CERAZETTE

Desogestrel, a prodrug, is a third generation progestogen and hence, a member of the gonane family which was largely used in Europe before being approved in the US and Canada.

It was firstly generated from a study that showed that 11-beta and 11-alkylidene substituent in nortestosterone can enhance the biological activity.

Desogestrel is now produced semi-synthetically from naturally occurred plant steroids.

In the

US, desogestrel is found only in combination with ethinyl estradiol.

The first approved drug containing desogestrel was developed by Organon USA Inc in and FDA approved in 1992.

Oral desogestrel is used in combination with ethinylestradiol as a contraceptive agent for the prevention of pregnancy.

Desogestrel is part of the combined oral contraceptives that contain a mix of estrogen and progestin which inhibit ovulation.

The effects of desogestrel are divided on reproductive including modification of luteinizing hormone and follicle stimulating hormone, declines on the onset of menstruation, and increases the viscosity of the vaginal fluid; and on metabolic that includes increase insulin secretion and resistance, increased lipase activity, and increased fat deposition.

The effect of desogestrel on the lipids has been studied extensively and the results are contradictory.

Desogestrel main therapeutic effect due to its mechanism of action is known to be related to the inhibition of the ovulation in 97% of the cycles.

This effect was proven in clinical trials in non-breastfeeding women from which the Pearl failure rate was reported to be of 0.17 per 100 women-years.

This result indicated that desogestrel is more efficient when compared to other progestogen-only pills.

All the therapeutic effect is produced by a transformation of the endometrium followed by an inhibition of the ovulation due to the suppression of other hormones.

Desogestrel has been widely confirmed to be related to an increase in the risk of venous thromboembolism due to the driven increased in blood coagulation factors, leading to a pronounced prothrombotic state.

However, the effects of desogestrel are known to not impact significantly the level of total cholesterol remaining in the range of change of 10% which allows it to be a molecule that presents a favorable lipid profile.

After oral administration, desogestrel is rapidly absorbed and it reaches a peak concentration of 2 ng/ml after 1.5 hours.

The bioavailability of desogestrel is reported to be in the range of 60-80% and the reported AUC is of 3000 ng.h/ml.

Almost all the administered dose is modified to the active metabolite, etonogestrel.

The apparent volume of distribution of desogestrel is of 1.5 L/kg.

Desogestrel is rapidly metabolized in the intestinal mucosa and by first-pass hepatic metabolism to form the major metabolite of desogestrel is etonogestrel which is the biologically active metabolite. 2, 3 This modification is described by the hydroxylation in C3 of the desogestrel molecule.

Later, etonogestrel is metabolized following the normal pathways of steroid metabolism.

On the other hand, due to the 11-methylene side chain, desogestrel cannot be metabolized to other progestins.

Hover over products below to view reaction partners Desogestrel 2-hydroxydesogestrel 3alpha-Hydroxydesogestrel Etonogestrel 3beta-Hydroxydesogestrel 6-alpha-hydroxydesogestrel 6-beta-hydroxydesogestrel 16-hydroxy-desogestrel Desogestrel-17-sulfate 15-alpha-hydroxydesogestrel Glucuronic acid 3-alpha-OH-desogestrel 3-beta-OH-desogestrel.

The elimination of desogestrel is found to be mainly renal corresponding to about 6 times the dose eliminated in the bile.

The elimination of desogestrel is only done as the metabolites and not as the unchanged drug and about 85% of the administered dose can be excreted as metabolites after 6-8 days.

The terminal half-life of desogestrel is determined to be of 30 hours.

The metabolic clearance rate of desogestrel is reported to be of about 2 ml/min/kg.

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Administration of large quantities of desogestrel has been shown to produce strong hormonal effects but to lack chronic toxicity.

The reported

LD50 in rats after oral administration of desogestrel is higher than 2000 mg/kg.

Overdose hasn't reported serious effects but only symptoms of nausea and withdrawal of bleeding.

Most reports haven't linked the administration of desogestrel with the increased risk of breast cancer.

The increased risk has been reported to be related to the duration of use.

However, several reports indicate a desogestrel-driven increased risk in cervical intra-epithelial neoplasia but the results are still not conclusive.

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use.

This risk increases with age and with heavy 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.

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors.

The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.

The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with formulations of higher doses of estrogens and progestogens than those in common use today.

The effect of long-term use of the oral contraceptives with formulations of lower doses of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiologic studies reported are of two types: retrospective or case control studies and prospective or cohort studies.

Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among non-users.

The relative risk does not provide information on the actual clinical occurrence of a disease.

Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and non-users.

The attributable risk does provide information about the actual occurrence of a disease in the population (Adapted from refs. 2 and with the author’s permission).

For further information, the reader is referred to a text on epidemiologic methods. 1.

Thromboembolic disorders and other vascular problems a.

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established.

Case control studies have found the relative risk of users compared to non-users to be for the first episode of superficial venous thromboembolic disease, 4 to for deep vein thrombosis or pulmonary embolism, and 1.5 to for women with predisposing conditions for venous thromboembolic disease (2, 3, 19 to 24).

Cohort studies have shown the relative risk to be somewhat lower, about for new cases and about 4.5 for new cases requiring hospitalization.

The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.

Several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives (102 to 104).

In general, these studies indicate an approximate two-fold increased risk, which corresponds to an additional to 2 cases of venous thromboembolism per 10,000 women-years of use.

However, data from additional studies have not shown this two-fold increase in risk.

A two.

• to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of 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, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization.

Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast-feed. b.

Myocardial infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use.

This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes.

The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six (4 to 10).

The risk is very low in women under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases.

Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, over the age of and non-smokers over the age of 40 ( Table 3) among women who use oral contraceptives.

TABLE 3: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS, AND ORAL CONTRACEPTIVE USE Adapted from P.M. Layde and V. Beral, ref. #12.

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.

In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (14 to 18).

Oral contraceptives have been shown to increase blood pressure among users.

Similar effects on risk factors have been associated with an increased risk of heart disease.

Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. c.

Cerebrovascular diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke.

Hypertension was found to be a risk factor for both users and non-users, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes (27 to 29).

In a large study, the relative risk of thrombotic strokes has been shown to range from for normotensive users to for users with severe hypertension.

The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.

The attributable risk is also greater in older women. d.

Dose-related risk of vascular disease from oral contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease (31 to 33).

A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (14 to 16).

A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease.

Because estrogens increase

HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptives.

The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics.

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

New acceptors of oral contraceptive agents should be started on preparations containing 0.035 mg or less of estrogen. e.

Persistence of risk of vascular disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives.

In a study in the United

States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women to 49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.

In another study in Great

Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.

However, both studies were performed with oral contraceptive formulations containing 50 micrograms or more of estrogen. 2.

Estimates of mortality from contraceptive use

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 4).

These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure.

Each method of contraception has its specific benefits and risks.

The study concluded that with the exception of oral contraceptive users and older who smoke and and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth.

The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s.

• but not reported until 1983.

However, current clinical practice involves the use of lower estrogen formulations combined with careful consideration of risk factors.

Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989.

Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

Therefore, the Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks.

Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.

TABLE 4: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NON-STERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44 No fertility control methods 7 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker † 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker† 2.2 3.4 6.6 13.5 51.1 117.2 IUD† 0.8 0.8 1 1 1.4 1.4 Condom 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence 2.5 1.6 1.6 1.7 2.9 3.6 Adapted from H.W. Ory, ref. #35. *Deaths are birth related †Deaths are method related 3.

Volnea™ is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive.

Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk.

Studies do not show an association between ever (current.

• Thrombophlebitis or thromboembolic disorders.

• A past history of deep vein thrombophlebitis or thromboembolic disorders.

• Cerebral vascular or coronary artery disease.

• Current diagnosis of, or history of, breast cancer, which may be hormone sensitive.

• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia.

• Undiagnosed abnormal genital bleeding.

• Cholestatic jaundice of pregnancy or jaundice with prior pill use.

• Hepatic adenomas or carcinomas.

• Known or suspected pregnancy.

• Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations See Warnings, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT.

To achieve maximum contraceptive effectiveness, Volnea™ (desogestrel and ethinyl estradiol and ethinyl estradiol) tablets must be taken exactly as directed and at intervals not exceeding 24 hours Volnea ™ may be initiated using either a Sunday start or a Day 1 start.

Each blister card is preprinted with the days of the week, starting with Sunday, to facilitate a Sunday start regimen.

Six different “day label strips” are provided with each blister card in order to accommodate a Day 1 start regimen.

In this case, the patient should place the self-adhesive “day label strip” that corresponds to her starting day over the preprinted days.

The possibility of ovulation and conception prior to initiation of use of Volnea ™ should be considered.

The use of

Volnea™ for contraception may be initiated 4 weeks postpartum in women who elect not to breast-feed.

When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered See CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS for Nursing Mothers.

If the patient starts on

Volnea™ postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a white tablet has been taken daily for 7 days.

SUNDAY START When initiating a

Sunday start regimen, another method of contraception should be used until after the first 7 consecutive days of administration.

Using a

Sunday start, tablets are taken daily without interruption as follows: The first white tablet should be taken on the first Sunday after menstruation begins (if menstruation begins on Sunday, the first white tablet is taken on that day).

One white tablet is taken daily for 21 days, followed by 1 green (inert) tablet daily for 2 days and 1 yellow (active) tablet daily for 5 days.

For all subsequent cycles, the patient then begins a new 28-tablet regimen on the next day (Sunday) after taking the last yellow tablet. [If switching from a Sunday Start oral contraceptive, the first Volnea™ (desogestrel/ethinyl estradiol and ethinyl estradiol) tablet should be taken on the second Sunday after the last tablet of a 21 day regimen or should be taken on the first Sunday after the last inactive tablet of a 28 day regimen.

If a patient misses 1 white tablet, she should take the missed tablet as soon as she remembers.

If the patient misses 2 consecutive white tablets in Week 1 or Week 2, the patient should take 2 tablets the day she remembers and 2 tablets the next day; thereafter, the patient should resume taking 1 tablet daily until she finishes the cycle pack.

The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills.

If the patient misses 2 consecutive white tablets in the third week or misses 3 or more white tablets in a row at any time during the cycle, the patient should keep taking 1 white tablet daily until the next Sunday.

On Sunday the patient should throw out the rest of that cycle pack and start a new cycle pack that same day. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills.

DAY 1 START Counting the first day of menstruation as “Day 1”, tablets are taken without interruption as follows: One white tablet daily for 21 days, one green (inert) tablet daily for 2 days followed by 1 yellow (ethinyl estradiol) tablet daily for 5 days.

For all subsequent cycles, the patient then begins a new 28-tablet regimen on the next day after taking the last yellow tablet. [If switching directly from another oral contraceptive, the first white tablet should be taken on the first day of menstruation which begins after the last ACTIVE tablet of the previous product.

If the patient misses 2 consecutive white tablets in the third week or if the patient misses 3 or more white tablets in a row at any time during the cycle, the patient should throw out the rest of that cycle pack and start a new cycle pack that same day. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills.

Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives.

In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, non-functional causes should be borne in mind.

In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy.

If both pregnancy and pathology have been excluded, time or a change to another preparation may solve the problem.

Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease.

Use of oral contraceptives in the event of a missed menstrual period: 1.

If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and oral contraceptive use should be discontinued until pregnancy is ruled out. 2.

If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use.

Volnea™ (desogestrel and ethinyl estradiol tablets, USP and ethinyl estradiol tablets, USP) contains 21 round white tablets, 2 round green tablets and 5 round yellow tablets in a blister card within a unit carton, as follows: Each white tablet (debossed with “ SZ ” on one side and “ D1 ” on the other side) contains 0.15 mg desogestrel and 0.02 mg ethinyl estradiol.

Each yellow tablet (debossed with “ SZ ” on one side and “ L1 ” on the other side) contains 0.01 mg ethinyl estradiol.

Each green tablet (debossed with “ SZ ” on one side and “ J1 ” on the other side) contains inert ingredients.

NDC 63629-2449-1, one box containing 3 individual unit cartons Store at 20° to 25°C (68° to 77°F) .

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.