined oral contraceptives may worsen existing gallbladder disease and may accelerate
the development of this disease in previously asymptomatic women.

Carbohydrate and Lipid Metabolic Effects

Evidence from clinical trials with LOETTE indicates that there are no clinically significant
changes in carbohydrate metabolism parameters.

Glucose intolerance has been reported in oral contraceptives users. In particular, some
progestogens are known to increase insulin secretion and create insulin resistance, while
oestrogens (>75 micrograms) may create a state of hyperinsulinism. However, in the non-
diabetic woman, low dose oral contraceptives appear to have no effect on fasting blood
glucose. Women with impaired glucose tolerance or diabetes mellitus should be carefully
monitored while taking oral contraceptives.

A small proportion of women will have adverse lipid changes while taking OCs. Non-
hormonal contraception should be considered in women with uncontrolled dyslipidaemias.

A small proportion of women may have persistent hypertriglyceridaemia while taking oral
contraceptive tablets. Elevations of plasma triglycerides in combined oral contraceptive users
may lead to pancreatitis and other complications.

Oestrogens increase serum high-density lipoproteins (HDL cholesterol), whereas a decline in

serum HDL cholesterol has been reported with many progestational agents. Some
progestogens may elevate low-density lipoprotein (LDL) levels and may render the control of
hyperlipidaemias more difficult. The net effect of a combined oral contraceptive depends on
the balance achieved between doses of oestrogen and progestogen and the nature and
absolute amount of progestogen used in the contraceptive. The amount of both hormones
should be considered in the choice of a combined oral contraceptive.

Women who are being treated for hyperlipidaemias should be followed closely if they elect to
use combined oral contraceptives (see CONTRAINDICATIONS).

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Elevated Blood Pressure
An increase in blood pressure has been reported in women taking oral contraceptives and this
increase is more likely in older oral contraceptive users and with continued use.

In women with hypertension, or a history of hypertension or hypertension-related diseases

(including certain renal diseases), another method of contraception may be preferable. If
combined oral contraceptives are used in such cases, close monitoring is recommended. If a
significant elevation of blood pressure occurs, the drug should be discontinued.

For most women, elevated blood pressure will generally return to baseline after stopping
combined oral contraceptives, and there appears to be no difference in the occurrence of
hypertension among ever- and never- users.

Combined oral contraceptive use is contraindicated in women with uncontrolled

hypertension.

Migraine/Headache
The onset or exacerbation of migraine or development of headache with a new pattern that is
recurrent, persistent or severe requires discontinuation of combined oral contraceptives and
evaluation of the cause.

Women with migraine (particularly migraine with aura) who take combined oral
contraceptives may be at increased risk of stroke (see PRECAUTIONS - Arterial Thrombosis
and Thromboembolism).

Angioedema
Exogenous oestrogens may induce or exacerbate symptoms of angioedema, particularly in
women with hereditary angioedema.

Genital Bleeding
Breakthrough bleeding and spotting are sometimes encountered in patients on oral
contraceptives, especially during the first three months of use. The type and dose of
progestogen may be important. If this bleeding persists or recurs, non-hormonal causes
should be considered and adequate diagnostic measures taken to rule out malignancy,
infection, pregnancy or other conditions. If pathology has been excluded, continued use of
LOETTE or a change to another formulation may solve the problem.

In some women, withdrawal bleeding may not occur during the usual inactive tablet interval.
If LOETTE has been taken according to directions, it is unlikely that the woman is pregnant.
However, if LOETTE has not been taken according to directions prior to the first missed
withdrawal bleed or if two consecutive withdrawal bleeds are missed, tablet taking should be
discontinued and a non-hormonal back up method of contraception should be used until the
possibility of pregnancy is excluded.

Some women may encounter post-tablet amenorrhoea (possibly with anovulation), or

oligomenorrhoea, especially when such a condition was pre-existent.

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Medical Examinations
A complete personal and family medical history and physical examination should be taken
prior to the initiation of LOETTE use, and should be repeated periodically during the use of
LOETTE. Special attention should be given to blood pressure, breasts, abdomen and pelvic
organs. A Papanicolaou smear and relevant laboratory tests should be carried out.

Precautions for Patients with Other Existing Pathology

The following conditions have been reported to occur or deteriorate with combined oral
contraceptive use: sickle cell anaemia, multiple sclerosis, epilepsy, otosclerosis, herpes
gestationis, systemic lupus erythematosus and renal dysfunction, but evidence for an
association of these conditions with combined oral contraceptive use is inconclusive. These
conditions require careful monitoring during the use of combined oral contraceptives.
Deterioration of these conditions may indicate that LOETTE be discontinued. When
prescribing combined oral contraceptives for women with any of the above conditions, the
risks and benefits of alternate contraceptive methods should be considered.

Vomiting and/or Diarrhoea

Diarrhoea and/or vomiting may reduce hormone absorption resulting in decreased serum
concentrations (see DOSAGE AND ADMINISTRATION).

Folate Levels
Serum folate levels may be depressed by oral contraceptive use. This may be of clinical
significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

Depression
Patients becoming significantly depressed while taking LOETTE should stop the medication
and use an alternative method of contraception in an attempt to determine whether the
symptom is drug-related. Women with a history of depression should be carefully observed
and the drug discontinued if depression recurs to a serious degree.

Chloasma
In predisposed women, use of an oral contraceptive may sometimes cause chloasma, which is
aggravated by exposure to the sun. Women who have this tendency should therefore avoid
prolonged exposure to the sun.

HIV Infection
Patients should be counselled that LOETTE does not protect against HIV infection (AIDS)
and other sexually transmitted diseases.

Contraceptive Efficacy
LOETTE is a low dose oral contraceptive. To ensure optimal contraceptive efficacy, it is
important that LOETTE is taken strictly as directed. A non-hormonal back-up method of
contraception (other than the rhythm or temperature methods) should also be used in any
instance where the tablets are not taken as directed (see DOSAGE AND
ADMINISTRATION).

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Use in Pregnancy
Category B3.

Pregnancy must be excluded before starting LOETTE. If pregnancy occurs during use of
LOETTE, the preparation must be withdrawn immediately.

Oral contraceptives have not been shown to have any deleterious effects on the foetus or to
increase the incidence of miscarriage in women who discontinue their use prior to
conception.

Studies do not suggest a teratogenic effect when oral contraceptives are taken inadvertently
during early pregnancy.

Animal studies have shown that high doses of progestogens can cause masculinisation of the
female foetus. The results of these experiments in animals do not seem to be relevant to
humans because of the low doses used in oral contraceptives.

Use in Lactation
Oestrogen-containing oral contraceptives given in the post-partum period may interfere with
lactation. There may be a decrease in the quantity and a change in the composition of the
breast milk. Furthermore, small amounts of contraceptive steroids and/or metabolites have
been identified in the milk of mothers receiving them. A few adverse effects on the child
have been reported, including jaundice and breast enlargement. The use of oestrogen-
containing oral contraceptives should be deferred until the infant has been completely
weaned.

Paediatric Use
Safety and efficacy of combined oral contraceptives have been established in women of
reproductive age. Use of these products before menarche is not indicated.

Use in the Elderly

Combined oral contraceptives are not indicated for use in postmenopausal women.

Carcinogenicity
Long term continuous administration of natural or synthetic oestrogens in certain animal
species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis and
liver. A long-term study with levonorgestrel in dogs showed an increased incidence of
benign mammary tumours, although a similar effect was not observed in studies in mice, rats
or monkeys. The occurrence of these mammary tumours in dogs may be due in part to a
hormonal feedback mechanism. The clinical relevance of these findings is uncertain. It must
be borne in mind that sex steroids can promote the growth of certain hormone-dependent
tissues and tumours (see PRECAUTIONS – Carcinoma of the Reproductive Organs and
Hepatic Neoplasia/Liver Disease).

Genotoxicity
There is some evidence in the literature suggesting that oestrogens may be weakly genotoxic
at high doses. Ethinyloestradiol was negative in studies for DNA-adduct formation in
cultured human liver slices and in assays for gene mutations (bacterial or mammalian cells in

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vitro) and gave equivocal results in assays for chromosomal damage (clastogenic effects were
not consistently seen and occurred at high doses). The genotoxic potential of levonorgestrel
has not been fully investigated, although limited data available to date suggest that it does not
appear to be genotoxic.

Interactions with Other Medicines

Interactions between ethinyloestradiol and other substances may lead to decreased or
increased ethinyloestradiol concentrations, respectively.

Decreased ethinyloestradiol serum concentrations may cause an increased incidence of

breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy of the
oral contraceptive.

Examples of substances that may decrease serum ethinyloestradiol concentrations include any
substance that reduces gastrointestinal transit time and, therefore, ethinyloestradiol
absorption, and substances that induce hepatic microsomal enzymes, such as rifampicin,
phenytoin, carbamazepine, primidone, rifabutin, dexamethasone, griseofulvin, topiramate,
some protease inhibitors, modafinil, ritonavir and barbiturates.

St. John's Wort (Hypericum perforatum) may induce hepatic microsomal enzymes, which
may result in reduced efficacy of oral contraceptives. This may also result in breakthrough
bleeding.

Certain antibiotics including ampicillin, other penicillins and tetracyclines may reduce the
efficacy of oral contraceptives by decreasing enterohepatic circulation of oestrogens.

During concomitant use of LOETTE and substances that may lead to decreased
ethinyloestradiol serum concentrations, it is recommended that a non-hormonal back-up
method of contraception (other than the rhythm or temperature methods) be used in addition
to the regular intake of LOETTE. In the case of prolonged use of such substances combined
oral contraceptives should not be considered the primary contraceptive.

After discontinuation of substances that may lead to decreased ethinyloestradiol serum

concentrations, use of a non-hormonal back-up method of contraception is recommended for
at least 7 days.

Longer use of a back-up method, a minimum of 4 weeks, is advisable after discontinuation of

substances that have lead to induction of hepatic microsomal enzymes, such as rifampicin. It
may sometimes take several weeks until enzyme induction has completely subsided,
depending on dosage, duration of use and rate of elimination of the inducing substance.

Examples of substances that may increase serum ethinyloestradiol concentrations include

atorvastatin, competitive inhibitors for sulfation in the gastrointestinal wall (e.g. ascorbic acid
and paracetamol), and substances that inhibit cytochrome P-450 3A4 isoenzymes (e.g.
itraconazole, fluconazole, and indinavir).

Ethinyloestradiol may inactivate certain CYP450 enzymes and may therefore reduce the
metabolism of other drugs. It may also induce hepatic drug conjugation, particularly
glucuronidation. Accordingly, plasma and tissue concentration may either be increased (e.g.
cyclosporin, theophylline, corticosteroids) or decreased (e.g., lamotrigine).

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It is not known if there are interactions between oral contraceptives and isotretinoin or topical
acne agents.

The prescribing information of concomitant medications should be consulted to identify

potential interactions.

Effect on Laboratory Tests

The use of oral contraceptives may influence the results of certain laboratory tests including:

 Biochemical parameters of liver function (including a decrease in bilirubin and alkaline

phosphatase), thyroid function (increased total T3 and T4 due to increased TBG,
decreased free T3 resin uptake), adrenal function (increased plasma cortisol, increased
cortisol binding globulin,), decreased dehydroepiandrosterone sulfate (DHEAS), and
renal function (increased plasma creatinine and creatinine clearance).

 Plasma levels of (carrier) proteins, such as corticosteroid-binding globulin and

lipid/lipoprotein fractions.

 Parameters of carbohydrate metabolism.

 Parameters of coagulation and fibrinolysis.

 Decreased serum folate levels.

ADVERSE EFFECTS
Use of combined oral contraceptives has been associated with increased risk of the following:

Arterial and venous thrombotic and thromboembolic events, including myocardial infarction,
stroke, venous thrombosis, transient ischemic attack and pulmonary embolism

Cervical intraepithelial neoplasia and cervical cancer

Breast cancer diagnosis

Benign hepatic tumours (e.g. focal nodular hyperplasia, hepatic adenomas)

Other adverse reactions, per CIOMS frequency categories, are listed below:

Very Common: 10%

Common: 1% and <10%

Uncommon: 0.1% and <1%

Rare: 0.01% and <0.1%

Very Rare: <0.01%

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Adverse Reactions by Body System

Infections and Infestations

Common Vaginitis, including candidiasis

Neoplasms benign, malignant, and unspecified

Very Rare Hepatic adenomas, hepatocellular carcinomas

Vascular Disorders
Very Rare Aggravation of varicose veins

Gastro-intestinal Disorders
Common Nausea, vomiting, abdominal pain

Uncommon Abdominal cramps, bloating,

Very Rare Pancreatitis; ischaemic colitis

Unknown Inflammatory bowel disease (Crohn’s disease, ulcerative colitis)

Hepato-biliary Disorders
Rare Cholestatic jaundice

Very Rare Gallbladder disease, including gallstones*

Unknown Hepatocellular injury (e.g. hepatitis, hepatic function abnormal)

Metabolism and Nutrition Disorders

Uncommon Changes in appetite (increase or decrease)

Rare Glucose intolerance

Very Rare Exacerbation of porphyria

Psychiatric Disorders
Common Mood changes, including depression, changes in libido

Nervous Disorders
Very Common Headache, including migraines

Common Nervousness, dizziness

Very Rare Exacerbation of chorea

Skin and Subcutaneous Tissue Disorders

Common Acne

Uncommon Rash, chloasma (melasma), which may persist, hirsutism, alopecia

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Rare Erythema nodosum

Very Rare Erythema multiforme

Eye Disorders
Rare Intolerance to contact lenses

Very Rare Optic neuritis**, retinal vascular thrombosis

Reproductive System and Breast Disorders

Very Common Metrorrhagia (breakthrough bleeding/spotting)

Common Breast pain, tenderness, enlargement, secretion, dysmenorrhoea,

change in menstrual flow, change in cervical ectropian and secretion,
amenorrhoea

Renal and Urinary Disorders

Very Rare Haemolytic uraemic syndrome

Immune System Disorders

Rare Anaphylactic/anaphylactoid reactions including very rare cases of
urticaria, angioedema and severe reactions with respiratory and
circulatory symptoms

Very Rare Exacerbation of systemic lupus erythematosus

General Disorders and Administration Site Conditions

Common Fluid retention/oedema

Investigations
Common Changes in weight (increase or decrease)

Uncommon Increase in blood pressure, changes in serum lipid levels, including

hypertriglyceridaemia

Rare Decrease in serum folate levels***

*Oral contraceptives may worsen existing gallbladder disease and may accelerate the
development of this disease in previously asymptomatic women.

**Optic neuritis may lead to partial or complete loss of vision.

***Serum folate levels may be depressed by oral contraceptive therapy.

DOSAGE AND ADMINISTRATION

How to Take LOETTE
Each package of LOETTE contains 21 active pink tablets and 7 white inactive tablets.

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To achieve maximum contraceptive effectiveness, LOETTE must be administered as directed
and at the same time every day, at intervals not exceeding 24 hours. The recommended dose
for the prevention of pregnancy and the treatment of acne is the same.

Where poor compliance is a concern, an oral contraceptive with higher levels of oestrogens
and progestogens should be considered (see CLINICAL TRIALS).

How to Start LOETTE

No Preceding Hormonal contraceptive Use (in the Past Month)
On the first day of the menstrual cycle, i.e. the first day of bleeding, the woman is instructed
to take a pink active tablet corresponding to that day of the week from the pink shaded
section of the LOETTE pack. Thereafter, one pink active tablet is taken daily, following the
arrows marked on the package, until all 21 pink active tablets have been taken. The woman
is then instructed to take one white inactive tablet daily for the next seven days following the
arrows marked on the LOETTE pack. Withdrawal bleeding should usually occur within 2 to
4 days after the last pink active tablet is taken.

LOETTE is effective for contraception from the first day of therapy if the tablets are begun
on Day 1 as described. If starting on days 2-7 of menstrual bleeding, a back-up method of
contraception is recommended for the first 7 days of tablet taking.

The back-up method of contraception must be an additional non-hormonal barrier method

such as condoms or a diaphragm with a spermicide. Back-up contraception does not include
the rhythm or temperature methods.

The next and all subsequent courses of LOETTE will begin on the day after the last package
was completed, even if withdrawal bleeding is still in progress. Each course of LOETTE is
thus begun on the same day of the week as the first course.

Any time a new cycle of LOETTE is started later than the eighth day after discontinuation of
the pink active tablet, the woman should use a back-up method of contraception (other than
the rhythm or temperature methods), until an active pink tablet has been taken for 7
consecutive days.

Missed Withdrawal Bleed

If withdrawal bleeding does not occur and LOETTE has been taken according to directions,
and conditions possibly impairing contraceptive effectiveness (refer to PRECAUTIONS -
Vomiting or Diarrhoea and Interactions with Other Medicines) can be ruled out, it is unlikely
that the woman has conceived. She should be instructed to begin a second course of
LOETTE on the usual day. If bleeding does not occur at the end of this second cycle,
LOETTE should not be taken until diagnostic procedures to exclude the possibility of
pregnancy have been performed.

If the woman has not adhered to the prescribed regimen (missed one or more tablets or started
taking them on a day later than recommended), the probability of pregnancy should be
considered at the time of the first missed period before LOETTE is resumed.

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Changing from another Combined Oral Contraceptive
The woman is advised to take the first pink LOETTE tablet from the pink shaded section,
which corresponds to the day of the week on the day after the last active tablet from her
previous oral contraceptive. However, the woman can also begin LOETTE on any day
during the tablet free or inactive tablet interval of her previous combined oral contraceptive.

During the first LOETTE cycle, a non-hormonal back-up method of contraception (other than
the rhythm or temperature methods) should be used until one active tablet has been taken
daily for 7 consecutive days. When changing to LOETTE a woman should be reminded
about the importance of compliance in order to maximise contraceptive efficacy (see
CLINICAL TRIALS).

If transient spotting or breakthrough bleeding occurs, the woman is instructed to continue the
regimen since such bleeding is usually without significance. If the bleeding is persistent or
prolonged, the woman is advised to consult her physician.

Changing from a Progestogen Only Method (Progestogen Only Tablets, Injection,

Implant)
The woman may switch any day from progestogen-only tablets and should begin LOETTE
the next day. She should start LOETTE on the day of an implant removal or, if using an
injection, on the day the next injection would be due. In all of these situations, the woman
should be advised to use a non-hormonal back-up method of contraception (other than the
rhythm or temperature methods) until one active tablet has been taken daily for 7 consecutive
days.

How to Delay a Withdrawal Bleed

To delay a withdrawal bleed the woman should discard the inactive white tablets from the
current pack and start the next pack on the day following the intake of the last pink tablet
from the current pack. The extension can be carried on for as long as wished until the end of
the second pack, when the white tablets are taken. During the extension the woman may
experience breakthrough bleeding or spotting. Regular intake of LOETTE is then resumed
with the next pack.

Following First Trimester Abortion

The woman may start LOETTE immediately. Additional contraceptive measures are not
needed.

Following Delivery or Second-Trimester Abortion

Since the immediate post-partum period is associated with an increased risk of
thromboembolism, LOETTE should be started no earlier than day 28 after delivery in the
non-lactating mother or after second-trimester abortion. The woman should be advised to
additionally use a back-up method of contraception (other than the rhythm or temperature
methods) until one active tablet has been taken daily 7 consecutive days. However, if
intercourse has already occurred, pregnancy should be excluded before the actual start of
LOETTE use or the woman has to wait for her first menstrual withdrawal bleed (see
PRECAUTIONS - Venous Thrombosis and Thromboembolism and Use in Pregnancy and
Use in Lactation).

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Management of Missed Tablets
Contraceptive efficacy may be reduced if tablets are missed and particularly if the missed
tablets extend the inactive tablet interval. If tablets were missed in the first week of the cycle
and intercourse took place in the week before the tablets were missed, the possibility of a
pregnancy should be considered.

If one active pink is missed, but is less than 12 hours late, it should be taken as soon as it is
remembered. Subsequent tablets should be taken at the usual time.

If one active pink tablet is missed and is more than 12 hours late or if more than one active
tablet is missed contraceptive protection may be reduced. The last missed pink tablet should
be taken as soon as it is remembered, even if this means taking two active pink tablets in one
day. Any earlier missed tablets should be discarded. The woman should then continue to
take tablets at her usual time. In addition, a non-hormonal back-up method of contraception
(other than the rhythm or temperature methods) should be used until one active tablet has
been taken daily for 7 consecutive days.

If the 7 days where back up is required run beyond the last active pink tablet in the current
pack, the next pack must be started on the day following the intake of the last pink tablet in
the current pack. All inactive (white) tablets should be discarded. This prevents an extended
break in the active tablet taking that may increase the risk of escape ovulation. The woman is
unlikely to have a withdrawal bleed until the inactive-tablet interval of the second pack, but
she may experience spotting or breakthrough bleeding on days when active tablets are taken.
If the woman does not have a withdrawal bleed at the end of the second pack, the possibility
of pregnancy must be ruled out before resuming tablet taking.

If the woman misses one or more white inactive tablets, she will still be protected against
pregnancy provided she begins the pink active tablets on the appropriate day.

Vomiting or Diarrhoea
If vomiting or diarrhoea occurs during or shortly after the intake of LOETTE, contraceptive
reliability may be jeopardised. If vomiting or diarrhoea occurs within 3-4 hours after tablet
taking, absorption may not be complete. In such an event, the advice concerning
Management of Missed Tablets is applicable. The woman must take the extra active
tablet(s) needed from a back-up pack.

OVERDOSAGE
Symptoms
Symptoms of oral contraceptive overdosage in adults and children may include nausea,
vomiting breast tenderness, dizziness, abdominal pain, drowsiness/fatigue; withdrawal
bleeding may occur in females. In children, serious ill effects have not been reported
following large doses of oral contraceptives.

Treatment
Treatment of overdose, if necessary, is directed to the symptoms.

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PRESENTATION
One-, two#-, three- and four#-month packs containing 1, 2, 3 and 4 blisters respectively.
Each blister contains 21 pink active tablets, each containing levonorgestrel 100g and
ethinyloestradiol 20g, and 7 white inactive tablets.

Store below 25C.

Protect from light.

NAME AND ADDRESS OF THE SPONSOR

Pfizer Australia Pty Ltd
ABN 50 008 422 348
38-42 Wharf Road
WEST RYDE NSW 2114

TGA Approval Date: 10 November 2004.

Date of most recent amendment: 23 June 2011

® Registered Trademark

# not currently marketed.

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