My thanks and acknowledgment also go to the Well come Trust for financial support. My special thanks go to Wendy Ewart. Vaginal wetness: an underestimated problem experienced by users of progestin injectable contraceptives in South Africa', Social Sciences and Medicine.
THE PHARMACOKINETICS OF DEPOT 241
MEDROXYPROGESTERONEACETATE
List of Tables List of Figures
LITERATURE REVIEW AND OBJECTIVES 244
- PHARMACOLOGY OF DEPOT MEDROXYPROGESTERONE 244 ACETATE
METHODS 272
- SERUM SAMPLES AND SAMPLING TIMEFRAME 292 2.3.3 SERUM MPA LEVELS FOCUSING ON TROUGH LEVELS 294
- POPULATION PHARMACOKINETIC ANALYSIS 297 .1 The Phannacokinetic Data File 297
- POPULATION PHARMACOKINETIC ANALYSIS 313
RECOMMENDATIONS FOR RATIONAL PROVISION 350 ·
OF INJECTABLE CONTRACEPTIVES
ABSTRACT
Use patterns of two injectable products (DMPA and NET-EN) were analyzed by means of a Pareto analysis of injectors dispensed from four South African provincial pharmaceutical depots over three financial years and 1999/2000). This involved using non-linear mixed-effects modeling (NONMEM) to fit the data and determine pharmacokinetic parameters, apparent clearance (CLIP) and apparent volume of distribution (VIP), and to assess the impact of covariates on CLIP and VIP (where P is bioavailability). The final model estimates for CLIP and VIP were 1080 (95% confidence interval) liter days and 86,200 liters (95% confidence interval) respectively.
PUBLICATIONS ARISING FROM THE THESIS
Where is the Condom? Contraceptive Practice in a Rural District of South Africa
Less than one-third (29.7%) of all women (N= 848) reported using a contraceptive method at the time of the study. Six of the women who gave this answer used the oral contraceptive and one used the withdrawal method.
Counting the costs: Comparing depot medroxyprogesterone
Menstrual irregularities are reported to occur more frequently with DMPA than with NET-EN. On the other hand, if only NET-EN were available, the additional burden would be 36.5%.
SOCIAL
SCIENCE
Twelve (24.0%) of the women participating in the focus group discussions, who were of reproductive age (15-49), used the injection method. This paper examines serum MPA levels among new and repeat South African DMPA users at the end of the dosing interval.
LIST OF PRESENTATIONS ARISING FROM THE THESIS
Poster presentation at the joint meeting of the South African Pharmacology Society and the Neuroscience Society, Durban, 20-23 September 2000. Vaginal wetness and the use of progestin-only injectable contraception vaginal wetness and the use of progestin-only injectable contraception.
List of Abbreviations and Acronyms
INTRODUCTION
An important component of the South African National Drug Policy is its emphasis on promoting the rational use of drugs (Department of Health, 1996). Additionally, research undertaken has been largely clinic-based among current users of the injectable contraceptive. The primary research involves one of the largest community-based surveys ever undertaken in a deeply rural area of South Africa.
This thesis also examines data from secondary sources as follows: .. primary data obtained from the community survey is compared with the contraceptive use patterns reported in the 1998 South African Demographic and Health Survey. A comprehensive review of the literature on the use of injectables is provided contraceptives in South Africa, Africa and other parts of the world, including a review of randomized clinical trials, pharmacokinetic and pharmacodynamic studies and other clinical studies of the injectable contraceptive. What side effects are experienced by users of the two progestogen-only injectable contraceptives? In the final chapter of the thesis, recommendations for rational provision of injectable contraceptives and priority areas for further research are presented.
A critical review of the design of these studies is long overdue and is another important contribution of this thesis.
INJECTABLE CONTRACEPTIVE USE IN RURAL SOUTH AFRICA
LIST OF TABLES: SECTION 1
LITERATURE REVIEW AND OBJECTIVES
- INJECTABLE CONTRACEPTIVE UTILISATION PATTERNS
- MECHANISM OF ACTION AND EFFICACY OF INJECTABLE PROGESTOGEN CONTRACEPTIVES
- Mechanism of Action
- Efficacy
- RETURN TO FERTILITY DMPA Studies
- SIDE EFFECTS
- Menstrual Disturbances
- Weight Gain
- Vaginal Discharge
- DISCONTINUATION PATTERNS
- Side Effects Leading to Discontinuation ofDMPA and NET-EN As described earlier in this chapter, bleeding disturbances are the most commonly
- Temporary Discontinuation
- CURRENT SAFETY CONCERNS
- Bone Mineral Density and IPCs
- Risk of HIV Acquisition and IPCs
- Breast Cancer and IPCs
- OBJECTIVES
Delayed return to fertility has been more extensively documented for DMPA than for NET-EN. There have been few studies directly comparing DMPA and NET-EN in terms of return to fertility. The approved package insert for the product NET-EN (Nur-Isteratef'j registered for use in South Africa) states that "after discontinuation, normal ability to conceive usually returns 7-8 months after the last injection" (Schering, 1992).
Menstrual irregularities are reported to be more common with DMPA than with NET-EN (World Health Organization, 1978; Fotherbyet al, 1980b; Howard et al, 1985; Salem et al, 1988). 15% of both DMPA and NET-EN users reported having a regular cycle by the fourth injection. Menstrual irregularities are reported to be more common with DMP A than with NET-EN use (Fraser, 1982; Fraser, 1986b).
Sale et al (1988) reported no statistically significant increase in mean weight gain between DMP A and NET-EN users. There appears to be little evidence of differences in weight gain between users of DMPA and NET-EN. Little research appears to have been undertaken on the risk of breast cancer among NET-EN users.
METHODOLOGY
- STUDY AREA
- STUDY DESIGN
- SAMPLING .1 Household Survey
- Focus Group Interviews
- Analysis of Family Planning Clinic Records
- COMMUNITY ENTRY AND ETHICAL SAFEGAURDS .1 Community Entry and Community Consultation
- DATA COLLECTION
- PILOT STUDY
- DATAANALYSIS
- Individual Household Interviews
- Focus Group Interviews
- LIMITATIONS
A baseline mapping exercise of the Hlabisa sub-district took place prior to the survey. Record the number and ages of the women living in the household on the sheet provided for this purpose. Names of women appearing on the records of the family planning clinic at Hlabisa Hospital were not recorded.
The study was approved by the Ethics Committees of the University of Durban-Westville (Ethics Approval Number 97296B) and the Nelson R Mandela School of Medicine, University of Natal (Ethics Approval Number H150/00). A description of the translation field worker training process is provided in the training section below. Six themes identified in the consultation phase of the study and from responses to interviews with individual households were included in the discussion.
A local office was established at Hlabisa Hospital with the kind help of the Medical Superintendent.
RESULTS (I). INJECTABLE CONTRACEPTIVE PREVALENCE, USER CHARACTERISTICS AND
CONTRACEPTIVE METHOD MIX
DESCRIPTION OF THE STUDY POPULATION
INJECTABLE PROGESTOGEN CONTRACEPTIVE PREVALENCE AND USER CHARACTERISTICS
- Residential Status
These three subsamples will be labeled as IPC users (injecting users), previous users or IPC quitters (those who previously used IPC but were not current users) and the never user group (those who never used IPC). A more detailed analysis of the age of injection users compared to users who stopped taking the drug and the group who never used the drug is given later in this chapter. The majority of IPC users (77.5%) were in a stable relationship and only 13.4% were married in a civil, religious, traditional or customary ceremony (Figure 1.3.2).
Four women, who indicated that they were not in any relationship but were using the injectable contraceptive method, had all lost their partners in the few weeks prior to the interview. Of the IPC users who were younger than 20 at the time of the survey, all but one, a 19-year-old, had been pregnant. The oral contraceptive was the first method for 9.1% of respondents and only one woman used the male condom first.
The majority of IDUs (98.4%), for the purposes of this study, were classified as residents of Hlabisa, as they slept in their home for at least 4 nights per week and for at least 50% of the time. In contrast, most of their partners did not live with them, with 88.2% of women married or in a steady relationship reporting that their partners lived elsewhere (ie for four nights a week or more, and for more than 50% of cases), and 76.3% of the partners lived outside the sub-district of Hlabia.
COMPARISON OF INJECTABLE CONTRACEPTIVE USERS WITH DISCONTINUED USERS AND THOSE WHO HAD NEVER USED THE
- Comparing Demographic Characteristics
- Characteristics Independently Associated with IPC Use
Forty percent of those who had never used an injection method had never been pregnant. Of those who had never used IPC and had ever been sexually active, 31.3% had never been pregnant. Most of those in the never-pregnant IPC group were under 20 years of age (60.5%).
Just over two-thirds (68.2%) of those who had never used an IPC and who had never been pregnant had ever had a relationship. More IPC users had only one child than other user categories (Table 1.3.4 and Figure 1.3.6), and many of those who had never injected had no children. While many current and discontinued IPC users in the under-20 age group had only one child, fewer adolescents who had never injected had one child (Figure 1.3.7).
Very few of those who have never used an injection have ever used any method.
CONTRACEPTIVE METHOD MIX
- Current Contraceptive Practice
- Reasons for Not Using a Method
- Method Mix according to Hlabisa Hospital Clinic Records
Less than one-third (29.7%) of all women (N=848) reported using a contraceptive method at the time of the survey. Contrary to the widespread use of the injection method (74.2% of women practicing contraception), the condom was used by only 4.4% of current users. In the 15-19 age group, 83.9% of those using a method used the injection, while only one woman reported the male condom as her current contraceptive method (Table 1.3.7).
In response to an open-ended question about reasons for choosing the injectable method, the most common reason given by 35.0% of respondents was convenience. A quarter (25.8%) of the women who practiced contraception used a method other than the injectable one, and the most common reason for method choice, given by 43.3% in response to an open question, was related to injectable side effects. Although almost half of the women who gave this answer had used the injectable method before, only 55.6% of these former injectable users gave this as their reason for current method choice. A few used a method on the recommendation of their partner (n=4), relatives or friends (n=I), or the health care provider (n=2).
Six of the women who gave this answer used the oral contraceptive and one used the abstinence method. It should be noted that 7 women used the condom and 3 used thigh sex, because these methods were considered to provide protection against both pregnancy and sexually.
MAIN FINDINGS
No intrauterine contraceptives were issued and no records were kept of the number of condoms distributed. Having ever been pregnant was strongly associated with IPC use, with almost all (97%) IPC users having been pregnant at least once. Many IPC users had only one child, suggesting that IPC use begins after the first pregnancy.
There is an unmet need for more appropriate contraceptive methods and services among many of the sexually active women who do not practice contraception. The survey findings on contraceptive method mix are consistent with methods issued by Hlabisa Hospital's family planning clinic.
RESULTS (11): INJECTABLE CONTRACEPTIVE PRODUCT MIX AND DISCONTINUATION PATTERNS
- DEMOGRAPHIC CHARACTERISTICS OF DMPA AND NET-EN USERS .1 Current DMPA and NET-EN Users
- UTILISATION PATTERNS AND REASONS FOR CHOICE .1 Product Mix
Significant difference between DMPA and NET-EN users based on the amount of researchers and students. NET-EN users were more likely to have fewer children and to start using a contraceptive method at a younger age than DMPA users (Table 1.4.2). A summary of key demographic characteristics of previous DMPA and NET-EN users is given in table 1.4.4. At the time of the survey, former NET-EN users were younger and had fewer children than former DMP A users.
Both injectable contraceptive products were widely used with more current users found to be using NET-EN and more former users having used DMPA (Table 1.4.5 and Figure 1.4.3). The data show that both DMPA and NET-EN were available through the public sector as early as 1994. The average duration of use for current users of DMPA and NET-EN was very similar.
In contrast, current NET-EN users had only used the method for up to 6 years, and all former NET-EN users (excluding those who had used both products) had discontinued use for 7 years.
