The P-I-E-N-O Parkinsn's List Drug Database

levonorgestrel /Norplant^TM

SYNTHETIC PROGESTIN STEROID:

Contraception

Description: Levonorgestrel is a synthetic progestin steroid used as a long-term implantation formulation for contraception. The kit consists of six capsules made of Silastic, each containing 36 mg of slow-release levonorgestrel, which are implanted under the skin. Contraceptive protection lasts for 5 years and is reversible upon removal of the capsules. In a study of teenage mothers in New York, the pregnancy rate was 1 of 48 subjects during 1 year of follow-up. Norplant^TM was approved by the FDA in December 1990.

Mechanism of Action: Levonorgestrel inhibits the pituitary secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), preventing follicular maturation and ovulation. It is also suggested that the contraceptive action results from an increase in the cervical mucus viscosity, which inhibits sperm migration into the uterus. After removal of the capsules, fertility rates rapidly return to normal.

Pharmacokinetics: After subcutaneous implantation of Norplant^TM capsules, levonorgestrel is essentially 100% bioavailable. Plasma concentrations average 0.3 ng/mL over 5 years but vary greatly depending on body weight and metabolism. The dose provided is about 85 æg/day initially, which drops to about 50 æg/day at 9 months and 35 æg/day at 18 months. Plasma concentrations decline to roughly 25-30 æg/day by the end of 5 years. Levonorgestrel is highly protein-bound to sex hormone-binding globulin (SHBG), albumin, and ›-1-glycoprotein. Levonorgestrel is hepatically metabolized and excreted in the urine. Elimination half-life ranges 11-45 hours.

CONTRAINDICATIONS/PRECAUTIONS: Levonorgestrel implants can cause irregular menstrual bleeding in most women. In general, these irregularities diminish with continuing use. Women should be counseled regarding irregular menstrual bleeding. Levonorgestrel is absolutely contraindicated in undiagnosed abnormal vaginal bleeding.

Levonorgestrel is absolutely contraindicated in pregnancy and suspected pregnancy; it is classified as pregnancy category X. Levonorgestrel is contraindicated in women who are breast-feeding.

Levonorgestrel also is absolutely contraindicated in patients with acute hepatic disease, benign or malignant liver tumor, and breast carcinoma.

Hormonal contraceptive agents have been associated with thromboembolic disease such as deep venous thrombosis (DVT) and thrombophlebitis. Because tobacco smoking increases the risk of serious cardiovascular side effects, levonorgestrel should be used cautiously, if at all, in smokers or those with coronary artery disease.

Hormonal contraceptives have been associated with retinal thrombosis. Although this is generally believed to be related to the estrogen component, patients should be monitored carefully for the development of ocular lesions, and levonorgestrel capsules should be removed if any unexplained visual disturbance occurs.

Altered glucose tolerance secondary to decreased insulin sensitivity has been reported during hormonal contraceptive therapy. Although the effects appear to be minimal during therapy with progestins, levonorgestrel implants should be used cautiously in patients with diabetes mellitus.

Levonorgestrel is relatively contraindicated in hyperlipidemia because some progestins increase LDL concentration, exacerbating the condition, particularly with long-term use.

Hormonal contraceptives can cause fluid retention. Levonorgestrel implants should be prescribed cautiously in patients with congestive heart failure, nephrotic syndrome, or other renal disease.

DRUG INTERACTIONS: Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during levonorgestrel therapy in patients receiving phenytoin or carbamazepine concurrently. Since the dosage of levonorgestrel implants cannot be modified, another form of contraception should be considered in patients requiring therapy with carbamazepine or phenytoin. Barbiturates and rifampin also can induce hepatic enzymes, so levonorgestrel should be used cautiously in patients receiving these drugs.

Levonorgestrel can cause amenorrhea and/or galactorrhea, which would counteract the desired effect of bromocriptine. The drugs should not be used together.

ADVERSE REACTIONS: Adverse reactions that have been reported frequently, particularly during the early months of levonorgestrel therapy, include breakthrough bleeding, spotting, menstrual irregularity, scanty bleeding, and amenorrhea.

Levonorgestrel implants can cause a type of injection site reaction. Pain or pruritus at the implant site have been reported in 5-6% of patients. In addition, there is growing concern regarding the removal of the six silicone rods that release levonorgestrel. Removal can require surgery and may be painful.

Other reported adverse reactions during levonorgestrel therapy include headache, nausea/vomiting, dizziness, dermatitis, acne, anorexia, appetite stimulation, weight gain, hirsutism, breast discharge, cervicitis, abdominal pain, leukorrhea, and vaginitis.

Hormonal contraceptives can cause edema or fluid retention. Levonorgestrel should be used cautiously in patients with heart failure or renal disease.

Hormonal contraceptives can cause mood lability. Patients receiving levonorgestrel can experience mental depression, anxiety, frustration, anger, or other emotional outbursts.

The following adverse reactions have been reported during hormonal contraceptive therapy, but they appear to be related more to an estrogen effect: thromboembolic disease, especially in cigarette smokers; retinal thrombosis; elevated blood pressure or hypertension; hepatic tumors; gallbladder disease; and hyperglycemia.

PATIENT INFORMATION:

What do levonorgestrel implant capsules do?

Levonorgestrel (Norplant^TM ) acts as a contraceptive by preventing ovulation (the release of an ovum or egg). Levonorgestrel is a man-made steroid similar to a female hormone-like agent. Levonorgestrel comes as a set of six filled capsules made of a special silicone-elastic material. These implant capsules are surgically implanted under the skin and provide contraceptive protection for 5 years. Once the implants are removed, fertility quickly returns to normal. Generic levonorgestrel implant capsules are not yet available.

What should my doctor, dentist, or pharmacist know before I use levonorgestrel?

They need to know if you have any of these conditions:

• blood vessel disease, or blood clotting disorder
• breast cancer
• diabetes
• disturbed eyesight
• heart disease
• kidney disease
• liver disease
• tobacco smoker
• vaginal bleeding
• an unusual or allergic reaction to levonorgestrel, other hormones, medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I use this medicine?

Levonorgestrel implant capsules are surgically implanted under the skin by a health-care professional.

Special precautions for use in children:

This medicine is not for children.

What if I miss a dose?

This does not apply.

What other medicines can interact with levonorgestrel?

• barbiturate medicines for inducing sleep or trating seizures (convulsions)
• bromocriptine
• carbamazepine
• phenytoin
• rifampin

Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.

What side effects may I notice from using levonorgestrel?

Serious side effects with levonorgestrel include:

• dizziness or fainting spells
• leg, arm or groin pain
• severe headache
• sudden shortness of breath
• swelling of the hands, feet or ankles, or rapid weight gain
• vision or speech problems

Call your doctor as soon as you can if you get any of these side effects.

Minor side effects with levonorgestrel include:

• acne
• breakthrough bleeding, spotting, irregular menstrual cycle, or no menstruation
• breast discharge
• facial hair growth
• fluid retention and swelling
• loss of appetite or increase in appetite
• mood changes, anxiety, depression, frustration, anger, or emotional outbursts
• nausea, vomiting
• pain or itching at the place where the implant was inserted
• skin rash
• stomach discomfort
• vaginal yeast infection (irritation and white discharge)

Let your doctor know about these side effects if they do not go away or if they annoy you.

What do I need to watch for while I use levonorgestrel?

Visit your doctor for regular checks on your progress. You should have a complete check-up every 6 to 12 months.

Tobacco smoking increases the risk of getting a blood clot or having a stroke while you are using levonorgestrel, especially if you are more than 35 years old. You are strongly advised not to smoke.

If you wear contact lenses and notice visual changes, or if the lenses begin to feel uncomfortable, consult your eye doctor.

Levonorgestrel implants do not protect you against HIV infection (AIDS) or other sexually transmitted diseases.

Where can I keep my medicine?

Keep out of the reach of children.

Store at room temperature, approximately 25C (77F). Protect from moisture and excessive heat.

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