Ledifer

Uses

Primarily for prevention of pregnancy and also to regularize menstrual cycle & helps to reduce discomforts experienced during menstruation.

Ledifer is also used to associated treatment for these conditions: Menopausal Osteoporosis, Mild to Moderate Acne, Premenstrual Dysphoric Disorder ( PMDD), Moderate Acne vulgaris, Moderate, severe, Vasomotor Symptoms caused by Menopause, Contraception, Folate supplementation therapyFolic acid antagonist overdose, Iron Deficiency (ID), Iron Deficiency Anemia (IDA), Oral ContraceptivesEndometrial Hyperplasia, Endometriosis, Hypermenorrhea, Postmenopausal Osteoporosis, Pregnant State, Moderate Menopausal Vasomotor Symptoms, Severe Vasomotor Symptoms Associated With Menopause, Emergency Contraception

How Ledifer works

Ethinylestradiol is a synthetic estrogenic compound. Use of estrogens have a number of effects on the body including reduced bone density. Combined oral contraceptives suppress ovulation by suppressing gonadotrophic hormone, thickening cervical mucus to prevent the travel of sperm, and preventing changes in the endometrium required for implantation of a fertilized egg. Ethinylestradiol decreases luteinizing hormone, decreasing vascularity in the endometrium. It also increases sex hormone binding globulin.

Iron is necessary for the production of hemoglobin. Iron-deficiency can lead to decreased production of hemoglobin and a microcytic, hypochromic anemia.

Mechanism of action on ovulation

Oral contraceptives containing levonorgestrel suppress gonadotropins, inhibiting ovulation. Specifically, levonorgestrel binds to progesterone and androgen receptors and slows the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. This process results in the suppression of the normal physiological luteinizing hormone (LH) surge that precedes ovulation. It inhibits the rupture of follicles and viable egg release from the ovaries. Levonorgestrel has been proven to be more effective when administered before ovulation.

Mechanism of action in cervical mucus changes

Similar to other levonorgestrel-containing contraceptives, the intrauterine (IUD) forms of levonorgestrel likely prevent pregnancy by increasing the thickness of cervical mucus, interfering with the movement and survival of sperm, and inducing changes in the endometrium, where a fertilized ovum is usually implanted. Levonorgestrel is reported to alter the consistency of mucus in the cervix, which interferes with sperm migration into the uterus for fertilization. Levonorgestrel is not effective after implantation has occurred. Interestingly, recent evidence has refuted the commonly believed notion that levonorgestrel changes the consistency of cervical mucus when it is taken over a short-term period, as in emergency contraception. Over a long-term period, however, levonorgestrel has been proven to thicken cervical mucus. The exact mechanism of action of levonorgestrel is not completely understood and remains a topic of controversy and ongoing investigation.

Effects on implantation*

The effects of levonorgestrel on endometrial receptivity are unclear, and the relevance of this mechanism to the therapeutic efficacy of levonorgestrel is contentious. Prescribing information for levonorgestrel IUDs state that they exert local morphological changes to the endometrium (e.g. stromal pseudodecidualization, glandular atrophy) that may play a role in their contraceptive activity.

Mechanism of action in hormone therapy

When combined with estrogens for the treatment of menopausal symptoms and prevention of osteoporosis, levonorgestrel serves to lower the carcinogenic risk of unopposed estrogen therapy via the inhibition of endometrial proliferation. Unregulated endometrial proliferation sometimes leads to endometrial cancer after estrogen use.

Dosage

Ledifer dosage

How to take Levonorgestrel, Ethinylestradiol & Ferrous Fumarate:

To achieve maximum contraceptive effectiveness, Levonorgestrel, Ethinylestradiol & Ferrous Fumarate must be taken in the order directed on the package and at intervals not exceeding 24 hours. Women should be instructed to take the pills at about the same time every day, preferably after the evening meal or at bedtime. One pill is to be taken daily for 28 consecutive days. Each subsequent pack is started on the day after the current pack is completed.

• If you have decided to take Levonorgestrel, Ethinylestradiol & Ferrous Fumarate for contraception, wait for your next menstruation begins.
• From the first day of your menstruation, start taking the first white pill from the left corner of the top row(with arrow mark) of your Levonorgestrel, Ethinylestradiol & Ferrous Fumarate pill pack.
• Continue taking one white pill each day along the arrow mark.
• After taking 21 white pills for 21 days, continue taking one brown iron pill every day from the last row in the foil for next 7 days.

It is most likely that your menstruation will start while taking the brown pills. Do not discontinue taking the brown pills. In addition to giving you iron supplementation regular taking of the brown tablets for 7 days will help you keep your pill taking routine. If your menstruation does not start during this time, check with your doctor to make sure you are not pregnant.After completing the seven iron pills, start taking white pills from another Levonorgestrel, Ethinylestradiol & Ferrous Fumarate pack and continue taking the pill as long as you don't want to be pregnant.

What to do after missing the pill?

How to delay a period: To delay a period you should continue with another new pack of Levonorgestrel, Ethinylestradiol & Ferrous Fumarate just after finishing the white active pill of the present pack(that is no need to take brownish inert tablet of present pack). The extension can be carried on for as long as wished until the end of the second pack. When you wish your period to begin, just stop tablet taking. While using the second pack woman may have some breakthrough bleeding or spotting. Start with your next pack after the usual 7 day red inactive pill interval.

Advice in case of Vomiting: If vomiting occurs within 4 hours after white active pill taking, absorption may not be complete. In such an event, the advice concerning Management of Missed Pills is applicable. The woman must take the extra active pill(s) needed from a back up pack after vomiting.

One tablet should be taken orally with a glass of water.

Side Effects

Different types of pill suit different types of woman. At the initial stage some women may experience side-effects like dizziness, headache, nausea or inter-menstrual bleeding. If taken regularly, such types of side-effects normally go away after 2-3 months. If she continues to have the side effects beyond 2-3 months, she could consult with a doctor. After starting one brand of oral contraceptive pills, if you feel any inconvenience such as migraine, changes in eyesight or speeh, unusual pain or swelling in your legs, sharp chest pains or shortness of breath, yellow skin or a rise in blood pressure take advice from your doctor or contact the nearest family planning centre.

Toxicity

Female patients experiencing and overdose may present with withdrawal bleeding, nausea, vomiting, breast tenderness, abdominal pain, drowsiness, and fatigue. Overdose should be treated with symptomatic and supportive care including monitoring for potassium concentrations, sodium concentrations, and signs of metabolic acidosis.

Acute iron overdosage can be divided into four stages. In the first stage, which occurs up to six hours after ingestion, the principal symptoms are vomiting and diarrhea. Other symptoms include hypotension, tachycardia and CNS depression ranging from lethargy to coma. The second phase may occur at 6-24 hours after ingestion and is characterized by a temporary remission. In the third phase, gastrointestinal symptoms recur accompanied by shock, metabolic acidosis, coma, hepatic necrosis and jaundice, hypoglycemia, renal failure and pulmonary edema. The fourth phase may occur several weeks after ingestion and is characterized by gastrointestinal obstruction and liver damage. In a young child, 75 milligrams per kilogram is considered extremely dangerous. A dose of 30 milligrams per kilogram can lead to symptoms of toxicity. Estimates of a lethal dosage range from 180 milligrams per kilogram and upwards. A peak serum iron concentration of five micrograms or more per ml is associated with moderate to severe poisoning in many.

The oral LD50 in rats is greater than 5000 mg/kg.

An overdose of this drug, like other contraceptives, may cause nausea and withdrawal bleeding. Provide symptomatic treatment in the case of a levonorgestrel overdose and contact the local poison control center. There is no specific antidote for a levonorgestrel overdose.

Precaution

Some medications may interfere with the efficacy of the pill. Contact your doctor if you are taking any drugs, such as antibiotics, rifampicin or medicines for seizures. You may have to use another method of contraception during this time.

Interaction

Interactions between ethinylestradiol and other drugs may lead to decreased or increased ethinylestradiol concentrations, respectively.Decreased ethinylestradiol serum concentrations may cause an increased incidence of breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy of the oral contraceptive. Example of substances that may decrease serum ethinylestradiol concentrations include rifampicin, phenytoin, primidone, rifabutin, dexamethasone, griseofulvin, topiramate, some protease inhibitors, modafinil, ritonavir and barbiturates. Certain antibiotics including ampicillin, other penicillins and tetracyclines may reduce the efficacy of oral contraceptives. During concomitant use of Levonorgestrel, Ethinylestradiol & Ferrous Fumarate & other drugs that may lead to decreased ethinylestradiol serum concentrations, it is recommended that a non-hormonal back-up method of contraception to be used in addition to the regular intake of Levonorgestrel, Ethinylestradiol & Ferrous Fumarate.

Volume of Distribution

A 30µg oral dose has an apparent volume of distribution of 625.3±228.7L and a 1.2mg topical dose has an apparent volume of distribution of 11745.3±15934.8L.

One pharmacokinetic study determined a mean steady-state volume of distribution of 1.5 mg of levonorgestrel to be 162.2 L in those with normal BMI and in the range of 404.7 L to 466.4 L in obese patients with a body mass index of at least 30. Mean volume of distribution in 16 patients receiving 0.75 mg of levonorgestrel in another pharmacokinetic study was 260 L. The Plan B one-step FDA label reports an apparent volume of distribution of 1.8 L/kg.

Elimination Route

A 30µg oral dose of ethinylestradiol reaches a C_max of 74.1±35.6pg/mL, with a T_max of 1.5±0.5h, and an AUC of 487.4±166.6pg*h/mL. A 1.2mg dose delivered via a patch reaches a C_max of 28.8±10.3pg/mL, with a T_max of 86±31h, and an AUC of3895±1423pg*h/mL.

The efficiency of absorption depends on the salt form, the amount administered, the dosing regimen and the size of iron stores. Subjects with normal iron stores absorb 10% to 35% of an iron dose. Those who are iron deficient may absorb up to 95% of an iron dose.

Orally administered levonorgestrel is absorbed in the gastrointestinal tract while levonorgestrel administered through an IUD device is absorbed in the endometrium. Levonorgestrel is absorbed immediately in the interstitial fluids when it is inserted as a subdermal implant. After insertion of the subdermal implant, the Cmax of levonorgestrel is attained within 2-3 days.The Cmax following one dose of 0.75 mg of oral levonorgestrel is reached within the hour after administration, according to one reference. In a pharmacokinetic study of 1.5 mg of levonorgestrel in women with a normal BMI and those considered to be obese (BMI>30), mean Cmax was found to be 16.2 ng/mL and 10.5 ng/mL respectively. Tmax was found to be 2 hours for those with normal BMI and 2.5 hours for patients with increased BMI. The bioavailability of levonorgestrel approaches 100%.

Mean AUC has been shown to be higher in patients with a normal BMI, measuring at 360.1 h × ng/mL versus a range of 197.28 to 208.1 h × ng/mL in an obese group of patients. Obesity may contribute to decreased efficacy of levonorgestrel in contraception.

Half Life

A 30µg oral dose has a half life of 8.4±4.8h and a 1.2mg topical dose has a half life of 27.7±34.2h.

The elimination half-life of a 0.75 mg dose of 1.5 mg of levonorgestrel ranges between 20-60 hours post-administration. A pharmacokinetic study of women with a normal BMI and BMI over revealed an elimination half-life of 29.7 h and 41.0-46.4 hours, respectively. Another pharmacokinetic study revealed a mean elimination half-life of 24.4 hours after a 0.75 mg dose of levonorgestrel was administered to 16 patients.

Clearance

Ethinylestradiol has an intravenous clearance of 16.47L/h, and an estimated renal clearance of approximately 2.1L/h. A 30µg oral dose has a clearance of 58.0±19.8L/h and a 1.2mg topical dose has a clearance of 303.5±100.5L/h.

Clearance was found to 4.8 L/h in healthy female volunteers with a normal BMI, and 7.70-8.51 L/h in obese patients after a single 1.5 mg dose. After a 0.75 mg dose of levonorgestrel in 16 patients in another pharmacokinetic study, mean clearance was calculated at 7.06 L/h. Following levonorgestrel implant removal, the serum concentration falls below 100 pg/mL within the first 96 hours and further falls below the sensitivity of detection within the range of 5 days to 2 weeks.

Elimination Route

Ethinylestradiol is 59.2% eliminated in the urine and bile, while 2-3% is eliminated in the feces. Over 90% of ethinylestradiol is eliminated as the unchanged parent drug.

Approximately 45% of an oral levonorgestrel dose and its conjugated or sulfate metabolites are found to be excreted in the urine. Approximately 32% of an orally ingested dose is found excreted in feces, primarily in the form of glucuronide conjugates of levonorgestrel.

Pregnancy & Breastfeeding use

Pregnancy Category B3.

During Pregnancy: Pregnancy must be excluded before starting Levonorgestrel, Ethinylestradiol & Ferrous Fumarate. If pregnancy occurs during use of Levonorgestrel, Ethinylestradiol & Ferrous Fumarate, the preparation must be withdrawn immediately. Oral contraceptives have not been shown to have any deleterious effects on the foetus or to increase the incidence of miscarriage in women who discontinue their use prior to conception. However, in women who discontinue oral contraceptives with the intent of becoming pregnant, a non-hormonal method of contraception is recommended for three months before attempting to conceive.

During Lactation: Estrogen-containing oral contraceptives given in the postpartum period may interfere with lactation. There may be a decrease in the quantity and a change in the composition of the breast milk. Furthermore, small amounts of contraceptive steroids and/or metabolites have been identified in the milk of mothers receiving them. A few adverse effects have been reported, including jaundice and breast enlargement. The use of oestrogen-containing oral contraceptives should be deferred until the infant has been completely weaned.

Contraindication

Levonorgestrel, Ethinylestradiol & Ferrous Fumarate is contraindicated in-

• Pregnant
• Over 45 years of age
• A heavy smoker (more than 20 cigarette/day)
• Attacked by heart disease, clotting of blood in the vein
• Suffer from liver disease or jaundice
• Suffer from high blood pressure, migraine, feel something hard in your breast, diabetes with vascular involvement, experience excessive bleeding for which no reason has yet been ascertained
• Hypersensitivity to any of the components of evonorgestrel, Ethinylestradiol & Ferrous Fumarate.

Acute Overdose

Symptoms of oral contraceptive overdosage in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/ fatigue; withdrawal bleeding may occur in females. There is no specific antidote and further treatment of overdose, if necessary, is directed to the symptoms.

Storage Condition

Store in 15° C to 30° C, dry place and keep away from light. Keep out of reach of children.

Innovators Monograph

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