DEPO-PROVERA (medroxyprogesterone acetate injectable suspension, USP) 8 Adverse Reactions

8.1 Adverse Reaction Overview

The following adverse reactions have been associated with the use of DEPO-PROVERA:

(A) Irregular Menstrual Patterns
The most common adverse reactions associated with the use of DEPO-PROVERA for contraception is the disruption of menstrual patterns. This includes irregular or unpredictable bleeding or spotting, or rarely heavy or continuous bleeding.

(B) Non-Menstrual Adverse Reactions
Other than menstrual changes, weight gain, headache and abdominal discomfort are the most common side effects.

In a few instances there have been undesirable sequelae at the site of injection, such as a residual lump, change in colour of the skin or a sterile abscess.

Anaphylactic and anaphylactoid reactions have been reported on rare occasions.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions.  The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

In clinical studies of 3,905 women receiving DEPO-PROVERA every 3 months, there were a total of 8,467 side effect reports.  Headache, abdominal distress, nervousness, dizziness and decreased libido were reported in greater than 5.0 percent of study patients.  Thrombophlebitis was reported by 4 women (0.10%).

(A) Total Adverse Reaction Experience:

Table 5 contains a list of reported side effects, the number of times each side effect was reported and the number and percent of patients who reported each side effect.  Table 6 contains the number of side effects reported by month and the number of side effect reports per 100 patients "exposed" by month.

According to Table 6, 1,135 (13.40%) of the total 8,467 side effect reports were reported during the first injection period (90 days); during the first two injection periods (first 180 days) 2,070 (24.45%) were reported; 2,826 (33.38%) were reported during the first three injection periods (first 270 days); and 3,536 (41.75%) were reported during the first four injection periods (first 360 days).  The number of patients not reporting any side effects was 2,117 (54.2%).

Bleeding Experience

In U.S. studies of 3,905 women receiving DEPO-PROVERA every 3 months, unpredictable bleeding or spotting were commonly reported during the first few menstrual cycles with frequency, duration and amount of bleeding diminishing gradually.  By month 12, amenorrhea was reported by 55% of the women, and by month 24, amenorrhea was reported by 68% of the women using DEPO-PROVERA.  Bleeding or spotting persisted for more than 10 days of the month in about 12% of the users.  Abnormally heavy or prolonged bleeding occurred in about 1 to 2% of users.  

The percent of patients with zero days of bleeding and/or spotting per 30-day month increases with time from start of study, as follows:

Bleeding and/or spotting occurred in the following percentage of the 90 days of the indicated injection period.

On hundred and ninety four (194) patients reported no bleeding or spotting from first injection to the end of their participation in the study. The median number of days of no spotting or bleeding for these 194 women was 120 days. The minimum number of days of no spotting or bleeding was 30 and the maximum was 1,674 days.

Thirteen (13) patients reported bleeding and/or spotting every day from first injection to the end of their participation in the study.

Weight Gain Experience

The U.S. studies of 3,905 women receiving DEPO-PROVERA every 3 months report a mean weight gain of 5.4 lbs (2.5 kg) at the end of 1 year, but only 2% of women discontinued treatment due to excessive weight gain.  Many studies indicate that weight gain occurs mainly in the first year of use, however, others report a slow and continuing increase which may reach a mean of 8 lbs (3.6 kg) by the end of 2 years.  However, some 20 to 40 percent of DEPO-PROVERA users actually lose weight during treatment.

A much higher proportion of patients had an increase as had a decrease of more than 15 pounds.  The mean body weight changes from baseline (in pounds) were as follows:

Laboratory Assay Results

Laboratory assays were performed on a sample of women, rather than on all women. There were no clinically significant changes in any of the haematology, urine or serum chemistry variables that were monitored.

The number of women having had an initial Pap smear taken is 2,052. Ten (10) patients dropped from the study due to a Grade IV Pap smear, while 4 patients dropped out due to a Grade III Pap smear.

(B) Non-Menstrual Adverse Reactions:

The occurrence rates for non-menstrual adverse reactions reported in U.S. studies of 3,905 women receiving DEPO-PROVERA every 3 months are listed below. 2,253 women were in the study for 12 months or more; 827 women were in the study for 36 months or more. The total number of patient-months of experience was 82,384. A total of 2,117 of the 3,905 women (54%) reported no side effects.

8.5 Post-Market Adverse Reactions

In post-marketing experience, there have been cases of osteoporosis including osteoporotic fractures reported in patients taking DEPO-PROVERA. Patient age ranged from 16 years to 48 years.  Other adverse events reported during post-marketing experience, regardless of causality and frequency, are listed below.  It should be noted that the nature of post-marketing surveillance makes it difficult to determine if a reported event was actually caused by DEPO-PROVERA.

Blood and lymphatic system disorders: hemolytic anemia, hemorrhagic disorder, sickle cell crisis, splenic infarction, thrombocytopenia, thrombotic thrombocytopenic purpura

Cardiac disorders: bradycardia, myocardial infarction, palpitations, pericarditis, possible exacerbation of prolonged QT interval syndrome (with fatal outcome), supraventricular tachycardia

Congenital and familial/genetic disorders: acute porphyria, in cases of failure of contraception: Trisomy 21, Trisomy 16, Turner’s syndrome

Ear and labyrinth disorders: change in hearing, tinnitus, vertigo

Endocrine disorders: adrenal dysfunction NOS, Cushingoid, estrogen deficiency, hyperthyroidism, hypoglycemia, hypopituitarism, hypothyroidism, thyroiditis

Eye disorders: macular edema, optic ischemic neuropathy, optic neuritis, papilloedema, ptosis, retinal vein occlusion, vision loss, visual changes

Gastrointestinal disorders: acute pancreatitis, dysphagia, intestinal infarction, mouth ulceration, oral mucosal blistering, salivary gland enlargement

General disorders and administration site conditions: fatigue, injection site reactions (including swelling, rash, ulcer, necrosis, edema, infection, abscess), injections site pain/tenderness, injection site persistent atrophy/indentation/dimpling/scar, injection site nodule/lump, malaise, sudden infant death syndrome (exposure-in utero)

Hepatobiliary disorders: Cholangitis, cholelithiasis, gallbladder disorder, hepatitis, hepatomegaly, obstructive jaundice, hepatic failure (with fatal outcome)

Immune system disorders: anaphylactic reaction (with fatal outcome in rare cases), hypersensitivity

Infections and infestations: salpingitis, sepsis, vulval abscess

Investigations: coagulation Factor X decreased, decreased blood folate, decreased blood pressure, decreased estrogen, decreased testosterone, elevated blood creatinine, hypernatremia, hypokalemia, increased alanine aminotransferase, increased alkaline phosphatase, increased blood pressure, increased creatine phosphokinase, increased triglycerides, leukocytosis, weight decreased

Metabolism and nutrition disorders: cachexia, excessive thirst

Musculoskeletal, connective tissue and bone disorders: joint swelling, muscle weakness, myalgia, osteonecrosis

Neoplasms benign, malignant and unspecified: acute leukemia, benign breast neoplasm, benign hydatidiform mole, fibroadenoma of breast, Hodgkin’s disease, kidney neoplasm, malignant melanoma, meningioma, neurofibroma, ovarian cancer, squamous cell carcinoma of the cervix, uterine leiomyoma

Nervous system disorders: amnesia, anosmia, ataxia, balance disorder, benign intracranial hypertension, cerebral hemorrhage, cerebral ischemia/infarct, cerebral venous thrombosis, cerebrovascular accident, confusion, dysarthria, dysgeusia, memory loss, migraine, myoclonus, Parkinsonism, seizures, speech disorder, stroke (with fatal outcome), third nerve palsy, transient ischemic attack, tremor

Pregnancy, peurperium and perinatal conditions: exposure-in-utero: abnormal genitalia, anencephaly, antepartum hemorrhage, blighted ovum, cleft palate, congenital adenomatoid malformation, congenital diaphragmatic hernia, congenital heart defects, congenital megacolon, ear malformation NOS, ectopic pregnancy, esophageal atresia, fetal hydrops, hydrocephalus, hypospadias, intrauterine growth retardation, limb deformity, microcephaly, missed abortion, polydactyly, polyhydramnios, prematurity, single umbilical artery, skull malformation, spina bifida, spontaneous abortion, stillbirth, Talipes, tracheoesophageal fistula

Psychiatric disorders: acute psychosis, agitation, anxiety, attention deficit/hyperactivity disorder, dysphemia, eating disorder, irritability, mood swings, paranoia, suicidality

Renal and urinary disorders: interstitial nephritis, nephrolithiasis, nephrotic syndrome, proteinuria, renal infarct, urinary retention

Reproductive system and breast disorders: cervical dysplasia, fibrocystic breast disease, menorrhagia, ovarian cyst, premature menopause, uterine cyst, vaginal dysplasia, vaginal mucosal blistering

Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, bronchospasm, epistaxis, laryngeal edema, laryngospasm, oropharyngeal swelling

Skin and subcutaneous tissue disorders: angioedema, erythema multiforme, erythema nodosum, facial edema, lipodystrophy acquired, porphyria aggravated

Vascular disorders: arterial thrombosis, embolism, Henoch-Schonlein purpura, postural hypotension, venous thrombosis (including rare cases with fatal outcome)