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depo-subQ provera 104 Injectable Suspension (Pharmacia & Upjohn)
- Drugs index
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
depo-subQ provera 104 contains medroxyprogesterone acetate (MPA), a derivative of progesterone, as its active ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is a white to off-white, odorless crystalline powder that is stable in air and that melts between 205[ordm ] and 209[ordm ]C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water.
The chemical name for medroxyprogesterone acetate is 17-hydroxy-6(alpha)-methylpregn-4-ene-3,20-dione 17-acetate. The structural formula is as follows:
depo-subQ provera 104 for subcutaneous (SC) injection is available in pre-filled syringes (160 mg/mL), each containing 0.65 mL (104 mg) of medroxyprogesterone acetate sterile aqueous suspension.
Each 0.65 mL contains:
When necessary, the pH is adjusted with sodium hydroxide or hydrochloric acid, or both.
depo-subQ provera 104 (medroxyprogesterone acetate injectable suspension), when administered at 104 mg/0.65 mL to women every 3 months (12 to 14 weeks), inhibits the secretion of gonadotropins, which prevents follicular maturation and ovulation and causes endometrial thinning. These actions produce its contraceptive effect.
Supression of serum estradiol concentrations and a possible direct action of depo-subQ provera 104 on the lesions of endometriosis are likely to be responsible for the therapeutic effect on endometriosis-associated pain.
The pharmacokinetic parameters of medroxyprogesterone acetate (MPA) following a single SC injection of depo-subQ provera 104 are shown in Table 1 and Figure 1.
Absorption: Following a single SC injection of depo-subQ provera 104, serum MPA concentrations reach >/= 0.2 ng/mL within 24 hours. The mean T max is attained approximately 1 week after injection.
In a study to assess accumulation and the achievement of steady state following multiple SC administrations, trough concentrations of MPA were determined after 6, 12, and 24 months, and in a subset of 8 subjects, bi-weekly concentrations were determined within one dosing interval in the second year of administration. The mean (SD) MPA trough concentrations were 0.67 (0.36) ng/mL (n=157), 0.79 (0.36) ng/mL (n=144), and 0.87 (0.33) ng/mL (n=106) at 6, 12 and 24 months, respectively.
Effect of Injection Site: depo-subQ provera 104 was administered into the anterior thigh or the abdomen to evaluate effects on the MPA concentration-time profile. MPA trough concentrations (C min ; Day 91) were similar for the two injection locations.
Distribution: Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG).
Metabolism: MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a combination of these positions, resulting in more than 10 metabolites.
Excretion: Residual MPA concentrations at the end of the first dosing interval (12 to 14 weeks) of depo-subQ provera 104 are generally below 0.5 ng/mL, consistent with its apparent terminal half-life of ~40 days after SC administration. Most MPA metabolites are excreted in the urine as glucuronide conjugates with only small amounts excreted as sulfates.
Linearity/Non-Linearity: Following a single SC administration of doses ranging from 50 to 150 mg, the AUC and C min (Day 91) increased with higher doses of depo-subQ provera 104, but there was considerable overlap across dose levels. Serum MPA concentrations at Day 91 increased in a dose proportional manner but C max did not appear to increase proportionally with increasing dose. The AUC data were suggestive of dose linearity.
Race: There were no significant differences in the pharmacokinetics and/or pharmacodynamics of MPA after SC administration of depo-subQ provera 104 in African-American and Caucasian women. The pharmacokinetics/pharmacodynamics of depo-subQ provera 104 were evaluated in Asian women in a separate study and also found to be similar to African-American and Caucasian women.
Effect of Body Weight: Although total MPA exposure was lower in obese women, no dosage adjustment of depo-subQ provera 104 is necessary based on body weight. The effect of body weight on the pharmacokinetics of MPA following a single dose was assessed in a subset of women (n = 42, body mass index [BMI] ranged from 18.2 to 46.7 kg/m 2 ). The AUC 0-91 values for MPA were 71.6, 67.9, and 46.3 ng·day/mL in women with BMI categories of </= 28 kg/m 2 , >28-38 kg/m 2 , and >38 kg/m 2 , respectively. The mean MPA C max was 1.74 ng/mL in women with BMI </= 28 kg/m 2 , 1.53 ng/mL in women with BMI >28-38 kg/m 2 , and 1.02 ng/mL in women with BMI > 38 kg/m 2 , respectively. The MPA trough (C min ) concentrations had a tendency to be lower in women with BMI >38 kg/m 2 .
Hepatic Insufficiency: No clinical studies have evaluated the effect of hepatic disease on the disposition of depo-subQ provera 104. However, steroid hormones may be poorly metabolized in patients with severe liver dysfunction (see CONTRAINDICATIONS ).
Renal Insufficiency: No clinical studies have evaluated the effect of renal disease on the pharmacokinetics of depo-subQ provera 104.
See PRECAUTIONS , section 9
INDICATIONS AND USAGE
depo-subQ provera 104 is indicated for the prevention of pregnancy in women of child bearing potential.
depo-subQ provera 104 also is indicated for management of endometriosis-associated pain.
In considering use for either indication, the loss of bone mineral density (BMD) in women of all ages and the impact on peak bone mass in adolescents should be considered, along with the decrease in BMD that occurs during pregnancy and/or lactation, in the risk/benefit assessment for women who use depo-subQ provera 104 long-term (see WARNINGS , section 1 ).
In three clinical studies, no pregnancies were detected among 2,042 women using depo-subQ provera 104 for up to 1 year. The Pearl Index pregnancy rate in women who were less than 36 years old at baseline, based on cycles in which they used no other contraceptive methods, was 0 pregnancies per 100 women-years of use (upper 95% confidence interval = 0.25).
Pregnancy rates for various contraceptive methods are typically reported for only the first year of use and are shown in Table 2.
The efficacy of depo-subQ provera 104 in the reduction of endometriosis-associated pain in women with the signs and symptoms of endometriosis was demonstrated in two active comparator-controlled studies. Each study assessed reduction in endometriosis-associated pain over 6 months of treatment and recurrence of symptoms for 12-months post treatment. Subjects treated with depo-subQ provera 104 for 6 months received a 104 mg dose every 3 months (2 injections), while women treated with leuprolide microspheres for 6 months received a dose of 11.25 mg every 3 months (2 injections) or 3.75 mg every month (6 injections). Study 268 was conducted in the U.S. and Canada and enrolled 274 subjects (136 on depo-subQ provera 104 and 138 on leuprolide). Study 270 was conducted in South America, Eur-ope and Asia, and enrolled 299 subjects (153 on depo-subQ provera 104 and 146 on leuprolide).
Reduction in pain was evaluated using a modified Biberoglu and Behrman scale that consisted of three patient-reported symptoms (dysmenorrhea, dyspareunia, and pelvic pain not related to menses) and two signs assessed during pelvic examination (pelvic tenderness and induration). For each category, a favorable response was defined as improvement of at least 1 unit (severity was assessed on a scale of 0 to 3) relative to baseline score (Figure 2).
Additionally, scores from each of the five categories were combined, with the total (composite score) considered a global measurement of overall disease improvement. For subjects with baseline scores for each of the 5 categories, a mean decrease of 4 points relative to baseline was considered a clinically meaningful improvement. Across both studies, for both treatment groups, the mean changes in the composite score met the protocol-defined criterion for improvement.
In the clinical trials, treatment with depo-subQ provera 104 was limited to six months. Data on the persistence of benefit with longer treatment are not available.
Subjects recorded daily the occurrence and severity of hot flushes. Of the depo-subQ provera 104 users, 28.6% reported experiencing moderate or severe hot flushes at baseline, 36.2% at month 3, and 26.7% at month 6. Of the leuprolide users, 32.8% reported experiencing moderate or severe hot flushes at baseline, 74.2% at month 3, and 68.5% at month 6.
1. Physical Examination
It is good medical practice for all women to have annual history and physical examinations, including women using depo-subQ provera 104. The physical examination, however, may be deferred until after initiation of depo-subQ provera 104 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 abnormal vaginal bleeding, appropriate measures 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 care.
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 Gain
Weight gain is a common occurrence in women using depo-subQ provera 104. In three large clinical trials using depo-subQ provera 104, the mean weight gain was 3.5 lb in the first year of use. In a small, two-year study comparing depo-subQ provera 104 to Depo-Provera CI (150 mg), the mean weight gain observed for women using depo-subQ provera 104 (7.5 lb) was similar to the mean weight gain for women using Depo-Provera CI, 150 mg (7.6 lb).
Although there are no data related to weight gain beyond 2 years for depo-subQ provera 104, the data on Depo-Provera CI (150 mg) may be relevant. In a clinical study, after five years, 41 women using Depo-Provera CI (150 mg) had a mean weight gain of 11.2 lb, while 114 women using non-hormonal contraception had a mean weight gain of 6.4 lb.
4. Return to Ovulation and Fertility
Return to ovulation is likely to be delayed after stopping therapy. Among 15 women who received multiple doses of depo-subQ provera 104:
However, ovulation has occurred as early as 14 weeks after a single dose of depo-subQ provera 104, and therefore it is important to follow the recommended dosing schedule.
Return to fertility also is likely to be delayed after stopping therapy. Among 28 women using depo-subQ provera 104 for contraception who stopped treatment to become pregnant, 1 became pregnant within 1 year of her last injection. A second woman became pregnant 443 days after her last injection. Seven women were lost to follow-up.
Patients with a history of treatment for clinical depression should be carefully monitored while receiving depo-subQ provera 104.
6. Injection Site Reactions
In 5 clinical studies of depo-subQ provera 104 involving 2,325 women (282 treated for up to 6 months, 1,780 treated for up to 1 year and 263 women treated for up to 2 years), 5% of women reported injection site reactions, and 1% had persistent skin changes, typically described as small areas of induration or atrophy.
Some patients receiving progestins may exhibit a decrease in glucose tolerance. Diabetic patients should be carefully observed while receiving such therapy.
8. Liver Function
If jaundice or any other liver abnormality develops in any woman receiving depo-subQ provera 104, treatment should be stopped while the cause is determined. Treatment may be resumed when liver function is acceptable and when the healthcare provider has determined that depo-subQ provera 104 did not cause the abnormality.
9. Drug Interactions
No drug-drug interaction studies have been conducted with depo-subQ provera 104. Aminoglutethimide administered concomitantly with depo-subQ provera 104 may significantly decrease the serum concentrations of MPA.
10. Laboratory Tests
The pathologist should be advised of progestin therapy when relevant specimens are submitted. The physician should be informed that certain endocrine and liver function tests, and blood components may be affected by progestin therapy:
11. Carcinogenesis, Mutagenesis, Impairment of Fertility
See WARNINGS , section 3 and PRECAUTIONS , section 4
Although depo-subQ provera 104 should not be used during pregnancy, there appears to be little or no increased risk of birth defects in women who have inadvertently been exposed to medroxyprogesterone acetate injections in early pregnancy. Neonates exposed to medroxyprogesterone acetate in-utero and followed to adolescence showed no evidence of any adverse effects on their health including their physical, intellectual, sexual or social development.
13. Nursing Mothers
Although the drug is detectable in the milk of mothers receiving Depo-Provera CI (150 mg), milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to medroxyprogesterone acetate from breast milk have been studied for developmental and behavioral effects through puberty, and no adverse effects have been noted.
14. Pediatric Use
depo-subQ provera 104 is not indicated before menarche. Use of depo-subQ provera 104 is associated with significant loss of bone mineral density (BMD). This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. It is unknown if use of depo-subQ provera 104 by younger women will reduce peak bone mass and increase the risk for osteoporotic fractures in later life. Other than concerns about loss of BMD, the safety and effectiveness are expected to be the same for postmenarchal adolescents and adult women.
15. Geriatric Use
depo-subQ provera 104 is intended for use in women with childbearing potential. Studies with depo-subQ provera 104 in geriatric women have not been conducted.
INFORMATION FOR THE PATIENT
See PATIENT LABELING.
In five clinical studies of depo-subQ provera 104 involving 2,325 women (282 treated for up to 6 months, 1,780 treated for up to 1 year and 263 treated for up to 2 years), 9% of women discontinued treatment for adverse reactions. Among these 212 women, the most common reasons for discontinuation were:
Adverse reactions reported by 5% or more of all women in these clinical trials included:
Adverse reactions reported by 1% to <5% of all women in these clinical trials included:
General disorders: fatigue, injection site pain
Gastrointestinal disorders: abdominal distention, abdominal pain, diarrhea, nausea
Infections: bronchitis, influenza, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection, vaginal candidiasis, vaginitis, vaginitis bacterial
Investigations: abnormal cervix smear
Musculoskeletal, connective tissue, and bone disorders: arthralgia, back pain, limb pain
Nervous system disorders: dizziness, insomnia
Psychiatric disorders: anxiety, depression, irritability, decreased libido
Reproductive system and breast disorders: breast pain, breast tenderness, menometrorrhagia, menorrhagia, menstruation irregular, uterine hemorrhage, vaginal hemorrhage
Skin disorders: acne
Vascular disorders: hot flushes
There have been rare cases of osteoporosis including osteoporotic fractures reported postmarketing in patients taking DEPO-PROVERA Contraceptive Injection. In addition, infrequent voluntary reports of anaphylaxis and anaphylactoid reaction have been received associated with use of Depo-Provera CI (150 mg).
The following additional reactions have been reported with Depo-Provera Contraceptive Injection and may occur with use of depo-subQ provera 104:
General disorders: asthenia, axillary swelling, chills, chest pain, fever, excessive thirst
Blood and lymphatic system disorders: anemia, blood dyscrasia
Cardiac disorders: tachycardia
Gastrointestinal disorders: gastrointestinal disturbances, rectal bleeding
Hepato-biliary disorders: jaundice
Immune system disorders: allergic reaction
Infections genitourinary infections
Investigations: decreased glucose tolerance
Musculoskeletal, connective tissue, and bone disorders: loss of bone mineral density, scleroderma
Neoplasms: breast cancer, cervical cancer
Nervous system disorders: convulsions, facial palsy, fainting, paralysis, paresthesia, somnolence
Psychiatric disorders: increased libido, nervousness
Reproductive system and breast disorders: breast lumps, galactorrhea, nipple discharge or bleeding, oligomenorrhea, prevention of lactation, prolonged anovulation, unexpected pregnancy, uterine hyperplasia, vaginal cyst
Respiratory disorders: asthma, dyspnea, hoarseness
Skin disorders: angioedema, dry skin, increased body odor, melasma, pruritus, urticaria
Vascular disorders: deep vein thrombosis, pulmonary embolus, thrombophlebitis
DOSAGE AND ADMINISTRATION
CONTRACEPTION AND ENDOMETRIOSIS INDICATIONS
Route of Administration
depo-subQ provera 104 must be given by subcutaneous injection into the anterior thigh or abdomen, once every 3 months (12 to 14 weeks). depo-subQ provera 104 is not formulated for intramuscular injection. Dosage does not need to be adjusted for body weight. The pre-filled syringe of depo-subQ provera 104 must be vigorously shaken just before use to create a uniform suspension.
Ensure that the patient is not pregnant at the time of the first injection. For women who are sexually active and having regular menses, the first injection should be given only during the first 5 days of a normal menstrual period. Women who are breast-feeding may have their first injection during or after their sixth postpartum week.
Second and Subsequent Injections
Dosing is every 12 to 14 weeks. If more than 14 weeks elapse between injections, pregnancy should be ruled out before the next injection.
IF USING FOR CONTRACEPTION AND SWITCHING FROM ANOTHER METHOD
When switching from other contraceptive methods, depo-subQ provera 104 should be given in a manner that ensures continuous contraceptive coverage. For example, patients switching from combined (estrogen plus progestin) contraceptives should have their first injection of depo-subQ provera 104 within 7 days after the last day of using that method (7 days after taking the last active pill, removing the patch or ring). Similarly, contraceptive coverage will be maintained in switching from Depo-Provera CI (150 mg) to depo-subQ provera 104, provided the next injection is given within the prescribed dosing period for Depo-Provera CI (150 mg).
IF USING FOR TREATMENT OF ENDOMETRIOSIS
Treatment for longer than two years is not recommended, due to the impact of long-term depo-subQ provera 104 on bone mineral density. If symptoms return after discontinuation of treatment, bone mineral density should be evaluated prior to retreatment.
Instructions for Administration of depo-subQ provera 104 for Subcutaneous Use
Ensure that the medication is at room temperature. Make sure the following components (Diagrams 1, 2, and 3) are available.
depo-subQ provera 104, as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration.
Step 1: Choosing and preparing the injection area.
Choose the injection area. Avoid boney areas and the umbilicus. See shaded areas (Diagram 4).
Upper thigh & Abdomen
Use an alcohol pad to wipe the skin in the injection area you have chosen. Allow the skin to dry.
Step 2: Syringe preparation
Gently twist off the protective end cap from the needle to break the seal (Diagram 5). Set aside.
While holding the syringe firmly by the barrel pointing upward, shake it forcefully for at least 1 minute to thoroughly mix the medication (Diagram 6).
Hold the syringe barrel firmly, remove the protective tip cap from the syringe and attach the needle by pushing it onto the barrel tip (Diagram 7).
While continuing to hold the syringe barrel firmly, remove the clear protective plastic cover from the needle, making sure the needle is still firmly attached to the syringe (Diagram 8).
While holding the syringe with the needle pointing upward, gently push in the plunger until the medicine is up to the top of the syringe (Diagram 9).
Step 3: Injecting the dose.
Gently grasp and squeeze a large area of skin in the chosen injection area between the thumb and fore-finger (Diagram 10) pulling it away from the body.
Insert the needle at a 45 degree angle so that most of the needle is in the fatty tissue. The plastic hub of the needle should be nearly or almost touching the skin (Diagram 11).
Inject the medication slowly until the syringe is empty (Diagram 12). This should take about 5-7 seconds.
The entire dose must be given to activate the needle guard. When the entire dose is completely injected, gently pull the needle out of the skin. Remove your finger from the plunger, allowing the syringe to move up inside the device until the needle guard completely covers the exposed needle. You will hear a 'click' when the needle guard is fully activated. It is very important that the entire dose of depo-subQ provera 104 is given.
Use a clean cotton pad to press lightly on the injection area for a few seconds. Do NOT rub the area.
Following the administration of each dose, the used syringe should be discarded in a safe and proper manner.
depo-subQ provera 104 for subcutaneous use (medroxyprogesterone acetate injectable suspension 104 mg/0.65 mL) is available as a pre-filled syringe, pre-assembled with an UltraSafe Passive Needle Guard * device, and packaged with a 26-gauge × 3/8 inch needle in the following presentation:
NDC 0009-4709-010.65 mL single-use, disposable syringe
Store at controlled room temperature 20[ordm ] to 25[ordm ] C (68[ordm ] to 77[ordm ]F) [see USP].
Rx only*UltraSafe Passive Needle Guard is a trademark of Safety Syringes, Inc.
Pharmacia and Upjohn Co
Division of Pfizer Inc, NY, NY 10017
LAB-0295-1.0i Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F, Contraceptive Technology: 17th Revised Edition. New York, NY: Irvington Publishers, 1998.
iiSkegg DCG, Noonan EA, Paul C, Spears GFS, Meirik O, Thomas DB. Depot Medroxyprogesterone Acetate and Breast Cancer: A Pooled Analysis from the World Health Organization and New Zealand Studies. JAMA. 1995; 273(10): 799-804.
iiiWHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and depot-medroxyprogesterone acetate: a multi-national study. Lancet. 1991; 338:833-838.
ivPaul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med J. 1989; 299:759-762.
vSurveillance, Epidemiology, and End Results: Incidence and Mortality Data, 1973-1977. National Cancer Institute Monograph, 57: June 1981. (NIH publication No. 81-2330).