Norplant

Uses

This is used for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. Oral contraceptives are highly effective. Table II lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

Norplant 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 therapyEndometrial Hyperplasia, Endometriosis, Hypermenorrhea, Postmenopausal Osteoporosis, Pregnant State, Moderate Menopausal Vasomotor Symptoms, Severe Vasomotor Symptoms Associated With Menopause, Emergency Contraception

How Norplant 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.

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

Norplant dosage

Monophasic combined oral contraceptive (COC): levonorgestrel 150-250 mcg + ethinylestradiol 30 mcg once daily.

Triphasic COC: levonorgestrel 50-125 mcg + ethinylestradiol 30-40 mcg once daily.

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

Side Effects

Menstrual irregularities; headache, dizziness; breast discomfort; gynaecomastia; depression; disturbance of appetite; wt changes; fluid retention; oedema; changes in libido; hair loss or hirsutism; GI disturbances (nausea and vomiting); genitourinary changes; haematologic disorders; endocrine and metabolic disorders; cholestatic jaundice; local skin reactions; chorea; contact lens intolerance; steeping of corneal curvature; pulmonary thromboembolism; carbohydrate and/or glucose intolerance; depression; chloasma; BP increase, liver impairment; reduced menstrual loss, 'spotting' in early cycles, absence of withdrawal bleeding; rarely photosensitivity; increased risk in breast cancer; elevation of plasma bound iodine, cortisol and thyroid binding, erythrocyte sedimentation may be accelerated; increases in plasma copper, iron and alkaline phosphatase; may affect serum triglyceride and lipoprotein levels; retinal vascular thrombosis.

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.

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

Sex-steroid dependent cancer; past ectopic pregnancy; malabsorption syndromes; functional ovarian cysts; active liver disease, recurrent cholestatic jaundice, history of jaundice in pregnancy; history of CV or renal impairment; DM; asthma; epilepsy; migraine; depression; lactation; conditions exacerbated by fluid retention; hypercalcaemia; CV and gall bladder diseases; lipid effects; familial defects of lipoprotein metabolism; patients at risk of venous thromboembolism, breast cancer, preexisting uterine leiomyomata and benign hepatic adenoma; family history of arterial disease in 1st degree relative <45 yr; BP > systolic 140 mmHg and diastolic 90 mmHg; >35 yr; BMI 30-39 kg/m2; migraine without focal aura, controlled with 5HT1; GI upset (vomiting and diarrhoea), missed pills and interaction with other drugs may require additional contraceptive precautions. Should be taken at same time each day.

Interaction

CYP3A4 inducers may decrease levels/effects eg aminoglutethimide, carbamazepine, nafcillin, nevirapine, atazanavir, nelfinavir, phenobarbital, phenytoin, lamotrigine, rifamycins, griseofulvin and ritonavir; ampicillin, tetracycline and other antibiotics may reduce efficacy; oestrogens may antagonise anticoagulant effect of coumarins; may inhibit metabolism of prednisolone and ciclosporin; may reduce clearance of alprazolam, chlordiazepoxide, diazepam; may increase clearance of lorazepam, oxazepam, temazepam.

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.

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

Category X: Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Contraindication

Pregnancy, undiagnosed vaginal bleeding, severe arterial disease (or family history of atherogenic lipid profile); liver adenoma; porphyria; after evacuation of hydatidiform mole; history of breast cancer; hepatic impairment; thrombophloebitis or thromboembolic disorders; breast carcinoma except in selected patients being treated for metastatic disease; oestrogen-dependent tumour; smoking ≥40 cigarettes daily; >50 yr; diabetes complications present; BMI >39 kg/m2; migraine with typical focal aura, lasting >72 hr despite treatment or migraine treated with ergot derivatives; BP >160 mmHg systolic and 100 mmHg diastolic; transient ischaemic attacks without headaches; SLE; gallstones; history of haemolytic uraemic syndrome, pruritis during pregnancy; cholestatic jaundice; chorea or deterioration of otosclerosis pemphigoid; breast feeding during 1st 6 mth after delivery.

Special Warning

Renal Impairment: Use with caution and monitor BP.

Hepatic Impairment: Contraindicated.

Acute Overdose

Symptoms: nausea and vomiting, withdrawal bleeding may occur in females.

Treatment: symptom specific and supportive; emesis and charcoal administration may be used.

Storage Condition

Store in a cool & dry place, protected from light. Keep out of reach of children

Innovators Monograph

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