| Levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena®) | Warnings and Precautions:
If pregnancy should occur with Mirena in place, remove Mirena. There is increased risk of ectopic pregnancy including loss of fertility, pregnancy loss, septic abortion (including septicemia, shock and death) and premature labor and delivery. Group A streptococcal infection has been reported; strict aseptic technique is essential during insertion. Before using Mirena, consider the risks of pelvic inflammatory disease (PID). Bleeding patterns become altered, may remain irregular and amenorrhea may ensue. Perforation may occur during insertion. Risk is increased in women with fixed retroverted uteri, during lactation, and postpartum. Embedment in the myometrium and partial or complete expulsion may occur. Persistent enlarged ovarian follicles should be evaluated.
Serious:
Ectopic pregnancy - Incidence in clinical trials excluding women with risk factors for ectopic was 0.1% per year. Intrauterine pregnancy - “As of September 2006, 390 live births out of an estimated 9.9 million Mirena users had been reported.” Group A streptococcal sepsis (GAS) – “As of September 2006, 9 cases of Group A streptococcal sepsis (GAS) out of an estimated 9.9 million Mirena users had been reported.” Pelvic Inflammatory Disease Embedment Perforation Breast cancer – “Spontaneous reports of breast cancer have been received during postmarketing experience with Mirena… Two observational studies have not provided evidence of an increased risk of breast cancer during the use of Mirena.”
Most common (≥5% users):
Uterine/vaginal bleeding alterations (51.9%) Amenorrhea (23.9%) Intermenstrual bleeding and spotting (23.4%) Abdominal/pelvic pain (12.8%) Ovarian cysts (12%) Headache/migraine (7.7%) Acne (7.2%) Depressed/altered mood (6.4%) Menorrhagia (6.3%) Breast tenderness/pain (4.9%) Vaginal discharge (4.9%) IUD expulsion (4.9%)
Other (<5% users):
Postmarketing reports of:
Device breakage Angioedema
| “The data provided reflect the experience with the use of Mirena in the adequate and well-controlled studies for contraception (n=2,339) and heavy menstrual bleeding (n=80). For the contraception indication, Mirena was compared to a copper IUD (n=1,855), to another formulation of levonorgestrel intrauterine system (n=390) and to a combined oral contraceptive (n=94) in women 18 to 35 years old. The data cover more than 92,000 woman-months of exposure. For the treatment of heavy menstrual bleeding indication (n=80), the subjects included women aged 26 to 50 with confirmed heavy bleeding and exposed for a median of 183 treatment days of Mirena (range 7 to 295 days). The frequencies of reported adverse drug reactions represent crude incidences. The adverse reactions seen across the 2 indications overlapped, and are reported using the frequencies from the contraception studies.”
Mirena [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals; 2009. |
| Contraceptive vaginal ring (NuvaRing®) | Warning:
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years of age and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke.
Most common (reported by 5-14% of women in clinical trials:
Adverse events leading to discontinuation in 1-2.5% of women using NuvaRing in trials:
Device-related events (foreign body sensation, coital problems, device explusion) Vaginal symptoms (discomfort/vaginitis/vaginal secretion) Headache Emotional lability Weight gain
Also any adverse reactions that are associated with the use of combination hormonal contraceptives are also likely to apply to combination vaginal hormonal contraceptives, such as NuvaRing. | NuvaRing [package insert]. Whitehouse Station, NJ: Merck & Co; 2012. |
| Tranexamic acid (oral; Lysteda®) | Warnings and Precautions:
The risk of thrombotic and thromboembolic events may increase further when hormonal contraceptives are administered with Lysteda, especially in women who are obese or smoke cigarettes. Women using hormonal contraception should use Lysteda only if there is a strong medical need and the benefit of treatment will outweigh the potential increased risk of a thrombotic event. Do not use Lysteda in women who are taking more than the approved dose of a hormonal contraceptive. Concomitant use of Lysteda with Factor IX complex concentrates, anti-inhibitor coagulant concentrates, or all-trans retinoic acid (oral tretinoin) may increase the risk of thrombosis. Visual or ocular adverse effects may occur with Lysteda. Immediately discontinue use if visual or ocular symptoms occur. Cerebral edema and cerebral infarction may be caused by use of Lysteda in women with subarachnoid hemorrhage. Ligneous conjunctivitis has been reported in patients taking tranexamic acid.
From RCTs for HMB:
G1: lysteda group (N=232)
G2: placebo group (N=139)
Total number of adverse events
G1: 1500
G1: 923
Headache, including tension headache
G1: 117 (50.4%)
G2: 65 (46.8%)
Nasal and sinus symptoms, including nasal, respiratory tract and sinus congestion, sinusitis, acute sinusitis, sinus headache, allergic sinusitis, and sinus pain, and multiple allergies and seasonal allergies
G1: 59 (25.4%)
G2: 24 (17.3%)
Back pain
G1: 48 (20.7%)
G2: 21 (15.1%)
Abdominal pain, including abdominal tenderness and discomfort
G1:46 (19.8%)
G2: 25 (18.0%)
Musculoskeletal pain, including musculoskeletal discomfort and myalgia
G1: 26 (11.2%)
G2: 4 (2.9%)
Arthralgia, including joint stiffness and swelling
G1: 16 (6.9%)
G2: 7 (5.0%)
Muscle cramps and spasms
G1: 15 (6.5%)
G2: 8 (5.8%)
Migraine
G1: 14 (6.0%)
G2: 8 (5.8%)
Anemia
G1: 13 (5.6%)
G2: 5 (3.6%)
Fatigue
G1: 12 (5.2%)
G2: 6 (4.3%)
Postmarketing reports in patients receiving tranexamic acid for various indications:
Nausea, vomiting, and diarrhea Allergic skin reactions Anaphylactic shock and anaphylactoid reactions Thrombotic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction) – including venous and arterial thrombotic events in women who have used Lysteda concomitantly with combined hormonal contraceptives Impaired color vision and other visual disturbances Dizziness
| “Lysteda safety derived from two randomized, double-blind, placebo-controlled studies on treatment of heavy menstrual bleeding. Long-term safety was studied in two open label studies.”
“In one study, subjects with physician-diagnosed heavy menstrual bleeding (not using the alkaline hematin methodology) were treated with 3900 mg/day for up to 5 days during each menstrual period for up to 27 menstrual cycles. A total of 781 subjects were enrolled and 239 completed the study through 27 menstrual cycles. A total of 12.4% of the subjects withdrew due to adverse events. Women using hormonal contraception were excluded from the study… A long-term open-label extension study of subjects from the two short-term efficacy studies was also conducted in which subjects were treated with 3900 mg/day for up to 5 days during each menstrual period for up to 9 menstrual cycles. A total of 288 subjects were enrolled and 196 subjects completed the study through 9 menstrual cycles. A total of 2.1% of the subjects withdrew due to adverse events… The types and severity of adverse events in these two long-term open-label trials were similar to those observed in the double-blind, placebo-controlled studies although the percentage of subjects reporting them was greater in the 27-month study, most likely because of the longer study duration.”
Lysteda [package insert]. Parsippany, NJ: Ferring Pharmaceutical; 2011. |
| 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel (oral; Nordette-28®, others) | Warning:
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke.
Reported in patients taking oral contraceptives and believed to be drug-related:
Nausea Vomiting Gastrointestinal symptoms (such as abdominal pain, cramps and bloating) Breakthrough bleeding Spotting Change in menstrual flow Amenorrhea Temporary infertility after discontinuation of treatment Edema/fluid retention Melasma/chloasma which may persist Breast changes: tenderness, pain, enlargement, secretion Change in weight or appetite (increase or decrease) Change in cervical erosion and secretion Diminution in lactation when given immediately postpartum Cholestatic jaundice Rash (allergic) Mood changes, including depression Vaginitis, including candidiasis Change in corneal curvature (steepening) Intolerance to contact lenses Mesenteric thrombosis Decrease in serum folate levels Exacerbation of systemic lupus erythematosus Exacerbation of porphyria Exacerbation of chorea Aggravation of varicose veins Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms.
Reported in patients taking oral contraceptives, with association neither confirmed nor refuted:
Congenital anomalies Premenstrual syndrome Cataracts Optic neuritis, which may lead to partial or complete loss of vision Cystitis-like syndrome Nervousness Dizziness Hirsutism Loss of scalp hair Erythema multiforme Erythema nodosum Hemorrhagic eruption Impaired renal function Hemolytic uremic syndrome Budd-Chiari syndrome Acne Changes in libido Colitis Sickle-cell disease Cerebral-vascular disease with mitral valve prolapse Lupus-like syndromes Pancreatitis Dysmenorrhea
| “The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.”
“Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep-vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (<50μg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5 to 3 per 10,000 woman-years for non-users. However, the incidence is substantially less than that associated with pregnancy (6 per 10,000 woman-years). The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.”
“In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension. The attributable risk is also greater in older women.”
Nordette [package insert]. Sellersville, PA: Teva Pharmaceuticals; 2010. |
| estradiol valerate and dienogest (oral; Natazia®) | Warning:
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke.
Serious:
Including reports from clinical trials of:
Myocardial infarction (2 cases) Ruptured ovarian cyst (2 cases) Deep vein thrombosis Focal nodular hyperplasia of the liver Uterine leiomyoma Acute cholecystitis Chronic acalculous cholecystitis
Commonly reported:
Common (≥2%):
Headache (including migraines) (12.7%) Breast pain, discomfort or tenderness (7.0%) Menstrual disorders (metrorrhagia, menstruation irregular, menorrhagia, vaginal hemorrhage, dysfunctional uterine bleeding, genital hemorrhage, abnormal withdrawal bleeding, uterine hemorrhage) (6.9%) Nausea or vomiting (6.0%) Acne (3.9%) Mood changes (depression, mood swings, depressed mood, mood altered, affect lability, dysthymic disorder, crying) (3.0%) Increased weight (2.9%)
Led to study discontinuation:
11.4% of the women discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were:
Menstrual disorder (metrorrhagia, menorrhagia, menstruation irregular, genital hemorrhage, vaginal hemorrhage, dysfunctional uterine bleeding) (2.3%) Mood changes (depression, mood swings, mood altered, depressed mood, dysthymic disorder, crying) (1.2%) Acne (1.1%), headache (including migraines) (1.1%) Weight increased (0.7 %)
Postmarketing experience:
Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, cerebral thrombosis, myocardial infarction and stroke), hypertension Hepatobiliary disorders: Gallbladder disease, hepatitis Immune system disorders: Hypersensitivity Metabolism and nutrition disorders: Fluid retention, hypertriglyceridemia Nervous system disorders: Dizziness Skin and subcutaneous tissue disorders: Chloasma, angioedema, erythema nodosum, erythema multiforme Gastrointestinal disorders: Gastrointestinal symptoms (for example, abdominal pain) Infections and infestations: Vulvovaginal candidiasis
| “A total of 2,131 women, 18 to 54 years of age, who took at least one dose of Natazia were enrolled in four clinical phase 3 trials. A total of 1,867 subjects were included in two clinical phase 3 studies with a treatment duration up to 28 cycles with Natazia as an oral contraceptive and 264 subjects in the two phase 3 clinical trials with a treatment duration of 7 cycles evaluating Natazia in the treatment of heavy, prolonged, and/or frequent menstrual bleeding in women without organic pathology.”
Natazia [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals; 2012. |
| 0.20mg ethinyl estradiol and 1mg norethindrone acetate (oral; Loestrin 21 1/20®, others) | Warning:
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke.
Increased risk of serious adverse reactions:
Evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed:
Mesenteric thrombosis Retinal thrombosis
Reported in patients receiving oral contraceptives and are believed to be drug-related:
Nausea Vomiting Gastrointestinal symptoms (such as abdominal cramps and bloating) Breakthrough bleeding Spotting Change in menstrual flow Amenorrhea Temporary infertility after discontinuation of treatment Edema Melasma which may persist Breast changes: tenderness, enlargement, secretion Change in weight (increase or decrease) Change in cervical erosion and secretion Diminution in lactation when given immediately postpartum Cholestatic jaundice Migraine Rash (allergic) Mental depression Reduced tolerance to carbohydrates Vaginal candidiasis Change in corneal curvature (steepening) Intolerance to contact lenses
Reported in users of oral contraceptives and the association has been neither confirmed nor refuted:
| Loestrin [package insert]. Pomona, NY: Barr Pharmaceuticals; 2009.
NOTE: package insert includes 89 references, many of which are related to adverse effects. |
| norgestimate ethinyl estradiol, triphasic (oral; Ortho Tri Cyclen®, others) | Warning:
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke.
An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives:
There is evidence of an association between the following conditions and the use of oral contraceptives:
Mesenteric thrombosis Retinal thrombosis
The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:
Nausea Vomiting Gastrointestinal symptoms (such as abdominal cramps and bloating) Breakthrough bleeding Spotting Change in menstrual flow Amenorrhea Temporary infertility after discontinuation of treatment Edema Melasma which may persist Breast changes: Tenderness, enlargement, secretion Change in weight (increase or decrease) Change in cervical erosion and secretion Diminution in lactation when given immediately postpartum Cholestatic jaundice Migraine Allergic reaction, including rash, urticaria, angioedema Mental depression Reduced tolerance to carbohydrates Vaginal candidiasis Change in corneal curvature (steepening) Intolerance to contact lenses
The following adverse reactions have been reported in users of oral contraceptives and a causal association has been neither confirmed nor refuted:
| Ortho Tri-cyclen [package insert]. Raritan, NJ: Ortho-McNeil-Janssen Pharmaceuticals; 2010.
NOTE: package insert includes 101 references, many of which are related to adverse effects. |
Dydrogesterone (oral; Gynorest)
NOTE: marketing discontinued in US; labels are not available. | As for progestogens in general.
Porphyria
The Drug Database for Acute Porphyria, compiled by the Norwegian Porphyria Centre (NAPOS) and the Porphyria Centre Sweden, classifies dydrogesterone as porphyrinogenic; it should be prescribed only for compelling reasons and precautions should be taken in all patients. (The Drug Database for Acute Porphyria. Available at: http://www.drugs-porphyria.org (accessed 04/10/11))
Pregnancy
Anomalies (non-virilising) of the genito-urinary tract were found in a 4-month-old baby whose mother had taken dydrogesterone 20 mg daily from the eighth to twentieth week of pregnancy and 10 mg daily from then until term.1 She had also been given hydroxyprogesterone caproate 250 mg by intramuscular injection weekly from the eighth to the twentieth week. (Roberts IF, West RJ. Teratogenesis and maternal progesterone. Lancet 1977; ii: 982. (PubMed id:72325))
| Dydrogesterone. In: Micromedex® Healthcare Series. Thomson Reuters (Healthcare) Inc. http://www.thomsonhc.com (accessed March 31, 2012).
Martindale: The Complete Drug Reference. Pharmaceutical Press. Electronic version, Thomson Reuters (Healthcare) Inc. http://www.thomsonhc.com (accessed March 31, 2012). |
| Medroxyprogesterone acetate (injectable; Depo-Provera CI®, others) | Warnings:
Intrauterine exposure: “Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias (5 to 8 per 1,000 male births in the general population) may be approximately doubled with exposure to these drugs. There are insufficient data to quantify the risk to exposed female fetuses, but insofar as some of these drugs induce mild virilization of the external genitalia of the female fetus, and because of the increased association of hypospadias in the male fetus, it is prudent to avoid the use of these drugs during the first trimester of pregnancy.” Thromboembolic disorders Ocular disorders Lactation
Reported:
Breakthrough bleeding Spotting Change in menstrual flow Amenorrhea Headache Nervousness Dizziness Edema Change in weight (increase or decrease) Changes in cervical erosion and cervical secretions Cholestatic jaundice, including neonatal jaundice Breast tenderness and galactorrhea Skin sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash Acne, alopecia and hirsutism Rash (allergic) with and without pruritis Anaphylactoid reactions and anaphylaxis Mental depression Pyrexia Fatigue Insomnia Nausea Somnolence
In a few instances there have been undesirable sequelae at the site of injection, such as residual lump, change in color of skin, or sterile abscess.
The following adverse reactions have been observed in patients receiving estrogen-progestin combination drugs:
The following laboratory results may be altered by the use of estrogen-progestin combination drugs:
Increased sulfobromophthalein retention and other hepatic function tests Coagulation tests: increase in prothrombin factors VII, VIII, IX, and X Metyrapone test Pregnanediol determinations Thyroid function: increase in PBI, and butanol extractable protein bound iodine and decrease in T3 uptake values
| Depo-Provera CI [package insert]. New York, NY: Pharmacia and Upjohn Company; 2011. |
| Medroxyprogesterone acetate (oral; Provera®) | Warnings:
The following adverse reactions have been reported in women taking progestins, including PROVERA tablets, without concomitant estrogens treatment:
Genitourinary system: Abnormal uterine bleeding (irregular, increase, decrease), change in menstrual flow, breakthrough bleeding, spotting, amenorrhea, changes in cervical erosion and cervical secretions. Breasts: Breast tenderness, mastodynia or galactorrhea has been reported. Cardiovascular: Thromboembolic disorders including thrombophlebitis and pulmonary embolism have been reported. Gastrointestinal: Nausea, cholestatic jaundice. Skin: Sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash have occurred. Acne, alopecia and hirsutism have been reported. Eyes: Neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis. Central nervous system: Mental depression, insomnia, somnolence, dizziness, headache, nervousness. Miscellaneous: Hypersensitivity reactions (e.g., anaphylaxis & anaphylactoid reactions, angioedema), rash (allergic) with and without pruritus, change in weight (increase or decrease), pyrexia, edema/fluid retention, fatigue, decreased glucose tolerance.
The following additional adverse reactions have been reported with estrogen and/or progestin therapy:
Genitourinary system: Abnormal uterine bleeding/spotting, or flow; breakthrough bleeding; spotting; dysmenorrheal/pelvic pain, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer. Breasts: Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer. Cardiovascular: Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure. Gastrointestinal: Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas. Skin: Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash. Eyes: Retinal vascular thrombosis, intolerance to contact lenses. Central nervous system: Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia. Miscellaneous: Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthalgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaplylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.
| Provera [package insert]. New York, NY: Pharmacia and Upjohn Company; 2009. |
| Norethisterone [norethindrone] (oral; Aygestin®) | Warnings:
Cardiovascular disorders Visual anomalies
The following adverse reactions have been observed in women taking progestins:
Breakthrough bleeding Spotting Change in menstrual flow Amenorrhea Edema Changes in weight (decreases, increases) Changes in the cervical squamo-columnar junction and cervical secretions Cholestatic jaundice Rash (allergic) with and without pruritus Melasma or chloasma Clinical depression Acne Breast enlargement/tenderness Headache/migraine Urticaria Abnormalities of liver tests (i.e., AST, ALT, Bilirubin) Decreased HDL cholesterol and increased LDL/HDL ratio Mood swings Nausea Insomnia Anaphylactic/anaphylactoid reactions Thrombotic and thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, cerebral thrombosis and embolism) Optic neuritis (which may lead to partial or complete loss of vision)
| Aygestin [package insert]. Sellersville, PA: Teva Pharmaceuticals; 2010. |
| Progesterone (vaginal gel; Crinone®) | Warnings:
The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis).
In one clinical study for assisted reproductive technology, AEs associated with treatment, occurring in 5% or more of women:
Bloating 7% Cramps NOS 15% Pain 8% Dizziness 5% Headache 13% Nausea 7% Breast Pain 13% Moniliasis Genital 5% Vaginal Discharge 7% Pruritus Genital 5%
In a second clinical study for assisted reproductive technology (ART), AEs associated with treatment, occurring in ≥5% of women:
Abdominal Pain 12% Perineal Pain Female 17% Headache 17% Constipation 27% Diarrhea 8% Nausea 22% Vomiting 5% Arthralgia 8% Depression 11% Libido Decreased 10% Nervousness 16% Somnolence 27% Breast Enlargement 40% Dyspareunia 6% Nocturia 13%
In three clinical studies for secondary amenorrhea taking (either 4%, 8%) Crinone along with estrogen, AEs associated with treatment, occurring in 5% or more of women:
Abdominal Pain 5%, 9% Appetite Increased 5%, 8% Bloating 13%, 12% Cramps NOS 19%, 26% Fatigue 21%, 22% Headache 19%, 15% Nausea 8%, 6% Back Pain 8%, 3% Myalgia 8%, 0% Depression 19%, 15% Emotional Lability 23%, 22% Sleep Disorder 18%, 18% Vaginal Discharge 11%, 3% Upper Respiratory Tract Infection 5%, 8% Pruitis genital 2%, 6%
Reported in women at a frequency <5% in Crinone ART and secondary amenorrhea studies and not listed above include:
Mouth dry Sweating increased Abnormal crying Allergic reaction Allergy Appetite decreased Asthenia Edema Face edema Fever Hot flushes Influenza-like symptoms Water retention Xerophthalmia Syncope Migraine Tremor Dyspepsia Eructation Flatulence Gastritis Toothache Thirst Cramps legs Leg pain Skeletal pain Benign cyst Purpura Aggressive reactions Forgetfulness Insomnia Anemia Dysmenorrheal Premenstrual tension Vaginal dryness Infection Pharyngitis Sinusitis Urinary tract infection Asthma Dyspnea Hyperventilation Rhinitis Acne Pruritus Rash Seborrhea Skin discoloration Skin disorder Urticaria Cystitis Dysuria Micturition frequency Conjunctivitis
| Crinone [package insert]. Livingston, NJ: Columbia Laboratories; 2009. |
Progesterone (coil; Progestasert)
NOTE: marketing discontinued in US; labels are not available. | See progesterone in general.
Common:
Abdominal pain (vaginal insert, 12%) Constipation (vaginal insert, 2% to 3%) Nausea (vaginal insert; 7% to 8%) Swollen abdomen (vaginal insert, 4%) Post-oocyte retrieval (vaginal insert, 25% to 28%) Fatigue (vaginal insert, 2% to 3%)
| Progesterone. In: Micromedex® Healthcare Series. Thomson Reuters (Healthcare) Inc. http://www.thomsonhc.com (accessed March 31, 2012).
“Progesterone.” In: DrugPoints® System. Thomson Reuters (Healthcare) Inc. http://www.thomsonhc.com (accessed March 31, 2012). |
| Flurbiprofen (oral; Ansaid®) | Reported adverse events in patients receiving Ansaid or other NSAIDs
Warnings and Precautions:
Cardiovascular thrombotic events, myocardial infarction, and stroke Hypertension Congestive heart failure and edema Gastrointestinal effects, including risk of ulceration, bleeding, and perforation Renal effects Advanced renal disease Anaphylactoid reactions Skin reactions Hepatic effects; borderline elevations of liver tests can occur in up to 15% of patients taking NSAIDs including flurbiprofen Hematological effects Vision changes (blurred and/pr diminished vision) Cross reactivity in patients with aspirin-sensitive asthma
Incidence ≥1% from clinical trials:
Edema Abdominal pain Constipation Diarrhea Dyspepsia/ heartburn Elevated liver enzymes Flatulence GI bleeding Nausea Vomiting Body weight changes Headache Nervousness and other manifestations of CNS stimulation (e.g., anxiety, insomnia, increased reflexes, tremor) Symptoms associated with CNS inhibition (e.g., amnesia, asthenia, depression, malaise, somnolence) Rash, Changes in vision Dizziness/ vertigo Tinnitus Signs and symptoms suggesting urinary tract infection
Incidence <1% from clinical trials, postmarketing surveillance, or literature, with probable causal relationship:
Anaphylactic reaction Chills Fever Congestive heart failure Hypertension Vascular diseases Vasodilation Bloody diarrhea Esophageal disease Gastric / peptic ulcer disease Gastritis Jaundice (cholestatic and noncholestatic) Hematemesis Hepatitis Stomatitis / glossitis Aplastic anemia (including agranulocytosis or pancytopenia) Decrease in hemoglobin and hematocrit Ecchymosis / purpura Eosinophilia Hemolytic anemia Iron deficiency anemia Leucopenia Thrombocytopenia Hyperuricemia Ataxia Cerebrovascular ischemia Confusion Paresthesia Twitching Asthma Epistaxis Angioedema Eczema Exfoliative dermatitis Photosensitivity Pruritus Toxic epidermal necrolysis Urticaria Conjunctivitis Parosmia Hematuria Interstitial nephritis Renal failure
Incidence <1% from clinical trials, postmarketing surveillance, or literature, with causal relationship unknown:
Angina pectoris Arrhythmias Myocardial infarction Appetite changes Cholecystitis Colitis Dry mouth Exacerbation of inflammatory bowel disease Periodontal abscess Small intestine inflammation with loss of blood and protein Lymphadenopathy Hyperkalemia Convulsion Cerebrovascular accident Emotional lability Hypertonia Meningitis Myasthenia Subarachnoid hemorrhage Bronchitis Dyspnea Hyperventilation Laryngitis Pulmonary embolism Pulmonary infarct Alopecia Dry skin Herpes simplex / zoster Nail disorder Sweating Changes in taste Corneal opacity Ear disease Glaucoma Retinal hemorrhage Retrobulbar neuritis Transient hearing loss Menstrual disturbances Prostate disease Vaginal and uterine hemorrhage Vulvovaginitis
| Ansaid [package insert]. New York City, NY: Pharmacia & Upjohn Co.; 2010. |
| Meclofenamate sodium (oral; Mecolmen®) | Warnings:
Reported incidence greater than 1%:
Reported incidence between 3% and 9%%:
Abdominal pain Pyrosis Flatulence Rash Headache Dizziness
Reported incidence less than 1%, probably causally related:
Bleeding and/or perforation with or without obvious ulcer formation Colitis Cholestatic jaundice Renal failure Neutropenia Thrombocytopenic purpura Leucopenia Agranulocytosis Hemolytic anemia Eosinophilia Decrease in hemoglobin and/or hematocrit Erythema multiforme Stevens-Johnson Syndrome Exfoliative dermatitis Alteration of liver function tests Lupus and serum sickness-like symptoms
Reported incidence less than 1%, causal relationship unknown:
Palpitations Malaise Fatigue Paresthesia Insomnia Depression Blurred vision Taste disturbances Decreased visual acuity Temporary loss of vision Reversible loss of color vision Retinal changes including macular fibrosis Macular and perimacular edema Conjunctivitis Iritis Nocturia Paralytic ileus Erythema nodosum Hair loss
| Meclofenamate sodium [package insert]. Morgantown, WV: Mylan Pharmaceuticals; 2006.
“[A]dverse reactions were observed in clinical trials and included observations from more than 2,700 patients, 594 of whom were treated for one year and 248 for at least two years.”
“In approximately 4% of the patients in controlled studies, diarrhea was severe enough to require discontinuation of meclofenamate sodium.” |
| Mefenamic acid (oral; Ponstel®) | Warnings and precautions:
Cardiovascular risk, including thrombotic events, hypertension, and congestive heart failure and edema Gastrointestinal risk
Most frequently reported, occurring in approximately 1-10% of patients:
Additional adverse experiences reported occasionally include:
Other adverse reactions, which occur rarely:
Anaphylactoid reactions Appetite changes Death Arrhythmia Hypotension Myocardial infarction Palpitations Vasculitis Eructation Liver failure Pancreatitis Agranulocytosis Hemolytic anemia Aplastic anemia Lymphadenopathy Pancytopenia Hyperglycemia Convulsions Coma Hallucinations Meningitis Respiratory depression Pneumonia Angioedema Toxic epidermal necrosis Erythema multiforme Exfoliative dermatitis Stevens-Johnson Syndrome Urticaria Conjunctivitis Hearing impairment
| Ponstel [package insert]. Atlanta, GA: Shionogi Pharma; 2010. |
| Naproxen (oral; EC-Naprosyn®, Naprosyn®, Anaprox®, Anaprox DS®, Naprosyn®, others) | Incidence 3-9% of patients in clinical trials with naproxen:
Heartburn Abdominal pain Nausea Constipation Headache Dizziness Drowsiness Pruritus Skin eruptions Ecchymoses Tinnitus Edema Dyspnea
Incidence <3% of patients in clinical trials with naproxen:
Diarrhea Dyspepsia Stomatitis Lightheadedness Vertigo Sweating Purpura Visual disturbances Hearing disturbances Palpitations Thirst
Incidence <1% of patients in clinical trials with naproxen:
Incidence <1% of patients in taking naproxen, from postmarketing reports:
Anaphylactoid reactions Angioneurotic edema Menstrual disorders Pyrexia (chills and fever) Congestive heart failure Vasculitis Hypertension Pulmonary edema Perforation Hematemesis Colitis Exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease) Nonpeptic gastrointestinal ulceration Ulcerative stomatitis Esophagitis, peptic ulceration Abnormal liver function tests Hepatitis (some cases have been fatal) Eosinophilia Leucopenia Granulocytopenia Hemolytic anemia Aplastic anemia Hyperglycemia Hypoglycemia Depression Dream abnormalities Insomnia Malaise Myalgia Muscle weakness Aseptic meningitis Cognitive dysfunction Convulsions Eosinophilic pneumonitis Asthma Alopecia Urticaria Toxic epidermal necrolysis Erythema multiforme Erythema nodosum Fixed drug eruption Lichen planus Pustular reaction Systemic lupus erythematoses Bullous reactions, including Stevens-Johnson Syndrome Photosensitive dermatitis Photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Hearing impairment Corneal opacity Papillitis Retrobulbar optic neuritis Papilledema Glomerular nephritis Hematuria Hyperkalemia Interstitial nephritis Nephrotic Syndrome Renal disease Renal failure Renal papillary necrosis Raised serum creatinine Infertility in women
| “Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed [here]. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea.”
EC-Naprosyn / Naprosyn / Anaprox / Anaprox DS / Naprosyn [package insert]. Nutley, NJ: Roche Pharmaceuticals; 1999-200X. |
| Cabergoline (oral) | Incidence during 4-week RCT (% in cabergoline group, % in placebo group):
Incidence during 8-week trial (% in cabergoline group, % in bromocriptine group):
Nausea (29, 43) Constipation (7, 9) Abdominal pain (5, 8) Dyspepsia (5, 7) Vomiting (4, 7) Dry mouth (2, 1) Diarrhea (2, 3) Flatulence (2, 1) Throat irritation (1, 0) Toothache (1, 0) Headache (26, 27) Dizziness (17, 18) Vertigo (4, 4) Paresthesia (2, 3) Asthenia (6, 6) Fatigue (5, 8) Syncope (1, 1) Influenza-like symptoms (1, 0) Malaise (1, 0) Periorbital edema (1, 1) Peripheral edema (1, 1) Depression (3, 2) Somnolence (2, 2) Anorexia (1, 1) Anxiety (1, 1) Insomnia (1, 1) Impaired concentration (1, 1) Nervousness (1, 2) Hot flashes (3, 1) Hypotension (1, 2) Dependent edema (1, 1) Palpitation (1, 2) Breast pain (2, 3) Dysmenorrhea (1, 1) Acne (1, 0) Pruritus (1, 1) Pain (2, 3) Arthralgia (1, 0) Rhinitis (1, 4) Abnormal vision (1, 1)
Reported at an incidence of < 1% in the overall clinical studies:
Facial edema Influenza-like symptoms Malaise Hypotension Syncope Palpitations Dry mouth Flatulence Diarrhea Anorexia Weight loss Weight gain Somnolence Nervousness Paresthesia Insomnia Anxiety Nasal stuffiness Epistaxis Acne Pruritus Abnormal vision Dysmenorrhea Increased libido
Postmarketing surveillance data:
| Cabergoline [package insert]. Sellersville, PA: Teva Pharmaceuticals; 2011. |
Etamsylate [ethamsylate] (oral)
NOTE: not available in US; labels are not available. | Precautions:
Patients with asthma, allergies, or a history of allergic-type reactions to medications (potential for allergic phenomena; tablets/ampules contain sodium sulfite) Patients with or a history of thromboembolism (eg, ischemic stroke, pulmonary embolism, deep-vein thrombosis) Renal impairment (most of a dose is excreted unchanged)
Adverse reactions:
Thromboembolic disorder Rash Acute intermittent porphyria Gastrointestinal tract findings: nausea, abdominal discomfort, bitter taste, and other nonspecific gastrointestinal disturbances have been reported occasionally during oral therapy Backache (causality uncertain) Headache (causality is questionable)
| Ethamsylate. In: Micromedex® Healthcare Series. Thomson Reuters (Healthcare) Inc. http://www.thomsonhc.com (accessed March 31, 2012).
DRUGDEX® System. Thomson Reuters (Healthcare) Inc. http://www.thomsonhc.com (accessed March 31, 2012). |
| Exenatide (injection; Byetta®, others) | Hypoglycemia is a common adverse effect.
Treatment-emergent ARs ≥2% incidence and greater incidence with BYETTA treatment used with metformin and/or a sulfonylurea, excluding hypoglycemia:
Treatment-emergent ARs ≥2% incidence and greater incidence with BYETTA treatment used with thiazolidinedione, with or without metformin, excluding hypoglycemia:
Treatment-emergent ARs ≥2% incidence and greater incidence with BYETTA treatment used with insulin glargine, with or without oral antihyperglycemic medications, excluding hypoglycemia:
Postmarketing experience:
Injection-site reactions Generalized pruritus and/or urticaria Macular or papular rash Angioedema Anaphylactic reaction International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding Nausea, vomiting, and/or diarrhea resulting in dehydration Abdominal distension Abdominal pain Eructation Constipation Flatulence Acute pancreatitis Hemorrhagic and necrotizing pancreatitis sometimes resulting in death Dysgeusia Somnolence Altered renal function, including increased serum creatinine Renal impairment Worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis) Kidney transplant and kidney transplant dysfunction Alopecia
| Byetta [package insert]. San Diego, CA: Amylin Pharmaceuticals; 2011. |
| Metformin (oral; Glucophage®, others) | Warning:
Most common (>5%) in placebo-controlled study of monotherapy:
Diarrhea Nausea/vomiting Flatulence Asthenia Indigestion Abdominal discomfort Headache
Also reported (≥1.0% to ≤5%):
Abnormal stools Hypoglycemia Myalgia Lightheaded Dyspnea Nail disorder Rash Sweating increased Taste disorder Chest discomfort Chills Flu Syndrome Flushing Palpitation
| Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2009. |
| N-acetyl-cysteine | Warning:
After proper administration of acetylcysteine, an increased volume of liquified bronchial secretions may occur. When cough is inadequate, the open airway must be maintained by mechanical suction if necessary. When there is a mechanical block due to foreign body or local accumulation, the airway should be cleared by endotracheal aspiration, with or without bronchoscopy. Asthmatics under treatment with acetylcysteine should be watched carefully. Most patients with bronchospasm are quickly relieved by the use of a bronchodilator given by nebulization. If bronchospasm progresses, this medication should be discontinued immediately.
Adverse reactions from intravenous include:
Tachycardia not otherwise specified Nausea Vomiting not otherwise specified Anaphylactoid reaction Pharyngitis Rhinorrhea Rhonchi Throat tightness Pruritus Rash not otherwise specified Flushing
Adverse reactions from solution include:
Adverse reactions from other oral preparations (e.g., tablets) are not listed in package inserts.
Adverse reactions reported in postmarketing safety study of IV formulation include:
| Acetadote [package insert]. Nashville, TN: Cumberland Pharmaceuticals; 2011.
Aceytlcysteine solution [package insert]. Lake Forest, IL: Hospira, Inc.; 2004. |
