Angeliq

drospirenone and estradiol

Dosage Form: tablet, film coated
Angeliq TABLETS

(Drospirenone and Estradiol)

0.5 mg/1 mg

Rx only

PRESCRIBING INFORMATION

Boxed Warnings

Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See WARNINGS, Cardiovascular disorders and Dementia.) The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated equine estrogens (CE 0.625mg) combined with medroxyprogesterone acetate (MPA 2.5mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.) The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with conjugated estrogens alone and during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.) Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials, and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Description

Angeliq TABLETS provide a hormone regimen consisting of film coated tablets each containing 0.5 mg of drospirenone and 1 mg of estradiol. The inactive ingredients are lactose monohydrate NF, corn starch NF, modified starch NF, povidone 25000 USP, magnesium stearate NF, hydroxylpropylmethyl cellulose USP, macrogol 6000 NF, talc USP, titanium dioxide USP, and ferric oxide pigment NF.

Drospirenone, (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3´,4´,6, 6a,7,8,9,10,11,12,13,14,15,15a,16-hexadecahydro-10,13-dimethylspiro-[ 17H-dicyclopropa[6,7:15,16]cyclopenta[a]phenanthrene- 17,2´(5H)-furan]-3,5´(2H)-dione (CAS) is a synthetic progestational compound and has a molecular weight of 366.5 and a molecular formula of C24H30O3.

Estradiol USP, (Estra-1,3,5(10)-triene-3,17-diol,17ß), has a molecular weight of 272.39 and the molecular formula is C18H24O2. The structural formulas are as follows:

Clinical Pharmacology

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol (E2) is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These will vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), through a negative feedback mechanism.

Drospirenone (DRSP) is a synthetic progestin and spironolactone analog with antimineralocorticoid activity. In animals and in vitro, drospirenone has antiandrogenic activity, but no glucocorticoid, antiglucocorticoid, estrogenic, or androgenic activity. Progestins counter estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.

Pharmacokinetics

Absorption

Serum concentrations of DRSP reach peak levels approximately 1 hour after administration of Angeliq and mean absolute bioavailability of DRSP ranges from 76–85%. Following oral administration, peak serum estradiol concentrations are typically reached 6–8 hours after dosing with Angeliq. The oral relative bioavailability of estradiol and DRSP following administration of Angeliq is 107% and 102%, respectively when compared to a combination oral suspension.

The pharmacokinetics of DRSP are dose proportional within the dose range of 0.5–4 mg. Following daily dosing of Angeliq, steady state DRSP concentrations were observed after 10 days. Mean accumulation ratios for estradiol and DRSP were 1.9 and 2.4, respectively. Mean concentrations at 2 hours for DRSP ranged between 5.9 and 6.7 ng/mL after treatment with Angeliq for 365 days. Mean steady state serum DRSP and E2 concentrations are shown in Figure 1, and a summary of primary pharmacokinetic parameters following the administration of 1mg E2/1mg DRSP for 28 days is presented in Table 1.

Figure 1: Mean steady state serum drospirenone and estradiol concentrations following daily oral administration of 1 mg E2/0.5 mg DRSP11DRSP levels are simulated based on data obtained after oral administration of 1 mg DRSP/1 mg Estradiol

Table 1: Mean Steady State Pharmacokinetic Parameters of Tablets Containing Drospirenone (1 mg)* and Estradiol (1 mg)

* Angeliq contains 0.5 mg DRSP † arithmetic mean ‡ SD = standard deviation. § Cmax = Maximum serum concentration, ¶ tmax = time of maximum serum concentration, # AUC = area under the curve Þ t1/2 = half-life, ß NA = Not available,
Drospirenone (Mean†** ± SD‡)
Dose	No. of Subjects	Cmax§ (ng/mL)	tmax¶ (h) Median (range)	AUC# (0–24h) (ng•h/mL)	t1/2Þ (h)
1mg E2/1mg DRSP	14	18.3±5.55	1.0 (1.0–2.0)	208±83	42.3±21.3
Estradiol (Mean ± SD‡)
Dose	No. of Subjects	Cmax§ (pg/mL)	tmax¶ (h) Median (range)	AUC# (0–24h) (pg•h/mL)	t1/2Þ (h)
1mg E2/1mg DRSP	14	43.8±10.0	2.5(0.5–12.0)	665±178	NAß
Estrone (Mean ± SD‡)
Dose	No. of Subjects	Cmax§ (pg/mL)	tmax¶ (h) Median (range)	AUC# (0–24h) (pg•h/mL)	t1/2Þ (h)
1mg E2/1mg DRSP	14	245±50.6	4.0 (3.0–6.0)	3814±1159	23±6.2

 

Effect of Food:

The effect of food on the absorption and bioavailability of DRSP and E2 have not been investigated following the administration of Angeliq. However, clinical studies with different formulations containing DRSP or E2 have shown that the bioavailability of both drugs is not affected by concomitant food intake.

Distribution

The mean volume of distribution of DRSP is 4.2 L/kg. DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol circulates in the blood bound to SHBG (37%) and to albumin (61%), while only approximately 1%–2% is unbound.

Metabolism

Mean clearance of DRSP is 1.2 mL/min/kg. DRSP is extensively metabolized after oral administration. The 2 main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, both of which are formed without the involvement of the cytochrome P450 system. These metabolites were shown not to be pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent mainly by Cytochrome P450 3A4 (CYP3A4).

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Excretion

DRSP serum levels are characterized by a terminal elimination half-life of approximately 36–42 hours. Excretion of DRSP was nearly complete after 10 days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38% to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17% to 20% of the metabolites were excreted as glucuronides and sulfates. Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Special Populations

Geriatric: No pharmacokinetic studies were conducted in the geriatric population.

Pediatric: No pharmacokinetic study for Angeliq has been conducted in a pediatric population.

Gender: Angeliq is indicated for use in women only.

Race: No studies were done to determine the effect of race on the pharmacokinetics of Angeliq.

Patients with Hepatic Impairment: Angeliq is contraindicated in patients with hepatic dysfunction (also see BOLDED Warnings). The mean exposure to DRSP in women with moderate liver impairment is approximately three times the exposure in women with normal liver function.

Patients with Renal Impairment: Angeliq is contraindicated in patients with renal insufficiency (also see BOLDED Warnings).

The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effects of DRSP on serum potassium levels were investigated in female subjects (n = 28, age 30–65) with normal renal function (11 patients), and mild (10 patients) and moderate (7 patients) renal impairment. All subjects were on a low potassium diet. During the study 7 subjects continued the use of potassium-sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr 30–50 mL/min) compared to those in the group with normal renal function. Serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50–80 mL/min) were comparable to those in the group with normal renal function (CLcr, >80 mL/min). DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in 5 of the 7 subjects who continued use of potassium sparing drugs during the study, individual mean serum potassium levels increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs.

Drug Interactions

Effects of Drospirenone on Other Drugs

Metabolic Interactions

Metabolism of DRSP and potential effects of DRSP on hepatic cytochrome P450 (CYP) enzymes have been investigated in in vitro and in vivo studies (see Metabolism). In in vitro studies, DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4 with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of 3mg DRSP for 14 days did not affect the systemic clearance of the CYP2C19 substrate omeprazole (40 mg) and the CYP2C19 product 5-hydroxy-omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrated that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo.

Two further clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4, were each performed in 24 healthy, postmenopausal women. The results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady-state DRSP concentrations achieved after administration of 3 mg DRSP/day.

Based on the available results of in vivo and in vitro studies, it can be concluded that, at clinical dose level, DRSP is unlikely to interact significantly with cytochrome P450 enzymes.

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Co-Administration with Drugs that Have the Potential to Increase Serum Potassium

There is a potential for an increase in serum potassium in women taking drospirenone with other drugs that may affect electrolytes, such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or non-steroidal anti-inflammatory drugs (NSAIDs).

Electrolytes were studied in 230 postmenopausal women with hypertension and/or diabetes mellitus requiring an ACE inhibitor or angiotensin receptor blocker (ARB). Of these, 26 patients had a creatinine clearance >50 mL/min to <80 mL/min. Patients were given 1 mg estradiol (E2) and 3 mg drospirenone (DRSP) (n=112) or placebo (n=118) over 28 days. Non-diabetic patients also received ibuprofen 1200 mg/day for 5 days during the study. There was a single case of serum potassium >6.0 mEq/L and a single case of serum sodium <130 mEq/L on treatment, both occurring following five days of ibuprofen therapy in two women taking E2/DRSP. Serum potassium levels ≥5.5 mEq/L were observed in 8 (7.3%) E2/DRSP-treated subjects (3 diabetic and 5 non-diabetic) and in 3 (2.6%) placebo-treated subjects (2 diabetic and 1 non-diabetic). After 28 days of exposure, the mean change from baseline in serum potassium was 0.11 mEq/L for the E2/DRSP group and 0.08 mEq/L for the placebo group. None of the subjects with serum potassium levels ≥5.5 mEq/L had cardiovascular adverse events. A drug-drug interaction study of DRSP 3 mg/estradiol (E2) 1 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium levels were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium levels in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were measured at multiple timepoints over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium Cmax and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.010 (90% CI: 0.944, 1.080), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations >5.5 mEq/L).

Of note, occasional or chronic use of NSAID medication was not restricted in any of the Angeliq clinical trials.

Clinical Studies

Support for the indications

Support for treatment of vasomotor symptoms and vaginal and vulvar atrophy was shown through bioequivalence of the E2 component of the combination product with a currently marketed E2 product (Estrace®). The multiple-dose bioequivalence study evaluated the bioequivalence of E2 from a tablet containing DRSP (2 mg) and E2 (1 mg) relative to Estrace (1 mg) tablet. DRSP/E2 tablets met the criteria for bioequivalence to Estrace.

Effects on Endometrium

In a one year clinical trial of 1,142 postmenopausal subjects treated with E2 alone or E2 + 0.5, 1, 2, or 3 mg DRSP, endometrial biopsies were performed on 966 (84.6%) subjects during the treatment period. Eight subjects in the E2 monotherapy group developed endometrial hyperplasia (4 simple hyperplasia with no cytological atypia, 3 complex hyperplasia with no cytological atypia, and 1 complex hyperplasia with cytological atypia), and one subject in the 1 mg E2 + 2 mg DRSP group developed simple hyperplasia with no cytological atypia. Table 2 shows that there were no diagnoses of endometrial hyperplasia in the Angeliq group.

Table 2: Incidence of Endometrial Hyperplasia after up to 12 Months of Treatment

	E2 1 mg	Angeliq
Total No. Subjects	226	227
Total No. of On-Treatment Biopsies	197 (87.2%)	191 (84.1%)
Hyperplasia	8 (4.0%)	0 (0%)

Effects on Uterine Bleeding or Spotting

In a cumulative analysis performed over 12 months in a double blind trial, the proportions of women with amenorrhea increased and at one year, 73.5% of subjects on Angeliq had amenorrhea. Results are shown in Figure 2.

Figure 2: Cumulative proportion of subjects with amenorrhea at a given cycle through cycle 13, LOCF

Women's Health Initiative Studies

The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated equine estrogens (CE) per day alone or the use of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA sub-study was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index". Results of the CE/MPA sub-study, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 3 below:

Table 3: Relative and Absolute Risk Seen in the CE/MPA Substudy of WHI*

* adapted from JAMA, 2002; 288:321–333 † nominal confidence intervals unadjusted for multiple looks and multiple comparisons ‡ includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer § a subset of the events was combined in a "global index", defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes ¶ not included in Global Index
Eventc	Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI†)	Placebo n = 8102	CE/MPA n = 8506
		Absolute Risk per 10,000 Person-years
CHD events Non-fatal MI CHD death	1.29 (1.02–1.63) 1.32 (1.02–1.72) 1.18 (0.70–1.97)	30 23 6	37 30 7
Invasive breast cancer ‡	1.26 (1.00–1.59)	30	38
Stroke	1.41 (1.07–1.85)	21	29
Pulmonary embolism	2.13 (1.39–3.25)	8	16
Colorectal cancer	0.63 (0.43–0.92)	16	10
Endometrial cancer	0.83 (0.47–1.47)	6	5
Hip fracture	0.66 (0.45–0.98)	15	10
Death due to causes other than the events above	0.92 (0.74–1.14)	40	37
Global Index §	1.15 (1.03–1.28)	151	170
Deep vein thrombosis ¶	2.07 (1.49–2.87)	13	26
Vertebral fractures ¶	0.66 (0.44–0.98)	15	9
Other osteoporotic fractures ¶	0.77 (0.69–0.86)	170	131

For those outcomes included in the "global index," absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

The absolute excess risk of events included in the "global index" was 19 per 10,000 person-years. There was no difference between the groups in terms of all-cause mortality. (See Boxed Warnings , Warnings, and Precautions.)

Women's Health Initiative Memory Study

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/progestin (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See Boxed Warnings and Warnings, 3. Dementia.)

Indications and Usage

Angeliq is indicated in women who have a uterus for the:

1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.

2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

Contraindications

Progestogens/estrogens should not be used in individuals with any of the following conditions:

1. Undiagnosed abnormal genital bleeding.

2. Known, suspected, or history of cancer of the breast.

3. Known or suspected estrogen-dependent neoplasia.

4. Active deep vein thrombosis, pulmonary embolism or history of these conditions.

5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).

6. Renal insufficiency.

7. Liver dysfunction or disease.

8. Adrenal insufficiency.

9. Angeliq should not be used in patients with known hypersensitivity to its ingredients.

10. Known or suspected pregnancy. There is no indication for Angeliq in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See Precautions).

Warnings

Angeliq contains 0.5 mg of the progestin drospirenone that has antialdosterone activity, including the potential for hyperkalemia in high-risk patients.

Angeliq should not be used in patients with conditions that predispose to hyperkalemia (i.e. renal insufficiency, hepatic dysfunction, and adrenal insufficiency).

Use caution when prescribing Angeliq to women who regularly take other medications that can increase potassium, such as NSAIDs, potassium-sparing diuretics, potassium supplements, ACE inhibitors, angiotensin-II receptor antagonists, and heparin. Consider checking serum potassium levels during the first treatment cycle in high-risk patients.

See Boxed Warnings .

1. Cardiovascular disorders

Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.

Risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately

a. Coronary heart disease and stroke

In the Women's Health Initiative study (WHI), an increase in the number of myocardial infarctions and strokes has been observed in women receiving oral CE compared to placebo. (See Clinical Pharmacology, Clinical Studies sections.)

In the CE/MPA substudy of WHI an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 person years). The increase in risk was observed in year one and persisted.

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 person-years). The increase in risk was observed after the first year and persisted.

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA-0.625mg/2.5mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years.

Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.

Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

b. Venous thromboembolism (VTE)

In the Women's Health Initiative study (WHI), an increase in VTE has been observed in women receiving CE compared to placebo. (See Clinical Pharmacology and Clinical Studies sections.)

In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the CE/MPA group compared to 16 per 10,000 woman-years in the placebo group. The increase in VTE risk was observed during the first year and persisted.

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

2. Malignant neoplasms

a. Endometrial cancer

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

b. Breast cancer

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative (WHI) substudy of CE/MPA (see Clinical Pharmacology,Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.

The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.

In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01–1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, and risk factors, and prior mammogram results.

3. Dementia

In the estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, 2,947 hysterectomized women aged 65 to 79 years were randomized to CE or placebo.

In the estrogen plus progestin WHIMS substudy, 4,532 postmenopausal women aged 65 to 79 years were randomized to CE/MPA or placebo. In the estrogen alone substudy, after an average follow-up of 5.2 years, 28 women in the estrogen alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen alone versus placebo was 1.49 (95% CI 0.83–2.66). The absolute risk of probable dementia for estrogen alone versus placebo was 37 versus 25 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See Clinical Pharmacology, Clinical Studies and Precautions, I. GERIATRIC USE .)

After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21–3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of proba

ble dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See Clinical Pharmacology, Clinical Studies and Precautions, I. GERIATRIC USE .)

4. Gallbladder disease

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5. Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

6. Visual abnormalities

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.

Precautions

A. GENERAL

1. Addition of a progestin when a woman has not had a hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer.

2. Elevated blood pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

3. Hypertriglyceridemia

In pati

Zinecard

Generic Name: Dexrazoxane Hydrochloride
Class: Protective Agents
ATC Class: V03AF02
VA Class: AN700
Chemical Name: (S)-4,4′-(1-Methyl-1,2-ethanediyl)bis-2,6-piperazinedione
Molecular Formula: C₁₁H₁₆N₄O₄
CAS Number: 24584-09-6

Introduction

Cardioprotective agent; a cyclic derivative of edetic acid (EDTA).^{1 2 3 4 5 6 7 8 9 10 11 13 16 44 45}

Uses for Zinecard

Anthracycline-induced Cardiomyopathy Prophylaxis

Reduction of the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of ≥300 mg/m² and would benefit from continued doxorubicin therapy (designated an orphan drug by FDA for this use).^{1 2 3 4 5 6 7 8 9 10 11 16 44 45 47}

Not recommended for use with initiation of doxorubicin therapy.^{1 2 4 5 16 18 35 39 46} (See Effectiveness of Cytotoxic Regimens under Cautions.)

Zinecard Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.¹

  
  

Administration

IV Administration

Administer by slow IV injection or by rapid IV infusion.^{1 2 3 4 6 7 8 9 13}

Handle cautiously; use protective equipment (e.g., latex gloves).¹

Administer dexrazoxane ≤30 minutes prior to initiating doxorubicin therapy; administer doxorubicin no later than 30 minutes after the start of dexrazoxane administration.^{1 2 3 4 5 6 7 8 9 10 11 46} Do not administer doxorubicin prior to dexrazoxane.^a

Reconstitution

Reconstitute vial containing 250 or 500 mg of dexrazoxane powder with 25 or 50 mL of (1/6) M sodium lactate injection (provided by manufacturer), respectively, to provide a solution containing 10 mg/mL.¹

Dilution

May be further diluted with 0.9% sodium chloride injection or 5% dextrose injection to a concentration of 1.3–5 mg/mL.^{a 1}

Rate of Administration

Administer by slow IV push or rapid IV infusion over 5–15 minutes.^{a 1 2 3 4 6 7 8 9 13}

Dosage

Available as dexrazoxane hydrochloride; dosage expressed in terms of dexrazoxane.^{a 1}

Administer in a dosage ratio relative to the IV dose of doxorubicin hydrochloride.¹

Adults

Prophylaxis of Anthracycline-induced Cardiomyopathy

IV

Recommended dosage ratio of dexrazoxane to doxorubicin is 10:1 (e.g., 500 mg/m² dexrazoxane should be administered with 50 mg/m² doxorubicin).^{1 2 4 5 8 9 13 44}

Prescribing Limits

Adults

Prophylaxis of Anthracycline-induced Cardiomyopathy

IV

Maximum 1000 mg/m² every 3 weeks was administered during clinical trials.^a

Special Populations

Hepatic Impairment

Reduced doxorubicin dose recommended in patients with hyperbilirubinemia; proportionally reduce dexrazoxane dosage maintaining 10:1 dexrazoxane to doxorubicin ratio.^a

Renal Impairment

Moderate to severe renal impairment (Cl_cr <40 mL/min): Reduce dosage ratio to 5:1 dexrazoxane to doxorubicin (e.g., 250 mg/m² dexrazoxane if 50 mg/m² doxorubicin is administered).^a

Not studied in those undergoing dialysis.^a

Geriatric Patients

No dosage adjustments except those related to renal impairment.^a (See Renal Impairment under Dosage and Administration.)

Cautions for Zinecard

Contraindications

Use with chemotherapy regimens that do not contain an anthracycline.^a

Warnings/Precautions

Warnings

Hematologic Effects

May add to myelosuppression caused by chemotherapeutic agents; perform CBCs frequently.^a

Effectiveness of Cytotoxic Regimens

Concurrent use of dexrazoxane with the initiation of fluorouracil, doxorubicin, and cyclophosphamide (FAC) therapy may interfere with the antitumor efficacy of the regimen; such use is not recommended.^a (See Prophylaxis of Anthracycline-induced Cardiotoxicity under Uses.)

Cardiotoxicity

Use of dexrazoxane does not eliminate potential for anthracycline induced cardiac toxicity; monitor cardiac function carefully.^a

Secondary Malignancies

Possible increased risk of secondary malignancies; acute myeloid leukemias, lymphomas, and cutaneous carcinomas reported in patients treated chronically with oral razoxane, a racemic mixture of which dexrazoxane is the S(+)-enantiomer.^a

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether dexrazoxane is distributed into milk.^a Discontinue nursing because of potential risk to nursing infants.^a

Pediatric Use

Safety and efficacy not established.^a

Geriatric Use

Response in patients >65 years of age does not appear to differ from that in younger adults; however, use with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.^a

Hepatic Impairment

Pharmacokinetics not evaluated; dosage adjustments may be required in patients with hyperbilirubinemia.^a (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Decreased clearance; dosage adjustments necessary in patients with moderate to severe renal impairment (Cl_cr <40 mL/min).^a (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Alopecia, nausea, vomiting, fatigue/malaise, anorexia, stomatitis, fever, infection, diarrhea, pain on injection, sepsis, neurotoxicity.^a

Interactions for Zinecard

Antineoplastic Agents

No significant change in pharmacokinetics of doxorubicin and its predominant metabolite reported with concurrent use of dexrazoxane.^a

Zinecard Pharmacokinetics

Distribution

Extent

Distributed primarily in total body water.^a

Plasma Protein Binding

Not bound to plasma proteins.^a

Elimination

Metabolism

Metabolized to a diacid-diamide cleavage product and two monoacid-monoamide ring products.^a

Elimination Route

Excreted principally in urine as unchanged drug (42%), a diacid-diamide cleavage product, and two monoacid-monoamide ring products.^a

Half-life

2.1–2.5 hours.^a

Stability

Storage

Parenteral

Injection

25°C (may be exposed to 15–30°C).^{a 1}

Reconstituted or diluted solutions are stable for 6 hours at 15–30°C or under refrigeration (2–8°C).¹

Discard unused solutions.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility^HID

Compatible
Dextrose 5% in water
Sodium chloride 0.9%

Drug Compatibility^HID

Y-Site Compatibility

Compatible
Gemcitabine HCl
Pemetrexed disodium

ActionsActions

• 
  

  Cardioprotective agent that readily penetrates cell membranes; however, exact mechanism of cardioprotective effect not clearly established.^a

  
  


• 
  

  Converts intracellularly to a ring-opened bidentate chelating agent that may prevent anthracycline-induced cardiotoxicity, at least in part, by chelating free iron and thus preventing the formation of the anthracycline-iron complex and resultant free radical generation.^{a 1 2 3 4 5 7 11 13 16 38 40 42}

  
  

Advice to Patients

• 
  

  Importance of recognizing and reporting signs and symptoms of CHF.^a

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^a

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^a

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Dexrazoxane Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV use	250 mg (of dexrazoxane)	Zinecard (with 25 mL sodium lactate injection 0.167 Molar [M/6] diluent)	Pfizer
		500 mg (of dexrazoxane)	Zinecard (with 50 mL sodium lactate injection 0.167 Molar [M/6] diluent)	Pfizer

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions September 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pharmacia Inc. Zinecard (dexrazoxane) for injection prescribing information. Columbus, OH; 1995 May.

2. Anon. Dexrazoxane. Phase III Drug Profiles. 1993; 3:20-7.

3. Speyer JL, Green MD, Zeleniuch-Jacquotte A et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol. 1992; 10:117-27. [PubMed 1727913]

4. Hochster H, Wasserheit C, Speyer J. Cardiotoxicity and cardioprotection during chemotherapy. Curr Opin Oncol. 1995; 7:304-9. [PubMed 7578376]

5. Seifert CF, Nesser ME, Thompson DF. Dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity. Ann Pharmacother. 1994; 28:1063-72. [IDIS 335811] [PubMed 7803884]

6. Speyer JL, Green MD, Kramer E et al. Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med. 1988; 319:745-52. [IDIS 246005] [PubMed 3137469]

7. Koning J, Palmer P, Franks CR et al. Cardioxane—ICRF-187: towards anticancer drug specificity through selective toxicity reduction. Cancer Treat Rev. 1991; 18:1-19. [PubMed 1933909]

8. Mailliard JA, Speyer JL, Hanson K et al. Prevention of chronic adriamycin cardiotoxicity with the bisdioxopiperazine dexrazoxane (ICRF-187, ADR-529, Zinecard) in patients with advanced or metastatic breast cancer. Proc ASCO. 1992; 11:A191.

9. Weisberg SR, Rosenfeld CS, York RM et al. Dexrazoxane, (ADR-529, ICRF-187, Zinecard) protects against doxorubicin-induced chronic cardiotoxicity. Proc ASCO. 1992; 11:A190.

10. Feldmann JE, Jones SE, Weisberg SR et al. Advanced small cell lung cancer treated with CAV (cyclophosphamide + adriamycin + vincristine) chemotherapy and the cardioprotective agent dexrazoxane (ADR-529, ICRF-187, Zinecard). Proc ASCO. 1992; 11:A993.

11. Rosenfeld CS, Weisberg SR, York RM et al. Prevention of adriamycin cardiomyopathy with dexrazoxane (ADR-529, ICRF-187). Proc ASCO. 1992; 11:A74.

12. Halliwell B, Bomford A. ICRF-187 and doxorubicin-induced cardiac toxicity. N Engl J Med. 1989; 320:399-400.

13. Hochster H, Liebes L, Wadler S et al. Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin. J Natl Cancer Inst. 1992; 84:1725-30. [PubMed 1433357]

14. Beijnen JH, Van Gijn R. Chemical stability of the cardioprotective agent ICRF-187 in infusion fluids. J Parenter Sci Technol. 1993; 47:166-71. [IDIS 318887] [PubMed 8410562]

15. Pharmacia Inc. Product information form for American hospital formulary service: Zinecard (dexrazoxane for injection). Columbus, OH; 1995 Jul.

16. Lewis C. A review of the use of chemoprotectants in cancer chemotherapy. Drug Saf. 1994; 11:153-62. [PubMed 7811398]

17. The United States pharmacopeia, 23rd rev, and The national formulary, 18th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1995:11.

18. ten Bokkel-Huinink WW, Schreuder JE, Dubbleman R et al. ICRF-187 protects against doxorubicin induced cardiomyopathy. Ann Oncol. 1992; 1(Suppl 3):A221.

19. Legha S, Wang YM, Mackay B et al. Clinical and pharmacological investigation of the effects of alpha-tocopherol on adriamycin cardiotoxicity. Ann NY Acad Sci. 1982; 393:411-8. [PubMed 6959564]

20. Myers CE, Monow R, Palmeri S et al. A randomised controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol. 1983; 1(Suppl 10):53-5.

21. Myers CE, Gianna L, Zweier J et al. Role of iron in adriamycin biochemistry. Fed Proc. 1986; 45:2792-7. [PubMed 3533644]

22. Sugioka KA, Nakano M. Mechanism of phospholipid peroxidation induced by ferric ion-ADP-adriamycin-co-ordination complex. Biochem Biophys Acta. 1982; 713: 333-43. [PubMed 6295497]

23. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Dec 12.

24. Anon. A drug for prevention of anthracycline-induced cardiac toxicity. Med Lett Drugs Ther. 1991; 33:85-6. [PubMed 1908544]

25. Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979; 91:710-7. [PubMed 496103]

26. Adria Laboratories, Inc. Adriamycin™ (doxorubicin hydrochloride for injection) for intravenous use only prescribing information. Wilmington, DE; 1974 Jul.

27. Blum RH, Carter SK. Adriamycin: a new anticancer drug with significant clinical activity. Ann Intern Med. 1974; 80:249-59. [IDIS 41143] [PubMed 4590654]

28. Bachur NR. Current status of studies with adriamycin (NSC-123127). Cancer Chemother Rep Part 3. 1973; 4:47-50.

29. Cortes EP, Holland JF, Wang JJ et al. Doxorubicin in disseminated osteosarcoma. JAMA. 1972; 221:1132-8. [IDIS 27992] [PubMed 4512088]

30. O’Bryan RM, Luce JK, Talley RW et al. Phase II evaluation of adriamycin in human neoplasia. Cancer. 1973; 32:1-8. [PubMed 4716773]

31. Haskell CM, Sullivan A. Comparative survival in tissue culture of normal and neoplastic human cells exposed to adriamycin. Cancer Res. 1974; 34:2991-4. [PubMed 4417828]

32. Benjamin RS, Riggs CE Jr, Bachur NR. Pharmacokinetics and metabolism of adriamycin in man. Clin Pharmacol Ther. 1973; 14:592-600. [IDIS 35937] [PubMed 4723268]

33. Gamble JF. Drug therapy of Hodgkin’s disease. Drug Ther. 1973; 3:35-52.

34. Gottlieb JA, Hill CS. Chemotherapy of thyroid cancer with adriamycin: experience with 30 patients. N Engl J Med. 1974; 290:193-7. [IDIS 39790] [PubMed 4808917]

35. Pharmacia. Adriamycin RDF (doxorubicin hydrochloride for injection, USP) and Adriamycin PFS (doxorubicin hydrochloride injection, USP) for intravenous use only prescribing information dated 1994 Dec 1. In: Physician’s desk reference. 50th ed. Medical Economics Company Inc; 1996; 1947-9.

36. Chiron Therapeutics. Cerubidine (daunorubicin hcl) for injection prescribing information (dated 1995 Jan). In: Physicians’ desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:795-6.

37. Hale JP, Lewis IJ. Anthracyclines: cardiotoxicity and its prevention. Arch Dis Child. 1994; 71:457-62. [IDIS 339358] [PubMed 7826122]

38. Jelic S, Radulovic S, Neskovic-Konstantinovic Z et al. Cardioprotection with ICRF- 187 (Cardioxane) in patients with advanced breast cancer having cardiac risk factors for doxorubicin cardiotoxicity, treated with the FDC regimen. Support Care Cancer. 1995; 3:176-82. [PubMed 7655778]

39. Hellmann K, Franks CR. Reduction of doxorubicin-induced cardiotoxicity by dexrazoxane. In: Zeller WJ, Eisenbrand G, Hellmann K, eds. Reduction of anticancer drug toxicity: pharmacologic, biologic, immunologic and gene therapeutic approaches. Contrib Oncol, Vol 48. Basel, Switzerland: Karger; 1995:40-7.

40. Hasinoff BB. NADPH-cytochrome-P450 reductase promotes hydroxyl radical production by the iron complex of ADR-925, the hydrolysis product of ICRF-187 (dexrazoxane). Free Radical Res. 1995; 22:319-25.

41. Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979; 91:710-7. [PubMed 496103]

42. Steinherz LJ, Yahalom J. Cardiac complications of cancer therapy. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:2370-4.

43. Von Hoff DD, Rozencweig M, Layard M et al. Daunomycin-induced cardiotoxicity in children and adults: a review of 110 cases. Am J Med. 1977; 62:200-8. [IDIS 82336] [PubMed 835599]

44. Wexler LH, Audrich MP, Venzon D et al. Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin. J Clin Oncol. 1996; 14:362-72. [IDIS 362031] [PubMed 8636745]

45. Swain SM, Whaley FS, Gerber MC et al. Congestive heart failure (CHF) after doxorubicin-containing therapy in advanced breast cancer patients treated with or without dexrazoxane (ICRF-187, ADR-529). Proc Am Soc Clin Oncol. 1996:15:A1739. Abstract.

46. Pharmacia & Upjohn, Kalamazoo, MI: Personal communication.

47. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

48. Steinherz LJ, Yahalom J. Cardiac complications of cancer therapy. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:2370-85.

49. Reviewers’ comments (personal observations) on doxorubicin hydrochloride. 1996 Dec.

50. Bu Lock FA, Mott MG, Oakhill A et al. Early identification of anthracycline cardiomyopathy: possibilites and implications. Arch Dis Child. 1996; 75:416-22. [IDIS 379000] [PubMed 8957955]

51. Steinherz LJ, Steinherz PG, Tan CTC et al. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA. 1991; 266:1672-7. [IDIS 285848] [PubMed 1886191]

52. Shan K, Lincoff M, Young JB et al. Anthracycline-induced cardiotoxicity. Ann Intern Med. 1996; 125:47-58. [IDIS 367329] [PubMed 8644988]

53. Gottlieb SL, Edmiston WA Jr, Haywood LJ. Late, late doxorubicin cardiotoxicity. Chest. 1980; 78:880-2. [IDIS 129724] [PubMed 7449470]

54. Freter CE, Lee TC, Billingham ME et al. doxorubicin cardiac toxicity manifesting seven years after tretament: case report and review. Am J Med. 1986; 80:483-5. [IDIS 213735] [PubMed 3513562]

55. Davis LE, Brown CEL. Peripartum heart failure in a patient treted previously with doxorubicin. Obstet Gynecol. 1988; 71:506-8. [IDIS 241012] [PubMed 3162299]

56. Wood WC, Budman DR, Korzun AH et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994;330:1253-9.

57. Steinherz LJ, Steinherz PG, Tan C. Cardiac failure and dysrhythmias 6–19 years after anthracycline therapy: a series of 15 patients. Med Pediatr Oncol. 1995; 24:352-61. [PubMed 7715541]

58. Wyeth Laboratories Inc. Cerubidine (daunorubicin hydrochloride) for injection prescribing information. Philadelphia, PA; 1992 May 14.

59. Ferrans VJ. Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treat Rep. 1978; 62:955-61. [IDIS 107253] [PubMed 352510]

60. Ito H, Miller SC, Billingham ME et al. Doxorubicin selectively inhibits muscle gene expression in cardiac muscle in vivo and in vitro. Proc Natl Acad Sci. 1990; 87:4275-9. [PubMed 2349236]

61. Billingham ME, Bristow MR, Glatstein E et al. Adriamycin cardiotoxicity: endomyocardial biopsy evidence of enhancement by irradiation. Am J Surg Pathol. 1977; 1:17-23. [PubMed 602969]

62. Mann DL, Young JB. Basic mechanisms in congestive heart failure: recognizing the role of proinflammatory cytokines. Chest. 1994; 897-904.

63. Matsumori A, Yamada T, Suzuki H et al. Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J. 1994; 72:561-6. [PubMed 7857740]

64. Kusuoka H, Futaki S, Koretsune Y et al. Alterations of intracellular calcium homeostasis and myocardial energetics in acute adriamycin-induced heart failure. J Cardiovasc Pharmacol. 1991; 18:437-4. [PubMed 1720844]

a. Pharmacia & Upjohn Co. Div. of Pfizer, Inc. Zinecard (dexrazoxane) for injection prescribing information. New York, NY; 2004 Oct.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:496.

More Zinecard resources

• Zinecard Side Effects (in more detail)
• Zinecard Use in Pregnancy & Breastfeeding
• Zinecard Support Group
• 0 Reviews for Zinecard - Add your own review/rating

• Zinecard Prescribing Information (FDA)


• Zinecard Advanced Consumer (Micromedex) - Includes Dosage Information


• Zinecard MedFacts Consumer Leaflet (Wolters Kluwer)


• Dexrazoxane Prescribing Information (FDA)


• Dexrazoxane Professional Patient Advice (Wolters Kluwer)


• Totect Consumer Overview


• Totect Prescribing Information (FDA)

Compare Zinecard with other medications

• Cardiomyopathy Prophylaxis

thiothixene

Generic Name: thiothixene (THYE oh THIX een)

Brand Names: Navane

What is thiothixene?

Thiothixene is an antipsychotic medication. It affects the actions of chemicals in your brain.

Thiothixene is used to treat schizophrenia.

Thiothixene may also be used for purposes not listed in this medication guide.

What is the most important information I should know about thiothixene?

Thiothixene is not for use in psychotic conditions related to dementia. Thiothixene may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions.

You should not use this medication if you are allergic to thiothixene, or if you have a blood cell disorder such as anemia or low white blood cells or platelets, or if you have decreased alertness caused by taking certain medications or drinking alcohol.

Call your doctor at once if you have twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs.

Thiothixene may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Do not drink alcohol. Thiothixene can increase the effects of alcohol, which could be dangerous.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Thiothixene can decrease perspiration and you may be more prone to heat stroke.

What should I discuss with my healthcare provider before taking thiothixene?

Thiothixene is not for use in psychotic conditions related to dementia. Thiothixene may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions. You should not use thiothixene if you are allergic to it, or if you have:

• 
  

  a blood cell disorder such as anemia, low white blood cell counts, or low platelets; or

  
  


• 
  

  drowsiness, slow breathing, weak pulse, or decreased alertness caused by taking certain medications or drinking alcohol.

  
  

To make sure you can safely take thiothixene, tell your doctor if you have any of these other conditions:

• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  heart disease;

  
  


• 
  

  a history of low white blood cell (WBC) counts;

  
  


• 
  

  a history of breast cancer; or

  
  


• 
  

  if you are addicted to alcohol.

  
  

Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Taking antipsychotic medication during the last 3 months of pregnancy may cause problems in the newborn, such as withdrawal symptoms, breathing problems, feeding problems, fussiness, tremors, and limp or stiff muscles. However, you may have withdrawal symptoms or other problems if you stop taking your medicine during pregnancy. If you become pregnant while taking thiothixene, do not stop taking it without your doctor's advice. It is not known whether thiothixene passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Thiothixene should not be given to a child younger than 12 years old.

How should I take thiothixene?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

You may not start feeling better right away when you start taking thiothixene. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve during treatment.

You will need regular medical tests to be sure this medication is not causing harmful effects. Visit your doctor regularly.

Store at room temperature away from moisture and heat.

See also: Thiothixene dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include drowsiness, dizziness, muscle stiffness or twitching, increased salivation, trouble swallowing, weakness, loss of balance or coordination, and fainting.

What should I avoid while taking thiothixene?

Thiothixene may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Do not drink alcohol. Thiothixene can increase the effects of alcohol, which could be dangerous.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Thiothixene can decrease perspiration and you may be more prone to heat stroke.

Avoid exposure to sunlight or tanning beds. Thiothixene can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Thiothixene side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop taking thiothixene and call your doctor at once if you have a serious side effect such as:

• 
  

  very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, feeling like you might pass out;

  
  


• 
  

  twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs;

  
  


• 
  

  tremor (uncontrolled shaking);

  
  


• 
  

  trouble swallowing;

  
  


• 
  

  vision changes;

  
  


• 
  

  swelling in your hands or feet;

  
  


• 
  

  seizure (convulsions);

  
  


• 
  

  pale skin, easy bruising or bleeding, unusual weakness; or

  
  


• 
  

  fever, chills, body aches, flu symptoms.

  
  

Less serious side effects may include:

• 
  

  dizziness or drowsiness;

  
  


• 
  

  feeling restless or agitated;

  
  


• 
  

  sleep problems (insomnia);

  
  


• 
  

  breast swelling or discharge;

  
  


• 
  

  changes in your menstrual periods;

  
  


• 
  

  nausea, vomiting, diarrhea, constipation;

  
  


• 
  

  changes in weight or appetite;

  
  


• 
  

  dry mouth, increased thirst; or

  
  


• 
  

  impotence, loss of interest in sex.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Thiothixene Dosing Information

Usual Adult Dose for Psychosis:

Oral: Initial dose (mild conditions): 2 to 3 mg orally 3 times a day.
Maintenance dose: May increase up to 15 mg/day.
Initial dose (severe conditions): 5 mg orally twice a day.
Maintenance dose: 20 to 30 mg/day.
Maximum dose: 60 mg/day.

Usual Pediatric Dose for Psychosis:

12 years of age or older:
Initial dose (mild conditions): 2 to 3 mg orally 3 times a day.
Maintenance dose: May increase up to 15 mg/day.
Initial dose (severe conditions): 5 mg orally twice a day.
Maintenance dose: 20 to 30 mg/day.
Maximum dose: 60 mg/day.

Less than 12 years:
Dose not well established (use not recommended): 0.25 mg/kg/day in divided doses

What other drugs will affect thiothixene?

Before using thiothixene, tell your doctor if you regularly use other medicines that make you sleepy (such as cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). You should not take thiothixene if you have drowsiness caused by other medications.

Tell your doctor about all other medications you use, especially:

• 
  

  carbamazepine (Carbatrol, Tegretol);

  
  


• 
  

  blood pressure medications;

  
  


• 
  

  atropine (Donnatal, and others), benztropine (Cogentin), dimenhydrinate (Dramamine), methscopolamine (Pamine), or scopolamine (Transderm-Scop);

  
  


• 
  

  bronchodilators such as ipratroprium (Atrovent) or tiotropium (Spiriva);

  
  


• 
  

  glycopyrrolate (Robinul);

  
  


• 
  

  mepenzolate (Cantil);

  
  


• 
  

  bladder or urinary medications such as darifenacin (Enablex), flavoxate (Urispas), oxybutynin (Ditropan, Oxytrol), tolterodine (Detrol), or solifenacin (Vesicare); or

  
  


• 
  

  irritable bowel medications such as dicyclomine (Bentyl), hyoscyamine (Anaspaz, Cystospaz, Levsin, and others), or propantheline (Pro-Banthine).

  
  

This list is not complete and other drugs may interact with thiothixene. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More thiothixene resources

• Thiothixene Side Effects (in more detail)
• Thiothixene Dosage
• Thiothixene Use in Pregnancy & Breastfeeding
• Drug Images
• Thiothixene Drug Interactions
• Thiothixene Support Group
• 3 Reviews for Thiothixene - Add your own review/rating

• thiothixene Advanced Consumer (Micromedex) - Includes Dosage Information


• Thiothixene Prescribing Information (FDA)


• Thiothixene Professional Patient Advice (Wolters Kluwer)


• Thiothixene Monograph (AHFS DI)


• Thiothixene MedFacts Consumer Leaflet (Wolters Kluwer)


• Navane Advanced Consumer (Micromedex) - Includes Dosage Information


• Navane Prescribing Information (FDA)

Compare thiothixene with other medications

• Psychosis

Where can I get more information?

• Your pharmacist can provide more information about thiothixene.

See also: thiothixene side effects (in more detail)

Nicoderm CQ Patch

Pronunciation: NIK-oh-teen
Generic Name: Nicotine
Brand Name: Nicoderm CQ

Nicoderm CQ Patch is used for:

Helping you to quit smoking.

Nicoderm CQ Patch is a smoking deterrent. It works by providing low levels of nicotine, which may help you to quit smoking by lessening the physical signs of withdrawal symptoms.

Do NOT use Nicoderm CQ Patch if:

• you are allergic to any ingredient in Nicoderm CQ Patch


• you have had a recent heart attack


• you have severe or worsening chest pain or a severely irregular heartbeat


• you continue to smoke, chew tobacco, use snuff, or any other nicotine-containing products (eg, nicotine gum)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Nicoderm CQ Patch:

Some medical conditions may interact with Nicoderm CQ Patch. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances (including adhesive tape)


• if you have skin problems at the application site


• if you have chest pain (eg, angina), heart problems (eg, coronary artery disease, irregular heartbeat), a history of a heart attack, high blood pressure, an overactive thyroid, an ulcer, a tumor on your adrenal gland (pheochromocytoma), diabetes, or blood vessel problems (eg, Buerger disease, Raynaud phenomena)


• if you take medicine for asthma or depression, or if you are using another medicine to stop smoking

Some MEDICINES MAY INTERACT with Nicoderm CQ Patch. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Acetaminophen, adrenergic antagonists (eg, prazosin), asthma medicines (eg, theophylline), beta-blockers (eg, labetalol, propranolol), caffeine, insulin, oxazepam, pentazocine, or tricyclic antidepressants (eg, imipramine) because the risk of their side effects may be increased when you stop smoking


• Adrenergic agonists (eg, isoproterenol, phenylephrine) because their effectiveness may be decreased when you stop smoking

Ask your health care provider if Nicoderm CQ Patch may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Nicoderm CQ Patch:

Use Nicoderm CQ Patch as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Nicoderm CQ Patch. Talk to your pharmacist if you have questions about this information.


• Do not apply to skin that is oily, burned, irritated, or damaged in any way.


• Remove backing from patch and immediately press onto a clean, dry, hairless part of your upper arm or hip. Press firmly and count to 10 to be sure it sticks well.


• Wash your hands after applying or removing the patch.


• Apply a new patch at the same time each day. Be sure to use a different skin site to avoid skin irritation.


• Do not cut the patch in half or into smaller pieces.


• Do not wear more than 1 patch at a time.


• After removing the used patch, fold it in half with the sticky sides together. Discard the patch out of the reach of children and away from pets.


• If you miss a dose of Nicoderm CQ Patch, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Nicoderm CQ Patch.

Important safety information:

• Nicoderm CQ Patch may cause dizziness, lightheadedness, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Nicoderm CQ Patch with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do NOT use more than the recommended dose or use for longer than 8 weeks without checking with your doctor.


• If you begin to have vivid dreams or other sleeping problems, remove the patch at bedtime (after wearing it for about 16 hours). Put on a new patch when you wake up the next day.


• Avoid getting Nicoderm CQ Patch in your eyes. If you get Nicoderm CQ Patch in your eyes, wash them out immediately with cool tap water.


• Do not smoke or use tobacco products while you are using Nicoderm CQ Patch. This includes times when you are not wearing the patch.


• Nicoderm CQ Patch should be used as part of a larger program to help you stop smoking. If you need help choosing a program, talk with your health care provider.


• Do not leave the patch on for more than 24 hours because it may irritate your skin and lose its strength.


• Tell your doctor, dentist, or other health care provider that you use Nicoderm CQ Patch before you receive any medical or dental care, emergency care, or surgery.


• Some patches may cause burns if left on the skin during certain medical procedures (eg, magnetic resonance imaging [MRI]). You may need to remove your patch before you have such tests.


• Nicoderm CQ Patch may cause harm if it is swallowed. If you, a child, or a pet may have taken it by mouth, contact your poison control center or emergency room right away.


• Use Nicoderm CQ Patch with caution in the ELDERLY; they may be more sensitive to its effects.


• Nicoderm CQ Patch should not be used in CHILDREN younger than 18 years old without first checking with the child's doctor; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Nicoderm CQ Patch may cause harm to the fetus. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Nicoderm CQ Patch while you are pregnant. Nicoderm CQ Patch is found in breast milk. If you are or will be breast-feeding while you use Nicoderm CQ Patch, check with your doctor. Discuss any possible risks to your baby.

When used for longer than a few weeks or at high doses, some people develop a need to continue taking Nicoderm CQ Patch. This is known as DEPENDENCE or addiction.

Do not suddenly stop taking Nicoderm CQ Patch without your doctor's approval. If you do, you may have WITHDRAWAL symptoms. These may include anxiety, craving, impaired concentration, increased appetite, irritability, nervousness, sleep disturbances, and weight gain.

Possible side effects of Nicoderm CQ Patch:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Abnormal dreams; headache; mild dizziness; mild redness, itching, or burning at the application site; nervousness; sweating; trouble sleeping; vivid dreams.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blurred vision; fast or irregular heartbeat; nausea; severe or persistent dizziness or headache; stomach pain or vomiting; swelling or persistent (more than 4 days) redness at the application site.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Nicoderm CQ side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include cold and clammy skin; confusion; diarrhea; difficulty breathing; dizziness; excessive drooling; fainting; fast, weak, or irregular heartbeat; headache; hearing and vision problems; nausea; seizures; stomach pain; sweating; tremor; vomiting; weakness. Nicoderm CQ Patch may be harmful if swallowed.

Proper storage of Nicoderm CQ Patch:

Store Nicoderm CQ Patch at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Nicoderm CQ Patch out of the reach of children and away from pets.

General information:

• If you have any questions about Nicoderm CQ Patch, please talk with your doctor, pharmacist, or other health care provider.


• Nicoderm CQ Patch is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Nicoderm CQ Patch. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Nicoderm CQ resources

• Nicoderm CQ Side Effects (in more detail)
• Nicoderm CQ Use in Pregnancy & Breastfeeding
• Nicoderm CQ Drug Interactions
• Nicoderm CQ Support Group
• 8 Reviews for Nicoderm CQ - Add your own review/rating

Compare Nicoderm CQ with other medications

• Smoking Cessation

Tri-Sprintec

Generic Name: ethinyl estradiol and norgestimate (ETH in ill ess tra DYE ol and nor JESS ti mate)

Brand Names: Mononessa, Ortho Tri-Cyclen, Ortho Tri-Cyclen Lo, Ortho-Cyclen, Previfem, Sprintec, Tri-Lo-Sprintec, Tri-Previfem, Tri-Sprintec, TriNessa

What is Tri-Sprintec (ethinyl estradiol and norgestimate)?

Ethinyl estradiol and norgestimate contains a combination of female hormones that prevent ovulation (the release of an egg from an ovary). This medication also causes changes in your cervical mucus and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus.

Ethinyl estradiol and norgestimate is used as contraception to prevent pregnancy. It is also used to treat severe acne.

Ethinyl estradiol and norgestimate may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Tri-Sprintec (ethinyl estradiol and norgestimate)?

This medication can harm an unborn baby or cause birth defects. Do not use birth control pills if you are pregnant or if you have recently had a baby. You should not take birth control pills if you have coronary artery disease, severe heart valve disorder, uncontrolled high blood pressure, a history of stroke or blood clot, circulation problems, a hormone-related cancer such as breast or uterine cancer, unusual vaginal bleeding, liver disease or liver cancer, severe migraine headaches, or a history of jaundice caused by pregnancy or birth control pills.

You may need to use back-up birth control, such as condoms or a spermicide, when you first start using this medication. Follow your doctor's instructions.

Taking hormones can increase your risk of blood clots, stroke, or heart attack, especially if you smoke and are older than 35.

Some drugs can make birth control pills less effective, which may result in pregnancy. Tell your doctor about all the prescription and over-the-counter medications you use, including vitamins, minerals and herbal products. Do not start using a new medication without telling your doctor.

What should I discuss with my healthcare provider before taking Tri-Sprintec (ethinyl estradiol and norgestimate)?

This medication can cause birth defects. Do not use if you are pregnant. Tell your doctor right away if you become pregnant, or if you miss two menstrual periods in a row. If you have recently had a baby, wait at least 4 weeks before taking birth control pills (6 weeks if you are breast-feeding). You should not take birth control pills if you have:

• 
  

  coronary artery disease, a severe or uncontrolled heart valve disorder, untreated or uncontrolled high blood pressure;

  
  


• 
  

  a history of a stroke, blood clot, or circulation problems;

  
  


• 
  

  a hormone-related cancer such as breast or uterine cancer;

  
  


• 
  

  unusual vaginal bleeding that has not been checked by a doctor;

  
  


• 
  

  liver disease or liver cancer;

  
  


• 
  

  severe migraine headaches; or

  
  


• 
  

  a history of jaundice caused by pregnancy or birth control pills.

  
  

To make sure you can safely take this medication, tell your doctor if you have any of these other conditions:

• 
  

  high blood pressure, heart disease, congestive heart failure, angina (chest pain), or a history of heart attack;

  
  


• 
  

  high cholesterol or triglycerides, or if you are overweight;

  
  


• 
  

  a history of depression;

  
  


• 
  

  gallbladder disease;

  
  


• 
  

  diabetes;

  
  


• 
  

  seizures or epilepsy;

  
  


• 
  

  a history of irregular menstrual cycles; or

  
  


• 
  

  a history of fibrocystic breast disease, lumps, nodules, or an abnormal mammogram.

  
  

The hormones in this medication can pass into breast milk and may harm a nursing baby. This medication may also slow breast milk production. Do not use if you are breast-feeding a baby.

How should I take Tri-Sprintec (ethinyl estradiol and norgestimate)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Take your first pill on the first day of your period or on the first Sunday after your period begins (follow your doctor's instructions).

You may need to use back-up birth control, such as condoms or a spermicide, when you first start using this medication. Follow your doctor's instructions.

The 28-day birth control pack contains seven "reminder" pills to keep you on your regular cycle. Your period will usually begin while you are using these reminder pills.

You may have breakthrough bleeding, especially during the first 3 months. Tell your doctor if this bleeding continues or is very heavy.

Take one pill every day, no more than 24 hours apart. When the pills run out, start a new pack the following day. You may get pregnant if you do not use this medication regularly. Get your prescription refilled before you run out of pills completely.

If you need surgery or medical tests or if you will be on bed rest, you may need to stop using this medication for a short time. Any doctor or surgeon who treats you should know that you are using birth control pills.

Your doctor will need to check your progress on a regular basis. Do not miss any scheduled appointments.

Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Missing a pill increases your risk of becoming pregnant.

If you miss one "active" pill, take two pills on the day that you remember. Then take one pill per day for the rest of the pack.

If you miss two "active" pills in a row in week one or two, take two pills per day for two days in a row. Then take one pill per day for the rest of the pack. Use back-up birth control for at least 7 days.

If you miss two "active" pills in a row in week three, or if you miss three pills in a row during any of the first 3 weeks, throw out the rest of the pack and start a new one the same day if you are a Day 1 starter. If you are a Sunday starter, keep taking a pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new one that day.

If you miss two or more pills, you may not have a period during the month. If you miss a period for two months in a row, call your doctor because you might be pregnant.

If you miss any reminder pills, throw them away and keep taking one pill per day until the pack is empty. You do not need back-up birth control if you miss a reminder pill.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include severe nausea or vaginal bleeding.

What should I avoid while taking Tri-Sprintec (ethinyl estradiol and norgestimate)?

Do not smoke while using birth control pills, especially if you are older than 35. Smoking can increase your risk of blood clots, stroke, or heart attack caused by birth control pills.

Birth control pills will not protect you from sexually transmitted diseases--including HIV and AIDS. Using a condom is the only way to protect yourself from these diseases.

Tri-Sprintec (ethinyl estradiol and norgestimate) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop taking this medicine and call your doctor at once if you have a serious side effect such as:

• 
  

  sudden numbness or weakness, especially on one side of the body;

  
  


• 
  

  sudden severe headache, confusion, problems with vision, speech, or balance;

  
  


• 
  

  sudden cough, wheezing, rapid breathing, coughing up blood;

  
  


• 
  

  pain, swelling, warmth, or redness in one or both legs;

  
  


• 
  

  chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;

  
  


• 
  

  a change in the pattern or severity of migraine headaches;

  
  


• 
  

  pain in your upper stomach, jaundice (yellowing of the skin or eyes);

  
  


• 
  

  a lump in your breast;

  
  


• 
  

  swelling in your hands, ankles, or feet; or

  
  


• 
  

  symptoms of depression (sleep problems, weakness, mood changes).

  
  

Less serious side effects may include:

• 
  

  mild nausea or vomiting, appetite or weight changes;

  
  


• 
  

  breast swelling or tenderness;

  
  


• 
  

  headache, nervousness, dizziness;

  
  


• 
  

  problems with contact lenses;

  
  


• 
  

  freckles or darkening of facial skin, loss of scalp hair; or

  
  


• 
  

  vaginal itching or discharge.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Tri-Sprintec (ethinyl estradiol and norgestimate)?

Some drugs can make ethinyl estradiol and norgestimate less effective, which may result in pregnancy. Before using ethinyl estradiol and norgestimate, tell your doctor if you are using any of the following drugs:

• 
  

  bosentan (Tracleer);

  
  


• 
  

  St. John's wort;

  
  


• 
  

  an antibiotic;

  
  


• 
  

  HIV or AIDS medications;

  
  


• 
  

  phenobarbital (Solfoton) and other barbiturates; or

  
  


• 
  

  seizure medication.

  
  

This list is not complete and other drugs may interact with birth control pills. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Tri-Sprintec resources

• Tri-Sprintec Side Effects (in more detail)
• Tri-Sprintec Use in Pregnancy & Breastfeeding
• Drug Images
• Tri-Sprintec Drug Interactions
• Tri-Sprintec Support Group
• 168 Reviews for Tri-Sprintec - Add your own review/rating

• Tri-Sprintec MedFacts Consumer Leaflet (Wolters Kluwer)


• Tri-Sprintec Prescribing Information (FDA)


• MonoNessa Prescribing Information (FDA)


• Ortho Tri-Cyclen Prescribing Information (FDA)


• Ortho Tri-Cyclen Consumer Overview


• Ortho Tri-Cyclen Lo Prescribing Information (FDA)


• Previfem Prescribing Information (FDA)


• Sprintec Prescribing Information (FDA)


• Tri-Lo-Sprintec Prescribing Information (FDA)


• Tri-Previfem Prescribing Information (FDA)


• TriNessa Prescribing Information (FDA)

Compare Tri-Sprintec with other medications

• Abnormal Uterine Bleeding
• Acne
• Birth Control
• Endometriosis
• Gonadotropin Inhibition
• Ovarian Cysts

Where can I get more information?

• Your pharmacist can provide more information about ethinyl estradiol and norgestimate.

See also: Tri-Sprintec side effects (in more detail)