Lolo: Indications, Dosage, Precautions, Adverse Effects
Россия
  • Россия
  • Украина

Lolo - Product Information

Manufacture: Actavis
Country: Canada
Condition: Birth Control (Contraception), Contraception (Birth Control)
Class: Contraceptives
Form: Tablets
Ingredients: norethindrone acetate, ethinyl estradiol, lactose monohydrate, mannitol, microcrystalline cellulose, magnesium stearate, povidone, sodium starch glycolate and vitamin E, the blue tablets also contain FD&C Blue No. 1 aluminum Lake, acacia, lactose monohydrate, magnesium stearate, corn starch, sugar, talc and colours (FD&C Blue No.1, FD&C Red No.3, FD&C Red No. 40).

Summary product information

Route of
Administration
Dosage Form / Strength

Clinically Relevant
Nonmedicinal Ingredients
Oral Tablets
1 mg norethindrone acetate and
0.010 mg ethinyl estradiol
and
0.010 mg ethinyl estradiol
Lactose monohydrate
For a complete listing see
Dosage Forms, Composition and Packaging section.

Indications and clinical use

LOLO (norethindrone acetate and ethinyl estradiol) is indicated for the prevention of pregnancy.

In a one year (thirteen 28-day cycles) multicenter open-label clinical trial 1,582 women were studied to assess the safety and efficacy of LOLO. In this study 1,270 women 18 to 35 years of age were studied to assess the efficacy of LOLO,completing the equivalent of 12,482 28-day evaluable cycles of exposure. The pregnancy rate (Pearl Index [PI]) in women 18-35 years of age was 2.92 pregnancies per 100 women-years of use (see CLINICAL TRIALS).

The efficacy of LOLO in women with a body mass index >35 kg/m2 has not been evaluated.

Exposure to exogenous estrogen with LOLO is less than with other combined oral contraceptives with similar synthetic estrogens. Any benefits from the lower estrogen exposure provided by LOLO have not been evaluated.

Contraindications

LOLO should not be used in women with:

  • a history of or actual thrombophlebitis or thromboembolic disorders (such as deep vein thrombosis or pulmonary embolism);
  • a history of or actual cerebrovascular disorders;
  • a history of or actual myocardial infarction or coronary artery disease;
  • valvular heart disease with complications;
  • history of or actual prodromi of a thrombosis (e.g., transient ischaemic attack, angina pectoris);
  • active liver disease, or history of or actual benign or malignant liver tumours;
  • known or suspected carcinoma of the breast;
  • carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia;
  • undiagnosed abnormal vaginal bleeding;
  • steroid-dependent jaundice, cholestatic jaundice, history of jaundice of pregnancy;
  • any ocular lesion arising from ophthalmic vascular disease, such as partial or complete loss of vision or defect in visual fields;
  • known or suspected pregnancy;
  • current or history of migraine with focal aura;
  • history of or actual pancreatitis if associated with severe hypertriglyceridaemia;
  • presence of severe or multiple risk factor(s) for arterial or venous or thrombosis such as:
    • severe hypertension (persistent values of ≥160/100 mmHg)
    • uncontrolled hypertension
    • hereditary or acquired predisposition for venous or arterial thrombosis such as Factor V Leiden mutation and activated protein C (APC-) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia (e.g., due to MTHFR C677T, A1298 mutations), prothrombin mutation G20210A, and antiphospholipid-antibodies (anticardiolipin antibodies, lupus anticoagulant)
    • severe dyslipoproteinemia o over age 35 and smoke
    • diabetes mellitus with vascular involvement
    • major surgery associated with an increased risk of postoperative thromboembolism
    • prolonged immobilization
  • hypersensitivity to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

Warnings and precautions

Serious Warnings and Precautions

Cigarette smoking increases the risk of serious cardiovascular events associated with the use of hormonal contraceptives. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, LOLO should not be used by women who are over 35 years of age and smoke (see Cardiovascular section below).

Patients should be counselled that birth control pills DO NOT PROTECT against sexually transmitted infections (STIs) including HIV/AIDS. For protection against STIs, it is advisable to use latex or polyurethane condoms IN COMBINATION WITH birth control pills.

General

Discontinue medication at the earliest manifestation of:

  1. Thromboembolic and cardiovascular disorders, such as thrombophlebitis, pulmonary embolism, cerebrovascular disorders, myocardial ischemia, mesenteric thrombosis, proptosis and retinal thrombosis.
  2. Conditions which predispose to venous stasis and to vascular thrombosis (eg, immobilization after accidents or confinement to bed during long-term illness). Other non-hormonal methods of contraception should be used until regular activities are resumed. For use of oral contraceptives when surgery is contemplated, see Perioperative Considerations, below.
  3. Visual defects- partial or complete
  4. Papilledema or ophthalmic vascular lesions
  5. Severe headache of unknown etiology or worsening of pre-existing migraine headache
  6. Increase in epileptic seizures

The following information is provided from studies of combination oral contraceptives (COCs).

The use of combination hormonal 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 and mortality is small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly if associated with the presence of other risk factors such as hypertension, hyperlipidemias, obesity and diabetes. Other medical conditions which have been associated with adverse circulatory events include systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis), sickle cell disease, valvular heart disease and atrial fibrillation.

The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, although a direct association with COCs has not been firmly established: porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham’s chorea, herpes gestationis, and otosclerosis-related hearing loss.

The information contained in this section is principally from studies carried out in women who used combination oral contraceptives with higher formulations of estrogens and progestins than those in common use today. The effect of long-term use of combination hormonal contraceptives with lower doses of both estrogen and progestin administered orally remains to be determined.

Carcinogenesis and Mutagenesis

Breast Cancer

Women who currently have or have had breast cancer should not use LOLO because breast cancer is a hormonally-sensitive tumour (see CONTRAINDICATIONS).

Increasing age and a strong family history are the most significant risk factors for the development of breast cancer. Other established risk factors include obesity, nulliparity and late age at first full-term pregnancy. The identified groups of women that may be at increased risk of developing breast cancer before menopause are long-term users of oral contraceptives (more than eight years) and starters at early age. In a few women, the use of oral contraceptives may accelerate the growth of an existing but undiagnosed breast cancer. Since any potential increased risk related to oral contraceptive use is small, there is no reason to change prescribing habits at present.

Women receiving oral contraceptives should be instructed in self-examination of their breasts. Their physicians should be notified whenever any masses are detected. A yearly clinical breast examination is also recommended because, if a breast cancer should develop, estrogen containing drugs may cause a rapid progression.

Cervical Cancer

The most important risk factor for cervical cancer is persistent human papilloma virus (HPV) infection. Some epidemiological studies have indicated that long-term use of Combination Oral Contraceptives (COCs) may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to the confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.

Hepatocellular Carcinoma

Hepatocellular carcinoma may be associated with oral contraceptives. The risk appears to increase with duration of hormonal contraceptive use (>8 years). However, the attributable risk (the excess incidence) of liver cancers in oral contraceptive users is extremely small (<1 case/million users). A liver tumor should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal hemorrhage occur in women taking COCs (See also Hepatic/Biliary/Pancreatic: Hepatic nodules).

Cardiovascular

Predisposing Factors for Coronary Artery Disease

Cigarette smoking increases the risk of serious cardiovascular events and mortality. Birth control pills increase this risk, particularly in women over 35 years of age, and with the number of cigarettes smoked. Convincing data are available to support an upper age limit of 35 years for oral contraceptive use by women who smoke.

Other women who are independently at high risk for cardiovascular disease include those with diabetes, hypertension, abnormal lipid profile, obesity or a family history of these. Whether oral contraceptives accentuate this risk is unclear.

In low risk, non-smoking women of any age, the benefits of oral contraceptive use outweigh the possible cardiovascular risks associated with low dose formulations. Consequently, oral contraceptives may be prescribed for these women up to the age of menopause.

Hypertension

COC use is contraindicated in women with uncontrolled hypertension (see CONTRAINDICATIONS).

Patients with essential hypertension whose blood pressure is well-controlled may be given hormonal contraceptives but only under close supervision. If a significant elevation of blood pressure in previously normotensive or hypertensive subjects occurs at any time during the administration of the drug, cessation of medication is necessary.

Endocrine and Metabolism

Diabetes

Current low-dose oral contraceptives exert minimal impact on glucose metabolism. Diabetic patients, or those with a family history of diabetes, should be observed closely to detect any worsening of carbohydrate metabolism. Patients predisposed to diabetes who can be kept under close supervision may be given oral contraceptives. Young diabetic patients whose disease is of recent origin, well-controlled, and not associated with hypertension or other signs of vascular disease such as ocular fundal changes, should be monitored more frequently while using oral contraceptives.

Lipid and Other Metabolic Effects

A small proportion of women will have adverse lipid changes while on oral contraceptives. Alternative contraception should be used in women with uncontrolled dyslipidemias. (See also CONTRAINDICATIONS). Elevations of plasma triglycerides may lead to pancreatitis and other complications.

Gastrointestinal

Published epidemiological studies indicate a possible association of COC use and the development of Crohn’s disease and ulcerative colitis, although this has not been firmly established.

Genitourinary

Vaginal Bleeding

Unscheduled (breakthrough or intra-cycle) bleeding and /or spotting (IB/S) sometimes occur in patients on COCs, especially during the first three months of use. In the pivotal trial for LOLO, a total of 1,257 women (85.9%) experienced IB/S at some time during Cycles 2-13 of this study. The incidence of IB/S was highest during Cycle 2 (53%) and lowest at Cycle 13 (36%). The mean number of days per cycle of IB/S decreased from 3.2 days in Cycle 2 to 1.8 days during Cycle 13 (See CLINICAL TRIALS - Bleeding Profile).

Persistent irregular vaginal bleeding requires assessment to exclude underlying pathology.

Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over the one year study, with an average of less than 2 days per cycle when including all women and all cycles.

Fibroids

Patients with fibroids (leiomyomata) should be carefully observed. Sudden enlargement, pain, or tenderness requires discontinuation of the use of oral contraceptives.

Hematologic

Epidemiological studies have suggested an association between the use of COCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, deep venous thrombosis, pulmonary embolism, and of cerebrovascular accidents.

Venous Thromboembolism

The use of any combined oral contraceptive carries an increased risk of venous thromboembolism (VTE) compared with no use. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive or restarts (following a 4-week or greater pill-free interval) the same or a different COC. Data from a large, prospective 3-armed cohort study suggest that this increased risk is mainly present during the first 3 months. VTE is fatal in 1% to 2% of cases.

A large, prospective 3-armed cohort study has shown that the frequency of VTE diagnosis ranges from about 8 to 10 per 10,000 woman-years in users of oral contraceptives with low estrogen content (<50 μg ethinyl estradiol). The most recent data suggest that the frequency of VTE diagnosis is approximately 4.4 per 10,000 woman-years in nonpregnant, non-COC users and ranges from 20 to 30 per 10,000 women-years in pregnant women or postpartum.

Overall the risk for VTE in users of COCs with low estrogen content (<50 μg ethinyl estradiol) is 2- to 3-fold higher than for nonusers of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery.

The risk of VTE with COCs has been shown to be related to the estrogen dose, as risk has decreased as doses have decreased from 100 μg to 50 μg to 30 μg. Whether doses as low as 10 μg are further protective is unknown. LOLO provides a daily dose of ethinyl estradiol of 10 μg, for 26 of 28 days each cycle.

Extremely rarely, thrombosis has been reported to occur in other blood vessels (eg, hepatic, mesenteric, renal, cerebral, or retinal veins and arteries) in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.

Arterial Thromboembolism

The risk for arterial thromboembolism (ATE) in users of oral contraceptives with <50 μg ethinyl estradiol ranges from about 1 to 3 cases per 10,000 woman-years. An ATE can include cerebrovascular accident, vascular occlusion, or myocardial infarction (MI).

Arterial thromboembolic events may be fatal.

Other Risk Factors for Venous or Arterial Thromboembolism or of a Cerebrovascular Accident

Other generalized risk factors for venous or arterial thromboembolism include but are not limited to age, severe obesity (body mass index >30 kg/m2), a personal history, a positive family history (the occurrence of VTE/ATE in a direct relative at a relatively early age may indicate genetic predisposition) and systemic lupus erythematosus. If a hereditary or acquired predisposition for venous or arterial thromboembolism is suspected, the woman should be referred to a specialist for advice before deciding on any COC use. The risk of VTE/ATE may be temporarily increased with prolonged immobilization, major surgery, or trauma. In these situations, it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume COC use until two weeks after complete remobilization. Also, patients with varicose veins and leg cast should be closely supervised. Other risk factors may include smoking (with heavier smoking and increasing age, the risk further increases, especially in women over 35 years of age), dyslipoproteinemia, hypertension, migraine, valvular heart disease, and atrial fibrillation.

Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Factor V Leiden mutation and activated protein C (APC-) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia (eg, due to MTHFR C677T, A1298 mutations), prothrombin mutation G20210A, and antiphospholipid-antibodies (anticardiolipin antibodies, lupus anticoagulant).

When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with COCs containing <0.05 mg ethinyl estradiol).

Hepatic/Biliary/Pancreatic

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal.

Jaundice

Patients who have had jaundice should be given oral contraceptives only with great care and under close observation. Oral contraceptive-related cholestasis has been described in women with a history of pregnancy-related cholestasis. Women with a history of cholestasis may have the condition recur with subsequent hormonal contraceptive use. The development of severe generalized pruritus or icterus requires that the medication be withdrawn until the problem is resolved.

If a patient develops jaundice that proves to be cholestatic in type, the use of oral contraceptives should not be resumed. In patients taking hormonal contraceptives, changes in the composition of the bile may occur and an increased incidence of gallstones has been reported.

Gallbladder Disease

Patients taking oral contraceptives have a greater risk of developing gallbladder disease requiring surgery within the first year of use. The risk may double after four or five years.

Hepatic Nodules

Hepatic nodules (adenoma and focal nodular hyperplasia) have been reported, particularly in long-term users of oral contraceptives. Although these lesions are extremely rare, they have caused fatal intra-abdominal hemorrhage and should be considered in women presenting with an abdominal mass, acute abdominal pain, or evidence of intra-abdominal bleeding.

Immune

Angioedema

Exogenous estrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.

Neurologic

Migraine and Headache

The onset or exacerbation of migraine or the development of headache of a new pattern that is recurrent, persistent or severe, requires discontinuation of hormonal contraceptives and evaluation of the cause. Women with migraine headaches who take oral contraceptives may be at increased risk of stroke (see CONTRAINDICATIONS).

Ophthalmologic

Ocular Disease

Patients who are pregnant or are taking oral contraceptives, may experience corneal edema that may cause visual disturbances and changes in tolerance to contact lenses, especially of the rigid type. Soft contact lenses usually do not cause disturbances. If visual changes or alterations in tolerance to contact lenses occur, temporary or permanent cessation of wear may be advised.

Ocular Lesions

With use of 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, papilledema, or retinal vascular lesions, LOLO should be discontinued and the cause immediately evaluated.

Peri-Operative Considerations

There is an increased risk of thromboembolic complications in oral contraceptive users after major surgery. If feasible, oral contraceptives should be discontinued and an alternative method substituted at least one month prior to MAJOR elective surgery. Oral contraceptives should not be resumed until the first menstrual period after hospital discharge following surgery.

Psychiatric

Patients with a history of emotional disturbances, especially the depressive type, may be more prone to have a recurrence of depression while taking oral contraceptives. In cases of a serious recurrence, a trial of an alternate method of contraception should be made which may help to clarify the possible relationship. Women with premenstrual syndrome (PMS) may have a varied response to oral contraceptives, ranging from symptomatic improvement to worsening of the condition.

Renal

Fluid Retention

Hormonal contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring in patients with conditions which might be aggravated by fluid retention.

Sexual Function/Reproduction

Return to Fertility

After discontinuing oral contraceptive therapy, the patient should delay pregnancy until at least one normal spontaneous cycle has occurred in order to date the pregnancy. An alternate contraceptive method should be used during this time.

Amenorrhea

Women on LOLO may not get a period each month. In the clinical trial with LOLO, the incidence of amenorrhea increased from 32% in Cycle 1 to 49% by Cycle 13 (see CLINICAL TRIALS - Bleeding Profile). If LOLO has been taken according to directions, it is unlikely that the woman is pregnant. However, if LOLO has not been taken according to directions prior to the first missed withdrawal bleed, or if two withdrawal bleeds are missed, pregnancy must be ruled out before LOLO use is continued.

Women having a history of oligomenorrhea, secondary amenorrhea, or irregular cycles may remain anovulatory or become amenorrheic following discontinuation of estrogen-progestin combination therapy.

Amenorrhea, especially if associated with breast secretion that continues for 6 months or more after withdrawal warrants a careful assessment of hypothalamic-pituitary function.

Reduced Efficacy

The efficacy of COCs may be reduced in the event of missed tablets, gastrointestinal disturbances or concomitant medication (see DRUG INTERACTIONS).

Skin

Chloasma may occasionally occur with use of COCs, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs. Chloasma is often not fully reversible.

Special Populations

Pregnant Women:

Oral contraceptives should not be taken by pregnant women. If pregnancy occurs during treatment with LOLO, further intake must be stopped. However, if conception accidentally occurs while taking the pill, there is no conclusive evidence that the estrogen and progestin contained in the oral contraceptive will damage the developing child.

Nursing Women:

In breastfeeding women, the use of oral contraceptives results in the hormonal components being excreted in breast milk and may reduce its quantity and quality. If the use of oral contraceptives is initiated after the establishment of lactation, there does not appear to be any effect on the quantity and quality of the milk. There is no evidence that low-dose oral contraceptives are harmful to the nursing infant.

If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child. There have been no formal studies of LOLO in nursing women.

Pediatrics

The safety and efficacy of LOLO have not been established in women under the age of 18 years. Use of this product before menarche is not indicated.

Geriatrics

LOLO is not indicated for use in postmenopausal women.

Body Mass Index (BMI)

The safety and efficacy of LOLO in women with a body mass index (BMI) > 35 kg/m2 has not been evaluated.

Monitoring and Laboratory Tests

Before oral contraceptives are used, a thorough history and physical examination should be performed, including a blood pressure determination and the family case history carefully noted. In addition, disturbances of the clotting system must be ruled out if any members of the family have suffered from thromboembolic diseases (e.g., deep vein thrombosis, stroke, myocardial infarction) at a young age. Breasts, liver, extremities and pelvic organs should be examined and a Papanicolaou (PAP) smear should be taken if the patient has been sexually active.

The first follow-up visit should be done three months after oral contraceptives are prescribed. Thereafter, examinations should be performed at least once a year or more frequently if indicated. At each annual visit, examination should include those procedures that were done at the initial visit as outlined above or per recommendations of the Canadian Task Force on the Periodic Health Examination.

Adverse reactions

Adverse Drug Reaction Overview

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives:

  • arterial and venous thromboembolism
  • being diagnosed with breast cancer
  • benign and malignant hepatic tumours
  • cerebral hemorrhage
  • cerebral thrombosis
  • congenital anomalies
  • gallbladder disease
  • hypertension
  • mesenteric thrombosis
  • myocardial infarction
  • neuro-ocular lesions (e.g., retinal thrombosis)
  • pulmonary embolism
  • thrombophlebitis

The following adverse reactions also have been reported in patients receiving oral contraceptives:

Nausea and vomiting, usually the most common adverse reaction, occurs in approximately 10% or fewer of patients during the first cycle. The following other reactions, as a general rule, are seen less frequently or only occasionally:

Blood and lymphatic system: hemolytic uremic syndrome

Ear and labyrinth: auditory disturbances, otosclerosis-related hearing lossa

Eye: cataracts, change in corneal curvature (steepening), intolerance to contact lenses, retinal thrombosis

Gastrointestinal: abdominal pain, Crohn’s diseasea, diarrhea, gastrointestinal symptoms (such as abdominal cramps and bloating), pancreatitis, ulcerative colitisa

General: edema

Hepatobiliary: cholestatic jaundice, gallstone formationa, liver function disturbancesa

Immune system: hypersensitivity

Infections and infestations: rhinitis, vaginal candidiasis, vaginitis,

Investigations: change in weight (increase or decrease), reduced tolerance to carbohydrates

Metabolism and nutrition: changes in appetite, hypertriglyceridemia (increased risk of pancreatitis when using COCs)a, porphyria

Musculoskeletal and connective tissue: systemic lupus erythematosusa

Neoplasms benign, malignant and unspecified (incl cyst and polyps): increase in size of uterine leiomyomata

Nervous system: chorea, dizziness, headache, migraine, optic neuritis, Sydenham’s choreaa

Psychiatric: changes in libido, mental depression, nervousness

Renal and urinary: cystitis-like syndrome, impaired renal function

Reproductive system and breast: amenorrhea during and after treatment, breakthrough bleeding, breast changes including tenderness, enlargement, and secretion, change in menstrual flow, dysmenorrhea, endocervical hyperplasias, possible diminution in lactation when given immediately post-partum, premenstrual-like syndrome, spotting, temporary infertility after discontinuance of treatment, vaginal discharge

Skin and subcutaneous tissue: chloasma or melasma which may persist, loss of scalp hair, hirsutism, erythema multiforme, erythema nodosum, hemorrhagic eruption, herpes gestationisa, pruritis related to cholestasisa, rash (allergic), urticaria

Vascular: hypertensiona, Raynaud's phenomenon

a Occurrence or deterioration of conditions for which association with COC use is not conclusive.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and approximate rates of occurrence.

A multicenter phase 3 clinical trial evaluated the safety and efficacy of LOLO for pregnancy prevention. The study was a one year, open-label, single-arm, uncontrolled study. A total of 1,660 women aged 18 to 45 were enrolled and took at least one dose of LOLO.

A list of adverse reactions experienced by ≥ 1% of the subjects is listed in Table 1.

Table 1 Treatment-related Adverse Reactions Reported in ≥1% of Subjects
MedDRA System Organ ClassEventLOLO
N= 1660
n (%)
Nervous System DisordersHeadache79 (4.8)
Gastrointestinal DisordersNausea53 (3.2)
Reproductive System and Brest DisordersMetrorrhagia54 (3.3)
Breast Tenderness50 (3.0)
Dysmenorrhea42 (2.5)
Metabolism and Nutrition DisordersWeight Fluctuation48 (2.9)
Skin and Subcutaneous Tissue DisordersAcne35 (2.1)
Psychiatric DisordersMood Swings23 (1.4)

The mean weight gain on LOLO was 1.7 lb (SD ±9.8 lb).

Serious Adverse Events leading to discontinuation included: deep vein thrombosis, ovarian vein thrombosis and cholecystitis.

Adverse Events Leading to Study Discontinuation: 10.7% of the women discontinued from the clinical trial due to an adverse event. Adverse events occurring in ≥1% of subjects leading to discontinuation of treatment were, in decreasing order: menstrual irregularities (including metrorrhagia, irregular menstruation, menorrhagia and vaginal hemorrhage) (4%), headache/migraine (1%), mood disorder (including mood swings, depression, anxiety) (1%), and weight fluctuation (1%). Less than 1% of subjects discontinued because of amenorrhea.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Rare adverse reactions (<1%) which were observed in clinical trials and deemed to be at least possibly related to LOLO are as follows:

Gastrointestinal: abdominal pain, vomiting, diarrhea, abdominal distension, gastroesophageal reflux disease, constipation, dyspepsia, stomach discomfort, abdominal discomfort.

General: fatigue, irritability, peripheral edema, swelling, edema, drug intolerance

Hepatobiliary: cholycystitis, cholelithiasis

Investigations: abnormal cervical smear, abnormal lab test, blood pressure increased, AST increased, blood cholesterol increased

Infections and Infestations: HPV cervicitis, fungal infection, bronchitis

Metabolism and Nutrition: hypercholesterolemia, hypertriglyceridemia, increased appetite, fluid retention, food craving, impaired glucose tolerance, lack of satiety

Musculoskeletal and Connective Tissue: pain in extremity, muscle spasms

Nervous System: migraine, dizziness, tension headache, lethargy, loss of consciousness, somnolence.

Ophthalmologic: vision blurred, contact lens intolerance, dry eye

Psychiatric: anxiety, depression, insomnia, decreased libido, mood altered, affect liability, tearfulness, suicidal ideation.

Renal and Urinary: urinary tract infection,

Reproductive System and Breast: bacterial vaginitis, vulvovaginal mycotic infection, amenorrhea, irregular menstruation, ovarian cyst, vaginal candidiasis, vaginal discharge, breast pain, menorrhagia, pelvic pain, breast mass, vaginal inflammation, fibrocystic breast disease, premenstrual syndrome, dypareunia, vulvovaginal dryness, breast cyst, breast discharge, breast hypertrophy, vaginal hemorrhage, coital bleeding, vaginal pain, adnexa uteri pain, breast atrophy, breast swelling, cervical discharge, dysfunctional uterine bleeding, nipple pain.

Respiratory: upper respiratory tract infection, alveolar proteinosis

Skin and Subcutaneous Tissue: rash, alopecia, urticaria, hyperhidrosis, night sweats, eczema, prurius, generalized rash, hair texture abnormal, pigmentation disorder, lip pigmentation, generalized pruritis.

Vascular: hypertension, hot flush, deep vein thrombosis, hemorrhage, venous thrombosis.

Abnormal Hematologic and Clinical Chemistry Findings

In the pivotal trial, a total of 80 abnormal laboratory results (not including positive pregnancy tests) in 31 subjects in the All Treated population were considered clinically significant, consisting mostly of elevated cholesterol and triglycerides; moderately elevated AST, ALT and GGT. In most of these cases values elevated at the end of the study were actually lower than the initial values. Slightly reduced hemoglobin and hematocrit were also common.

Post-Market Adverse Drug Reactions

The following serious adverse events have been reported in users of LOLO in the post marketing period. These adverse events are compiled from spontaneous reports and are listed regardless of frequency and whether or not a causal relationship with LOLO has been established.

Congenital, Familial and Genetic Disorders: heart disease (congenital)

General Disorders and Administration Site Conditions: chest pain

Hepatobiliary Disorders: gallbladder disorder, liver disorder

Musculoskeletal and Connective Tissue Disorders: muscular weakness

Neoplasms Benign, Malignant and Unspecified (incl. cysts and polyps): benign breast neoplasm

Nervous System Disorders: cerebrovascular accident, convulsion, epilepsy, grand mal convulsion, hypoaesthesia, intracranial aneurysm, paralysis

Pregnancy, Puerperium and Perinatal Conditions: abortion spontaneous, premature delivery

Psychiatric Disorders: Suicidal ideation

Renal and urinary Disorders: Renal infarct

Reproductive System and Breast Disorders: menorrhagia

Respiratory, Thoracic and Mediastinal Disorders: pulmonary embolism

Vascular Disorders: deep vein thrombosis, thrombosis

Drug interactions

Overview

The concurrent administration of oral contraceptives with other drugs may lead to breakthrough bleeding and/or may result in an altered response to either agent (see Table 2 and Table 3). Reduced effectiveness of the oral contraceptive, should it occur, is more likely with the low-dose formulations. It is important to ascertain all drugs that a patient is taking, both prescription and non-prescription, before oral contraceptives are prescribed.

No formal drug-drug interaction studies were conducted with LOLO.

Drug-Drug Interactions

Table 2 Drugs which may decrease the efficacy of oral contraceptives
Class of CompoundDrugProposed MechanismSuggested Management
AntacidsDecreased intestinal absorption of progestins.Dose two hours apart.
AntibioticsAmpicillin
Cotrimoxazole
Penicillin
Enterohepatic circulation disturbance, intestinal hurry For short course, use additional method or use another drug. For long course, use another method.
Rifabutin
Rifampin
Increased metabolism of progestins. Suspected acceleration of estrogen metabolism.Use another method.
Chloramphenicol
Metronidazole
Neomycin
Nitrofurantoin
Sulfonamides
Tetracyclines
Induction of hepatic microsomal enzymes. Also disturbance of enterohepatic circulation.For short course, use additional method or use another drug. For long course, use another method.
TroleandomycinMay retard metabolism of oral contraceptives, increasing the risk of cholestatic jaundice.
AnticonvulsantsCarbamazepine
Ethosuximide
Felbamate
Lamotrigine
Oxcarbazepine
Phenobarbital
Phenytoin
Primidone
Topiramate
Induction of hepatic microsomal enzymes. Rapid metabolism of estrogen and increased binding of progestin and ethinyl estradiol to SHBG.Use higher dose oral contraceptives (50 μg ethinyl estradiol), another drug or another method.
AntifungalsGriseofulvinStimulation of hepatic metabolism of contraceptive steroids may occur.Use another method.
Cholesterol Lowering AgentsClofibrateReduces elevated serum triglycerides and cholesterol; this reduces oral contraceptive efficacy.Use another method.
HCV Protease InhibitorsBoceprevir
Telaprevir
Uncertain, but may be due to an effect on GI transporters, leading to a decrease in the AUC of ethinyl estradiol.Exposure to ethinyl estradiol was decreased when co-administered with telaprevir or boceprevir. Additional methods of non-hormonal contraception should be used when hormonal contraceptives are co-administered with telaprevir or boceprevir.
HIV Protease InhibitorsRitonavirInduction of hepatic microsomal enzymes.Use another drug or another method.
Non-nucleoside reverse transcriptase inhibitorsNevirapineInduction of hepatic microsomal enzymes.Use another drug or another method.
Sedatives and Hypnotics Barbiturates
Benzodiazepines
Chloral hydrate
Glutethimide
Meprobamate
Induction of hepatic microsomal enzymes. For short course, use additional method or another drug. For long course, use another method or higher dose oral contraceptives.
Other DrugsAntihistamines
Analgesics
Antimigraine
preparations
Phenylbutazone
preparations
Vitamin E
Reduced oral contraceptive efficacy has been reported.Remains to be confirmed.
BosentanInduction of hepatic microsomal enzymes.Consider switching to a non-hormonal contraceptive method or adding a barrier method to oral contraceptive therapy

Table 3 Modification of other drug action by oral contraceptives
Class of CompoundDrugModification of other drug
action
Suggested Management
AlcoholPossible increased levels of ethanol or acetaldehyde.Use with caution.
Alpha-II
adrenoreceptor
agents
ClonidineSedation effect increased.Use with caution.
AnticoagulantsAllOral contraceptives increase clotting factors, decrease efficacy. However, oral contraceptives may potentiate action in some patients.Use another method
AnticonvulsantsAllEstrogens may increase risk of seizures.Use another method.
LamotrigineDecreased lamotrigine levels, may lead to breakthrough seizures.Use another method.
Antidiabetic drugsOral hypoglycemics and insulinOral contraceptives may impair glucose tolerance and increase blood glucose.Use low-dose estrogen and progestin oral contraceptive or another method. Monitor blood glucose.
Antihypertensive
agents
Guanethidine and
methyldopa
Estrogen component causes sodium retention, progestin has no effect.Use low-dose estrogen oral contraceptive or use another method.
Beta blockersIncreased drug effect (decreased metabolism).Adjust dose of drug if necessary. Monitor cardiovascular status.
AntipyreticsAcetaminophenIncreased metabolism and renal clearance.Dose of drug may have to be increased.
AntipyrineImpaired metabolism.Decrease dose of drug.
ASAEffects of ASA may be decreased by the short-term use of oral contraceptives.Patients on chronic ASA therapy may require an increase in ASA dosage.
Aminocaproic acidTheoretically, a hypercoagulable state may occur because oral contraceptives augment clottingfactors.Avoid concomitant use.
Betamimetic agentsIsoproterenolEstrogen causes decreased response to these drugs.Adjust dose of drug as necessary. Discontinuing oral contraceptives can result in excessive drug activity.
CaffeineThe actions of caffeine may be enhanced as oral contraceptives may impair the hepatic metabolism of caffeine.Use with caution.
Cholesterol lowering agentsClofibrateTheir action may be antagonized by oral contraceptives. Oral contraceptives may also increase metabolism of clofibrate.May need to increase dose of clofibrate.
CorticosteroidsPrednisoneMarkedly increased serum levels.Possible need for decrease in dose.
CyclosporineMay lead to an increase in cyclosporine levels and hepatotoxicity.Monitor hepatic function. The cyclosporine dose may have to be decreased.
Folic acidOral contraceptives have been reported to impair folate metabolism.May need to increase dietary intake, or supplement.
MeperidinePossible increased analgesia and CNS depression due to decreased metabolism of meperidine.Use combination with caution.
Phenothiazine tranquilizersAll phenothiazines, reserpine and similar drugsEstrogen potentiates the hyperprolactinemia effect of these drugs.Use other drugs or lower dose oral contraceptives. If galactorrhea or hyperprolactinemia occurs, use other method.
Sedatives and hypnoticsChlordiazepoxide
Lorazepam
Oxazepam
Diazepam
Increased effect (increased metabolism).Use with caution.
TheophyllineAllDecreased oxidation, leading to possible toxicity.Use with caution. Monitor theophylline levels.
Tricyclic antidepressantsClomipramine (possibly others)Increased side effects: eg, depressionUse with caution.
Vitamin B12Oral contraceptives have been reported to reduce serum levels of Vitamin B12May need to increase dietary intake, or supplement.

Several of the anti-HIV protease inhibitors (eg, ritonavir) and non-nucleoside reverse transcriptase inhibitors (eg, nevirapine) have been studied with coadministration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the mean AUC of the estrogen and progestin and the potential to affect hepatic metabolism have been noted in some cases. The efficacy and safety of oral contraceptive products may be affected. Healthcare providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Drug-Food Interactions

LOLO tablets may be administered without regard to meals.

Administration of food with a single-dose of a LOLO combination tablet did not affect the maximum concentration of norethindrone and increased the extent of absorption by 24%; it decreased the maximum concentration of ethinyl estradiol by 23% and did not affect the extent of absorption.

Administration of food with a single-dose of a LOLO ethinyl estradiol alone tablet decreased the maximum concentration of ethinyl estradiol by 31% and did not affect the extent of absorption.

Drug-Herb Interactions

Herbal products containing St. John’s wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.

Drug-Laboratory Test Interactions

Results of laboratory tests should be interpreted with the knowledge that the patient is taking an oral contraceptive. The following laboratory tests are modified:

Liver Function Tests

Aspartate serum transaminase (AST) - variously reported elevations
Alkaline phosphatase and gamma glutamine transaminase (GGT) - slightly elevated

Coagulation Tests

Minimal elevation of test values reported for such parameters as prothrombin and factors VII, VIII, IX, and X.

Thyroid Function Tests

Protein binding of thyroxine is increased as indicated by increased total serum thyroxine concentrations and decreased T3 resin uptake.

Lipoproteins

Small changes of unproven clinical significance may occur in lipoprotein cholesterol fractions.

Gonadotropins

LH and FSH levels are suppressed by the use of oral contraceptives. Wait 2 weeks after discontinuing the use of oral contraceptives before measurements are made.

Glucose Tolerance

Oral glucose tolerance remained unchanged or was slightly decreased.

Tissue Specimens

Pathologists should be advised of oral contraceptive therapy when specimens obtained from surgical procedures and PAP smears are submitted for examination.

Drug-Lifestyle Interactions

No studies on the effects of LOLO on the ability to drive or use machines have been performed.

Noncontraceptive Benefits of Oral Contraceptives

Several health advantages other than contraception have been reported:

  1. Combination oral contraceptives reduce the incidence of cancer of the endometrium and ovaries.
  2. Oral contraceptives reduce the likelihood of developing benign breast disease and, as a result, decrease the incidence of breast biopsies.
  3. Oral contraceptives reduce the likelihood of development of functional ovarian cysts.
  4. Pill users have less menstrual blood loss and have more regular cycles, thereby reducing the chance of developing iron-deficiency anemia.
  5. The use of oral contraceptives may decrease the severity of dysmenorrhea and premenstrual syndrome, and may improve acne vulgaris, hirsutism, and other androgen- mediated disorders.
  6. Oral contraceptives decrease the incidence of acute pelvic inflammatory disease and, thereby, reduce as well the incidence of ectopic pregnancy.
  7. Oral contraceptives have potential beneficial effects on endometriosis.

Dosage and administration

Dosing Considerations

To achieve maximum contraceptive effectiveness, LOLO should be taken exactly as directed and at intervals not exceeding 24 hours.

LOLO tablets may be administered without regard to meals.

LOLO provides a regimen consisting of 24 blue estrogen-progestin tablets, 2 white estrogen-only tablets, and 2 lilac placebo tablets.

Recommended Dose

During the first cycle of use:

The possibility of ovulation and conception prior to initiation of medication should be considered. The patient is instructed to begin taking LOLO on either Day 1 of menstruation (Day 1 Start) or the first Sunday after the onset of menstruation (Sunday Start). If menstruation begins on a Sunday, the first tablet (blue) is taken that day. One blue tablet should be taken daily for 24 consecutive days followed by one white tablet for 2 consecutive days, followed by one lilac tablet daily for 2 consecutive days. During the first cycle with a Sunday start, contraceptive reliance should not be placed on LOLO until a blue tablet has been taken daily for 7 consecutive days and a non-hormonal back-up method of birth control (such as latex or polyurethane condoms or spermicide) should be used during those 7 days. LOLO is effective from the first day of therapy if the tablets are begun on the first day of the menstrual cycle.

The patient begins her next and all subsequent 28-day courses of tablets on the same day of the week on which she began her first course, following the same schedule: 24 days on blue tablets – 2 days on white tablets - 2 days on lilac tablets. If in any cycle the patient starts tablets later than the proper day, she should protect herself against pregnancy by using a non-hormonal back-up method of birth control until she has taken a blue tablet daily for 7 consecutive days.

Special Notes on Administration

Switching from another hormonal method of contraception:

When the patient is switching to LOLO after completing a 21-day regimen of oral contraceptive tablets, transdermal patches, or a vaginal ring, she should wait 7 days after her last tablet, patch, or ring before she starts LOLO. She will probably experience withdrawal bleeding during that week. She should be sure that no more than 7 days pass after her previous 21-day regimen. When the patient is switching to LOLO after completing a 28-day regimen of oral contraceptive tablets, she should start her first pack of LOLO on the day after her last tablet. She should not wait any days between packs. The patient may switch any day from a progestin-only pill and should begin LOLO the next day. If switching from an implant or injection, the patient should start LOLO on the day of implant removal or, if using an injection, the day the next injection would be due. If switching from an IUD, depending on the timing of removal, back-up contraception may be needed.

If spotting or breakthrough bleeding occurs:

Breakthrough bleeding or spotting may occur in women taking COCs, especially during the first 3 months of use. The patient is instructed to continue on the same regimen. This type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her healthcare provider.

If withdrawal bleeding does not occur:

Although pregnancy is unlikely if LOLO is taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. If the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. Hormonal contraceptives should be discontinued if pregnancy is confirmed.

Use after pregnancy, abortion or miscarriage:

LOLO should be initiated no earlier than 28 days postpartum in the nonlactating mother due to the increased risk for thromboembolism. When the tablets are administered in the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered (see CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS concerning thromboembolic disease). The patient should be advised to use a non-hormonal back- up method for the first 7 days of tablet taking. However, if intercourse has already occurred, the possibility of ovulation and conception prior to initiation of medication should be considered.

LOLO may be initiated immediately after a first-trimester abortion or miscarriage; if the patient starts LOLO immediately, additional contraceptive measures are not needed.

Missed Dose

The possibility of follicular growth, ovulation, and risk of pregnancy increases with each successive day that scheduled blue or white tablets are missed. If the patient misses one or more lilac tablets, she is still protected against pregnancy provided she begins taking the active blue tablets again on the proper day. Delayed restarting of active pills may result in reduction of contraceptive reliability.

Missing pills can cause spotting or light bleeding, even if the missed pills are made up. If breakthrough bleeding occurs following missed blue or white tablets, it will usually be transient and of no consequence. Nausea may also occur on the days two pills are taken to make up for missed pills.

The patient should be instructed to use the following chart if she misses 1 or more of her birth control pills. She should be told to match the number of pills missed with the appropriate starting time for her dosing regimen.

Sunday StartDay 1 Start
Miss 1 blue PillMiss 1 blue Pill
Take it as soon as you remember, and take the next pill at the usual time. This means that you might take two pills in one day.
Miss 2 blue pills in a row in Week 1 or Week 2Miss 2 blue pills in a row in Week 1 or Week 2
  1. Take two pills the day you remember and two pills the next day.
  2. Then take one pill a day until you finish the pack.
  3. Use a back-up (barrier) method of birth control if you have sex in the seven days after you miss the pills.
Miss 2 pills (blue or white) in a row in Week 3 or Week4Miss 2 pills (blue or white) in a row in Week 3 or Week 4
  1. Keep taking one pill a day until Sunday.
  2. On Sunday, safely discard the rest of the pack and start a new pack that day.
  3. Use a back-up (barrier) method of birth control if you have sex in the seven days after you miss the pills.
  4. You may not have a period this month.
  1. Safely dispose of the rest of the pill pack and start a new pack that same day.
  2. Use a back-up (barrier) method of birth control if you have sex in the seven days after you miss the pills.
  3. You may not have a period this month.
If you miss two periods in a row, call your doctor or clinic.
Miss 3 or more (blue or white) pills in a row at any timeMiss 3 or more pills (blue or white) in a row
  1. Keep taking one pill a day until Sunday.
  2. On Sunday, safely discard the rest of the pack and start a new pack that day.
  3. Use a back-up (barrier) method of birth control if you have sex in the seven days after you miss the pills.
  4. You may not have a period this month
  1. Safely dispose of the rest of the pill pack and start a new pack that same day.
  2. Use a back-up (barrier) method of birth control if you have sex in the seven days after you miss the pills.
  3. You may not have a period this month.
If you miss two periods in a row, call your doctor or clinic.

Advice in case of vomiting or diarrhea: If vomiting or diarrhea occurs within 3 to 4 hours after a blue or white tablet is taken, absorption may not be complete. In such an event, the advice concerning management of missed pills is applicable.

Overdosage

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and vomiting, and withdrawal bleeding may occur in females. There is no antidote and further treatment should be symptomatic.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and clinical pharmacology

Mechanism of Action

Like other combination oral contraceptives, LOLO acts by suppression of gonadotropins. These actions include: suppression of follicular development and 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).

Pharmacodynamics

No pharmacodynamic studies were conducted with LOLO.

Pharmacokinetics

Table 4 Summary of Pharmacokinetic Parameters LOLO (n=15)
RegimenStudy
Day
Arithmetic Meana (%CV) by Pharmacokinetic Parameter
AnalyteCmax
(pg/mL)
tmax
(h)
AUC0-24h
(pg/mL·h)
Cmin
(pg/mL)
Cavg
(pg/mL)
Single Dose
LOLO combination
tabletc
1NE7360 (21)1.7
(1.3-6.0)
33280 (33)----
EE50.9 (27)1.3
(1.0-6.0)
389.9 (27)----
SHBG------54.8 (33)b--
Multiple Dose
LOLO combination
tabletd x 24 days
24NE13900 (34)1.3
(0.7-3.0)
84160 (41)917 (84)3510 (41)
EE71.3 (33)1.3
(0.3-2.0)
621.3 (41)10.0 (92)25.9 (41)
SHBG------109 (38)--
Multiple Dose
LOLO combination
tablet x 24 days and EE
alone tabletd x 2 days
26EE49.9 (34)1.3
(0.7-3.0)
403.6 (50)----

EE: ethinyl estradiol; NE: norethindrone; SHBG = Sex hormone binding globulin (nmol/L)
Cmax = Maximum plasma concentration (pg/mL); tmax = Time of Cmax (h); AUC0−24h = Area under plasma concentration versus time curve from 0 to 24 hours (pg·h/mL); Cmin = Minimum plasma concentration (pg/mL); Cavg = Average plasma concentration = AUC0–24h/24 (pg/mL); %CV = Coefficient of Variation (%);
a The median (range) is reported for tmax
b The Cmin concentration reported for SHBG is the pre-dose concentration
c LOLO combination tablets contain 1 mg norethindrone acetate and 10 mcg ethinyl estradiol
d LOLO EE alone tablets contain 10 mcg ethinyl estradiol

Absorption

Norethindrone acetate is completely and rapidly deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are rapidly absorbed from LOLO, with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 55% for ethinyl estradiol.

The rate of norethindrone and ethinyl estradiol absorption from LOLO tablets containing the combination of 1 mg norethindrone acetate and 10 mcg ethinyl estradiol is slower than that from a norethindrone suspension/ethinyl estradiol solution, but the extent of absorption is equivalent.

Ethinyl estradiol bioavailability from LOLO tablets containing 10 mcg ethinyl estradiol alone is equivalent to that from an ethinyl estradiol solution.

The plasma norethindrone and ethinyl estradiol pharmacokinetic profiles and serum sex hormone binding globulin (SHBG) concentrations following multiple-dose administration of LOLO were characterized in 15 healthy female volunteers. The mean plasma concentrations are shown below (Figures 1 and 2), and pharmacokinetic parameters are found in Table 4.

Ethinyl estradiol and norethindrone Cmax values increase by a factor of 1.4 and 1.9, respectively, following 24 days administration of LOLO combination tablets as compared to single-dose administration. Ethinyl estradiol and norethindrone AUC0–24h values increase by a factor of 1.6 and 2.5, respectively, following 24 days administration of LOLO combination tablets as compared to single-dose administration. Norethindrone concentrations more than double by Day 24 due to both accumulation and increased SHBG concentration. Steady state with respect to ethinyl estradiol and norethindrone is reached by Day 5 and Day 13, respectively.

Figure 1 Mean plasma ethinyl estradiol concentration versus time profiles following single- and multiple-dose oral administration of LOLO to healthy female volunteers (n = 15)


Figure 2 Mean plasma norethindrone concentration versus time profiles following single- and multiple-dose oral administration of LOLO to healthy female volunteers (n = 15)


Distribution

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (>95%); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.

Metabolism

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol.

Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation.

Excretion

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Elimination half-lives of norethindrone and ethinyl estradiol following administration of 1 mg norethindrone acetate/10 mcg ethinyl estradiol tablets are approximately 10 hours and 16 hours, respectively.

Special Populations and Conditions

Race

The effect of race on the disposition of norethindrone and ethinyl estradiol after LOLO administration has not been evaluated.

Hepatic Insufficiency

The effect of hepatic disease on the disposition of norethindrone and ethinyl estradiol after LOLO administration has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function.

Renal Insufficiency

The effect of renal disease on the disposition of norethindrone and ethinyl estradiol after LOLO administration has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.

Storage and stability

Keep this drug and all drugs out of the reach of children.
Store at controlled room temperature (20 - 25oC).

Special handling instructions

Any unused portion or waste material should be disposed of in accordance with local requirements.

Dosage forms, composition and packaging

LOLO is available in blister cards (dispensers) containing 24 blue active tablets, 2 white active tablets and 2 lilac placebo tablets. Each blue, round tablet contains 1 mg of norethindrone acetate and 10 mcg of ethinyl estradiol and is imprinted with WC on one side and 421 on the other. Each white, hexagonal tablet contains 10 mcg of ethinyl estradiol and is imprinted with WC on one side and 422 on the other. Round, lilac placebo tablets are unmarked.

Non-medicinal ingredients for the blue tablets and white tablets include: Lactose monohydrate, mannitol, microcrystalline cellulose, magnesium stearate, povidone, sodium starch glycolate and vitamin E. The blue tablets also contain FD&C Blue No. 1 Aluminum Lake.

Ingredients for the lilac tablets include: Acacia, lactose monohydrate, magnesium stearate, corn starch, sugar talc and colours FD&C Blue No.1, FD&C Red No.3 and FD&C Red No. 40.