PREMARIN® Adverse Reactions

(conjugated estrogens)

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in labeling:

Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)]
Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)]

6.1 Clinical Study Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During the first year of a 2-year clinical trial with 2,333 postmenopausal women with a uterus between 40 and 65 years of age (88 percent Caucasian), 1,012 women were treated with conjugated estrogens, and 332 were treated with placebo.

Table 1 summarizes treatment-related adverse reactions that occurred at a rate of ≥ 1 percent in any treatment group.

Table 1: TREATMENT RELATED ADVERSE REACTIONS AT A FREQUENCY ≥ 1 PERCENT
PREMARIN
0.625 mg
(n=348)
PREMARIN
0.45 mg (n=338)
PREMARIN
0.3 mg
(n=326)
Placebo
(n=332)

Body as a whole

  Abdominal pain

38 (11)

28 (8)

30 (9)

21 (6)

  Asthenia

16 (5)

8 (2)

14 (4)

3 (1)

  Back pain

18 (5)

11 (3)

13 (4)

4 (1)

  Chest pain

2 (1)

3 (1)

4 (1)

2 (1)

  Generalized edema

7 (2)

6 (2)

4 (1)

8 (2)

  Headache

45 (13)

47 (14)

44 (13)

46 (14)

  Moniliasis

5 (1)

4 (1)

4 (1)

1 (0)

  Pain

17 (5)

10 (3)

12 (4)

14 (4)

  Pelvic pain

10 (3)

9 (3)

8 (2)

4 (1)

Cardiovascular system

  Hypertension

4 (1)

4 (1)

7 (2)

5 (2)

  Migraine

7 (2)

1 (0)

0

3 (1)

  Palpitation

3 (1)

3 (1)

3 (1)

4 (1)

  Vasodilatation

2 (1)

2 (1)

3 (1)

5 (2)

Digestive system

  Constipation

7 (2)

6 (2)

4 (1)

3 (1)

  Diarrhea

4 (1)

5 (1)

5 (2)

8 (2)

  Dyspepsia

7 (2)

5 (1)

6 (2)

14 (4)

  Eructation

1 (0)

1 (0)

4 (1)

1 (0)

  Flatulence

22 (6)

18 (5)

13 (4)

8 (2)

  Increased appetite

4 (1)

1 (0)

1 (0)

2 (1)

  Nausea

16 (5)

10 (3)

15 (5)

16 (5)

Metabolic and nutritional

  Hyperlipidemia

2 (1)

4 (1)

3 (1)

2 (1)

  Peripheral edema

5 (1)

2 (1)

4 (1)

3 (1)

  Weight gain

11 (3)

10 (3)

8 (2)

14 (4)

Musculoskeletal system

  Arthralgia

6 (2)

3 (1)

2 (1)

5 (2)

  Leg cramps

10 (3)

5 (1)

9 (3)

4 (1)

  Myalgia

2 (1)

1 (0)

4 (1)

1 (0)

Nervous system

  Anxiety

6 (2)

4 (1)

2 (1)

4 (1)

  Depression

17 (5)

15 (4)

10 (3)

17 (5)

  Dizziness

9 (3)

7 (2)

4 (1)

5 (2)

  Emotional lability

3 (1)

4 (1)

5 (2)

8 (2)

  Hypertonia

1 (0)

1 (0)

5 (2)

3 (1)

  Insomnia

16 (5)

10 (3)

13 (4)

14 (4)

  Nervousness

9 (3)

12 (4)

2 (1)

6 (2)

Skin and appendages

  Acne

3 (1)

1 (0)

8 (2)

3 (1)

  Alopecia

6 (2)

6 (2)

5 (2)

2 (1)

  Hirsutism

4 (1)

2 (1)

1 (0)

0

  Pruritus

11 (3)

11 (3)

10 (3)

3 (1)

  Rash

6 (2)

3 (1)

1 (0)

2 (1)

  Skin discoloration

4 (1)

2 (1)

0

1 (0)

  Sweating

4 (1)

1 (0)

3 (1)

4 (1)

Urogenital system

  Breast disorder

6 (2)

3 (1)

3 (1)

6 (2)

  Breast enlargement

3 (1)

4 (1)

7 (2)

3 (1)

  Breast neoplasm

4 (1)

4 (1)

7 (2)

7 (2)

  Breast pain

37 (11)

39 (12)

24 (7)

26 (8)

  Cervix disorder

8 (2)

4 (1)

5 (2)

0

  Dysmenorrhea

12 (3)

10 (3)

4 (1)

2 (1)

  Endometrial disorder

4 (1)

2 (1)

2 (1)

0

  Endometrial hyperplasia

16 (5)

8 (2)

1 (0)

0

  Leukorrhea

17 (5)

17 (5)

12 (4)

6 (2)

  Metrorrhagia

11 (3)

4 (1)

3 (1)

1 (0)

  Urinary tract infection

1 (0)

2 (1)

1 (0)

4 (1)

  Uterine fibroids enlarged

6 (2)

1 (0)

2 (1)

2 (1)

  Uterine spasm

11 (3)

5 (1)

3 (1)

2 (1)

  Vaginal dryness

1 (0)

2 (1)

1 (0)

6 (2)

  Vaginal hemorrhage

46 (13)

13 (4)

6 (2)

0

  Vaginal moniliasis

14 (4)

10 (3)

12 (4)

5 (2)

  Vaginitis

18 (5)

7 (2)

9 (3)

1 (0)

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of PREMARIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible always to reliably estimate their frequency or establish a causal relationship to drug exposure.

Genitourinary system

Abnormal uterine bleeding; dysmenorrheal or pelvic pain, increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis, change in cervical secretion, ovarian cancer, endometrial hyperplasia, endometrial cancer, leukorrhea.

Breasts

Tenderness, enlargement, pain, discharge, galactorrhea, fibrocystic breast changes, breast cancer, gynecomastia in males.

Cardiovascular

Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, increase in blood pressure.

Gastrointestinal

Nausea, vomiting, abdominal pain, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas, ischemic colitis.

Skin

Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, loss of scalp hair, hirsutism, pruritus, rash.

Eyes

Retinal vascular thrombosis, intolerance to contact lenses.

Central nervous system

Headache, migraine, dizziness , mental depression, nervousness, mood disturbances, irritability, exacerbation of epilepsy, dementia, possible growth potentiation of benign meningioma.

Miscellaneous

Increase or decrease in weight, glucose intolerance, aggravation of porphyria, edema, arthralgias, leg cramps, changes in libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity.

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Health Professional Information

Adverse Reactions

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in labeling:

Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)]
Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)]

6.1 Clinical Study Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During the first year of a 2-year clinical trial with 2,333 postmenopausal women with a uterus between 40 and 65 years of age (88 percent Caucasian), 1,012 women were treated with conjugated estrogens, and 332 were treated with placebo.

Table 1 summarizes treatment-related adverse reactions that occurred at a rate of ≥ 1 percent in any treatment group.

Table 1: TREATMENT RELATED ADVERSE REACTIONS AT A FREQUENCY ≥ 1 PERCENT
PREMARIN
0.625 mg
(n=348)
PREMARIN
0.45 mg (n=338)
PREMARIN
0.3 mg
(n=326)
Placebo
(n=332)

Body as a whole

  Abdominal pain

38 (11)

28 (8)

30 (9)

21 (6)

  Asthenia

16 (5)

8 (2)

14 (4)

3 (1)

  Back pain

18 (5)

11 (3)

13 (4)

4 (1)

  Chest pain

2 (1)

3 (1)

4 (1)

2 (1)

  Generalized edema

7 (2)

6 (2)

4 (1)

8 (2)

  Headache

45 (13)

47 (14)

44 (13)

46 (14)

  Moniliasis

5 (1)

4 (1)

4 (1)

1 (0)

  Pain

17 (5)

10 (3)

12 (4)

14 (4)

  Pelvic pain

10 (3)

9 (3)

8 (2)

4 (1)

Cardiovascular system

  Hypertension

4 (1)

4 (1)

7 (2)

5 (2)

  Migraine

7 (2)

1 (0)

0

3 (1)

  Palpitation

3 (1)

3 (1)

3 (1)

4 (1)

  Vasodilatation

2 (1)

2 (1)

3 (1)

5 (2)

Digestive system

  Constipation

7 (2)

6 (2)

4 (1)

3 (1)

  Diarrhea

4 (1)

5 (1)

5 (2)

8 (2)

  Dyspepsia

7 (2)

5 (1)

6 (2)

14 (4)

  Eructation

1 (0)

1 (0)

4 (1)

1 (0)

  Flatulence

22 (6)

18 (5)

13 (4)

8 (2)

  Increased appetite

4 (1)

1 (0)

1 (0)

2 (1)

  Nausea

16 (5)

10 (3)

15 (5)

16 (5)

Metabolic and nutritional

  Hyperlipidemia

2 (1)

4 (1)

3 (1)

2 (1)

  Peripheral edema

5 (1)

2 (1)

4 (1)

3 (1)

  Weight gain

11 (3)

10 (3)

8 (2)

14 (4)

Musculoskeletal system

  Arthralgia

6 (2)

3 (1)

2 (1)

5 (2)

  Leg cramps

10 (3)

5 (1)

9 (3)

4 (1)

  Myalgia

2 (1)

1 (0)

4 (1)

1 (0)

Nervous system

  Anxiety

6 (2)

4 (1)

2 (1)

4 (1)

  Depression

17 (5)

15 (4)

10 (3)

17 (5)

  Dizziness

9 (3)

7 (2)

4 (1)

5 (2)

  Emotional lability

3 (1)

4 (1)

5 (2)

8 (2)

  Hypertonia

1 (0)

1 (0)

5 (2)

3 (1)

  Insomnia

16 (5)

10 (3)

13 (4)

14 (4)

  Nervousness

9 (3)

12 (4)

2 (1)

6 (2)

Skin and appendages

  Acne

3 (1)

1 (0)

8 (2)

3 (1)

  Alopecia

6 (2)

6 (2)

5 (2)

2 (1)

  Hirsutism

4 (1)

2 (1)

1 (0)

0

  Pruritus

11 (3)

11 (3)

10 (3)

3 (1)

  Rash

6 (2)

3 (1)

1 (0)

2 (1)

  Skin discoloration

4 (1)

2 (1)

0

1 (0)

  Sweating

4 (1)

1 (0)

3 (1)

4 (1)

Urogenital system

  Breast disorder

6 (2)

3 (1)

3 (1)

6 (2)

  Breast enlargement

3 (1)

4 (1)

7 (2)

3 (1)

  Breast neoplasm

4 (1)

4 (1)

7 (2)

7 (2)

  Breast pain

37 (11)

39 (12)

24 (7)

26 (8)

  Cervix disorder

8 (2)

4 (1)

5 (2)

0

  Dysmenorrhea

12 (3)

10 (3)

4 (1)

2 (1)

  Endometrial disorder

4 (1)

2 (1)

2 (1)

0

  Endometrial hyperplasia

16 (5)

8 (2)

1 (0)

0

  Leukorrhea

17 (5)

17 (5)

12 (4)

6 (2)

  Metrorrhagia

11 (3)

4 (1)

3 (1)

1 (0)

  Urinary tract infection

1 (0)

2 (1)

1 (0)

4 (1)

  Uterine fibroids enlarged

6 (2)

1 (0)

2 (1)

2 (1)

  Uterine spasm

11 (3)

5 (1)

3 (1)

2 (1)

  Vaginal dryness

1 (0)

2 (1)

1 (0)

6 (2)

  Vaginal hemorrhage

46 (13)

13 (4)

6 (2)

0

  Vaginal moniliasis

14 (4)

10 (3)

12 (4)

5 (2)

  Vaginitis

18 (5)

7 (2)

9 (3)

1 (0)

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of PREMARIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible always to reliably estimate their frequency or establish a causal relationship to drug exposure.

Genitourinary system

Abnormal uterine bleeding; dysmenorrheal or pelvic pain, increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis, change in cervical secretion, ovarian cancer, endometrial hyperplasia, endometrial cancer, leukorrhea.

Breasts

Tenderness, enlargement, pain, discharge, galactorrhea, fibrocystic breast changes, breast cancer, gynecomastia in males.

Cardiovascular

Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, increase in blood pressure.

Gastrointestinal

Nausea, vomiting, abdominal pain, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas, ischemic colitis.

Skin

Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, loss of scalp hair, hirsutism, pruritus, rash.

Eyes

Retinal vascular thrombosis, intolerance to contact lenses.

Central nervous system

Headache, migraine, dizziness , mental depression, nervousness, mood disturbances, irritability, exacerbation of epilepsy, dementia, possible growth potentiation of benign meningioma.

Miscellaneous

Increase or decrease in weight, glucose intolerance, aggravation of porphyria, edema, arthralgias, leg cramps, changes in libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity.

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