Dr. MANISH NIVSARKAR B.V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Sarkhej-Gandhinagar Highway, Thaltej, Ahmedabad-380054 Telephone: 91 79 27439375, Fax: 91 79 27450449 Current Position: Director …………………………………………………………………………………………………………… Joint Director, Head Department
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Depo-Provera®Contraceptive Injectionmedroxyprogesterone acetateinjectable suspension, USP Patients should be counseled that this product does
not protect against HIV infection (AIDS) and other
sexually transmitted diseases.
DEPO-PROVERA Contraceptive Injection contains medroxyprogesterone acetate, a derivative of proges-terone, as its active ingredient. Medroxyprogesteroneacetate is active by the parenteral and oral routes ofadministration. It is a white to off-white, odorless crys-t a l l i n e p o w d e r t h a t i s s t a b l e i n a i r a n d t h a t m e l t sbetween 200°C and 210°C. It is freely soluble in chloro-form, soluble in acetone and dioxane, sparingly solublein alcohol and methanol, slightly soluble in ether, andinsoluble in water.
The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-,(6α)-. The structural formula is as follows: DEPO-PROVERA Contraceptive Injection for intra - muscular (IM) injection is available in vials and prefilledsyringes, each containing 1 mL of medroxyprogesteroneacetate sterile aqueous suspension 150 mg/mL.
Each mL contains:Medroxyprogesterone acetate When necessary, pH is adjusted with sodium hydrox- CLINICAL PHARMACOLOGY
DEPO-PROVERA Contraceptive Injection (medroxy- progesterone acetate), when administered at the recom-mended dose to women every 3 months, inhibits thesecretion of gonadotropins which, in turn, prevents fol-licular maturation and ovulation and results in endome-trial thinning. These actions produce its contraceptiveeffect. Following a single 150 mg IM dose of DEPO-PROVERA Contraceptive Injection, medroxyprogesterone acetateconcentrations, measured by an extracted radioim -munoassay procedure, increase for approximately 3weeks to reach peak plasma concentrations of 1 to 7ng/mL. The levels then decrease exponentially untilthey become undetectable (<100 pg/mL) between 120to 200 days following injection. Using an unextractedradioimmunoassay procedure for the assay of medroxy-progesterone acetate in serum, the apparent half-life formedroxyprogesterone acetate following IM administra-tion of DEPO-PROVERA Contraceptive Injection isapproximately 50 days.
Women with lower body weights conceive sooner than women with higher body weights after discontinuingDEPO-PROVERA Contraceptive Injection.
The effect of hepatic and/or renal disease on the pharmacokinetics of DEPO-PROVERA ContraceptiveInjection is unknown.
INDICATIONS AND USAGE
DEPO-PROVERA Contraceptive Injection is indicated only for the prevention of pregnancy. To ensure thatDEPO-PROVERA Contraceptive Injection is not admin- Depo-ProveraContraceptive Injectionbrand of medroxyprogesterone acetate injectable suspension, USP istered inadvertently to a pregnant woman, the first
injection must be given ONLY during the first 5 days of
a normal menstrual period; ONLY within the first 5-days
postpartum if not breast-feeding, and if exclusively
breast-feeding, ONLY at the sixth postpartum week.
T h e e f f i c a c y o f D E P O - P R O V E R A C o n t r a c e p t i v e
Injection depends on adherence to the recommended
dosage schedule (see DOSAGE AND ADMINISTRA-
TION). It is a long-term injectable contraceptive in
women when administered at 3-month (13-week) inter-
vals. Dosage does not need to be adjusted for body
In five clinical studies using DEPO-PROVERA Contra- ceptive Injection, the 12-month failure rate for the groupof women treated with DEPO-PROVERA ContraceptiveInjection was zero (no pregnancies reported) to 0.7 byLife-Table method. Pregnancy rates with contraceptivemeasures are typically reported for only the first year ofuse as shown in Table 1. Except for intrauterine devices(IUD), implants, sterilization, and DEPO-PROVERAContraceptive Injection, the efficacy of these contracep-tive measures depends in part on the reliability of use.
The effectiveness of DEPO-PROVERA ContraceptiveInjection is dependent on the patient returning every 3months (13 weeks) for reinjection.
Lowest Expected and Typical Failure Rates*
Expressed as Percent of Women Experiencing
an Accidental Pregnancy
in the First Year of Continuous Use
Source: Trussell et al 1* Lowest expected - when used exactly as directed.
T y p i c a l - i n c l u d e s t h o s e n o t f o l l o w i n g d i r e c t i o n sexactly.
1. Known or suspected pregnancy or as a diagnostic
2. Undiagnosed vaginal bleeding.
3. Known or suspected malignancy of breast.
4. Active thrombophlebitis, or current or past history of t h r o m b o e m b o l i c d i s o r d e r s , o r c e r e b r a l v a s c u l a rdisease.
5. Liver dysfunction or disease.
6. Known hypersensitivity to DEPO-PROVERA Contra- ceptive Injection (medroxyprogesterone acetate orany of its other ingredients).
1. Bleeding Irregularities
Most women using DEPO-PROVERA Contraceptive
Injection experience disruption of menstrual bleeding
patterns. Altered menstrual bleeding patterns include
irregular or unpredictable bleeding or spotting, or rarely,
heavy or continuous bleeding. If abnormal bleeding per-
sists or is severe, appropriate investigation should be
instituted to rule out the possibility of organic pathology,
and appropriate treatment should be instituted when
Depo-ProveraContraceptive Injectionbrand of medroxyprogesterone acetate injectable suspension, USP As women continue using DEPO-PROVERA Contra- ceptive Injection, fewer experience irregular bleedingand more experience amenorrhea. By month 12 amen-orrhea was reported by 55% of women, and by month24 amenorrhea was reported by 68% of women usingDEPO-PROVERA Contraceptive Injection.22. Bone Mineral Density ChangesUse of DEPO-PROVERA Contraceptive Injection maybe considered among the risk factors for developmentof osteoporosis. The rate of bone loss is greatest in theearly years of use and then subsequently approachesthe normal rate of age related fall.
3. Cancer RisksL o n g - t e r m c a s e - c o n t r o l l e d s u r v e i l l a n c e o f u s e r s o fDEPO-PROVERA Contraceptive Injection found slightor no increased overall risk of breast cancer3 and nooverall increased risk of ovarian,4 liver,5 or cervical6cancer and a prolonged, protective effect of reducingthe risk of endometrial7 cancer in the population ofusers. A pooled analysis14 from two case-control studies, the World Health Organization Study 3 and the New ZealandStudy13, reported the relative risk (RR) of breast cancerf o r w o m e n w h o h a d e v e r u s e d D E P O - P R O V E R AContraceptive Injection as 1.1 (95% confidence interval(CI) 0.97 to 1.4). Overall, there was no increase in riskwith increasing duration of use of DEPO-PROVERAContraceptive Injection. The RR of breast cancer forwomen of all ages who had initiated use of DEPO-PROVERA Contraceptive Injection within the previous 5years was estimated to be 2.0 (95% CI 1.5 to 2.8).
The World Health Organization Study 3, a component of the pooled analysis14 described above, showed anincreased RR of 2.19 (95% CI 1.23 to 3.89) of breastc a n c e r a s s o c i a t e d w i t h u s e o f D E P O - P R O V E R AContraceptive Injection in women whose first exposureto drug was within the previous 4 years and who wereunder 35 years of age. However, the overall RR forever-users of DEPO-PROVERA Contraceptive Injectionwas only 1.2 (95% CI 0.96 to 1.52).
[NOTE: A RR of 1.0 indicates neither an increased
nor a decreased risk of cancer associated with the useof the drug, relative to no use of the drug. In the case ofthe subpopulation with a RR of 2.19, the 95% CI is fairlywide and does not include the value of 1.0, thus infer-ring an increased risk of breast cancer in the definedsubgroup relative to nonusers. The value of 2.19 meansthat women whose first exposure to drug was within theprevious 4 years and who are under 35 years of agehave a 2.19-fold (95% CI 1.23 to 3.89-fold) increasedrisk of breast cancer relative to nonusers. The NationalCancer Institute8 reports an average annual incidencerate for breast cancer for US women, all races, age 30to 34 years of 26.7 per 100,000. A RR of 2.19, thus,increases the possible risk from 26.7 to 58.5 cases per100,000 women. The attributable risk, thus, is 31.8 per100,000 women per year.] A statistically insignificant increase in RR estimates of invasive squamous-cell cervical cancer has been
associated with the use of DEPO-PROVERA Contracep-
tive Injection in women who were first exposed before
the age of 35 years (RR 1.22 to 1.28 and 95% CI 0.93
to 1.70). The overall, nonsignificant relative rate of inva-
sive squamous-cell cervical cancer in women who ever
used DEPO-PROVERA Contraceptive Injection was
estimated to be 1.11 (95% CI 0.96 to 1.29). No trends in
risk with duration of use or times since initial or most
recent exposure were observed.
4. Thromboembolic Disorders
The physician should be alert to the earliest manifesta-
t i o n s o f t h r o m b o t i c d i s o r d e r s ( t h r o m b o p h l e b i t i s ,
pulmonary embolism, cerebrovascular disorders, and
retinal thrombosis). Should any of these occur or be
suspected, the drug should not be readministered.
5. Ocular Disorders
Medication should not be readministered pending exam-
ination if there is a sudden partial or complete loss of
v i s i o n o r i f t h e r e i s a s u d d e n o n s e t o f p r o p t o s i s ,
diplopia, or migraine. If examination reveals papille-
dema or retinal vascular lesions, medication should not
6. Unexpected Pregnancies
To ensure that DEPO-PROVERA Contraceptive Injec-
tion is not administered inadvertently to a pregnant
woman, the first injection must be given ONLY during
the first 5 days of a normal menstrual period; ONLY
within the first 5-days postpartum if not breast-feeding,
and if exclusively breast-feeding, ONLY at the sixth
postpartum week (see DOSAGE AND ADMINISTRA-
Neonates from unexpected pregnancies that occur 1 to 2 months after injection of DEPO-PROVERA Contracep-tive Injection may be at an increased risk of low birthweight, which, in turn, is associated with an increased Depo-ProveraContraceptive Injectionbrand of medroxyprogesterone acetate injectable suspension, USP risk of neonatal death. The attributable risk is lowbecause such pregnancies are uncommon.9,10 A significant increase in incidence of polysyndactyly a n d c h r o m o s o m a l a n o m a l i e s w a s o b s e r v e d a m o n ginfants of users of DEPO-PROVERA ContraceptiveInjection, the former being most pronounced in womenunder 30 years of age. The unrelated nature of thesedefects, the lack of confirmation from other studies, thedistant preconceptual exposure to DEPO-PROVERAContraceptive Injection, and the chance effects due tomultiple statistical comparisons, make a causal associa-tion unlikely.11 Neonates exposed to medroxyprogesterone acetate in utero and followed to adolescence, showed no evidenceof any adverse effects on their health including theirphysical, intellectual, sexual, or social development.
Several reports suggest an association between intra- uterine exposure to progestational drugs in the firsttrimester of pregnancy and genital abnormalities inmale and female fetuses. The risk of hypospadias (fiveto eight per 1,000 male births in the general population)may be approximately doubled with exposure to thesedrugs. There are insufficient data to quantify the risk toexposed female fetuses, but because some of thesedrugs induce mild virilization of the external genitalia ofthe female fetus and because of the increased associa-tion of hypospadias in the male fetus, it is prudent toavoid the use of these drugs during the first trimester ofpregnancy.
T o e n s u r e t h a t D E P O - P R O V E R A C o n t r a c e p t i v e Injection is not administered inadvertently to a pregnantwoman, it is important that the first injection be givenonly during the first 5 days after the onset of a normalmenstrual period within 5 days postpartum if not breast-feeding and if breast-feeding, at the sixth week postpar-tum (see DOSAGE AND ADMINISTRATION).
7. Ectopic PregnancyHealth-care providers should be alert to the possi-bility of an ectopic pregnancy among women using DEPO-PROVERA Contraceptive Injection whobecome pregnant or complain of severe abdominalpain.
8. Lactation Detectable amounts of drug have been identifiedin the milk of mothers receiving DEPO-PROVERAC o n t r a c e p t i v e I n j e c t i o n . I n n u r s i n g m o t h e r st r e a t e d w i t h D E P O - P R O V E R A C o n t r a c e p t i v eInjection, milk composition, quality, and amountare not adversely affected. Neonates and infantsexposed to medroxyprogesterone from breast milk havebeen studied for developmental and behavioral effectsthrough puberty. No adverse effects have been noted.
9. Anaphylaxis and Anaphylactoid ReactionAnaphylaxis and anaphylactoid reaction have beenreported with the use of DEPO-PROVERA Contracep-tive Injection. If an anaphylactic reaction occurs appro-priate therapy should be instituted. Serious anaphylac-tic reactions require emergency medical treatment.
1. Physical Examination
It is good medical practice for all women to have annual
history and physical examinations, including women
using DEPO-PROVERA Contraceptive Injection. The
physical examination, however, may be deferred until
after initiation of DEPO-PROVERA if requested by the
woman and judged appropriate by the clinician. The
physical examination should include special reference
to blood pressure, breasts, abdomen and pelvic organs,
including cervical cytology and relevant laboratory
tests. In case of undiagnosed, persistent or recurrent
a b n o r m a l v a g i n a l b l e e d i n g , a p p r o p r i a t e m e a s u r e s
should be conducted to rule out malignancy. Women
with a strong family history of breast cancer or who
have breast nodules should be monitored with particular
2. Fluid Retention
Because progestational drugs may cause some degree
of fluid retention, conditions that might be influenced by
this condition, such as epilepsy, migraine, asthma, and
cardiac or renal dysfunction, require careful observation.
3. Weight Changes
There is a tendency for women to gain weight while on
therapy with DEPO-PROVERA Contraceptive Injection.
From an initial average body weight of 136 lb, women
who completed 1 year of therapy with DEPO-PROVERA
Contraceptive Injection gained an average of 5.4 lb.
Women who completed 2 years of therapy gained an
average of 8.1 lb.
Women who completed 4 years gained an average of 13.8 lb. Women who completed 6 years gained an aver-age of 16.5 lb. Two percent of women withdrew from alarge-scale clinical trial because of excessive weight gain.
Depo-ProveraContraceptive Injectionbrand of medroxyprogesterone acetate injectable suspension, USP 4. Return of FertilityDEPO-PROVERA Contraceptive Injection has a pro-longed contraceptive effect. In a large US study ofwomen who discontinued use of DEPO-PROVERA Con-traceptive Injection to become pregnant, data are avail-able for 61% of them. Based on Life-Table analysis ofthese data, it is expected that 68% of women who dobecome pregnant may conceive within 12 months, 83%may conceive within 15 months, and 93% may conceivewithin 18 months from the last injection. The mediantime to conception for those who do conceive is 10months following the last injection with a range of 4 to31 months, and is unrelated to the duration of use. Nodata are available for 39% of the patients who discon-tinued DEPO-PROVERA Contraceptive Injection tobecome pregnant and who were lost to follow-up orchanged their mind.
5. CNS Disorders and ConvulsionsPatients who have a history of psychic depressionshould be carefully observed and the drug not be read-ministered if the depression recurs.
There have been a few reported cases of convulsions in patients who were treated with DEPO-PROVERAContraceptive Injection. Association with drug use orpre-existing conditions is not clear.
6. Carbohydrate Metabolism A decrease in glucose tolerance has been observed ins o m e p a t i e n t s o n D E P O - P R O V E R A C o n t r a c e p t i v eInjection treatment. The mechanism of this decrease isobscure. For this reason, diabetic patients should becarefully observed while receiving such therapy.
7. Liver FunctionIf jaundice develops, consideration should be given tonot readministering the drug.
8. Protection Against Sexually Transmitted Diseases Patients should be counseled that this product does not protect against HIV infection (AIDS) and othersexually transmitted diseases.
Aminoglutethimide administered concomitantly w i t h t h e D E P O - P R O V E R A C o n t r a c e p t i v eInjection may significantly depress the serumc o n c e n t r a t i o n s o f m e d r o x y p r o g e s t e r o n ea c e t a t e . 12 U s e r s o f D E P O - P R O V E R A C o n-traceptive Injection should be warned of the pos-sibility of decreased efficacy with the use of thisor any related drugs.
LABORATORY TEST INTERACTIONS
The pathologist should be advised of progestin therapy when relevant specimens are submitted.
The following laboratory tests may be affected by progestins including DEPO-PROVERA ContraceptiveInjection:(a) Plasma and urinary steroid levels are decreased (eg, progesterone, estradiol, pregnanediol, testos-terone, cortisol).
(b) Gonadotropin levels are decreased.
(c) Sex-hormone-binding-globulin concentrations are (d) Protein-bound iodine and butanol extractable pro- tein-bound iodine may increase.
T3-uptake values may decrease.
(e) Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase.
( f ) Sulfobromophthalein and other liver function test (g) The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases anddecreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-den-s i t y l i p o p r o t e i n ( H D L ) c h o l e s t e r o l h a v e b e e nobserved in studies.
See “WARNINGS” section 3.
Pregnancy Category X. See “WARNINGS” section 6.
See “WARNINGS” section 8.
Safety and effectiveness in pediatric patients have not
been established. See “WARNINGS” section 6.
INFORMATION FOR THE PATIENT
See Patient Labeling.
Patient labeling is included with each single-dose vial and prefilled syringe of DEPO-PROVERA ContraceptiveInjection to help describe its characteristics to thepatient. It is recommended that prospective users begiven this labeling and be informed about the risks andbenefits associated with the use of DEPO-PROVERAContraceptive Injection, as compared with other forms Depo-ProveraContraceptive Injectionbrand of medroxyprogesterone acetate injectable suspension, USP of contraception or with no contraception at all. It is rec-o m m e n d e d t h a t p h y s i c i a n s o r o t h e r h e a l t h - c a r eproviders responsible for those patients advise them atthe beginning of treatment that their menstrual cyclemay be disrupted and that irregular and unpredictableb l e e d i n g o r s p o t t i n g r e s u l t s , a n d t h a t t h i s u s u a l l ydecreases to the point of amenorrhea as treatment withDEPO-PROVERA Contraceptive Injection continues,without other therapy being required.
In the largest clinical trial with DEPO-PROVERA Contraceptive Injection, over 3,900 women, who weretreated for up to 7 years, reported the following adversereactions, which may or may not be related to the useof DEPO-PROVERA Contraceptive Injection.
The following adverse reactions were reported by more than 5% of subjects:Menstrual irregularities (bleeding or amenorrhea, or both)Abdominal pain or discomfort Weight changesDizziness HeadacheAsthenia (weakness or fatigue) Nervousness Adverse reactions reported by 1% to 5% of subjects using DEPO-PROVERA Contraceptive Injection were:Decreased libido or anorgasmiaPelvic painBackache Breast painLeg crampsNo hair growth or alopeciaDepressionBloatingNauseaRashInsomniaEdemaLeukorrheaHot flashesAcneArthralgiaVaginitis E v e n t s r e p o r t e d b y f e w e r t h a n 1 % o f s u b j e c t s included: galactorrhea, melasma, chloasma, convul-s i o n s , c h a n g e s i n a p p e t i t e , g a s t r o i n t e s t i n a l d i s t u r -b a n c e s , j a u n d i c e , g e n i t o u r i n a r y i n f e c t i o n s , v a g i n a lcysts, dyspareunia, paresthesia, chest pain, pulmonaryembolus, allergic reactions, anemia, drowsiness, syn-cope, dyspnea and asthma, tachycardia, fever, exces-sive sweating and body odor, dry skin, chills, increasedlibido, excessive thirst, hoarseness, pain at injectionsite, blood dyscrasia, rectal bleeding, changes in breastsize, breast lumps or nipple bleeding, axillary swelling,breast cancer, prevention of lactation, sensation ofpregnancy, lack of return to fertility, paralysis, facialpalsy, scleroderma, osteoporosis, uterine hyperplasia,cervical cancer, varicose veins, dysmenorrhea, hir -sutism, unexpected pregnancy, thrombophlebitis, deepvein thrombosis.
In addition, voluntary reports have been received of anaphylaxis and anaphylactoid reaction with use ofDEPO-PROVERA Contraceptive Injection.
DOSAGE AND ADMINISTRATION
Both the 1 mL vial and the 1 mL prefilled syringe of DEPO-PROVERA Contraceptive Injection should be vig-orously shaken just before use to ensure that the dosebeing administered represents a uniform suspension.
The recommended dose is 150 mg of DEPO-PROVERA Contraceptive Injection every 3 months (13 weeks)
administered by deep, IM injection in the gluteal or del-
toid muscle. To ensure the patient is not pregnant at the
time of the first injection, the first injection MUST be
given ONLY during the first 5 days of a normal men-
strual period; ONLY within the first 5-days postpartum if
not breast-feeding; and if exclusively breast-feeding,
ONLY at the sixth postpartum week. If the time interval
between injections is greater than 13 weeks, the physi-
cian should determine that the patient is not pregnant
b e f o r e a d m i n i s t e r i n g t h e d r u g . T h e e f f i c a c y o f
DEPO-PROVERA Contraceptive Injection depends on
adherence to the dosage schedule of administration.
DEPO-PROVERA Contraceptive Injection (medroxy- progesterone acetate sterile aqueous suspension 150mg/mL) is available as: Depo-ProveraContraceptive Injectionbrand of medroxyprogesterone acetate injectable suspension, USP Store at controlled room temperature 20 ° to 25°C REFERENCES
1. Trussell J, Hatcher RA, Cates W Jr, Stewart FH, Kost K. A guide to interpreting contraceptive effi-cacy studies. Obstet Gynecol. 1990; 76:558-567.
2. Schwallie PC, Assenzo JR. Contraceptive use-effi- cacy study utilizing medroxyprogesterone acetateadministered as an intramuscular injection onceevery 90 days. Fertil Steril. 1973; 24:331-339.
3. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and depot-medroxy-p r o g e s t e r o n e a c e t a t e : a m u l t i - n a t i o n a l s t u d y .
Lancet. 1991; 338:833-838.
4. WHO Collaborative Study of Neoplasia and Steroid C o n t r a c e p t i v e s . D e p o t - m e d r o x y p r o g e s t e r o n eacetate (DMPA) and risk of epithelial ovarian can-cer. Int J Cancer. 1991; 49:191-195.
5. WHO Collaborative Study of Neoplasia and Steroid C o n t r a c e p t i v e s . D e p o t - m e d r o x y p r o g e s t e r o n ea c e t a t e ( D M P A ) a n d r i s k o f l i v e r c a n c e r . I n t JCancer. 1991; 49:182-185.
6. WHO Collaborative Study of Neoplasia and Steroid C o n t r a c e p t i v e s . D e p o t - m e d r o x y p r o g e s t e r o n eacetate (DMPA) and risk of invasive squamous-cellcervical cancer. Contraception. 1992; 45:299-312.
7. WHO Collaborative Study of Neoplasia and Steroid C o n t r a c e p t i v e s . D e p o t - m e d r o x y p r o g e s t e r o n eacetate (DMPA) and risk of endometrial cancer. IntJ Cancer. 1991; 49:186-190.
8. S u r v e i l l a n c e , E p i d e m i o l o g y , a n d E n d R e s u l t s : Incidence and Mortality Data, 1973-1977. NationalCancer Institute Monograph, 57: June 1981. (NIHpublication No. 81-2330).
9. Gray RH, Pardthaisong T. In Utero exposure to steroid contraceptives and survival during infancy.
Am J Epidemiol. 1991; 134:804-811.
10. Pardthaisong T, Gray RH. In Utero exposure to steroid contraceptives and outcome of pregnancy.
Am J Epidemiol. 1991; 134:795-803.
11. Pardthaisong T, Gray RH, McDaniel EB, Chan - dacham A. Steroid contraceptive use and preg-nancy outcome. Teratology. 1988; 38:51-58.
12. Van Deijk WA, Biljham GH, Mellink WAM, Meulen- b e r g P M M . I n f l u e n c e o f a m i n o g l u t e t h i m i d e o nplasma levels of medroxyprogesterone acetate: itscorrelation with serum cortisol. Cancer TreatmentReports. 1985; 69:1, 85-90.
13. Paul C, Skegg DCG, Spears GFS. Depot medroxy- progesterone (Depo-Provera) and risk of breastcancer. Br Med J. 1989; 299:759-762.
14. Skegg DCG, Noonan EA, Paul C, Spears GFS, Meirik O, Thomas DB. Depot MedroxyprogesteroneAcetate and Breast Cancer: A Pooled Analysis fromthe World Health Organization and New ZealandStudies. JAMA. 1995; 273(10):799-804.
DEPO-PROVERA Contraceptive Injection 1 mL vials aremanufactured by:Pharmacia & Upjohn CompanyKalamazoo, MI 49001, USA DEPO-PROVERA Contraceptive Injection 1 mL prefilledsyringes are manufactured by:Pharmacia & Upjohn, N.V./S.A.
Puurs, Belgiumfor:Pharmacia & Upjohn CompanyKalamazoo, MI 49001, USA
OBEZITATEA – O PROBLEM Ă A SOCIET ĂȚ II NOASTRE dr. Buduru Alina , medic specialist Diabet, Nutriție, Boli metabolice Spitalul Jude ț ean ”dr. Constantin Opri ș ” Baia Mare prof. Bolo ș Milica , limba și literatura română Colegiul Tehnic „Transilvania”, Baia Mare În ultimii ani, obezitatea a devenit o problemă extrem de importantă a societății noastre,