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Update on Contraception 2010 by 6S8whiQ

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									   Update on Contraception 2010

          Vanessa M. Givens, M.D.
            Associate Professor
       Department of Family Medicine
University of Tennessee Health Science Center
            Memphis, Tennessee
           Conflicts to Declare


• Implanon Training Instructor
What’s New In Contraception In the
         United States

         Not Much !!!


           So What
    U.S. Pregnancies: Unintended vs. Intended
                                   Miscarriage 9%
Unintended 48%                                                 Intended 52%

          Miscarriage 6%




   Unintended Births 19%




                                                               Elective Abortions 23%
The Alan Guttmacher Institute: Fulfilling the Promise, 2000.
Contraceptive Methods Lost Last 5 Years

Lunelle

 FDA Approved October 2000

 Recall Oct 2003 Due to Potency Concerns of Vials

 Pharmacia Acquired by Pfizer April 2003

 Product Discontinued October 2003
    Contraceptive Methods Lost Last 5 Years

•    Norplant
    Originally Available US 1991
    No Longer Produced in US Since 2002
• Today Sponge 1983-1995
    Discontinued US Due to Manufacturing Issues
    Available US June 2005
                      Overview

Recently Developed Contraceptives
Recently Developed Contraceptives



                      Single-rod Implant

                                           Essure




   Levonorgestrel
Intrauterine System


                       Vaginal Ring        Patch
         Vaginal Ring

Etonogestrel/Ethinyl Estradiol
Etonogestrel/Ethinyl Estradiol
       Vaginal Ring
       Vaginal Ring
                 Vaginal Ring

          Patient Management
          Patient Management


• Patient inserts ring and it is supposed to
  remain in the vagina for 3 weeks
• Ring is removed during the fourth week,
  menstrual period should begin
• If ring is removed or slips out of place for
  > 3 hrs, back-up contraception is
  necessary for 7 days
                                     Vaginal Ring

                       Patient Acceptability
                       Patient Acceptability

• 3.6% of women discontinue due to foreign
  body sensation, coital problems, expulsion
  and vaginal discomfort
• 67% of those who completed the study
  would recommend the ring to other women




Roumen FJ, et al. Human Reprod. 2001;16:469-475.
                                      Vaginal Ring

                                      Summary
                                      Summary

• Good cycle control
     – Irregular bleeding was rare (2.6% - 6.4% of
       evaluable cycles)
     – Withdrawal bleeding occurred in
       97.9% - 99.4% of evaluable cycles
• Compliance with the regimen was met in
  90.8% of cycles

Roumen FJ, et al. Hum Reprod. 2001;16(3):469-475.
               Implantable Rods
               Implantable Rods
• Norplant
     Available US February 1992
     Discontinued Production US 2002
• Twin Rod Implant
     Jadelle
• Single Rod Implant
     Implanon
Jadelle
    AKA Norplant 2
    2 Rod Subdermal Implant
    Levonorgestrel
                 Jadelle

FDA Approved 1996
1996    Approved For 3 Year Use in US
2002    Approved For 5 Year Use in US


20??    Marketed United States
                  Single-Rod Implant

      Single Contraceptive Implant:
      Single Contraceptive Implant:
               Description
               Description

• Single 40-mm  2-mm rod
• Rod is made of ethylene-vinyl-acetate copolymer
• Contains 68 mg of etonogestrel (3-keto-desogestrel),
  the active metabolite of desogestrel, and comes in
  disposable sterile inserter
• Inhibits ovulation during the entire treatment period
• Effective for 3 years
          Single-Rod Implant

Single Contraceptive Implant:
Single Contraceptive Implant:
           Design
           Design

     Rate-controlling membrane (0.06 mm)



 2.0 mm                                      Core


            40 mm

 Core:      40%     Ethylene vinyl acetate
            60%     Etonogestrel
 Membrane: 100%     Ethylene vinyl acetate
                                  Single-Rod Implant

                       Insertion and Removal
                       Insertion and Removal


  • Single-rod system with disposable inserter
  • Average insertion time = 2.2 minutes
  • Average removal time = 5.4 minutes




Croxatto HB. Eur J Contracept Reprod Health Care. 2000;5(suppl 2):21-28.
                                 Single-Rod Implant

                     Contraceptive Efficacy
                     Contraceptive Efficacy


• No pregnancies during 1200 women-years of
  exposure (Pearl Index, 0; 95% CI 0.0-0.2)
• Effective contraception that lasts for 3 years




Croxatto HB. Eur J Contracept Reprod Health Care. 2000;5(suppl 2):21-28.
                                Single-Rod Implant

                   Vaginal Bleeding Pattern

                                                                       Discontinuations Due to
                                                                       Bleeding Disturbances
                                                                            (%) (n = 635)


Frequent irregular bleeding                                                69 (10.9)

Spotting                                                                   21 (3.3)

Prolonged bleeding                                                         16 (2.5)

Amenorrhea                                                                 11 (1.7)

Heavy bleeding                                                              2 (0.3)

Other                                                                       2 (0.3)

Croxatto HB. Eur J Contracept Reprod Health Care. 2000;5(suppl 2):21-28.
                  Single-Rod Implant

                      Summary
                      Summary

• Efficacious
• Good safety profile
• Irregular bleeding is most common AE
• Requires clinician visit for initiation and
  discontinuation
• Single implant systems using newer progestins
  may solve some of the adverse effects and
  problems presented by earlier implants
                 Intrauterine System

Levonorgestrel Intrauterine System
Levonorgestrel Intrauterine System
 32 mm     (LNG IUS)
           (LNG IUS)



                                 Steroid reservoir




         levonorgestrel 20 mcg/day
                                  Intrauterine System

                        Levonorgestrel IUS:
                        Levonorgestrel IUS:
                        Mechanism of Action
                        Mechanism of Action
 • Fertilization inhibition:
       – Cervical mucus thickened
       – Sperm motility and function
         inhibited
       – Endometrium suppressed
       – Weak foreign body reaction
         induced
       – Ovulation inhibited (in some
         cycles)
Jonsson B, et al. Contraception. 1991;43:447-458.
Videla-Rivero L, et al. Contraception. 1987;36:217-226.
Myth: IUD Prevents Implantation

• Most evidence now suggests that all
  IUDs induce a foreign body reaction
  that is spermicidal, preventing
  fertilization
• Today’s intrauterine contraceptives
  have other mechanisms of action that
  prevent fertilization
                        Alvarez et al. Fertil Steril 1988;49:768
                                 Intrauterine System

                           Levonorgestrel IUS:
                           Levonorgestrel IUS:
                                Efficacy
                                Efficacy

• Overall failure rate 0.14 per 100 women1

• Gross cumulative five-year failure rate is 0.7 per
  100 women2




Luukkainen T, et al. Contraception. 1987;36:169-179.
Mirena Package Insert.
                 Intrauterine System

              Levonorgestrel IUS:
              Levonorgestrel IUS:
                   Insertion
                   Insertion
• Recommended timing
  – Within 7 days of onset of menses
• Slightly larger caliber than Copper T
• Different insertion technique than other intrauterine
  contraception
   – One-handed insertion technique
   – Hands-on training recommended
• As with all IUDs,efficacy and continuation
  dependent on skillful insertion
                                   Intrauterine System

                           Levonorgestrel IUS:
                           Levonorgestrel IUS:
                               Expulsion
                               Expulsion

• Andersson et al. noted undetected expulsion
  was etiological factor in 2 of 5 contraceptive
  failures1
• Half of all expulsions occur during first year
  of use2



Andersson K, et al. Contraception. 1994;49:56-72.
Sivin I, et al. Contraception. 1990;42:361-378.
  LNG IUS: Percentage Reduction of
       Menstrual Blood Loss
  0


                                   LNG IUS
 -25
                                   Placebo

 -50                               Prostaglandin
                                   Synthetase Inhibitor
                                   Combination OCs
 -75



-100
                  Milsom et al. Am J Obstet Gynecol 1991;164:879
                Intrauterine System

           Levonorgestrel IUS:
           Levonorgestrel IUS:
               Summary
               Summary
• High efficacy
• Requires clinician visit for initiation and
  discontinuation
• Early spotting
• Reduction in menstrual blood loss
• Low systemic levels of LNG
• Possible use for hormone replacement
Hysteroscopic Sterilization Techniques



                           P-Block Device     Intra-tubal Device
Uterotubal Junction Device Brundin, 1981
                                                 Hamou, 1982
     Hossenian, 1976




   OvaPlug, 1981                Essure 2002          Adriana 20??
Essure System
Essure System Placement
  Other Transcervical Sterilization
     Methods in Development

• Quinacrine

• Erythromycin

• Intratubal Ligation Device (ILD)

• Adiana
                   Quinacrine
• One of the most widely studied chemicals for
 female non-surgical sterilization
• The method involves
  • Transcervical insertion of 2 doses of 250 mg of
    quinacrine pellets using an IUD introducer
  • Placed in 2 procedures, 1 month apart between
    days 7 and 10 of menstrual cycle
• Carcinogenic?
                   Quinacrine
               Long-Term Interim Analysis
           5 year Pregnancy Rates (Vietnam)
All ages               1 insertion    27.3%
(unadjusted)           2 insertions   12.9%


2 insertions           >35            6.8%
(by age)               <35            13.0%


CREST data             35-44           0.4 – 1.9%
               Erythromycin

• Antibiotic Intended To Create Scar Tissue

 Permanently Occluding Fallopian Tubes

• May Be More Effective Than Quinacrine

• Formulation Issues In The Research Domain
         Intratubal Ligation Device


• Catheter, balloon,
  and O-ring used to
  create a sphincter,
  causing occlusion
• Scar tissue causes
  permanent
  occlusion
                     Adiana
• Catheter inserted into the fallopian tube
• Superficial lesion created
    Bipolar low radio-frequency energy
• Porous non-biodegradable implant inserted in lesion
• Currently in clinical trials
                               Contraceptive Patch

         Estrogen and Progestin Delivery
         Estrogen and Progestin Delivery
  • Patch contains 6.00 mg norelgestromin and 0.75
    mg ethinyl estradiol

  • Delivers continuous systemic doses of hormones
       – 150 µg norelgestromin (NGMN)
                        +                            Per day
       – 20 µg ethinyl estradiol (EE)

  • Direct comparisons to oral contraceptive delivery
    doses cannot be made

Abrams L, et al. FASEB J. 2000;14:A1479.
                                 Contraceptive Patch

                  Review of Norgestimate in
                  Review of Norgestimate in
                       OCs and HRT
                        OCs and HRT
 • Most widely used progestin in US
 • Long established safety profile
 • Minimal androgenicity
 • Minimal alteration of estrogen’s beneficial effect
   on lipid profile
 • Little/no effect on carbohydrate metabolism
 • Good cycle control
Phillips A. Acta Obstet Gynecol Scand. 1990;152(suppl):21-24.
Phillips A. Steroids. 1990;55:373-375.
Corson SL. Clin Obstet Gynecol. 1995;38:841-848.
                                                     Contraceptive Patch

                                                 NGMN and EE Levels
                                                 NGMN and EE Levels
                                                   Patch vs OC*
                                                    Patch vs OC*




                                                                                                             NGMN Serum Concentration (ng/mL)
  EE Serum Concentration (pg/mL)




                                   150                                                  Patch EE       2.1
                                                                                        Patch NGMN
                                   125                                                                 1.8
                                                                                        EE
                                                                                        NGMN
                                   100                                                                 1.5
                                                                                   Reference Range
                                    75                                                                 1.2
                                                                        Patch Removed
                                    50                                                                 .9

                                    25                                                                 .6

                                    0                                                                  .3
                                         0   1   2   3   4   5    6     7      8   9    10   11   12
                                                                 Days

Abrams L, et al. Contraception. 2001;64:287-294.                            *Noncomparative data
                                              Contraceptive Patch

                            Dosing Reserve Beyond 7 Days:
                            Dosing Reserve Beyond 7 Days:
                              Results for NGMN and EE
                               Results for NGMN and EE
                                              Patch EE                            Patch NGMN

                            100                         Day 8:               Day 15:
                                  1st Patch           2nd Patch          Scheduled Patch
   Concentration (pg/mL)




                             90
   Mean Ethinyl Estradiol




                                  Applied              Applied             Change Day               1.3
                             80                                                                     1.2




                                                                                                          Concentration (ng/mL)
                                                                                                           Mean Norgestimate
                             70                                                                     1.1
                             60                                                                     1.0
                             50                                                                     0.9
                                                                                                    0.8
                             40
                                                                                                    0.7
                             30
                                                                                                    0.6
                             20                                              2-day Forgiveness      0.5
                             10                                                                     0.4
                                                                                                    0.3
                                  1 2   3 4   5   6    7   8   9 10 11 12 13 14 15 16 17 18 19 20
                                                           Time (days)
Abrams L, et al. Int J Gyn & Obstet. 2000;70(suppl 1):78.
                                  Contraceptive Patch

                       Combined Data: Efficacy
                       Combined Data: Efficacy
                        (pregnancies per 100 women years)
                        (pregnancies per 100 women years)
                                                                      Pearl Indices
                                    Cycles            Pregnancies   Overall   Method
    Study                            (n)                  (n)       Pearl*     Pearl**

   Smallwood et al.                  10994                    6      0.71       0.59

   Hedon et al.                       5921                    4      0.88       0.66

   Audet et al.                       5240                    5      1.24       0.99



   Total                             22155                    15     0.88       0.70
  *User failure plus method failure
  **Failure when taken as directed
Zieman M, et al. Fertil Steril. 2001;76:S19. Abstract O-48.
                                   Contraceptive Patch
       Distribution of Pregnancies by Baseline
       Distribution of Pregnancies by Baseline
                    Body Weight Deciles (n=3319 subjects)
                    Body Weight Deciles (n=3319 subjects)
                 Decile                           Weight               Total
                                                 Range (kg)         Pregnancies
                    1                                <52                1
                    2                              52 - <55             2
                    3                              55 - <58             0
                    4                              58 - <60             0
                    5                              60 - <63             2
                    6                              63 - <66             0
                    7                              66 - <69             1
                    8                              69 - <74             0
                    9                              74 - <80             2
                    10                               80                7
                                                          80 - 85           1
                                                          85 – 90           1
                                                          > 90              5
Zieman M, et al. Fertil Steril. 2001;76:S19. Abstract O-48.
               Contraceptive Patch

                Precautions
                Precautions


• Body weight 198 lbs. (90 kg)
  – Results of clinical trials suggest that the
    contraceptive patch may be less effective in
    women with body weight >198 lbs (90 kg)
    than in women with lower body weights
• No other changes
    AP Associated Press July 17, 2005



Birth control patch linked to higher fatality rate

Report: Device has three times greater risk of
         stroke, blood clot than pill
Updated: 5:33 p.m. ET July 17, 2005
         Seasonale / Seasoneque
FDA approved Sept 5, 2003
Ethinyl estradiol 0.3 mg
Levonorgestrel 1.5 mg


Seasonale
• 84 active pill + 7 placebo
Seasoneque
• 84 active pills + 7 pills (0.1 mg ethinyl estradiol)
                    Lybrel

FDA approved May 22, 2007

Ethinyl estradiol 0.2 mg

Levonorgestrel 0.9 mg



Dispensed in 28 day packs
Seasonale / Seasoneque
Lybrel
   Male Hormonal Contraceptives

Testosterone Udecanotae
  1000 mg IM Initially
  500 mg q 4-6 weeks
  Phase III trials China
  Efficacy
    1 pregnancy per 100 men per year use
     Male Hormonal Contraceptives

• Testosterone plus Progestin or GNRH analog

 Decrease side effects testosterone only methods

• Testosterone only not as effective in non Asian
     men

• Efficacy

 1.4 pregnancies per 100 men per year use
                         RISUG
Reversible Inhibition of Sperm under Guidance
• Clear Polymer Gel
 styrene maleic anhydride plus DMSO
• Injected into Vas Deferens
• Partially blocks Vas
• Ruptures membranes passing sperm
• Reversible with DMSO or Na bicarbonate flushing
  Nonivasive –massage, vibration and electric current
          Intra Vas Device (VD)

Originally called the Shug

Two plugs implanted each vas

Removable

Does not require special surgical training

								
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