Kefadim Vials

1. Name Of The Medicinal Product

'Kefadim'.

2. Qualitative And Quantitative Composition

			Vial Size
		500mg	1g	2g
Active constituent
	Ceftazidime pentahydrate	580mg	1.16g	2.33g
	equivalent to ceftazidime	500mg	1.0g	2.0g
Other constituents
	Sodium carbonate	59mg	118mg	236mg

3. Pharmaceutical Form

Powder for solution for injection

4. Clinical Particulars

4.1 Therapeutic Indications

Kefadim is indicated in the treatment of the following infections when due to susceptible micro- organisms:

Lower respiratory tract infections

Skin and soft tissue infections

Bone and joint infections

Urinary tract infections

Gynaecological infections

Intra-abdominal infections, including peritonitis

Septicaemia

Central nervous system infections, including meningitis. In meningitis, it is recommended that the results of a sensitivity test are known before treatment with ceftazidime as a single agent.

Kefadim may be used alone in cases of confirmed or suspected sepsis. It may also be used concomitantly with other antibiotics, such as aminoglycosides, in severe and life-threatening infections and in the immunocompromised patient.

4.2 Posology And Method Of Administration

Ceftazidime may be given intravenously or by deep intramuscular injection into a large muscle mass (such as the upper outer quadrant of the gluteus maximus, or lateral part of the thigh).

The guidelines for dosage of Kefadim are listed in Table 1.

Table 1: Recommended Dosage Schedule for Kefadim

	DOSE	FREQUENCY
Adults
Usual recommended dose	1g IV or im	q 8 or 12 h
Uncomplicated urinary tract infections	250mg IV or im	q 12 h
Bone and joint infections	2g IV	q 12 h
Complicated urinary tract infections	500mg IV or im	q 8 or 12 h
Uncomplicated pneumonia; mild skin and skin-structure infections	500mg-1g IV or im	q 8 h
Serious gynaecological and intra-abdominal infections	2g IV	q 8 h
Meningitis	2g IV	q 8 h
Very severe life-threatening infections, especially in immunocompromised patients	2g IV	q 8 h
Pseudomonal lung infections in patients with cystic fibrosis with normal renal function*	30-50mg/kg IV to a maximum of 6g/day	q 8 h
Neonates and children up to 2 months	12.5-30mg/kg IV	q 12 h
Infants and children (2 months to 12 years of age)	17-50mg/kg IV to a maximum of 6g/day**	q 8 h

*Although clinical improvement has been shown, complete eradication of infecting organisms cannot be expected in patients with chronic respiratory disease and cystic fibrosis.

**The higher dose should be reserved for immunocompromised children or children with cystic fibrosis or meningitis.

Adults and the elderly: The usual dosage range for ceftazidime is 500mg to 2g every eight to twelve hours. The dosage and route of administration should be determined by the susceptibility of the causative organisms, the severity of infection, and the condition and renal function of the patient.

In view of the reduced clearance of ceftazidime in acutely ill elderly patients, the daily dosage should not normally exceed 2g, especially in those over 80 years of age (Table 2).

Infants and children over 2 months of age: The dosage range is 50-150mg/kg/day IV, in three divided doses, with a maximum of 6g/day. The higher dose should be reserved for immunocompromised children, or children with cystic fibrosis or meningitis.

Neonates and children up to 2 months of age: The dosage range is 25 to 60mg/kg/day, given as two divided doses. In the neonate, the serum half-life of ceftazidime can be three to four times that in adults.

Dosage in impaired renal function: Ceftazidime is excreted by the kidneys, almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function (GFR <50ml/min), it is recommended that the dose of ceftazidime should be reduced to compensate for its slower excretion. In patients with suspected renal insufficiency, an initial loading dose of 1g may be given. An estimate of GFR should be made to determine the appropriate maintenance dose. The recommended dosage is shown in Table 2.

Table 2: Recommended Maintenance Dosage of Kefadim in Patients with Renal Insufficiency

CREATININE CLEARANCE (ML/MIN)	RECOMMENDED DOSE OF KEFADIM	FREQUENCY
50-31	1g	q 12 h
30-16	1g	q 24 h
15-6	500mg	q 24 h
<5	500mg	q 48 h

When only serum creatinine is available, the following formula (Cockcroft's equation) may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:

Males:

Females:

0.85 x above value

In patients with severe infections who would normally receive 6g of Kefadim daily, were it not for renal insufficiency, the dose in Table 2 may be increased by 50% or the dosing frequency increased appropriately. Continued dosage should be determined by further monitoring of creatinine clearance, severity of the infection, and susceptibility of the causative organism. In such patients, it is recommended that ceftazidime serum levels should be monitored and trough levels should not exceed 40mg/litre.

In children, as for adults, the creatinine clearance should be adjusted for body surface area or lean body mass and the dosing frequency reduced in cases of renal insufficiency.

The serum half-life of ceftazidime during haemodialysis ranges from 3 to 5 hours.

In patients undergoing haemodialysis, a loading dose of 1g of Kefadim is recommended, followed by 1g after each haemodialysis period. Kefadim can also be used in patients undergoing intraperitoneal and continuous ambulatory peritoneal dialysis (CAPD). In such patients, a loading dose of 1g of Kefadim may be given, followed by 500mg every 24 hours. In addition to intravenous use, Kefadim can be incorporated in the dialysis fluid at a concentration of 250mg for 2 litres of dialysis fluid.

NOTE: Kefadim should generally be continued for 2 days after the signs and symptoms of infection have disappeared, however, in complicated infections, longer therapy may be required.

Intramuscular administration: Kefadim should be reconstituted with Water for Injections PhEur or 0.5% or 1% Lignocaine Hydrochloride Injection BP. Refer to Table 3

Table 3:Preparation of Solutions of Kefadim

	AMOUNT OF DILUENT TO BE ADDED (ML)	APPROXIMATE AVAILABLE VOLUME (ML)	APPROXIMATE CEFTAZIDIME CONCENTRATION (MG/ML)
Intramuscular
500mg	1.5	1.925	260
1g	3.0	3.85	260
Intravenous
500mg	5	5.425	92
1g	10	10.85	92
2g	10	11.7	170
Infusion (100ml)
2g	100*	101.7	20

*Note: Addition should be in 2 stages (see 'Instructions for reconstitution' below).

Intravenous administration: For direct intermittent intravenous administration, reconstitute Kefadim with Water for Injections PhEur (see Table 3). Slowly inject the solution directly into the vein over a period of 3 to 5 minutes or give through the tubing of a giving set. Ceftazidime is compatible with the most commonly used intravenous fluids (see section 6.6).

For intravenous infusion, reconstitute the 2g infusion (100ml) vial with 100ml Water for Injections PhEur or one of the compatible intravenous fluids. Alternatively, reconstitute the 500mg, 1g or 2g vial and add an appropriate quantity of the resulting solution to an IV container with one of the compatible intravenous fluids.

Intermittent intravenous infusion with a Y-type giving set can be accomplished with compatible solutions. However, during infusion of a solution containing ceftazidime, it is desirable to discontinue the other solution.

When Kefadim is dissolved, carbon dioxide is released and a positive pressure develops. For ease of use, please follow the recommended techniques of reconstitution described below.

Instructions for reconstitution:

For 500mg im/IV, 1g im/IV and 2g IV vials

1. Inject the diluent and shake well to dissolve. The vials may contain a vacuum to assist injection of the diluent.

2. Carbon dioxide is released as the antibiotic dissolves, generating pressure within the vial. The solution will become clear within 1 to 2 minutes.

3. Invert the vial and completely depress the syringe plunger prior to insertion.

4. Insert the needle through the vial stopper. Be sure the needle remains within the solution and withdraw contents of the vial in the usual manner. Pressure in the vial may aid withdrawal.

5. The withdrawn solution may contain carbon dioxide bubbles, which should be expelled from the syringe before injection.

For 2g infusion vials

1. Inject 10ml of the diluent and shake to dissolve. The vials may contain a vacuum to assist injection of the diluent.

2. Carbon dioxide is released as the antibiotic dissolves, generating pressure within the vial. The solution will become clear within 1 to 2 minutes.

3. Insert a vent needle to release pressure before adding additional diluent to the vial. Add diluent and then remove the vent needle.

4. Additional pressure that may develop in the vial, especially after storage, should be relieved prior to administration to the patient.

NOTE: To preserve product sterility, it is important that a gas relief needle is not inserted through the vial closure before the product has dissolved.

4.3 Contraindications

Ceftazidime is contra-indicated in patients with known hypersensitivity to ceftazidime or cephalosporin antibiotics.

4.4 Special Warnings And Precautions For Use

Warnings

Before therapy with ceftazidime is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to ceftazidime, cephalosporins, penicillins, or other drugs. Ceftazidime should be given only with special caution to patients with type 1 or immediate hypersensitivity reactions to penicillin. If an allergic reaction to ceftazidime occurs, discontinue the drug. Serious acute hypersensitivity reactions may require epinephrine (adrenaline), hydrocortisone, antihistamine, or other emergency measures.

Pseudomembranous colitis has been reported with the use of ceftazidime, other cephalosporins and virtually all broad-spectrum antibiotics, therefore, it is important to consider its diagnosis in patients who develop diarrhoea in association with antibiotic use. Such colitis may range in severity from mild to life-threatening. Symptoms can appear during or after treatment.

Mild cases of pseudomembranous colitis usually respond to drug discontinuance alone. In moderate to severe cases, appropriate measures should be taken.

Precautions

Kefadim has not been shown to be nephrotoxic, however, because high and prolonged serum antibiotic concentrations can occur from usual doses in patients with transient or persistent reduction of urinary output because of renal insufficiency, the total daily dosage should be reduced when ceftazidime is administered to such patients to avoid the clinical consequences, eg, seizures due to elevated levels of antibiotics (see section 4.2). Continued dosage should be determined by degree of renal impairment, severity of infection and susceptibility of causative organisms.

As with other antibiotics, prolonged use of Kefadim may result in the overgrowth of non-susceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Kefadim should be used with caution in individuals with a history of gastro-intestinal disease, particularly colitis.

Ceftazidime does not interfere with enzyme-based tests for glycosuria. Slight interference with copper reduction methods (Benedict's, Fehling's, Clinitest) may be observed.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics or potent diuretics, such as furosemide (frusemide). Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity and ototoxicity were not noted when Kefadim was given alone in clinical trials.

4.6 Pregnancy And Lactation

Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Kefadim. There are, however, no controlled studies in pregnant women. As animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Ceftazidime is excreted in human milk in low concentrations and consequently caution should be exercised when ceftazidime is administered to a nursing woman.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

The most common side-effects were local reactions following intravenous injection and allergic and gastro-intestinal reactions.

Local effects: Phlebitis or thrombophlebitis, and inflammation at the site of injection.

Hypersensitivity: Pruritus, urticarial rash, fever and very rarely angioedema and anaphylaxis (bronchospasm and/or hypotension).

Skin and subcutaneous tissue disorders: As with other cephalosporins, there have been rare reports of toxic epidermal necrolysis reported in association with ceftazidime.

Gastro-intestinal: Diarrhoea, nausea, vomiting and abdominal pain, pseudomembranous colitis (see section 4.4 - 'Warnings'). Very rarely, oral thrush.

Central nervous system: Headache, dizziness, paraesthesias and bad taste. There have been reports of neurological sequelae, including tremor, myoclonica, convulsions and encephalopathy, in patients with renal impairment in whom the dose of ceftazidime has not been appropriately reduced.

Reproductive system disorder: Candidiasis and vaginitis.

Laboratory test changes (usually transient): Eosinophilia, positive Coombs' test without haemolysis, thrombocytosis and slight elevations in one or more hepatic enzymes: AST (SGOT), ALT (SGPT), LDH, GGT and alkaline phosphatase. Transient elevations of blood urea, blood urea nitrogen and/or serum creatinine have been observed occasionally. Transient leucopenia, neutropenia, agranulocytosis, thrombocytopenia and lymphocytosis have been seen very rarely.

4.9 Overdose

Signs and symptoms: Toxic signs and symptoms following an overdose of ceftazidime may include pain, inflammation and phlebitis at the injection site. Overdosage can lead to neurological sequelae, including encephalopathy, convulsions and coma.

The administration of inappropriately large doses of parenteral cephalosporins may cause dizziness, paraesthesias and headaches. Seizures may occur following overdosage with some cephalosporins, particularly in patients with renal impairment in whom accumulation is likely to occur.

Laboratory abnormalities that may occur after an overdose include elevations in creatinine, BUN, liver enzymes and bilirubin, a positive Coombs' test, thrombocytosis, thrombocytopenia, eosinophilia, leucopenia and prolongation of the prothrombin time.

The subcutaneous median lethal dose in rats and mice ranged from 5.8 to 20g/kg and the intravenous median lethal dose in rabbits was >2g/kg.

Treatment: If seizures occur, the drug should be discontinued promptly; anti-convulsant therapy may be administered if clinically indicated. An airway should be established. Cardiac and vital signs monitoring is recommended, along with general symptomatic and supportive measures.

In cases of severe overdosage, especially in a patient with renal failure, combined haemodialysis and haemoperfusion may be considered if response to more conservative therapy fails.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ceftazidime is a semi-synthetic, beta-lactam antibiotic, for parenteral administration.

In vitro tests demonstrate that ceftazidime is bactericidal. It acts against a wide range of Gram-negative organisms, including strains resistant to gentamicin and other aminoglycosides. It is also active against Gram-positive organisms, and is highly stable to most clinically important beta-lactamases, whether plasmid or chromosomally mediated.

Ceftazidime has been shown to have in vitro activity against the following organisms:

Pseudomonas spp. (including Pseudomonas aeruginosa); Klebsiella spp. (including Klebsiella pneumoniae); Proteus mirabilis and Proteus vulgaris; Morganella morganii (formerly Proteus morganii); Providencia spp. (including Providencia rettgeri, formerly Proteus rettgeri); Escherichia coli; Enterobacter spp.; Citrobacter spp.; Serratia spp.; Salmonella spp.; Shigella spp.; Yersinia enterocolitica; Pasteurella multocida; Acinetobacter spp.; Neisseria gonorrhoeae; Neisseria meningitidis; Haemophilus influenzae (including ampicillin-resistant strains); Haemophilus parainfluenzae (including ampicillin-resistant strains); Staphylococcus aureus (methicillin-sensitive strains); Staphylococcus epidermidis (methicillin-sensitive strains); Streptococcus pyogenes; Streptococcus Group B; Streptococcus pneumoniae; Streptococcus spp.; Peptococcus spp.; Peptostreptococcus spp.; Clostridium spp.; (but not C. difficile); Bacteroides spp. (but most strains of B. fragilis are resistant).

Using the ICS agar dilution method (or its equivalent) for susceptibility testing, the criteria for dilution methods are:

MIC <16mg/litre:	Susceptible
MIC>16 but <64mg/litre:	Moderately susceptible (ie, susceptible to high dosage or if infection confined to tissues or fluids [eg, urine] in which high antibiotic levels are attained)
MIC	Resistant

and for the standard disc test using a 30 microgram ceftazidime disc, are (zone diameters):

Zone	Susceptible
Zone 15-17mm:	Moderately susceptible
Zone	Resistant

Ceftazidime is not active in vitro against methicillin-resistant staphylococci; Streptococcus faecalis and many other enterococci; Listeria monocytogenes; Campylobacter spp. or C. difficile.

Ceftazidime and the aminoglycosides have been shown to be synergistic in vitro against some strains of P. aeruginosa and the Enterobacteriaceae. Ceftazidime and carbenicillin have also been shown to be synergistic in vitro against P. aeruginosa

5.2 Pharmacokinetic Properties

After intravenous administration of 500mg or 1g of ceftazidime, over 5 minutes, to normal adults, mean peak serum concentrations were 45mg/litre and 90mg/litre, respectively. Following intravenous infusion of 500mg, 1g and 2g of ceftazidime, over 20 to 30 minutes, to normal adults, mean peak serum concentrations of 42, 69 and 170mg/litre, respectively, were achieved. The average serum concentrations in these adults, over an 8 hour period, are given in Table 4.

Table 4:Ceftazidime Concentrations in Serum

CEFTAZIDIME DOSAGE (IV)	SERUM CONCENTRATIONS (MG/LITRE)
	0.5h	1h	2h	4h	8h
500mg	42	25	12	6	2
1g	60	39	23	11	3
2g	129	75	42	13	5

Following intramuscular administration of 500mg and 1g ceftazidime to normal adults, mean peak serum concentrations at approximately 1 hour were 17mg/litre and 39mg/litre, respectively. Serum concentrations remained above 4mg/litre for 6 and 8 hours after the intramuscular administration of 500mg and 1g doses, respectively.

The half-life of ceftazidime was approximately 1.9 hours after intravenous administration and 2 hours after intramuscular administration.

Less than 10% of ceftazidime was protein bound and the degree of protein binding was independent of concentration.

Following multiple intravenous doses of 1g and 2g every 8 hours for 10 days, there was no evidence of accumulation of ceftazidime in the serum of individuals with normal renal function.

The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals who received 2g intravenously every 8 hours for 5 days. Therefore, dosage adjustment is not required for patients with hepatic dysfunction, unless renal function is also impaired.

Approximately 80% to 90% of a dose of ceftazidime is excreted unchanged by the kidneys over a 24 hour period. The elimination of ceftazidime by the kidneys resulted in high urinary concentrations.

Concentrations of ceftazidime in excess of the minimum inhibitory levels of common pathogens can be achieved in tissues such as bone, heart, bile, sputum, aqueous humour, synovial, pleural and peritoneal fluids.

Transplacental transfer of the antibiotic readily occurs.

Ceftazidime penetrates the intact blood-brain barrier poorly and low levels are achieved in the CSF in the absence of inflammation. Therapeutic levels of 4 to 20mg/litre or more are achieved in the CSF when the meninges are inflamed.

5.3 Preclinical Safety Data

Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, a mouse micronucleus test and an Ames test were both negative for mutagenic effects.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium carbonate.

6.2 Incompatibilities

Solutions of Kefadim, like those of most beta-lactam antibiotics, should not be added to solutions of aminoglycoside antibiotics because of potential interaction. However, if concurrent therapy with Kefadim and an aminoglycoside is indicated, each of these antibiotics should be administered in different sites.

Precipitation has been reported when vancomycin has been added to ceftazidime in solution. Therefore, it would be prudent to flush giving sets and intravenous lines between administration of these two agents.

Kefadim is less stable in Sodium Bicarbonate Injection than in other intravenous fluids. Sodium Bicarbonate Injection is not recommended as a diluent. Solutions of Kefadim in 5% Dextrose or 0.9% Sodium Chloride Injection are stable for at least 6 hours at room temperature in plastic tubing, drip chambers and volume control devices of common intravenous infusion sets

6.3 Shelf Life

Unreconstituted vials: 2 years.

Reconstituted vials: It is good practice to reconstitute immediately prior to use. If this is not feasible, Kefadim should be stored in a refrigerator and used within 24 hours. After reconstitution, protection from light is not necessary. The pH of freshly reconstituted solutions ranges from 5.0 to 7.5.

6.4 Special Precautions For Storage

Unreconstituted vials: Protect from light. Do not store above 25°C.

6.5 Nature And Contents Of Container

Kefadim is supplied as a sterile dry powder in single-dose flint Type I or III glass vial with a rubber closure and aluminium seal containing 500mg, 1g and 2g ceftazidime (as pentahydrate) with sodium carbonate (118mg per gram of ceftazidime).

The total sodium content of the mixture is approximately 54mg (2.3mEq) per gram of ceftazidime

6.6 Special Precautions For Disposal And Other Handling

Solutions of Kefadim range from light yellow to amber, depending on the diluent and concentration.

Kefadim is compatible with the more commonly used intravenous infusion fluids. Solutions at concentrations between 1mg/ml and 40mg/ml in the following infusion fluids may be stored for up to 24 hours at room temperature: 0.9% Sodium Chloride Injection BP; M/6 Sodium Lactate Injection BP; Ringer's Injection USP; Lactated Ringer's Injection USP; 5% Dextrose Injection BP; 0.225% Sodium Chloride and 5% Dextrose Injection BP; 0.45% Sodium Chloride and 5% Dextrose Injection BP; 0.9% Sodium Chloride and 5% Dextrose Injection BP; 10% Dextrose Injection BP; and 10% Invert Sugar in Water for Injection.

At a concentration of 4mg/ml, Kefadim has been found compatible for 24 hours at room temperature in 0.9% Sodium Chloride Injection or 5% Dextrose Injection when admixed with cefuroxime sodium, 3mg/ml; heparin, 10u/ml or 50u/ml; or potassium chloride, 10mEq/l or 40mEq/l.

Parenteral drug products should be inspected visually and cloudy solutions should be discarded.

Kefadim powder and solutions will darken, depending on storage conditions. However, product potency is not adversely affected if storage conditions and storage periods are observed.

7. Marketing Authorisation Holder

Flynn Pharma Ltd

Alton House

4 Herbert Street

Dublin 2

Ireland

8. Marketing Authorisation Number(S)

Vials 500mg:	PL 13621/0014
Vials 1g:	PL 13621/0015
Vials 2g:	PL 13621/0016

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation:	1st June 2005

10. Date Of Revision Of The Text

1^st June 2005

Analpram Advanced

Generic Name: diosmiplex, hydrocortisone, and pramoxine (dye OS me plex, HYE droe KORT i sone, and pra MOX een)

Brand Names: Analpram Advanced

What is diosmiplex, hydrocortisone, and pramoxine ?

Diosmiplex (Vasculera) is a medical food for people with chronic venous insufficiency, a blood circulation disorder. Diosmiplex affects the function of blood vessels in the body.

Pramoxine is an anesthetic. It works by interfering with pain signals sent from the nerves to the brain.

Hydrocortisone is a steroid. It reduces the actions of chemicals in the body that cause inflammation, redness, and swelling.

Diosmiplex is a oral tablet you take by mouth. Diosmiplex, hydrocortisone, and pramoxine are combined into a cream to be applied to the rectum. The two forms of medicine are supplied in a kit that also contains cleansing wipes.

The diosmiplex, hydrocortisone, and pramoxine kit is used to treat itching, swelling, or irritation caused by hemorrhoids.

Diosmiplex, hydrocortisone, and pramoxine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about diosmiplex, hydrocortisone, and pramoxine ?

You should not use this medication if you are allergic to diosmiplex, hydrocortisone, or pramoxine.

Before using diosmiplex, hydrocortisone, and pramoxine , tell your doctor if you have liver or kidney disease, diabetes, or a history of cancer.

Do not use this medication on a child without a doctor's advice. Children are more sensitive to the effects of topical hydrocortisone. Do not cover the treated rectal areas with a bandage or other covering unless your doctor has told you to. If you are treating the diaper area of a baby, do not use plastic pants or tight-fitting diapers. Covering the area that is treated with hydrocortisone topical can increase the amount of the drug your skin absorbs, which may lead to unwanted side effects. Follow your doctor's instructions. Contact your doctor if your condition does not improve or if it gets worse after using this medication. Do not use diosmiplex, hydrocortisone, and pramoxine to treat any condition that has not been checked by your doctor.

What should I discuss with my healthcare provider before taking diosmiplex, hydrocortisone, and pramoxine ?

You should not use this medication if you are allergic to diosmiplex, hydrocortisone, or pramoxine.

To make sure you can safely use this medication, tell your doctor if you have any of these other conditions:

• 
  

  liver disease;

  
  


• 
  

  kidney disease; or

  
  


• 
  

  if you have ever had cancer.

  
  

Also tell your doctor if you have diabetes. Steroid medicines may increase the glucose (sugar) levels in your blood or urine. You may also need to adjust the dose of your diabetes medications.

FDA pregnancy category C. It is not known whether diosmiplex, hydrocortisone, and pramoxine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether this medication passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Do not use this medication on a child without a doctor's advice. Children are more sensitive to the effects of topical hydrocortisone.

How should I use diosmiplex, hydrocortisone, and pramoxine ?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Wash your hands before and after applying this medication.

Before you apply the rectal cream, clean the rectal area with a cleansing wipe provided with the Analpram Advanced kit. Follow the directions on the label.

Use only a small amount of medicine when applying the hydrocortisone and pramoxine cream around the outside of the rectum. You may apply the cream 3 to 4 times daily or as directed by your doctor.

Do not cover the treated rectal area with a bandage or other covering unless your doctor has told you to. If you are treating the diaper area of a baby, do not use plastic pants or tight-fitting diapers. Covering the area that is treated with hydrocortisone topical can increase the amount of the drug your skin absorbs, which may lead to unwanted side effects. Follow your doctor's instructions.

Do not use diosmiplex, hydrocortisone, and pramoxine for any condition that has not been checked by a doctor.

Contact your doctor if your condition does not improve or if it gets worse after using this medication. Store at room temperature away from moisture, heat, and light.

What happens if I miss a dose?

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

An overdose of hydrocortisone applied to the rectum is not expected to produce life-threatening symptoms. However, long-term use of high steroid doses can lead to symptoms such as thinning skin, easy bruising, changes in the shape or location of body fat (especially in your face, neck, back, and waist), increased acne or facial hair, menstrual problems, impotence, or loss of interest in sex.

What should I avoid while taking diosmiplex, hydrocortisone, and pramoxine ?

Avoid getting this medication in your eyes.

Avoid applying other rectal medications on the same treatment area with diosmiplex, hydrocortisone, and pramoxine , unless your doctor has told you to.

Diosmiplex, hydrocortisone, and pramoxine side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as:

• 
  

  severe burning, itching or irritation of the treated area; or

  
  


• 
  

  rectal bleeding.

  
  

Less serious side effects may include:

• 
  

  mild burning, itching, or dryness of the treated area.

  
  


• 
  

  headache;

  
  


• 
  

  mild skin rash;

  
  


• 
  

  leg cramps;

  
  


• 
  

  upset stomach; or

  
  


• 
  

  swelling in your hands or feet.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect diosmiplex, hydrocortisone, and pramoxine ?

There may be other drugs that can interact with diosmiplex, hydrocortisone, and pramoxine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Analpram Advanced resources

• Analpram Advanced Drug Interactions
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• Hemorrhoids

Where can I get more information?

• Your pharmacist can provide more information about diosmiplex, hydrocortisone, and pramoxine .

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Oxytrol

oxybutynin

Dosage Form: patch
Oxytrol®

Oxybutynin Transdermal System

Revised: January 2011

Rx only

Oxytrol Description

Oxytrol, oxybutynin transdermal system, is designed to deliver oxybutynin continuously and consistently over a 3- to 4-day interval after application to intact skin. Oxytrol is available as a 39 cm2 system containing 36 mg of oxybutynin. Oxytrol has a nominal in vivo delivery rate of 3.9 mg oxybutynin per day through skin of average permeability (interindividual variation in skin permeability is approximately 20%).

Oxybutynin is an antispasmodic, anticholinergic agent. Oxybutynin is administered as a racemate of R- and S-isomers. Chemically, oxybutynin is d, l (racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycolate. The empirical formula of oxybutynin is C22H31NO3. Its structural formula is:

Oxybutynin is a white powder with a molecular weight of 357. It is soluble in alcohol, but relatively insoluble in water.

Transdermal System Components

Oxytrol is a matrix-type transdermal system composed of three layers as illustrated in Figure 1 below. Layer 1 (Backing Film) is a thin flexible polyester/ethylene-vinyl acetate film that provides the matrix system with occlusivity and physical integrity and protects the adhesive/drug layer. Layer 2 (Adhesive/Drug Layer) is a cast film of acrylic adhesive containing oxybutynin and triacetin, USP. Layer 3 (Release Liner) is two overlapped siliconized polyester strips that are peeled off and discarded by the patient prior to applying the matrix system.

Figure 1: Side and top views of the Oxytrol system.

(Not to scale)

Oxytrol - Clinical Pharmacology

The free base form of oxybutynin is pharmacologically equivalent to oxybutynin hydrochloride. Oxybutynin acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle. In patients with conditions characterized by involuntary detrusor contractions, cystometric studies have demonstrated that oxybutynin increases maximum urinary bladder capacity and increases the volume to first detrusor contraction. Oxybutynin thus decreases urinary urgency and the frequency of both incontinence episodes and voluntary urination.

Oxybutynin is a racemic (50:50) mixture of R- and S-isomers. Antimuscarinic activity resides predominantly in the R-isomer. The active metabolite, N-desethyloxybutynin, has pharmacological activity on the human detrusor muscle that is similar to that of oxybutynin in in vitro studies.

Pharmacokinetics

Absorption

Oxybutynin is transported across intact skin and into the systemic circulation by passive diffusion across the stratum corneum. The average daily dose of oxybutynin absorbed from the 39 cm2 Oxytrol system is 3.9 mg. The average (SD) nominal dose, 0.10 (0.02) mg oxybutynin per cm2 surface area, was obtained from analysis of residual oxybutynin content of systems worn over a continuous 4-day period during 303 separate occasions in 76 healthy volunteers. Following application of the first Oxytrol 3.9 mg/day system, oxybutynin plasma concentration increases for approximately 24 to 48 hours, reaching average maximum concentrations of 3 to 4 ng/mL. Thereafter, steady concentrations are maintained for up to 96 hours. Absorption of oxybutynin is bioequivalent when Oxytrol is applied to the abdomen, buttocks, or hip. Average plasma concentrations measured during a randomized, crossover study of the three recommended application sites in 24 healthy men and women are shown in Figure 2.

Figure 2: Average plasma oxybutynin concentrations (Cp) in 24 healthy male and female volunteers during single-dose application of Oxytrol 3.9 mg/day to the abdomen, buttock, and hip (System removal at 96 hours).

Steady-state conditions are reached during the second Oxytrol application. Average steady-state plasma concentrations were 3.1 ng/mL for oxybutynin and 3.8 ng/mL for N-desethyloxybutynin (Figure 3). Table 1 provides a summary of pharmacokinetic parameters of oxybutynin in healthy volunteers after single and multiple applications of Oxytrol.

Figure 3: Average (SEM) steady-state oxybutynin and N-desethyloxybutynin plasma concentrations (Cp) measured in 13 healthy volunteers following the second transdermal system application in a multiple-dose, randomized, crossover study.

Table 1: Mean (SD) oxybutynin pharmacokinetic parameters from single and multiple dose studies in healthy men and women volunteers after application of Oxytrol on the abdomen.

Dosing	Oxybutynin
	Cmax (SD) (ng/mL)	Tmax1 (hr)	Cavg (SD) (ng/mL)	AUC (SD) (ng/mLxh)
Single	3.0 (0.8)	48	—	245 (59) 2
	3.4 (1.1)	36	—	279 (99) 2
Multiple	6.6 (2.4)	10	4.2 (1.1)	408 (108) 3
	4.2 (1.0)	28	3.1 (0.7)	259 (57) 4

1 Tmax given as median

2 AUCinf

3 AUC0-96

4 AUC0-84 Distribution

Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of distribution was estimated to be 193 L after intravenous administration of 5 mg oxybutynin chloride.

Metabolism

Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly CYP3A4, found mostly in the liver and gut wall. Metabolites include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and N-desethyloxybutynin, which is pharmacologically active.

After oral administration of oxybutynin, pre-systemic first-pass metabolism results in an oral bioavailability of approximately 6% and higher plasma concentration of the N-desethyl metabolite compared to oxybutynin (see Figure 4). The plasma concentration AUC ratio of N-desethyl metabolite to parent compound following a single 5 mg oral dose of oxybutynin chloride was 11.9:1.

Transdermal administration of oxybutynin bypasses the first-pass gastrointestinal and hepatic metabolism, reducing the formation of the N-desethyl metabolite (see Figure 4). Only small amounts of CYP3A4 are found in skin, limiting pre-systemic metabolism during transdermal absorption. The resulting plasma concentration AUC ratio of N-desethyl metabolite to parent compound following multiple Oxytrol applications was 1.3:1.

Figure 4: Average plasma concentrations (Cp) measured after a single, 96-hour application of the Oxytrol 3.9 mg/day system (AUCinf/96) and a single, 5 mg, oral immediate-release dose of oxybutynin chloride (AUCinf/8) in 16 healthy male and female volunteers.

Following intravenous administration, the elimination half-life of oxybutynin is approximately 2 hours. Following removal of Oxytrol, plasma concentrations of oxybutynin and N-desethyloxybutynin decline with an apparent half-life of approximately 7 to 8 hours.

Excretion

Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the administered dose excreted unchanged in the urine. Also, less than 0.1% of the administered dose is excreted as the metabolite N-desethyloxybutynin.

Special Populations

Geriatric: The pharmacokinetics of oxybutynin and N-desethyloxybutynin were similar in all patients studied.

Pediatric: The pharmacokinetics of oxybutynin and N-desethyloxybutynin were not evaluated in individuals younger than 18 years of age. See PRECAUTIONS: Pediatric Use. 

Gender: There were no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following application of Oxytrol.

Race: Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of Oxytrol. Japanese volunteers demonstrated a somewhat lower metabolism of oxybutynin to N-desethyloxybutynin compared to Caucasian volunteers.

Renal Insufficiency: There is no experience with the use of Oxytrol in patients with renal insufficiency.

Hepatic Insufficiency: There is no experience with the use of Oxytrol in patients with hepatic insufficiency.

Drug-Drug Interactions: See PRECAUTIONS: Drug Interactions.

Adhesion

Adhesion was periodically evaluated during the Phase 3 studies. Of the 4,746 Oxytrol evaluations in the Phase 3 trials, 20 (0.4%) were observed at clinic visits to have become completely detached and 35 (0.7%) became partially detached during routine clinic use. Similar to the pharmacokinetic studies, > 98% of the systems evaluated in the Phase 3 studies were assessed as being ≥ 75% attached and thus would be expected to perform as anticipated.

Clinical Studies

The efficacy and safety of Oxytrol were evaluated in patients with urge urinary incontinence in two Phase 3 controlled studies and one open-label extension. Study 1 was a Phase 3, placebo controlled study, comparing the safety and efficacy of Oxytrol at dose levels of 1.3, 2.6, and 3.9 mg/day to placebo in 520 patients. Open-label treatment was available for patients completing the study. Study 2 was a Phase 3 study, comparing the safety and efficacy of Oxytrol 3.9 mg/day versus active and placebo controls in 361 patients.

Study 1 was a randomized, double-blind, placebo-controlled, parallel group study of three dose levels of Oxytrol conducted in 520 patients. The 12-week double-blind treatment included Oxytrol doses of 1.3, 2.6, and 3.9 mg/day with matching placebo. An open-label, dose titration treatment extension allowed continued treatment for up to an additional 40 weeks for patients completing the double-blind period. The majority of patients were Caucasian (91%) and female (92%) with a mean age of 61 years (range, 20 to 88 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge), urge incontinence episodes of ≥ 10 per week, and ≥ 8 micturitions per day. The patient’s medical history and a urinary diary during the treatment-free baseline period confirmed the diagnosis of urge incontinence. Approximately 80% of patients had no prior pharmacological treatment for incontinence. Reductions in weekly incontinence episodes, urinary frequency, and urinary void volume between placebo and active treatment groups are summarized in Table 2.

Table 2: Mean and median change from baseline to end of treatment (Week 12 or last observation carried forward) in incontinence episodes, urinary frequency, and urinary void volume in patients treated with Oxytrol 3.9 mg/day or placebo for 12 weeks (Study 1).

Parameter	Placebo (N = 127)		Oxytrol 3.9 mg/day (N = 120)
	Mean (SD)	Median	Mean (SD)	Median
Weekly Incontinence Episodes
Baseline	37.7 (24.0)	30	34.3 (18.2)	31
Reduction	19.2 (21.4)	15	21.0 (17.1)	19
p value vs. placebo	—		0.0265*
Daily Urinary Frequency
Baseline	12.3 (3.5)	11	11.8 (3.1)	11
Reduction	1.6 (3.0)	1	2.2 (2.5)	2
p value vs. placebo	—		0.0313*
Urinary Void Volume (mL)
Baseline	175.9 (69.5)	166.5	171.6 (65.1)	168
Increase	10.5 (56.9)	5.5	31.6 (65.6)	26
p value vs. placebo	—		0.0009**

*Comparison significant if p < 0.05

**Comparison significant if p ≤ 0.0167

Study 2 was a randomized, double-blind, double-dummy, study of Oxytrol 3.9 mg/day versus active and placebo controls conducted in 361 patients. The 12-week double-blind treatment included an Oxytrol dose of 3.9 mg/day, an active comparator, and placebo. The majority of patients were Caucasian (95%) and female (93%) with a mean age of 64 years (range, 18 to 89 years). Entry criteria required that all patients have urge or mixed incontinence (with a predominance of urge) and had achieved a beneficial response from the anticholinergic treatment they were using at the time of study entry. The average duration of prior pharmacological treatment was greater than 2 years. The patient’s medical history and a urinary diary during the treatment-free baseline period confirmed the diagnosis of urge incontinence. Reductions in daily incontinence episodes, urinary frequency, and urinary void volume between placebo and active treatment groups are summarized in Table 3.

Table 3: Mean and median change from baseline to end of treatment (Week 12 or last observation carried forward) in incontinence episodes, urinary frequency, and urinary void volume in patients treated with Oxytrol 3.9 mg/day or placebo for 12 weeks (Study 2).

Parameter	Placebo (N = 117)		Oxytrol 3.9 mg/day (N = 121)
	Mean (SD)	Median	Mean (SD)	Median
Daily Incontinence Episodes
Baseline	5.0 (3.2)	4	4.7 (2.9)	4
Reduction	2.1 (3.0)	2	2.9 (3.0)	3
p value vs. placebo	—		0.0137*
Daily Urinary Frequency
Baseline	12.3 (3.3)	12	12.4 (2.9)	12
Reduction	1.4 (2.7)	1	1.9 (2.7)	2
p value vs. placebo	—		0.1010*
Urinary Void Volume (mL)
Baseline	175.0 (68.0)	171.0	164.8 (62.3)	160
Increase	9.3 (63.1)	5.5	32.0 (55.2)	24
p value vs. placebo	—		0.0010*

*Comparison significant if p < 0.05

Indications and Usage for Oxytrol

Oxytrol is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.

Contraindications

Oxytrol is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions. Oxytrol is also contraindicated in patients who have demonstrated hypersensitivity to oxybutynin or other components of the product.

Warnings

Angioedema requiring hospitalization and emergency medical treatment has occurred with the first or subsequent doses of oral oxybutynin. In the event of angioedema, oxybutynin-containing products should be discontinued and appropriate therapy promptly provided.

Precautions

General

Oxytrol should be used with caution in patients with hepatic or renal impairment.

Urinary Retention: Oxytrol should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention (see CONTRAINDICATIONS).

Gastrointestinal Disorders: Oxytrol should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention (see CONTRAINDICATIONS).

Oxytrol, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis. Oxytrol should be used with caution in patients who have gastroesophageal reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis.

Information for Patients

Patients should be informed that heat prostration (fever and heat stroke due to decreased sweating) can occur when anticholinergics such as oxybutynin are used in a hot environment. Because anticholinergic agents such as oxybutynin may produce drowsiness (somnolence), dizziness or blurred vision, patients should be advised to exercise caution. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin.

Patients should be informed that angioedema has been reported with oral oxybutynin use. Patients should be advised to promptly discontinue oxybutynin therapy and seek immediate medical attention if they experience symptoms consistent with angioedema.

Oxytrol should be applied to dry, intact skin on the abdomen, hip, or buttock. A new application site should be selected with each new system to avoid re-application to the same site within 7 days. Details on use of the system are explained in the patient information leaflet that should be dispensed with the product.

Drug Interactions

The concomitant use of oxybutynin with other anticholinergic drugs or with other agents that produce dry mouth, constipation, somnolence, and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Pharmacokinetic studies have not been performed with patients concomitantly receiving cytochrome P450 enzyme inhibitors, such as antimycotic agents (e.g. ketoconazole, itraconazole, and miconazole) or macrolide antibiotics (e.g. erythromycin and clarithromycin). No specific drug-drug interaction studies have been performed with Oxytrol.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 24-month study in rats at dosages of oxybutynin chloride of 20, 80 and 160 mg/kg showed no evidence of carcinogenicity. These doses are approximately 6, 25 and 50 times the maximum exposure in humans taking an oral dose based on body surface area.

Oxybutynin chloride showed no increase of mutagenic activity when tested in Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae, and Salmonella typhimurium test systems. Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no definite evidence of impaired fertility.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no definite evidence of impaired fertility or harm to the animal fetus. Subcutaneous administration to rats at doses up to 25 mg/kg (approximately 50 times the human exposure based on surface area) and to rabbits at doses up to 0.4 mg/kg (approximately 1 times the human exposure) revealed no evidence of harm to the fetus due to oxybutynin chloride. The safety of Oxytrol administration to women who are or who may become pregnant has not been established. Therefore, Oxytrol should not be given to pregnant women unless, in the judgment of the physician, the probable clinical benefits outweigh the possible hazards.

Nursing Mothers

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

Pediatric Use

The safety and efficacy of Oxytrol in pediatric patients have not been established.

Geriatric Use

Of the total number of patients in the clinical studies of Oxytrol, 49% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations: Geriatric).

Adverse Reactions

The safety of Oxytrol was evaluated in a total of 417 patients who participated in two Phase 3 clinical efficacy and safety studies and an open-label extension. Additional safety information was collected in Phase 1 and Phase 2 trials. In the two pivotal studies, a total of 246 patients received Oxytrol during the 12-week treatment periods. A total of 411 patients entered the open-label extension and of those, 65 patients and 52 patients received Oxytrol for at least 24 weeks and at least 36 weeks, respectively.

No deaths were reported during treatment. No serious adverse events related to treatment were reported.

Adverse events reported in the pivotal trials are summarized in Tables 4 and 5 below.

Table 4: Number (%) of adverse events occurring in ≥ 2% of Oxytrol-treated patients and greater in Oxytrol group than in placebo group (Study 1).

Adverse Event*	Placebo (N = 132)		Oxytrol (3.9 mg/day) (N=125)
	N	%	N	%
Application site pruritus	8	6.1%	21	16.8%
Dry mouth	11	8.3%	12	9.6%
Application site erythema	3	2.3%	7	5.6%
Application site vesicles	0	0.0%	4	3.2%
Diarrhea	3	2.3%	4	3.2%
Dysuria	0	0.0%	3	2.4%
*includes adverse events judged by the investigator as possibly, probably or definitely treatment-related.

 

Table 5: Number (%) of adverse events occurring in ≥ 2% of Oxytrol-treated patients and greater in Oxytrol group than in placebo group (Study 2).

Adverse Event*	Placebo (N = 117)		Oxytrol (3.9 mg/day) (N = 121)
	N	%	N	%
Application site pruritus	5	4.3%	17	14.0%
Application site erythema	2	1.7%	10	8.3%
Dry mouth	2	1.7%	5	4.1%
Constipation	0	0.0%	4	3.3%
Application site rash	1	0.9%	4	3.3%
Application site macules	0	0.0%	3	2.5%
Abnormal vision	0	0.0%	3	2.5%
*includes adverse events judged by the investigator as possibly, probably or definitely treatment-related.

Other adverse events reported by > 1% of Oxytrol-treated patients, and judged by the investigator to be possibly, probably or definitely related to treatment include: abdominal pain, nausea, flatulence, fatigue, somnolence, headache, flushing, rash, application site burning and back pain.

Most treatment-related adverse events were described as mild or moderate in intensity. Severe application site reactions were reported by 6.4% of Oxytrol-treated patients in Study 1 and by 5.0% of Oxytrol-treated patients in Study 2.

Treatment-related adverse events that resulted in discontinuation were reported by 11.2% of Oxytrol-treated patients in Study 1 and 10.7% of Oxytrol-treated patients in Study 2. Most of these were secondary to application site reaction. In the two pivotal studies, no patient discontinued Oxytrol treatment due to dry mouth.

In the open-label extension, the most common treatment-related adverse events were: application site pruritus, application site erythema and dry mouth.

Post Marketing Surveillance

The following event has been reported in association with Oxytrol use in clinical practice: dizziness. Because spontaneously reported events are from worldwide post marketing experiences, the frequency of events and the role of Oxytrol in their causation cannot be reliably determined.

Overdosage

Plasma concentration of oxybutynin declines within 1 to 2 hours after removal of transdermal system(s). Patients should be monitored until symptoms resolve. Overdosage with oxybutynin has been associated with anticholinergic effects including CNS excitation, flushing, fever, dehydration, cardiac arrhythmia, vomiting, and urinary retention. Ingestion of 100 mg oral oxybutynin chloride in association with alcohol has been reported in a 13 year old boy who experienced memory loss, and in a 34 year old woman who developed stupor, followed by disorientation and agitation on awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both patients recovered fully with symptomatic treatment.

Oxytrol Dosage and Administration

Oxytrol should be applied to dry, intact skin on the abdomen, hip, or buttock. A new application site should be selected with each new system to avoid re-application to the same site within 7 days.

The dose of Oxytrol is one 3.9 mg/day system applied twice weekly (every 3 to 4 days).

How is Oxytrol Supplied

Oxytrol 3.9 mg/day (oxybutynin transdermal system). Each 39 cm2 system imprinted with Oxytrol 3.9 mg/day contains 36 mg oxybutynin for nominal delivery of 3.9 mg oxybutynin per day when dosed in a twice weekly regimen.

NDC 52544-920-08 Patient Calendar Box of 8 Systems

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture and humidity. Do not store outside the sealed pouch. Apply immediately after removal from the protective pouch. Discard used Oxytrol in household trash in a manner that prevents accidental application or ingestion by children, pets, or others.

Rx only

A subsidiary of Watson Pharmaceuticals, Inc.

Corona, CA 92880 USA

Revised: January 2011

U.S. Patent Nos. 5,601,839; 5,834,010; and 7,179,483

PATIENT INFORMATION

Information for the Patient

Oxytrol® Oxybutynin Transdermal System

Read this information carefully before you begin treatment. Read the information whenever you get more medicine, there may be something new. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Oxytrol, ask your doctor. Only your doctor can determine if Oxytrol is right for you.

What is Oxytrol?

Oxytrol is a transdermal system (skin patch) to treat overactive bladder. It delivers the active ingredient, oxybutynin, through your skin and into your bloodstream. Overactive bladder makes it hard to control when you urinate (pass water). Overactive bladder can make you urinate more often (increased frequency) or make you feel the need to urinate often (urgency). Overactive bladder can also lead to accidental urine loss (leaking or wetting oneself).

The active ingredient in Oxytrol, oxybutynin, is dissolved in the thin layer of adhesive that sticks the patch to your skin. Oxytrol delivers the medicine slowly and constantly through your skin and into your bloodstream for the 3 or 4 days that you wear the patch. Oxytrol contains the same active ingredient as oxybutynin tablets and syrup.

Who should not use Oxytrol?

Do not use Oxytrol if you have the following medical conditions:

• Urinary retention. Your bladder does not empty or does not empty completely when you urinate.


• Gastric retention. Your stomach empties slowly or incompletely after a meal.


• Uncontrolled narrow-angle glaucoma (high pressure in your eye). Tell your doctor if you have glaucoma or a family history of glaucoma.


• Pregnancy or breastfeeding. Tell your doctor if you are pregnant or breastfeeding. Oxytrol may not be right for you.


• Allergy to oxybutynin or the inactive ingredients in Oxytrol. If you need to know the inactive ingredients, ask your doctor or pharmacist. If you have allergies to medical tape products or other skin patches, tell your doctor.

If you have certain other medical conditions, use Oxytrol with caution. Tell your doctor about all your medical conditions, especially if you have any of the following:

• Liver disease


• Kidney disease


• Bladder obstruction (blockage)


• Gastrointestinal obstruction (blockage in the digestive system)


• Ulcerative colitis (inflamed bowels)


• Myasthenia gravis (nerve weakness)


• Gastric reflux disease or esophagitis (inflamed esophagus, the tube between your mouth and stomach)

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines and supplements. Some of them may cause problems if you take Oxytrol. Also, Oxytrol may affect how some of them work.

What should I avoid while using Oxytrol?

Do not expose the patch to sunlight. Therefore, wear it under clothing.

What are the possible side effects of Oxytrol?

You may see mild redness at the site when a patch is removed. This redness should disappear within several hours after removing the patch. If uncomfortable irritation or excessive itchiness continues, tell your doctor.

Oxybutynin may cause sleepiness or blurred vision, so be careful when driving or operating machinery. In addition, sleepiness may be increased by drinking alcohol (beer, wine or hard liquor).

Since oxybutynin treatment may decrease sweating, you may overheat or have fever or heat stroke if you are in warm or hot temperatures.

The most common side effects of Oxytrol are skin reactions where the patch is put on. These include itching and redness. Other side effects include dry mouth, constipation, abnormal vision, headache and dizziness. If you take other medicines that cause dry mouth, constipation, sleepiness or dizziness, Oxytrol can increase those effects.

These are not all the side effects of Oxytrol. For a complete list, ask your doctor or pharmacist.

How should I use Oxytrol?

Put on a new patch of Oxytrol 2 times a week (every 3 to 4 days) according to your doctor’s instructions. Wear the patch all the time until it is time to apply a new one. Wear only 1 patch of Oxytrol at a time. Try to change the patch on the same 2 days each week. Your package of Oxytrol has a calendar checklist printed on the back to help you remember your schedule. Mark the schedule you plan to follow. Always change Oxytrol on the 2 days of the week you mark on the calendar.

Put the patch on a clean, dry, and smooth (fold-free) area of skin on your abdomen (stomach area), hips or buttocks (as shown in the picture). Avoid your waistline area, since tight clothing may rub against the patch. The areas you choose should not be oily, damaged (cut or scraped), irritated (rashes) or have any other skin problems. Do not put Oxytrol on areas that have been treated with oils, lotions, or powders that could keep the patch from sticking well to your skin.

When you put on a new patch, use a different area of skin from the most recent patch site. You may find it useful to change the site from one side of your body to the other. Do not use the same area for the patch for at least 1 week. You may wish to try different locations when using Oxytrol to find the locations that are most comfortable for you and where clothing will not rub against it.

Each patch is sealed in its own protective pouch. When you are ready to put on the Oxytrol patch, tear open the pouch and remove the patch. Apply the patch to your skin right away. Do not keep or store the patch outside the sealed pouch.

The sticky adhesive side of the patch is covered by 2 strips of overlapping protective liner. Remove the first piece of the protective liner and place the patch, adhesive face down, firmly onto the skin.

Bend the patch in half and gently roll the remaining part onto your skin using the tips of your fingers. As you roll the patch in place, the second piece of the protective liner should move off the patch. Apply firm pressure over the surface of the patch with your fingers to make sure the patch stays on. When putting on the patch, avoid touching the sticky adhesive side. Touching the adhesive may cause the patch to fall off early. Throw away the protective liners.

Contact with water when you are bathing, swimming, showering or exercising will not change the way that Oxytrol works. However, try to avoid rubbing the patch area during these activities.

If the patch partly or completely falls off, press it back in place and continue to follow your application schedule. If the patch does not stay on, throw it away. You should then put on a new patch in a different area, but continue to follow your original application schedule. If you forget to change your patch after 3 or 4 days, remove the old patch, put on a new patch in a different area and continue to follow your original application schedule.

When changing Oxytrol, remove the old patch slowly and carefully to avoid damaging the skin. Once off, fold the patch in half with the sticky sides together. Since the patch will still contain some oxybutynin, throw it away so that it cannot be accidentally worn or swallowed by another person, especially a child, or a pet.

Gently washing the application site with warm water and a mild soap should remove any adhesive that stays on your skin after removing the patch. A small amount of baby oil may also be used to remove any excess residue. Rings of adhesive that become dirty may require a medical adhesive removal pad that you can get from your pharmacist. Alcohol or other dissolving liquids (nail polish remover or other solvents) may cause skin irritation and should not be used.

Store at room temperature, 25°C (77°F). Temporary storage between 15 and 30°C (59 to 86°F) is also permitted. Keep Oxytrol and all medications in a safe, secure place and out of the reach of children.

General advice about Oxytrol

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not give Oxytrol to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Oxytrol. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Oxytrol that is written for health professionals. You can get more information about Oxytrol from the product information department at 1-888-OXY-TROL (1-888-699-8765) or by selecting patient information at the Oxytrol Website located at www.Oxytrol.com.

A subsidiary of Watson Pharmaceuticals, Inc.

Corona, CA 92880 USA

Revised: January 2011

©2001 Watson Pharma, Inc.

PRINCIPAL DISPLAY PANEL

Oxytrol® Oxybutynin Transdermal System

3.9 mg/day carton x 8 transdermal systems (outside and inside views below)

NDC 52544-920-08

Oxytrol  oxybutynin  patch

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 52544-920 Route of Administration TRANSDERMAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength OXYBUTYNIN (OXYBUTYNIN) OXYBUTYNIN 3.9 mg  in 1 d

Inactive Ingredients Ingredient Name Strength TRIACETIN

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 52544-920-08 8 POUCH In 1 BOX contains a POUCH (52544-920-54) 1 52544-920-54 1 PATCH In 1 POUCH This package is contained within the BOX (