Cesia

desogestrel and ethinyl estradiol

Dosage Form: tablets

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Cesia Description

Cesia® (desogestrel/ethinyl estradiol) Tablets are a triphasic oral contraceptive containing two active components, desogestrel and ethinyl estradiol. Each 28-day treatment cycle pack consists of three active dosing phases: 7 light yellow tablets containing 0.100 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol) and 0.025 mg ethinyl estradiol (19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3, 17-diol); 7 orange tablets containing 0.125 mg desogestrel and 0.025 mg ethinyl estradiol, and 7 red tablets containing 0.150 mg desogestrel and 0.025 mg ethinyl estradiol. Inactive ingredients include vitamin E, pregelatinized starch, stearic acid, lactose monohydrate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, talc, yellow ferric oxide (in light yellow and orange tablets), and red ferric oxide (in orange and red tablets). Cesia® also contains 7 green tablets with the following inert ingredients: lactose monohydrate, corn starch, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, FD&C Blue No. 2 aluminum lake, yellow ferric oxide, and talc. The molecular weights for desogestrel and ethinyl estradiol are 310.48 and 296.40, respectively. The structural formulas are as follows:

DESOGESTREL	ETHINYL ESTRADIOL
C22H30O	C20H24O2

Cesia - Clinical Pharmacology

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Receptor-binding studies, as well as studies in animals, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity (91,92). The relevance of this latter finding in humans is unknown.

Pharmacokinetics

Absorption

Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, based on the lowest and highest tablet strengths, 0.100 mg desogestrel/0.025 mg ethinyl estradiol and 0.150 mg desogestrel/0.025 mg ethinyl estradiol, compared to solution, as measured by serum levels of etonogestrel, is approximately 100%. Ethinyl estradiol is rapidly and almost completely absorbed. When the lowest and highest tablet strengths, 0.100 mg desogestrel/0.025 mg ethinyl estradiol and 0.150 mg desogestrel/0.025 mg ethinyl estradiol, were compared to solution, the relative bioavailability of ethinyl estradiol was 92% and 98%, respectively. The effect of food on the bioavailability of Cesia® (desogestrel/ethinyl estradiol) Tablets following oral administration has not been evaluated.

The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of Cesia® tablets were determined during the third cycle in 21 subjects. After multiple dosing with Cesia®, plasma concentrations of etonogestrel reached steady-state after four days of treatment during dosing Phases 1 and 3. During dosing Phase 2, steady-state was reached after five days of treatment. The dose-normalized AUC0–24 for etonogestrel was increased approximately 20% from Phase 1 to Phase 2 and approximately 10% from Phase 2 to Phase 3. SHBG concentrations were shown to be induced by the daily administration of ethinyl estradiol. Steady state for ethinyl estradiol was reached after four days of dosing in all dosing phases. The pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of Cesia® tablets are summarized in Table 1.

TABLE 1: MEAN (SD) PHARMACOKINETIC PARAMETERS OF Cesia® OVER A 28-DAY DOSING PERIOD IN THE THIRD CYCLE (n=21).

Cmax – maximum serum drug concentration tmax – time at which maximum serum drug concentration occurs n-AUC0–24 – area under the concentration- vs. time curve -0 to 24 hours normalized to 1 µg administered CL/F – apparent clearance Note: for information on t1/2 for Day 21, see the Excretion section.
* Desogestrel † n=20
Etonogestrel
Phase (days)	Dose* mg	Cmax pg/mL	tmax hr	n-AUC0–24 pg∙hr/mL/µg	CL/F L/hr
1 (1–7)	0.100	2163.3 (856.4)	1.6 (0.7)	196.0 (75.4)	6.1 (2.3)
2 (8–14)	0.125	3241.5 (1296.5)†	1.1 (0.3)†	234.4 (85.0)†	5.1 (1.9)†
3 (15–21)	0.150	3855.7 (1273.1)	1.5 (0.8)	256.6 (104.0)	4.6 (1.6)
Ethinyl Estradiol
Phase (days)	Dose mg	Cmax pg/mL	tmax hr	n-AUC0–24 pg∙hr/mL/µg	CL/F L/hr
1 (1–7)	0.025	85.4 (51.7)	1.5 (0.8)	26.4 (11.5)	43.5 (15.0)
2 (8–14)	0.025	91.3 (52.2)†	1.2 (1.2)†	29.0 (15.5)†	41.7 (15.5)†
3 (15–21)	0.025	90.1 (48.2)	1.2 (0.7)	28.3 (13.2)	42.5 (18.7)

Distribution

Etonogestrel, the active metabolite of desogestrel, was found to be 98% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is primarily bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in SHBG, resulting in lower serum levels of free testosterone (96–99).

Metabolism

Desogestrel

Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. In vitro data suggest an important role for the cytochrome P450 CYP2C9 in the bioactivation of desogestrel. Further metabolism of etonogestrel into 6β-hydroxy, etonogestrel and 6β-13ethyl-dihydroxylated metabolites as major metabolites is catalyzed by CYP3A4. Other metabolites (i.e., 3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel) also have been identified and these metabolites may undergo glucuronide and sulfate conjugation.

Ethinyl estradiol

Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol, escaping gut wall conjugation, undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.

Excretion

Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces. At steady state, on Day 21, the elimination half-lives of etonogestrel and ethinyl estradiol are 37.1±14.8 hours and 28.2±10.5 hours, respectively.

Special Populations

Race

There is no information to determine the effect of race on the pharmacokinetics of Cesia® (desogestrel/ethinyl estradiol) Tablets.

Hepatic Insufficiency

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Cesia®. However, steroid hormones may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS).

Renal Insufficiency

No formal studies were conducted to evaluate the effect of renal disease on the disposition of Cesia®.

Drug-Drug Interactions

Interactions between desogestrel/ethinyl estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted with Cesia® (see PRECAUTIONS).

Indications and Usage for Cesia

Cesia® (desogestrel/ethinyl estradiol) Tablets are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.

Oral contraceptives are highly effective. Table 2 lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and implants, depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates.

TABLE 2: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF TYPICAL USE AND THE FIRST YEAR OF PERFECT USE OF CONTRACEPTION AND THE PERCENTAGE CONTINUING USE AT THE END OF THE FIRST YEAR, UNITED STATES.

	% of Women Experiencing an Unintended Pregnancy within the First Year of Use		% of Women Continuing Use at One Year*
Method	Typical Use†	Perfect Use‡
(1)	(2)	(3)	(4)
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces risk of pregnancy by at least 75%.§ Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.¶ Source: Trussell J, Stewart F, Contraceptive Efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998.
* Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year † Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason ‡ Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason § The treatment schedule is one dose within 72 hours after unprotected intercourse and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 2 light orange pills), Lo/Ovral® (1 dose is 4 white pills), Triphasil® or Tri-Levlen® (1 dose is 4 yellow pills) ¶ However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced or the baby reaches six months of age # The percentage of women becoming pregnant noted in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% became pregnant in one year. This estimate was lowered slightly (to 85%) to represent the percentage that would become pregnant within one year among women now relying on reversible methods of contraception if they abandon contraception altogether Þ Foams, creams, gels, vaginal suppositories and vaginal film ß Cervical mucous (ovulation) method supplemented by calendar in the preovulatory and basal body temperature in the postovulatory phases à With spermicidal cream or jelly è Without spermicides
Chance#	85	85
SpermicidesÞ	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation Method		3
Sympto-Thermalß		2
Post-Ovulation		1
Withdrawal	19	4
Capà
Parous Women	40	26	42
Nulliparous Women	20	9	56
Sponge
Parous Women	40	20	42
Nulliparous Women	20	9	56
Diaphragmà	20	6	56
Condomè
Female (Reality)	21	5	56
Male	14	3	61
Pill	5		71
Progestin Only		0.5
Combined		0.1
IUD
Progesterone T	2.0	1.5	81
Copper T 380A	0.8	0.6	78
LNg 20	0.1	0.1	81
Depo-Provera	0.3	0.3	70
Norplant and Norplant-2	0.05	0.05	88
Female sterilization	0.5	0.5	100
Male sterilization	0.15	0.10	100

Contraindications

Oral contraceptives should not be used in women who currently have the following conditions:

• Thrombophlebitis or thromboembolic disorders


• A past history of deep vein thrombophlebitis or thromboembolic disorders


• Cerebral vascular or coronary artery disease (current or history)


• Valvular heart disease with thrombogenic complications


• Severe hypertension


• Diabetes with vascular involvement


• Headaches with focal neurological symptoms


• Major surgery with prolonged immobilization


• Known or suspected carcinoma of the breast (or personal history of breast cancer)


• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia


• Undiagnosed abnormal genital bleeding


• Cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive use


• Hepatic tumors (benign or malignant) or active liver disease


• Known or suspected pregnancy


• Heavy smoking (≥15 cigarettes per day) and over age 35


• Hypersensitivity to any of the components of Cesia® (desogestrel/ethinyl estradiol) Tablets

Warnings

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

The use of oral contraceptives is associated with increased risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke) hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited thrombophilias, hypertension, hyperlipidemias, obesity, and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.

The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with formulations of higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with formulations of lower doses of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiologic studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among non-users. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and non-users. The attributable risk does provide information about the actual occurrence of a disease in the population (Adapted from refs. 2 and 3 with the authors' permission). For further information, the reader is referred to a text on epidemiological methods.

1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS

a. Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. 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 (2,3,19–24). 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 (25). The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped (2).

Several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives (102–104). In general, these studies indicate an approximate two-fold increased risk, which corresponds to an additional 1–2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this two-fold increase in risk.

A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives (9,26). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (9,26). If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breast-feed.

b. Myocardial infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six (4–10). The risk is very low in women under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases (11). Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Table 3) among women who use oral contraceptives.

TABLE 3: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS, AND ORAL CONTRACEPTIVE USE.

AGE	EVER-USERS NON-SMOKERS	EVER-USERS SMOKERS	CONTROLS NON-SMOKERS	CONTROLS SMOKERS
Adapted from P.M. Layde and V. Beral, ref. #12.
15–24	0.0	10.5	0.0	0.0
25–34	4.4	14.2	2.7	4.2
35–44	21.5	63.4	6.4	15.2
45+	52.4	206.7	11.4	27.9

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity (13). In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (14–18). Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

c. Cerebrovascular diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and non-users, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes (27–29).

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 (30). The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers 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 (30). The attributable risk is also greater in older women (3). Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias, hyperlipidemias, and obesity. Women with migraine (particularly migraine with aura) who take combination oral contraceptives may be at an increased risk of stroke.

d. Dose-related risk of vascular disease from oral contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease (31–33). A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (14–16). A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptives. The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on a product containing the lowest hormone content that provides satisfactory results in the individual.

e. Persistence of risk of vascular disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40–49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups (8). In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small (34). However, both studies were performed with oral contraceptive formulations containing 50 micrograms or more of estrogens.

2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 4). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth.

The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's - but not reported until 1983 (35). However, current clinical practice involves the use of lower estrogen formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.

Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (100,101), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

Therefore, the Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective and meets the individual patient needs.

TABLE 4: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NON-STERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE.

Method of control and outcome	15–19	20–24	25–29	30–34	35–39	40–44
Adapted from H.W. Ory, ref. #35.
* Deaths are birth related † Deaths are method related
No fertility control methods*	7.0	7.4	9.1	14.8	25.7	28.2
Oral contraceptives non-smoker†	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives smoker†	2.2	3.4	6.6	13.5	51.1	117.2
IUD†	0.8	0.8	1.0	1.0	1.4	1.4
Condom*	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/spermicide*	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence*	2.5	1.6	1.6	1.7	2.9	3.6

3. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS

Numerous epidemiologic studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. Although the risk of breast cancer may be slightly increased among current users of oral contraceptives (RR = 1.24), this excess risk decreases over time after oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. The risk does not increase with duration of use, and no relationships have been found with dose or type of steroid. The patterns of risk are also similar regardless of a woman's reproductive history or her family breast cancer history. The subgroup for whom risk has been found to be significantly elevated is women who first used oral contraceptives before age 20, but because breast cancer is so rare at these young ages, the number of cases attributable to this early oral contraceptive use is extremely small. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less advanced clinically than in never-users. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone-sensitive tumor.

Some studies suggest that combination oral contraceptive use has been associated with an increase in the risk of cervical intra-epithelial neoplasia in some populations of women (45–48). However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established.

4. HEPATIC NEOPLASIA

Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose (49). Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (50,51).

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (52–54) in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

5. OCULAR LESIONS

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

6. ORAL CONTRACEPTIVE USE BEFORE OR DURING EARLY PREGNANCY

Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (55–57). Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned (55,56,58,59), when oral contraceptives are taken inadvertently during early pregnancy.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed.

7. GALLBLADDER DISEASE

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens (60,61). More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (62–64). The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS

Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users (17). Oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (65). Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (17,66). However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (67). Because of these demonstrated effects, prediabetic and diabetic women should be carefully monitored while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1.a. and 1.d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

9. ELEVATED BLOOD PRESSURE

Women with severe hypertension should not be started on hormonal contraceptives. An increase in blood pressure has been reported in women taking oral contraceptives (68) and this increase is more likely in older oral contraceptive users (69) and with continued use (61). Data from the Royal College of General Practitioners (12) and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens.

Women with a history of hypertension or hypertension-related diseases, or renal disease (70) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives (69), and there is no difference in the occurrence of hypertension between ever- and never-users (68,70,71).

10. HEADACHE

The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause.

11. BLEEDING IRREGULARITIES

Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. If bleeding persists or recurs, non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out.

Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.

12. ECTOPIC PREGNANCY

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

Precautions

1. SEXUALLY TRANSMITTED DISEASES

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

2. PHYSICAL EXAMINATION AND FOLLOW UP

It is good medical practice for all women to have annual history an

Poly Vitamin Drops with Fluoride

Dosage Form: solution / drops
Poly-Vitamin Drops with Fluoride

Poly Vitamin Drops with Fluoride Description

* U.S. Recommended Daily Allowance has not been established.
Each 1.0 mL supplies:		Percentage of U.S. Recommended Daily Allowance
		Infants	Children Under 4
Vitamin A	1500 IU	100	60
Vitamin C	35 mg	100	88
Vitamin D	400 IU	100	100
Vitamin E	5 IU	100	50
Thiamine	0.5 mg	100	71
Riboflavin	0.6 mg	100	75
Niacin	8 mg	100	89
Vitamin B6	0.4 mg	100	57
Vitamin B12	2 mcg	100	67
Fluoride	0.25 mg	*	*

This product does not contain the essential vitamin folic acid.

See INDICATIONS AND USAGE section below for use by infants and young children 6 months to 3 years of age.

Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.

Other Ingredients: Ascorbic acid, caramel color, cherry flavor, cholecalciferol, cyanocobalamin, ferrous sulfate, glycerin, methylparaben, niacinamide, oil of orange, polysorbate 80, purified water, pyridoxine hydrochloride, riboflavin-5-phosphate sodium, sodium benzoate, sodium hydroxide, thiamine hydrochloride, d-alpha tocopheryl acid succinate, vitamin A palmitate. Citric acid may be added to adjust pH.

Poly Vitamin Drops with Fluoride - Clinical Pharmacology

It is well established that fluoridation of the water supply (1 ppm fluoride) during the period of tooth development leads to a significant decrease in the incidence of dental caries.

Hydroxyapatite is the principal crystal for all calcified tissue in the human body. The fluoride ion reacts with the hydroxyapatite in the tooth as it is formed to produce the more caries-resistant crystal, fluorapatite. The reaction may be expressed by the equation:1

Three stages of fluoride deposition in tooth enamel can be distinguished:1

1. Small amounts (reflecting the low levels of fluoride in tissue fluids) are incorporated into the enamel crystals while they are being formed.


2. After enamel has been laid down, fluoride deposition continues in the surface enamel. Diffusion of fluoride from the surface inward is apparently restricted.


3. After eruption, the surface enamel acquires fluoride from water, food, supplementary fluoride and smaller amounts from saliva.

Indications and Usage for Poly Vitamin Drops with Fluoride

Supplementation of the diet with nine essential vitamins.

Supplementation of the diet with fluoride for caries prophylaxis. The American Academy of Pediatrics recommends that children up to age 16, in areas where drinking water contains less than optimal levels of fluoride, receive daily fluoride supplementation.

Multivitamin and Fluoride 0.25 mg drops provide fluoride in drop form for infants and young children 6 months to 3 years of age, in areas where the drinking water contains less than 0.3 ppm of fluoride and for children ages 3-6 years, in areas where the drinking water contains 0.3 through 0.6 ppm of fluoride. Each 1.0 mL supplies sodium fluoride (0.25 mg fluoride) plus nine essential vitamins.

The American Academy of Pediatrics2 and the American Dental Association3 currently recommend that infants and young children 6 months to 3 years of age, in areas where drinking water contains less than 0.3 ppm of fluoride, and children 3-6, in areas where the drinking water contains 0.3 through 0.6 ppm of fluoride, receive 0.25 mg of supplemental fluoride daily which is provided in a full dose (1 mL) of Multivitamin and Fluoride 0.25 mg drops. A half dose (0.5 mL) of Multivitamin and Fluoride Drops 0.5 mg drops could also provide a daily fluoride intake of 0.25 mg; however, this dosage reduces vitamin supplementation by half.

Multivitamin and Fluoride 0.25 mg and 0.5 mg drops supply significant amounts of vitamins A, C, D, E, thiamine, riboflavin, niacin, pyridoxine, and cyanocobalamin to supplement the diet, and to help assure that nutritional deficiences of these vitamins will not develop. Thus, in a single easy-to-use preparation, infants and children obtain nine essential vitamins and fluoride.

A comprehensive 5-1/2 year series of studies of the effectiveness of Tri-Vi-Flor® and Poly-Vi-Flor® products in caries protection has been published.4-7 Children in this continuing study lived in an area where the water supply contained only 0.05 ppm fluoride. The subjects were divided into two groups, one which used only non-fluoridated Vi-Sol® vitamin products and the other Tri-Vi-Flor® and Poly-Vi-Flor® vitamin-fluoride products.

The three-year interim report showed 63% fewer carious surfaces in primary teeth and 43% fewer carious surfaces in permanent teeth of the children taking Vi-Flor® vitamin-fluoride products.4

After four years the studies continued to support the effectiveness of Tri-Vi-Flor® and Poly-Vi-Flor®, showing a reduction in carious surfaces of 68% in primary teeth and 46% in permanent teeth.5 Results at the end of 5-1/2 years further confirmed the previous findings and indicated that significant reductions in dental caries are apparent with the continued use of Vi-Flor® vitamin-fluoride products.6

Warnings

As in the case of all medications, keep out of reach of children.

Precautions

The suggested dose should not be exceeded since dental fluorosis may result from continued ingestion of large amounts of fluoride. When prescribing vitamin fluoride products:

1. Determine the fluoride content of the drinking water.


2. Make sure the child is not receiving significant amounts of fluoride from other medications and swallowed toothpaste.


3. Periodically check to make sure that the child does not develop significant dental fluorosis.

Multivitamin and Fluoride Drops 0.25 mg should be dispensed in the original plastic container, since contact with glass leads to instability and precipitation. (The amount of sodium fluoride in the 50-mL size is well below the maximum to be dispensed at one time according to recommendations of the American Dental Association.)

Adverse Reactions

Allergic rash and other idiosyncrasies have been rarely reported.

To report SUSPECTED ADVERSE REACTIONS, contact Hi-Tech Pharmacal Co., Inc. at 1-800-262-9010.

Poly Vitamin Drops with Fluoride Dosage and Administration

1.0 mL daily or as prescribed by physician. May be dropped directly into mouth with dropper; or mixed with cereal, fruit juice or other food.

How is Poly Vitamin Drops with Fluoride Supplied

Multivitamin and Fluoride 0.25 mg drops are available in 50 mL bottles with accompanying calibrated dropper.

RECOMMENDED STORAGE:

Store at controlled room temperature, 15º-30ºC (59º-86ºF). After opening, store away from direct light. Close tightly after each use. Occasional deepening of color has no significant effect on vitamin potency.

REFRIGERATION IS NOT REQUIRED

REFERENCES

1. Brudevoid F, McCann HG: Fluoride and caries control - Mechanism of action, in Nizel AE (ed): The Science of Nutrition and its Application in Clinical Dentistry. Philadelphia, WB Saunders Co, 1966, pp 331-347.


2. American Academy of Pediatrics Committee on Nutrition: Fluoride supplementation, Pediatrics 1986;77:758.


3. American Dental Association Council on Dental Therapeutics: Accepted Dental Therapeutics, ed 38, Chicago, 1979, p 321.


4. Hennon DK, Stookey GK, Muhler JC: The clinical anticariogenic effectiveness of supplementary fluoride-vitamin preparations - Results at the end of three years. J Dent Children 1966; 33 January:3-12.


5. Hennon DK, Stookey GK, Muhler JC: The clinical anticariogenic effectiveness of supplementary fluoride-vitamin preparations - Results at the end of four years. J Dent Children 1967; 34 November;439- 443.


6. Hennon DK, Stookey GK, Muhler JC:The clinical anticariogenic effectiveness of supplementary fluoride-vitamin preparations - Results at the end of five and a half years. Phar and Ther in Dent 1970; 1:1.


7. Hennon DK, Stookey GK, Beiswanger BB: Fluoride-vitamin supplements: Effects on dental caries and fluorosis when used in areas with suboptimum fluoride in the water supply. J Am Dent Assoc 1977; 95-965.

Manufactured By:

HI-TECH PHARMACAL CO., INC.

Amityville, N.Y. 11701

Rev. 642:06 4/09

PRINCIPAL DISPLAY PANEL

NDC 50383-642-50

Poly-Vitamin Drops

WITH FLUORIDE

0.25 mg

MULTIVITAMIN AND FLUORIDE SUPPLEMENT DROPS

Rx Only

1 2/3 FL. OZ. (50 mL)

POLY-VITAMIN WITH FLUORIDE  multivitamin and fluoride  solution/ drops

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 50383-642 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength VITAMIN A PALMITATE (VITAMIN A PALMITATE) VITAMIN A PALMITATE 1500 [iU]  in 1 mL ASCORBIC ACID (ASCORBIC ACID) ASCORBIC ACID 35 mg  in 1 mL CHOLECALCIFEROL (CHOLECALCIFEROL) CHOLECALCIFEROL 400 [iU]  in 1 mL .ALPHA.-TOCOPHEROL SUCCINATE, D- (.ALPHA.-TOCOPHEROL, D-) .ALPHA.-TOCOPHEROL SUCCINATE, D- 5 [iU]  in 1 mL THIAMINE HYDROCHLORIDE (THIAMINE) THIAMINE HYDROCHLORIDE 0.5 mg  in 1 mL RIBOFLAVIN (RIBOFLAVIN) RIBOFLAVIN 0.6 mg  in 1 mL NIACINAMIDE (NIACINAMIDE) NIACINAMIDE 8 mg  in 1 mL PYRIDOXINE HYDROCHLORIDE (PYRIDOXINE) PYRIDOXINE HYDROCHLORIDE 0.4 mg  in 1 mL CYANOCOBALAMIN (CYANOCOBALAMIN) CYANOCOBALAMIN 2 ug  in 1 mL SODIUM FLUORIDE (FLUORIDE ION) SODIUM FLUORIDE 0.25 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength ANHYDROUS CITRIC ACID   FERROUS SULFATE   GLYCERIN   METHYLPARABEN   OIL ORANGE SS   POLYSORBATE 80   SODIUM BENZOATE   SODIUM HYDROXIDE   WATER

Product Characteristics Color      Score      Shape Size Flavor CHERRY Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 50383-642-50 1  In 1 CARTON contains a BOTTLE 1 50 mL In 1 BOTTLE This package is contained within the CARTON (50383-642-50)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Unapproved drug other		07/01/1990	05/03/2012

Labeler - Hi-Tech Pharmacal Co., Inc. (101196749)

Revised: 01/2012Hi-Tech Pharmacal Co., Inc.

Kolephrin

Generic Name: acetaminophen, chlorpheniramine, and pseudoephedrine (a seet a MIN oh fen, klor fen IR a meen, soo doe e FED rin)

Brand Names: Alka-Seltzer Plus Cold Liquigel, Allerest Headache Strength, Allerest Sinus, Cold Medicine Plus, Comtrex Allergy Sinus, Comtrex Allergy Sinus Maximum Strength, Comtrex Allergy Sinus Night and Day, Kolephrin, Sinarest, Sinutab Ex-Strength, Theraflu Cold & Sore Throat (pseudoephedrine), Theraflu Flu & Sore Throat (pseudoephedrine), Theraflu Maximum Strength

What is Kolephrin (acetaminophen, chlorpheniramine, and pseudoephedrine)?

Acetaminophen is a pain reliever and fever reducer.

Chlorpheniramine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Pseudoephedrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of acetaminophen, chlorpheniramine, and pseudoephedrine is used to treat headache, fever, body aches, runny or stuffy nose, sneezing, itching, watery eyes, and sinus congestion caused by allergies, the common cold, or the flu.

Acetaminophen, chlorpheniramine, and pseudoephedrine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Kolephrin (acetaminophen, chlorpheniramine, and pseudoephedrine)?

Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death. Do not take this medication without a doctor's advice if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You should not use this medicine if you have severe constipation, a blockage in your stomach or intestines, or if you are unable to urinate. Do not use this medicine if you have untreated or uncontrolled diseases such as glaucoma, asthma or COPD, high blood pressure, heart disease, coronary artery disease, or overactive thyroid. Avoid drinking alcohol. It may increase your risk of liver damage while taking acetaminophen and can increase certain side effects of chlorpheniramine. Do not use this medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects. Ask a doctor or pharmacist before using any other cold, allergy, pain, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose.

What should I discuss with my healthcare provider before taking Kolephrin (acetaminophen, chlorpheniramine, and pseudoephedrine)?

You should not use this medicine if you have severe constipation, a blockage in your stomach or intestines, or if you are unable to urinate. Do not take this medication without a doctor's advice if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You may not be able to take medicine that contains acetaminophen. Do not use this medicine if you have untreated or uncontrolled diseases such as glaucoma, asthma or COPD, high blood pressure, heart disease, coronary artery disease, or overactive thyroid. Do not use this medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you have:

• 
  

  liver disease, cirrhosis, or a history of alcoholism;

  
  


• 
  

  a blockage in your digestive tract (stomach or intestines);

  
  


• 
  

  diabetes;

  
  


• 
  

  kidney disease;

  
  


• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  cough with mucus, or cough caused by smoking, emphysema, or chronic bronchitis;

  
  


• 
  

  enlarged prostate or urination problems;

  
  


• 
  

  low blood pressure;

  
  


• 
  

  pheochromocytoma (an adrenal gland tumor); or

  
  


• 
  

  if you take potassium (Cytra, Epiklor, K-Lyte, K-Phos, Kaon, Klor-Con, Polycitra, Urocit-K).

  
  

It is not known whether acetaminophen, chlorpheniramine, and pseudoephedrine will harm an unborn baby. Do not use this medicine without your doctor's advice if you are pregnant. This medication may pass into breast milk and may harm a nursing baby. Antihistamines and decongestants may also slow breast milk production. Do not use this medicine without your doctor's advice if you are breast-feeding a baby.

How should I take Kolephrin (acetaminophen, chlorpheniramine, and pseudoephedrine)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. This medicine is usually taken only for a short time until your symptoms clear up.

Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death.

Dissolve one packet of the powder in at least 4 ounces of water. Stir this mixture and drink all of it right away.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children.

Do not take for longer than 7 days in a row. Stop taking the medicine and call your doctor if you still have a fever after 3 days of use, you still have pain after 7 days (or 5 days if treating a child), if your symptoms get worse, or if you have a skin rash, ongoing headache, or any redness or swelling.

If you need surgery or medical tests, tell the surgeon or doctor ahead of time if you have taken this medicine within the past few days. Store at room temperature away from moisture and heat. Do not allow liquid medicine to freeze.

What happens if I miss a dose?

Since this medicine is taken when needed, you may not be on a dosing schedule. If you are taking the medication regularly, 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. An overdose of acetaminophen can be fatal.

The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness. Later symptoms may include pain in your upper stomach, dark urine, and yellowing of your skin or the whites of your eyes.

Overdose symptoms may also include severe forms of some of the side effects listed in this medication guide.

What should I avoid while taking Kolephrin (acetaminophen, chlorpheniramine, and pseudoephedrine)?

Ask a doctor or pharmacist before using any other cold, allergy, pain, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose. Check the label to see if a medicine contains acetaminophen or APAP. Avoid drinking alcohol. It may increase your risk of liver damage while taking acetaminophen, and can increase certain side effects of chlorpheniramine. This medicine may cause blurred vision or impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

Kolephrin (acetaminophen, chlorpheniramine, and pseudoephedrine) 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 using this medication and call your doctor at once if you have a serious side effect such as:

• 
  

  chest pain, rapid pulse, fast or uneven heart rate;

  
  


• 
  

  confusion, hallucinations, severe nervousness;

  
  


• 
  

  tremor, seizure (convulsions);

  
  


• 
  

  easy bruising or bleeding, unusual weakness;

  
  


• 
  

  urinating less than usual or not at all;

  
  


• 
  

  nausea, pain in your upper stomach, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of your skin or eyes); or

  
  


• 
  

  dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, chest pain, shortness of breath, uneven heartbeats, seizure).

  
  

Less serious side effects may include:

• 
  

  dizziness, drowsiness;

  
  


• 
  

  mild headache;

  
  


• 
  

  dry mouth, nose, or throat;

  
  


• 
  

  constipation;

  
  


• 
  

  blurred vision;

  
  


• 
  

  feeling nervous; or

  
  


• 
  

  sleep problems (insomnia);

  
  

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 Kolephrin (acetaminophen, chlorpheniramine, and pseudoephedrine)?

Ask a doctor or pharmacist before using this medicine if you regularly use other medicines that make you sleepy (such as narcotic pain medication, sedatives, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety). They can add to sleepiness caused by chlorpheniramine.

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

• 
  

  leflunomide (Arava);

  
  


• 
  

  topiramate (Topamax);

  
  


• 
  

  zonisamide (Zonegran);

  
  


• 
  

  an antibiotic, antifungal medicine, sulfa drug, or tuberculosis medicine;

  
  


• 
  

  an antidepressant;

  
  


• 
  

  birth control pills or hormone replacement therapy;

  
  


• 
  

  bladder or urinary medications;

  
  


• 
  

  blood pressure medication;

  
  


• 
  

  a bronchodilator;

  
  


• 
  

  cancer medicine;

  
  


• 
  

  cholesterol-lowering medications such as Lipitor, Niaspan, Zocor, Vytorin, and others;

  
  


• 
  

  gout or arthritis medications (including gold injections);

  
  


• 
  

  HIV/AIDS medication;

  
  


• 
  

  medication for nausea and vomiting, stomach ulcers, or irritable bowel syndrome;

  
  


• 
  

  medicines to treat psychiatric disorders;

  
  


• 
  

  an NSAID such as Advil, Aleve, Arthrotec, Cataflam, Celebrex, Indocin, Motrin, Naprosyn, Treximet, Voltaren, others; or

  
  


• 
  

  seizure medication.

  
  

This list is not complete and other drugs may interact with acetaminophen, chlorpheniramine, and pseudoephedrine. 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 Kolephrin resources

• Kolephrin Use in Pregnancy & Breastfeeding
• Kolephrin Drug Interactions
• Kolephrin Support Group
• 0 Reviews for Kolephrin - Add your own review/rating

• Children's Tylenol Cold Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Kolephrin with other medications

• Cold Symptoms
• Hay Fever

Where can I get more information?

• Your pharmacist can provide more information about acetaminophen, chlorpheniramine, and pseudoephedrine.

Zocor

Generic Name: simvastatin (Oral route)

sim-va-STAT-in

Commonly used brand name(s)

In the U.S.

• Zocor

Available Dosage Forms:

• Tablet


• Tablet, Disintegrating

Therapeutic Class: Antihyperlipidemic

Pharmacologic Class: HMG-COA Reductase Inhibitor

Uses For Zocor

Simvastatin is used together with a proper diet to treat high cholesterol and triglyceride (fats) levels in the blood. This medicine may help prevent medical problems caused by clogged blood vessels such as heart attacks and strokes.

Simvastatin belongs to the group of medicines called HMG-CoA reductase inhibitors or "statins." It works to reduce the amount of cholesterol in the blood by blocking an enzyme that is needed to make cholesterol.

This medicine is available only with your doctor's prescription.

Before Using Zocor

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of simvastatin in children 10 to 17 years of age. The safety and efficacy of simvastatin in children younger than 10 years of age have not been established.

Teenage girls taking simvastatin should be counseled on appropriate birth control methods to prevent pregnancy.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of simvastatin in the elderly. However, elderly patients are more likely to have age-related muscle problems, which may require caution in patients receiving simvastatin.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	X	Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amprenavir


• Atazanavir


• Boceprevir


• Clarithromycin


• Cyclosporine


• Danazol


• Darunavir


• Erythromycin


• Fosamprenavir


• Gemfibrozil


• Indinavir


• Itraconazole


• Ketoconazole


• Lopinavir


• Mibefradil


• Nefazodone


• Nelfinavir


• Posaconazole


• Ritonavir


• Saquinavir


• Telaprevir


• Telithromycin


• Tipranavir

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acenocoumarol


• Amiodarone


• Amlodipine


• Azithromycin


• Bezafibrate


• Ciprofibrate


• Ciprofloxacin


• Clofibrate


• Colchicine


• Conivaptan


• Dalfopristin


• Daptomycin


• Delavirdine


• Diltiazem


• Everolimus


• Fenofibrate


• Fluconazole


• Fusidic Acid


• Niacin


• Quinupristin


• Ranolazine


• Risperidone


• Tadalafil


• Verapamil


• Voriconazole


• Warfarin

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alitretinoin


• Bosentan


• Carbamazepine


• Dasatinib


• Digoxin


• Dronedarone


• Efavirenz


• Fosphenytoin


• Imatinib


• Levothyroxine


• Oat Bran


• Oxcarbazepine


• Pectin


• Phenytoin


• Rifampin


• St John's Wort


• Ticagrelor

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse, or history of or


• Chinese ancestry or


• Electrolyte disorders or


• Hypotension (low blood pressure) or


• Hypothyroidism (an underactive thyroid), uncontrolled or


• Kidney disease, severe or


• Liver disease, history of


• Seizures or


• Sepsis (severe infection)—Use with caution. May cause side effects to become worse.

• Hypercholesterolemia (high cholesterol in the blood), familial homozygous—Dosage may be adjusted in this condition.

• Liver disease, active or


• Liver enzymes elevated—Should not be used in patients with these conditions.

• Muscle pain or tenderness, history of or


• Muscle weakness, history of—Use with caution. May make these conditions worse.

Proper Use of Zocor

Take this medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.

In addition to this medicine, your doctor may change your diet to one that is low in fat, sugar, and cholesterol. Carefully follow your doctor's orders about any special diet.

If you are taking diltiazem (Cardizem®), or verapamil (Calan®, Isoptin®, Verelan®) together with simvastatin, your simvastatin dose should not be higher than 10 milligrams (mg) per day, unless otherwise directed by your doctor. Do not use more than 20 mg per day of simvastatin together with amiodarone (Cordarone®), amlodipine (Norvasc®) or ranolazine (Ranexa®). When used together with higher doses of simvastatin, these medicines may increase your risk of muscle injury and could result in kidney problems.

Avoid large amounts of grapefruit juice (more than 1 quart each day) while you are taking this medicine. Grapefruit juice may increase your risk of muscle injury and could result in kidney problems.

Do not drink large amounts of alcohol with simvastatin. This could cause unwanted effects on the liver.

This medicine comes with a patient information insert. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  
  • For high cholesterol:
    
    • Adults—At first, 10 to 20 milligrams (mg) once a day in the evening. For high risk patients who may develop heart disease, your doctor may start your dose at 40 mg per day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 40 mg per day.
    
    
    • Children 10 to 17 years of age—At first, 10 mg once a day in the evening. Your doctor may increase your dose as needed. However, the dose is usually not more than 40 mg per day.
    
    
    • Children younger than 10 years of age—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Zocor

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it. Blood tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Do not use simvastatin if you are also taking any of the following medicines: cyclosporine (Gengraf®, Neoral®, Sandimmune®), danazol (Danocrine®), gemfibrozil (Lopid®), nefazodone (Serzone®), certain antibiotics (such as clarithromycin, erythromycin, itraconazole, ketoconazole, posaconazole, telithromycin, Biaxin®, Ery-Tab®, Ketek®, Nizoral®, Noxafil®, or Sporanox®), or medicines to treat HIV/AIDS (such as atazanavir, indinavir, nelfinavir, ritonavir, saquinavir, Agenerase®, Crixivan®, Invirase®, Kaletra®, Lexiva®, Norvir®, Reyataz®, or Viracept®). Using these medicines together with simvastatin may increase your risk of muscle injury and could result in kidney problems.

Chinese patients who are taking large amounts of niacin (greater than or equal to 1 gram or 1000 milligrams per day) together with this medicine may have an increased risk for muscle injury. Talk to your doctor if you are Chinese or have Chinese ancestry and take large amounts of niacin (Niacor®, Niaspan®). You may need a different dose of this medicine.

Stop using this medicine and call your doctor right away if you have unexplained muscle pain, tenderness, or weakness, especially if you also have unusual tiredness or a fever. These could be symptoms of a serious muscle problem called myopathy. Myopathy is more common when high doses of simvastatin (eg, 80 milligrams) are used, but some people get myopathy with lower doses.

Stop using this medicine and check with your doctor right away if you have dark-colored urine, diarrhea, a fever, muscle cramps or spasms, muscle pain or stiffness, or feel very tired or weak. These could be symptoms of a serious muscle problem called rhabdomyolysis, which can cause kidney problems.

Stop using this medicine and check with your doctor right away if you get a headache, stomach pain, vomiting, dark-colored urine, loss of appetite, weight loss, general feeling of tiredness or weakness, light-colored stools, upper right stomach pain, or yellow eyes or skin. These could be symptoms of liver damage.

Before having any kind of surgery or emergency treatment, tell the medical doctor in charge that you are using this medicine. You may need to stop using this medicine several days before having surgery or medical procedures. Talk to your doctor if you have any questions about this.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Zocor Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Dizziness


• fainting


• fast or irregular heartbeat

Less common

• Bladder pain


• bloody or cloudy urine


• blurred vision


• body aches or pain


• chills


• cough


• dark-colored urine


• difficult, burning, or painful urination


• difficulty with breathing


• difficulty with moving


• dry mouth


• ear congestion


• fever


• flushed, dry skin


• frequent urge to urinate


• fruit-like breath odor


• headache


• increased hunger


• increased thirst


• increased urination


• joint pain


• loss of consciousness


• loss of voice


• lower back or side pain


• muscle cramps, spasms, or stiffness


• muscular pain, tenderness, wasting, or weakness


• nasal congestion


• nausea


• runny nose


• sneezing


• sore throat


• stomachache


• sweating


• swelling


• swollen joints


• troubled breathing


• unexplained weight loss


• unusual tiredness or weakness


• vomiting

Rare

• Blindness


• decreased vision

Incidence not known

• Blistering, peeling, or loosening of the skin


• bloating


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• constipation


• diarrhea


• difficulty with swallowing


• general tiredness and weakness


• hives


• indigestion


• itching


• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs


• light-colored stools


• loss of appetite


• pains in the stomach, side, or abdomen, possibly radiating to the back


• pale skin


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• red skin lesions, often with a purple center


• red, irritated eyes


• shortness of breath


• skin rash


• sores, ulcers, or white spots in the mouth or on the lips


• tightness in the chest


• troubled breathing with exertion


• unusual bleeding or bruising


• upper right abdominal or stomach pain


• weakness in the arms, hands, legs, or feet


• wheezing


• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Acid or sour stomach


• belching


• burning feeling in the chest or stomach


• dizziness or lightheadedness


• excess air or gas in the stomach or intestines


• feeling of constant movement of self or surroundings


• full feeling


• heartburn


• lack or loss of strength


• pain or tenderness around the eyes and cheekbones


• passing gas


• sensation of spinning


• skin rash, encrusted, scaly, and oozing


• sleeplessness


• stomach discomfort, upset, or pain


• stuffy nose


• tenderness in the stomach area


• trouble sleeping


• unable to sleep

Incidence not known

• Being forgetful


• decreased interest in sexual intercourse


• depression


• discoloration of the skin


• hair loss or thinning of the hair


• inability to have or keep an erection


• loss in sexual ability, desire, drive, or performance

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Zocor side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Zocor resources

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

• Zocor Prescribing Information (FDA)


• Zocor Consumer Overview


• Zocor MedFacts Consumer Leaflet (Wolters Kluwer)


• Simvastatin Prescribing Information (FDA)


• Simvastatin Monograph (AHFS DI)


• Simvastatin Professional Patient Advice (Wolters Kluwer)

Compare Zocor with other medications

• Cardiovascular Risk Reduction
• High Cholesterol
• High Cholesterol, Familial Heterozygous
• High Cholesterol, Familial Homozygous
• Hyperlipoproteinemia
• Hyperlipoproteinemia Type IIa, Elevated LDL
• Hyperlipoproteinemia Type IIb, Elevated LDL VLDL
• Hyperlipoproteinemia Type III, Elevated beta-VLDL IDL
• Hyperlipoproteinemia Type IV, Elevated VLDL