MTP Kit: Mifepristone 200mg + Misoprostol 800mcg for Medical Termination of Pregnancy

Product description

• Introduction
• Evolution of Medical Abortion
• Discovery of Prostaglandins
• Discovery of Mifepristone
• Approval of Medical Abortion
• Counseling
• Confirmation of Pregnancy Termination
• Efficacy of these Regimens
• Birth Control
• Contraindications
• Caution is Required When
• Special Situations
• Continuing Pregnancy After Administration (Failure of Medication Abortion)
• FAQ’s

Introduction

Unsafe abortion is still a significant health problem in the world. For example, of the 6.4 million abortions performed in India in 2002 and 2003, 56%, or 3.6 million, were unsafe (Abortion Assessment Project I, 2004). Induced abortion is the most frequently performed intervention in obstetrics and gynecology, with an estimated 46 million abortions globally each year.

Medical Abortion with Mifepristone and prostaglandin was first introduced in 1988 and is now approved in 31 countries. Since the introduction of this method, research has primarily focused on improving its efficacy and defining the optimal type, dose, and route of administration of the prostaglandin analog. In addition, many studies have also focused on finding the minimum effective dose of Mifepristone needed to induce an abortion.

An essential reason for reducing the dosage of Mifepristone has been the relatively high price. This booklet will help you understand the evolution and concerns of Medical Abortion over time.

Evolution of Medical Abortion

Inducing abortion by administering drugs is not a new concept. Historic documents list many medications, tablets, decoctions, and other substances like papaya, abrus precatorius, etc., which women have swallowed to induce abortion. However, most of these drugs have been either ineffective as an abortifacient or dangerous to the health and/or even the women’s life.

This has led to a perception amongst lay people that medication abortion may not be very efficacious. This is a patently wrong perception, and modern drugs’ safety and efficacy should be emphasized during counseling.

Discovery of Prostaglandins

This was an essential step in the development of safer methods. The first studies were performed using an intra- amniotic injection of prostaglandin. However, these methods were only suitable for inducing abortion in the second trimester. Very quickly, a vaginally-applicable prostaglandin was developed, which was also efficacious during early pregnancy. But the drawbacks of the prostaglandin analogs available then, i.e., associated pain and gastrointestinal side effects, were significant obstacles to widespread use.

However, besides the above problems, myocardial infarction attributed to coronary spasm induced by sulprostone and the disadvantages of gemeprost (being unstable at room temperature, difficult to store and transport, expensive, and only available in a limited number of countries) led to the substitution of sulprostone and gemeprost by the safer drug- Misoprostol.

Misoprostol

Misoprostol is a synthetic prostaglandin E₁. Misoprostol acts on the cervix to efface (soften) and the uterus to contract. It also inhibits gastric acid secretion in humans.

Mode of Action of Misoprostol

Misoprostol causes myometrial contractions by interacting with specific receptors on myometrial cells. This interaction results in a change in calcium concentrations, thereby initiating muscle contraction. In addition, by interacting with prostaglandin receptors, Misoprostol causes the cervix to soften and the uterus to contract, expulsing the uterine contents.

Pharmacokinetics of Oral and Vaginal Misoprostol

Misoprostol is extensively absorbed and readily metabolized to the free acid, the biologically active form, and is responsible for its clinical activity.
After oral administration, the plasma Misoprostol levels increased rapidly, peaked at 30 minutes, declined quickly, and remained low after that.

In contrast, after vaginal administration, the plasma concentration gradually increased, reaching maximum levels after 70-80 minutes, and slowly declined, with detectable levels present after 6 hours. Vaginal Misoprostol was present in the circulation longer than oral Misoprostol; hence, its duration of stimulation of the uterus exceeds that of oral Misoprostol.

But, when used alone for Medical Abortion, a higher dose of Misoprostol was required causing severe gastrointestinal side effects like cramps, nausea, vomiting, and diarrhea.

The Turning Point (Discovery of Mifepristone)

Mode of Action of Mifepristone

Mifepristone is an anti-progesterone drug; thereby, it inhibits progesterone’s activity and results in pregnancy termination. The anti-progestational activity of Mifepristone results from competitive interaction with progesterone at progesterone-receptor sites. Therefore, it inhibits the activity of endogenous or exogenous progesterone, thereby causing the termination of pregnancy.

Doses of 1 mg/kg or greater of Mifepristone have been shown to antagonize the endometrial and myometrial effects of progesterone in women. In addition, the receptor-Mifepristone complex inhibits transcription, resulting in the down-regulation of progesterone-dependent genes, with decidual necrosis and detachment of the products of conception.

However, it became clear that Mifepristone had maximal effectiveness of 80% when used alone, which was not sufficiently effective to be used as an abortifacient drug in clinical routine.

The final breakthrough came with the discovery that Mifepristone increased the sensitivity of the pregnant myometrium to prostaglandins, which allowed the use of a reduced dose of prostaglandin. This led to the development of a combined treatment using Mifepristone followed by Misoprostol.

In straightforward terms, Mifepristone is used to detach the pregnancy and Misoprostol to expel it.

Approval of Medical Abortion

Medical Abortion was first approved in France in 1988, followed by approvals in the UK (1991) and Sweden (1992). Finally, Medical Abortion was approved in India in 2002.

The MTP act allows medication abortion up to 49 days of gestation. However, this is conditional to the provider following the MTP act in its entirety, including filling Form C and the MTP register.
Day 1: Mifepristone 200 mg orally Inj. Anti-D to Rh – negative patient
Day 3: Misoprostol 400 μg vaginally or orally
Day 14: Follow-up visit to assess for completion of abortion, preferably clinically or by ultrasonography if indicated.

Combipack of Mifepristone & Misoprostol has been approved for use up to 77 days from LMP by the Drug Controller Authority of India.
Regime – 49 to 77 days
Day 1: Mifepristone 200 mg orally. Inj. Anti-D to Rh negative patient
Day 3 : Misoprostol 800 mcg vaginal preferred / sublingual / buccal
Day 14: Follow-up visit for clinical assessment
As per the MTP Act, Medical methods for termination of pregnancy not exceeding seven weeks may be prescribed by a registered medical practitioner (as defined in the act) as prescribed under Section 2 (d). Rule 3, having access to a place approved by the Government under Section 4 (b) & Rule 5 of MTP Rules. RMP should display a certificate to this effect from the owner of the approved place.

Besides the regimen mentioned above, the following regimens are also practiced.

1. US FDA approved-regimen 2000
The regimen is approved for up to 49 days of gestation.
Day 1: Mifepristone 600 mg orally
Day 3: Misoprostol 400 μg orally
Day 14: Follow-up visit to assess for completion of abortion clinically, by ultrasonography, or by documenting a significant decrease in serum beta-hCG levels.
Surgical termination is recommended if a viable pregnancy is detected at this time by ultrasonography because the pregnancy may continue, and there is a risk of fetal malformation.

2. Regimen recommended by Royal College Of Obstetrics and Gynaecology (RCOG), World Health Organization (WHO)
The regimen is recommended for up to 77 days of gestation.
Day 1: Mifepristone 200 mg orally
Day 3: Misoprostol 800 mcg vaginally
For women at 49-77 days of gestation, if abortion has not occurred 4 hours after administration of Misoprostol, the second dose of Misoprostol 400? g may be administered vaginally or orally.
Day 14: Follow-up visit to assess for completion of abortion clinically, by ultrasonography, or by documenting a significant decrease in serum beta-hCG levels.
Surgical termination is recommended if a viable pregnancy is detected at follow-up because the pregnancy may continue, and there is a risk of fetal malformation.

Counseling

It may be appropriate to say that patient perception of medication abortion depends mainly on the counseling. Therefore, counseling should be adequate, nonjudgmental, and confidential. It should cover at least the following talking points and address all patient’s doubts.

Vaginal bleeding may occur for up to 10-14 days. It usually resembles heavy, prolonged menses. If the patient feels that the bleeding is excessive or she is passing clots, she should report to the provider immediately.

• Occasionally, the patient may see the products of conception on expulsion. She should be told that these usually look like a pinkish mass. She should be reassured that this is a part of the procedure and is not abnormal.
• Three visits are usually essential for the procedure.
• In case of failure of the medical method (not very common) or retained products of conception or excessive bleeding, the abortion may have to be completed surgically.

Post-abortion contraception is vital in preventing another unwanted pregnancy.

Confirmation of Pregnancy Termination

Patients should be scheduled for a follow-up visit approximately 14 days after administration of Mifepristone to confirm that the pregnancy is completely terminated and assess the degree of bleeding. Vaginal bleeding is not evidence of the termination of pregnancy. Termination can be confirmed by clinical examination or an ultrasonographic scan. Lack of bleeding following treatment, however, usually indicates failure. Therefore, Medical Abortion failures should be managed with surgical termination.

It is important to stress that ultrasound should not be considered mandatory in the entire process of medication abortion. Instead, it is an aide that the clinician must use as indicated.

Efficacy of these Regimens

Actual drug failure is defined as the presence of cardiac activity two weeks following Mifepristone and Misoprostol administration. It occurs in < 1 % of women, and the process should be completed surgically.

A study using 600 mg of Mifepristone followed by 400 mcg of Misoprostol orally in women seeking termination of pregnancy for up to 77 days of gestation resulted in complete abortion in 92% of patients, with Surgical Abortion being required in 8% of the patients. In the latter, the reasons for Surgical Abortion were incomplete abortion in 5% and continuing pregnancy in 1%. While 0.6% of the patients requested an intervention, it was a medical indication in 2%.

A consecutive case series of 2,000 women with pregnancies of up to 77 days of gestation and using 200 mg of Mifepristone orally followed by 800 μg of Misoprostol orally resulted in complete abortion in 97.5% of the patients. The surgical evacuation was required in 2.5% of the patients, with the reasons being incomplete abortion in 1.4%, missed abortion in 0.4%, and continuing pregnancy in 0.6% of the patients.

Birth Control

Counseling for post-abortion contraception forms is as essential a part of the procedure as the technology itself. The woman may conceive immediately after the abortion, even before the next menstruation. Therefore, the patient must adopt a method of contraception immediately after the abortion.
Birth control methods should be started as soon as it is determined that the pregnancy is terminated. After that, practically all methods of contraception can be used.

Contraindications

Abortion per se and medication abortion, in particular, are amongst the safest medical procedures. There are very few absolute contraindications to Medical Abortion. These include:

1. Previous allergic reaction to one of the drugs involved.
2. Inherited porphyria.
3. Chronic adrenal failure.
4. Known or suspected ectopic pregnancy.

Caution is Required When

1. The woman is on long-term corticosteroid therapy (including those with severe, uncontrolled asthma).
2. She has a hemorrhagic disorder.
3. She has severe anemia.
4. She has pre-existing heart disease or cardiovascular risk factors (e.g., hypertension and smoking).

Special Situations

Age

Neither adolescence nor older age (e.g., over 35 years) should be considered a contraindication to Medical Abortion.

Anemia

This need not be regarded as a contraindication. However, anemia detected at the time of abortion should be treated. In addition, average blood loss in Medical Abortion may be more than that in Surgical Abortion, and the incidence of heavy bleeding may be higher.

Breastfeeding

Mifepristone likely passes into breast milk. Small amounts of Misoprostol also enter breast milk soon after administration, but it is unknown whether this could affect the infant. As Misoprostol levels decline rapidly, it has been recommended that Misoprostol should be taken immediately after a feed and the next feed given after 4 hours in case of oral administration.

After vaginal administration, Misoprostol levels stay high for longer, and the meal should preferably be provided more than 6 hours later. Unfortunately, the available data do not allow a precise recommendation on optimum timing.

Continuing Pregnancy After Administration (Failure of Medication Abortion)

Mifepristone

Mifepristone is indicated for use in the termination of pregnancy (through 77 days of pregnancy) and has no other approved indication for use during pregnancy.
At the last visit, patients with an ongoing pregnancy risk of fetal malformation from the treatment. Therefore, surgical termination is recommended to manage Medical Abortion treatment failures.

Misoprostol

Several reports in the literature indicate that prostaglandins, including Misoprostol, may have teratogenic effects on human beings. Skull deformations, for example, skull cranial nerve palsies, delayed growth and psychomotor development, facial malformation, and limb defects, have all been reported after exposure during the first trimester.

Insulin-Dependent Diabetes or Thyroid Disorder

There is no evidence that Medical Abortion causes particular problems in women with these disorders. However, Mifepristone has been shown to alter insulin sensitivity in vitro, and these effects may or may not be reflected in blood sugar and insulin levels.

Multiple Pregnancy (Current Gestation)

There is no evidence that the failure rate of Medical Abortion is increased or that a different dosage regimen is required in the case of multiple pregnancy.

Obesity

There is no evidence that the failure rate of Medical Abortion is increased or that a different dosage regimen is required in obese women.

Bronchial Asthma

Mifepristone & Misoprostol can be used.

Previous Caesarean Section

One study shows that the safety and efficacy of early Medical Abortion are unaffected by previous cesarean sections.

Smoking

There is no evidence of interaction between smoking and Medical Abortion risks. However, smoking contributes to cardiovascular risk, which should be considered when assessing a woman’s overall suitability for Medical Abortion.

Uterine Malformations, Congenital and Acquired; Previous Cervical Surgery

There is no evidence that these represent contraindications.

FAQ’s

Some of the issues which need to be addressed are given below. There are, of course, more questions than one can outline, but we hope that the following will be helpful:

1. Is the interval Between the Administration of Mifepristone and the Prostaglandin Crucial?

The licensed and most commonly used interval of 36-48 hours corresponds to the time when the uterus is most sensitive to prostaglandin after priming with Mifepristone; hence, the therapeutic dose can be reduced to the minimum. It has been shown recently, however, that the interval can be shortened to 24 hours or lengthened to 72 hours without loss of efficacy when Mifepristone is used in combination with 800 mcg of vaginally-administered Misoprostol. Therefore, if Misoprostol is given as an oral dose of 400 mcg, the interval of 36-48 hours should be adhered to. Other time intervals are currently being studied.

2. What Pain Relief Should be Available to Women During Medical Abortion?

Pain is caused both by the abortion process and as a side effect of prostaglandin. It is most likely to be felt in the few hours after administration of the prostaglandin when the gestational sac/embryo is being expelled from the uterus.

Healthcare providers should make adequate analgesia easily available to all women who request it during a Medical Abortion. Common preparations are paracetamol 500-1,000 mg or non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen 200 mg. In cases of severe pain, codeine 30-40 mg may be added to either of the treatments mentioned above (see “Pain in Medical Abortion“).

3. Are there any Undesirable Effects Due to the Drugs Used for Medical Abortion?

The treatment procedure is designed to induce the vaginal bleeding and uterine cramping necessary to produce an abortion. Nearly all women who receive Mifepristone and Misoprostol will report adverse reactions, and many can be expected to register more than one such reaction. These are as follows:

1. Gastrointestinal side effects like diarrhea, abdominal pain, nausea, flatulence, dyspepsia, headache, vomiting, and constipation.
2. Shivering.
3. Hyperthermia.
4. Dizziness.
5. Pain due to uterine contractions.
6. Severe genital bleeding.
7. Shock.
8. Pelvic pain.
9. Uterine rupture (requiring surgical repair, hysterectomy, and/or salpingo-oophorectomy).

4. Is there a Risk of Overdosage with Mifepristone and Misoprostol?

Mifepristone

No severe adverse reactions were reported in tolerance studies in healthy non-pregnant women where Mifepristone was administered in single doses greater than threefold of 600 mg (1,800 mg) for termination of pregnancy. However, if a patient ingests a massive overdose, she should be observed closely for signs of adrenal failure.

Mifepristone’s oral acute lethal dose in mice, rats, and dogs is more significant than 1,000 mg/kg.

Misoprostol

Clinical signs that may indicate an overdose are a sedation, tremor, convulsions, dyspnoea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. Symptoms should be treated with supportive therapy. It is not known if Misoprostol acid is dialysable. However, because Misoprostol is metabolized like a fatty acid, it is unlikely that dialysis would be an appropriate treatment for overdosage.

5. Are There any Warnings and Precautions to be Taken During and after Medical Abortion?