hydrocortisone and lidocaine topical with psyllium

Generic Name: hydrocortisone and lidocaine topical with psyllium (HYE droe KORT i sone, LYE doe kane TOP ik al, SIL ee um)

Brand Names: Xyralid RC

What is hydrocortisone and lidocaine topical with psyllium?

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

Lidocaine is a local anesthetic (numbing medication). It works by blocking nerve signals in your body.

Psyllium is a type of soluble fiber used as a bulk-forming stool softener. Psyllium is not a laxative.

The combination of hydrocortisone and lidocaine topical (for the skin) is used to relieve itching, pain or other discomforts caused by conditions such as hemorrhoids or anal fissures (tiny tears in the tissues surrounding the anus). Psyllium is provided as a medication you take by mouth to help soften your stools, making them easier and less painful to pass while your rectal condition is being treated.

Hydrocortisone and lidocaine topical may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about hydrocortisone and lidocaine topical with psyllium?

You should not use this medication if you are allergic to hydrocortisone, lidocaine (or any other type of numbing medicine), or psyllium, or if you have severe liver disease, a fungal infection, smallpox, chickenpox, herpes, or tuberculosis.

Before using hydrocortisone and lidocaine topical with psyllium, tell your doctor if you have liver or kidney disease, a heart rhythm problem, congestive heart failure, stomach or intestinal conditions, diabetes, or any type of infection.

Do not take hydrocortisone rectal by mouth. It is for use only in your rectum. Do not cover the treated rectal areas with a bandage, plastic pants or other covering unless your doctor has told you to. Covering the skin that is treated with hydrocortisone and lidocaine topical can increase the amount of the drug your skin absorbs, which may lead to unwanted side effects. Your body may also absorb more of this medication if you use too much. Contact your doctor if your condition does not improve or if it gets worse after using this medication. Do not use this medication in a child without a doctor's advice. Children are more sensitive to the effects of hydrocortisone and lidocaine topical.

What should I discuss with my healthcare provider before using hydrocortisone and lidocaine topical with psyllium?

You should not use this medication if you are allergic to hydrocortisone, lidocaine, or psyllium, or if you have:

• 
  

  severe liver disease;

  
  


• 
  

  a fungal infection;

  
  


• 
  

  herpes;

  
  


• 
  

  smallpox or chickenpox; or

  
  


• 
  

  tuberculosis.

  
  

If you have certain conditions, you may need a dose adjustment or special tests to safely use this medication. Before using hydrocortisone and lidocaine topical with psyllium, tell your doctor if you have liver disease or a heart rhythm problem.

• 
  

  liver disease;

  
  


• 
  

  kidney disease;

  
  


• 
  

  a heart rhythm problem;

  
  


• 
  

  congestive heart failure;

  
  


• 
  

  a stomach or intestinal disorder; or

  
  


• 
  

  any type of infection.

  
  

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 hydrocortisone and lidocaine topical with psyllium is harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether hydrocortisone and lidocaine topical with psyllium 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 in a child without a doctor's advice. Children are more sensitive to the effects of hydrocortisone and lidocaine topical.

How should I use hydrocortisone and lidocaine topical with psyllium?

Use this medication exactly as directed on the label, or as it has been prescribed by your doctor. Do not use the medication in larger or smaller amounts, or use it for longer than recommended.

Do not take hydrocortisone rectal by mouth. It is for use only in your rectum.

Hydrocortisone and lidocaine topical rectal cream is supplied in 14 medicine tubes with 14 disposable applicators. Each tube and applicator one is for a single use only. This medication is usually applied 2 times daily.

Peel off the seal under the tube cap and screw the applicator tip firmly onto the tube. Squeeze the tube to push the medication into the applicator. With the tube still attached to the applicator, insert only the tip of the applicator into the rectum. Continue squeezing the tube to apply the medicine. Also apply to the outer areas of the anus.

Do not insert the applicator deep into the rectum. Use only applicators that come with this medication, and throw each one away after one use.

Wash your hands before and after using the hydrocortisone and lidocaine rectal cream. Follow the application instructions provided with the medication.

Use the moist towelettes supplied with the medication to gently clean the rectal area before each time you apply the rectal cream. Each towelette is for one use only.

The hydrocortisone and lidocaine topical kit comes with 7 packets of psyllium labeled as Konsyl. A reusable shaker cup is also provided. Empty the contents of a psyllium packet into the shaker cup and fill the cup about half way with fruit juice or other desired liquid.

Place the cap tightly onto the shaker cup and shake vigorously for 3 to 5 seconds or until the psyllium granules are mixed well with the liquid. Drink all of this mixture right away. To make sure you get the entire dose, add a little more liquid to the shaker cup, swirl gently and drink right away.

Wash the shaker cup with soap and water between uses.

Do not cover the treated rectal areas with a bandage, plastic pants or other covering unless your doctor has told you to. Covering the skin that is treated with hydrocortisone and lidocaine topical can increase the amount of the drug your skin absorbs, which may lead to unwanted side effects. Your body may also absorb more of this medication if you use too much.

Your body may also absorb more of this medication if you use too much.

Contact your doctor if your condition does not improve or if it gets worse after using this medication.

Hydrocortisone and lidocaine topical will not treat a bacterial, fungal, or viral infection.

Store the rectal cream and psyllium packets at room temperature away from moisture and heat.

What happens if I miss a dose?

Use the medication as soon as you remember. If it is almost time for the next dose, skip the missed dose and use the medicine at the next regularly scheduled time. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

An overdose of hydrocortisone topical applied to the skin 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.

Lidocaine topical applied to the skin is not likely to cause an overdose unless you apply more than the recommended dose. Lidocaine overdose symptoms may include drowsiness, confusion, nervousness, ringing in your ears, blurred vision, feeling hot or cold, numbness, muscle twitches, uneven heartbeats, seizure (convulsions), slowed breathing, or respiratory failure (breathing stops).

What should I avoid while using hydrocortisone and lidocaine topical with psyllium?

Avoid getting the rectal cream in your eyes, ears, mouth, and nose, or on your lips. If it does get into any of these areas, rinse well with water or saline solution.

Avoid using other topical medications on the affected area unless your doctor has told you to.

Hydrocortisone and lidocaine topical with psyllium 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 severe irritation or burning of the treated area, or if you show signs of absorbing hydrocortisone topical through your skin, such as:

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  blurred vision, or seeing halos around lights;

  
  


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  mood changes;

  
  


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  sleep problems (insomnia);

  
  


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  weight gain, puffiness in your face; or

  
  


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  muscle weakness, feeling tired.

  
  

Less serious side effects may include:

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  mild stinging, burning, or redness where the medication is applied;

  
  


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  thinning of your skin;

  
  


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  numbness in places where the medicine is accidentally applied.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Hydrocortisone and lidocaine topical with psyllium Dosing Information

Usual Adult Dose for Hemorrhoids:

Apply rectal cream to the affected area twice daily. Remove peel seal under the cap of the tube and screw the applicator tip firmly onto the end of the tube and tightened. While holding the tube, squeeze the tube to fill applicator until a small amount of cream shows and lubricate the end of the tip with cream. Gently insert the applicator tip with attached tube in the anal area. Continue squeezing the body of the tube as it is moved around the areas of discomfort, and lastly, around and in the anal opening. Once application is completed, the tube and applicator tip should be gently removed from the area and disposed.

Put one psyllium fiber packet (6 grams) into a shaker cup or closed container; add at least 8 ounces of juice, water or other beverage; shake 3 to 5 seconds; drink promptly; if mixture thickens, add more fluid, stir; follow with additional fluid to aid product action.

Usual Pediatric Dose for Hemorrhoids:

Apply rectal cream to the affected area twice daily. Remove peel seal under the cap of the tube and screw the applicator tip firmly onto the end of the tube and tightened. While holding the tube, squeeze the tube to fill applicator until a small amount of cream shows and lubricate the end of the tip with cream. Gently insert the applicator tip with attached tube in the anal area. Continue squeezing the body of the tube as it is moved around the areas of discomfort, and lastly, around and in the anal opening. Once application is completed, the tube and applicator tip should be gently removed from the area and disposed. Dosage in pediatric patients would be reduced commensurate with age, body weight and physical condition.

12 years or older:
Put one psyllium fiber packet (6 grams) into a shaker cup or closed container; add at least 8 ounces of juice, water or other beverage; shake 3 to 5 seconds; drink promptly; if mixture thickens, add more fluid, stir; follow with additional fluid to aid product action.

6 years to 11 years:
Put one half of the psyllium fiber packet (3 grams) into a shaker cup or closed container; add at least 8 ounces of juice, water or other beverage; shake 3 to 5 seconds; drink promptly; if mixture thickens, add more fluid, stir; follow with additional fluid to aid product action.

What other drugs will affect hydrocortisone and lidocaine topical with psyllium?

Tell your doctor about all other medications you use, especially a heart rhythm medication such as:

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  quinidine (Quinaglute, Quinidex, Quin-Release);

  
  


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  procainamide (Procan, Procanbid, Pronestyl);

  
  


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  disopyramide (Norpace);

  
  


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  flecaininde (Tambocor);

  
  


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  mexiletine (Mexitil);

  
  


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  morizicine (Ethmozine); or

  
  


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  propafenone, (Rythmol).

  
  

This list is not complete and there may be other drugs that can interact with hydrocortisone and lidocaine topical with psyllium. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More hydrocortisone and lidocaine topical with psyllium resources

• Hydrocortisone and lidocaine topical with psyllium Use in Pregnancy & Breastfeeding
• Hydrocortisone and lidocaine topical with psyllium Drug Interactions
• Hydrocortisone and lidocaine topical with psyllium Support Group
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Compare hydrocortisone and lidocaine topical with psyllium with other medications

• Hemorrhoids

Where can I get more information?

• Your pharmacist can provide more information about hydrocortisone and lidocaine topical with psyllium.

Detrunorm 15 mg Tablets

1. Name Of The Medicinal Product

Detrunorm^® 15 mg Coated Tablets

¹Propiverine Hydrochloride 15mg Coated Tablets

¹PL 20072/0015-0003; 29/06/2006

2. Qualitative And Quantitative Composition

Each coated tablet contains 15 mg propiverine hydrochloride equivalent to 13.64 mg propiverine.

For excipients, see section 6.1.

3. Pharmaceutical Form

Coated tablets.

Rose-coloured, lenticular glazing coated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

The treatment of urinary incontinence, as well as urgency and frequency in patients who have either idiopathic detrusor overactivity (overactive bladder) or neurogenic detrusor overactivity (detrusor hyperreflexia) from spinal cord injuries, e.g. transverse lesion paraplegia.

4.2 Posology And Method Of Administration

Coated tablets for oral application.

The recommended daily doses are as follows:

Adults: As a standard dose one coated tablet (= 15 mg propiverine hydrochloride) twice a day is recommended, this may be increased to three times a day. Some patients may already respond to a dosage of 15 mg a day.

For neurogenic detrusor overactivity a dose of one coated tablet three times a day is recommended. This may be increased to four times a day if necessary and tolerated (maximum recommended daily dose).

Elderly: Generally there is no special dosage regimen for the elderly (see 5.2).

There is no clinically relevant effect of food on the pharmacokinetics of propiverine (see 5.2). Accordingly, there is no particular recommendation for the intake of propiverine in relation to food.

This medicinal product contains 0.61 mg of glucose. Accordingly, a daily dose of 2 coated tablets supplies 1.22 mg of glucose.

4.3 Contraindications

The drug is contraindicated in patients who have demonstrated hypersensitivity to the active substance or to any of the excipients and in patients suffering from one of the following disorders:

- obstruction of the bowel

- significant degree of bladder outflow obstruction where urinary retention may be anticipated

- myasthenia gravis

- intestinal atony

- severe ulcerative colitis

- toxic megacolon

- uncontrolled angle closure glaucoma

- moderate or severe hepatic impairment

- tachyarrhythmias.

4.4 Special Warnings And Precautions For Use

The drug should be used with caution in patients suffering from:

- autonomic neuropathy.

Symptoms of the following diseases may be aggravated following administration of the drug:

- severe congestive heart failure (NYHA IV)

- prostatic hypertrophy

- hiatus hernia with reflux oesophagitis

- cardiac arrhythmia

- tachycardia.

Propiverine, like other anticholinergics, induces mydriasis. Therefore, the risk to induce acute angle-closure glaucoma in individuals predisposed with narrow angles of the anterior chamber may be increased.

Drugs of this class have been reported to induce or precipitate acute angle-closure glaucoma.

Pollakiuria and nocturia due to renal disease or congestive heart failure as well as organic bladder diseases (e.g. urinary tract infections, malignancy) should be ruled out prior to treatment.

Cochineal red A (E124, lake) may cause allergic reactions.

Due to a lack of data Detrunorm^® 15 mg Coated Tablets should not be used in children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Increased effects due to concomitant medication with tricyclic antidepressants (e.g. imipramine), tranquillisers (e.g. benzodiazepines), anticholinergics, amantadine, neuroleptics (e.g. phenothiazines) and beta-adrenoceptor agonists (beta-sympathomimetics). Decreased effects due to concomitant medication with cholinergic drugs. Reduced blood pressure in patients treated with isoniazid. The effect of prokinetics such as metoclopramide may be decreased.

Pharmacokinetic interactions are possible with other drugs metabolised by cytochrome P450 3A4 (CYP 3A4). However, a very pronounced increase of concentrations for such drugs is not expected as the effects of propiverine are small compared to classical enzyme inhibitors (e.g. ketoconazole or grapefruit juice). Propiverine may be considered as weak inhibitor of cytochrome P450 3A4. Pharmacokinetic studies with patients concomitantly receiving potent CYP 3A4 inhibitors such as azole antifungals (e.g. ketoconazole, itraconazole) or macrolide antibiotics (e.g. erythromycin, clarithromycin) have not been performed.

4.6 Pregnancy And Lactation

There are no adequate data from the use of propiverine hydrochloride in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

The drug is secreted into the milk of lactating mammals.

Propiverine hydrochloride should not be used during pregnancy and should not be administered to nursing women.

4.7 Effects On Ability To Drive And Use Machines

Propiverine hydrochloride may produce drowsiness and blurred vision. This may impair the patient's ability to exert activities that require mental alertness such as operating a motor vehicle or other machinery, or to exert hazardous work while taking this drug.

Sedative drugs may enhance the drowsiness caused by propiverine hydrochloride.

4.8 Undesirable Effects

Adverse reactions	System organ class (Disorders according to MedDRA)
Very common (>1/10)
- dry mouth	Gastrointestinal
Common (>1/100, <1/10)
- accommodation abnormal, accommodation disturbances, vision abnormal	Eye
- constipation	Gastrointestinal
Uncommon (>1/1,000, <1/100)
- fatigue	General disorders and administration site conditions
- nausea/vomiting	Gastrointestinal
- dizziness	Nervous system
- tremor	Nervous system
- urinary retention	Urinary system
- flushing	Vascular
- decreased blood pressure with drowsiness	Vascular
Rare (>1/10,000, <1/1,000)
- rash due to idiosyncrasy (propiverine hydrochloride) or hypersensitivity (excipients, e.g. colorant)	Skin and subcutaneous tissue
Very rare (<1/10,000, including isolated reports)
- palpitation	Cardiac
- restlessness, confusion	Psychiatric
2Not Known (cannot be estimated from the available data)
- hallucinations	Psychiatric

²PL20072/0015-0007; 27/08/2008

All undesirable effects are transient and recede after a dose reduction or termination of the therapy after maximum 1 - 4 days.

During long-term therapy hepatic enzymes should be monitored, because reversible changes of liver enzymes might occur in rare cases. Monitoring of intraocular pressure is recommended in patients at risk of developing glaucoma.

Particular attention should be paid to the residual urine volume in cases of urinary tract infection.

4.9 Overdose

Overdose with the muscarinic receptor antagonist propiverine hydrochloride can potentially result in central anticholinergic effects, e.g. restlessness, dizziness, vertigo, disorders in speech and vision and muscular weakness. Moreover, severe dryness of mucosa, tachycardia and urinary retention may occur.

Treatment should be symptomatic and supportive. Management of overdose may include initiation of vomiting or gastric lavage using an oiled tube (attention: dryness of mucosa!), followed by symptomatic and supportive treatment as for atropine overdose (e.g. physostigmine) with a dosage of 1.0 to 2.0 mg in adults by slow intravenous injection (may be repeated as necessary to a total of 5 mg).

A 14-year old girl who ingested 450 mg propiverine hydrochloride presented with confabulation. The adolescent fully recovered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: G04B D06

Pharmacotherapeutic group: spasmolytic, anticholinergic.

Mechanism of action

Inhibition of calcium influx and modulation of intracellular calcium in urinary bladder smooth muscle cells causing musculotropic spasmolysis.

Inhibition of the efferent connection of the nervus pelvicus due to anticholinergic action.

- Pharmacodynamic effects

In animal models propiverine hydrochloride causes a dose-dependent decrease of the intravesical pressure and an increase in bladder capacity.

The effect is based on the sum of the pharmacological properties of propiverine and three active urinary metabolites as shown in isolated detrusor strips of human and animal origin.

5.2 Pharmacokinetic Properties

General characteristics of the active substance

Propiverine is nearly completely absorbed from the gastrointestinal tract. It undergoes extensive first pass metabolism. Effects on urinary bladder smooth muscle cells are due to the parent compound and three active metabolites as well, which are rapidly excreted into the urine.

Absorption

After oral administration of Detrunorm^® 15 mg Coated Tablets propiverine is rapidly absorbed from the gastrointestinal tract with maximal plasma concentrations reached after 2.3 hours. The mean absolute bioavailability of Detrunorm^® 15 mg Coated Tablets is 40.5% (arithmetic mean value for AUC_0(p.o.) / AUC_0(i.v.)).

Food intake increases the bioavailability of propiverine (mean increase 1.3 fold), but does not significantly affect the maximum plasma concentrations of propiverine or of its main metabolite, propiverine-N-oxide. This difference in bioavailability is unlikely to be of clinical significance and adjustment of dose in relation to food intake is not required.

Distribution

After administration of Detrunorm^® 15 mg Coated Tablets t.i.d., steady state is reached after four to five days at a higher concentration level than after single dose application (C_average = 61 ng/ml). The volume of distribution was estimated in 21 healthy volunteers after intravenous administration of propiverine hydrochloride to range from 125 to 473 l (mean 279 l) indicating that a large amount of available propiverine is distributed to peripheral compartments. The binding to plasma proteins is 90 - 95% for the parent compound and about 60% for the main metabolite.

Plasma concentrations of propiverine in 16 healthy volunteers after single and repeated administration of Detrunorm^®15 mg Coated Tablets (t.i.d. for 6 days):

single dose

multiple dose

Steady state characteristics of propiverine following multiple-dose administration to 16 healthy volunteers of Detrunorm^® 15 mg Coated Tablets (t.i.d. for 6 days):

Dose interval	AUC0-	PTF	Caverage
[h]	[ng	CV [%]	[%]	CV [%]	[ng/ml]	CV [%]
0 – 8	515	35	57	16	64	36
8 – 16	460	33	70	25	57	33
16 – 24	421	36	52	39	52	36
CV: coefficient of variation PTF: peak-trough fluctuation

Biotransformation

Propiverine is extensively metabolised by intestinal and hepatic enzymes. The primary metabolic route involves the oxidation of the Piperidyl-N and is mediated by CYP 3A4 and Flavin-monoxygenases (FMO) 1 and 3 and leads to the formation of the much less active N-oxide, the plasma concentration of which greatly exceeds that of the parent substance. Four metabolites were identified in urine; two of them are pharmacologically active and may contribute to the therapeutic efficacy of Detrunorm^® 15 mg Coated Tablets.

In vitro there is a slight inhibition of CYP 3A4 and CYP 2D6 detectable which occurs at concentrations exceeding therapeutic plasma concentrations 10- to 100-fold (see section 4.5).

Elimination

Following administration of 30 mg oral dose of ¹⁴C-propiverine hydrochloride to healthy volunteers, 60% of radioactivity was recovered in urine and 21% was recovered in faeces within 12 days. Less than 1% of an oral dose is excreted unchanged in the urine. Mean total clearance after single dose administration of 30 mg is 371 ml/min (191 – 870 ml/min). In three studies including a total of 37 healthy volunteers the mean elimination half-life was 14.1, 20.1, and 22.1 hours, respectively.

Linearity/non-linearity

Pharmacokinetic parameters of propiverine and propiverine-N-oxide following oral administration of 10 - 30 mg of propiverine hydrochloride are linearly related to dose. There are no changes of pharmacokinetics during steady state compared to single dose administration.

Characteristics in patients

Renal impairment

Severe renal impairment does not significantly alter the disposition of propiverine and its main metabolite, propiverine-N-oxide, as deduced from a single dose study in 12 patients with creatinine clearance < 30 ml/min. No dose adjustment is to be recommended as long as the total daily dose does not exceed 30 mg (i.e. Detrunorm^® 15 mg Coated Tablets given b.i.d.). In case that higher dose (i.e. 45 mg) shall be administered a careful titration of dose is recommended considering anticholinergic effects as a marker for tolerability.

Hepatic insufficiency

There were similar steady state pharmacokinetics in 12 patients with mild to moderate impairment of liver function due to fatty liver disease as compared to 12 healthy controls. No data are available for severe hepatic impairment.

Age

The comparison of trough plasma concentrations during steady state (Detrunorm^® 15 mg Coated Tablets t.i.d. for 28 days) reveals no difference between older patients (60 – 85 years; mean 68) and young healthy subjects. The ratio of parent drug to metabolite remains unchanged in older patients indicating the metabolic conversion of propiverine to its main metabolite, propiverine-N-oxide, not to be an age-related or limiting step in the overall excretion.

Patients with glaucoma

Intraocular pressure in patients with open angle glaucoma and in patients with treated (controlled) angle closure glaucoma is not increased by Detrunorm^® 15 mg Coated Tablets t.i.d., as demonstrated by two placebo-controlled studies.

5.3 Preclinical Safety Data

In long term oral dose studies in two mammalian species the main treatment related effects were changes in the liver (including elevation of hepatic enzymes). These were characterised by hepatic hypertrophy and fatty degeneration. The fatty degeneration was reversible upon cessation of treatment.

In animal studies, skeletal retardation in the offspring occurred when the drug was administered orally at high doses to pregnant females. In lactating mammals propiverine hydrochloride was excreted into the milk.

There was no evidence of mutagenicity of propiverine and its main metabolites. Carcinogenicity studies in rodents revealed three types of tumours which were considered to be species specific and therefore not of clinical relevance.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate, powdered cellulose, magnesium stearate, sucrose, talc, heavy kaolin, calcium carbonate, titanium dioxide (E171), acacia gum, colloidal anhydrous silica, Macrogol 6000, glucose monohydrate, Cochineal red A (E124, lake), montan wax.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

No special precautions for storage.

6.5 Nature And Contents Of Container

PVC/aluminium blisters in carton with 28 or 56 coated tablets per carton.

7 per blister	10 per blister
14 (2 blisters per carton)	20 (2 blisters per carton)
28 (4 blisters per carton)	30 (3 blisters per carton)
56 (8 blisters per carton)	50 (5 blisters per carton)
112 (16 blisters per carton)	60 (6 blisters per carton) 100 (10 blisters per carton) 300 (30 blisters per carton)

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Amdipharm Plc

Regency House

Miles Gray Road

Basildon

Essex

SS14 3AF

8. Marketing Authorisation Number(S)

PL 20072/0015

9. Date Of First Authorisation/Renewal Of The Authorisation

15 July 2004

21/05/2008

10. Date Of Revision Of The Text

August 2008

Urocit-K 15 Oral

Generic Name: potassium citrate (Oral route)

poe-TAS-ee-um SIT-rate

Commonly used brand name(s)

In the U.S.

• Urocit-K 10


• Urocit-K 15


• Urocit-K 5

Available Dosage Forms:

• Patch, Extended Release


• Tablet, Extended Release


• Tablet


• Solution

Therapeutic Class: Urinary Alkalinizer

Uses For Urocit-K 15

Potassium citrate is used to treat a kidney stone condition called renal tubular acidosis. It is also used to prevent kidney stones that may occur with gout.

Potassium citrate is a urinary alkalinizer. It works by making the urine more alkaline (less acid).

This medicine is available only with your doctor's prescription.

Before Using Urocit-K 15

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

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of potassium citrate in the pediatric population. Safety and efficacy have not been established.

Geriatric

No information is available on the relationship of age to the effects of potassium citrate in geriatric patients.

Pregnancy

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

Breast Feeding

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

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

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

• Acidosis (high acid in the blood) or


• Electrolyte imbalance (high or low sodium, chloride, or carbon dioxide in the blood) or


• Heart disease or


• Kidney disease—Use with caution. May make these conditions worse.

• Adrenal problems or


• Dehydration or


• Diabetes mellitus, uncontrolled or


• Hyperkalemia (high potassium in the blood) or


• Kidney failure or


• Infection (e.g., urinary tract infection) or


• Peptic ulcer or


• Stomach problems (e.g., intestinal blockage, digestion problems) or


• Tissue injury—Should not be used in patients with these conditions.

Proper Use of potassium citrate

This section provides information on the proper use of a number of products that contain potassium citrate. It may not be specific to Urocit-K 15. Please read with care.

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

In addition to the use of this medicine, treatment for your kidney stones may include changes in the types of foods you eat, especially foods high in sodium (salt). Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet.

It is best to take this medicine with a meal or bedtime snack, or within 30 minutes after meals.

Swallow the extended-release tablet whole. Do not break, crush, chew, or suck it. Doing so, may cause irritation in the mouth or throat.

Tell your doctor if you have trouble swallowing the tablets, or if the tablet seems to stick or gets stuck in your throat.

While taking the extended-release tablet, part of it may pass into your stools. This is normal and is nothing to worry about.

Drink extra fluids so you will pass more urine while you are using this medicine. This will keep your kidneys working well and help prevent kidney problems.

Dosing

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

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

• For oral dosage form (extended-release tablets):
  
  • For treatment and prevention of kidney stones:
    
    • Adults—At first, 15 to 30 milliequivalents (mEq) two times a day, or 10 to 20 mEq three times a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 100 mEq per day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

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

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Urocit-K 15

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

You should not take this medicine if you are also using atropine, benztropine (Cogentin®), glycopyrrolate (Robinul®), or a diuretic or "water pill" (such as amiloride, spironolactone, triamterene, Aldactone®, Dyrenium®, or Midamor®). Using these medicines together may cause serious problems.

Hyperkalemia (high potassium in the blood) may occur while you are using this medicine. Stop using this medicine and check with your doctor right away if you have the following symptoms: abdominal or stomach pain; confusion; difficulty with breathing; irregular heartbeat; nausea or vomiting; nervousness; numbness or tingling in the hands, feet, or lips; shortness of breath; or weakness or heaviness of the legs.

Stop using this medicine and check with your doctor right away if you have bloody or black, tarry stools; constipation; severe stomach pain; or vomiting of blood or material that looks like coffee grounds. These may be symptoms of a serious stomach problem.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Urocit-K 15 Side Effects

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

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

Incidence not known

• Abdominal or stomach discomfort


• diarrhea


• nausea


• vomiting

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Abdominal or stomach pain


• confusion


• difficult breathing


• irregular heartbeat


• nervousness


• numbness or tingling in the hands, feet, or lips


• shortness of breath


• weakness or heaviness of the legs

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

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

See also: Urocit-K5 Oral side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Urocit-K 15 Oral resources

• Urocit-K 15 Oral Side Effects (in more detail)
• Urocit-K 15 Oral Use in Pregnancy & Breastfeeding
• Drug Images
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• Nephrolithiasis
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Rivastigmine Sandoz 1.5 mg hard capsules

1. Name Of The Medicinal Product

Rivastigmine Sandoz 1.5 mg hard capsules

2. Qualitative And Quantitative Composition

Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 1.5 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Hard capsule

Off-white to slightly yellow powder in a capsule with yellow cap and yellow body, with red imprint “RIV 1.5 mg” on the body.

4. Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment of mild to moderately severe Alzheimer's dementia.

Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.

4.2 Posology And Method Of Administration

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia or dementia associated with Parkinson's disease. Diagnosis should be made according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is available who will regularly monitor intake of the medicinal product by the patient.

Rivastigmine should be administered twice a day, with morning and evening meals. The capsules should be swallowed whole.

Initial dose

1.5 mg twice a day.

Dose titration

The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level.

If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with Parkinson's disease are observed during treatment, these may respond to omitting one or more doses. If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated dose or the treatment may be discontinued.

Maintenance dose

The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day.

Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the patient's rate of decline in dementia symptoms is not altered favourably, the treatment should be discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no longer present.

Individual response to rivastigmine cannot be predicted. However, a greater treatment effect was seen in Parkinson's disease patients with moderate dementia. Similarly a larger effect was observed in Parkinson's disease patients with visual hallucinations (see section 5.1).

Treatment effect has not been studied in placebo-controlled trials beyond 6 months.

Re-initiation of therapy

If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above.

Renal and hepatic impairment

Due to increased exposure in moderate renal and mild to moderate hepatic impairment, dosing recommendations to titrate according to individual tolerability should be closely followed (see section 5.2).

Patients with severe liver impairment have not been studied (see section 4.3).

Children

Rivastigmine is not recommended for use in children.

4.3 Contraindications

The use of this medicinal product is contraindicated in patients with

- hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients used in the formulation,

- severe liver impairment, as it has not been studied in this population.

4.4 Special Warnings And Precautions For Use

The incidence and severity of adverse reactions generally increase with higher doses. If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the possibility of adverse reactions (e.g. vomiting).

Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia associated with Parkinson's disease) have been observed shortly after dose increase. They may respond to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8).

Gastrointestinal disorders such as nausea and vomiting may occur particularly when initiating treatment and/or increasing the dose. These adverse reactions occur more commonly in women. Patients with Alzheimer's disease may lose weight. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. During therapy patient's weight should be monitored.

In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as recommended in section 4.2 must be made. Some cases of severe vomiting were associated with oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments or high doses of rivastigmine.

Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8).

Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients with active gastric or duodenal ulcers or patients predisposed to these conditions.

Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such diseases.

The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related cognitive decline) has not been investigated and therefore use in these patient populations is not recommended.

Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity of tremor have been observed in patients with dementia associated with Parkinson's disease (see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to tremor 1.7% on rivastigmine vs 0% on placebo). Clinical monitoring is recommended for these adverse reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed.

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products.

No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine.

According to its metabolism, metabolic interactions with other medicinal products appear unlikely, although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.

4.6 Pregnancy And Lactation

For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.

In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed.

4.7 Effects On Ability To Drive And Use Machines

Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician.

4.8 Undesirable Effects

The most commonly reported adverse reactions are gastrointestinal, including nausea (38%) and vomiting (23%), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss.

The following adverse reactions, listed below in Table 1, have been accumulated in patients with Alzheimer's dementia treated with rivastigmine.

Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (

Table 1

Infections and infestations Very rare	Urinary infection
Metabolism and nutritional disorders Very common	Anorexia
Psychiatric disorders Common Common Uncommon Uncommon Very rare	Agitation Confusion Insomnia Depression Hallucinations
Nervous system disorders Very common Common Common Common Uncommon Rare Very rare	Dizziness Headache Somnolence Tremor Syncope Seizures Extrapyramidal symptoms (including worsening of Parkinson's disease)
Cardiac disorders Rare Very rare	Angina pectoris Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, atrial fibrillation and tachycardia)
Vascular disorders Very rare	Hypertension
Gastrointestinal disorders Very common Very common Very common Common Rare Very rare Very rare Not known	Nausea Vomiting Diarrhoea Abdominal pain and dyspepsia Gastric and duodenal ulcers Gastrointestinal haemorrhage Pancreatitis Some cases of severe vomiting were associated with oesophageal rupture (see section 4.4).
Hepatobiliary disorders Uncommon	Elevated liver function tests
Skin and subcutaneous tissue disorders Common Rare Not known	Sweating increased Rash Pruritus
General disorders and administration site conditions Common Common Uncommon	Fatigue and asthenia Malaise Accidental fall
Investigations Common	Weight loss

The following additional adverse reactions have been observed with rivastigmine transdermal patches: anxiety, delirium, pyrexia (common).

Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson's disease treated with rivastigmine.

Table 2

Metabolism and nutritional disorders Common Common	Anorexia Dehydration
Psychiatric disorders Common Common Common	Insomnia Anxiety Restlessness
Nervous system disorders Very common Common Common Common Common Common Common Uncommon	Tremor Dizziness Somnolence Headache Worsening of Parkinson's disease Bradykinesia Dyskinesia Dystonia
Cardiac disorders Common Uncommon Uncommon	Bradycardia Arial fibrillation Atrioventricular block
Gastrointestinal disorders Very common Very common Common Common Common	Nausea Vomiting Diarrhoea Abdominal pain and dyspepsia Salivary hypersecretion
Skin and subcutaneous tissue disorders Common	Sweating increased
Musculoskeletal and connective tissue disorders Common	Muscle rigidity
General disorders and administration site conditions Common Common	Fatigue and asthenia Gait abnormality

Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined adverse events that may reflect worsening of parkinsonian symptoms.

Table 3

Pre-defined adverse events that may reflect worsening of parkinsonian symptoms in patients with dementia associated with Parkinson's disease	Rivastigmine n (%)	Placebo n (%)
Total patients studied Total patients with pre-defined AE(s)	362 (100) 99 (27.3)	179 (100) 28 (15.6)
Tremor Fall Parkinson's disease (worsening) Salivary hypersecretion Dyskinesia Parkinsonism Hypokinesia Movement disorder Bradykinesia Dystonia Gait abnormality Muscle rigidity Balance disorder Musculoskeletal stiffness Rigors Motor dysfunction	37 (10.2) 21 (5.8) 12 (3.3) 5 (1.4) 5 (1.4) 8 (2.2) 1 (0.3) 1 (0.3) 9 (2.5) 3 (0.8) 5 (1.4) 1 (0.3) 3 (0.8) 3 (0.8) 1 (0.3) 1 (0.3)	7 (3.9) 11 (6.1) 2 (1.1) 0 1 (0.6) 1 (0.6) 0 0 3 (1.7) 1 (0.6) 0 0 2 (1.1) 0 0 0

4.9 Overdose

Symptoms

Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient fully recovered within 24 hours.

Treatment

As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary.

In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03

Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and Parkinson's disease.

Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in CSF by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar to that of AChE.

Clinical studies in Alzheimer's dementia

The efficacy of rivastigmine has been established through the use of three independent, domain specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities relating to finances, etc.).

The patients studied had an MMSE (Mini-Mental State Examination) score of 10–24.

The results for clinically relevant responders pooled from two flexible dose studies out of the three pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% improvement on the PDS.

In addition, a post-hoc definition of response is provided in the same table. The secondary definition of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6-12 mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this indication vary and direct comparisons of results for different therapeutic agents are not valid.

Table 4

Patients with Clinically Significant Response (%)
	Intent to Treat	Last Observation Carried Forward
Response Measure	Rivastigmine 6–12 mg N=473	Placebo   N=472	Rivastigmine 6–12 mg N=379	Placebo   N=444
ADAS-Cog: improvement of at least 4 points	21***	12	25***	12
CIBIC-Plus: improvement	29***	18	32***	19
PDS: improvement of at least 10%	26***	17	30***	18
At least 4 points improvement on ADAS-Cog with no worsening on CIBIC-Plus and PDS	10*	6	12**	6

*p<0.05, **p<0.01, ***p<0.001

Clinical studies in dementia associated with Parkinson's disease

The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score of 10–24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change).

Table 5

Dementia associated with Parkinson's Disease	ADAS-Cog Rivastigmine	ADAS-Cog Placebo	ADCS-CGIC Rivastigmine	ADCS-CGIC Placebo
ITT + RDO population Mean baseline ± SD Mean change at 24 weeks ± SD	(n=329) 23.8 ± 10.2 2.1 ± 8.2	(n=161) 24.3 ± 10.5 -0.7 ± 7.5	(n=329) n/a 3.8 ± 1.4	(n=165) n/a 4.3 ± 1.5
Adjusted treatment difference p-value versus placebo	2.881 <0.0011	n/a 0.0072
ITT - LOCF population Mean baseline ± SD Mean change at 24 weeks ± SD	(n=287) 24.0 ± 10.3 2.5 ± 8.4	(n=154) 24.5 ± 10.6 -0.8 ± 7.5	(n=289) n/a 3.7 ± 1.4	(n=158) n/a 4.3 ± 1.5
Adjusted treatment difference p-value versus placebo	3.541 <0.0011	n/a <0.0012

¹ Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.

² Mean data shown for convenience, categorical analysis performed using van Elteren test

ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward

Although a treatment effect was demonstrated in the overall study population, the data suggested that a larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia associated with Parkinson's disease. Similarly a larger treatment effect was observed in those patients with visual hallucinations (see Table 6).

Table 6

Dementia associated with Parkinson's Disease	ADAS-Cog Rivastigmine	ADAS-Cog Placebo	ADAS-Cog Rivastigmine	ADAS-Cog Placebo
	Patients with visual hallucinations	Patients without visual hallucinations
ITT + RDO population Mean baseline ± SD Mean change at 24 weeks ± SD	(n=107) 25.4 ± 9.9 1.0 ± 9.2	(n=60) 27.4 ± 10.4 -2.1 ± 8.3	(n=220) 23.1 ± 10.4 2.6 ± 7.6	(n=101) 22.5 ± 10.1 0.1 ± 6.9
Adjusted treatment difference p-value versus placebo	4.271 0.0021	2.091 0.0151
	Patients with moderate dementia (MMSE 10-17)	Patients with mild dementia (MMSE 18-24)
ITT + RDO population Mean baseline ± SD Mean change at 24 weeks ± SD	(n=87) 32.6 ± 10.4 2.6 ± 9.4	(n=44) 33.7 ± 10.3 -1.8 ± 7.2	(n=237) 20.6 ± 7.9 1.9 ± 7.7	(n=115) 20.7 ± 7.9 -0.2 ± 7.5
Adjusted treatment difference p-value versus placebo	4.731 0.0021	2.141 0.0101

¹ Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.

ITT: Intent-To-Treat; RDO: Retrieved Drop Outs

5.2 Pharmacokinetic Properties

Absorption

Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of rivastigmine's interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about 36%±13%. Administration of rivastigmine with food delays absorption (t_max) by 90 min and lowers C_max and increases AUC by approximately 30%.

Distribution

Protein binding of rivastigmine is approximately 40%. It readily crosses the blood brain barrier and has an apparent volume of distribution in the range of 1.8–2.7 l/kg.

Metabolism

Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%). Based on evidence from in vitro and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose.

Excretion

Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of ¹⁴C-rivastigmine, renal elimination was rapid and essentially complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer's disease.

Elderly subjects

While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age.

Subjects with hepatic impairment

The C_max of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Subjects with renal impairment

C_max and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment compared with healthy subjects; however there were no changes in C_max and AUC of rivastigmine in subjects with severe renal impairment.

5.3 Preclinical Safety Data

Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human exposure were achieved in the animal studies due to the sensitivity of the animal models used.

Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a chromosomal aberration test in human peripheral lymphocytes at a dose 10⁴ times the maximum clinical exposure. The in vivo micronucleus test was negative.

No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, although the exposure to rivastigmine and its metabolites was lower than the human exposure. When normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the maximum human dose, a multiple of approximately 6-fold was achieved in animals.

In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats and rabbits gave no indication of teratogenic potential on the part of rivastigmine.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Gelatin

Magnesium stearate

Hypromellose

Microcrystalline cellulose

Silica, colloidal anhydrous

Yellow iron oxide (E172)

Red iron oxide (E172)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

5 years

6.4 Special Precautions For Storage

Do not store above 30°C.

6.5 Nature And Contents Of Container

- Bliste