Azurette

Name: Azurette

What do I need to tell my doctor BEFORE I take Azurette?

  • If you have an allergy to ethinyl estradiol, desogestrel, or any other part of Azurette.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have had any of these health problems: Blood clots, blood clotting problem, breast cancer, diseased arteries in the brain, disease of a heart valve with problems, heart disease, chest pain caused by angina, heart attack, stroke, high blood pressure, high cholesterol, a pancreas problem (pancreatitis) due to high blood triglycerides, liver disease, liver tumor, very bad headache or migraine, diabetes that affects blood flow, or tumor where estrogen makes it grow.
  • If you have had any of these health problems: Endometrial cancer, cancer of the cervix or vagina, or vaginal bleeding where the cause is not known.
  • If you have ever had a cancer where hormones make it grow.
  • If you have eyesight problems like loss of eyesight from blood vessel problems in the eye.
  • If you have surgery and need bedrest.
  • If you turned yellow during pregnancy or with estrogen-based or hormone contraceptive use.
  • If you are pregnant or may be pregnant. Do not take this medicine if you are pregnant.
  • If you are breast-feeding or plan to breast-feed.
  • If you are taking ombitasvir, paritaprevir, and ritonavir (with or without dasabuvir).

This is not a list of all drugs or health problems that interact with Azurette.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

What are some things I need to know or do while I take Azurette?

  • Tell all of your health care providers that you take Azurette. This includes your doctors, nurses, pharmacists, and dentists. This medicine may need to be stopped before certain types of surgery as your doctor has told you. If this medicine is stopped, your doctor will tell you when to start taking Azurette again after your surgery or procedure.
  • This medicine may raise the chance of blood clots, a stroke, or a heart attack. Talk with the doctor.
  • Talk with your doctor if you will need to be still for long periods of time like long trips, bedrest after surgery, or illness. Not moving for long periods may raise your chance of blood clots.
  • If you have high blood sugar (diabetes), talk with your doctor. This medicine may raise blood sugar.
  • Check your blood sugar as you have been told by your doctor.
  • High blood pressure has happened with drugs like this one. Have your blood pressure checked as you have been told by your doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Be sure to have regular breast exams and gynecology check-ups. Your doctor will tell you how often to have these. You will also need to do breast self-exams as your doctor has told you. Talk with your doctor.
  • If you drink grapefruit juice or eat grapefruit often, talk with your doctor.
  • This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take this medicine.
  • Certain drugs, herbal products, or health problems could cause Azurette to not work as well. Be sure your doctor knows about all of your drugs and health problems.
  • This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
  • Do not use in children who have not had their first menstrual period.
  • If you have any signs of pregnancy or if you have a positive pregnancy test, call your doctor right away.

Azurette Description

Azurette® (desogestrel/ethinyl estradiol and ethinyl estradiol tablets USP) provides an oral contraceptive regimen of 21 white, round tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn- 4-en- 20-yn-17-ol), 0.02 mg ethinyl estradiol, USP (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol), and inactive ingredients which include colloidal silicon dioxide, hypromellose, lactose monohydrate, polyethylene glycol, povidone, pregelatinized corn starch, stearic acid, and vitamin E, followed by 2 inert light-green, round tablets with the following inactive ingredients: FD&C blue no. 1 aluminum lake, FD&C yellow no. 6 aluminum lake, D&C yellow no. 10 aluminum lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch. Azurette also contains 5 light-blue, round tablets containing 0.01 mg ethinyl estradiol, USP (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol) and inactive ingredients which include colloidal silicon dioxide, FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum lake, hypromellose, lactose monohydrate, polydextrose, polyethylene glycol, povidone, pregelatinized corn starch, stearic acid, titanium dioxide, triacetin and vitamin E. The structural formulas are as follows:

DESOGESTREL

C22H30O M.W. 310.48

ETHINYL ESTRADIOL, USP

C20H24O2 M.W. 296.40

The 21 white tablets meet USP Dissolution Test 2.

Azurette - Clinical Pharmacology

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Receptor binding studies, as well as studies in animals, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity (91, 92). The relevance of this latter finding in humans is unknown.

Pharmacokinetics

Absorption

Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel compared to a solution, as measured by serum levels of etonogestrel, is approximately 100%. Azurette (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets provide two different regimens of ethinyl estradiol; 0.02 mg in the combination tablet [white] as well as 0.01 mg in the light-blue tablet. Ethinyl estradiol is rapidly and almost completely absorbed. After a single dose of Azurette combination tablet [white], the relative bioavailability of ethinyl estradiol is approximately 93% while the relative bioavailability of the 0.01 mg tablet [light-blue] is 99%. The effect of food on the bioavailability of Azurette tablets following oral administration has not been evaluated.

The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of Azurette tablets were determined during the third cycle in 17 subjects. Plasma concentrations of etonogestrel and ethinyl estradiol reached steady state by Day 21. The AUC(0–24) for etonogestrel at steady state on Day 21 was approximately 2.2 times higher than AUC(0–24) on Day 1 of the third cycle. The pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of Azurette tablets are summarized in Table I.

TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF Azurette OVER A 28 DAY DOSING PERIOD IN THE THIRD CYCLE (n = 17).

Etonogestrel

 


Day

Dose


mg

Cmax

pg/mL

Tmax

h

t1/2

h

AUC0–24

pg/mL•hr

CL/F

L/h

1

0.15

2503.6 (987.6)

2.4 (1)

29.8 (16.3)

17,832 (5674)

5.4 (2.5)

21

0.15

4091.2 (1186.2)

1.6 (0.7)

27.8 (7.2)

39,391 (12,134)

4.4 (1.4)

1. Desogestrel

Ethinyl Estradiol

Day

Dose

mg

Cmax

pg/mL

Tmax

h

t1/2

h

AUC0–24 pg/mL•hr

CL/F

L/h

1

0.02

51.9 (15.4)

2.9 (1.2)

16.5 (4.8)

566 (173) 

25.7 (9.1)

21

0.02

62.2 (25.9)

2 (0.8)

23.9 (25.5)

597 (127)

35.1 (8.2)

24

0.01

24.6 (10.8)

2.4 (1)

18.8 (10.3)

246 (65)

43.6 (12.2)

28

0.01

35.3 (27.5)

2.1 (1.3)

18.9 (8.3)

312 (62)

33.2 (6.6)

Cmax – measured peak concentration

Tmax – observed time of peak concentration

t1/2 – elimination half-life, calculated by 0.693/Kelim

AUC0–24 – area under the concentration-time curve calculated by the linear trapezoidal rule (Time 0 to 24 hours)

CL/F – apparent clearance

1. n = 16 Distribution

Etonogestrel, the active metabolite of desogestrel, was found to be 99% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is approximately 98.3% bound, mainly to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in SHBG, resulting in lower serum levels of free testosterone (96 to 99).

Metabolism

Desogestrel

Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. Other metabolites (i.e., 3a-OH-desogestrel, 3ß-OH-desogestrel, and 3a-OH-5a-H-desogestrel) with no pharmacologic actions also have been identified and these metabolites may undergo glucuronide and sulfate conjugation.

Ethinyl estradiol

Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol escaping gut wall conjugation undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.

Excretion

Etonogestrel and ethinyl estradiol are excreted in urine, bile, and feces. At steady state, on Day 21, the elimination half-life of etonogestrel is 27.8 ± 7.2 hours and the elimination half-life of ethinyl estradiol for the combination tablet is 23.9 ± 25.5 hours. For the 0.01 mg ethinyl estradiol tablet [light-blue], the elimination half-life at steady state, Day 28, is 18.9 ± 8.3 hours.

Special Populations

Race

There is no information to determine the effect of race on the pharmacokinetics of Azurette.

Hepatic Insufficiency

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Azurette.

Renal Insufficiency

No formal studies were conducted to evaluate the effect of renal disease on the disposition of Azurette.

Drug-Drug Interactions

Interactions between desogestrel/ethinyl estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted (see PRECAUTIONS section).

Non-contraceptive health benefits

The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiologic studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol (73 to 78).

Effects on menses:

• increased menstrual cycle regularity • decreased blood loss and decreased incidence of iron deficiency anemia • decreased incidence of dysmenorrhea

Effects related to inhibition of ovulation:

• decreased incidence of functional ovarian cysts • decreased incidence of ectopic pregnancies

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

For Healthcare Professionals

Applies to desogestrel / ethinyl estradiol: oral tablet

Genitourinary

Common (1% to 10%): Breast pain/tenderness, amenorrhea, irregular bleeding
Uncommon (0.1% to 1%): Breast enlargement/hypertrophy, metrorrhagia
Rare (0.01% to 0.1%): Vaginal/breast discharge, vaginal candidiasis
Frequency not reported: Breakthrough bleeding, spotting, menstrual flow change, cervical ectropion and secretion, temporary infertility (after discontinuation), vaginitis, candidiasis, lactation diminution, premenstrual syndrome, dysmenorrhea, endometriosis, uterine myoma[Ref]

Diminution of lactation may theoretically occur when this drug is given immediately postpartum.[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, abdominal pain
Uncommon (0.1% to 1%): Vomiting, diarrhea
Frequency not reported: Gallbladder disease, mesenteric thrombosis, gastrointestinal symptoms (e.g., abdominal pain, cramps, bloating), pancreatitis, colitis, Crohn's disease, ulcerative colitis[Ref]

Psychiatric

Common (1% to 10%): Depressed mood, altered mood
Uncommon (0.1% to 1%): Decreased libido, nervousness
Rare (0.01% to 0.1%): Increased libido
Frequency not reported: Depression/mental depression[Ref]

Nervous system

Common (1% to 10%): Headache, dizziness
Uncommon (0.1% to 1%): Migraine
Frequency not reported: Stroke, transient ischemic attack, cerebral hemorrhage/thrombosis, chorea exacerbation, Sydenham's chorea, epilepsy[Ref]

Metabolic

Common (1% to 10%): Increased weight
Uncommon (0.1% to 1%): Fluid retention
Rare (0.01% to 0.1%): Decreased weight
Frequency not reported: Decreased serum folate, porphyria exacerbation, decreased carbohydrate tolerance, increased/decreased folate[Ref]

Dermatologic

Uncommon (0.1% to 1%): Rash/allergic rash, urticaria, acne
Rare (0.01% to 0.1%): Erythema nodosum/multiforme, pruritus, alopecia, hirsutism
Frequency not reported: Scalp hair loss, melasma/chloasma or persistent melasma/chloasma, gestational herpes gestationis, hemorrhagic eruption[Ref]

Cardiovascular

Uncommon (0.1% to 1%): Hypertension, fluid retention/edema
Rare (0.01% to 0.1%): Arterial/venous thromboembolism
Frequency not reported: Myocardial infarction, venous thrombosis, arterial/venous thromboembolic disorders, varicose vein aggravation, thrombophlebitis and venous thrombosis with/without embolism[Ref]

Ocular

Rare (0.01% to 0.1%): Contact lens intolerance, cataract
Frequency not reported: Retinal thrombosis, optic neuritis, partial/complete vision loss, corneal curvature change/steepening[Ref]

Hypersensitivity

Rare (0.01% to 0.1%): Hypersensitivity
Frequency not reported: Anaphylactic/anaphylactoid reactions, hereditary angioedema/angioedema, severe reactions with respiratory and circulatory symptoms[Ref]

Other

Rare (0.01% to 0.1%): Otosclerosis[Ref]

Hepatic

Frequency not reported: Cholestatic jaundice, Budd-Chiari syndrome, acute/chronic liver function disturbances, liver tumors/hepatic adenomas or benign liver tumors[Ref]

Oncologic

Frequency not reported: Hormone-dependent tumors, breast cancer[Ref]

Renal

Frequency not reported: Cystitis-like syndrome, impaired renal function[Ref]

Respiratory

Frequency not reported: Pulmonary embolism[Ref]

Hematologic

Frequency not reported: Hemolytic uremic syndrome[Ref]

Musculoskeletal

Frequency not reported: Systemic lupus erythematosus[Ref]

Some side effects of Azurette may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

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