LOETTE* 21 TABLETS

(levonorgestrel and ethinylestradiol)

DESCRIPTION
LOETTE is a combined oral contraceptive (COC) tablet containing the synthetic progestin,
levonorgestrel, and the synthetic estrogen, ethinylestradiol.
Levonorgestrel is a white, odorless, crystalline powder. It is practically insoluble in water, slightly
soluble in alcohol, acetone, ether, and soluble in chloroform. Chemically, levonorgestrel is (-)-
13ethyl-17-hydroxy-18, 19-dinor-17α-pregn-4-en-20-yn-3-one and has the following structure:

Ethinylestradiol is a white to creamy white, odorless, crystalline powder. It is insoluble in water

and soluble in alcohol, chloroform, ether, vegetable oils, and aqueous solutions of alkali
hydroxides. Chemically, ethinylestradiol is 19-nor-17α-pregn-1,3,5(10)-trien-20-yne-3, 17-diol
and has the following structure:

CLINICAL PHARMACOLOGY
Oral Contraception
The contraceptive effect of the hormonal components contained in LOETTE is based on the
interaction of various factors, the most important of which are the inhibition of ovulation (by
suppression of gonadotropin release) and changes in the cervical mucus (which increase the
difficulty of sperm penetration into the uterus). Additionally, changes in the endometrium reduce
the likehood of implantation.

Acne
Acne treatment with LOETTE is based on estrogen-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-androstanediol glucoronide (a
marker of peripheral 5 a-reductase activity) are also reduced. These biochemical changes
produced by the co-administration of levonorgestrel and ethinyl estradiol are associated with
improvement of acne in otherwise healthy women.

PHARMACOKINETICS
Levonorgestrel is rapidly and completely absorbed from the gastrointestinal tract. It is subject to
minimal first-pass metabolism and is almost completely bioavailable following oral
administration. Levonorgestrel is primarily metabolized by reduction of the A-ring followed by
glucuronidation. The majority of an oral dose of levonorgestrel is eliminated as conjugates of
glucuronide or sufate with considerably smaller portions appearing as free metabolites.
Approximately 43-45% of levonorgestrel is eliminated in the urine and approximately 32% in the
feces.
After a single dose of LOETTE, maximum plasma concentrations (Cmax) of levonorgestrel of 2.8
± 0.9 ng/ml (mean ± SD) are reached at 1.6 ± 0.9 hours. The area under the the curve (AUC 0-¥ is
35.2 ± 12.8 ng hr/ml after a single dose. Following 21 days of LOETTE therapy, steady state
Cmax values of 6.0 ± 2.7 ng/ml are attained at 1.5 ± 0.5 hours after the daily dose. The minimum
plasma concentrations of levonorgestrel at steady state are 1.9 ± 1.0 ng/ml. The AUC 0-24 at
steady state is 68.3 ± 32.5 ng hr/ml. The mean AUC0-? for levonorgestrel after a single dose is
significantly lower than the mean AUC 0-24 at steady state. In addition, sex hormone-binding
globulin (SHGB) levels increased significantly from day 1 (57 ± 18 nmol/l) to day 21 (93 ± 40
nmol/l), induced by the daily administration of ethinylestradiol. Therefore, the non linear kinetics
of levonorgestrel are due to an increase in binding of levonorgestrel to SHBG. The elimination
half-life for levonorgestrel in combination with ethinylestradiol is approximately 36 ± 13 hours at
steady state.
Ethinylestradiol is rapidly and almost completely absorbed from the gastrointestinal tract.
Ethinylestradiol undergoes extensive first-pass metabolism. The mean bioavailability is about
43% with marked interindividual variation. Ethinylestradiol is highly bound to albumin and
induces an increase in the plasma concentration of SHBG. Ethinylestradiol is primarily
metabolized by aromatic hydroxylation, but a wide variety of hydroxylated and methylated
metabolites are formed, and these are present as free metabolites and as conjugates with
glucuronide or sulfate. Conjugated ethinylestradiol is excreted in bile and is subject to
enterohepatic recirculation.
After a single dose of LOETTE, Cmax values of ethinylestradiol of 62 ± 21 pg/ml are reached at
1.5 ± 0.5 hours. The AUC 0-¥ is 653 ± 227 pg hr/ml after a single dose.
Following at least 6 daily doses of LOETTE treatment, steady state Cmax values of
ethinylestradiol are 77 ± 30 pg/ml and reached at 1.3 ± 0.7 hours.
The AUC 0-24 at steady state is 604 ± 231 pg hr/ml. Following 21 days of treatment, steady state
Cmax values of ethinylestradiol of 82 ± 33 pg/ml are reached at 1.4 ± 0.6 hours after the daily
dose. The minimum plasma concentrations of ethinylestradiol at steady state are 10.5 ± 5.1
pg/ml. The AUC 0-24 at the end of 21 days of treatment is 776 ± 308 pg hr/ml. The elimination half-
life of ethinylestrdiol in combination with levonorgestrel is 18 ± 4.7 hours at steady state.

CLINICAL STUDIES
Oral Contraception
An open-label multicenter phase III clinical study was conducted in 1,447 women receiving
LOETTE. Of 7,720 cycles of exposure evaluable 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. This rate includes patients who did not take the drug correctly. Cycle
control was also evaluated by analyzing cycle characteristics such as duration and intensity of
withdrawal bleeding and the incidence of breakthrough bleeding and amenorrhea. A total of
7,508 cycles were valid for cycle control analysis; the overall incidence of intermenstrual
bleeding was low . Breakthrough bleeding alone and spotting alone occurred during 4.3% and
12.1% of cycles, respectively. Breakthrough bleeding and spotting occurred in 11.0% of the
cycles, while breakthrough bleeding and/or spotting occurred in 27.3% of the cycles. Overall,
2.6% of cycles were amenorrheic. The length of withdrawal bleeding was 3 to 7 days in 86% of
cycles, 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.
Acne
Two (2) randomised, double blind, placebo-controlled, 6-cycle, multicenter, phase III clinical
studies were done to evaluate the efficacy and safety of levonorgestrel/ethinylestradiol (LNG/EE)
100µg/20µg for the treatment of moderate acne. Study 1 was conducted at 12 sites in the United
States and at 1 site 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
postules) 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).

NON-CONTRACEPTIVE HEALTH BENEFITS

The following noncontraceptive health benefits related to the use of combination oral
contraceptives are supported by epidemiological studies which largely utilized oral contraceptive
formulations containing doses exceeding 0.035 mg of ethinylestradiol or 0.05 mg of mestranol.

1. Effects on menses
Increased menstrual cycle regularity.
Decreased blood loss and decreased incidence of iron deficiency anemia.
Decreased incidence of dysmenorrhea.

2. Effects related to inhibition of ovulation

Decreased incidence of ectopic pregnancies.
Decreased incidence of functional ovarian cysts.

3. Effects from long-term use

Decreased incidence of fibroadenomas and fibrocystic disease of the breast.
Decreased incidence of acute pelvic inflammatory disease.
Decreased incidence of endometrial cancer.
Decreased incidence of ovarian cancer.

INDICATION

1. LOETTE is indicated for the prevention of pregnancy.

2. LOETTE is also indicated for the treatment of moderate acne vulgaris not
controlled by conventional therapy (e.g. topical preparations and oral
antibiotics) in postmenarchal, premenopausal women ≥ 14 years of age who
accept contraception.

CONTRAINDICATIONS
LOETTE is contraindicated in patients with:
 1. Current or previous history of deep vein thrombosis, thromboembolic disorders;
thrombogenic valvulopathies or thrombogenic rhythm disorders. Hereditary or
acquired predisposition for venous or arterial thrombosis.
2. Active liver diseases, as long as liver function has not returned to normal,
current or previous history of liver tumors.
3. Current or previous history of kown or suspected sex steroid-dependent
neoplasias (eg, breast or endometrial carcinoma). Diabetes with vascular
involvement.
4. Undignosed vaginal bleeding.
5. Known or suspected pregnancy.
6. Hypersensitivity to any of the components of LOETTE.
7. Cerebrovascular or coronary artery disease.
8. Uncontrolled hypertension.
9. Headache with focal neurological symptoms such as aura.

REASONS FOR THE IMMEDIATE DISCONTINUATION OF LOETTE

1. Occurrence for the first time of migrainous headaches or the more frequent
occurrence of unusually severe headaches.
2. Acute disturbances of vision, hearing, or speech.
3. First symptoms of thrombophlebitis or thromboembolism (eg. unusual pain in or
swelling of the legs, stabbing pain on breathing, or coughing for no apparent
reason).
4. Feeling of pain or tightness in the chest.
5. During prolonged periods of immobilization.
6. Development of jaundice (cholestasis), hepatitis, or generalized pruritus.
7. Increase in epileptic seizures.
8. Significant rise in blood pressure.
9. Onset of severe clinical depression.
10. Severe upper abdominal pain or liver enlargement.
11. Pregnancy.

WARNINGS
Cigarette smoking increases the risk of serious cardiovascular adverse reactions from
COC use. This risk increases with age and with the extent of smoking and is quite
marked in women over 35 years of age. Women who use COCs should be strongly
advised not to smoke. For any particular estrogen/progestin combination, the dosage
regimen prescribed should be one which contains the least amount of estrogen and
progestin that is compatible with a low failure rate and the needs of the individual
patient. New acceptors of COCs should be started on preparations containing less
than 50µg of estrogen.

1. Venous and arterial thrombosis and thromboembolism

Use of COCs is associated with an increased risk of venous and arterial
thrombotic and thromboembolic events.
Full recovery from these disorders does not always occur, and it should be
realized that in a few cases they are fatal. The physician should therefore be
alert to the earliest manifestations of these disorders. Should any of these occur
or be suspected, oral contraceptives should be discontinued immediately.
Venous thrombosis and thromboembolism
Use of COCs increases the risk of venous thrombotic and thromboembolic
events. The use of any COC carries an increased risk of venous thrombotic and
thromboembolic events compared with no use. The excess risk is highest
during the first year a woman ever uses a combined oral contraceptive. This
increased risk is less than the risk of venous thrombotic and thromboembolic
events associated with pregnancy which is estimated as 60 cases per 100,000
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
thromboembolism are:
- obesity
- surgery or trauma with increased risk of thrombosis
- recent delivery or second-trimester abortion
- prolonged immobilization
- increasing age

If feasible, COCs should be discontinued:

- for four weeks prior to and for two weeks after elective surgery with increased
risk of thrombosis, and
- during prolonged immobilization.
Since the immediate post-partum period is associated with an increased risk of
thromboembolism, COCs should be started no earlier than day 28 after delivery
or second-trimester abortion.

Arterial thrombosis and thromboembolism

The use of COCs increases the risk of arterial thrombotic and thromboembolic
events.
Reported events include myocardial infarction and cerebrovascular events
(ischemic and hemorrhagic stroke, transient ischemic attack).
The risk of arterial thrombotic and thromboembolic events is furthr increased in
women with underlying risk factors.
Caution must be exercised when prescribing COCs for women with risk factors
for arterial thrombotic and thromboembolic events.
Examples of risk factors for arterial thrombotic and thromboembolic events are:
- smoking
- hypertension
- hyperlipidemias
- obesity
- increasing age
- diabetes mellitus
COC users with migraine (particularly migraine with aura) may be at increased
risk of stroke. The onset or exacerbation of migraine or development of
headache with a new pattern that is recurrent, persistent or severe requires
discontinuation of COCs and evaluation of the cause.
THE RISK OF ARTERIAL THROMBOSES (eg, STROKE, MYOCARDIAL
INFARCTION) ASSOCIATED WITH COMBINED ORAL CONTRACEPTIVES
INCREASES WITH AGE AND WITH HEAVY SMOKING. FOR THIS REASON,
 WOMEN OVER 35 YEARS OF AGE WHO USE OARAL CONTRACEPTIVE
SHOULD BE STRONGLY ADVISED NOT TO SMOKE.

2. Carcinoma of the Breasts and Cervix

Some studies suggest that COC use may be associated with an increase in the
risk of cervical intraepithelial neoplasia or invasive cervical cancer in some
populations of women. However, there continues to be controversy about the
extent to which such findings may be due to differences in sexual behavior and
other factors. In cases of undiagnosed abnormal genital bleeding, adequate
diagnostic measures are indicated. A meta-analysis from 54 epidemiological
studies reported that there is a slightly increased relative risk (RR=1.24) of
having breast cancer diagnosed in women who are using COCs compared to
never-users. The increased risk gradually disappears during the course of the
10 years after cessation of COC use. These studies do not provide evidence for
causation. The observed pattern of increased risk of breast cancer diagnosis
may be due to earlier detection of breast cancer in COC users (due to more
regular clinical monitoring), the biological effects of COCs, 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 COC 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.

3. Hepatic Neoplasia / Liver Disease

In very rare cases, hepatic adenomas, and in extremely rare cases,
hepatocellular carcinoma may be associatedwith COC use. The risk appears to
increase with duration of COC use. Rupture of hepatic adenomas may cause
death through intra-abdominal hemorrhage. Women with a history of COC-
related cholestasis or women with cholestasis during pregnancy are more likely
to have this condition with COC use. If these patients receive a COC they
should be carefully monitored and, if the condition recurs, the COC should be
discontinued.

4. Gallbladder Disease
Ealier studies reported an increased risk of surgically confirmed gallbladder
disease in users of estrogens and oral contraceptives. However, more recent
studies have shown that the relative risk of developing gallbladder disease may
be minimal.

5. Lipid and Carbohydarate Metabolic Effects

Changes in serum triglyceride, cholesterol, and lipoprotein levels have been
reported in users of oral contraceptives. Oral contraceptives may also cause a
decrease in glucose tolerance.

6. Elevated Blood Pressure

An increase in blood pressure has been reported in women taking COCs.
Elevated blood pressure usually returns to normal after discontinuing oral
contraceptives.
In women with hypertension, a history of hypertension or hypertension-related
 diseases, another method of contraception may be preferable. If COCs are used
in such cases, close monitoring is recommended and, if a significant increase in
blood pressure occurs, COCs should be discontinued. COC use is
contraindicated in women with uncontrolled hypertension.

7. Bleeding Irreguraties
Breakthrough bleeding and spotting are sometimes encountered primarily
during the first three months of use, and usually cease spontaneously. The
woman, therefore, should continue to take LOETTE, even if irregular bleeding
occurs. Should breakthrough bleeding persist or recur, appropriate diagnostic
measures to exclude an organic cause are indicated and may include curettage.
The same applies in the case of spotting which occurs at irregular intervals in
several consecutive cycles or which occurs for the first time after long-term use
of LOETTE.
After discontinuation of oral contraceptives, some women may experience
amenorrhea or oligomenorrhea, especially when these conditions existed prior
to use.
Women should be informed of these possibility.

8. Use During Pregnancy

Pregnancy must be excluded before starting LOETTE. If pregnancy occurs
during use of LOETTE, the preparation must be withdrawn immediately.
Extensive epidemiology studies have revealed no increased risk of birth defects
in children born to women who used COCs prior to prergnancy. Studies do not
suggest a teratogenic effect, when taken inadvertently during early pregnancy
(See also Contraindications).
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.

9. Use during Lactation

Small amounts of contraceptive steroids and/or metabolites have been
identified in the milk of nursing mothers and a few adverse effects on the child
have been reported, including jaundice and breast enlargement. Lactation may
be influenced by COCs as they may reduce the quantity and change the
composition of breast milk.
The use of COCs is generally not recommended until the nursing mother has
completely weaned her child.

10. Ocular lesions

With use COCs, there have been reports of retinal vascular thrombosis, which
may lead to partial or complete loss of vision. If there are signs or symptoms
such as visual changes, onset of proptosis or diplopia, or retinal vascular
lesions, the COC should be discontinued and the cause immediately evaluated.

PRECAUTIONS

1. A complete personal and family medical history and physical examination,

including blood pressure, should be taken prior to the initation of COC use.
Such medical examination should be repeated periodically during the use of
 COCs.

2. The following conditions require strict medical supervision during the use of oral
contraceptives. Deterioration of some of these conditions may indicate that the
oral contraceptive should be discontinued: diabetes mellitus or a tendency
towards diabetes mellitus, hypertension, varicose veins, a history of phlebitis,
otosclerosis, multiple sclerosis, migraine, epilepsy, porphyria, tetany, chorea,
renal dysfunction, systemic lupus erythematosus, obesity, family history of
breast cancer and patient history of breast nodules, history of clinical
depression, and conditions aggravated by fluid retention.
Glucose intolerance has been reported in COC users, Women with impaired
glucose tolerance or diabetes mellitus who use diabetes mellitus who use
COCs should be carefully monitored.
A small proportion of women will have adverse lipid changes while taking OCs.
Nonhormonal contraception should be considered in women with uncontrolled
dyslipidemias.
Persistent hypertriglyceridemia may occur in a small proportion of COC users.
Elevations of plasma triglycerides which may lead to pancreatic and other
complications.
Women who are being treated for hyperlipidemias should be followed closely if
they elect to use COCs.

3. 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.

4. Individual cases of intolerance to contact lenses have been reported in users of

oral contraceptives. Contact lens wearers who develop changes in lens
tolerance should be assessed by an ophthalmologist.

5. Occasionally, withdrawal bleeding may not occur during the day 7-day tablet-
free interval. If LOETTE has been taken according to directions, it is unlikely that
the patient has conceived. She should be instructed to begin the next pack on
the usual day. If bleeding does not occur at the end of the second pack, tablet-
taking should be discontinued and a nonhormonal back-up method of
contraception should be used until the possibity of pregnancy is excluded.
Breakthrough bleeding/spotting may occur in women taking COCs, especially
during the first three months of use. If this bleeding persists of recurs,
nonhormonal causes should be considered and adequate diagnostic measures
may be indicated. If pathology has been excluded, continued use of the COC or
a change to another formulation may solve the problem.
Some women may encounter post-pill amenorrhea (possibly with anovulation)
or oligomenorrhea, especially when such a condition was preexistent.

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

7. Vomiting or diarrhea may reduce the efficacy of oral contraceptives. During

these gastrointestinal disturbances, tablet taking should be continued in order to
 avoid premature withdrawal bleeding. Also, additional nonhormonal methods of
contraception (with the exception of the rhythm or temperature methods) should
be used for the duration of the gastrointestinal disturbances and for 7 days
following the upset. If the 7 days run beyond the end of the pack, the tablet-free
interval is disregarded, and a new pack is started on the day following the intake
of the last tablet in the previous pack. The user is unlikely to have a withdrawal
bleed until the end of the second pack, but she may experience spotting or
breakthrough bleeding on tablet-taking days. If the user 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 gastrointestinal
disturbance is protracted, other methods of contraception should be considered.

8. In women receiving long-term therapy with hepatic enzyme inducers, another

method of contraception should be advised (see DRUG INTERACTION).
Women receiving short courses of therapy with hepatic enzyme inducers or
certain broad spectrum broad spectrum antibiotics should use additional
nonhormonal methods of contraception (with the exception of the rhythm or
temperature methods) in addition to regular intake of LOETTE during the time of
concomitant administration of interacting drugs (see DRUG INTERACTION).
The additional contraception should continue during the intake of the concurrent
medication and for 7 days after its discontinuation. If these 7 days run beyond
the end of the pack, the next pack should be started without a break. In this
situation, a withdrawal bleed should not be expected until the end of the second
pack. If the woman does not experience a withdrawal bleed at the end of the
second pack, the possibility of pregnancy must be ruled out before resuming
with the next pack.
With rifampin, additional contraceptive precautions should be continued for 4
weeks after the drug’s discontinuation, even if only a short course was
administered.

9. LOETTE (like all oral contraceptives) does not protect against HIV infections
(AIDS) and other sexually transmitted diseases.

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

ADVERSE REACTIONS

SYSTEM ORGAN CLASS ADVERSE REACTION

Infection and infestations

Common Vaginitis, including candidiasis

Neoplasms benign, malignant and unspecified

 Very rare Hepatic adenomas; hepatocellular carcinomas

Immune system disorders

Anaphylactic/anaphylactoid reactions, including

very rare cases of urticaria, angioedema, and
Rare
severe reactions with respiratory and circulatory
symptoms

Very Rare Exacerbation of systemic lupus erythematosus

Metabolism and nutrition disorders

Uncommom Changes in appetite (increase or decrease)

Rare Glucose intolerance

Very are Exacerbation of porphyria

Psychiatric disorders

Mood changes, including depression; changes

Common
in libido

Nervous system disorders

Very common Headache, including migraines

Common Nervousness; dizziness

Very Rare Exacerbation of chorea

Eye disorders

Rare Intolerance to contact lenses

Very Rare Optic neuritis*; retinal vascular thrombosis

Vascular disorders

Very Rare Aggravation of varicose veins

Gastrointestinal disorders

Common Nausea; vomiting; abdominal pain

Uncommon Abdominal cramps; bloating

Very Rare Pancreatitis;

Hepato-biliary disorders

Rare Cholestatic jaundice

Very Rare Gallbladder disease, including gallstones**

Skin and subcutaneous tissue disorders

Common Acne

Rash; chloasma (melasma), which may persist;

Uncommon
hirsutism; alopecia

Rare Erythema nodosum

Very Rare Erythema multiforme

Renal and urinary disorders

Very Rare Hemolytic uremic syndrome

Reproductive system and breast disorders

Very common Breakthrough bleeding/spotting

Breast pain, tenderness, enlargement,

secretion; dysmenorrhea; change in menstrual
Common
flow; change in cervical ectropion and secretion;
amenorrhea

General disorders and administration site conditions

Common Fluid retention/edema

Investigations

Common Changes in weight (increase or decrease)

Increase in blood pressure; changes in serum

Uncommon
lipid levels, including hypertriglyceridemia

Rare Decrease in serum folate levels***

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

** COCs may worsen existing gallbladder disease and may accelerate the
development of this disease in previously asymptomatic women.
*** Serum folate levels may be depressed by COC therapy. This may be of clinical
significance if the woman becomes pregnant shortly after discontinuing COCs.

Refer to WARNINGS and PRECAUTIONS for additional information.

DRUG INTERACTIONS
Interactions between ethynil estradiol (EE) other substances may lead to decreased
or increased serum EE concentrations, respectively.
Decreased EE serum concentrations may cause an increased incidence of
breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy
of the COC.
During concomitant use of EE-containing products and substances that may lead to
decreased EE serum concentrations , it is recommended that a nonhormonal back-up
method of birth control (such as condoms and spermicide) be used in addition to the
regular intake of LOETTE. In the case of prolonged use of such substance COCs
should not be considered the primary contraceptive.
After discontinuation of substances that may lead to decreased EE serum
concentrations , use of a nonhormonal back-up method is recommended for at least 7
days. Longer use of a back-up method is a advisable after discontinuation of
substances that have lead to induction of hepatic microsomal enzymes, resulting in
decreased EE serum concentrations. 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 decrease serum EE concentrations:

Any substance that reduces gastrointestinal transit time, and therefore, EE

absorption
Substances that induce hepatic microsomal enzymes, such as rifampicin,
rifabutin, barbiturates, primidone, phenylbutazone phenytoin, dexamethasone,
griseofulvin, topiramate, someprotease inhibitors, modafinil
Hypericum perforatum, also known as St. John’s wort, and ritonavir (possibly by
induction of hepatic microsomal enzymes)
Certain antibiotics (eg, penicillins, tetracyclines), by a decrease of enterohepatic
circulation of estrogens

Examples of substances that may increase serum EE concentrations:

Atorvastatin
Competitive inhibitors for sulfation in the gastrointestinal wall, such as ascorbic
acid (vitamin C) and paracetamol
Substances that inhibit cytochrome P450 3A4 isoenzymes such as indinavir,
fluconazole, and troleandomycin

Troleandomycin may increase the risk of intrahepatic cholestasis during

coadministration with COCs.
EE may interfere with the metabolism of other drugs by inhibiting hepatic microsomal
enzymes, or by inducing hepatic drug conjugation, particularly glucuronidation.
Accordingly, plasma and tissue concentrations may either be increased (eg,
cyclosporine, theophylline, corticosteroids) or decreased (e.g. lamotrigine).
The prescribing information of concomitant medications should be consulted to
identify potential interactions.
The requirements for oral antidiabetic agents and insulin may be altered as a result of
an effect on glucose tolerance.

DRUG/LABORATORY TEST INTERACTIONS

The use of oral contraceptive may influence the results of certain laboratory teasts
including biochemical parameters of liver, thyroid, adrenal, and renal function, plasma
levels of binding proteins and lipid/lipoprotein fractions, parameters of carbohydrate
metabolism, and parameters of coagulation and fibrinolysis.
Estrogen-containing preparations affect the following blood components and
endocrine and liver-function tests:

1. Increased prothrombin and Factors VII, VIII, IX, and X; decreased antithrombin
3; increased noradrenaline-induced platelet aggregabillity;
2. Increased thyroid-binding globulin (TBG) leading to increased circulating total-
thyroid hormones, as measured by protein-bound iodine (PBI), T4 by column, or
T4 by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the
elevated TBG; free T4 concentration is unaltered;
3. Decreased pregnanediol excretion;
4. Reduced response to metyrapone test;
5. Increased sulphobromophtalein retention;
6. Oral contraceptives may produce false positive results when neutrophil alkaline
phosphatese activity is evaluated for the early diagnosis of pregnancy.

DOSAGE & ADMINISTRATION

The recommended dose for the prevention of pregnancy and the treatment of acne is
the same.
To achieve maximum contraceptive effectiveness, LOETTE must be administered as
directed and at and at the same time every day, preferably after the evening meal or at
bedtime.

1. First Cycle in women with no preceding hormonal contraceptive use

During the first cycle of administration, the woman is instructed to take one
LOETTE tablet daily for 21 consecutive days, beginning on Day 1 of her
menstrual cycle (i.e., the first day of menstrual bleeding). This is followed by a
tablet-free interval of 7 days during which time a withdrawal bleed occurs.
LOETTE is effective from the first day of therapy if the tablets are begun on Day
1 as described.
Starting on days 2-7 is allowed, but for the first 7 days of tablet-taking during the
first cycle a nonhormonal back-up method of birth control (with the exception of
the rhythm and temperature methods) is recommended.

2. Subsequent Cycle
Tablet taking from the next pack of LOETTE is continued after the 7-day tablet-
free interval, that is on the eighth day, even if withdrawal bleeding is still in
progress.
Each 21-day course of LOETTE is thus begun on the same day of the week as
the first course and follows the same schedule of 21 days on and 7 days off.
Any time a new cycle of LOETTE is started later than the eighth day after
discontinuance, the woman should use additional nonhormonal methods of
contraception (with the exception of the rhythm or temperature methods), until a
tablet has been taken daily for 7 consecutive days.

3. Changing from Another Combined Oral Contraceptive to LOETTE

The woman should start LOETTE preferably on the day after the last active
tablet of her previous COC, but at the latest, on the day following the usual
tablet-free or inactive tablet interval of her previous combined oral contraceptive.
When changing to Loette a woman should be reminded about the importance of
compliance in order to maximise contraceptive efficacy. 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.

4. Changing from a progestin-only method (progestin-only pill, injection, implant)

The woman may switch any day from the progestin-only pill and should begin
LOETTE the next day. She should start LOETTE on the day of an implant
removal or, if using an injection, the day the next injection would be due. In all of
these situations, the woman should be advised to use a nonhormonal back-up
method for the first 7 days of tablet taking.

5. Missed Tablets Contraceptive reliability may be reduced if active tablets are

missed and particularly if the missed tablets extend the tablet-free interval.
If one active tablet is missed, but is less than 12 hours late, it should be
taken as soon as it is remembered. Further tablets should be taken at the
usual time.
If one active 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 tablet should be taken as soon as it is remembered, even if
this means taking two tablets in one day.
Any earlier missed tablets are left in the pack, and the remaining tablets
taken as usual. Additionally, nonhormonal methods of contraception (with
the exception of the rhythm or temperature methods) should be used for
the next 7 days. If these 7 days run beyond the end of the pack, the tablet-
free interval is disregarded, and a new pack is started on the day following
the intake of the last tablet in the previous pack. This prevents an
extended break in tablet-taking which may increase the risk of escape
ovulation. The user is unlike to have a withdrawal bleed until the end of
the second pack, but she may experience spotting or breakthrough
bleeding on tablet-taking days. If the user 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.

6. Postpartum or Postabortum Use

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, COCs
should be started no earlier than day 28 after delivery in the nonlactating mother
or after second-trimester abortion. The woman should be advised to use a
nonhormonal back-up method for the first 7 days of tablet-taking. However, if
intercourse has already occurred, pregnancy should be excluded before the
actual start of COC use of the woman must wait for her first menstrual period.
When oral contraceptive are administered in the immediate
postpartum/postabortum period, the increased risk of thromboembolic disease
must be considered.

OVERDOSAGE
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. Thereis no specific antidote and further
treatment of overdose, if necessary, is directed to the symptoms.

HOW SUPPLIED
LOETTE is supplied in blisters of 21 tablets.

PRODUCT COMPOSITION
Each tablet contains :
Levonorgestrel 100 mcg; ethinylestradiol 20 mcg.

STORAGE CONDITIONS
Store below 250 C.

KEEP OUT REACH OF CHILDREN

HARUS DENGAN RESEP DOKTER

Reg No. DKI…………..

* Trademark
Manufactured by: Wyeth PharmaceuticalInc., Guayama, Puerto Rico
Packaged by: Wyeth Medica Ireland
Newbridge, Co Kildare, Ireland

Imported by :
PT Wyeth Indonesia
Jakarta - Indonesia