Boots Pharmacy Thrush 150mg Capsule

1. Name Of The Medicinal Product

Fluconazole 150mg capsules

Boots Thrush 150mg Capsule (Fluconazole)

2. Qualitative And Quantitative Composition

Each capsule contains Fluconazole 150mg

For excipients, see 6.1

3. Pharmaceutical Form

Capsule for oral administration

White to off white powder filled in Blue/Blue coloured hard gelatin capsules of size '1'.

4. Clinical Particulars

4.1 Therapeutic Indications

Fluconazole 150 is indicated for the treatment of the following conditions:

Vaginal candidiasis, acute or recurrent or candidal balanitis associated with vaginal candidiasis.

4.2 Posology And Method Of Administration

Route of administration

Oral.

Fluconazole 150mg capsules should be swallowed whole

In adults aged 16 - 60 years

Vaginal candidiasis or candidal balanitis - 150mg single oral dose.

In children - Not recommended in children aged under 16 years.

Use in elderly - Not recommended in patients aged over 60 years.

Use in renal impairment Fluconazole is excreted predominantly in the urine as unchanged drug. No adjustments in single dose therapy are required.

4.3 Contraindications

Fluconazole 150 should not be used in patients with known hypersensitivity to fluconazole or to related azole compounds or any other ingredient in the formulation.

Fluconazole should not be co-administered with cisapride or terfenadine which are known to both prolong the QT-interval and are metabolized by CYP3A4 ( See “Interactions with medicinal products and other forms of interaction”).

4.4 Special Warnings And Precautions For Use

Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patients has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy. Fluconazole should not be used again if clinical signs or symptoms consistent with liver disease develop that may be attributable to fluconazole.

Rarely patients have developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many drugs. Fluconazole should not be used again, if a rash develops, which is considered attributable to fluconazole.

In rare cases, as with other azoles, anaphylaxis has been reported.

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Although the association of fluconazole and QT-prolongation has not been fully established, fluconazole should be used with caution in patients with potentially proarrythmic conditions such as:

Congenital or documented acquired QT prolongation

Cardiomyopathy, in particular when heart failure is present

Sinus bradycardia

Existing symptomatic arrythmias

Concomitant medication not metabolized by CY34A but known to prolong QT interval.

Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalaemia

(See Section 4.5 Interactions with other medicinal products and other forms of interaction)

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The product intended for pharmacy availability without prescription will carry a leaflet which will advise the patient:

Do not use Fluconazole 150mg without first consulting your doctor:

If you are under 16 or over 60 years of age.

If you have an intolerance to lactose.

If you are taking any medicine other than the Pill.

If you have had thrush more than twice in the last six months.

If you suffer from heart disease including heart rhythm problems.

If you have low potassium, magnesium or calcium in your blood (ask your doctor if you are not sure).

If you have any disease or illness affecting your liver or have had unexplained jaundice.

If you suffer from any other chronic disease or illness.

If you or your partner have had exposure to a sexually transmitted disease.

If you are unsure about the cause of your symptoms.

• Women Only:

If you are pregnant, suspect you might be pregnant or are breast-feeding.

If you have any abnormal or irregular vaginal bleeding or a blood-stained discharge.

If you have vulval or vaginal sores, ulcers or blisters.

If you are experiencing lower abdominal pain or burning on passing urine.

• Men Only:

If your sexual partner does not have vaginal thrush

If you have penile sores, ulcers or blisters

If you have an abnormal penile discharge (leakage)

If your penis has started to smell

If you have pain on passing urine.

The product should never be used again if the patient experiences a rash or anaphylaxis follows the use of the drug.

Recurrent use (men and women): Patients should be advised to consult their physician if the symptoms have not been relieved within one week of taking Fluconaole 150mg. Fluconazole 150mg can be used if the candidal infection returns after 7 days. However, if the candidal infection recurs more than twice within six months, patients should be advised to consult their physician.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The following drug interactions relate to the use of multiple-dose fluconazole, and the relevance to single-dose Fluconazole 150 has not yet been established. Patients on other medications should consult their doctor or pharmacist before starting fluconazole.

Rifampicin Concomitant administration of Fluconazole and rifampicin resulted in a 25% decrease in the AUC and 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase in the Fluconazole dose should be considered.

Hydrochlorothiazide In a kinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving Fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the Fluconazole dose regimen in subjects receiving concomitant diuretics, although the prescriber should bear it in mind.

Anticoagulants In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, haematuria and melaena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Prothrombin time in patients receiving coumarin-type anticoagulants should be carefully monitored.

Benzodiazepines (Short Acting) Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage and the patients should be appropriately monitored.

Sulphonylureas Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulphonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulphonylureas may be co-administered to diabetic patients, but the possibility of a hypoglycaemic episode should be borne in mind.

Phenytoin Concomitant administration of fluconazole and phenytoin may increase the levels of phenytoin to a clinically significant degree. If it is necessary to administer both drugs concomitantly, phenytoin levels should be monitored and the phenytoin dose adjusted to maintain therapeutic levels.

Oral contraceptives Three kinetic studies with combined oral contraceptives have been performed using multiple doses of fluconazole. There were no relevant effects on either hormone level in the 50mg fluconazole study, while at 200mg daily the AUCs of ethinyloestradiol and levonorgestrel were increased 40% and 24% respectively.

In a 300 mg once weekly fluconazole study, the AUCs of ethinyl estradiol and norethindrone were increased by 24% and 13%, respectively. Thus single dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.

Ciclosporin A kinetic study in renal transplant patients found fluconazole 200mg daily to slowly increase ciclosporin concentrations. However, in another multiple dose study with 100mg daily, fluconazole did not affect ciclosporin levels in patients with bone marrow transplants. Ciclosporin plasma concentration monitoring in patients receiving fluconazole is recommended.

Theophylline In a placebo controlled interaction study, the administration of fluconazole 200mg for 14 days resulted in an 18% decrease in the mean plasma clearance of theophylline. Patients who are receiving high doses of theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole, and the therapy modified appropriately if signs of toxicity develop.

Terfenadine Because of the occurrence of serious dysrhythmias secondary to prolongation of the QTc interval in patients receiving other azole antifungals in conjunction with terfenadine, interactions studies have been performed. One study at a 200mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400mg and 800mg daily dose of fluconazole demonstrated that fluconazole taken in multiple doses of 400mg per day or greater significantly increased plasma levels of terfenadine when taken concomitantly. There have been spontaneously reported cases of palpitations, tachycardia, dizziness, and chest pain in patients taking concomitant fluconazole and terfenadine where the relationship of the reported adverse events to drug therapy or underlying medical conditions was not clear. Because of the potential seriousness of such an interaction, it is recommended that terfenadine not be taken in combination with fluconazole. (See “Contra-indications”).

Cisapride There have been reports of cardiac events including torsades de pointes in patients to whom fluconazole and cisapride were co-administered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval.

Co-administration of cisapride is contra-indicated in patients receiving fluconazole. (See “Contra-indications”).

Zidovudine The AUC of zidovudine can be significantly increased during co-administration with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.

Rifabutin There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. There have been reports of uveitis in patients to whom fluconazole and rifabutin were co-administered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored.

Tacrolimus There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were co-administered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored.

The use of fluconazole in patients concurrently taking astemizole or other drugs metabolised by the cytochrome P450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when co-administering fluconazole. This is particularly important for drugs known to prolong QT interval. Patients should be carefully monitored.

Interaction studies have shown that when oral fluconazole is co-administered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs.

Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but that such interactions may occur.

4.6 Pregnancy And Lactation

Use during pregnancy There are no adequate and well controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis. The relationship between fluconazole and these events is unclear (see section 5.3 Preclinical safety data). Accordingly, Fluconazole 150 should not be used in pregnancy, or in women of childbearing potential unless adequate contraception is employed.

Use during lactation Fluconazole is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.

4.7 Effects On Ability To Drive And Use Machines

Experience with Fluconazole indicates that therapy is unlikely to impair a patient's ability to drive or use machinery.

4.8 Undesirable Effects

Fluconazole 150mg is generally well tolerated.

Nervous System Disorders: Headache, dizziness, seizures, taste perversion.

Gastrointestinal disorders: Abdominal pain, diarrhoea, flatulence, nausea, dyspepsia, vomiting.

Hepatobiliary Disorders Hepatic failure, hepatitis, hepatocellular necrosis, jaundice (see section 4.4 Special warnings and precautions for use).

Skin and Subcutaneous Tissue Disorders :Rash, Alopecia, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrosis.

Blood and Lymphatic System Disorders: Leukopenia including neutropenia and agranulocytosis, thrombocytopenia.

Immune System Disorders:

Anaphylaxis(including angioedema, face oedema, pruritus, urticaria).

Metabolic/Nutritional Disorders:

Hypercholesterolaemia, hypertriglyceridaemia, hypokalaemia.

Cardiac Disorders: QT prolongation, torsade de pointes ( see section 4.4 Special Warnings and Special Precautions for Use).

4.9 Overdose

There have been reports of overdosage with fluconazole and in one case, a 42 year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behaviour after reportedly ingesting 8200mg of fluconazole,. The patient was admitted to the hospital and his condition resolved within 48 hours.

In the event of overdosage, supportive measures and symptomatic treatment, with gastric lavage if necessary, may be adequate.

As fluconazole is largely excreted in the urine, forced volume diuresis would probably increase the elimination rate. A three hour haemodialysis session decreases plasma levels by approximately 50%.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Triazole derivatives, ATC code J02AC

Fluconazole, a member of the triazole class of antifungal agents, is a potent and selective inhibitor of fungal enzymes necessary for the synthesis of ergosterol.

Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 50mg daily given up to 28 days has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in females of child-bearing age. Fluconazole 200-400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers.

There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy.

5.2 Pharmacokinetic Properties

After oral administration fluconazole is well absorbed and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose with a plasma elimination half-life of approximately 30 hours. Plasma concentrations are proportional to dose. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%).

Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels.

The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites.

The long plasma elimination half-life provides the basis for single dose therapy for genital candidiasis.

5.3 Preclinical Safety Data

Reproductive toxicity

Adverse foetal effects have been seen in animals only at high dose levels associated with maternal toxicity. There were no foetal effects at 5 or 10 mg/kg; increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50mg/kg and higher doses. At doses ranging from 80mg/kg (approximately 20-60 times the recommended human dose) to 320mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are consistent with the inhibition of oestrogen synthesis in rats and may be a result of known effects of lowered oestrogen on pregnancy, organogenesis and parturition.

Carcinogenesis

Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10mg/kg/day (approximately 2-7 times the recommended human dose). Male rats treated with 5 and 10mg/ kg/day had an increased incidence of hepatocellular adenomas.

Mutagenesis

Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S.typhimurium and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000μg/ml) showed no evidence of chromosomal mutations.

Impairment of fertility

Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10 or 20 mg/kg or with parenteral doses of 5, 25 or 75 mg/kg, although the onset of parturition was slightly delayed at 20mg/kg orally. In an intravenous perinatal study in rats at 5, 20 and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5-15 times the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole (see section 5.1 Pharmacodynamic properties).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Colloidal anhydrous silica

Anhydrous lactose

Magnesium Stearate

Maize Starch

Sodium Lauryl Sulphate

Capsule shell contains

Patent blue ( E 131)

Titanium dioxide (E171)

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Gelatin

6.2 Incompatibilities

No specific incompatibilities have been noted.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Blisters : Do not store above 25°C. Store in the original package.

6.5 Nature And Contents Of Container

PVC/PVdC/Al blister pack size of 1 capsule

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Bristol Laboratories Limited

Unit 3, Canalside

Northbridge Road

Berkhamsted

HP4 1EG

United Kingdom

8. Marketing Authorisation Number(S)

PL 17907/0055

9. Date Of First Authorisation/Renewal Of The Authorisation

24^th May 2005

10. Date Of Revision Of The Text

24/06/2010

Levonest

levonorgestrel and ethinyl estradiol

Dosage Form: tablets
Levonest™ (Levonorgestrel and Ethinyl Estradiol Tablets USP, Triphasic Regimen)

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

DESCRIPTION

Each Levonest™ (levonorgestrel and ethinyl estradiol tablets—triphasic regimen) cycle of 28 tablets consists of three different drug phases as follows:

Phase 1 comprised of 6 yellow tablets, each containing 0.050 mg of levonorgestrel (d(-)-13 beta-ethyl-17-alpha-ethinyl-17-beta-hydroxygon-4-en-3-one), a totally synthetic progestogen, and 0.030 mg of ethinyl estradiol (19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3, 17-diol); phase 2 comprised of 5 green tablets, each containing 0.075 mg levonorgestrel and 0.040 mg ethinyl estradiol; and phase 3 comprised of 10 light brown tablets, each containing 0.125 mg levonorgestrel and 0.030 mg ethinyl estradiol; then followed by 7 white inert tablets. The inactive ingredients present in the yellow, green and light brown tablets are lactose, magnesium stearate and pregelatinized corn starch.

Each yellow tablet also contains FD&C Yellow #5 Aluminum Lake, FD&C Yellow #6 Aluminum Lake, FD&C Blue #2 Aluminum Lake, titanium dioxide, macrogol/ polyethylene glycol 3350 NF, lecithin (soya), talc, and polyvinyl alcohol. Each green tablet also contains FD&C Yellow #5 Aluminum Lake, FD&C Red #40 Aluminum Lake, FD&C Blue #2 Aluminum Lake, titanium dioxide, macrogol/ polyethylene glycol 3000 NF, lecithin (soya), talc, and polyvinyl alcohol. Each light brown tablet also contains iron oxide yellow, iron oxide red, iron oxide black, titanium dioxide, macrogol/ polyethylene glycol 3350 NF, lecithin (soya), talc, and polyvinyl alcohol. Each inactive, white tablet (7) contains the following inactive ingredients: Titanium dioxide, polydextrose, hypromellose, triacetin, macrogol/polyethylene glycol 8000, lactose, magnesium stearate and pregelatinized corn starch.

CLINICAL PHARMACOLOGY

Combination oral contraceptives primarily 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

Levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%). Levonorgestrel is not subject to first-pass metabolism or enterohepatic circulation and therefore does not undergo variations in absorption after oral administration. 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 between 38% and 48%.

There have been no formal multiple-dose studies conducted using levonorgestrel and ethinyl estradiol tablets – triphasic regimen. However, a multiple-dose study was done in 22 women using a monophasic, low dose combination of 0.10 mg levonorgestrel and 0.02 mg ethinyl estradiol. Maximum serum concentrations of levonorgestrel were found to be 2.8 ± 0.9 ng/mL (mean ± SD) at 1.6 ± 0.9 hours after a single dose, reaching a steady state at day 19. Observed levonorgestrel concentrations increased from day 1 to days 6 and 21 by 34% and 96%, respectively. Unbound levonorgestrel concentrations subsequently increased from day 1 to days 6 and 21 by 25% and 83%, respectively, however, the accumulation of unbound levonorgestrel was approximately 14% less than total levonorgestrel accumulation. The kinetics of total levonorgestrel were non-linear due to an increase in binding of levonorgestrel to SHBG, which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol. Ethinyl estradiol reached maximum serum concentrations of 62 ± 21 pg/mL at 1.5 ± 0.5 hours after a single dose, reaching steady state at day 6. Ethinyl estradiol concentrations increased by 19% from days 1 to 21 consistent with an elimination half-life of 18 hours.

Single-dose studies with levonorgestrel and ethinyl estradiol tablets – triphasic regimen have been conducted with the following data reported below in Table I. Plasma concentrations have been corrected below to reflect single tablet dosing/day.

TABLE I: MEAN (SE) PHARMACOKINETIC PARAMETERS OF LEVONORGESTREL AND ETHINYL ESTRADIOL TABLETS – TRIPHASIC REGIMEN IN SINGLE-DOSE STUDIES

Levonorgestrel (LNG)
Dose LNG/EE	Cmax	tmax	t1/2	AUC
mcg	ng/mL	h	h	ng•h/mL
50/30	1.7 (0.1)	1.3 (0.1)	23 (2.2)	17 (1.5)
75/40	2.1 (0.2)	1.5 (0.2)	15 (1.2)	21 (2.0)
125/30	2.5 (0.2)	1.6 (0.1)	23 (1.4)	34 (3.0)
Ethinyl Estradiol (EE)
Dose LNG/EE	Cmax	tmax	t1/2	AUC
mcg	pg/mL	h	h	pg•h/mL
50/30	141 (9)	1.4 (0.1)	8.1 (1.0)	1126 (113)
75/40	179 (13)	1.6 (0.2)	14 (1.7)	2177 (244)
125/30	115 (10)	1.5 (0.1)	8.8 (1.6)	1072 (170)

Distribution

Levonorgestrel is bound to SHBG and albumin. Levonorgestrel has high binding affinity for SHBG that is 60% of that of testosterone. Ethinyl estradiol is about 97% bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but will induce SHBG synthesis.

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 predominately 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 observed 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 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 is approximately 36 ± 13 hours at steady state. Levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in the feces. The elimination half-life of ethinyl estradiol is 18 ± 4.7 hours at steady state.

Special Populations

Hepatic Insufficiency

No formal studies have evaluated the effect of hepatic disease on the disposition of levonorgestrel and ethinyl estradiol tablets – triphasic regimen. 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 levonorgestrel and ethinyl estradiol tablets – triphasic regimen.

Drug-Drug Interactions

See “PRECAUTIONS” section - Drug Interactions

INDICATIONS AND USAGE

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 II 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 and the IUD, 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 USE OF A CONTRACEPTIVE METHOD

NA – not available
*Depending on method (calendar, ovulation, symptothermal, post-ovulation) Adapted from Hatcher RA et al, Contraceptive Technology: 17th Revised Edition. NY, NY: Ardent Media, Inc., 1998
Method	Perfect Use	Typical Use
Levonorgestrel implants	0.05	0.05
Male sterilization	0.1	0.15
Female sterilization	0.5	0.5
Depo-Provera®      (injectable progestogen)	0.3	0.3
Oral contraceptives		5
Combined	0.1	NA
Progestin only	0.5	NA
IUD
Progesterone	1.5	2.0
Copper T 380A	0.6	0.8
Condom (male) without spermicide	3	14
(Female) without spermicide	5	21
Cervical cap
Nulliparous women	9	20
Parous women	26	40
Vaginal sponge
Nulliparous women	9	20
Parous women	20	40
Diaphragm with      spermicidal cream or jelly	6	20
Spermicides alone       (foam, creams, jellies, and vaginal suppositories)	6	26
Periodic abstinence (all methods)	1-9*	25
Withdrawal	4	19
No contraception (planned pregnancy)	85	85

CONTRAINDICATIONS

Combination oral contraceptives should not be used in women with any of the following conditions:

Thrombophlebitis or thromboembolic disorders.

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

Cerebral-vascular or coronary-artery disease.

Thrombogenic valvulopathies.

Thrombogenic rhythm disorders.

Diabetes with vascular involvement.

Uncontrolled hypertension.

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, or active liver disease, as long as liver function has not returned to normal.

Known or suspected pregnancy.

Hypersensitivity to any of the components of Levonest™ (levonorgestrel and ethinyl estradiol tablets–triphasic regimen).

WARNINGS

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

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

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 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 III) among women who use oral contraceptives.

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

TABLE III. (Adapted from P.M. Layde and V. Beral, Lancet, 1:541-546, 1981.)

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”). 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.

b. Thromboembolism

An increased risk of venous 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 mcg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5 to 3 per 10,000 woman-years for non-users. However, the incidence is substantially less than that associated with pregnancy (6 per 10,000 woman-years). The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.

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 to six weeks after delivery in women who elect not to breast-feed, or a midtrimester pregnancy termination.

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 less than 50 mcg of estrogen.

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 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 IV). 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 IV – 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

*Deaths are birth related
**Deaths are method related
Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983.
Method of control andoutcome	15 to 19	20 to 24	25 to 29	30 to 34	35 to 39	40 to 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
IUD**	0.8	0.8	1.0	1.0	1.4	1.4
Condom*	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/spermicide*	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence*	2.5	1.6	1.6	1.7	2.9	3.6

3. Carcinoma Of The Reproductive Organs

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR=1.24) of having breast cancer diagnosed in women who are currently using combination oral contraceptives compared to never-users. The increased risk gradually disappears during the course of the 10 years after cessation of combination oral-contraceptive use. These studies do not provide evidence for causation. The observed pattern of increased risk of breast cancer diagnosis may be due to earlier detection of breast cancer in combination oral contraceptive users, the biological effects of combination oral contraceptives, or a combination of both. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent combination oral contraceptive users is small in relation to the lifetime risk of breast cancer. Breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

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 and cervical cancers, a cause-and-effect relationship has not been established.

4. Hepatic Neoplasia

Benign hepatic adenomas are associated with oral-contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use. Rupture of rare, benign, 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

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 insofar 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.

It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral-contraceptive use. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral-contraceptive use should be discontinued if pregnancy is confirmed.

7. Gallbladder Disease

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. 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

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 quantities 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

Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. The type and dose of progestogen may be important. If bleeding persists or recurs, nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out if the oral contraceptive has not been taken according to directions prior to the first missed withdrawal bleed or if two consecutive withdrawal bleeds have been missed. Some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such a condition was preexistent.

PRECAUTIONS

1. General

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

This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

2. Physical Examination And Follow-Up

A periodic personal and family medical history and complete physical examination are appropriate for all women, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

3. Lipid Disorders

Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. (See “WARNINGS,” 1d.)

In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, there have been case reports of significant elevations of plasma triglycerides leading to pancreatitis.

4. Liver Function

If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.

5. Fluid Retention

Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

6. Emotional Disorders

Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

7. Contact Lenses

Contact-lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

8. Gastrointestinal Motility

Diarrhea and/or vomiting may reduce hormone absorption.

9 Drug Interactions

Interactions between ethinyl estradiol and other substances may lead to decreased or increased serum ethinyl estradiol concentrations.

Decreased ethinyl estradiol plasma concentrations may cause an increased incidence of breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy of the combination oral contraceptive.

Reduced ethinyl estradiol concentrations have been associated with concomitant use of substances that induce hepatic microsomal enzymes, such as rifampin, rifabutin, barbiturates, phenylbutazone, phenytoin sodium, griseofulvin, topiramate, some protease inhibitors, modafinil, and possibly St. John’s wort.

Substances that may decrease plasma ethinyl estradiol concentrations by other mechanisms include any substance that reduces gut transit time and certain antibiotics (e.g. ampicillin and other penicillins, tetracyclines) by a decrease of enterohepatic circulation of estrogens. During concomitant use of ethinyl estradiol containing products and substances that may lead to decreased plasma steroid hormone concentrations, it is recommended that a nonhormonal back-up method of birth control be used in addition to the regular intake of Levonest™ (levonorgestrel and ethinyl estradiol tablets-triphasic regimen). If the use of a substance which leads to decreased ethinyl estradiol plasma concentrations is required for a prolonged period of time, combination oral contraceptives should not be considered the primary contraceptive.

After discontinuation of substances that may lead to decreased ethinyl estradiol plasma concentrations, use of a nonhormonal back-up method of birth control is recommended for 7 days. Longer use of a back-up method is advisable after discontinuation of substances that have led to induction of hepatic microsomal enzymes, resulting in decreased ethinyl estradiol concentrations. It may take several weeks until enzyme induction has completely subsided, depending on dosage, duration of use, and rate of elimination of the inducing substance.

Some substances may increase plasma ethinyl estradiol concentrations. These include:

• Competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, such as ascorbic acid (vitamin C) and acetaminophen.


• Substances that inhibit cytochrome P450 3A4 isoenzymes such as indinavir, fluconazole, and troleandomycin. Troleandomycin may increase the risk of intrahepatic cholestasis during coadministration with combination oral contraceptives.


• Atorvastatin (unknown mechanism).

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

The prescribing information of concomitant medications should be consulted to identify potential interactions.

10. Interactions With Laboratory Tests

Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives:

1. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.


2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.


3. Other binding proteins may be elevated in serum.


4. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.


5. Triglycerides may be increased.


6. Glucose tolerance may be decreased.


7. Serum folate levels may be depressed by oral-contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly afterdiscontinuing oral contraceptives.

11. Carcino

halofantrine

hal-oh-FAN-treen

Available Dosage Forms:

• Tablet

Therapeutic Class: Antimalarial

Chemical Class: Phenanthrenemethanol

Uses For halofantrine

Halofantrine belongs to a group of medicines known as antimalarials. It is used to treat malaria, a red blood cell infection transmitted by the bite of a mosquito.

Malaria transmission occurs in large areas of Central and South America, Hispaniola, sub-Saharan Africa, the Indian subcontinent, Southeast Asia, the Middle East, and Oceania. Country-specific information on malaria can be obtained from the Centers for Disease Control and Prevention (CDC) or from the CDC's web site at http://www.cdc.gov/travel/yellowbk.

halofantrine may cause serious side effects. Therefore, it usually is used to treat serious malaria infections in areas where it is known that other medicines may not work.

Halofantrine is available only with your doctor's prescription.

Before Using halofantrine

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

Allergies

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

Pediatric

Although there is no specific information comparing use of halofantrine in children with use in other age groups, halofantrine is not expected to cause different side effects or problems in children than it does in adults.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of halofantrine in the elderly with use in other age groups.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

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

Interactions with Medicines

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

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

• Aurothioglucose


• Bepridil


• Cisapride


• Dronedarone


• Levomethadyl


• Mesoridazine


• Pimozide


• Posaconazole


• Sparfloxacin


• Thioridazine


• Ziprasidone

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

• Acecainide


• Ajmaline


• Alfuzosin


• Amiodarone


• Amisulpride


• Amitriptyline


• Amoxapine


• Apomorphine


• Aprindine


• Arsenic Trioxide


• Asenapine


• Astemizole


• Azimilide


• Azithromycin


• Bretylium


• Chloral Hydrate


• Chloroquine


• Chlorpromazine


• Ciprofloxacin


• Citalopram


• Clarithromycin


• Clomipramine


• Clozapine


• Crizotinib


• Dasatinib


• Desipramine


• Disopyramide


• Dofetilide


• Dolasetron


• Dothiepin


• Doxepin


• Droperidol


• Encainide


• Enflurane


• Erythromycin


• Flecainide


• Fluconazole


• Fluoxetine


• Foscarnet


• Gemifloxacin


• Granisetron


• Haloperidol


• Halothane


• Hydroquinidine


• Ibutilide


• Iloperidone


• Imipramine


• Isoflurane


• Isradipine


• Itraconazole


• Lapatinib


• Levofloxacin


• Lidoflazine


• Lofepramine


• Lopinavir


• Lorcainide


• Lumefantrine


• Mefloquine


• Methadone


• Moxifloxacin


• Nilotinib


• Norfloxacin


• Nortriptyline


• Octreotide


• Ofloxacin


• Ondansetron


• Opipramol


• Paliperidone


• Pazopanib


• Pentamidine


• Perflutren Lipid Microsphere


• Pirmenol


• Prajmaline


• Probucol


• Procainamide


• Prochlorperazine


• Promethazine


• Propafenone


• Protriptyline


• Quetiapine


• Quinidine


• Quinine


• Ranolazine


• Risperidone


• Salmeterol


• Saquinavir


• Sematilide


• Sertindole


• Sodium Phosphate


• Sodium Phosphate, Dibasic


• Sodium Phosphate, Monobasic


• Solifenacin


• Sorafenib


• Sotalol


• Spiramycin


• Sulfamethoxazole


• Sultopride


• Sunitinib


• Tedisamil


• Telavancin


• Telithromycin


• Terfenadine


• Tetrabenazine


• Toremifene


• Trazodone


• Trifluoperazine


• Trimethoprim


• Trimipramine


• Vandetanib


• Vardenafil


• Vasopressin


• Vemurafenib


• Voriconazole


• Zolmitriptan


• Zotepine

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

• Cola Nut

Interactions with Food/Tobacco/Alcohol

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

Using halofantrine with any of the following is not recommended. Your doctor may decide not to treat you with this medication, change some of the other medicines you take, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

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

• Heart problems, especially abnormal heartbeat or


• Thiamine deficiency or


• Unexplained sudden fainting—These conditions increase the chance of side effects affecting the heart, including fast irregular heartbeat

Proper Use of halofantrine

Halofantrine is best taken on an empty stomach to decrease the chance of side effects.

To help clear up your infection completely, take halofantrine exactly as directed by your doctor for the full time of treatment. Your symptoms may come back if you stop your treatment too early. Your doctor may instruct you to take a second course of treatment after 1 week.

Dosing

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

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

• For oral dosage forms (oral suspension and tablets):
  
  • Adults and children over 37 kilograms (81 pounds) of body weight—500 mg, taken on an empty stomach every six hours three times a day for one day. Treatment may need to be repeated after one week.
  
  
  • Children—Dose is based on body weight and must be determined by your doctor. Treatment may need to be repeated after one week.
    
    • Up to 23 kilograms (51 pounds) of body weight: Dose must be determined by your doctor.
    
    
    • 23 to 31 kilograms (51 to 68 pounds) of body weight: 250 mg, taken on an empty stomach every six hours three times a day for one day.
    
    
    • 32 to 37 kilograms (70 to 81 pounds) of body weight: 375 mg, taken on an empty stomach every six hours three times a day for one day.
    
    
  
  

Missed Dose

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

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Keep the liquid form of halofantrine from freezing.

Precautions While Using halofantrine

It is important that your doctor check your progress after treatment. This is to make sure that the infection is cleared up completely, and to allow your doctor to check for any unwanted effects.

If your symptoms do not improve after you have taken halofantrine for the full course of treatment, or if they become worse, check with your doctor.

Malaria is spread by the bites of certain kinds of infected female mosquitoes. If you are living in, or will be traveling to, an area where there is a chance of getting malaria, the following mosquito-control measures will help to prevent infection:

• If possible, avoid going out between dusk and dawn because it is at these times that mosquitoes most commonly bite.


• Wear long-sleeved shirts and long trousers to protect your arms and legs, especially from dusk through dawn when mosquitoes are out.


• Apply insect repellant, preferably one containing DEET, to uncovered areas of the skin from dusk through dawn when mosquitoes are out.


• If possible, sleep in a screened or air-conditioned room or under mosquito netting sprayed with insecticide to avoid being bitten by malaria-carrying mosquitoes.


• Use mosquito coils or sprays to kill mosquitoes in living and sleeping quarters during evening and nighttime hours.

halofantrine Side Effects

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

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

Less common

• Coughing


• noisy, rattling, or troubled breathing

Rare

• Abdominal pain


• chest pain


• confusion


• convulsions (seizures)


• diarrhea


• difficulty in breathing or swallowing


• hives


• itching, especially of feet or hands


• nausea


• pounding heartbeat


• reddening of skin, especially around ears


• swelling of eyes, face or inside of nose


• unusual tiredness or weakness


• vomiting

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

More Common

• Headache

Less common

• Aches and pain in joints


• constipation


• frequent urination


• indigestion


• loss of appetite


• skin itching or rash

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

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

See also: halofantrine side effects (in more detail)

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Loteprednol Ointment

Pronunciation: LOE-te-PRED-nol
Generic Name: Loteprednol
Brand Name: Lotemax

Loteprednol Ointment is used for:

Treating swelling and pain after eye surgery

Loteprednol Ointment is a corticosteroid. It decreases inflammation (eg, redness, swelling, warmth, pain) of the eye.

Do NOT use Loteprednol Ointment if:

• you are allergic to any ingredient in Loteprednol Ointment


• you have a viral eye infection (eg, herpes simplex keratitis, vaccinia, varicella)


• you have a mycobacterial or fungal eye infection

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

Before using Loteprednol Ointment:

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

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


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


• if you have allergies to medicines, foods, or other substances


• if you wear contact lenses


• if you have diabetes, glaucoma or increased pressure in they eye, eye discharge, or thinning of the cornea or sclera


• if you have an eye infection or a history of herpes simplex infection of the eye


• if you have recently had or will be having cataract surgery

Some MEDICINES MAY INTERACT with Loteprednol Ointment. However, no specific interactions with Loteprednol Ointment are known at this time.

Ask your health care provider if Loteprednol Ointment 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 Loteprednol Ointment:

Use Loteprednol Ointment as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Loteprednol Ointment is only for the eye. Do not get it in your nose or mouth.


• Wash your hands before using Loteprednol Ointment.


• To use Loteprednol Ointment in the eye, first, wash your hands. Using your index finger, pull the lower eyelid away from your eye to form a pouch. Squeeze a thin strip of ointment into the pouch. After using Loteprednol Ointment, gently close your eyes for 1 to 2 minutes. Wash your hands to remove any medicine that may be on them. Wipe the applicator tip with a clean, dry tissue.


• Do not wear contact lenses while you are using Loteprednol Ointment. Take care of your contact lenses as directed by the manufacturer. Check with your doctor before you use them.


• To prevent germs from contaminating your medicine, do not touch the applicator tip to any surface, including the eye. Keep the container tightly closed.


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

Ask your health care provider any questions you may have about how to use Loteprednol Ointment.

Important safety information:

• Loteprednol Ointment may cause blurred vision. Use Loteprednol Ointment with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• If Loteprednol Ointment is used for more than 10 days, your eyes and vision may need to monitored. Discuss any questions or concerns with your doctor.


• If your symptoms do not get better within 2 days or if they get worse, check with your eye doctor.


• Loteprednol Ointment may delay wound healing. Tell your doctor if your eye does not appear to be healing as it should.


• Loteprednol Ointment should be not be used in CHILDREN after eye surgery; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Loteprednol Ointment while you are pregnant. It is not known if Loteprednol Ointment is found in breast milk after topical use. If you are or will be breast-feeding while you use Loteprednol Ointment, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Loteprednol Ointment:

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:

Temporary blurred vision.

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); changes in vision; eye pain, redness, or swelling.

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: Loteprednol 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 Loteprednol Ointment:

Store Loteprednol Ointment at room temperature, between 59 and 77 degrees F (15 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Loteprednol Ointment out of the reach of children and away from pets.

General information:

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


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


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


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

This information is a summary only. It does not contain all information about Loteprednol Ointment. 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 Loteprednol resources

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

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