Depot Formulation of MPA

Medroxyprogesterone acetate

• Is a 17-acetoxy-6-methylprogestin that has progestogenic activity in the human

• Not metabolized as rapidly as the parent compound progesterone so it can be given in smaller amounts than progesterone, with an equivalent amount of progestational activity.

Depot medroxyprogesterone acetate DMPA

• Long-acting injectable formulation of MPA, consists of a crystalline suspension of this progestational hormone.

• The original contraceptive dosage with the intramuscular formulation (IM-DMPA) is 150mg.

• Given by injection deep into the gluteal or deltoid muscle, after which the progestin is released slowly into the systemic circulation

• The area should not be massaged, so that the drug is released slowly into the circulation and maintains its contraceptive effectiveness for at least 4 months.

• The newer subcutaneous formulation contains 104 mg of DMPA in 0.65 mL of diluent and is injected into the subcutaneous tissue of the anterior thigh or abdominal wall

• Subcutaneous DMPA, though delivers a lower total dose of MPA than IM-DMPA, has a similar very high level of contraceptive effectiveness

MULTIPLE MECHANISMS OF ACTIONtherefore one of the most effective reversible methods of

contraception currently available

Three mechanisms of action are involved.• First (the major effect): is

inhibition of ovulation. • Second: keeps the cervical

mucus thick and viscous, so sperm are unlikely to reach the oviduct and fertilize an egg.

• Third: the endometrium becomes thin and does not secrete sufficient glycogen to provide nutrition for a blastocyst entering the endometrial cavity

Pharmacokinetics

• MPA can be detected in the systemic circulation within 30 minutes after its IM injection.

• Although serum MPA levels vary among individuals, they rise steadily to contraceptively effective bloodlevels (>0.2ng/mL) within 24 hours after both IM and SC injection

• The pattern of IM-MPA clearance from the circulation varies among different studies according to the type of assay used.

• After IM-DMPA was administered to three subjects, Ortiz and coworkers assayed blood MPA levels-

Daily for 2 weeks, then 3x a week for the next 3 months,

and then Weekly until MPA was

undetectable.

• In two subjects, MPA levels initially plateaued at 1.0 to 1.5 ng/mL for about 3months, after which they declined slowly to about 0.2 ng/mL during the fifth month

• In a third subject, the blood levels were higher during the first month, then ranged between 1.0 and 1.5 ng/mL for the next 2 months, after which there was a further decline.

• MPA levels remained detectable in the circulation, above 0.2ng/mL, for 7 to 9 months in all three subjects, after which it was not detectable.

• Estradiol (E2) levels were found to be in the early to mid follicular phase range, but consistently below 100 pg/mL during the first 4 months after injection.

• After 4 to 6 months, when MPA levels decreased to less than 0.5ng/ml

• Estradiol (E2) concentrations rose preovulatory levels, indicating follicular activity, but ovulation did not occur, as evidenced by persistently low progesterone levels.

• Return of follicular activity preceded the return of luteal activity by 2 to 3 months.

• This delay in resumption of luteal activity is probably due to the fact that the circulating MPA levels inhibit the positive feedback effect of the rise of estradiol (E2) on the hypothalamic-pituitary axis, which in the absence of MPA would stimulate the midcycle release of LH.

• The return of luteal activity in this study, indicated by a rise in serum progesterone levels, did not occur until 7 to 9 months after the injection, when the MPA levels were less than 0.1ng/mL.

• Following injections of Subcutaneous-DMPA, absorption of MPA is rapid and rises above 0.2ng/mL (the contraceptive effective level) within 24 hours.

• Serum MPA levels peak about 8 days after the injection and gradually decline thereafter, but mean levels remain above the contraceptively effective level of 0.2 ng/mL for about 4 months

• Following injections of both IM-DMPA and SC-DMPA, serum levels of FSH, E2, and progesterone are similar.

• FSH levels remain in the mid follicular range for 3 months without the midcycle FSH peak.

• E2 levels remain suppressed and are similar to the levels on days 1 to 3 of a pretreatment control cycle (40 to 60 pg/mL).

• Progesterone levels are completely suppressed with both types of formulations.

• Thus, although low levels of ovarian follicular activity do occur after IM-DMPA and SC-DMPA, ovulation is completely suppressed.

• To obtain suppression of ovulation in the initial injection cycle, DMPA has to be administered within several days after the onset of menses.

• The product labeling states that to ensure the woman is not pregnant at the time of the first injection, it must be given during the first 5 days of the cycle.

• Use of contraceptive doses of DMPA does not decrease endogenous E2 levels to the postmenopausal range and does not cause symptoms of estrogen deficiency