Ours is the first quinacrine sterilization (QS) report for women at high risk of surgery.  To understand the need for such a trial one must consider our situation at a government medical school in a predominantly rural area of the Punjab in India.  First, our government advises against surgical sterilization for women with hemoglobin less than 7 g/dl.  But 57% of women in our area are so anemic.  Second, as a referral center we see women whose life would be endangered by another pregnancy but who are very poor risks for any surgery.  Third, sterilization failures are frequently referred to us, but it is known that previous pelvic surgery increases the risk of a serious complication for surgical sterilization.  Fourth, we find many women desiring no more children who fear any surgery, despite obvious need for sterilization.  And finally, our department has a leadership tradition of promoting choice among well-informed women.  One must also consider the general situation of women and their children in the Punjab — 52% are illiterate with mean number of years of schooling being 2.0 years.  Our women have an average of 2.9 children compared to 3.4 for all of India.  But 46% of children under 4 years of age in the Punjab are underweight and 40% are stunted.  Less than half of women who say they want no more children are actually protected by sterilization.

It was in this context, and after reviewing published reports showing the safety and reasonable efficacy of QS, that we decided to make this method available in our department.

From December 1993 through June 1999, we studied 132 women of reproductive age who had two transcervical insertions of 7 quinacrine pellets (252 mg) with 2 diclofenac pellets (50 gm) a month apart during the proliferative phase of the menstrual cycle.  A modified IUD inserter was used to place the pellets at the fundus following the standard protocol.  One 150 mg injection of depo medroxyprogesterone acetate (DMPA) was given with the first insertion as an additional contraceptive.

Of this group, 90 women were considered at high risk for surgery (mainly anemia, cardio-vascular disease, bronchial asthma and history of pelvic inflammatory disease); 27 had voluntarily chosen a nonsurgical procedure; and 15 were cases of earlier surgical sterilization failure or those for whom this operation was not technically feasible.  All of these women had given their informed consent to undergo this procedure.

No pregnancy failures or serious complications have been reported.  The mean follow-up was 3.46 years with minimum follow-up of 1 year.  The main side effect was transient menstrual irregularities, probably due to the DMPA injection.  Other side effects included transient lower abdominal pain, oligomenorrhea or amenorrhea and mild post insertion bleeding.

Although this service has been interrupted by a government ban, we conclude that QS is a reasonable option, especially for women who are at high risk for the surgical procedure.

My quinacrine sterilization (QS) trial is conducted in a private clinic in Tehran.  Only women whom I was confident could be followed were admitted to the study, which was initiated in September 1990 and continues.

The first 160 cases included 2 protocols, the first using 3 insertions of 252 mg quinacrine and the second only 2 insertions.  Efficacy of each is shown in Table 1.  Complications and side effects are seen in Table 2.

Starting in February 1994 some patients requested hysterosalpingogram (HSG) documentation of tubal closure.  They were referred to a radiologist with my request that minimal pressure be used.  Table 3 shows the pregnancy rate among patients having HSG is three times that of other women in the study.

We conclude that QS is an excellent option for women who are sure they want no more children.  We advise against HSG to determine efficacy of the method.

*Vol. 22, No.  3, September 1996, p. 122

I have followed two quinacrine sterilization protocols since 1988.  The first group, 150 women, had  two applications of 252 mg in consecutive menstrual cycles.  The second group, 222 women, underwent the same procedure, except for 55.5 mg of ibuprofen which I added to the 252 mg quinacrine pellets.  There were no complications in either group.  There were mild complaints:  yellowish discharge, some pruritus of the vulvar area, and elevated body temperature, which did not exceed 38°C.  The fever was present in 7% of the first group and 5% of the second.  After 5 years the life table pregnancy rate was 6.02 in the first group and 6.53 in the second.  All pregnancies were intrauterine, none of them ectopics, and all ended in an induced abortion.  When the pregnancy rates of the two groups were compared we concluded that the addition of ibuprofen did not indicate any improvement.

Women who come to our clinic for sterilization are offered both surgical and non-surgical procedures.  Even when we tell them that the Quinacrine method may be less effective, 90% will choose it because they don’t want to have surgery if it is not necessary.

A critique of WHO’s position
on QS

Elton Kessel, MD

On 10 December 1999, the World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction (WHO/HRP) issued a statement entitled, Quinacrine for Female Sterilization:  A Review.  They define intrauterine administration of quinacrine as a ‘new’ drug by nature of the route of administration, gender of recipient and the dose.  A list of what they consider as outstanding issues is provided in the form of questions which we now attempt to answer.

Is the preclinical pharmacology of the proposed ‘new’ drug adequate?

Our answer is yes, considering publications (1-3) of studies conducted to meet a US Food and Drug Administration approval of a Phase I study (4).

Are its pharmacokinetic and pharmacodynamic data adequate to allow wide-scale human use?

Yes, they are based on the references cited and in particular reference 4 which indicated that quinacrine is rapidly absorbed from the uterus and redistributed to all tissues of the body depending on blood supply to tissues.  Because of quinacrine’s slow excretion and degradation, repeated doses, as needed for approved uses of the drug, raise tissue levels higher than the two monthly doses recommended for sterilization (QS)(5).  We conclude that quinacrine levels in uterine tissue are higher for approved uses of quinacrine than for QS, except for a few hours during absorption and redistribution to all tissues of the body.

Is the drug manufactured according to Good Manufacturing Practices?

Clearly it is, for the Swiss manufacture of pellets by Sipharm.

Have the clinical studies been conducted according to Good Clinical Practices or their equivalent?

The Guideline for Good Clinical Practice was developed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.  The QS trials by the governments of India, Indonesia and Vietnam met this Guideline as did numerous trials in government facilities, including medical schools.  Some NGOs decided QS was suitable for their service programs, which, while evaluated, were not clinical studies and did not follow the Guideline.

Are the available toxicology, genotoxicity, teratology and carcinogenicity data sufficient to assess the probable long-term safety of the ‘new’ drug in humans?

These animal studies are meant to predict risk of side effects, complications, birth defects and cancer in human use.  But, a large experience in human use exists that indicates these risks are very low (6).  Both the Declaration of Helsinki and the Guideline for Good Clinical Practice require a risk/benefit assessment.  This must be made by each locality to reflect its own risks and benefits.  In every place where QS has been used this evaluation was made in favor of QS use.

In summary, while we answer each concern in the affirmative, WHO/HRP gives the answer as either ‘No’ or ‘Unknown.’  In our opinion this difference stems primarily from the fact that WHO/HRP guidelines for clinical trials do not require risk/benefit assessment.  Until this is corrected, our differences will remain.

References

1. Dubin NH, Strandberg JD, Craft CF, Parmley TH, Blake DA, King TM.  Effect of intrauterine and intravascular quinacrine administration on histopathology, blood chemistry, and hematology in cynomolgus monkeys.  Fertil Steril 1982; 38:741-7.

2. Dubin NH, Blake DA, DiBlasi MC, Parmley TH, King TM.  Pharmacokinetic studies on quinacrine following administration to cynomolgus monkeys.  Fertil Steril 1982; 38:735-40.

3. Blake DA, Dubin NH, Blasé MC, Parmley TM, Stetten G, King TM.  Teratologic and mutagenic studies with intrauterine quinacrine hydrochloride.  In:  Zatuchni GI, Shelton JD, Goldsmith A, Sciarra JJ, eds. Female transcervical sterilization.  Philadelphia, Harper and Row, 1983, p. 71-88.

4. Laufe LE, Sokal DC, Cole LP, Shoupe D, Schenken RS.  Phase I prehysterectomy studies of the transcervical administration of quinacrine pellets.  Contraception 1996; 54:181-6.

5. Shannon JA, Earle DP Jr, Brodie BB, Taggart JV, Berliner RW.  The pharmacological basis for the rational use of atabrine in the treatment of malaria.  J Pharmacol Exp Ther 1944; 81:307-30.

6. Kessel E.  Quinacrine sterilization:  an assessment of risks for ectopic pregnancy, birth defects and cancer.  Adv Contracept 1998; 14:81-90.