Levlite

levonorgestrel and ethinyl estradiol

Dosage Form: tablets

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

 

Rx only

Levlite Description

Each cycle of Levlite® 28 (levonorgestrel and ethinyl estradiol tablets, USP) consists of 21 pink active tablets each containing 0.100 mg levonorgestrel and 0.020 mg ethinyl estradiol; and seven white tablets—inert. The inactive ingredients are Calcium Carbonate USP, Corn Starch NF, Ferric Oxide/red/E 172 NF, Ferric Oxide/yellow/E 172 NF, Glycerin 85% Ph. Eur./DAB, Lactose Monohydrate NF, Magnesium Stearate NF, Montanglycol Wax (Wax E) DAB, Polyethylene glycol 6,000 NF, Povidone 25,000 USP, Povidone 700,000 USP, Pregelatinized Starch NF (Modified Starch), Sucrose NF, Talc USP and Titanium Dioxide, E 171 USP.

Levonorgestrel has a molecular weight of 312.4 and a molecular formula of C21H28O2. Ethinyl estradiol has a molecular weight of 296.4 and a molecular formula of C20H24O2. The structural formulas are as follows:

Levlite - Clinical Pharmacology

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

PHARMACOKINETICS

Absorption

No specific investigation of the absolute bioavailability of levonorgestrel and ethinyl estradiol of Levlite in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration 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 absolute bioavailability of ethinyl estradiol is about 40%.

After a single dose of three Levlite Tablets to 17 women under fasting conditions, the extents of absorption of levonorgestrel and ethinyl estradiol were 98.6% and 99.0%, respectively, relative to the same dose of the 2 drugs when given as a microcrystalline suspension in water. The effect of food on the bioavailability of Levlite Tablets following oral administration has not been evaluated.

The pharmacokinetics of levonorgestrel and ethinyl estradiol following daily administration of Levlite Tablets for 21 days per cycle for three cycles, were determined in 18 women. Estimates of the pharmacokinetic parameters of levonorgestrel and ethinyl estradiol following single and multiple dose administration of Levlite Tablets are summarized in Table I. Mean levonorgestrel and ethinyl estradiol levels after a single dose and on day 21 at steady state are shown in Figure I.

The pharmacokinetics of total levonorgestrel are non-linear due to an increase in binding to SHBG, which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol. Increased binding of levonorgestrel to SHBG leads to decreased clearance of levonorgestrel. Observed maximum levonorgestrel concentrations increased from day 1 to day 21 of the 1st and 3rd cycles by 66% and 83%, respectively.

FIGURE I Mean Levonorgestrel Concentrations in Serum after single dose and on Day 21 of Cycles 1 and 3

Mean Ethinyl Estradiol Concentrations in Serum after single dose and on Day 21 of Cycles 1 and 3

In calculating the mean concentration for ethinyl estradiol, any individual subject value below the quantifiable limit (i.e., 20 pg/mL) was converted to 0; and the 0 values were included for calculation of the mean concentration. Table I provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters.

TABLE I MEAN (SD) PHARMACOKINETIC PARAMETERS OF Levlite AFTER SINGLE DOSE AND AFTER MULTIPLE DOSING FOR 3 CYCLES

* Cmax = maximum concentration † tmax = time to maximum concentration ‡ AUC = area under the drug concentration curve from time 0 to infinity § CL/f = oral clearance ¶ Vz = volume of distribution # SHBG = sex hormone-binding globulin Þ AUC (0-24) = area under the drug concentration time curve from time 0 to 24 hours; this represents the area for one dosing interval at steady state.
Levonorgestrel
Day (cycle)	Cmax* ng/mL	tmax† h	AUC‡ ng•h/mL	CL/F§ mL/min/kg	Vz¶ L	SHBG# nmol/L
1	2.36 (0.79)	1.3 (0.4)	29.2 (10.0)	1.0 (0.3)	129 (46)	64.5 (22.0)
			AUC (0-24h)Þ ng•h/mL
21 (1)	4.04 (2.08)	1.0 (0.3)	43.8 (22.4)	0.73 (0.34)	106 (42)	94.7 (37.4)
21 (3)	4.53 (1.94)	1.0 (0.3)	49.5 (24.5)	0.65 (0.33)	96 (35)	107.4 (45.8)

* Cmax = maximum concentration † tmax = time to maximum concentration ‡ AUC (0-24) = area under the drug concentration time curve from time 0 to 24 hours; this represents the area for one dosing interval at steady state.
Ethinyl Estradiol
Day (cycle)	Cmax* pg/mL	tmax† h	AUC(0-24)‡ pg•h/mL
1	49.5 (13.4)	1.5 (0.4)	298 (215)
21 (1)	66.2 (29.5)	1.4 (0.4)	596 (494)
21 (3)	58.1 (19.3)	1.4 (0.3)	417 (289)

Distribution

Levonorgestrel in serum is primarily bound to SHBG. Protein binding values for levonorgestrel are provided in Table II. Ethinyl estradiol is about 97% bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.

TABLE II. Protein binding (mean ± SD) of levonorgestrel in pools of serum samples collected from 18 women after a single dose of Levlite, and following administration (once daily) over 3x21 days.

Parameter	Single Dose	Cycle 2	Cycle 4
% free	1.11 (0.27)	0.79 (0.22)	0.80 (0.23)
% SHBG-bound	64.5 (8.54)	75.6 (6.59)	74.7 (7.89)
% albumin-bound	34.4 (8.28)	23.6 (6.41)	24.5 (7.67)

Metabolism

Levonorgestrel

The most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17β-sulfate. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation in levonorgestrel concentrations among users.

Ethinyl estradiol

Cytochrome P450 enzymes (CYP3A4) in the liver are responsible for the 2-hydroxylation that is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion. Levels of Cytochrome P450 (CYP3A) vary widely among individuals and can explain the variation in the rates of ethinyl estradiol 2-hydroxylation. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.

Excretion

The elimination half-life for levonorgestrel after a single dose of Levlite® is 25.4 ± 9.7 hours. Levonorgestrel and its metabolites are primarily excreted in the urine. The elimination half-life of ethinyl estradiol has been reported to be between 15 and 25 hours.

SPECIAL POPULATIONS

Hepatic Insufficiency

No formal studies have evaluated the effect of hepatic disease on the disposition of Levlite. However, steroid hormones may be poorly metabolized in patients with impaired liver function.

Renal Insufficiency

No formal studies have evaluated the effect of renal disease on the disposition of Levlite.

Drug-Drug Interactions

Interactions between ethinyl estradiol and other drugs have been reported in the literature.

Interactions with Absorption. Diarrhea may increase gastrointestinal motility and reduce hormone absorption. Similarly, any drug which reduces gut transit time may reduce hormone concentrations in the blood.

Interactions with Metabolism

Gastrointestinal Wall

Sulfation of ethinyl estradiol has been shown to occur in the gastrointestinal wall. Therefore, drugs which act as competitive inhibitors for sulfation in the gastrointestinal wall may increase ethinyl estradiol bioavailability.

Hepatic metabolism

Interactions can occur with drugs that induce microsomal enzymes which can decrease ethinyl estradiol concentrations (e.g., rifampin, barbiturates, phenylbutazone, phenytoin, griseofulvin).

Interference with Enterohepatic Circulation

Some clinical reports suggest that enteroheptic circulation of estrogens may decrease when certain antibiotic agents are given, which may reduce ethinyl estradiol concentrations (e.g., ampicillin, tetracycline).

Interference in the Metabolism of Other Drugs

Ethinyl estradiol may interfere with the metabolism of other drugs by inhibiting hepatic microsomal enzymes or by inducing hepatic drug conjugation, particularly glucuronidation. Accordingly, plasma and tissue concentrations may either be increased or decreased, respectively (e.g., cyclosporin, theophylline).

Indications and Usage for Levlite

Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.

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

TABLE III. Percentage of women experiencing an unintended pregnancy during the first year of typical use and first year of perfect use of contraception and the percentage continuing use at the end of the first year. United States.

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.
* Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. † Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. ‡ Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. § The percentages 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. ¶ Foams, creams, gels, vaginal suppositories, vaginal film. # Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. Þ With spermicidal cream or jelly. ß Without spermicides.
	% of Women Experiencing an Accidental Pregnancy within the First Year of Use		% of Women Continuing Use at One Year*
Method (1)	Typical Use† (2)	Perfect Use‡ (3)	(4)
Chance §	85	85
Spermicides¶	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation method		3
Sympto-thermal#		2
Post Ovulation		1
Withdrawal	19	4
CapÞ
Parous women	40	26	42
Nulliparous women	20	9	56
Sponge
Parous women	40	20	42
Nulliparous women	20	9	56
DiaphragmÞ	20	6	56
Condomß
Female (Reality)	21	5	56
Male	14	3	61
Pill	5		71
progestin only		0.5
combined		0.1
IUD
Progesterone T	2	1.5	81
Copper T 380A	0.8	0.6	78
Lng 20	0.1	0.1	81
Depo Provera	0.3	0.3	70
Norplant and Norplant-2	0.05	0.05	88
Female sterilization	0.5	0.5	100
Male sterilization	0.15	0.10	100

Contraindications

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

• Thrombophlebitis or thromboembolic disorders


• A past history of deep-vein thrombophlebitis or thromboembolic disorders


• Cerebral-vascular or coronary-artery disease


• Known or suspected carcinoma of the breast


• 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


• Known or suspected pregnancy

Warnings

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

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as 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 based principally 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 formulations of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiologic studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among 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 epidemiologic methods.

THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS

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 infarctions 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 (Table IV) among women who use oral contraceptives.

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

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

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. ln 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"). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

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 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 the relative risk of post-operative 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 from 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 to six weeks after delivery in women who elect not to breast-feed.

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.

ln 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.

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 provides satisfactory results in the individual.

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. ln a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women aged 40 to 49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. ln 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.

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 V). 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 V ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY-CONTROL METHOD ACCORDING TO AGE

Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983.
* Deaths are birth related † Deaths are method related
Method of Control and Outcome	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 non­smoker†	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
lUD†	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

CARCINOMA OF THE REPRODUCTIVE ORGANS

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives. The overwhelming evidence in the literature suggests that use of oral contraceptives is not associated with an increase in the risk of developing breast cancer, regardless of the age and parity of first use or with most of the marketed brands and doses. The Cancer and Steroid Hormone (CASH) study also showed no latent effect on the risk of breast cancer for at least a decade following long-term use. A few studies have shown a slightly increased relative risk of developing breast cancer, although the methodology of these studies, which included differences in examination of users and nonusers and differences in age at start of use, has been questioned.

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia 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.

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

Livostin

levocabastine hydrochloride

Dosage Form: Ophthalmic Suspension

Livostin®

0.05% (levocabastine hydrochloride ophthalmic suspension)

Livostin Description

Livostin™ 0.05% (levocabastine hydrochloride ophthalmic suspension) is a selective histamine H1-receptor antagonist for topical ophthalmic use. Each mL contains 0.54 mg levocabastine hydrochloride equivalent to 0.5 mg levocabastine; 0.15 mg benzalkonium chloride; propylene glycol; polysorbate 80; dibasic sodium phosphate, anhydrous; monobasic sodium phosphate, monohydrate; disodium edetate; hydroxypropyl methylcellulose; and purified water. It has a pH of 6.0 to 8.0.

The chemical name for levocabastine hydrochloride is (–)-trans-1-[cis-4-Cyano-4- (p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecotic acid monohydrochloride, and is represented by the following chemical structure:

	● HCl

Livostin - Clinical Pharmacology

Levocabastine is a potent, selective histamine H1-antagonist.

Antigen challenge studies performed two and four hours after initial drug instillation indicated activity was maintained for at least two hours.

In an environmental study, Livostin™ 0.05% (levocabastine hydrochloride ophthalmic suspension) instilled four times daily was shown to be significantly more effective than its vehicle in reducing ocular itching associated with seasonal allergic conjunctivitis.

After instillation in the eye, levocabastine is systemically absorbed. However, the amount of systemically absorbed levocabastine after therapeutic ocular doses is low (mean plasma concentrations in the range of 1-2 ng/mL).

Indications and Usage for Livostin

Livostin™ 0.05% (levocabastine hydrochloride ophthalmic suspension) is indicated for the temporary relief of the signs and symptoms of seasonal allergic conjunctivitis.

Contraindications

This product is contraindicated in persons with known or suspected hypersensitivity to any of its components. It should not be used while soft contact lenses are being worn.

Warning

For topical use only. Not for injection.

Precautions

Information for Patients

SHAKE WELL BEFORE USING. To prevent contaminating the dropper tip and suspension, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when not in use. Do not use if the suspension has discolored. Store at controlled room temperature. Protect from freezing.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Levocabastine was not carcinogenic in male or female rats or in male mice when administered in the diet for up to 24 months. In female mice, levocabastine doses of 5,000 and 21,500 times the maximum recommended ocular human use level resulted in an increased incidence of pituitary gland adenoma and mammary gland adenocarcinoma possibly produced by increased prolactin levels. The clinical relevance of this finding is unknown with regard to the interspecies differences in prolactin physiology and the very low plasma concentrations of levocabastine following ocular administration.

Mutagenic potential was not demonstrated for levocabastine when tested in Ames’ Salmonella reversion test or in Escherichia coli, Drosophila melanogaster, a mouse Dominant Lethal Assay or in rat Micronucleus test.

In reproduction studies in rats, levocabastine showed no effects on fertility at oral doses of 20 mg/kg/day (8,300 times the maximum recommended human ocular dose).

PREGNANCY

Teratogenic Effects

Pregnancy Category C.

Levocabastine has been shown to be teratogenic (polydactyly) in rats when given in doses 16,500 times the maximum recommended human ocular dose. Teratogenicity (polydactyly, hydrocephaly, brachygnathia), embryotoxicity, and maternal toxicity were observed in rats at 66,000 times the maximum recommended ocular human dose. There are no adequate and well-controlled studies in pregnant women. Levocabastine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Based on determinations of levocabastine in breast milk after ophthalmic administration of the drug to one nursing woman, it was calculated that the daily dose of levocabastine in the infant was about 0.5 µg.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 have not been established.

Adverse Reactions

The most frequent adverse experiences reported with the use of Livostin™ 0.05% (levocabastine hydrochloride ophthalmic suspension) were mild, transient stinging and burning (29%) and headache (5%).

Other adverse experiences reported in approximately 1-3% of patients treated with Livostin™ were visual disturbances, dry mouth, fatigue, pharyngitis, eye pain/dryness, somnolence, red eyes, lacrimation/discharge, cough, nausea, rash/erythema, eyelid edema, and dyspnea.

Livostin Dosage and Administration

SHAKE WELL BEFORE USING. The usual dose is one drop instilled in affected eyes four times per day.

How is Livostin Supplied

Livostin™ 0.05% (levocabastine hydrochloride ophthalmic suspension), 2.5 mL, 5 mL, and 10 mL is provided in white, polyethylene dropper tip squeeze bottles.

Keep tightly closed when not in use.

Do not use if the suspension has discolored.

Store at controlled room temperature 15°to 30°C (59° to 86°F).

Protect from freezing.

NDC 58768-610-10 (10.0 mL)

NDC 58768-610-05 (5.0 mL)

NDC 58768-610-99 (2.5 mL)

Rx Only

Levocabastine hydrochloride is an original product of Janssen Pharmaceutica Inc.

Mfd. by OMJ Pharmaceuticals, Inc.,

San Germán, P.R., 00683 for:

Novartis Ophthalmics, Duluth, GA 30097

5035-E

Livostin  levocabastine hydrochloride  suspension

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 58768-610 Route of Administration OPHTHALMIC DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength levocabastine hydrochloride (levocabastine) Active 0.5 MILLIGRAM  In 1 MILLILITER benzalkonium chloride Inactive 0.15 MILLIGRAM  In 1 MILLILITER dibasic sodium phosphate, anhydrous Inactive   disodium edetate Inactive   hydroxypropyl methylcellulose Inactive   monobasic sodium phosphate, monohydrate Inactive   polysorbate 80 Inactive   propylene glycol Inactive   water Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 58768-610-05 5 mL (MILLILITER) In 1 BOTTLE, DROPPER None 2 58768-610-10 10 mL (MILLILITER) In 1 BOTTLE, DROPPER None 3 58768-610-99 2.5 mL (MILLILITER) In 1 BOTTLE, DROPPER None

Revised: 01/2006Novartis Ophthalmics

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• Conjunctivitis, Allergic

Catacrom Sodium Cromoglicate 2% Preservative Free Unit Dose Eye Drops

Catacrom 2 % w/v Eye Drops, solution

Sodium Cromoglicate 2% w/v (20mg/ml) Eye Drops BP without preservative (unit dose).

Read all of this leaflet carefully because it contains important information for you.

For brevity, this medicine will be referred to as Catacrom Eye Drops throughout this leaflet.

Catacrom eye drops are available without prescription but you still need to take care to get the best results from them.

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


• Ask your pharmacist if you need more information or advice.


• You must contact a doctor if your symptoms worsen or do not improve after a few days.


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

In this leaflet:

1. What Catacrom Eye Drops are and what they are used for

2. Before you use Catacrom Eye Drops

3. How to use Catacrom Eye Drops

4. Possible side effects

5. How to store Catacrom Eye Drops

6. Further information

What Catacrom Eye Drops are and what they are used for

Catacrom Eye Drops are for the relief and treatment of allergic red, watery, itchy and puffy eyes caused by hayfever, house mites, and other causes of allergy such as pet hairs. Eye allergy can happen when sensitive eyes are exposed to these causes of allergy.

Catacrom Eye Drops is a medicine which affects cells called mast cells. It prevents them from releasing chemical substances which cause symptoms such as the redness, watering, itching and puffiness of allergic reactions.

These eye drops can be used by wearers of rigid or gas permeable contact lenses and can be used by people who are sensitive to preservatives in other kinds of eye drops.

Before you use Catacrom Eye Drops

Do not use Catacrom Eye Drops:

• if you know that you are allergic to the active ingredient, Sodium Cromoglicate or any of the other ingredients of Catacrom Eye Drops (see section 6 of this leaflet).

Take special care with Catacrom Eye Drops:

Before using these eye drops, you must be sure that your eye irritation is the result of allergy (or have been previously diagnosed by your doctor as suffering from allergy).

You can be confident that you have allergic eyes if:

• both eyes are affected


• you have a blocked or runny nose as well


• your eyesight is not affected

but if:

• you have no nose symptoms


• only one eye is affected


• your sight is affected

you cannot be sure that you are suffering from allergic eyes and should consult your doctor before you use these drops.

• If you have any questions concerning the use of these eye drops in a child, or are unsure whether the child has allergic eyes, you should seek advice from your doctor or pharmacist.


• If you have any questions about using these eye drops with other eye treatments, speak to your doctor or pharmacist.

Taking other medicines

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

Please let the doctor know if you are pregnant, think you might be pregnant, are planning to become pregnant or are breast-feeding.

Your doctor may prefer a different treatment to be given under these circumstances.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

If there are changes to your vision after using these eye drops, wait until you can see clearly before driving or using machines.

How to use Catacrom Eye Drops

Catacrom Eye Drops are for use in the eye only.

Usual dose

Catacrom Eye Drops are suitable for use in adults, the elderly and children.

The drops are in single dose units. Put one or two drops into each eye four times a day, or as directed by your doctor. Avoid touching the eye with the dropper.

Wash your hands before and after you use these eye drops.

Steps for Using Catacrom Eye Drops

1. Break off one unit dose container from the strip.
2. Open the unit dose container by bending/twisting the tab (Figure 1).

3. Tilt your head backwards.
4. Gently pull down the lower lid to form a pouch (Figure 2).

5. With the unit dose in the other hand, put one drop inside the pouch by gently squeezing the container. Try not to touch anything with the tip (Figure 3).

6. Close the eye for about 30 seconds and at the same time gently press a finger against the corner of the closed eye, nearest the nose. (Figure 4).

7. Some drops may roll down your face. This is normal. The eye holds less than one drop. Wipe away the excess with a clean tissue. If the drop of medication is not retained for any reason, another drop should be dropped into the eye pouch.
8. If you use more than one type of eye drop, wait five minutes before putting in the next one. This prevents the first drop from being washed away.
9. Repeat instructions 3-8 for the other eye.

If you use more Catacrom Eye Drops than you should:

There are no known effects of taking too much of this medicine.

If you are concerned, please speak to your doctor or pharmacist.

If you forget to use your Catacrom Eye Drops:

If you forget to use this medicine, use it as soon as you remember.

Possible side effects

Like all medicines, Catacrom Eye Drops can cause side effects, although not everybody gets them. Some people find that their eyes can become irritated or sting for a short while after taking the eye drops.

If the stinging lasts a long time or is severe you should talk to your doctor or pharmacist. Rarely, other symptoms of eye irritation have occurred.

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

How to store Catacrom Eye Drops

Keep out of the reach and sight of children.

Once opened, use the unit dose straight away and then throw away the container.

Do not use Catacrom Eye Drops after the expiry date which is stated on the carton, sachet and unit dose.

Do not store above 25°C.

Store in the original package. After opening sachet, use contents within 28 days.

Further information

What Catacrom Eye Drops look like and contents of the pack

The active ingredient of the eye drops is Sodium Cromoglicate 2%w/v (20mg/ml).

Each unit dose container holds 0.3ml Catacrom 2% Eye Drops without preservative and there are 10, 12, 18, 20, 24, 30 or 90 single dose containers in each carton.

Not all pack sizes may be marketed.

Each individual single-dose unit contains 6mg of Sodium Cromoglicate in 0.3ml of solution.

Catacrom Eye Drops also contain sodium chloride and purified water.

Marketing Authorisation Holder and Manufacturer

Catacrom Eye Drops are manufactured by:

Laboratoire Unither

ZI Longpré

10 rue André Durouchez

80052 AMIENS cedex2

France

or

Laboratoire Unither

Route de Saint Lô

ZI de la Guérie

50200 Coutances

France

The marketing authorisation holder is

Moorfields Eye Hospital NHS Foundation Trust

Trading as Moorfields Pharmaceuticals

34 Nile Street

London

N1 7TP

UK

Moorfields Pharmaceuticals and CATACROM are trade marks.

This leaflet was last approved in July 2009.

Letrac

Letrac may be available in the countries listed below.

Ingredient matches for Letrac

Loxoprofen

Loxoprofen sodium salt (a derivative of Loxoprofen) is reported as an ingredient of Letrac in the following countries:

• Japan

International Drug Name Search

Teraside

Teraside may be available in the countries listed below.

Ingredient matches for Teraside

Thiocolchicoside

Thiocolchicoside is reported as an ingredient of Teraside in the following countries:

• Italy

International Drug Name Search

Chloroprocaine

Dosage Form: injection, solution
Chloroprocaine

Hydrochloride

Injection, USP

Rx only

Chloroprocaine Description

Chloroprocaine Hydrochloride Injection, USP is a sterile, nonpyrogenic, isotonic, isobaric solution. Each milliliter of 2% solution contains 20 mg of Chloroprocaine hydrochloride; 4 mg sodium chloride; with 1.8 mg sodium metabisulfite added in water for injection. Each milliliter of 3% solution contains 30 mg of Chloroprocaine hydrochloride; 2.1 mg sodium chloride; with 1.8 mg sodium metabisulfite added in water for injection. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. It contains no bacteriostat, antimicrobial agent or added buffer. Discard unused portion.

It is intended for production of local anesthesia by nerve block, infiltration, caudal or other epidural blocks.

Chloroprocaine Hydrochloride Injection has a pH of 3.1 (2.7 to 4.0).

Sodium Chloride, USP is chemically designated NaCl, a white crystalline compound freely soluble in water.

Chloroprocaine Hydrochloride Injection is identified chemically as 2-(diethylamino) ethyl 4‑amino-2 chlorobenzoate monohydrochloride. Its molecular Formula is: C13H19ClN2O2•HCl and the molecular weight is 307.22. It has the following structural formula:

Chloroprocaine - Clinical Pharmacology

Chloroprocaine, like other local anesthetics, blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest. In addition, with toxic blood concentrations myocardial contractility may be depressed and peripheral vasodilation may occur, leading to decreased cardiac output and arterial blood pressure.

Following systemic absorption, toxic blood concentrations of local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation may be manifested as restlessness, tremors and shivering, which may progress to convulsions. Depression and coma may occur, possibly progressing ultimately to respiratory arrest.

However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior stage of central nervous system stimulation.

Pharmacokinetics

The rate of systemic absorption of local anesthetic drugs is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic injection. Epinephrine usually reduces the rate of absorption and plasma concentration of local anesthetics and is sometimes added to local anesthetic injections in order to prolong the duration of action.

The onset of action with Chloroprocaine is rapid (usually within 6 to 12 minutes), and the duration of anesthesia, depending upon the amount used and the route of administration, may be up to 60 minutes.

Local anesthetics appear to cross the placenta by passive diffusion. However, the rate and degree of diffusion varies considerably among the different drugs as governed by: (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, since only the free, unbound drug is available for placental transfer. Thus, drugs with the highest protein binding capacity may have the lowest fetal/maternal ratios. The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.

Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues with high concentrations found in highly perfused organs such as the liver, lungs, heart and brain.

Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of administration, and the age of the patient. The in vitro plasma half-life of Chloroprocaine in adults is 21 ± 2 seconds for males and 25 ± 1 seconds for females. The in vitro plasma half-life in neonates is 43 ± 2 seconds.

Chloroprocaine is rapidly metabolized in plasma by hydrolysis of the ester linkage by pseudocholinesterase. The hydrolysis of Chloroprocaine results in the production of ß-diethyl-aminoethanol and 2-chloro-4-aminobenzoic acid, which inhibits the action of the sulfonamides (see PRECAUTIONS).

The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH.

Indications and Usage for Chloroprocaine

Chloroprocaine Hydrochloride Injection in single-dose containers without preservative and without EDTA, is indicated for the production of local anesthesia by infiltration, peripheral and central nerve block, including lumbar and caudal epidural blocks.

Chloroprocaine Hydrochloride Injection is not to be used for subarachnoid administration.

Contraindications

Chloroprocaine Hydrochloride Injection is contraindicated in patients hypersensitive (allergic) to drugs of the PABA ester group.

Lumbar and caudal epidural anesthesia should be used with extreme caution in persons with the following conditions: existing neurological disease, spinal deformities, septicemia and severe hypertension.

Warnings

LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER ENSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES (See also ADVERSE REACTIONS and PRECAUTIONS.) DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH.

Chloroprocaine Hydrochloride Injection, contains no preservative; discard unused injection remaining in vial after initial use.

Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some  required arthroplasty or shoulder replacement.

Vasopressors should not be used in the presence of ergot-type oxytocic drugs, since a severe persistent hypertension may occur.

To avoid intravascular injection, aspiration should be performed before the anesthetic solution is injected. The needle must be repositioned until no blood return can be elicited. However, the absence of blood in the syringe does not guarantee that intravascular injection has been avoided.

Mixtures of local anesthetics are sometimes employed to compensate for the slower onset of one drug and the shorter duration of action of the second drug. Experiments in primates suggest that toxicity is probably additive when mixtures of local anesthetics are employed, but some experiments in rodents suggest synergism. Caution regarding toxic equivalence should be exercised when mixtures of local anesthetics are employed.

Chloroprocaine Hydrochloride Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Precautions

General:

The safety and effective use of Chloroprocaine depend on proper dosage, correct technique, adequate precautions and readiness for emergencies. Resuscitative equipment, oxygen and other resuscitative drugs should be available for immediate use. (See WARNINGS and ADVERSE REACTIONS). The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. During the administration of epidural anesthesia, it is recommended that a test dose be administered (3 mL of 3% or 5 mL of 2% Chloroprocaine Hydrochloride Injection) initially and that the patient be monitored for central nervous system toxicity and cardiovascular toxicity, as well as for signs of unintended intrathecal administration, before proceeding. When clinical conditions permit, consideration should be given to employing a Chloroprocaine solution that contains epinephrine for the test dose because circulatory changes characteristic of epinephrine may also serve as a warning sign of unintended intravascular injection. An intravascular injection is still possible even if aspirations for blood are negative. With the use of continuous catheter techniques, it is recommended that a fraction of each supplemental dose be administered as a test dose in order to verify proper location of the catheter.

Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the physical condition of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physical status. Local anesthetics should also be used with caution in patients with hypotension or heart block.

Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be accomplished after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression or drowsiness may be early warning signs of central nervous system toxicity.

Local anesthetic injections containing a vasoconstrictor should be used cautiously and in carefully circumscribed quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result.

Since ester-type local anesthetics are hydrolyzed by plasma cholinesterase produced by the liver, Chloroprocaine should be used cautiously in patients with hepatic disease.

Local anesthetics should also be used with caution in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs.

Use in Ophthalmic Surgery:

When local anesthetic injections are employed for retrobulbar block, lack of corneal sensation should not be relied upon to determine whether or not the patient is ready for surgery. This is because complete lack of corneal sensation usually precedes clinically acceptable external ocular muscle akinesia.

Information for Patients:

When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of epidural anesthesia.

Clinically Significant Drug Interactions:

The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors, tricyclic antidepressants or phenothiazines may produce severe prolonged hypotension or hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.

Concurrent administration of vasopressor drugs (for the treatment of hypotension related to obstetric blocks) and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.

The para-aminobenzoic acid metabolite of Chloroprocaine inhibits the action of sulfonamides. Therefore, Chloroprocaine should not be used in any condition in which a sulfonamide drug is being employed.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

Long-term studies in animals to evaluate carcinogenic potential and reproduction studies to evaluate mutagenesis or impairment of fertility have not been conducted with Chloroprocaine.

Pregnancy Category C:

Animal reproduction studies have not been conducted with Chloroprocaine. It is also not known whether Chloroprocaine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Chloroprocaine should be given to a pregnant woman only if clearly needed. This does not preclude the use of Chloroprocaine at term for the production of obstetrical anesthesia.

Labor and Delivery:

Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity.

(See CLINICAL PHARMACOLOGY–Pharmacokinetics).

The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function.

Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. However, epidural anesthesia has also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance.

The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown.

Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic injection have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth which correlates with high local anesthetic serum levels and usually manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication.

Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of each drug should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a 5-minute interval between sides.

There are no data concerning use of Chloroprocaine for obstetrical paracervical block when toxemia of pregnancy is present or when fetal distress or prematurity is anticipated in advance of the block; such use is, therefore, not recommended. The following information should be considered by clinicians who select Chloroprocaine for obstetrical paracervical block anesthesia: 1) Fetal bradycardia (generally a heart rate of less than 120 per minute for more than 2 minutes) has been noted by electronic monitoring in about 5 to 10 percent of the cases (various studies) where initial total doses of 120 mg to 400 mg of Chloroprocaine were employed. The incidence of bradycardia, within this dose range, might not be dose related. 2) Fetal acidosis has not been demonstrated by blood gas monitoring around the time of bradycardia or afterwards. These data are limited and generally restricted to nontoxemic cases where fetal distress or prematurity was not anticipated in advance of the block. 3) No intact Chloroprocaine and only trace quantities of a hydrolysis product, 2-chloro-4-aminobenzoic acid, have been demonstrated in umbilical cord arterial or venous plasma following properly administered paracervical block with Chloroprocaine. 4) The role of drug factors and non-drug factors associated with fetal bradycardia following paracervical block are unexplained at this time.

Nursing Mothers:

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Chloroprocaine is administered to a nursing woman.

Pediatric Use:

Guidelines for the administration of Chloroprocaine Hydrochloride Injection to children are presented in DOSAGE AND ADMINISTRATION.

Geriatric Use:

Clinical studies of Chloroprocaine Hydrochloride Injection did not include sufficient number of subjects 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 usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse Reactions

Systemic:

The most commonly encountered acute adverse experiences that demand immediate countermeasures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose-related and may result from rapid absorption from the injection site, diminished tolerance or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea (“Total Spinal”). Factors influencing plasma protein binding, such as acidosis, systemic diseases that alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. Plasma cholinesterase deficiency may also account for diminished tolerance to ester-type local anesthetics.

Central Nervous System Reactions:

These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest.

The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1 percent of local anesthetic administrations.

Cardiovascular System Reactions:

High doses, or unintended intravascular injection, may lead to high plasma levels and related depression of the myocardium, hypotension, bradycardia, ventricular arrhythmias and, possibly, cardiac arrest.

Allergic:

Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic. These reactions are characterized by signs such as urticaria, pruritis, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid-type symptomatology (including severe hypotension). Cross sensitivity among members of the ester-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established.

Neurologic:

In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter may occur (see PRECAUTIONS). Subsequent adverse observations may depend partially on the amount of drug administered intrathecally. These observations may include spinal block of varying magnitude (including total spinal block), hypotension secondary to spinal block, loss of bladder and bowel control, and loss of perineal sensation and sexual function. Arachnoiditis, persistent motor, sensory and/or autonomic (sphincter control) deficit of some lower spinal segments with slow recovery (several months) or incomplete recovery have been reported in rare instances. (See DOSAGE AND ADMINISTRATION discussion of Caudal and Lumbar Epidural Block). Backache and headache have also been noted following lumbar epidural or caudal block.

Overdosage

Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution (see ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS).

In mice, the intravenous LD50 of Chloroprocaine HCl is 97 mg/kg and the subcutaneous LD50 of Chloroprocaine HCl is 950 mg/kg.

Management of Local Anesthetic Emergencies:

The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered.

The first step in the management of convulsions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously; the clinician should be familiar, prior to the use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine to enhance myocardial contractile force).

If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Recovery has been reported after prolonged resuscitative efforts.

Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated.

Chloroprocaine Dosage and Administration

Chloroprocaine may be administered as a single injection or continuously through an indwelling catheter. As with all local anesthetics, the dose administered varies with the anesthetic procedure, the vascularity of the tissues, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, and the physical condition of the patient. The smallest dose and concentration required to produce the desired result should be used. Dosage should be reduced for children, elderly and debilitated patients and patients with cardiac and/or liver disease. The maximum single recommended doses of Chloroprocaine in adults are: without epinephrine, 11 mg/kg, not to exceed a maximum total dose of 800 mg; with epinephrine (1:200,000), 14 mg/kg, not to exceed a maximum total dose of 1000 mg. For specific techniques and procedures, refer to standard textbooks.

There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Chloroprocaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

Caudal and Lumbar Epidural Block:

In order to guard against adverse experiences sometimes noted following unintended penetration of the subarachnoid space, the following procedure modifications are recommended:

1. Use an adequate test dose (3 mL of 3% or 5 mL of 2% Chloroprocaine Hydrochloride Injection) prior to induction of complete block. This test dose should be repeated if the patient is moved in such a fashion as to have displaced the epidural catheter. Allow adequate time for onset of anesthesia following administration of each test dose. 2. Avoid the rapid injection of a large volume of local anesthetic injection through the catheter. Consider fractional doses, when feasible. 3. In the event of the known injection of a large volume of local anesthetic injection into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

As a guide for some routine procedures, suggested doses are given below:

 1. Infiltration and Peripheral Nerve Block: Chloroprocaine Hydrochloride Injection

Anesthetic Procedure	Solution Concentration %	Volume (mL)	Total Dose (mg)
Mandibular	2	2 – 3	40 – 60
Infraorbital	2	0.5 – 1	10 – 20
Brachial plexus	2	30 – 40	600 – 800
Digital (without epinephrine)	1	3 – 4	30 – 40
Pudendal	2	10 each side	400
Paracervical	1	3 per each of 4 sites	up to 120
(see also PRECAUTIONS)

    2.  Caudal and Lumbar Epidural Block: For caudal anesthesia, the initial dose is 15 to 25 mL of a 2% or 3% solution. Repeated doses may be given at 40 to 60 minute intervals.

For lumbar epidural anesthesia, 2 to 2.5 mL per segment of a 2% or 3% solution can be used. The usual total volume of Chloroprocaine Hydrochloride Injection is from 15 to 25 mL. Repeated doses 2 to 6 mL less than the original dose may be given at 40 to 50 minute intervals.

The above dosages are recommended as a guide for use in the average adult. Maximum dosages of all local anesthetics must be individualized after evaluating the size and physical condition of the patient and the rate of systemic absorption from a particular injection site.

Pediatric Dosage:

It is difficult to recommend a maximum dose of any drug for children, since this varies as a function of age and weight. For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is determined by the child’s age and weight and should not exceed 11 mg/kg (5 mg/lb). For example, in a child of 5 years weighing 50 lbs (23 kg), the dose of Chloroprocaine HCl without epinephrine would be 250 mg. Concentrations of 0.5 – 1% are suggested for infiltration and 1 – 1.5% for nerve block. In order to guard against systemic toxicity, the lowest effective concentration and lowest effective dose should be used at all times. Some of the lower concentrations for use in infants and smaller children are not available in pre-packaged containers; it will be necessary to dilute available concentrations with the amount of 0.9% sodium chloride injection necessary to obtain the required final concentration of Chloroprocaine injection.

Preparation of Epinephrine Injections:

To prepare a 1:200,000 epinephrine-Chloroprocaine HCl injection, add 0.15 mL of 1 to 1000 Epinephrine Injection to 30 mL of Chloroprocaine Hydrochloride Injection.

Chloroprocaine is incompatible with caustic alkalis and their carbonates, soaps, silver salts, iodine and iodides.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever injection and container permit. As with other anesthetics having a free aromatic amino group, Chloroprocaine Hydrochloride Injection is slightly photosensitive and may become discolored after prolonged exposure to light. It is recommended that this product be stored in the original outer containers, protected from direct sunlight. Discolored injection should not be administered. If exposed to low temperatures, Chloroprocaine Hydrochloride Injection may deposit crystals of Chloroprocaine HCl which will redissolve with shaking when returned to room temperature. The product should not be used if it contains undissolved (e.g., particulate) material.

How is Chloroprocaine Supplied

Chloroprocaine Hydrochloride Injection, USP is supplied in single-dose containers as follows:

Concentration	NDC No.	Container	Container Size
2%	0409-4169-01	Vial	30 mL
3%	0409-4170-01	Vial	30 mL

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]

Revised: March, 2010

Printed in USA                            EN-2433

Hospira, Inc., Lake Forest, IL 60045 USA

RL-1392

 

RL-1393

 

Chloroprocaine HYDROCHLORIDE  Chloroprocaine hydrochloride  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0409-4169 Route of Administration EPIDURAL, INFILTRATION DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Chloroprocaine HYDROCHLORIDE (Chloroprocaine) Chloroprocaine HYDROCHLORIDE 20 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE 4 mg  in 1 mL SODIUM METABISULFITE 1.8 mg  in 1 mL WATER   HYDROCHLORIC ACID   SODIUM HYDROXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0409-4169-01 25 VIAL In 1 TRAY contains a VIAL, SINGLE-DOSE 1 30 mL In 1 VIAL, SINGLE-DOSE This package is contained within the TRAY (0409-4169-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA087447	03/24/2010

Chloroprocaine HYDROCHLORIDE  Chloroprocaine hydrochloride  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0409-4170 Route of Administration INFILTRATION, EPIDURAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Chloroprocaine HYDROCHLORIDE (Chloroprocaine) Chloroprocaine HYDROCHLORIDE 30 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE 2.1 mg  in 1 mL SODIUM METABISULFITE 1.8 mg  in 1 mL WATER   HYDROCHLORIC ACID   SODIUM HYDROXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0409-4170-01 25 VIAL In 1 TRAY contains a VIAL, SINGLE-DOSE 1 30 mL In 1 VIAL, SINGLE-DOSE This package is contained within the TRAY (0409-4170-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA087446	03/24/2010

Labeler - Hospira, Inc. (141588017)

Revised: 08/2011Hospira, Inc.

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