Proloprim

trimethoprim

Dosage Form: Tablets

Description:

Proloprim (trimethoprim) is a synthetic antibacterial available in tablet form for oral administration. Each scored white tablet contains 100 mg trimethoprim and the inactive ingredients corn starch, lactose, magnesium stearate, and sodium starch glycolate. Each scored yellow tablet contains 200 mg trimethoprim and the inactive ingredients corn starch, D & C Yellow No. 10, magnesium stearate, and sodium starch glycolate.

Trimethoprim is 5-[(3,4,5,-trimethoxyphenyl)methyl]-2,4-pyrimidinediamine. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.32 and the molecular formula C14H18N4O3. The structural formula is:

Clinical Pharmacology:

Trimethoprim is rapidly absorbed following oral administration. It exists in the blood as unbound, protein-bound, and metabolized forms. Ten to twenty percent of trimethoprim is metabolized, primarily in the liver; the remainder is excreted unchanged in the urine. The principal metabolites of trimethoprim are the 1- and 3-oxides and the 3’- and 4’- hydroxy derivatives. The free form is considered to be the therapeutically active form. Approximately 44% of trimethoprim is bound to plasma proteins.

Mean peak serum concentrations of approximately 1.0 mcg/mL occur 1 to 4 hours after oral administration of a single 100-mg dose. A single 200-mg dose will result in serum levels approximately twice as high. The half-life of trimethoprim ranges from 8 to 10 hours. However, patients with severely impaired renal function exhibit an increase in the half-life of trimethoprim, which requires either dosage regimen adjustment or not using the drug in such patients (see DOSAGE AND ADMINISTRATION). During a 13-week study of trimethoprim administered at a daily dosage of 200 mg (50 mg qid), the mean minimum steady-state concentration of the drug was 1.1 mcg/mL. Steady-state concentrations were achieved within 2 to 3 days of chronic administration and were maintained throughout the experimental period.

Excretion of trimethoprim is primarily by the kidneys through glomerular filtration and tubular secretion. Urine concentrations of trimethoprim are considerably higher than are the concentrations in the blood. After a single oral dose of 100 mg, urine concentrations of trimethoprim ranged from 30 to 160 mcg/mL during the 0- to 4-hour period and declined to approximately 18 to 91 mcg/mL during the 8- to 24-hour period. A 200 mg single oral dose will result in trimethoprim urine levels approximately twice as high. After oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of this being unmetabolized trimethoprim.

Since normal vaginal and fecal flora are the source of most pathogens causing urinary tract infections, it is relevant to consider the distribution of trimethoprim into these sites. Concentrations of trimethoprim in vaginal secretions are consistently greater than those found simultaneously in the serum, being typically 1.6 times the concentrations of simultaneously obtained serum samples. Sufficient trimethoprim is excreted in the feces to markedly reduce or eliminate trimethoprim-susceptible organisms from the fecal flora.

Trimethoprim also passes the placental barrier and is excreted in human milk.

Microbiology : Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. This binding is much stronger for the bacterial enzyme than for the corresponding mammalian enzyme. Thus, trimethoprim selectively interferes with bacterial biosynthesis of nucleic acids and proteins.

In vitro serial dilution tests have shown that the spectrum of antibacterial activity of trimethoprim includes the common urinary tract pathogens with the exception of Pseudomonas aeruginosa.

The dominant non-Enterobacteriaceae fecal organisms, Bacteroides spp. and Lactobacillus spp., are not susceptible to trimethoprim concentrations obtained with the recommended dosage.

Trimethoprim has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic gram-positive microorganisms:

Staphylococcus species (coagulase-negative strains, including S. saprophyticus )

Aerobic gram-negative microorganisms:

Enterobacter species

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Susceptibility Testing Methods

Dilution techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of trimethoprim powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae and Staphylococcus spp.:

MIC (mcg/mL)	Interpretation
≤ 8	Susceptible (S)
≥ 16	Resistant (R)

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard trimethoprima powder should provide the following MIC values:

Microorganism		MIC (mcg/mL)
Escherichia coli	ATCC 25922	0.5–2.0
Staphylococcus aureus	ATCC 29213	1.0–4.0

a Very medium-dependent.

Diffusion techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-mcg trimethoprim to test the susceptibility of microorganisms to trimethoprim.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-mcg trimethoprim disk should be interpreted according to the following criteria:

For testing Enterobacteriaceae and Staphylococcus spp.:

Zone Diameter (mm)	Interpretation
≥ 16	Susceptible (S)
11–15	Intermediate (I)
≤ 10	Resistant (R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC of trimethoprim.

As with standardized dilution techniques, diffusion methods require the use of the laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-mcg trimethoprim disk should provide the following zone diameters in these laboratory test quality control strains:

Microorganism		MIC (mcg/mL)
Escherichia coli	ATCC 25922	0.5–2.0
Microorganism		Zone Diameter (mm)
Escherichia coli	ATCC 25922	21–28
Staphylococcus aureus	ATCC 25923	19–26

b Mueller-Hinton agar should be checked for excessive levels of thymidine. To determine whether Mueller-Hinton medium has sufficiently low levels of thymidine and thymine, an Enterococcus faecalis (ATCC 29212 or ATCC 33186) may be tested with trimethoprim/sulfamethoxazole disks. A zone of inhibition ≥ 20 mm that is essentially free of fine colonies indicates a sufficiently low level of thymidine and thymine.

Indications and Usage:

For the treatment of initial episodes of uncomplicated urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species, and coagulase-negative Staphylococcus species, including S. saprophyticus.

Cultures and susceptibility tests should be performed to determine the susceptibility of the bacteria to trimethoprim. Therapy may be initiated prior to obtaining the results of these tests.

Contraindications:

Proloprim is contraindicated in individuals hypersensitive to trimethoprim and in those with documented megaloblastic anemia due to folate deficiency.

Warnings:

Serious hypersensitivity reactions have been reported rarely in patients on trimethoprim therapy. Trimethoprim has been reported rarely to interfere with hematopoiesis, especially when administered in large doses and/or for prolonged periods.

The presence of clinical signs such as sore throat, fever, pallor, or purpura may be early indications of serious blood disorders (see OVERDOSAGE: Chronic).

Complete blood counts should be obtained if any of these signs are noted in a patient receiving trimethoprim and the drug discontinued if a significant reduction in the count of any formed blood element is found.

Precautions:

General:

Trimethoprim should be given with caution to patients with possible folate deficiency. Folates may be administered concomitantly without interfering with the antibacterial action of trimethoprim. Trimethoprim should also be given with caution to patients with impaired renal or hepatic function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Drug Interactions:

Proloprim may inhibit the hepatic metabolism of phenytoin. Trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 51% and decreased the phenytoin metabolic clearance rate by 30%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.

Drug and Laboratory Test Interactions:

Trimethoprim can interfere with a serum methotrexate assay as determined by the Competitive Binding Protein Technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA).

The presence of trimethoprim may also interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Carcinogenesis:

Long-term studies in animals to evaluate carcinogenic potential have not been conducted with trimethoprim.

Mutagenesis:

Trimethoprim was demonstrated to be nonmutagenic in the Ames assay. In studies at two laboratories, no chromosomal damage was detected in cultured Chinese hamster ovary cells at concentrations approximately 500 times human plasma levels; at concentrations approximately 1000 times human plasma levels in these same cells, a low level of chromosomal damage was induced at one of the laboratories. No chromosomal abnormalities were observed in cultured human leukocytes at concentrations of trimethoprim up to 20 times human steady-state plasma levels. No chromosomal effects were detected in peripheral lymphocytes of human subjects receiving 320 mg of trimethoprim in combination with up to 1600 mg of sulfamethoxazole per day for as long as 112 weeks.

Impairment of Fertility:

No adverse effects on fertility or general reproductive performance were observed in rats given trimethoprim in oral dosages as high as 70 mg/kg/day for males and 14 mg/kg/day for females.

Pregnancy:

Teratogenic Effects:

Pregnancy Category C. Trimethoprim has been shown to be teratogenic in the rat when given in doses 40 times the human dose. In some rabbit studies, the overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with doses six times the human therapeutic dose.

While there are no large, well-controlled studies on the use of trimethoprim in pregnant women, Brumfitt and Pursell,4 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or trimethoprim in combination with sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.

Because trimethoprim may interfere with folic acid metabolism, Proloprim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects:

The oral administration of trimethoprim to rats at a dose of 70 mg/kg/day commencing with the last third of gestation and continuing through parturition and lactation caused no deleterious effects on gestation or pup growth and survival.

Nursing Mothers:

Trimethoprim is excreted in human milk. Because trimethoprim may interfere with folic acid metabolism, caution should be exercised when Proloprim is administered to a nursing woman.

Pediatric Use:

Safety and effectiveness in pediatric patients below the age of 2 months have not been established. The effectiveness of trimethoprim as a single agent has not been established in pediatric patients under 12 years of age.

Geriatric Use:

Clinical studies of Proloprim (trimethoprim) Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience4,5 has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Case reports of hyperkalemia in elderly patients receiving trimethoprim-sulfaethoxazole have been published.6 Trimethoprim is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor potassium concentrations and to monitor renal function by calculating creatinine clearance.

Adverse Reactions:

The adverse effects encountered most often with trimethoprim were rash and pruritus.

Dermatologic:

Rash, pruritus, and phototoxic skin eruptions. At the recommended dosage regimens of 100 mg b.i.d. or 200 mg q.d., each for 10 days, the incidence of rash is 2.9% to 6.7%. In clinical studies which employed high doses of Proloprim, an elevated incidence of rash was noted. These rashes were maculopapular, morbilliform, pruritic, and generally mild to moderate, appearing 7 to 14 days after the initiation of therapy.

Hypersensitivity:

Rare reports of exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell Syndrome), and anaphylaxis have been received.

Gastrointestinal:

Epigastric distress, nausea, vomiting, and glossitis. Elevation of serum transaminase and bilirubin has been noted, but the significance of this finding is unknown. Cholestatic jaundice has been rarely reported.

Hematologic:

Thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia, and methemoglobinemia.

Metabolic:

Hyperkalemia, hyponatremia.

Neurologic:

Aseptic meningitis has been rarely reported.

Miscellaneous:

Fever, and increases in BUN and serum creatinine levels.

Overdosage:

Acute:

Signs of acute overdosage with trimethoprim may appear following ingestion of 1 gram or more of the drug and include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression (see Chronic subsection).

Treatment consists of gastric lavage and general supportive measures. Acidification of the urine will increase renal elimination of trimethoprim. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating the drug.

Chronic:

Use of trimethoprim at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia, and/or megaloblastic anemia. If signs of bone marrow depression occur, trimethoprim should be discontinued and the patient should be given leucovorin; 5 to 15 mg leucovorin daily has been recommended by some investigators.

Dosage and Administration:

The usual oral adult dosage is 100 mg of Proloprim every 12 hours or 200 mg Proloprim every 24 hours, each for 10 days. The use of trimethoprim in patients with a creatinine clearance of less than 15 mL/min is not recommended. For patients with a creatinine clearance of 15 to 30 mL/min, the dose should be 50 mg every 12 hours.

How Supplied:

100-mg Tablets (white, scored, round-shaped), containing 100 mg trimethoprim–bottle of 100 (NDC 61570-057-01). Imprint on tablets “Proloprim 09A.”Store at 15° to 25°C (59° to 77°F) in a dry place.

200-mg Tablets (yellow, scored, round-shaped), containing 200 mg trimethoprim–bottle of 100 (NDC 61570-058-01). Imprint on tablets “Proloprim 200.”Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light.

Rx Only.

References:

1. 
   

   National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. 3rd ed.; Approved Standard. NCCLS Document M7-A4, Vol. 17, No. 2. NCCLS, Wayne, PA, January, 1997.

   
   


2. 
   

   National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests. Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1, NCCLS, Wayne, PA, January, 1997.

   
   


3. 
   

   Brumfitt W, Pursell R. Trimethoprim-sulfamethoxazole in the treatment of bacteriuria in women. J Infect Dis . 1973;128(suppl):S657-S663.

   
   


4. 
   

   Lacey RW, Simpson MHC, Fawcett C, et al. Comparison of single-dose trimethoprim with a five-day course for the treatment of urinary tract infections in the elderly. Age and Ageing 10: 179–185, 1981.

   
   


5. 
   

   Ewer TC, Bailey RR, Gilchrist NL, et al. Comparative study of norfloxacin and trimethoprim for the treatment of elderly patients with urinary tract infection. NZ Med J 101: 537–539, 1988.

   
   


6. 
   

   Marinella MA. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontology 45: 209–212, 1999.

   
   

Prescribing Information as of February 2003.

Distributed by: Monarch Pharmaceuticals, Inc. Bristol, TN 37620

Manufactured by: DSM Pharmaceuticals, Inc. Greenville, NC 27834

Proloprim  trimethoprim  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 61570-057 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength trimethoprim (trimethoprim) Active 100 MILLIGRAM  In 1 TABLET corn starch Inactive   lactose Inactive   magnesium stearate Inactive   sodium starch glycolate Inactive

Product Characteristics Color WHITE Score 2 pieces Shape ROUND Size 9mm Flavor Imprint Code Proloprim;09A Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 61570-057-01 100 TABLET In 1 BOTTLE None

Proloprim  trimethoprim  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 61570-058 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength trimethoprim (trimethoprim) Active 200 MILLIGRAM  In 1 TABLET corn starch Inactive   D&C Yellow No. 10 Inactive   magnesium stearate Inactive   sodium starch glycolate Inactive

Product Characteristics Color YELLOW Score 2 pieces Shape ROUND Size 9mm Flavor Imprint Code Proloprim;200 Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 61570-058-01 100 TABLET In 1 BOTTLE None

Revised: 10/2006Monarch Pharmaceuticals, Inc.

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Colestipol

Pronunciation: koe-LES-ti-pol
Generic Name: Colestipol
Brand Name: Colestid

Colestipol is used for:

Lowering blood cholesterol levels. It is used along with changes in diet.

Colestipol is a bile acid sequestrant. It works in the bowel to help remove bile acids from the body. The body then uses cholesterol to make more bile acids. This causes blood cholesterol levels to decrease.

Do NOT use Colestipol if:

• you are allergic to any ingredient in Colestipol


• you have severe constipation, bile blockage or drainage problems, certain types of high blood lipid levels, or hyperchloremic metabolic acidosis (a type of high blood acid level)

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

Before using Colestipol:

Some medical conditions may interact with Colestipol. 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 constipation, hemorrhoids, or problems swallowing, or if you choke easily


• if you have heart disease, blood problems (eg, bleeding or clotting problems), high blood triglyceride levels, kidney or liver problems, or underactive thyroid


• if you cannot absorb nutrients properly into your body

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

• Beta-blockers (eg, propranolol) because their effectiveness may be altered by Colestipol


• Chlorothiazide, digoxin, furosemide, gemfibrozil, hydrochlorothiazide, oral hydrocortisone, oral phosphate supplements, penicillin, or tetracycline because their effectiveness may be decreased by Colestipol

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

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

• Take Colestipol by mouth with or without food.


• Swallow Colestipol whole. Do not cut, crush, or chew tablets.


• Always take one tablet at a time. Swallow the tablet right away.


• Take each dose with at least one full glass (8 oz/240 mL) of water or other liquid. Swallowing the tablet will be easier if you drink plenty of liquids as you swallow each tablet.


• Take any other medicines at least 1 hour before or 4 hours after you take Colestipol.


• Drinking extra fluids and making sure you get enough fiber is recommended while you are taking Colestipol. Check with your doctor for instructions.


• Continue to take Colestipol even if you feel well. Do not miss any doses.


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

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

Important safety information:

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


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


• Do not take more than the recommended dose or use for longer than prescribed without checking with your doctor.


• If severe or persistent constipation occurs, ask your doctor about taking a stool softener while you take Colestipol.


• If the tablet gets stuck after you swallow it, you may notice chest pressure or discomfort. If this happens, contact your doctor right away. Do not take another tablet unless your doctor tells you otherwise.


• Lab tests, including blood cholesterol and blood triglyceride levels, may be performed while you use Colestipol. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


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

Possible side effects of Colestipol:

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:

Bloating; constipation; diarrhea; gas; heartburn; indigestion; loose stools; nausea; stomach pain or cramping; 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); blood in the stools; chest pressure or discomfort; irregular heartbeat; muscle weakness; severe constipation; trouble swallowing; unusual bruising or bleeding.

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: Colestipol 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 Colestipol:

Store Colestipol at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Colestipol out of the reach of children and away from pets.

General information:

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


• Colestipol 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 Colestipol. 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.

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Celestone

betamethasone

Dosage Form: oral solution
Celestone®

brand of betamethasone

Oral Solution USP

PRODUCT INFORMATION

Celestone Description

Celestone® Oral Solution, for oral administration, contains 0.6 mg betamethasone in each 5 mL. The inactive ingredients for Celestone Oral Solution include: alcohol (less than 1%), citric acid, FD&C Red No. 40, FD&C Yellow No. 6, flavors, propylene glycol, sodium benzoate, sodium chloride, sorbitol, sugar, and water.

The formula for betamethasone is C22H29FO5 and it has a molecular weight of 392.47. Chemically, it is 9-fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione and has the following structure:

Betamethasone is a white to practically white, odorless crystalline powder. It melts at about 240°C with some decomposition. Betamethasone is sparingly soluble in acetone, alcohol, dioxane, and methanol; very slightly soluble in chloroform and ether; and is insoluble in water.

Celestone - Clinical Pharmacology

Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract.

Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs, such as betamethasone, are primarily used for their anti-inflammatory effects in disorders of many organ systems. A derivative of prednisolone, betamethasone has a 16β-methyl group that enhances the anti-inflammatory action of the molecule and reduces the sodium- and water-retaining properties of the fluorine atom bound at carbon 9.

Indications and Usage for Celestone

Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness.

Dermatologic Diseases Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome).

Endocrine Disorders Congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis.

Hydrocortisone or cortisone is the drug of choice in primary or secondary adrenocortical insufficiency. Synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance.

Gastrointestinal Diseases To tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis.

Hematologic Disorders Acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, idiopathic thrombocytopenic purpura in adults, pure red cell aplasia, selected cases of secondary thrombocytopenia.

Miscellaneous Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used with appropriate antituberculous chemotherapy.

Neoplastic Diseases For the palliative management of leukemias and lymphomas.

Nervous System Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor, craniotomy, or head injury.

Ophthalmic Diseases Sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids.

Renal Diseases To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus.

Respiratory Diseases Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis.

Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus.

Contraindications

Celestone® Oral Solution is contraindicated in patients who are hypersensitive to any components of this product.

Warnings

General

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS).

In patients on corticosteroid therapy subjected to any unusual stress, hydrocortisone or cortisone is the drug of choice as a supplement during and after the event.

Cardio-renal

Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Endocrine

Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

Infections

General

Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection.

Fungal Infections

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS, Drug Interactions, Amphotericin B Injection and Potassium-Depleting Agents section).

Special Pathogens

Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, and Toxoplasma.

It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea.

Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids should not be used in cerebral malaria.

Tuberculosis

The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Vaccination

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison's disease.

Viral Infections

Chickenpox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents should be considered.

Ophthalmic

Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex.

Precautions

General

The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual.

Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.

Cardio-renal

As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.

Endocrine

Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy. Therefore, in any situation of stress occurring during that period, naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, rather than betamethasone, are the appropriate choices as replacement therapy in adrenocortical deficiency states.

Gastrointestinal

Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation.

Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent.

There is an enhanced effect of corticosteroids in patients with cirrhosis.

Musculoskeletal

Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (e.g., postmenopausal women) before initiating corticosteroid therapy.

Neuropsychiatric

Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect (see DOSAGE AND ADMINISTRATION).

An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

Ophthalmic

Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.

Information for Patients

Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids, and to seek medical advice at once should they develop fever or other signs of infection.

Persons who are on corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

Drug Interactions

Aminoglutethimide

Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression.

Amphotericin B Injection and Potassium-Depleting Agents

When corticosteroids are administered concomitantly with potassium-depleting agents (e.g., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.

Antibiotics

Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance.

Anticholinesterases

Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.

Anticoagulants, oral

Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect.

Antidiabetics

Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.

Antitubercular Drugs

Serum concentrations of isoniazid may be decreased.

Cholestyramine

Cholestyramine may increase the clearance of corticosteroids.

Cyclosporine

Increased activity of both cyclosporine and corticosteroids may occur when the 2 are used concurrently. Convulsions have been reported with this concurrent use.

Digitalis Glycosides

Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia.

Estrogens, including oral contraceptives

Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.

Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin)

Drugs which induce hepatic microsomal drug-metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased.

Ketoconazole

Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects.

Nonsteroidal Anti-inflammatory Agents (NSAIDS)

Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids.

Skin Tests

Corticosteroids may suppress reactions to skin tests.

Vaccines

Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination section).

Carcinogenesis, Mutagenesis, Impairment of Fertility

No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis.

Steroids may increase or decrease motility and number of spermatozoa in some patients.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Nursing Mothers

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when corticosteroids are administered to a nursing woman.

Pediatric Use

The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids, which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations.

The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose.

Geriatric Use

No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Adverse Reactions

(listed alphabetically, under each subsection)

Allergic reactions Anaphylactoid reaction, anaphylaxis, angioedema.

Cardiovascular Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.

Dermatologic Acne, allergic dermatitis, dry scaly skin, ecchymoses and petechiae, edema, erythema, impaired wound healing, increased sweating, rash, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.

Endocrine Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients.

Fluid and Electrolyte Disturbances Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention.

Gastrointestinal Abdominal distention, elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis.

Metabolic Negative nitrogen balance due to protein catabolism.

Musculoskeletal Aseptic necrosis of femoral and humeral heads, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, steroid myopathy, tendon rupture, vertebral compression fractures.

Neurologic/Psychiatric Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo.

Ophthalmic Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts.

Other Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain.

Overdosage

Treatment of acute overdosage is by immediate gastric lavage or emesis followed by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced.

Celestone Dosage and Administration

The initial dosage of Celestone® Oral Solution may vary from 0.6 to 7.2 mg per day depending on the specific disease entity being treated.

IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT.

After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient's individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient's condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

In the treatment of acute exacerbations of multiple sclerosis, daily doses of 30 mg of betamethasone for a week followed by 12 mg every other day for 1 month are recommended (see PRECAUTIONS, Neuropsychiatric section).

In pediatric patients, the initial dose of betamethasone may vary depending on the specific disease entity being treated. The range of initial doses is 0.02 to 0.3 mg/kg/day in 3 or 4 divided doses (0.6–9 mg/m2 bsa/day).

For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids:

Cortisone, 25	Triamcinolone, 4
Hydrocortisone, 20	Paramethasone, 2
Prednisolone, 5	Betamethasone, 0.75
Prednisone, 5	Dexamethasone, 0.75
Methylprednisolone, 4

These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered.

How is Celestone Supplied

Celestone® Oral Solution, 0.6 mg per 5 mL, orange-red colored liquid, bottle of 4 fluid ounces (118 mL) (NDC 0085-0942-05). Protect from light.

Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].

Manufactured by: Schering-Plough Canada, Inc.,

Pointe Claire, Quebec, Canada

Distributed by: Schering Corporation, a subsidiary of

MERCK & CO., INC.

Whitehouse Station, NJ 08889, USA

Rev. 10/10

31471311T

Copyright © 1968, 2007 Schering Corporation, a subsidiary of Merck & Co., Inc. All rights reserved.

PRINCIPAL DISPLAY PANEL - 0.6 mg Carton

NDC 0085-0942-05

4 fluid ounces (118 mL)

Celestone®

brand of

betamethasone

Oral Solution USP

0.6

mg

per 5 mL

Rx only

Celestone  betamethasone  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0085-0942 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Betamethasone (Betamethasone) Betamethasone 0.6 mg  in 5 mL

Inactive Ingredients Ingredient Name Strength alcohol   citric acid monohydrate   FD&C Red No. 40   FD&C Yellow No. 6   propylene glycol   sodium benzoate   sodium chloride   sorbitol   sucrose   water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0085-0942-05 1 BOTTLE In 1 CARTON contains a BOTTLE 1 118 mL In 1 BOTTLE This package is contained within the CARTON (0085-0942-05)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA014215	08/18/2011

Labeler - Schering Corporation (001317601)

Establishment
Name	Address	ID/FEI	Operations
Schering Plough Canada Inc.		207093332	MANUFACTURE

Revised: 08/2011Schering Corporation

More Celestone resources

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

• Celestone Concise Consumer Information (Cerner Multum)


• Celestone Solution MedFacts Consumer Leaflet (Wolters Kluwer)


• Betamethasone Professional Patient Advice (Wolters Kluwer)


• Betamethasone Monograph (AHFS DI)


• betamethasone Topical application Advanced Consumer (Micromedex) - Includes Dosage Information


• Betamethasone MedFacts Consumer Leaflet (Wolters Kluwer)


• Betamethasone Dipropionate topical Monograph (AHFS DI)

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Metformin Hydrochloride 500mg / 5ml Oral Solution

1. Name Of The Medicinal Product

Metformin Hydrochloride 500mg/5ml Oral Solution

2. Qualitative And Quantitative Composition

Each 5ml oral solution contains 500mg Metformin Hydrochloride.

1ml of oral solution contains 100mg Metformin Hydrochloride.

Excipients: Sodium methyl parahydroxybenzoate (E219), sodium propyl parahydroxybenzoate (E217) and maltitol liquid (E965).

Sodium = 5.3mg/5ml

Potassium = 14.5mg/5ml

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Oral Solution

Clear brown liquid.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of type 2 diabetes mellitus, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control.

• In adults, Metformin Hydrochloride Oral Solution may be used as monotherapy or in combination with other oral anti-diabetic agents or with insulin.

• In children from 10 years of age and adolescents, Metformin Hydrochloride Oral Solution may be used as monotherapy or in combination with insulin.

A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients treated with metformin as first-line therapy after diet failure (see 5.1. Pharmacodynamic properties).

4.2 Posology And Method Of Administration

Adults:

Monotherapy and combination with other oral antidiabetic agents:

• The usual starting dose is one 5ml spoonful (500mg) 2 or 3 times daily given during or after meals.

• After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 3g (six 5ml spoonfuls) daily, taken as 3 divided doses.

• If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate metformin hydrochloride at the dose indicated above.

Combination with insulin:

Metformin hydrochloride and insulin may be used in combination therapy to achieve better blood glucose control. Metformin hydrochloride is given at the usual starting dose of one 5ml spoonful (500mg) 2-3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

Elderly:

Due to the potential for decreased renal function in elderly subjects, the metformin hydrochloride dosage should be adjusted based on renal function. Regular assessment of renal function is necessary (see section 4.4).

Children and adolescents:

Monotherapy and combination with insulin

• Metformin Hydrochloride Oral Solution can be used in children from 10 years of age and adolescents.

• The usual starting dose is one 5ml spoonful (500mg) once daily, given during meals or after meals.

• After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 2g (four 5ml spoonfuls) daily, taken as 2 or 3 divided doses.

4.3 Contraindications

• Hypersensitivity to metformin hydrochloride or any of the excipients.

• Diabetic ketoacidosis, diabetic pre-coma.

• Renal failure or renal dysfunction (creatinine clearance < 60mL/min).

• Acute conditions with the potential to alter renal function such as:

- dehydration

- severe infection

- shock

- Intravascular administration of iodinated contrast agents (see 4.4 Warnings and special precautions for use).

• Acute or chronic disease which may cause tissue hypoxia such as:

- cardiac or respiratory failure

- recent myocardial infarction

- shock

• Hepatic insufficiency, acute alcohol intoxication, alcoholism

• Lactation

4.4 Special Warnings And Precautions For Use

Lactic acidosis

Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin hydrochloride accumulation. Reported cases of lactic acidosis in patients on metformin hydrochloride have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.

Diagnosis:

The risk of lactic acidosis must be considered in the event of non-specific signs such as muscular cramps with digestive disorders as abdominal pain and severe asthenia.

Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5mmol/L, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin hydrochloride should be discontinued and the patient should be hospitalised immediately (see section 4.9).

Renal function

As metformin hydrochloride is excreted by the kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter:

• at least annually in patients with normal renal function.

• at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly subjects.

Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with an NSAID.

Administration of iodinated contrast agent

As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure, metformin hydrochloride must be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.5).

Surgery

Metformin hydrochloride must be discontinued 48 hours before elective surgery under general, spinal or epidural anaesthesia and should not be usually resumed earlier than 48 hours afterwards and only after resumption of oral nutrition and only if normal renal function has been established.

Children and adolescents

The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin hydrochloride is initiated.

No effect of metformin hydrochloride on growth and puberty has been detected during controlled clinical studies of one year duration but no long term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially pre-pubescent children is recommended.

Children aged between 10 and 12 years:

Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although metformin efficacy and safety in children below 12 did not differ from efficacy and safety in older children, particular caution is recommended when prescribing to children aged between 10 and 12 years.

Other precautions

All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.

The usual laboratory tests for diabetes monitoring should be performed regularly.

Metformin hydrochloride alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or sulfonylureas.

Excipient warnings

This product contains:

• Parahydroxybenzoates. These may cause allergic reactions (possibly delayed).

• Liquid maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. This may have a mild laxative effect. The calorific value is 2.3kcal per gram of maltitol (31.5kcal in maximum daily dose)

• Sodium – 5.3mg per 5ml dose. This should be taken into consideration for patients on a controlled sodium diet.

• Potassium – 14.5mg per 5ml dose. This should be taken into consideration for patients with reduced kidney function or patients on controlled potassium diets.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use not recommended

Alcohol

Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of:

- fasting or malnutrition

- hepatic insufficiency

Avoid consumption of alcohol and alcohol-containing medications.

Iodinated contrast agents (see section 4.4)

Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin hydrochloride accumulation and a risk of lactic acidosis.

Metformin hydrochloride must be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.

Combinations requiring precautions for use

Glucocorticoids (systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.

ACE-inhibitors may decrease the blood glucose levels. Therefore, dose adjustment of metformin hydrochloride may be necessary during and after addition or discontinuation of such medicinal products.

4.6 Pregnancy And Lactation

To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or fetal development, parturition or postnatal development (see also section 5.3).

When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with metformin hydrochloride but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of fetal malformations associated with abnormal blood glucose levels.

Metformin hydrochloride is excreted into milk in lactating rats. Similar data are not available in humans and a decision should be made whether to discontinue nursing or to discontinue metformin hydrochloride, taking into account the importance of the medicinal product to the mother.

4.7 Effects On Ability To Drive And Use Machines

Metformin Hydrochloride Oral Solution monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines.

However, patients should be alerted to the risk of hypoglycaemia when metformin hydrochloride is used in combination with other antidiabetic agents (sulfonylureas, insulin, repaglinide).

4.8 Undesirable Effects

The following undesirable effects may occur under treatment with metformin hydrochloride. Frequencies are defined as follows: very common>1/10; common>1/100, <1/10; uncommon>1/1,000, <1/100; rare>1/10,000, <1/1,000; very rare <1/10,000 and isolated reports.

Metabolism and nutrition disorders:

Very rare : Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin hydrochloride. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.

Very rare : Lactic acidosis (see 4.4. Special warnings and precautions for use).

Nervous system disorders:

Common : Taste disturbance

Gastrointestinal disorders:

Very common : Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin hydrochloride be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

Hepatobiliary disorders:

Isolated reports : Liver function tests abnormalities or hepatitis resolving upon metformin hydrochloride discontinuation.

Skin and subcutaneous tissue disorders:

Very rare : Skin reactions such as erythema, pruritus, urticaria

In published and post marketing data and in controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year, adverse event reporting was similar in nature and severity to that reported in adults.

4.9 Overdose

Hypoglycaemia has not been seen with metformin hydrochloride doses of up to 85g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin hydrochloride may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin hydrochloride is haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Oral blood glucose lowering drugs, Biguanides

ATC Code: A10B A02

Metformin hydrochloride is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Metformin hydrochloride may act via 3 mechanisms:

(1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis (2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation (3) and delay of intestinal glucose absorption.

Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Metformin hydrochloride increases the transport capacity of all types of membrane glucose transporters (GLUT).

In humans, independently of its action on glycaemia, metformin hydrochloride has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin hydrochloride reduces total cholesterol, LDL cholesterol and triglyceride levels.

Clinical efficacy:

The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes.

Analysis of the results for overweight patients treated with metformin hydrochloride after failure of diet alone showed:

• a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034.

• a significant reduction of the absolute risk of diabetes-related mortality: metformin 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;

• a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021);

• a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01)

For metformin hydrochloride used as second-line therapy, in combination with a sulfonylurea, benefit regarding clinical outcome has not been shown.

In type 1 diabetes, the combination of metformin hydrochloride and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.

Controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year demonstrated a similar response in glycaemic control to that seen in adults.

5.2 Pharmacokinetic Properties

Absorption:

After an oral dose of metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a 500mg dose is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.

After oral administration, metformin hydrochloride absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin hydrochloride absorption are non-linear.

At the usual metformin hydrochloride doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 μg/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 μg/ml, even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin hydrochloride. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown.

Distribution:

Plasma protein binding is negligible. Metformin hydrochloride partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean Vd ranged between 63-276 L.

Metabolism:

Metformin hydrochloride is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination:

Renal clearance of metformin hydrochloride is> 400 ml/min, indicating that metformin hydrochloride is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.

When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

Paediatrics:

Single dose study: After single doses of metformin hydrochloride 500 mg, paediatric patients have shown similar pharmacokinetic profile to that observed in healthy adults.

Multiple dose study: Data are restricted to one study. After repeated doses of 500 mg BID for 7 days in paediatric patients the peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively compared to diabetic adults who received repeated doses of 500 mg BID for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity reproduction.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Methyl parahydroxybenzoate (E219)

Sodium Propyl parahydroxybenzoate (E217)

Sodium Dihydrogen Phosphate Dihydrate

Di-sodium Hydrogen Phosphate Anhydrous (E339)

Liquid Maltitol (E965)

Acesulfame Potassium (E950)

Ammonia Caramel (E150c)

Peppermint Flavour (containing propylene glycol, isopropyl alcohol and pulegone)

Peach Flavour (containing propylene glycol and isopropyl alcohol)

Purified Water

6.2 Incompatibilities

None known.

6.3 Shelf Life

1 year unopened

28 days opened

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Amber (Type III) glass bottles

Closures: HDPE, EPE wadded, tamper evident, child resistant closure

Pack Size: 100ml and 150ml

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

UK

8. Marketing Authorisation Number(S)

PL 00427/0139

9. Date Of First Authorisation/Renewal Of The Authorisation

10/07/2007

10. Date Of Revision Of The Text

June 2010