Quasense

levonorgestrel and ethinyl estradiol

Dosage Form: tablets
PHYSICIAN LABELING

Quasense®

(Levonorgestrel and Ethinyl Estradiol Tablets USP) 0.15 mg/0.03 mg (91-Day Regimen)

Rx only

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

DESCRIPTION

Quasense® is an extended-cycle oral contraceptive consisting of 84 white active tablets each containing 0.15 mg of levonorgestrel, a synthetic progestogen and 0.03 mg of ethinyl estradiol, and 7 peach inert tablets (without hormones).

The chemical formula of levonorgestrel USP is 18, 19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-, (-)-, and the chemical formula of ethinyl estradiol USP is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-. The structural formulas are as follows:

C21H28O2   MW: 312.4              C20H24O2   MW: 296.4

Each white active tablet contains the following inactive ingredients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, and povidone USP. Each peach inert tablet contains the following inactive ingredients: anhydrous lactose NF, FD&C yellow #6 Lake, lactose monohydrate NF, magnesium stearate NF, and microcrystalline cellulose NF.

CLINICAL PHARMACOLOGY

Mode of Action

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 changes in the endometrium (which reduce the likelihood of implantation).

Pharmacokinetics

Absorption

No specific investigation of the absolute bioavailability of Quasense® in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is approximately 43%.

TABLE I: MEAN ± SD PHARMACOKINETIC PARAMETERS FOLLOWING A SINGLE DOSE ADMINISTRATION OF TWO TABLETS OF LEVONORGESTREL AND ETHINYL ESTRADIOL IN HEALTHY FEMALE SUBJECTS UNDER FASTING CONDITIONS.

Analyte	AUCt	Cmax	Tmax	T1/2
	(mean ± SD)	(mean ± SD)	(mean ± SD)	(mean ± SD)
Levonorgestrel	60.8 ± 25.6	5.6 ± 1.5	1.4 ± 0.3 hours	29.8 ± 8.3
	ng*hr/mL	ng/mL		hours
Ethinyl estradiol	1307 ± 361	145 ± 45	1.6 ± 0.5 hours	15.4 ± 3.2
	pg*hr/mL	pg/mL		hours

The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Quasense® has not been evaluated.

Distribution

The apparent volume of distribution of levonorgestrel and ethinyl estradiol are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5 - 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Ethinyl estradiol is about 95 - 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of combination levonorgestrel/ethinyl estradiol oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose kinetics, due in part, to increased SHBG levels that are induced by ethinyl estradiol, and a possible reduction in hepatic metabolic capacity.

Metabolism

Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5β-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.

First-pass metabolism of ethinyl estradiol involves formation of ethinyl estradiol-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed ethinyl estradiol by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol hydroxylation. Hydroxylation at the 4-,6-, and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.

Excretion

About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of Quasense was about 30 hours.

Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of ethinyl estradiol after a single dose of Quasense was found to be about 15 hours.

SPECIAL POPULATIONS

Race

No formal studies on the effect of race on the pharmacokinetics of levonorgestrel and ethinyl estradiol tablets were conducted.

Hepatic Insufficiency

No formal studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Quasense®. However, steroid hormones may be poorly metabolized in patients with impaired liver function.

Renal Insufficiency

No formal studies have been conducted to evaluate the effect of renal disease on the pharmacokinetics of Quasense.

Drug-Drug Interactions

See PRECAUTIONS section – Drug Interactions.

INDICATIONS AND USAGE

Quasense tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

In a 1-year controlled clinical trial, 4 pregnancies occurred in women 18-35 years of age during 809 completed 91-day cycles of Quasense during which no backup contraception was utilized. This represents an overall use-efficacy (typical user efficacy) Pregnancy rate of 1.98 per 100 women-years of use.

Oral contraceptives are highly effective for pregnancy prevention. 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 Norplant® Implant System, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

TABLE II: 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 3
Method	Typical Use 1	Perfect Use 2
(1)	(2)	(3)	(4)
1 Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an unintended pregnancy during the first year if they do not stop use for any other reason.
2 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 unintended pregnancy during the first year if they do not stop use for any other reason.
3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
4 The percentages of women becoming pregnant 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% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percentage who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
5 Foams, creams, gels, vaginal suppositories and vaginal film.
6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
7 With spermicidal cream or jelly.
8 Without spermicides.
9 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 two 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).
10 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.
Chance4	85	85
Spermicides5	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation method		3
Sympto-thermal6		2
Post-ovulation		1
Withdrawal	19	4
Cap7
Parous women	40	26	42
Nulliparous women	20	9	56
Sponge
Parous women	40	20	42
Nulliparous women	20	9	56
Diaphragm7	20	6	56
Condom8
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
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10
Source: Trussell J, 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.

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

  
  


• 
  

  Cerebrovascular or coronary artery disease (current or history)

  
  


• 
  

  Valvular heart disease with thrombogenic complications

  
  


• 
  

  Uncontrolled 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 pill use

  
  


• 
  

  Hepatic adenomas or carcinomas, or active liver disease

  
  


• 
  

  Known or suspected pregnancy

  
  


• 
  

  Hypersensitivity to any component of this product

  
  

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 risk 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. 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 higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower doses of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological 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 nonusers. 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 nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiological methods.

1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS

Use of Quasense (91-Day Regimen) provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing similar strength synthetic estrogens and progestins (an additional 9 weeks per year). While this added exposure may pose an additional risk of thrombotic and thromboembolic disease, studies to date with Quasense (91-Day Regimen) have not suggested an increased risk of these disorders.

a. 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. The risk is very low 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. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Figure 1) among women who use oral contraceptives.

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

b. 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 nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The approximate incidence of deep vein thrombosis and pulmonary embolism in users of low dose (< 50 μg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5-3 per 10,000 woman-years for non-users. However, the incidence is less than that associated with pregnancy (6 per 10,000 woman-years). The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. 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 also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast-feed.

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 nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women. 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. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. 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 progestogen used in the contraceptive. 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 preparations containing the lowest estrogen content which is judged appropriate for the individual patient.

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 to 49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. 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. However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher 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 3). 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 less than 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. However, current clinical practice involves the use of lower estrogen dose 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, 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 nonsmoking women (even with the newer low-dose formulations), there are 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 oral contraceptive use by healthy nonsmoking 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.

TABLE III: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY-CONTROL METHOD AND ACCORDING TO AGE

Method of control and outcome	AGE
	15-19	20-24	25-29	30-34	35-39	40-44
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
* Deaths are birth related
** Deaths are method related
Adapted from H.W.Ory, Family Planning Perspectives, 15: 57-63, 1983.

3. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives. Although the risk of having breast cancer diagnosed may be slightly increased among current and recent users of combined oral contraceptives (RR=1.24), this excess risk decreases over time after combination oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. The risk does not increase with duration of use and no consistent 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 clinically advanced 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 oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. 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 cancer 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 their occurrence 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. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma 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 that may lead to partial or complete loss of vision. 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

Because women using Quasense will likely have withdrawal bleeding only 4 times per year, pregnancy should be ruled out at the time of any missed menstrual period (see DOSAGE AND ADMINISTRATION section). Oral contraceptive use should be discontinued if pregnancy is confirmed.

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy (see CONTRAINDICATIONS section).

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.

7. GALLBLADDER DISEASE

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. 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 glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.

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

9. ELEVATED BLOOD PRESSURE

Women with significant hypertension should not be started on hormonal contraceptive. An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens. Women with a history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. If women with hypertension elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (see CONTRAINDICATIONS section). For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users.

10. HEADACHE

The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. (See WARNINGS, 1c.)

11. BLEEDING IRREGULARITIES

When prescribing Quasense, the convenience of fewer planned menses (4 per year instead of 13 per year) should be weighed against the inconvenience of increased intermenstrual bleeding and/or spotting.

The clinical trial (SEA 301) that compared the efficacy of levonorgestrel and ethinyl estradiol tablets (91-day cycles) to an equivalent dosage 28-day cycle regimen also assessed intermenstrual bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting ≥ 10 consecutive days on oral contraceptives were excluded from the study. More levonorgestrel and ethinyl estradiol (91-Day Regimen) subjects, compared to subjects on the 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% levonorgestrel and ethinyl estradiol (91-Day Regimen) vs. 1.8% [28-day cycle regimen]).

Table 4 shows the percentages of women with ≥ 7 days and ≥ 20 days of intermenstrual spotting and/or bleeding in the levonorgestrel and ethinyl estradiol tablets (91-Day Regimen) and the 28-day cycle treatment groups.

Table IV: Percentage of Subjects with Intermenstrual Bleeding and/or Spotting

Days of intermenstrual bleeding and/or spotting	Percentage of Subjects*
* Based on spotting and/or bleeding on days 1-84 of a 91 day cycle in the levonorgestrel and ethinyl estradiol tablets (91-Day Regimen) subjects and days 1-21 of a 28-day cycle over 4 cycles in the 28-day dosing regimen.
Levonorgestrel and ethinyl	Cycle 1 (N=385)	Cycle 4 (N=261)
estradiol tablets
(91-Day Regimen)
≥ 7 days	65%	42%
≥ 20 days	35%	15%
28-day regimen	Cycles 1-4 (N=194)	Cycles 10-13 (N=158)
≥ 7 days	38%	39%
≥ 20 days

Innovace tablets

INNOVACE 2.5 mg, 5 mg, 10 mg or 20 mg tablets

enalapril maleate

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, please ask your doctor or your pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What Innovace is and what it is used for


• 2. Before you take Innovace


• 3. How to take Innovace


• 4. Possible side effects


• 5. How to store Innovace


• 6. Further information

What Innovace Is And What It Is Used For

Innovace contains an active substance called enalapril maleate. This belongs to the group of medicines called ACE inhibitors (angiotensin converting enzyme inhibitors).

Innovace is used:

• to treat high blood pressure (hypertension).


• to treat heart failure (weakening of heart function). It can lower the need to go to hospital and can help some patients live longer.


• to prevent the signs of heart failure. The signs include: shortness of breath, tiredness after light physical activity such as walking, or swelling of the ankles and feet.

Innovace works by widening your blood vessels. This lowers your blood pressure. The medicine usually starts to work within an hour, and the effect lasts for at least 24 hours. Some people will require several weeks of treatment until the best effect on your blood pressure is seen.

Before You Take Innovace

Do not take Innovace if:

• you are allergic (hypersensitive) to enalapril maleate or any of the other ingredients of Innovace (listed in Section 6).


• you have ever had an allergic reaction to a type of medicine similar to Innovace called an ACE inhibitor.


• you have ever had swelling of your face, lips, mouth, tongue or throat which caused difficulty in swallowing or breathing (angioedema) when the reason why was not known or it was inherited.


• you are more than 3 months pregnant (it is also better to avoid Innovace in early pregnancy – see Pregnancy section).

Do not take Innovace if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking Innovace.

Take special care with Innovace

Check with your doctor or pharmacist before taking your medicine if:

• you have a heart problem.


• you have a condition involving the blood vessels in the brain.


• you have a blood problem such as low or lack of white blood cells (neutropenia/agranulocytosis), low blood platelet count (thrombocytopenia) or a decreased number of red blood cells (anaemia).


• you have a liver problem.


• you have a kidney problem (including kidney transplantation). These may lead to higher levels of potassium in your blood which can be serious. Your doctor may need to adjust your dose of Innovace or monitor your blood level of potassium.


• you are having dialysis.


• you have been very sick (excessive vomiting) or had bad diarrhoea recently.


• you are on a salt-restricted diet, are taking potassium supplements, potassium-sparing agents, or potassium-containing salt substitutes.


• you are over 70 years of age.


• you have diabetes. You should monitor your blood for low blood glucose levels, especially during the first month of treatment. The level of potassium in your blood can also be higher.


• you have ever had an allergic reaction with swelling of the face, lips, tongue or throat with difficulty in swallowing or breathing. You should be aware that black patients are at increased risk of these types of reactions to ACE inhibitors.


• you have low blood pressure (you may notice this as faintness or dizziness, especially when standing).


• you have collagen vascular disease (e.g. lupus erthematosus, rheumatoid arthritis or scleroderma), are on therapy that suppresses your immune system, are taking the drugs allopurinol or procainamide, or any combinations of these.


• you think you are (or might become) pregnant. Innovace is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see Pregnancy section).


• you are breast-feeding or about to start breast-feeding (see Breast-feeding section).

You should be aware that Innovace lowers the blood pressure in black patients less effectively than in non-black patients.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Innovace.

If you are about to have a procedure

If you are about to have any of the following, tell your doctor that you are taking Innovace:

• any surgery or receive anaesthetics (even at the dentist).


• a treatment to remove cholesterol from your blood called 'LDL apheresis'.


• a desensitisation treatment, to lower the effect of an allergy to bee or wasp stings.

If any of the above apply to you, talk to your doctor or dentist before the procedure.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This includes herbal medicines. This is because Innovace can affect the way some medicines work. Also some other medicines can affect the way Innovace works:

In particular tell your doctor or pharmacist if you are taking any of the following medicines:

• other medicines to lower blood pressure, such as beta-blockers or water tablets (diuretics).


• medicines containing potassium (including dietary salt substitutes).


• medicines for diabetes (including oral antidiabetic medicines and insulin).


• lithium (a medicine used to treat a certain kind of depression).


• medicines for depression called 'tricyclic antidepressants'.


• medicines for mental problems called ‘antipsychotics'.


• certain cough and cold medicines and weight reducing medicines which contain something called a ‘sympathomimetic agent'.


• certain pain or arthritis medicines including gold therapy.


• aspirin (acetylsalicylic acid).


• medicines used to dissolve blood clots (thrombolytics).


• alcohol.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Innovace.

Taking Innovace with food and drink

Innovace can be taken with or without food. Most people take Innovace with a drink of water.

Pregnancy and breast-feeding

Pregnancy

You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Innovace before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Innovace. Innovace is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Breast-feeding newborn babies (first few weeks after birth), and especially premature babies, is not recommended whilst taking Innovace. In the case of an older baby your doctor should advise you on the benefits and risks of taking Innovace whilst breast-feeding, compared to other treatments.

Driving and using machinery

You may feel dizzy or sleepy while taking Innovace. If this happens, do not drive or use any tools or machines.

Important information about some of the ingredients of Innovace

Innovace contains lactose, which is a type of sugar. If you have been told by your doctor that you have intolerance to some sugars, talk to your doctor before taking this medicine.

How To Take Innovace

Always take Innovace exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

• It is very important to continue taking Innovace for as long as your doctor prescribes it.


• Do not take more tablets than prescribed.

High Blood Pressure

• The usual starting dose ranges from 5 to 20 mg taken once a day.


• Some patients may need a lower starting dose.


• The usual long term dose is 20 mg taken once a day.


• The maximal long term dose is 40 mg taken once a day.

Heart Failure

• The usual starting dose is 2.5 mg taken once a day.


• Your doctor will raise this amount step by step until the dose that is right for you has been achieved.


• The usual long term dose is 20 mg each day, taken in one or two doses.


• The maximal long term dose is 40 mg each day, divided in two doses.

Patients with kidney problems

Your dose of medicine will be changed depending on how well your kidneys are working:

• moderate kidney problems - 5 mg to 10 mg each day.


• severe kidney problems - 2.5 mg each day.


• if you are having dialysis - 2.5 mg each day. On days you are not having dialysis, your dose may be changed depending on how low your blood pressure is.

Elderly patients

Your dose will be decided by your doctor, and will be based on how well your kidneys are working.

Children

Experience in the use of Innovace in children with high blood pressure is limited. If the child can swallow tablets, the dose will be worked out using the child’s weight and blood pressure. The usual starting doses are:

• between 20 kg and 50 kg – 2.5 mg each day.


• more than 50 kg – 5 mg each day.

The dose can be changed according to the needs of the child:

• a maximum of 20 mg daily can be used in children who are between 20 kg and 50 kg.


• a maximum of 40 mg daily can be used in children who are more than 50kg.

Innovace is not recommended in newborn babies (first few weeks after birth) and in children with kidney problems.

If you take more Innovace than you should

If you take more Innovace than you should, talk to your doctor or go to a hospital straight away. Take the medicine pack with you. The following effects may happen: feeling of light-headed or dizziness. This is due to a sudden or excessive drop in blood pressure.

If you forget to take Innovace

• If you forget to take a tablet, skip the missed dose.


• Take the next dose as usual.


• Do not take a double dose to make up for a forgotten dose.

If you stop taking Innovace

Do not stop taking your medicine unless your doctor tells you to.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Innovace tablets Side Effects

Like all medicines Innovace can cause side effects, although not everybody gets them. The following side effects may happen with this medicine:

Stop taking Innovace and talk to a doctor straight away, if you notice any of the following:

• swelling of your face, lips, tongue or throat which may cause difficulty in breathing or swallowing.


• swelling of your hands, feet or ankles.


• if you develop a raised red skin rash (hives).

You should be aware that black patients are at increased risk of these types of reactions. If any of the above happen, stop taking Innovace and talk to a doctor straight away.

When you start taking Innovace you may feel faint or dizzy. If this happens, it will help to lie down. This is caused by your blood pressure lowering. It should improve as you continue to take the medicine. If you are worried, please talk to your doctor.

Other side effects include:

Very Common (affects more than 1 in 10 people)

• feeling dizzy, weak or sick.


• blurred vision.


• cough.

Common (affects less than 1 in 10 people)

• low blood pressure, changes in heart rhythm, fast heartbeat, angina or chest pain.


• headache, fainting (syncope).


• change in sense of taste, shortness of breath.


• diarrhoea or abdominal pain, rash.


• tiredness (fatigue), depression.


• allergic reactions with swelling of the face, lips, tongue or throat with difficulty in swallowing or breathing.


• increased blood potassium level, increased levels of creatinine in your blood (both are usually detected by a test).

Uncommon (affects less than 1 in 100 people)

• sudden fall in blood pressure.


• fast or uneven heart beats (palpitations).


• heart attack (possibly due to very low blood pressure in certain high-risk patients, including those with blood flow problems of the heart or brain).


• anaemia (including aplastic and haemolytic).


• stroke (possibly due to very low blood pressure in high-risk patients).


• confusion, sleeplessness or sleepiness, nervousness.


• feeling your skin prickling or being numb.


• vertigo.


• ringing in your ears (tinnitus).


• runny nose, sore throat or hoarseness.


• asthma.


• slow movement of food through your intestine, inflammation of your pancreas.


• being sick (vomiting), indigestion, constipation, anorexia.


• irritated stomach (gastric irritations), dry mouth, ulcer, impaired kidney function, kidney failure.


• increased perspiration.


• itching or nettle rash.


• loss of hair.


• muscle cramps, flushing, generally feeling unwell (malaise), high temperature (fever), impotence.


• high level of proteins in your urine (measured in a test).


• low level of blood sugar or sodium, high level of blood urea (all measured in a blood test).

Rare (affects less than 1 in 1,000 people)

• ‘Raynaud’s phenomenon’ where your hands and feet may become very cold and white due to low blood flow.


• changes in blood values such as a lower number of white and red blood cells, lower haemoglobin, lower number of blood platelets.


• bone marrow depression.


• autoimmune diseases.


• strange dreams or sleep problems.


• pulmonary infiltrates.


• inflammation of your nose.


• pneumonia.


• inflammation of the cheeks, gums, tongue, lips, throat.


• lower amount of urine produced.


• erythema multiforme.


• ‘Stevens-Johnson syndrome’ a serious skin condition where you have reddening and scaling of your skin, blistering or raw sores, or detachment of the top layer of skin from bottom layers.


• liver problems such as lower liver function, inflammation of your liver, jaundice (yellowing of the skin or eyes), higher levels of liver enzymes or bilirubin (measured in a blood test).


• enlargement of the mammary glands in males.

Very Rare (affects less than 1 in 10,000 people)

• swelling in your intestine (intestinal angioedema).

If any of these side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. You can ask your doctor or pharmacist for more information about side effects. Both have a more complete list of side effects.

How To Store Innovace

Keep out of the reach and sight of children.

Do not use Innovace after the expiry date which is stated on the blister and the carton after ‘EXP’. The expiry date refers to the last day of that month.

Do not store Innovace above 25°C. Store in the original package in order to protect from moisture.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What Innovace contains:

• The active ingredient is enalapril maleate (either 2.5 mg, 5 mg, 10 mg, or 20 mg).


• The other ingredients are lactose monohydrate, sodium hydrogen carbonate, maize starch, pregelatinised starch, magnesium stearate. The 10 mg tablet also contains iron oxide red (E172) and the 20 mg tablet also contains iron oxide red (E172) and iron oxide yellow (E172).

What Innovace looks like and the contents of the pack

Innovace tablets are available in 4 strengths.

The white round shaped tablets, one side marked 'MSD 14', the other side plain, contain 2.5 mg of enalapril maleate.

The white, rounded triangle shaped tablets one side scored^* and the other side marked 'MSD 712' contain 5 mg enalapril maleate.

The rust-red, rounded triangle shaped tablets, one side scored^*, the other side marked 'MSD 713' contain 10 mg enalapril maleate.

The peach, triangle shaped tablets, one side scored^*, the other marked 'MSD 714' contain 20 mg enalapril maleate.

* The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

Innovace is supplied in the following pack sizes:

Innovace 2.5 mg – All-aluminum blister packages containing 2, 11, 20, 28, 30, 40, 49 x 1, 50, or 100 tablets.

Innovace 5 mg - All-aluminum blister packages containing 2, 14, 20, 28, 28 x 1, 30, 49 x 1, 50, 60, 98, or 100 tablets.

Innovace 10 mg - All-aluminum blister packages containing 28, 49 x 1, 30, 50, 98 or 100 tablets.

Innovace 20 mg - All-aluminum blister packages containing 10, 14, 20, 28, 28 x 1, 30, 49 x 1, 50, 56, 60, 84, 90, 98, 100 or 500 tablets.

Not all pack sizes may be marketed

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation Holder is

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

UK

The product is manufactured by

Merck Manufacturing Division

Merck Sharp & Dohme Limited

Shotton Lane

Northumberland

NE23 3JU

UK

This medicinal product is authorised in the Member States of the EEA under the following names:

Austria, Belgium, Finland, France, Greece, Luxembourg, Netherlands, Portugal, Spain, Sweden:

RENITEC

Germany:

XANEF

Italy:

ENAPREN

UK, Ireland:

INNOVACE

This leaflet was last approved in May 2010

denotes registered trademark of Merck Sharp & Dohme Corp., a subsidiary of

Merck & Co., Inc.

Whitehouse Station

NJ

USA

© Merck Sharp & Dohme Limited 2010. All rights reserved.

(logo) MSD

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

UK

PIL.RNT.10.UK/IRL.3229 (IB-020)

Trilipix Delayed-Release Capsules

Pronunciation: FEN-oh-FYE-bric AS-id
Generic Name: Fenofibric Acid
Brand Name: Trilipix

Trilipix Delayed-Release Capsules are used for:

Lowering high cholesterol and triglyceride levels in the blood. It also increases high-density lipoprotein (HDL, "good") cholesterol levels. It is used along with an appropriate diet. It may also be used in combination with other cholesterol-lowering medicines.

Trilipix Delayed-Release Capsules are a lipid-lowering agent. It works by increasing a certain substance that helps to remove triglycerides from the blood. This also helps the body to decrease the amount of other bad cholesterol in the blood.

Do NOT use Trilipix Delayed-Release Capsules if:

• you are allergic to any ingredient in Trilipix Delayed-Release Capsules or to fenofibrate


• you have gallbladder problems, liver problems (including cirrhosis), or persistent abnormal liver function tests


• you have severe kidney problems or are receiving dialysis


• you are breast-feeding

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

Before using Trilipix Delayed-Release Capsules:

Some medical conditions may interact with Trilipix Delayed-Release Capsules. 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 or other substances


• if you have a history of diabetes, an underactive thyroid, heart problems (eg, heart blood vessel problems), gallbladder problems, pancreatitis, kidney problems, or certain muscle problems (myopathy)


• if you have a history of blood clots in your veins or lungs (deep vein thrombosis or pulmonary embolism)


• if you are very overweight, have an inactive lifestyle, have a poor diet, or you drink large amounts of alcohol


• if you are taking a beta-blocker (eg, propranolol), estrogen, or thiazide diuretic (eg, hydrochlorothiazide)

Some MEDICINES MAY INTERACT with Trilipix Delayed-Release Capsules. Tell your health care provider if you are taking any other medicines, especially any of the following:

• HMG-CoA reductase inhibitors (eg, simvastatin) because the risk of serious muscle problems leading to kidney failure may be increased


• Immunosuppressants (eg, cyclosporine) or other medicines that may harm the kidney (eg, aminoglycoside antibiotics [eg, gentamicin], amphotericin B, nonsteroidal anti-inflammatory drugs [NSAIDs] [eg, ibuprofen], tacrolimus, vancomycin) because they may increase the risk of Trilipix Delayed-Release Capsules's side effects


• Anticoagulants (eg, warfarin) because the risk of their side effects may be increased by Trilipix Delayed-Release Capsules

This may not be a complete list of all interactions that may occur. Ask your health care provider if Trilipix Delayed-Release Capsules 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 Trilipix Delayed-Release Capsules:

Use Trilipix Delayed-Release Capsules as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Trilipix Delayed-Release Capsules comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Trilipix Delayed-Release Capsules refilled.


• Take Trilipix Delayed-Release Capsules by mouth with or without food.


• Swallow Trilipix Delayed-Release Capsules whole. Do not break, crush, chew, or dissolve before swallowing.


• If you also take a bile acid-binding resin (eg, cholestyramine), do not take it within 4 to 6 hours before or 1 hour after taking Trilipix Delayed-Release Capsules. Check with your doctor if you have any questions.


• Take Trilipix Delayed-Release Capsules on a regular schedule to get the most benefit from it. Taking Trilipix Delayed-Release Capsules at the same time each day will help you remember to take it.


• Continue to take Trilipix Delayed-Release Capsules even if you feel well. Do not miss any doses.


• If you miss a dose of Trilipix Delayed-Release Capsules, take 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 take 2 doses at once. Do not take more than 1 dose of Trilipix Delayed-Release Capsules in the same day unless your doctor tells you otherwise.

Ask your health care provider any questions you may have about how to use Trilipix Delayed-Release Capsules.

Important safety information:

• Trilipix Delayed-Release Capsules may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Trilipix Delayed-Release Capsules with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Follow the diet, exercise, and weight loss program given to you by your health care provider.


• Do NOT change your dose or stop taking Trilipix Delayed-Release Capsules without checking with your doctor.


• Lab tests, including liver function, kidney function, blood cholesterol, and other blood tests, may be performed while you use Trilipix Delayed-Release Capsules. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Trilipix Delayed-Release Capsules with caution in the ELDERLY; they may be more sensitive to its effects, especially severe muscle problems.


• Trilipix Delayed-Release Capsules should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: It is not known if Trilipix Delayed-Release Capsules can cause harm to the fetus. If you become pregnant or plan on becoming pregnant, contact your doctor. You will need to discuss the benefits and risks of using Trilipix Delayed-Release Capsules while you are pregnant. It is not known if Trilipix Delayed-Release Capsules are found in breast milk. Do not breast-feed while taking Trilipix Delayed-Release Capsules.

Possible side effects of Trilipix Delayed-Release Capsules:

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:

Back pain; diarrhea; dizziness; headache; heartburn or indigestion; nausea; sore throat; stomach upset; upper respiratory tract infection.

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); calf or leg pain, swelling, redness, or tenderness; chest pain; coughing up blood; dark urine; decrease in amount of urine produced; fever, chills, or persistent sore throat; loss of appetite; muscle pain, tenderness, or weakness (especially along with fever or unusual tiredness); pale stools; red, swollen, blistered, or peeling skin; severe or persistent headache; severe or persistent nausea, stomach pain, or vomiting; shortness of breath; unusual bruising or bleeding; unusual tiredness or weakness; yellowing of the skin or eyes.

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: Trilipix 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.

Proper storage of Trilipix Delayed-Release Capsules:

Store Trilipix Delayed-Release Capsules at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Trilipix Delayed-Release Capsules out of the reach of children and away from pets.

General information:

• If you have any questions about Trilipix Delayed-Release Capsules, please talk with your doctor, pharmacist, or other health care provider.


• Trilipix Delayed-Release Capsules are 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 Trilipix Delayed-Release Capsules. 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 Trilipix resources

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

Compare Trilipix with other medications

• High Cholesterol
• Hypertriglyceridemia

Sporanox injection

itraconazole

Dosage Form: injection

Congestive Heart Failure

When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur during administration of Sporanox® (itraconazole) Injection, continued Sporanox® use should be reassessed. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.)

Drug Interactions

Coadministration of cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol (levomethadyl) with Sporanox® (itraconazole) Capsules, Injection or Oral Solution is contraindicated. Sporanox®, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with Sporanox® and/or other CYP3A4 inhibitors. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.)

DESCRIPTION

For intravenous infusion (NOT FOR IV BOLUS INJECTION)

Sporanox® is the brand name for itraconazole, a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature:

(±) - 1 - [(R*) - sec - butyl] - 4 - [p - [4 - [p - [[(2R*,4S*) - 2 - (2,4 - dichlorophenyl) - 2 - (1H - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl]phenyl] - Δ2 - 1,2,4 - triazolin - 5 - one mixture with (±) - 1 - [(R*) - sec - butyl] - 4 - [p - [4 - [p - [[(2S*,4R*) - 2 - (2,4 - dichlorophenyl) - 2 - (1H - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl]phenyl] - Δ2-1,2,4-triazolin-5-one.

        or

(±) - 1 - [(RS) - sec - butyl] - 4 - [p - [4 - [p - [[(2R,4S) - 2 - (2,4 - dichlorophenyl) - 2 - (1H - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 1 - piperazinyl]phenyl] - Δ2-1,2,4-triazolin-5-one.

Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.

Sporanox® (itraconazole) Injection is a sterile pyrogen-free clear, colorless to slightly yellow solution for intravenous infusion. Each mL contains 10 mg of itraconazole, solubilized by hydroxypropyl-β-cyclodextrin (400 mg) as a molecular inclusion complex, with 3.8 µL hydrochloric acid, 25 µL propylene glycol, and sodium hydroxide for pH adjustment to 4.5, in water for injection. Sporanox® Injection is packaged in 25 mL colorless glass ampules, containing 250 mg of itraconazole, contents of which are diluted in 50 mL 0.9% Sodium Chloride Injection, USP (Normal Saline) prior to infusion. When properly administered, contents of one ampule will supply 200 mg of itraconazole.

Sporanox - Clinical Pharmacology

Pharmacokinetics and Metabolism

NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported may be higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.)

The pharmacokinetics of Sporanox® (itraconazole) Injection (200 mg b.i.d. for two days, then 200 mg q.d. for five days) followed by oral dosing of Sporanox® Capsules were studied in patients with advanced HIV infection. Steady-state plasma concentrations were reached after the fourth dose for itraconazole and by the seventh dose for hydroxyitraconazole. Steady-state plasma concentrations were maintained by administration of Sporanox® Capsules, 200 mg b.i.d. Pharmacokinetic parameters for itraconazole and hydroxyitraconazole are presented in the table below:

Parameter	Injection Day 7 n=29		Capsule, 200 mg b.i.d. Day 36 n=12
	itraconazole	hydroxyitraconazole	itraconazole	hydroxyitraconazole
* mean ± standard deviation
Cmax (ng/mL)	2856 ± 866*	1906 ± 612	2010 ± 1420	2614 ± 1703
tmax (hr)	1.08 ± 0.14	8.53 ± 6.36	3.92 ± 1.83	5.92 ± 6.14
AUC0–12h (ng∙h/mL)	--	--	18768 ± 13933	28516 ± 19149
AUC0–24h (ng∙h/mL)	30605 ± 8961	42445 ± 13282	--	--

The estimated mean ±SD half-life at steady-state of itraconazole after intravenous infusion was 35.4 ± 29.4 hours. In previous studies, the mean elimination half-life for itraconazole at steady-state after daily oral administration of 100 to 400 mg was 30–40 hours. Approximately 93–101% of hydroxypropyl-β-cyclodextrin was excreted unchanged in the urine within 12 hours after dosing.

The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 ± 185 L.

Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3–18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381 ± 95 mL/min following intravenous administration. Approximately 80–90% of hydroxypropyl-β-cyclodextrin is eliminated through the kidneys. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.)

Special Populations

Renal Insufficiency

Plasma concentrations of itraconazole in patients with mild to moderate renal insufficiency were comparable to those obtained in healthy subjects. The majority of the 8-gram dose of hydroxypropyl-β-cyclodextrin was eliminated in the urine during the 120-hour collection period in normal subjects and in patients with mild to severe renal insufficiency. Following a single intravenous dose of 200 mg to subjects with severe renal impairment (creatinine clearance ≤ 19 mL/minute), clearance of hydroxypropyl-β-cyclodextrin was reduced six-fold compared with subjects with normal renal function. Sporanox® Injection should not be used in patients with creatinine clearance < 30 mL/min.

In patients with mild (creatinine clearance 50–80 mL/min) and moderate (creatinine clearance 30–49 mL/min) renal impairment, Sporanox® Injection should be used with caution. Serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to changing to Sporanox® Capsules, if clinically indicated and consistent with approved indications.

Hepatic Insufficiency

Patients with impaired hepatic function should be carefully monitored when taking itraconazole. The prolonged elimination half-life of itraconazole observed in a clinical trial with itraconazole capsules in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.)

Decreased Cardiac Contractility

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of Sporanox® Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of Sporanox® Injection, monitor carefully and consider other treatment alternatives which may include discontinuation of Sporanox® Injection administration. (See WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.)

MICROBIOLOGY

Mechanism of Action

In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

Activity In Vitro and In Vivo

Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Itraconazole also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species, Candida krusei, and other Candida species. The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum and Blastomyces dermatitidis. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents.

Itraconazole administered orally was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Fungistatic activity has been demonstrated against disseminated fungal infections caused by Blastomyces dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes.

Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes increased survival rates and sterilized organ systems in normal and immunosuppressed guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus fumigatus infection, respectively. Itraconazole has demonstrated antifungal activity in a variety of animal models infected with Candida albicans and other Candida species.

Resistance

Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy.

Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated.

Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown.

Clinical Studies

Empiric Therapy in Febrile Neutropenic Patients

An open randomized trial compared the efficacy and safety of itraconazole (intravenous followed by oral solution) with amphotericin B for empiric therapy in 384 febrile, neutropenic patients with hematologic malignancies who had suspected fungal infections. Patients received either itraconazole (injection, 200 mg b.i.d. for 2 days followed by 200 mg once daily for up to 14 days, followed by oral solution, 200 mg b.i.d.) or amphotericin B (total daily dose of 0.7–1.0 mg/kg body weight). The longest treatment duration was 28 days. An outcome assignment of "success" required (a) patient survival with resolution of fever and neutropenia within 28 days of treatment, (b) absence of emergent fungal infections, (c) no discontinuation of therapy due to toxicity or lack of efficacy, and (d) treatment for three or more days. The success rate using an intent-to-treat analysis was 47% for the itraconazole group and 38% for the amphotericin B arm.

Overview of Efficacy (Intent-to-Treat Population)

Efficacy Parameters	Sporanox® N=179 (%)	Amphotericin B N=181 (%)
* Treatment duration ≤ 3 days (including patients who died within 3 days, withdrew because of adverse events or were deemed ineligible due to a confirmed pre-treatment infection).
Success	84 (47%)	68 (38%)
Unevaluable*	24 (13%)	44 (24%)
Failure	71 (40%)	69 (38%)
Reason for Failure
Intolerance after > 3 days of antifungal medication	12	37
Persistent fever	20	7
Change in antifungal medication due to fever	13	1
Emergent fungal infection	10	9
Documented bacterial or viral infection	7	8
Insufficient response	6	5
Deterioration of signs and symptoms	2	0
Death after > 3 days antifungal medication	1	2
Resolution of fever	131 (73%)	127 (70%)
Survival	161 (90%)	156 (86%)

Indications and Usage for Sporanox

Sporanox® (itraconazole) Injection/Oral Solution is indicated for empiric therapy of febrile neutropenic patients with suspected fungal infections. (NOTE: In a comparative trial, the overall response rate for itraconazole-treated subjects was higher than for amphotericin B-treated subjects. However, compared to amphotericin B-treated subjects, a larger number of itraconazole-treated subjects discontinued treatment due to persistent fever and a change in antifungal medication due to fever. Whereas, a larger number of amphotericin B-treated subjects discontinued due to drug intolerance. (See CLINICAL STUDIES section.)

Sporanox® (itraconazole) Injection is also indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients:

1. Blastomycosis, pulmonary and extrapulmonary;


2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; and


3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.

Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

(See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information).

Contraindications

Drug Interactions

Concomitant administration of Sporanox® (itraconazole) Capsules, Injection, or Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, pimozide, quinidine, dofetilide, triazolam and levacetylmethadol (levomethadyl) are contraindicated with Sporanox®. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with Sporanox®. Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with Sporanox®. (See BOX WARNING, and PRECAUTIONS: Drug Interactions.)

Sporanox® is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing Sporanox® to patients with hypersensitivity to other azoles.

Warnings

Sporanox® (itraconazole) Injection contains the excipient hydroxypropyl-β-cyclodextrin which produced pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these findings is unknown. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.)

Hepatic Effects

Sporanox® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be=discontinued and liver function testing performed. Continued Sporanox® use or reinstitution of treatment with Sporanox® is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.)

Cardiac Dysrhythmias

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with Sporanox® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with Sporanox® is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.)

Cardiac Disease

Sporanox® Injection should not be used in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of Sporanox® therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of Sporanox® Injection, monitor carefully and consider other treatment alternatives which may include discontinuation of Sporanox® Injection administration.

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of Sporanox® Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.

Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.)

Precautions

General

Rare cases of serious hepatotoxicity have been observed with Sporanox® treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with Sporanox® is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving Sporanox®. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction.

If neuropathy occurs that may be attributable to Sporanox® Injection, the treatment should be discontinued.

As severe renal impairment prolongs the elimination rate of hydroxypropyl-β-cyclodextrin, Sporanox® (itraconazole) Injection should not be used in patients with severe renal dysfunction (creatinine clearance < 30 mL/min). (See CLINICAL PHARMACOLOGY: Special Populations.)

Information for Patients

Sporanox® Injection contains the excipient hydroxypropyl-β-cyclodextrin which produced pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these findings is unknown. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.)

Drug Interactions

Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (See Table 1 below and the following drug class subheadings that follow):

1. Sporanox® may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with Sporanox®. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant Sporanox® therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.


2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. Sporanox® may not be effective in patients concomitantly taking Sporanox® and one of these drugs. Therefore, administration of these drugs with Sporanox® is not recommended.


3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take Sporanox® concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of Sporanox®.

Table 1 Selected Drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by Sporanox®*

* This list is not all-inclusive. † Contraindicated with Sporanox® based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.) ‡ For information on parenterally administered midazolam, see the Benzodiazepine paragraph below.
Drug plasma concentration increased by itraconazole
Antiarrhythmics	digoxin, dofetilide†, quinidine†, disopyramide
Anticonvulsants	carbamazepine
Antimycobacterials	rifabutin
Antineoplastics	busulfan, docetaxel, vinca alkaloids
Antipsychotics	pimozide†
Benzodiazepines	alprazolam, diazepam, midazolam,†,‡ triazolam†
Calcium Channel Blockers	dihydropyridines, verapamil
Gastrointestinal Motility Agents	cisapride†
HMG CoA-Reductase Inhibitors	atorvastatin, cerivastatin, lovastatin,† simvastatin†
Immunosuppressants	cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics	oral hypoglycemics
Protease Inhibitors	indinavir, ritonavir, saquinavir
Other	levacetylmethadol (levomethadyl), ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, trimetrexate, warfarin, cilostazol, eletriptan
Decrease plasma concentration of itraconazole
Anticonvulsants	carbamazepine, phenobarbital, phenytoin
Antimycobacterials	isoniazid, rifabutin, rifampin
Reverse Transcriptase Inhibitors	nevirapine
Increase plasma concentration of itraconazole
Macrolide Antibiotics	clarithromycin, erythromycin
Protease Inhibitors	indinavir, ritonavir

Antiarrhythmics

The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with Sporanox® may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of Sporanox® and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)

The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when Sporanox® and disopyramide are administered concomitantly.

Concomitant administration of digoxin and Sporanox® has led to increased plasma concentrations of digoxin.

Anticonvulsants

Reduced plasma concentrations of itraconazole were reported when Sporanox® was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of Sporanox® and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of Sporanox® and carbamazepine may inhibit the metabolism of carbamazepine.

Antimycobacterials

Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. Sporanox® may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of Sporanox® could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended.

Antineoplastics

Sporanox® may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids.

Antipsychotics

Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with Sporanox® could result in serious cardiovascular events. Therefore, concomitant administration of Sporanox® and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)

Benzodiazepines

Concomitant administration of Sporanox® and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of Sporanox® and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged.

Calcium Channel Blockers

Edema has been reported in patients concomitantly receiving Sporanox® and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary.

Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.)

Gastrointestinal Motility Agents

Coadministration of Sporanox® with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of Sporanox® with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)

HMG CoA-Reductase Inhibitors

Human pharmacokinetic data suggest that Sporanox® inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of Sporanox® with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS, and WARNINGS.)

Immunosuppressants

Concomitant administration of Sporanox® and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of Sporanox® and sirolimus could increase plasma concentrations of sirolimus.

Macrolide Antibiotics

Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC 0–∞ of itraconazole increased by 44% (90% CI: 119–175%) and 36% (90% Cl:108–171%), respectively.

Oral Hypoglycemic Agents

Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when Sporanox® and oral hypoglycemic agents are coadministered.

Polyenes

Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined.

Protease Inhibitors

Concomitant administration of Sporanox® and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of Sporanox® and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when Sporanox® and protease inhibitors must be given concomitantly.

Reverse Transcriptase Inhibitors

Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of Sporanox® and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with Sporanox® Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied.

Other

• Levacetylmethadol (levomethadyl) is known to prolong the QT interval and is metabolized by CYP3A4. Co-administration of levacetylmethadol with Sporanox® could result in serious cardiovascular events. Therefore, concomitant administration of Sporanox® and levacetylmethadol is contraindicated.


• Elevated concentrations of ergot alkaloids can cause ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) with Sporanox® is contraindicated.


• Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when Sporanox® and halofantrine are administered concomitantly.


• In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with Sporanox® may increase plasma concentrations of alfentanil.


• Human pharmacokinetic data suggest that concomitant administration of Sporanox® and buspirone results in significant increases in plasma concentrations of buspirone.


• Sporanox® may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone and methylprednisolone.


• In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole on trimetrexate metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of Sporanox® and trimetrexate may inhibit the metabolism of trimetrexate.


• Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with Sporanox®.


• Sporanox® enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10× the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1× MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25× MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant.

Hydroxypropyl-β-cyclodextrin (HP-β-CD), the solubilizing excipient used in Sporanox® Injection and Oral Solution, was found to produce pancreatic exocrine hyperplasia and neoplasia when administered orally to rats at doses of 500, 2000 or 5000 mg/kg/day for 25 months. Adenocarcinomas of the exocrine pancreas produced in the treated animals were not seen in the untreated group and are not reported in the historical controls. Development of these tumors may be related to a mitogenic action of cholecystokinin. This finding was not observed in the mouse carcinogenicity study at doses of 500, 2000 or 5000 mg/kg/day for 22–23 months; however, the clinical relevance of these findings is unknown. Based on body surface area comparisons, the exposure to humans of HP-β-CD at the recommended clinical dose of Sporanox® Oral Solution, is approximately equivalent to 1.7 times the exposure at the lowest dose in the rat study. The relevance of the findings with orally administered HP-β-CD to potential carcinogenic effects for Sporanox® Injection is uncertain.

Itraconazole produced no mutagenic effects when assayed in a DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats.

Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5× MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20× MRHD).

Pregnancy

Teratogenic Effects

Pregnancy Category C

Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40–160 mg/kg/day (5–20× MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10× MRHD). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.

There are no studies in pregnant women. Sporanox® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.

During post-marketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS, Post-marketing Experience.)

Nursing Mothers

Itraconazole is excreted in human milk; therefore, the expected benefits of Sporanox® therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.

Pediatric Use

The efficacy and safety of Sporanox® have not been established in pediatric patients. No pharmacokinetic data on Sporanox® Capsules or Injection are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse effects have been reported. Sporanox® Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26, ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported.

The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5× MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10× MRHD) over 1 year or 160 mg/kg/day (20× MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients.

Geriatric Use

Clinical studies of Sporanox® Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Adverse Reactions

Sporanox® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of Sporanox® use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: General andInformation for Patients.)

Adverse Events Reported in Trials in Patients with Sporanox® Injection

Adverse events considered at least possibly drug related are shown in Table 2 a