Larin 24 Fe

1 INDICATIONS AND USAGE LARIN 24 Fe is a combination of norethindrone acetate, a progestin, and ethinyl estradiol, an estrogen, indicated for use by women to prevent pregnancy. The efficacy of LARIN 24 Fe in women with a body mass index (BMI) of >35 kg/m 2 has not been evaluated. ( 1 , 8.8 ) Larin 24 Fe is indicated for use by women to prevent pregnancy . The efficacy of LARIN 24 Fe in women with a body mass index (BMI) of > 35 kg/m 2 has not been evaluated.

Take one tablet by mouth at the same time every day for 28 days Take tablets in the order directed on the blister pack LARIN 24 Fe may be administered without regard to meals

2.1How to Start Larin

24 Fe Larin 24 Fe is dispensed in a in 28-tablet blister card . Larin 24 Fe may be started using either a Day 1 start or a Sunday start . The plastic compact is pre-set for a Sunday start. Day 1 Start day-label stickers are available. For the first cycle of a Sunday Start regimen, an additional method of contraception must be used until after the first 7 consecutive days of administration.

2.2How to Take Larin

24 Fe S t arting Larin 24 Fe after Abortion or Miscarriage First-trimester After a first-trimester abortion or miscarriage, Larin 24 Fe may be started immediately. An additional method of contraception is not needed if Larin 24 Fe is started immediately. If Larin 24 Fe is not started within 5 days after termination of the pregnancy, the patient must use additional non-hormonal contraception (such as condoms and spermicide) for the first 7 days of her first 28-day course of Larin 24 Fe.

Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Larin 24 Fe following the instructions in Table 1 for Day 1 or Sunday start, as desired. If using Sunday start, use additional non-hormonal contraception (such as condoms and spermicide) for the first 7 days of the patient’s first 28-day course of Larin 24 Fe . Starting Larin 24 Fe after Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease.

Start contraceptive therapy with Larin 24 Fe following the instructions in Table 1 for women not currently using hormonal contraception. If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of Larin 24 Fe .

2.3Missed Tablets

2.4Advice in Case of Gastrointestinal Disturbances In

case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures must be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking a pale yellow tablet, handle this as a missed tablet . 1 2

Thrombotic Disorders and Other Vascular Problems: Stop Larin 24 Fe if a thrombotic event occurs. Stop at least 4 weeks before through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. Liver disease: Discontinue Larin 24 Fe if jaundice occurs. High blood pressure: If used in women with well-controlled hypertension, monitor blood pressure and stop Larin 24 Fe if blood pressure rises significantly. Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Larin 24 Fe . Consider an alternative contraceptive method for women with uncontrolled dyslipidemia. Headache: Evaluate significant change in headaches and discontinue Larin 24 Fe if indicated. Bleeding Irregularities and Amenorrhea: Evaluate irregular bleeding or amenorrhea.

5.1Thrombotic Disorders and Other Vascular Problems

Stop Larin 24 Fe if an arterial thrombotic event or venous thromboembolic (VTE) event occurs. Stop Larin 24 Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately . If feasible, stop Larin 24 Fe at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during the following prolonged immobilization.

Start Larin 24 Fe no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs.

The risk of VTE in women using COCs is 3 to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COCs and when restarting oral contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes). This risk increases with age, particularly in women over 35 years of age who smoke.

Use COCs with caution in women with cardiovascular disease risk factors.

5.2Liver Disease Impaired Liver Function

Do not use Larin 24 Fe in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver . Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Discontinue Larin 24 Fe if jaundice develops. Liver Tumors Larin 24 Fe is contraindicated in women with benign and malignant liver tumors . Hepatic adenomas are associated with COC use.

An estimate of the attributable risk is 3.3 cases per 100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) COC users. However, the risk of liver cancers in COC users is less than one case per million users.

5.3Risk of Liver Enzyme Elevations with Concomitant

Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue Larin 24 Fe prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir . Larin 24 Fe can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.4High Blood Pressure Larin

24 Fe is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease . For women with well- controlled hypertension, monitor blood pressure and stop Larin 24 Fe if blood pressure rises significantly. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin.

5.5Gallbladder Disease Studies

suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC related cholestasis.

5.6Carbohydrate and Lipid Metabolic Effects Carefully

monitor prediabetic and diabetic women who are taking Larin 24 Fe. COCs may decrease glucose tolerance. Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of women will have adverse lipid changes while on COCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

5.7Headache If a

woman taking Larin 24 Fe develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Larin 24 Fe if indicated. Consider discontinuation of Larin 24 Fe in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

5.8Bleeding Irregularities and Amenorrhea Unscheduled Bleeding

and Spotting Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different contraceptive product.

In a clinical trial of norethindrone acetate and ethinyl estradiol tablets, the frequency and duration of unscheduled bleeding and/or spotting was assessed in 743 women (3,823 28-day cycles). A total of 10 subjects (1.3%) discontinued norethindrone acetate and ethinyl estradiol tablets, at least in part, due to bleeding or spotting. Based on data from the clinical trial, [24-38%] of women using norethindrone acetate and ethinyl estradiol tablets experienced unscheduled bleeding per cycle in the six months of the trial.

The percent of women who experienced unscheduled bleeding tended to decrease over time. Amenorrhea and Oligomenorrhea Women who use Larin 24 Fe may experience absence of withdrawal bleeding, even if they are not pregnant. In the clinical trial with norethindrone acetate and ethinyl estradiol tablets, 31 to 41% of the women using norethindrone acetate and ethinyl estradiol tablets did not have a withdrawal menses in at least one of 6 cycles of use.

Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs, especially when such a condition was preexistent. If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures.

If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.

5.9COC Use Before or During Early

Pregnancy Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue Larin 24 Fe use if pregnancy is confirmed.

Administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy .

5.10Depression Carefully

observe women with a history of depression and discontinue Larin 24 Fe if depression recurs to a serious degree.

5.11Malignant Neoplasms Breast Cancer Larin

24 Fe is contraindicated in females who currently have or have had breast cancer because breast cancer is a 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 or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use . Cervical Cancer Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia.

However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors.

5.12Effect on Binding Globulins The

estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.

5.13Monitoring A

woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

5.14Hereditary Angioedema In

women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

5.15Chloasma Chloasma

may occasionally occur, 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 Larin 24 Fe.

4 CONTRAINDICATIONS A high risk of arterial or venous thrombotic diseases Liver tumors or liver disease Undiagnosed abnormal uterine bleeding Breast cancer Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Larin 24 Fe is contraindicated in females who are known to have the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: Smoke, if over age 35 Have deep vein thrombosis or pulmonary embolism, now or in the past Have inherited or acquired hypercoagulopathies Have cerebrovascular disease Have coronary artery disease Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) Have uncontrolled hypertension Have diabetes mellitus with vascular disease Have headaches with focal neurological symptoms or have migraine headaches with aura Women over age 35 with any migraine headaches Liver tumors, benign or malignant, or liver disease Undiagnosed abnormal uterine bleeding Current diagnosis of, or history of, breast cancer, which may be hormone sensitive Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations

8.1Pregnancy Risk Summary There

is no use for contraception in pregnancy; therefore, Larin 24 Fe should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively.

Data Human Data Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy.

8.2Location Risk Summary Contraceptive

hormones and/or metabolites are present in human milk. CHCs can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breastfeeding The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Larin 24 Fe and any potential adverse effects on the breastfed child from Larin 24 Fe or from the underlying maternal condition.

The most common adverse reactions (≥2%) were: headache, vaginal candidiasis, nausea, menstrual cramps, breast tenderness, mood changes, bacterial vaginitis, acne, and weight gain. To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and stroke Vascular events Liver disease Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache

6.1Clinical Trial Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of norethindrone acetate and ethinyl estradiol tablets was evaluated in 743 subjects who participated in an open- label, randomized, active-controlled, multicenter clinical trial of norethindrone acetate and ethinyl estradiol tablets for contraception. This trial examined healthy, non-pregnant volunteers aged 18 to 45 years, who were sexually active and had a body mass index of ≤35 kg/m 2 . Subjects were followed for up to six 28-day cycles providing a total of 3,823 treatment-cycles of exposure.

Common Adverse Reactions ( ≥2% of all subjects) : The most common adverse reactions reported by at least 2% of the 743 women using norethindrone acetate and ethinyl estradiol tablets were the following, in order of decreasing incidence: headache (6.3%), vaginal candidiasis (6.1%), nausea (4.6%), menstrual cramps (4.4%), breast tenderness (3.4%), mood changes (including mood swings (2.2%) and depression (1.1%)), bacterial vaginitis (3.1%), acne (2.7%), and weight gain (2.0%). Adverse Reactions Leading to Study Discontinuation : Among the 743 women using norethindrone acetate and ethinyl estradiol tablets, 46 women (6.2%) withdrew because of an adverse event. Adverse events occurring in 3 or more subjects leading to discontinuation of treatment were, in decreasing order: abnormal bleeding (0.9%), nausea (0.8%), mood changes (0.8%), menstrual cramps (0.4%), increased blood pressure (0.4%), and irregular bleeding (0.4%).

6.2Postmarketing Experience Five

studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 1). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1). One of these studies reported no association between breast cancer risk and COC use.

The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use. RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs.

The following adverse reactions have been identified during post approval use of norethindrone acetate and ethinyl estradiol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Cardiovascular: chest pain, palpitations, tachycardia, angina pectoris, myocardial infarction.

Endocrine disorders: hypothyroidism, hyperthyroidism. Eye disorders: blurred vision, visual impairment, transient blindness, corneal thinning, change in corneal curvature (steepening). GI disorders: nausea, vomiting, abdominal pain, constipation, pancreatitis. Hepatobiliary disorders: cholelithiasis, cholecystitis, hepatic adenoma, hemangioma of liver.

I mmune system disorders: anaphylactic reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms. Infections: vaginal infection. Metabolism and nutrition disorders: change in weight or appetite (increase or decrease). hypoglycemia, diabetes mellitus, anemia.

Musculoskeletal and connective tissue disorders: myalgia. Skin and subcutaneous disorders : alopecia, rash (generalized and allergic), pruritus, skin discoloration, night sweats, swelling face or lips, hirsutism, skin burning sensation, erythemamultiforme, erythema nodosum, hemorrhagic eruption. Nervous systemdisorders: headache, dizziness,migraine, hyperesthesia, paraesthesia, hypoaesthesia, somnolence, loss of consciousness, sensory disturbance.

Psychiatric disorders: mood swings, depression, insomnia, anxiety, suicidal ideation, panic attack, changes in libido, bipolar disorder, dissociation, homicidal ideation. Renal and urinary disorders: pollakiuria, dysuria, cystitis-like syndrome. Reproductive system and breast disorders: breast changes (tenderness, pain, enlargement, and secretion), premenstrual syndrome, ovarian cyst, pelvic pain, ovarian cyst ruptured, pelvic fluid collection.

Vascular disorders: hot flush, thrombosis/embolism (coronary artery, pulmonary, cerebral, deep vein), migraine, transient ischemic attack, ischemic stroke. image description