Jay Phyl

dyphylline and guaifenesin

Dosage Form: syrup
Jay-Phyl Syrup

Jay-Phyl Syrup

Bronchodilator/Expectorant

Rx Only


DESCRIPTION:

Jay-Phyl Syrup is a bronchodilator/expectorant combination supplied as a Orange, Vanilla flavored,

alcohol free and gluten free liquid for oral administration.


Each teaspoonful (5 mL) contains:

Dyphylline........... 100 mg

Guaifenesin........... 50 mg


Inactive ingredients: Glycerin, Propylene Glycol, Sorbitol, Citric Acid, Sodium Citrate, Sodium

Saccharin, Vanilla Flavor, FD and C Yellow No. 6, Purified Water.


Dyphylline is 7-(2,3-dihydroxypropyl)-theophylline, a white, extremely bitter, amorphous powder that is fully

soluble in water and soluble in alcohol to the extent of 2 g/100 mL. Dyphylline forms a neutral solution that

is stable in gastrointestinal fluids over a wide range of pH. It has the following chemical structure:

Guaifenesin is an expectorant which occurs as a white to slightly gray, crystalline powder, having a bitter

taste. It may have a slight characteristic odor. It is soluble in water, alcohol, chloroform, glycerin, and

propylene glycol. The chemical name is 1,2-Propanediol, 3-(2-methoxyphenoxy)-, (±)-. It has the following

chemical structure:

Jay Phyl - Clinical Pharmacology

Dyphylline is a xanthine derivative with pharmacological actions similar to theophylline and other

members of this class of drugs. Its primary action is that of bronchodilation, but it also exhibits

peripheral vasodilatory and other smooth muscle relaxant activity to a lesser degree. The

bronchodilatory action of dyphylline, as with other xanthines, is thought to be mediated through

competitive inhibition of phosphodiesterase with a resulting increase in cyclic AMP producing

relaxation of bronchial smooth muscle.


Dyphylline was reported to be the least toxic of seven theophylline derivatives, including the piperazine,

N, N-diethylamino ethyl and the 2-hydroxy ethyl derivatives. The toxicity of dyphylline is only one-fifth

that of aminophylline as determined intraperitoneally in mice, and only one-half as toxic in rats. Unlike

the hydrolysable salts of theophylline, dyphylline is not converted to free theophylline in vivo. It is

absorbed rapidly in therapeutically active form and in healthy volunteers reaches a mean peak plasma

concentraion of 17.1 mcg/mL in approximately 45 minutes following a single oral dose of 1000 mg of

dyphylline.


Dyphylline exerts its bronchodilatory effects directly and, unlike theophylline, is excreted unchanged

by the kidneys without being metabolized by the liver. Because of this, dyphylline pharmacokinetics

and plasma levels are not influenced by various factors that affect liver function and hepatic enzyme

activity, such as smoking, age, or concomitant use of drugs which affect liver function.


The elimination half-life of dyphylline is approximately two hours (1.8-2.1 hr) and approximately 88%

of a single oral dose can be recovered from the urine unchanged. The renal clearance would be

correspondingly reduced in patients with impaired function. In anuric patients, the half-life may be

increased 3 to 4 times normal. Dyphylline plasma levels are dose-related and generally predictable.

The therapeutic range of plasma levels within which dyphylline can be expected to produce effective

bronchodilation has not been determined.


Dyphylline plasma concentrations can be accurately determined using high pressure liquid

chromatography (HPLC) or gas-liquid chromatography (GLC). Guaifenesin is an expectorant whose

action helps increase the output of thin respiratory tract fluid to facilitate mucociliary clearance and

removal of inspissated mucus.


Guaifenesin is an expectorant which increases respiratory tract fluid secretions and helps to loosen

phlegm and bronchial secretions. By reducing the viscosity of secretions, guaifenesin increases the

efficiency of the cough reflex and of ciliary action in removing accumulated secretions from the trachea

and bronchi. Guaifenesin is readily absorbed from the gastrointestinal tract and is rapidly metabolized

and excreted in the urine. Guaifenesin has a plasma half-life of one hour. The major urinary metabolite

is p-(2-methoxyphenoxy) lactic acid.

INDICATIONS AND USAGE:

Jay-Phyl Syrup is indicated as a bronchodilator-expectorant for treating bronchial asthma,

emphysema, bronchitis, pneumonitis and other related bronchopulmonary insufficiency conditions.

Jay-Phyl Syrup acts to dilate bronchioles and liquefy mucus, giving relief from dyspnea,

non-productive cough and tracheobronchial irritation.

CONTRAINDICATIONS:

As with other theophylline-type drugs, combining dyphylline with epehdrine or other sympathomimetic

drugs can cause excessive CNS stimulation. Such combinations are contraindicated in children unless

accompanied by sufficient sedation to prevent undue CNS stimulation.

Warnings

This product is not indicated in the management of status asthmaticus, which is a serious

medical emergency.


Although the relationship between plasma levels of dyphylline and appearance of toxicity is

unknown, excessive doses may be expected to be associated with an increased risk of

adverse effects.

PRECAUTIONS:

General: Use this product with caution in patients with severe cardiac disease, hypertension,

glaucoma, hypothyroidism, severe renal and hepatic disease, acute myocardial injury or peptic

ulcer. Do not use in children under age six. Do not exceed 3 mg of dyphylline per pound

of body weight daily in older children. Because the xanthines also act as diuretics, special

precaution regarding hydration and avoidance of acidosis should be observed in children. The

long term use of xanthine derivatives may result in a cumulative effect with increase in adverse

reactions, as well as the development of tolerance.

Drug Interactions:

Synergism between xanthine bronchodilators (e.g., theophylline), ephedrine and other sympathomimetic

bronchodilators has been reported. This should be considered whenever these agents are prescribed

concomitantly. Concurrent administration of dyphylline and probenecid, which competes for tubular secretion,

has been shown to increase plasma half-life and dyphylline (See Clinical Pharmacology).

Carcinogenesis, Mutagenesis, Impairment of Fertility:

No long-term animal studies have been performed with this product.

Pregnancy: Teratogenic effects- Pregnancy Category C.

Animal reproduction studies have not been conducted with this formulation. It is also not known whether

this product can cause fetal harm when administered to a pregnant woman or can affect reproduction

capacity. This medication should be given to a pregnant woman only if clearly needed.

Nursing Mothers:

Dyphylline is present in human milk at approximately twice the maternal plasma concentration.

Caution should be exercised when this product is administered to a nursing woman.

Pediatric Use:

Safety and effectiveness in children below the age of six have not been established.

Use caution when administering to children six years of age or older.

Adverse Reactions

This formulation may cause nausea, headache, cardiac palpitation and CNS stimulation.


Postprandial administration may help avoid gastric discomfort.


The following adverse reactions which have been reported with other xanthine bronchodilators,

and which have most often been related to excessive drug plasma levels, should be considered

as potential adverse effects when dyphylline is administered.


Gastrointestinal: nausea, vomiting, epigastric pain, hematemesis, diarrhea.


Central Nervous System: headache, irritability, restlessness, insomnia, hyperexcitability,

agitation, muscle twitching, generalized clonic and tonic convulsions.


Cardiovascular: palpitation, tachycardia, extrasystoles, flushing, hypotension, circulatory failure,

ventricular arrhythmias.


Respiratory: tachypnea.


Renal: albuminuria, gross and microscopic hematuria, diuresis.


Other: hyperglycemia, inappropriate ADH syndrome.


Large doses of Guaifenesin may produce emesis, but gastrointestinal upset at ordinary dosage

levels is rare.

Overdosage

Signs and Symptoms: Restlessness, anorexia, nausea, vomiting, diarrhea, insomnia, irritability,

and headache are typical symptoms resulting from a xanthine drug overdose. Marked overdosage

with resulting severe toxicity has produced agitation, severe vomiting, dehydration, excessive thirst,

tinnitus, cardiac arrhythmias, hyperthermia, diaphoresis, and generalized clonic and tonic

convulsions. Cardiovascular collapse has also occurred, with some fatalities. Seizures have

occured in some cases associated with very high theophylline plasma concentrations, without

any premonitory symptoms of toxicity.


Treatment: There is no specific antidote for overdosage with drugs of the xanthine class.

Symptomatic treatment and general supportive measures should be instituted with careful

monitoring and maintenance of vital signs, fluids and electrolytes. The stomach should be

emptied by inducing emesis if the patient is conscious and responsive, or by gastric lavage,

taking care to protect against aspiration, especially in stuporous or comatose patients.

Maintenance of an adequate airway is essential in case oxygen or assisted respiration is needed.

Sympathomimetic agents should be avoided but sedatives such as short acting barbiturates may

be useful.


Dypyhlline is dialyzable and although not recommended as routine procedure in overdosage cases,

hemodialysis may be of some benefit with severe intoxication is present or when the patient has

not responded to general supportive and symptomatic treatment.

DOSAGE AND ADMINISTRATION:

The usual adult dose is 1 or 2 teaspoonfuls of liquid 3 or 4 times a day. In severe cases, dosage may

be doubled or tripled if necessary. Maintenance dosage should be adjusted according to patient response.


Use in Children:

Altough pediatric dosages of dyphylline are established, no firm dosage for a combination of dyphylline

and guaifenesin USP can be recommended for children under the age of six. Dosage for children over

six may be calculated on the basis of 2 to 3 mg of dyphylline per pound of body weight daily in divided doses.

HOW SUPPLIED:

Jay-Phyl Syrup is supplied as a orange, vanilla flavored, alcohol free and gluten free liquid in pint

bottles, NDC 64661-0814-16 and in 15 mL bottles, NDC 64661-0814-15.


Rx Only


WARNING: KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

IN CASE OF ACCIDENTAL OVERDOSE, SEEK PROFESSIONAL ASSISTANCE OR

CONTACT A POISON CONTROL CENTER IMMEDIATELY.

STORAGE:

Store at controlled room temperature 15o-30oC (59o-86oF).


Tamper evident by foil seal under cap. Do not use if foil seal is broken or missing.


Manufactured by:

Great Southern Laboratories

Houston, TX 77099


Manufactured for:

JayMac Pharmaceuticals, Inc.

Sunset, LA 70584


Rev. 10/08

PRODUCT PACKAGING:

The packaging below represents the labeling currently used:


Principal Display Panel and Side Panel for 15 mL Label:


NDC 64661-814-15


Jay-Phyl Syrup


Each 5 mL contains:

Dyphylline............. 100 mg

Guaifenesin........... 50 mg


Sugar and Alcohol Free


Rx Only


1/2 fl oz (15 mL)


DOSAGE AND ADMINISTRATION:

Adults: 2 teaspoonfuls (10 mL) 3 or 4 times daily. Children 6 to 12 should be started on low doses

which are gradually increased to the lowest effective dose, not to exceed 10mg/kg/day in divided

doses. Not recommended for pediatric patients under 6 years.


See package insert for full prescribing information.


Store at controlled room temperature, 15o-30oC (59o-86oF).


Tamper evident by foil seal under cap. Do not use if foil seal is broken or missing.


KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

IN CASE OF ACCIDENTAL OVERDOSE, CONTACT A POISON CONTROL

CENTER AND SEEK PROFESSIONAL ASSISTANCE IMMEDIATELY.


Manufactured for:

JayMac Pharmaceuticals

Sunset, LA 70584                 Rev. 11/07


PROFESSIONAL SAMPLE

NOT FOR RESALE

JAY-PHYL  dyphylline and guaifenesin  syrup

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 64661-814 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Dyphylline (Dyphylline) Dyphylline 100 mg  in 5 mL Guaifenesin (Guaifenesin) Guaifenesin 100 mg  in 5 mL

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor VANILLA Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 64661-814-15 15 mL In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved drug other		05/02/2006

Labeler - JayMac Pharmaceuticals LLC (830767260)

Registrant - Great Southern Laboratories (056139553)

Establishment
Name	Address	ID/FEI	Operations
Great Southern Laboratories		056139553	manufacture

Revised: 12/2009JayMac Pharmaceuticals LLC

More Jay Phyl resources

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

Compare Jay Phyl with other medications

• Asthma
• Bronchitis

Second generation cephalosporins

A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Cephalosporins are a group of broad spectrum, semi-synthetic beta-lactam antibiotics derived from the mould Cephalosporium. They are divided into three groups: Cephalosporin N and C are chemically related to penicillins and Cephalosporin P a steroid antibiotic resembles fusidic acid.

The mechanism of action of cephalosporins is the same as penicillins. They interfere with bacterial cell wall synthesis.

Semisynthetic broad-spectrum cephalosporins have been produced by the addition of different side chains, to the Cephalosporin C nucleus.

They are classified according to the chronological order in which they were produced.

Second generation cephalosporins followed the first generation cephalosporins.

See also

Medical conditions associated with second generation cephalosporins:

• Aspiration Pneumonia
• Bacterial Infection
• Bladder Infection
• Bone infection
• Bronchitis
• Cesarean Section
• Cholecystitis
• Deep Neck Infection
• Endometritis
• Epiglottitis
• Gonococcal Infection, Disseminated
• Gonococcal Infection, Uncomplicated
• Hysterectomy
• Impetigo
• Intraabdominal Infection
• Joint Infection
• Kidney Infections
• Lyme Disease
• Meningitis
• Otitis Media
• Pelvic Inflammatory Disease
• Peritonitis
• Pneumonia
• Sepsis
• Septicemia
• Sinusitis
• Skin and Structure Infection
• Skin Infection
• Strep Throat
• Surgical Prophylaxis
• Tonsillitis/Pharyngitis
• Upper Respiratory Tract Infection
• Urinary Tract Infection

Drug List:

Lorabid

Cefotan

Zinacef

Ceftin

Cefzil

Lorabid-Pulvules

Mefoxin

Raniclor

Anakinra

Pronunciation: an-ah-KIN-rah
Generic Name: Anakinra
Brand Name: Kineret

Anakinra may put your body at an increased risk for serious infections. This drug is not recommended if you have an infection or an infection-related illness (eg, pneumonia, tuberculosis). Tell your doctor if you have, or if you develop, any symptoms of an infection such as fever, persistent sore throat, productive cough (eg, sputum-producing), or unusual weakness. The risk of developing serious infections is even greater if you are also using a tumor necrosis factor medicine such as etanercept.

Anakinra is used for:

Reducing moderately to severely active rheumatoid arthritis in patients 18 years of age and older who have not successfully responded to other medicines. It may be used alone or with other medicines. It may also be used for other conditions as determined by your doctor.

Anakinra is an interleukin-1 (IL-1) blocker. It works by blocking the activity of interleukin-1 by binding to its receptor, which reduces inflammation and other signs and symptoms of arthritis.

Do NOT use Anakinra if:

• you are allergic to any ingredient in Anakinra


• you are allergic to proteins derived from Escherichia coli (E. coli)

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

Before using Anakinra:

Some medical conditions may interact with Anakinra. 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 have impaired kidney function


• if you have an infection that requires treatment with prescription antibiotics or is serious enough for you to be admitted to the hospital, or if you have an infection or develop an infection before undergoing therapy


• if you are planning to receive a live vaccine

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

• Tumor necrosis factor-blocking agents (eg, adalimumab) because the risk of severe infection and/or low white blood cell counts may be increased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Anakinra 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 Anakinra:

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

• Anakinra comes with an additional patient leaflet. Read it carefully and reread it each time you get Anakinra refilled.


• Anakinra is usually administered as an injection at your doctor's office, hospital, or clinic. If you are using Anakinra at home, carefully follow the injection procedures taught to you by your health care provider. Ask your doctor or other health care provider if you have any questions about how to administer Anakinra.


• Anakinra should be administered at the same time each day.


• Wash your hands thoroughly with soap and warm water before using Anakinra.


• Use a new syringe every day. Use the prefilled syringe only once. Throw away any unused portion of the medicine. Do not save for future use.


• If Anakinra contains particles or is discolored, or if the vial is cracked or damaged in any way, do not use it.


• Do not use a syringe that has been dropped or broken. Properly dispose of the damaged syringe and replace it with the syringe that would be used on the last day of the week in your current box. For example, if you start on Wednesday, the last day of the week in your series is Tuesday. After using all of the remaining syringes in your current box, start your next box.


• Do not use Anakinra beyond the expiration date on the container.


• Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Dispose of properly after use. Ask your doctor or pharmacist to explain local regulations for proper disposal.


• If you miss a dose of Anakinra, 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 on the same day.

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

Important safety information:

• If swelling or bruising at the injection site occurs, apply a cold pack on the injection site immediately after injection.


• Pain during or after injection can be lessened by using different injection locations, such as the stomach; by allowing the solution to warm to room temperature for 60 to 90 minutes before injecting; and by applying a cold pack on the injection site a few minutes before injection, and allowing the injection site to dry before injection.


• Improvement in rheumatoid arthritis symptoms usually occurs after 1 to 3 months of treatment with Anakinra.


• Anakinra may lower your body's ability to fight infection. Prevent infection by avoiding contact with people with colds or other infections. Notify your doctor of any signs of infection, including fever, sore throat, rash, or chills.


• Before you have any medical or dental treatments, emergency care, or surgery, tell the doctor or dentist that you are using Anakinra.


• Avoid vaccinations with live virus vaccines (eg, measles, mumps, oral polio) while you are taking Anakinra. Check with your doctor before having any vaccinations while you are using Anakinra.


• LAB TESTS, including white blood cell counts, may be performed to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments.


• Anakinra is not recommended for use in CHILDREN. Safety and effectiveness have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, discuss with your doctor the benefits and risks of using Anakinra during pregnancy. It is unknown if Anakinra is excreted in breast milk. If you are or will be breast-feeding while you are using Anakinra, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Anakinra:

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:

Diarrhea; flu-like symptoms; headache; nausea; reaction at the injection site (eg, redness, swelling, bruising, itching, pain, stinging); sinus inflammation; stomach pain; upper respiratory tract infection.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); cough; infection (fever, chills, sore throat); unexplained bone or joint pain.

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: Anakinra 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 Anakinra:

Store unopened syringes of Anakinra in the refrigerator, between 36 and 46 degrees F (2 to 8 degrees C). Store away from heat, moisture, and light. Do not shake or freeze. Do not use a syringe that has been left at room temperature for more than 24 hours. Do not use after the expiration date. Do not store in the bathroom. Keep Anakinra out of the reach of children and away from pets.

General information:

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


• Anakinra 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 Anakinra. 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 Anakinra resources

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

• Anakinra Professional Patient Advice (Wolters Kluwer)


• Anakinra Monograph (AHFS DI)


• anakinra Subcutaneous Advanced Consumer (Micromedex) - Includes Dosage Information


• Kineret Prescribing Information (FDA)


• Kineret Consumer Overview

Compare Anakinra with other medications

• Rheumatoid Arthritis
• Schnitzler Syndrome
• Still's Disease

Sporanox

Pronunciation: IT-ra-KON-a-zole
Generic Name: Itraconazole
Brand Name: Sporanox

Sporanox has been shown to cause decreased heart function. Contact your doctor immediately if you experience symptoms of congestive heart failure, such as swelling of the hands, ankles, feet, or abdomen; bloating; shortness of breath; fast or irregular heartbeat; severe or persistent nausea; or confusion.

Use of Sporanox along with certain other medicines may increase your risk of serious and sometimes fatal heart problems, including irregular heartbeat. Do not take Sporanox if you are also taking cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol (levomethadyl).

Sporanox is used for:

Treating fungal infections. It may also be used for other conditions as determined by your doctor.

Sporanox is an azole antifungal. It kills sensitive fungi by interfering with the formation of the fungal cell membrane.

Do NOT use Sporanox if:

• you are allergic to any ingredient in Sporanox


• you have severe kidney problems or kidney failure


• you are taking an aldosterone blocker (eg, eplerenone), alprazolam, astemizole, cisapride, conivaptan, dofetilide, an ergot alkaloid (eg, ergotamine), certain HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin), levacetylmethadol (levomethadyl), oral midazolam, nevirapine, nisoldipine, pimozide, a quinazoline (eg, alfuzosin), quinidine, rifabutin, rifampin, terfenadine, triazolam, or certain 5-HT receptor agonists (eg, eletriptan)

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

Before using Sporanox:

Some medical conditions may interact with Sporanox. 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 are allergic to other azole antifungals (eg, ketoconazole)


• if you have HIV infection, a weakened immune system, kidney or liver problems, abnormal liver function tests, lung or breathing problems (eg, chronic obstructive pulmonary disease [COPD]), low stomach acid (eg, hypochlorhydria), nerve problems, or problems with swelling or fluid retention


• if you have an irregular heartbeat or other heart problems (eg, congestive heart failure, coronary artery disease, heart valve problems)


• if you have had serious liver problems caused by Sporanox or other medicines

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

• Many prescription and nonprescription medicines (eg, used for infections, HIV, seizures, anxiety, sleep, heartburn, diabetes, high cholesterol, heart problems, high blood pressure, allergies, irregular heartbeat, pain, blood thinning, asthma, migraines, mood or mental problems, cancer, prostate problems, immune system suppression, erectile dysfunction, urinary problems, or birth control [eg, birth control pills]), multivitamin products, and herbal or dietary supplements may interact with Sporanox, increasing the risk of serious side effects


• Nevirapine, rifabutin, or rifampin because they may decrease Sporanox's effectiveness


• Astemizole, cisapride, dofetilide, levacetylmethadol (levomethadyl), nisoldipine, pimozide, quinidine, or terfenadine because the risk of severe heart effects may be increased


• Alprazolam, midazolam, or triazolam because their actions and the risk of their side effects may be increased by Sporanox, resulting in increased risk of sedation and breathing difficulties


• Aldosterone blockers (eg, eplerenone), calcium channel blockers (eg, verapamil), conivaptan, ergot alkaloids (eg, ergotamine), certain HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin), 5-HT receptor agonists (eg, eletriptan), or quinazolines (eg, alfuzosin) because the risk of their side effects may be increased by Sporanox

This may not be a complete list of all interactions that may occur. Ask your health care provider if Sporanox 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 Sporanox:

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

• Sporanox is usually administered as an injection at your doctor's office, hospital, or clinic. If you are using Sporanox at home, carefully follow the injection procedures taught to you by your health care provider.


• Do not use Sporanox if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


• To clear up your infection completely, use Sporanox for the full course of treatment. Keep using it even if you feel better in a few days. Do not miss any doses.


• Sporanox works best if it is taken at the same time each day.


• If you miss a dose of Sporanox, 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 Sporanox.

Important safety information:

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


• Rarely, Sporanox has been associated with serious, sometimes fatal liver damage. Contact your doctor right away if you notice dark urine, pale stools, a swollen or tender stomach, or yellowing of the skin or eyes.


• Sporanox only works against fungi; it does not treat viral infections (eg, the common cold).


• Be sure to use Sporanox for the full course of treatment. If you do not, the medicine may not clear up your infection completely. The fungus could also become less sensitive to this or other medicines. This could make the infection harder to treat in the future.


• Do not switch between the capsule and oral solution forms of Sporanox without checking with your doctor. Effectiveness and side effects of these forms of Sporanox may be different even at the same dose.


• Diabetes patients - Sporanox may increase the risk of low blood sugar from your diabetes medicine. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Hormonal birth control (eg, birth control pills) may not work as well while you are using Sporanox. To prevent pregnancy, use an extra form of birth control (eg, condoms).


• Tell your doctor or dentist that you take Sporanox before you receive any medical or dental care, emergency care, or surgery.


• Lab tests, including liver function, may be performed while you use Sporanox. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Sporanox with caution in the ELDERLY; they may be more sensitive to its effects, especially loss of hearing.


• Sporanox should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


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

Possible side effects of Sporanox:

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:

Diarrhea; dizziness; gas; headache; nausea; runny nose; stomach pain or upset; vomiting.

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); bloating; chest pain; confusion; coughing up white or pink mucus; dark urine; decreased sexual ability; depression; fast or irregular heartbeat; fever, chills, or sore throat; hair loss; increased or uncontrolled urination; joint pain; loss of appetite; loss of hearing; muscle pain, weakness, or cramping; numbness, burning, or tingling of the hands, arms, legs, or feet; pain, redness, or swelling at the injection site; pale stools; red, swollen, blistered, or peeling skin; ringing in the ears; sensitivity to sunlight; severe or persistent nausea or vomiting; severe stomach or back pain; shortness of breath; sudden weight gain; swelling of the hands, ankles, or feet; swollen or tender stomach; trouble sleeping; unusual bruising or bleeding; unusual tiredness or fatigue; vision changes (eg, blurred vision, double vision); yellowing of the skin or eyes.

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

See also: Sporanox 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 Sporanox:

Sporanox is usually handled and stored by a health care provider. If you are using Sporanox at home, store Sporanox as directed by your pharmacist or health care provider. Keep Sporanox out of the reach of children and away from pets.

General information:

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


• Sporanox 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 Sporanox. 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 Sporanox resources

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

• Sporanox Prescribing Information (FDA)


• Sporanox Consumer Overview


• Sporanox Monograph (AHFS DI)


• Sporanox Advanced Consumer (Micromedex) - Includes Dosage Information


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• Itraconazole Professional Patient Advice (Wolters Kluwer)

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Fesoterodine Fumarate

Class: Genitourinary Smooth Muscle Relaxants
ATC Class: G04BD11
VA Class: AU350
Chemical Name: isobutyric acid 2-((R)-3diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate
Molecular Formula: C₂₆H₃₇NO₃
CAS Number: 286930-03-8
Brands: Toviaz

Introduction

Genitourinary antispasmodic; an antimuscarinic agent.^{1 2 3 4 6}

Uses for Fesoterodine Fumarate

Overactive Bladder

Relief of symptoms associated with voiding (e.g., urge urinary incontinence, urgency, frequency).^{1 2 3 4 6 11}

Fesoterodine Fumarate Dosage and Administration

Administration

Oral Administration

Administer orally once daily with liquids without regard to meals.^{1 5}

Swallow extended-release tablets whole; do not chew, divide, or crush.^{1 5}

Dosage

Available as fesoterodine fumarate; dosage expressed in terms of the salt.¹

Adults

Overactive Bladder

Oral

Initially, 4 mg once daily.¹ Depending on individual response and tolerability, may increase to 8 mg once daily.¹

Prescribing Limits

Adults

Overactive Bladder

Oral

Maximum 8 mg daily.¹

Special Populations

Hepatic Impairment

Manufacturer does not recommend dosage adjustments for patient with mild or moderate hepatic impairment.¹ Some clinicians recommend caution when increasing dosage from 4 mg to 8 mg daily in patients with mild hepatic impairment (Child-Pugh class A) and a maximum dosage of 4 mg daily in patients with moderate hepatic impairment (Child-Pugh class B).^{2 10} (See Absorption: Special Populations, under Pharmacokinetics.)

Use not recommended in patients with severe hepatic impairment (Child-Pugh class C).^{1 10}

Renal Impairment

Manufacturer does not recommend dosage adjustments for patient with mild or moderate renal impairment (Cl_cr 30–80 mL/minute); some clinicians recommend caution when increasing dosage from 4 mg to 8 mg daily in such patients.^{1 2 10} (See Absorption: Special Populations, under Pharmacokinetics.)

In patients with severe renal impairment (Cl_cr <30 mL/minute), maximum dosage 4 mg daily.^{1 10}

Geriatric Patients

No dosage adjustment required.¹

Cautions for Fesoterodine Fumarate

Contraindications

• 
  

  Urinary retention, gastric retention, or uncontrolled angle-closure glaucoma.¹

  
  


• 
  

  Known hypersensitivity to fesoterodine fumarate or any ingredient in the formulation.¹

  
  

Warnings/Precautions

General Precautions

Urinary Retention

Risk of urinary retention; use with caution in patients with clinically important bladder outflow obstruction.¹

Decreased GI Motility

Use with caution in patients with decreased GI motility (e.g., patients with severe constipation).¹

Controlled Angle-closure Glaucoma

Use with caution in patients being treated for angle-closure glaucoma and only when potential benefits outweigh risks.¹ (See Cautions: Contraindications.)

Myasthenia Gravis

Use with caution in patients with myasthenia gravis.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether fesoterodine is distributed into milk in humans; do not use unless benefit to woman outweighs potential risk to the infant.¹

Pediatric Use

Safety and efficacy not established in pediatric patients.¹

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.¹

Incidence of adverse antimuscarinic events (e.g., dry mouth, constipation, dyspepsia, increase in residual urine, dizziness [only at a dosage of 8 mg daily]) and urinary tract infection was higher in patients ≥75 years of age compared with younger patients.¹

Hepatic Impairment

Not studied in patients with severe hepatic impairment (Child-Pugh class C); use not recommended in these patients.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Dosage adjustment recommended in patients with severe renal impairment.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Dry mouth, constipation.^{1 9}

Interactions for Fesoterodine Fumarate

Rapidly metabolized to active metabolite, 5-hydroxymethyl tolterodine (5-HMT), by nonspecific esterases; active metabolite is further metabolized, principally via CYP2D6 and CYP3A4.^{1 2 10} 5-HMT does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 and does not induce CYP isoenzymes 1A2, 2B6, 2C9, 2C19, or 3A4.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma 5-HMT concentrations).¹ Do not exceed 4 mg daily when used concomitantly with potent CYP3A4 inhibitors.¹

Weak or moderate inhibitors of CYP3A4: Effects on 5-HMT pharmacokinetics not studied; pharmacokinetic interaction is expected, albeit less than that observed with potent CYP3A4 inhibitors.¹ Carefully assess tolerability at 4-mg daily dosage of fesoterodine fumarate prior to increasing dosage to 8 mg daily in patients concomitantly receiving weak or moderate CYP3A4 inhibitors.¹

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma 5-HMT concentrations); no dosage adjustments are recommended.¹

Inhibitors of CYP2D6: Effects on 5-HMT pharmacokinetics not tested clinically.¹ However, increased plasma 5-HMT concentrations observed in subjects with poor metabolizer phenotype for CYP2D6; no dosage adjustments recommended when CYP2D6 inhibitors are used concomitantly.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1isoenzymeA2 s, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4: Pharmacokinetic interactions unlikely.¹

Orally Administered Drugs

Potential pharmacokinetic interaction (altered absorption because of anticholinergic effects on GI motility).¹ (See Decreased GI Motility under Cautions.)

Specific Drugs

Drug	Interaction	Comments
Antimuscarinic agents	Potential increased frequency and/or severity of adverse anticholinergic effects (e.g., dry mouth, constipation, urinary retention) 1
Azole antifungals (itraconazole, ketoconazole)	Possible increased plasma 5-HMT concentrations1 Ketoconazole: Increased plasma 5-HMT concentrations1	Do not exceed a fesoterodine fumarate dosage of 4 mg daily when used concomitantly1
Clarithromycin	Possible increased plasma 5-HMT concentrations1	Do not exceed a fesoterodine fumarate dosage of 4 mg daily when used concomitantly1
Hormonal contraceptives, oral (ethinyl estradiol-levonorgestrel)	Pharmacokinetic interaction unlikely1
Erythromycin	Effects on 5-HMT pharmacokinetics not studied; pharmacokinetic interaction is expected1	Carefully assess tolerability at fesoterodine fumarate 4-mg daily dosage prior to increasing dosage to 8 mg daily1
Rifampin	Decreased plasma 5-HMT concentrations and AUC1	No fesoterodine fumarate dosage adjustments recommended1

Fesoterodine Fumarate Pharmacokinetics

Absorption

Bioavailability

Following oral administration of fesoterodine, peak plasma concentrations of active metabolite, 5-hydroxymethyl tolterodine (5-HMT), are achieved in approximately 5 hours; because of rapid metabolism, fesoterodine itself is not detected in plasma.¹

Bioavailability of 5-HMT is 52%.¹

Onset

Symptomatic improvement (i.e., reduction in number of urge incontinence episodes) observed as early as 2 weeks after starting fesoterodine therapy.¹

Food

Food has no clinically important effect on fesoterodine pharmacokinetics.¹

Special Populations

In individuals with poor metabolizer phenotypes of CYP2D6 (approximately 7% of Caucasians and 2% of African Americans), peak plasma concentrations of 5-HMT increased by 1.7-fold and AUC increased twofold as compared with extensive metabolizers.¹

In patients with mild or moderate renal insufficiency (Cl_cr 30–80 mL/minute), peak plasma concentrations and AUC of 5-HMT were increased up to 1.5- and 1.8-fold, respectively, as compared with those in healthy subjects.¹ In patients with severe renal impairment (Cl_cr <30 mL/minute), peak plasma concentrations and AUC of 5-HMT were increased twofold and 2.3-fold, respectively.¹ (See Renal Impairment under Dosage and Administration.)

In patients with moderate (Child-Pugh class B) hepatic impairment, peak plasma concentrations and AUC of 5-HMT were increased 1.4 and 2.1-fold, respectively, as compared with those in healthy subjects.¹ Subjects with severe hepatic impairment (Child-Pugh class C) have not been studied.¹ (See Hepatic Impairment under Dosage and Administration.)

Distribution

Extent

Not known whether distributed into human milk.¹

Plasma Protein Binding

5-HMT: Approximately 50%, principally to albumin and α₁-acid glycoprotein.¹

Elimination

Metabolism

Fesoterodine is a prodrug: rapidly and extensively hydrolyzed by nonspecific esterases to 5-HMT, which is responsible for the antimuscarinic effects of fesoterodine.^{1 2 6 10} Tolterodine, another antimuscarinic agent used in the treatment of overactive bladder, also is metabolized to 5-HMT; however, tolterodine metabolism to 5-HMT is via CYP2D6.^{1 2 10}

5-HMT is further metabolized to various metabolites in the liver, principally via CYP2D6 and CYP3A4.^{1 2 6 10} None of these metabolites contribute substantially to the antimuscarinic activity of fesoterodine.^{1 10}

Elimination Route

Recovered in urine (70%) and feces (7%) as various active and inactive metabolites.^{1 6}

Half-life

Terminal half-life of 5-HMT following oral administration of fesoterodine fumarate is approximately 7 hours.^{1 2 10}

Special Populations

Pharmacokinetics not substantially affected by gender or age; pharmacokinetics not studied in pediatric patients.¹

Available data indicate no differences in pharmacokinetics between Caucasian and black subjects.¹

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).¹ Protect from moisture.¹

ActionsActions

• 
  

  Fesoterodine is a competitive antimuscarinic agent.¹

  
  


• 
  

  Fesoterodine is a prodrug: rapidly and extensively hydrolyzed to 5-hydroxymethyl tolterodine (5-HMT), which is responsible for the antimuscarinic effects of fesoterodine.^{1 2 6 10}

  
  


• 
  

  Fesoterodine and 5-HMT inhibit contraction of the urinary bladder smooth muscle.^{1 6}

  
  


• 
  

  In urodynamic study, fesoterodine administration increased volume at first detrusor contraction and bladder capacity in dose-dependent manner.¹

  
  

Advice to Patients

• 
  

  Importance of reading manufacturer's patient information before beginning fesoterodine therapy.^{1 5}

  
  


• 
  

  Risk of dry mouth, constipation, dry eyes, urinary retention, decreased sweating and heat prostration (when used in a hot environment).^{1 5}

  
  


• 
  

  May cause blurred vision and drowsiness.^{1 5} Use caution when driving or performing dangerous activities until effects are known.⁵ Alcohol may enhance the drowsiness caused by fesoterodine.^{1 5}

  
  


• 
  

  Importance of taking fesoterodine with liquids and swallowing the extended-release tablet whole; do not chew, divide, or crush.^{1 5}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 5}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^{1 5}

  
  


• 
  

  Importance of advising patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

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

Fesoterodine Fumarate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, extended-release	4 mg	Toviaz	Pfizer
		8 mg	Toviaz	Pfizer

Disclaimer

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

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

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer. Toviaz (fesoterodine fumarate) extended-release tablets prescribing information. NY, NY; 2008 Nov.

2. Michel MC. Fesoterodine: a novel muscarinic receptor antagonist for the treatment of overactive bladder syndrome. Expert Opin Pharmacother. 2008; 9:1787-96. [PubMed 18570610]

3. Nitti VW, Dmochowski R, Sand PK et al. Efficacy, safety and tolerability of fesoterodine for overactive bladder syndrome. J Urol. 2007; 178:2488-94. [PubMed 17937959]

4. Chapple C, Van Kerrebroeck P, Tubaro A et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol. 2007; 52:1204-12. [PubMed 17651893]

5. Pfizer. Toviaz (fesoterodine fumarate) extended-release tablets patient information. NY, NY; 2008 Nov.

6. McKeage K, Keating GM. Fesoterodine. Drugs. 2009; 69:731-8. [PubMed 19405552]

7. Kelleher CJ, Tubaro A, Wang JT et al. Impact of fesoterodine on quality of life: pooled data from two randomized trials. BJU Int. 2008; 102:56-61. [PubMed 18564231]

8. Chapple C, Van Kerrebroeck P, Tubaro A et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol. 2007; 52:1204-12. [PubMed 17651893]

9. Khullar V, Rovner ES, Dmochowski R et al. Fesoterodine dose response in subjects with overactive bladder syndrome. Urology. 2008; 71:839-43. [PubMed 18342923]

10. Witte LP, Mulder WM, de la Rosette JJ et al. Muscarinic receptor antagonists for overactive bladder treatment: does one fit all?. Curr Opin Urol. 2009; 19:13-9. [PubMed 19057211]

11. Chapple CR, Khullar V, Gabriel Z et al. The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol. 2008; 54:543-62. [PubMed 18599186]

More Fesoterodine Fumarate resources

• Fesoterodine Fumarate Side Effects (in more detail)
• Fesoterodine Fumarate Use in Pregnancy & Breastfeeding
• Fesoterodine Fumarate Drug Interactions
• Fesoterodine Fumarate Support Group
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• Overactive Bladder
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Ichtex

Ichtex may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Ichtex

Malachite Green

Malachite Green oxalate (a derivative of Malachite Green) is reported as an ingredient of Ichtex in the following countries:

• Switzerland

International Drug Name Search

Clonidine Tablets

Generic Name: clonidine hydrochloride

Dosage Form: tablet
Clonidine HCL 0.1 mg USP 1 Tablet Blister Pack

Description

Clonidine Hydrochloride is a centrally acting alpha-agonist hypotensive agent available as tablets for oral administration in three dosage strengths: 0.1 mg, 0.2 mg, and 0.3 mg. The 0.1 mg tablet is equivalent to 0.087 mg of the free base. The following inactive ingredients are contained in these products: corn starch, D and C yellow #10 Aluminum Lake, FD and C yellow #6 Aluminum Lake (Sunset Yellow Lake), lactose monohydrate, magnesium stearate, and sodium starch glycolate. Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-(2,6- dichlorophenylamino)-2-imidazoline hydrochloride. The following is the structural formula:

Structural Formula

Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol.

Clinical Pharmacology

Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. Clonidine hydrochloride, acts relatively rapidly. The patient’s blood pressure declines within 30 to 60 minutes after an oral dose, the maximum

decrease occurring within 2 to 4 hours. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact, therefore, orthostatic symptoms are mild and infrequent. Acute studies with clonidine hydrochloride in humans have demonstrated a moderate reduction (15% to 20%) of cardiac output in the supine position with no change in the peripheral resistance: at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral resistance. During long term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise. Tolerance to the antihypertensive effect may develop in some patients, necessitating a reevaluation of therapy. Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. The exact relationship of these pharmacologic actions to the antihypertensive effect of clonidine has not been fully

elucidated. Clonidine acutely stimulates growth hormone release in both children and adults, but does not produce a chronic elevation of growth hormone with long-term use. Pharmacokinetics: The plasma level of clonidine peaks in approximately 3 to 5 hours and the plasma half-life ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Following oral administration about 40-60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver.

Indications and Usage

Clonidine hydrochloride is indicated in the treatment of hypertension. Clonidine hydrochloride may be employed alone or concomitantly with other antihypertensive agents.

Contraindications

Clonidine hydrochloride tablets should not be used in patients with known hypersensitivity to clonidine (see PRECAUTIONS).

Warnings

Withdrawal: Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with clonidine hydrochloride, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptomatology. An excessive rise in blood pressure following discontinuation of clonidine therapy can be reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine.

Because children commonly have gastrointestinal illnesses that lead to vomiting, they may be particularly susceptible to hypertensive episodes resulting from abrupt inability to take medication.

Precautions

General

In patients who have developed localized contact sensitization to transdermal clonidine, continuation of transdermal clonidine or substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash. In patients who develop an allergic reaction to transdermal clonidine, substitution of oral clonidine hydrochloride may also elicit an

allergic reaction (including generalized rash, urticaria, or angioedema). Clonidine hydrochloride should be used with caution in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease or chronic renal failure.

Perioperative Use: Administration of clonidine hydrochloride should be continued to within four hours of surgery and resumed as soon as possible thereafter. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required.

Information for Patients

Patients should be cautioned against interruption of clonidine hydrochloride therapy without their physician’s advice. Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of a possible sedative effect of clonidine. They should also be informed that this sedative effect may be increased by concomitant use of alcohol,

barbiturates, or other sedating drugs.

Drug Interactions

Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine hydrochloride is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose. Due to a potential for additive effects such as bradycardia and AV block, caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction, e.g. digitalis, calcium channel blockers and beta-blockers. Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats (see Toxicology).

Toxicology: In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for six months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid. In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 patients before, and periodically after, the start of clonidine therapy. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged. In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78 weeks) dosed, respectively, at up to 46 or 70 times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD on a mg/m2 basis). There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity. Fertility of male or female rats was unaffected by clonidine doses as high as 150 mcg/kg (approximately 3 times MRDHD). In a separate experiment, fertility of female rats appeared to be affected at dose levels of 500 to 2000 mcg/kg (10 to 40 times the oral MRDHD on a mg/kg basis, 2 to 8 times the MRDHD on a mg/m2 basis).

Usage In Pregnancy

Teratogenic Effects

Pregnancy Category C

Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of clonidine hydrochloride produced no evidence of a teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m2 basis) of clonidine were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment at the same time or at higher dose levels (up to 3 times the oral MRDHD) when the dams were treated on gestation days 6-15. Increases in resorption were observed at much higher dose levels (40 times the oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m2 basis) in mice and rats treated on gestation days 1-14 (lowest dose employed in the study was 500 mcg/kg). No adequate, well-controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

As clonidine hydrochloride is excreted in human milk, caution should be exercised when clonidine hydrochloride is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of twelve have not been established (See WARNINGS on Withdrawal).

Adverse Reactions

Most adverse effects are mild and tend to diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients; drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100. The following less frequent adverse experiences have also been reported in patients receiving clonidine hydrochloride, but in many cases patients were receiving concomitant medication and a causal relationship has not been established.

Body As A Whole: Weakness, about 10 in 100 patients; fatigue, about 4 in 100; headache and withdrawal syndrome each about 1 in 100. Also reported were pallor; a weakly positive Coombs’ test, increased sensitivity to alcohol; and fever.

Cardiovascular: Orthostatic symptoms, about 3 in 100 patients; palpitations and tachycardia, and bradycardia, each about 5 in 1000. Syncope, Raynaud’s phenomenon, congestive heart failure, and electrocardiographic abnormalities (i.e. sinus node arrest, functional bradycardia, high degree AV block and arrhythmias) have been reported rarely. Rare cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

Central Nervous System: Nervousness and agitation, about 3 in 100 patients; mental depression, about 1 in 100 and insomnia, about 5 in 1000. Other behavioral changes, vivid dreams or nightmares, restlessness, anxiety, visual and auditory hallucinations and delirium have rarely been reported.

Dermatological: Rash, about 1 in 100 patients; pruritus, about 7 in 1000; hives, angioneurotic edema and urticaria, about 5 in 1000; alopecia, about 2 in 1000.

Gastrointestinal: Nausea and vomiting, about 5 in 100 patients; anorexia and malaise, each about 1 in 100; mild transient abnormalities in liver function tests, about 1 in 100; hepatitis, parotitis, constipation, pseudo-obstruction, and abdominal pain, rarely.

Genitourinary: Decreased sexual activity, impotence and loss of libido, about 3 in 100 patients; nocturia, about 1 in 100; difficulty in micturition, about 2 in 1000; urinary retention, about 1 in 1000.

Hematologic: Thrombocytopenia, rarely.

Metabolic: Weight gain, about 1 in 100 patients; gynecomastia, about 1 in 1000; transient elevation of blood glucose or serum creatine phosphokinase, rarely.

Musculoskeletal: Muscle or joint pain, about 6 in 1000 and leg cramps, about 3 in 1000.

Oro-otolaryngeal: Dryness of the nasal mucosa was rarely reported.

Ophthalmological: Dryness of eyes, burning of the eyes and blurred vision were reported.

Overdosage

Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. As little as 0.1 mg of clonidine has produced signs of toxicity in children. There is no specific antidote for clonidine overdosage. Clonidine overdosage may result in the rapid development of CNS depression; therefore, induction of vomiting with ipecac syrup is not recommended. Gastric lavage may be indicated following recent and/or large ingestions. Administration of activated charcoal and/or a cathartic may be beneficial. Supportive care may include atropine sulfate

for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Tolazoline administration has yielded inconsistent results and is not recommended as first-line therapy. Dialysis is not likely to significantly enhance the elimination of clonidine.

The largest overdose reported to date involved a 28-year old male who ingested 100 mg of clonidine hydrochloride powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/ml after 1 hour, 190 ng/ml after 1.5 hours, 370 ng/ml after 2 hours, and 120 ng/ml after 5.5 and 6.5 hours. In mice and rats, the oral LD50 of clonidine is 206 and 465 mg/kg, respectively.

Dosage and Administration

Adults: The dose of clonidine hydrochloride must be adjusted according to the patient’s individual blood pressure response. The following is a general guide to its administration.

Initial Dose: 0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower initial dose.

Maintenance Dose: Further increments of 0.1 mg per day may be made at weekly intervals if necessary until the desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects of dry mouth and drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses. Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this have rarely been employed.

Renal Impairment: Dosage must be adjusted according to the degree of impairment, and patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

How Supplied

0.1 mg — Each orange, round tablet imprinted with Imprint Image and 127 on one side and bisect on the other side contains 0.1 mg of Clonidine hydrochloride USP and is supplied in unit dose box of 100 (NDC 0904-5656-61).

0.2 mg — Each orange, round tablet imprinted with Imprint Image on one side and 128 and bisect on the other side contains 0.2 mg of Clonidine hydrochloride USP and is supplied in unit dose box of 100 (NDC 0904-5657-61).

0.3 mg — Each orange, round tablet imprinted with Imprint Image on one side and 129 and bisect on the other side contains 0.3 mg of Clonidine hydrochloride USP and is supplied in unit dose box of 100 (NDC 0904-5658-61).

Dispense in a tight, light-resistant container as defined in the USP.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Manufactured by:                                 Distributed by:

Actavis Elizabeth LLC                          Major Pharmaceuticals

Elizabeth, NJ 07207 USA                     Livonia, MI 48150

40-9009

Revised — January 2008

Outer Package Label

CLONIDINE HYDROCHLORIDE   clonidine hydrochloride  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 52584-656 (0904-5656) Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Clonidine Hydrochloride (Clonidine) Clonidine Hydrochloride 0.1 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color orange Score 2 pieces Shape ROUND Size 6mm Flavor Imprint Code R127 Contains

Packaging # NDC Package Description Multilevel Packaging 1 52584-656-61 1 BLISTER In 1 BAG contains a BLISTER PACK 1 1 TABLET In 1 BLISTER PACK This package is contained within the BAG (52584-656-61)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA070974	03/01/2010

Labeler - General Injectables & Vaccines, Inc (108250663)

Revised: 11/2011General Injectables & Vaccines, Inc

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