Boots Acid Reflux 10 mg Gastro-Resistant Tablets

1. Name Of The Medicinal Product

Boots Acid Reflux 10 mg Gastro-Resistant Tablets

Care Heartburn Relief 10 mg Tablets

Co-op Heartburn Relief 10 mg Tablets

Dexcel Heartburn Relief 10 mg Tablets

Galpharm Heartburn Relief 10 mg Tablets

Numark Heartburn Relief 10 mg Tablets

Sainsbury's Heartburn Relief 10 mg Tablets

Superdrug Heartburn Relief 10 mg Tablets

Tesco Heartburn Relief 10 mg Tablets

Unichem Heartburn Relief 10 mg Tablets

Vantage Pharmacy Heartburn Relief 10 mg Tablets

Lloydspharmacy Heartburn Relief 10mg Tablets

2. Qualitative And Quantitative Composition

Omeprazole 10 mg

For excipients, see section 6.1.

3. Pharmaceutical Form

Gastro-resistant tablets.

Brownish-pink, capsule-shaped film-coated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Relief of reflux-like symptoms (e.g. heartburn) in patients aged 18 and over.

4.2 Posology And Method Of Administration

The tablets should be swallowed whole with plenty of liquid (e.g., water or fruit juice) prior to a meal. It is important that the tablets should not be crushed or chewed.

Initially the dosage is 20mg once daily.

Subsequently, symptomatic relief from heartburn can be achieved in some subjects by taking 10mg once daily, increasing to 20mg if symptoms return.

The lowest effective dose should always be used.

If no relief is obtained within two weeks then the patient should be referred to their doctor.

If continuous treatment for more than 4 weeks is required to relieve symptoms then the patient should be referred to their doctor.

4.3 Contraindications

Known hypersensitivity to omeprazole or to any of the other ingredients.

4.4 Special Warnings And Precautions For Use

Decreased gastric acidity, due to any means - including proton- pump inhibitors - increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs leads to a slightly increased risk of gastrointestinal infections such as salmonella or campylobacter.

Special warnings and precautions for patients taking non-prescription indigestion or heartburn remedies:

Patients should be referred to their doctor if:

• They have had to take an indigestion or heartburn remedy continuously for 4 or more weeks in order to control their symptoms

• They are aged over 45 years with new or recently changed symptoms

• They have unintentional weight loss, anaemia, gastrointestinal bleeding, dysphagia, pain on swallowing, persistent vomiting or vomiting with blood, epigastric mass, previous gastric ulcer or surgery, jaundice or any other significant medical condition (including hepatic and renal impairment).

Patients with long-term recurrent symptoms of indigestion or heartburn should see their doctor at regular intervals. Patients aged over 45 years taking any “over the counter” (OTC, non-prescription) indigestion or heartburn remedy on a daily basis should inform their pharmacist or doctor.

Patients should not take another “acid suppressor” e.g. H₂ antagonist concomitantly.

Patients should consult their doctor before taking this product if they are due to have an endoscopy.

The Patient Information Leaflet will contain advice that the tablets will not provide immediate relief of symptoms.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

As with many indigestion and heartburn remedies, omeprazole may interact with other medications. Therefore, patients who are also taking other medications should first consult with either their pharmacist or doctor before taking omeprazole.

As omeprazole is metabolized in the liver through cytochrome P450 it can delay the elimination of diazepam, phenytoin and warfarin. Monitoring of patients receiving warfarin or phenytoin is recommended and a reduction of the warfarin or phenytoin dose may be necessary. However concomitant treatment with omeprazole 20 mg daily did not change the blood concentration of phenytoin in patients on continuous treatment with phenytoin. Similarly, concomitant treatment with omeprazole 20 mg daily did not change coagulation time in patients on continuous treatment with warfarin. Interactions with other medicinal products which are also metabolized via the cytochrome P-450 isoenzyme of group 2C cannot be excluded.

Due to the decreased intragastric acidity, the absorption of ketoconazole or itraconazole may be reduced during omeprazole treatment, as it is during treatment with other acid secretion inhibitors.

Concomitant use of omeprazole and cilostazol results in an increase in the plasma concentration of cilostazol, therefore concomitant use should be avoided. It is possible that omeprazole also increases the plasma-tacrolimus concentration, whereas voriconazole increases the plasma concentration of omeprazole.

Simultaneous treatment with omeprazole and digoxin in healthy subjects led to a 10% increase in the bioavailability of digoxin as a consequence of the increased intragastric pH.

Omeprazole as so far tested has no influence on the metabolism of the following substances: amoxycillin, antacids, quinidine, caffeine, ciclosporin, diclofenac, estradiol, lidocaine, metoprolol, naproxen, phenacetin, piroxicam, propranolol, theophylline.

Treatment with omeprazole may cause false negative results in ¹³C-Urea breath tests.

Alcohol and food do not affect the absorption of omeprazole.

4.6 Pregnancy And Lactation

This product should not be used during pregnancy or whilst breast feeding.

Pregnancy

There is no evidence on the safety of omeprazole in human pregnancy. Animal studies have revealed no teratogenic effect, but reproduction studies have revealed reduced litter weights. Avoid in pregnancy, unless there is no safer alternative.

Lactation

There is no information available on the passage of omeprazole into breast milk or its effects on the neonate. Breast-feeding should therefore be discontinued if the use of omeprazole is considered essential.

4.7 Effects On Ability To Drive And Use Machines

In rare cases, drowsiness has been reported. If affected, patients should not drive or operate machinery.

4.8 Undesirable Effects

Omeprazole is well tolerated and adverse reactions have generally been mild and reversible. The following have been reported as adverse events in clinical trials or reported from routine use but in many cases a relationship to treatment with omeprazole has not been established.

Skin and subcutaneous tissue disorders

Skin rash, urticaria and pruritus have been reported, usually resolving after discontinuation of treatment. In addition photosensitivity, bullous eruption, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, alopecia and increased sweating have been reported in isolated cases.

Musculoskeletal disorders

Arthritic and myalgic symptoms have been reported and have usually resolved when therapy is stopped.

Respiratory disorders

In isolated cases bronchospasm has been reported.

Gastrointestinal disorders

Diarrhoea has been reported and may be severe enough to require discontinuation of therapy. Constipation, abdominal pain, nausea/vomiting and flatulence have been reported. In isolated cases dry mouth, stomatitis and candidiasis have been reported.

Hepato-biliary disorders

Increases in liver enzyme have been observed. In isolated cases, encephalopathy in patients with pre-existing severe liver disease, hepatitis with or without jaundice and rarely hepatic failure.

Renal & urinary disorders

Interstitial nephritis which has resulted in acute renal failure has been reported in isolated cases.

Reproductive disorders

In isolated cases gynaecomastia and impotence have been reported.

Nervous system disorders

Headache has been reported which may be severe enough to require discontinuation of therapy. Rarely paraesthesia has also been reported. Taste disturbances have been reported in isolated cases.

Psychiatric disorders

In isolated cases reversible mental confusion, agitation, depression and hallucinations occurring predominantly in severely ill patients. Agression has also been reported in isolated cases.

Disorders of the eye

In isolated cases blurred vision has been reported.

Haematological

In isolated cases leucopenia, thrombocytopenia, agranulocytosis, hyponatraemia and pancytopenia have been reported.

Disorders of the ear

Vertigo has been reported.

Disorders of the immune system

Anaphylactic shock and angioedema have been reported in isolated cases.

General disorders

Dizziness, light-headedness and feeling faint have been associated with treatment, but all usually resolve on cessation of therapy. Somnolence and insomnia have also been reported. In isolated cases peripheral oedema, malaise and fever have been reported.

4.9 Overdose

There is no information available on the effects of overdosage in man. Beside ventilatory and circulatory control according to general guidelines on the treatment of intoxication no further direct therapeutic measures are indicated. Single oral doses of omeprazole of up to 400 mg have not resulted in any severe symptoms; elimination remained first order and no specific treatment was needed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Omeprazole, a substituted benzimidazole, is a selective proton pump inhibitor which inhibits directly and in dose-dependent fashion the H+/K+-ATPase of the parietal cells of the stomach responsible for gastric acid secretion. By this selective intracellular attack, independently from membrane located receptors like histamine H2-, muscarine M1- or gastrineric receptors, omeprazole belongs to an independent class of inhibitors which block the terminal secretion process. By its mode of action, omeprazole reduces not only basal but also stimulus-induced acid secretion, independently of the kind of stimulus. Omeprazole thus increases the pH-value and reduces the secretory volume.

Oral dosing with 20 mg omeprazole once daily produces inhibition of gastric acid secretion within 1-2 hours of the first dose. The maximum effect is achieved within 4 days of starting treatment after which the degree of inhibition remains constant. The mean decrease in pentagastrin-stimulated peak acid output twenty-four hours after dosing is about 70%.

During long-term treatment an increased frequency of gastric glandular cysts have been reported. These changes are a physiological consequence of pronounced inhibition of acid secretion. The cysts are benign and appear to be reversible. No other treatment related mucosal changes have been observed in patients treated continuously with omeprazole for periods of up to 5 years.

Site and Mechanism of Action: Omeprazole is a weak base and is concentrated and converted to the active form by protonation in the acid environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme, H+,K+-ATPase - the proton pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for effective inhibition of both basal acid secretion and stimulated acid secretion irrespective of the stimulus. All pharmacodynamic effects observed are explained by the effect of omeprazole on acid secretion.

5.2 Pharmacokinetic Properties

Absorption of omeprazole takes place in the small intestine and is usually completed within 3-6 hours. The systemic bioavailability of omeprazole from a single oral dose is approximately 35%. After repeated once-daily administration, the bioavailability increases to about 60%. Concomitant intake of food has no influence on bioavailability. The plasma protein binding of omeprazole is about 95%.

The average half-life of the terminal phase of the plasma concentration-time curve is approximately 40 minutes. There is no change in half-life during treatment. The inhibition of acid secretion is related to the area under the plasma concentration time-curve (AUC) but not to actual plasma concentration at a time.

Omeprazole is entirely metabolized, mainly in the liver. Identified metabolites in plasma are the sulphone, the sulphide and hydroxy-omeprazole; these metabolites have no significant effect on acid secretion. About 80% of the metabolites are excreted in the urine and the rest in the faeces. The two main urinary metabolites are hydroxy-omeprazole and the corresponding carboxylic acid.

The systemic bioavailability of omeprazole is not significantly altered in patients with reduced renal function. The area under the plasma concentration time-curve is increased in patients with impaired liver function, but no tendency to accumulation of omeprazole has been found.

Available data from children (1 year and older) suggest that the pharmacokinetics within the recommended doses is similar to those reported in adults. At steady state, lower plasma levels of omeprazole were seen in some children.

5.3 Preclinical Safety Data

Omeprazole is a well-established drug for which there are adequate published safety data. Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or toxicity to reproduction.

Carcinogenic Potential: 2 years' carcinogenicity studies in rats (i.e., life-long treatment) showed development of ECL-cell-carcinoids; but rats which have been treated with high doses of omeprazole over a year have not shown any carcinoids in the later 1-year period. The mechanism for the build-up of the stomach carcinoids has been investigated very carefully and various studies lead to the conclusion that this is a secondary reaction due to the extreme increased serum gastrin levels of the rats during the treatment period. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition and not from a direct effect of any individual drug. Similar development of ECL-cell-carcinoids was observed in rats subjected to partial fundectomy. ECL-cell-carcinoids were not seen in mice or dog studies.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core

lactose monohydrate

sodium starch glycollate

sodium stearate

sodium stearyl fumarate

Enteric Coating

hydroxypropyl methylcellulose (HPMC) acetate succinate

talc

triethyl citrate

monoethanolamine

sodium lauryl sulphate

Sepisperse AP-3527 (containing:

propylene glycol titanium dioxide (E-171) red iron oxide (E-172) yellow iron oxide (E-172) hydroxypropyl methylcellulose)

Polish

carnauba wax

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store in the original package. Do not store above 30°C.

6.5 Nature And Contents Of Container

Aluminium/aluminium blisters strips containing 7, 14 or 28 tablets, in a cardboard box.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Dexcel-Pharma Limited

7 Sopwith Way, Drayton Fields, Daventry, Northamptonshire NN11 8PB

United Kingdom

8. Marketing Authorisation Number(S)

PL 14017/0069

9. Date Of First Authorisation/Renewal Of The Authorisation

19 January 2004

10. Date Of Revision Of The Text

June 2011

Pradaxa

Pronunciation: DA-bi-GAT-ran
Generic Name: Dabigatran
Brand Name: Pradaxa

Pradaxa is used for:

Reducing the risk of stroke and serious blood clots in certain patients with atrial fibrillation.

Pradaxa is a direct thrombin inhibitor. It works by preventing the formation of a blood clot.

Do NOT use Pradaxa if:

• you are allergic to any ingredient in Pradaxa


• you have certain types of active bleeding


• you have severe kidney problems and you are also taking dronedarone or ketoconazole


• you are taking St. John's wort

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

Before using Pradaxa:

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

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


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


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


• if you have blood or bleeding problems, kidney problems, or are on dialysis


• if you have had recent or repeated stomach or intestinal bleeding, or if you have a history of stomach ulcers


• if you will be having surgery or other medical procedures (including dental procedures)

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

• Abciximab, anticoagulants (eg, warfarin), antiplatelet agents (eg, clopidogrel, prasugrel), aspirin, direct factor Xa inhibitors (eg, rivaroxaban), dronedarone, eptifibatide, heparin, ketoconazole, nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen), quinidine, sulfinpyrazone, thrombolytics (eg, alteplase), ticlopidine, or tirofiban because the risk of bleeding may be increased


• Rifampin or St. John's wort because they may decrease Pradaxa's effectiveness

This may not be a complete list of all interactions that may occur. Ask your health care provider if Pradaxa may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Pradaxa:

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

• Pradaxa comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Pradaxa refilled.


• Take Pradaxa by mouth with or without food.


• Swallow Pradaxa whole. Do not break, crush, chew, or open before swallowing.


• Keep Pradaxa in the original bottle or blister package. Do not store it in any other bottle or container, such as pill boxes or pill organizers.


• When it is time to take your dose of Pradaxa, only remove 1 dose of medicine from the bottle. Close the bottle tightly right away after you remove your dose.


• Open only 1 bottle of Pradaxa at a time. Finish your opened bottle before you open a new bottle.


• If you miss a dose of Pradaxa, take it as soon as possible. If it is less than 6 hours until your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

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

Important safety information:

• Do not suddenly stop taking Pradaxa without checking with your doctor. Doing so may increase the risk of stroke.


• Pradaxa decreases blood clotting. It may make you bleed more easily or bleed longer. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding; pink or brown urine; dark, tarry, or bloody stools; if you cough up blood; or have vomit that looks like blood or coffee grounds.


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


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


• Use Pradaxa with caution in the ELDERLY; they may be more sensitive to its effects, especially unusual or severe bleeding.


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


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

Possible side effects of Pradaxa:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; heartburn; indigestion; mild stomach pain or upset; nausea.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; wheezing); black, tarry, or bloody stools; chest pain; confusion; coughing up blood; dizziness, weakness, or unusual headaches; fainting; joint pain, swelling, or discomfort; one-sided weakness; pink, brown, or dark urine; severe or persistent sore throat or stomach pain; slurred speech; unusual bruising or bleeding (eg, excessive bleeding from cuts, unusually heavy menstrual or vaginal bleeding, repeated nosebleeds, unusual bleeding from gums); vision problems; vomit that looks like blood or coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch .

See also: Pradaxa side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include unusual or severe bruising or bleeding.

Proper storage of Pradaxa:

Store this between 59 and 86 degrees F (15 and 30 degrees C) in its original package. Store away from heat, moisture, and light. Do not store in the bathroom. Pradaxa may be packaged in a blister pack or a bottle. If your medicine comes in a bottle, it must be used within 4 months after opening the bottle. Throw away any unused medicine 4 months after opening the bottle. Keep Pradaxa out of the reach of children and away from pets.

General information:

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


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


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


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

This information is a summary only. It does not contain all information about Pradaxa. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Pradaxa resources

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

• Pradaxa Prescribing Information (FDA)


• Pradaxa Advanced Consumer (Micromedex) - Includes Dosage Information


• Pradaxa Consumer Overview

Compare Pradaxa with other medications

• Prevention of Thromboembolism in Atrial Fibrillation

Benadryl for Children Allergy Solution

1. Name Of The Medicinal Product

Benadryl for Children Allergy Solution

OR

Benadryl Allergy Children's 6+ 1mg/ml Oral Solution

2. Qualitative And Quantitative Composition

One ml of solution contains 1 mg cetirizine dihydrochloride
Excipients:	- one ml of solution contains 450 mg sorbitol (solution at 70 %, non crystallizing) - one ml of solution contains 1.35 mg methylparahydroxybenzoate - one ml of solution contains 0.15 mg propylparahydroxybenzoate
For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Oral solution

Clear and colorless liquid

4. Clinical Particulars

4.1 Therapeutic Indications

In adults and children 6 year and above:

- Cetirizine is indicated for the relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis.

- Cetirizine is indicated for the relief of symptoms of chronic idiopathic urticaria.

4.2 Posology And Method Of Administration

Children aged from 6 to 12 years: 5 mg twice daily (5 ml oral solution bid (a full spoon twice daily).

Adults and adolescents over 12 years of age: 10 mg once daily (10 ml oral solution (2 full spoons)).

The solution can be swallowed as such.

Elderly subjects: data do not suggest that the dose needs to be reduced in elderly subjects provided that the renal function is normal.

Patients with moderate to severe renal impairment: there are no data to document the efficacy/safety ratio in patients with renal impairment. Since cetirizine is mainly eliminated via renal route (see section 5.2), in cases no alternative treatment can be used, the dosing intervals must be individualized according to renal function. Refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CL_cr) in ml/min is needed. The CL_cr (ml/min) may be estimated from serum creatinine (mg/dl) determination using the following formula:

Dosing adjustments for adult patients with impaired renal function

Group	Creatinine clearance (ml/min)	Dosage and frequency
Normal		10 mg once daily
Mild	50 – 79	10 mg once daily
Moderate	30 – 49	5 mg once daily
Severe	< 30	5 mg once every 2 days
End-stage renal disease - Patients undergoing dialysis	< 10	Contra-indicated

In pediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance of the patient, his age and his body weight.

Patients with hepatic impairment: no dose adjustment is needed in patients with solely hepatic impairment.

Patients with hepatic impairment and renal impairment: dose adjustment is recommended (see Patients with moderate to severe renal impairment above).

4.3 Contraindications

Hypersensitivity to the active substance, to any of the excipients, to hydroxyzine or to any piperazine derivatives.

Patients with severe renal impairment at less than 10 ml/min creatinine clearance.

Patients with rare hereditary problems of fructose intolerance should not take cetirizine 1 mg/ml oral solution.

4.4 Special Warnings And Precautions For Use

At therapeutic doses, no clinically significant interactions have been demonstrated with alcohol (for a blood alcohol level of 0.5 g/L). Nevertheless, precaution is recommended if alcohol is taken concomitantly.

Caution in epileptic patients and patients at risk of convulsions is recommended.

The use of the product is not recommended in children aged less than 6 years.

Methyl parahydroxybenzoate and propyl parahydroxybenzoate may cause allergic reactions (possibly delayed).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Due to the pharmacokinetic, pharmacodynamic and tolerance profile of cetirizine, no interactions are expected with this antihistamine. Actually, neither pharmacodynamic nor significant pharmacokinetic interaction was reported in drug-drug interactions studies performed, notably with pseudoephedrine or theophylline (400 mg/day).

The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased.

4.6 Pregnancy And Lactation

For cetirizine very rare clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant or breast feeding women because cetirizine passes into breast milk.

4.7 Effects On Ability To Drive And Use Machines

Objective measurements of driving ability, sleep latency and assembly line performance have not demonstrated any clinically relevant effects at the recommended dose of 10 mg.

Patients intending to drive, engaging in potentially hazardous activities or operating machinery should not exceed the recommended dose and should take their response to the medicinal product into account. In these sensitive patients, concurrent use with alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.

4.8 Undesirable Effects

Clinical studies have shown that cetirizine at the recommended dosage has minor undesirable effects on the CNS, including somnolence, fatigue, dizziness and headache. In some cases, paradoxical CNS stimulation has been reported.

Although cetirizine is a selective antagonist of peripheral H₁-receptors and is relatively free of anticholinergic activity, isolated cases of micturition difficulty, eye accommodation disorders and dry mouth have been reported.

Instances of abnormal hepatic function with elevated hepatic enzymes accompanied by elevated bilirubin have been reported. Mostly this resolves upon discontinuation of the treatment with cetirizine dihydrochloride.

Clinical trials

Double blind controlled clinical or pharmacoclinical trials comparing cetirizine to placebo or other antihistamines at the recommended dosage (10 mg daily for cetirizine), of which quantified safety data are available, included more than 3200 subjects exposed to cetirizine.

From this pooling, the following adverse events were reported for cetirizine 10 mg in the placebo-controlled trials at rates of 1.0 % or greater:

Adverse event (WHO-ART)	Cetirizine 10 mg (n= 3260)	Placebo (n = 3061)
Body as a whole – general disorders Fatigue	1.63 %	0.95 %
Central and peripheral nervous system disorders Dizziness Headache	1.10 % 7.42 %	0.98 % 8.07 %
Gastro-intestinal system disorders Abdominal pain Dry mouth Nausea	0.98 % 2.09 % 1.07 %	1.08 % 0.82 % 1.14 %
Psychiatric disorders Somnolence	9.63 %	5.00 %
Respiratory system disorders Pharyngitis	1.29 %	1.34 %

Although statistically more common than under placebo, somnolence was mild to moderate in the majority of cases. Objective tests as demonstrated by other studies have demonstrated that usual daily activities are unaffected at the recommended daily dose in healthy young volunteers.

Adverse drug reactions at rates of 1 % or greater in children aged from 6 months to 12 years, included in placebo-controlled clinical or pharmacoclinical trials are:

Adverse drug reactions (WHO-ART)	Cetirizine (n=1656)	Placebo (n =1294)
Gastro-intestinal system disorders Diarrhoea	1.0 %	0.6 %
Psychiatric disorders Somnolence	1.8 %	1. 4 %
Respiratory system disorders Rhinitis	1.4 %	1.1 %
Body as a whole – general disorders Fatigue	1.0 %	0.3 %

Post-marketing experience

In addition to the adverse effects reported during clinical studies and listed above, isolated cases of the following adverse drug reactions have been reported in post-marketing experience. For these less frequently reported undesirable effects, the estimated frequencies (uncommon:

Blood and lymphatic disorders:

Very rare: thrombocytopenia

Immune system disorders:

Rare: hypersensitivity

Very rare: anaphylactic shock

Psychiatric disorders:

Uncommon: agitation

Rare: aggression, confusion, depression, hallucination, insomnia

Very rare: tic

Nervous system disorders:

Uncommon: paraesthesia

Rare: convulsions, movements disorders

Very rare: dysgeusia, syncope, tremor, dystonia, dyskinesia

Eye disorders:

Very rare: accommodation disorder, blurred vision, oculogyration

Cardiac disorders:

Rare: tachycardia

Gastro-intestinal disorders:

Uncommon: diarrhoea

Hepatobiliary disorders:

Rare: hepatic function abnormal (increased transaminases, alkaline phosphatase, γ-GT and bilirubin)

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, rash

Rare: urticaria

Very rare: angioneurotic oedema, fixed drug eruption

Renal and urinary disorders:

Very rare: dysuria, enuresis

General disorders and administration site conditions:

Uncommon: asthenia, malaise

Rare: oedema

Investigations:

Rare: weight increased

4.9 Overdose

Symptoms

Symptoms observed after an overdose of cetirizine are mainly associated with CNS effects or with effects that could suggest an anticholinergic effect.

Adverse events reported after an intake of at least 5 times the recommended daily dose are: confusion, diarrhoea, dizziness, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor, and urinary retention.

Management

There is no known specific antidote to cetirizine.

Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage should be considered following ingestion of a short occurrence.

Cetirizine is not effectively removed by dialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Piperazine derivatives, ATC code: R06A E07

Cetirizine, a human metabolite of hydroxyzine, is a potent and selective antagonist of peripheral H₁-receptors. In vitro receptor binding studies have shown no measurable affinity for other than H₁-receptors.

In addition to its anti-H₁ effect, cetirizine was shown to display anti-allergic activities: at a dose of 10 mg once or twice daily, it inhibits the late phase recruitment of eosinophils, in the skin and conjunctiva of atopic subjects submitted to allergen challenge.

Studies in healthy volunteers show that cetirizine, at doses of 5 and 10 mg strongly inhibits the wheal and flare reactions induced by very high concentrations of histamine into the skin, but the correlation with efficacy is not established.

In a 35-day study in children aged 5 to 12, no tolerance to the antihistaminic effect (suppression of wheal and flare) of cetirizine was found. When a treatment with cetirizine is stopped after repeated administration, the skin recovers its normal reactivity to histamine within 3 days.

In a six-week, placebo-controlled study of 186 patients with allergic rhinitis and concomitant mild to moderate asthma, cetirizine 10 mg once daily improved rhinitis symptoms and did not alter pulmonary function. This study supports the safety of administering cetirizine to allergic patients with mild to moderate asthma.

In a placebo-controlled study, cetirizine given at the high daily dose of 60 mg for seven days did not cause statistically significant prolongation of QT interval.

At the recommended dosage, cetirizine has demonstrated that it improves the quality of life of patients with perennial and seasonal allergic rhinitis.

5.2 Pharmacokinetic Properties

The steady - state peak plasma concentrations is approximately 300 ng/ml and is achieved within 1.0 ± 0.5 h. No accumulation is observed for cetirizine following daily doses of 10 mg for 10 days. The distribution of pharmacokinetic parameters such as peak plasma concentration (C_max) and area under curve (AUC), is unimodal in human volunteers.

The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased. The extent of bioavailability is similar when cetirizine is given as solutions, capsules or tablets.

The apparent volume of distribution is 0.50 l/kg. Plasma protein binding of cetirizine is 93 ± 0.3 %. Cetirizine does not modify the protein binding of warfarin.

Cetirizine does not undergo extensive first pass metabolism. About two third of the dose are excreted unchanged in urine. The terminal half-life is approximately 10 hours.

Cetirizine exhibits linear kinetics over the range of 5 to 60 mg.

Special populations

Elderly: Following a single 10 mg oral dose, half-life increased by about 50 % and clearance decreased by 40 % in 16 elderly subjects compared to the normal subjects. The decrease in cetirizine clearance in these elderly volunteers appeared to be related to their decreased renal function.

Children, infants and toddlers: The half-life of cetirizine was about 6 hours in children of 6-12 years and 5 hours in children 2-6 years. In infants and toddlers aged 6 to 24 months, it is reduced to 3.1 hours.

Renally impaired patients: The pharmacokinetics of the drug were similar in patients with mild impairment (creatinine clearance higher than 40 ml/min) and healthy volunteers. Patients with moderate renal impairment had a 3-fold increase in half-life and 70 % decrease in clearance compared to healthy volunteers.

Patients on hemodialysis (creatinine clearance less than 7 ml/min) given a single oral 10 mg dose of cetirizine had a 3-fold increase in half-life and a 70 % decrease in clearance compared to normals. Cetirizine was poorly cleared by haemodialysis. Dosing adjustment is necessary in patients with moderate or severe renal impairment (see section 4.2).

Hepatically impaired patients: Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20 mg of cetirizine as a single dose had a 50 % increase in half-life along with a 40 % decrease in clearance compared to healthy subjects.

Dosing adjustment is only necessary in hepatically impaired patients if concomitant renal impairment is present.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sorbitol solution at 70 % (non crystallizing) (E420)

Glycerol

Propylene glycol

Sodium saccharinate

Methylparahydroxybenzoate (E218)

Propylparahydroxybenzoate (E216)

Banana flavor 54.330/A (Firmenich)

Sodium acetate

Glacial acetic acid

Purified water.

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

5 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions

6.5 Nature And Contents Of Container

Amber glass bottle (type III) of 70 ml, closed with a white polypropylene child-resistant closure.

A 5ml Dosing spoon with a line at 2.5 ml is provided with the bottle.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

Administrative Data

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Berkshire SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0124

9. Date Of First Authorisation/Renewal Of The Authorisation

27/11/2008

10. Date Of Revision Of The Text

11 May 2010

Acitretin

Pronunciation: A-si-TRE-tin
Generic Name: Acitretin
Brand Name: Soriatane

Acitretin causes severe birth defects. Do not take Acitretin if you are pregnant or if you may become pregnant during therapy or at any time within 3 years after you stop taking Acitretin. Women who are able to become pregnant should use Acitretin only if they are unable to use other medicines to treat psoriasis or if they have severe psoriasis that is not helped by other medicines.

The Do Your P.A.R.T. (Pregnancy Prevention Actively Required During and After Treatment) program provides information about the serious risks associated with Acitretin. It also provides information about preventing pregnancy while you use Acitretin and for at least 3 years after you stop. Ask your doctor or pharmacist any questions that you may have about the information, the program, or Acitretin. Do not take Acitretin if there is anything you do not understand.

You must have at least 2 negative pregnancy tests before you start Acitretin. You must also have monthly pregnancy tests while you take Acitretin. You must also have a pregnancy test every 3 months for at least 3 years after you stop taking Acitretin. Contact your doctor immediately if you think you may be pregnant.

The risk of birth defects lasts for at least 3 years after you stop Acitretin. Do not become pregnant while you take Acitretin and for at least 3 years after you stop taking it. You must use 2 effective forms of birth control for at least 1 month before you start Acitretin, while you take it, and for at least 3 years after you stop treatment.

Do not drink alcohol or take medicines that contain alcohol while you take Acitretin and for 2 months after you stop treatment. The risk of birth defects may last longer after you stop treatment if you drink alcohol or take any product that contains alcohol.

Women must sign a Patient Agreement/Informed Consent for Female Patients form before they start to take Acitretin. This form contains information on the risk of birth defects, birth control failure, and the need to avoid alcohol. Contact your doctor before you take Acitretin if you have any questions or if you have not signed this form.

Small amounts of Acitretin are found in semen. It is not known if this poses any risk to the fetus. Discuss any questions that you may have with your doctor.

Patients must not donate blood during treatment and for at least 3 years after treatment is stopped.

Serious liver problems have occurred in some patients taking Acitretin. Contact your doctor right away if you develop dark urine, pale stools, severe or persistent stomach pain, or yellowing of the skin or eyes.

Acitretin comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Acitretin refilled.

Acitretin is used for:

Treating severe psoriasis.

Acitretin is a kit that contains a vitamin A derivative (retinoid) and moisturizing foam. Exactly how the retinoid works is not known. The moisturizing foam relieves dry and chapped skin.

Do NOT use Acitretin if:

• you are allergic to any ingredient in Acitretin or to another retinoid (eg, tretinoin)


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


• you have severe liver or kidney problems


• you have persistent high blood lipid levels


• you are taking methotrexate, a tetracycline, or vitamin A

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

Before using Acitretin:

Tell your health care provider if you have any medical conditions, especially if any of the following apply to you:

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


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


• if you have diabetes or high blood lipid levels, are very overweight, or have a family member with any of these problems


• if you have a history of liver or kidney problems, bone problems, pancreas problems (eg, pancreatitis), heart disease, or mental or mood problems (eg, depression, suicidal thoughts or actions)


• if you receive phototherapy or drink alcohol


• if you take St. John's wort; it may decrease the effectiveness of hormonal contraceptives (eg, birth control pills)


• if you take a progestin-only birth control pill (mini-pill); your doctor may need to prescribe a different form of hormonal birth control

Some MEDICINES MAY INTERACT with Acitretin. Tell your health care provider if you are taking any of the following medicines.

• Certain medicines for diabetes (eg, glyburide) because the risk of low blood sugar may be increased


• Methotrexate or tetracyclines (eg, doxycycline) because liver damage or increased pressure in the brain may occur


• Vitamin A because it may increase the risk of Acitretin's side effects


• Certain hormonal contraceptives (eg, low-dose progestin-only birth control pill, mini-pill) because their effectiveness may be decreased by Acitretin


• Phenytoin because the risk of its side effects may be increased by Acitretin

This may not be a complete list of all interactions that may occur. Ask your health care provider if Acitretin may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Acitretin:

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

• Acitretin comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Acitretin refilled.


• Take the capsule(s) by mouth with a meal at about the same time each day, or as directed by your doctor.


• Continue to use Acitretin even if your condition does not improve right away. Your condition may become worse for a short time before it improves. It may take 2 to 3 months before you see the full benefits of Acitretin.


• If you miss a dose of Acitretin, you may take it later the same day. If you do not remember until the next day, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

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

Important safety information:

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


• Acitretin may cause decreased night vision. Use caution or avoid driving at night if you experience this effect.


• Do not drink alcohol while you are taking Acitretin without first checking with your doctor.


• Your condition may return after you stop treatment with Acitretin. Check with your doctor if this occurs. Do not use any leftover medicine to treat your skin condition.


• Acitretin is similar to vitamin A. Before you start any new medicine, check the label to see if it has vitamin A in it too. Do not take other medicines that contain vitamin A without checking with your doctor.


• Acitretin may cause you to become sunburned more easily. Avoid the sun, sunlamps, or tanning booths until you know how you react to Acitretin. Use a sunscreen or wear protective clothing if you must be outside for more than a short time.


• Dental problems (eg, mouth sores, gum bleeding) may occur while you take Acitretin. Contact your doctor or dentist if these problems persist or become bothersome.


• If you wear contact lenses, you may notice increased irritation with them while you are taking Acitretin. If these effects continue, check with your doctor.


• Women who are able to become pregnant must use 2 effective forms of birth control for at least 1 month before they start Acitretin, while they take it, and for at least 3 years after they stop treatment.


• Diabetes patients - Acitretin may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


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


• Use Acitretin with caution in the ELDERLY; they may be more sensitive to its effects.


• Acitretin is not recommended for use in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Do not use Acitretin if you are pregnant. If you think that you may be pregnant, contact your doctor right away. Women of childbearing age should either abstain from sexual intercourse or use 2 effective methods of birth control for at least 1 month before, while taking, and for 3 years after taking Acitretin. Do not breast-feed while you are using Acitretin and for at least 3 years after stopping treatment.

Possible side effects of Acitretin:

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Dry mouth, lips, or nose; dry or irritated eyes; hair loss; runny nose; thinning of the eyebrows or eyelashes; thinning, peeling, or scaling of the skin; weak nails.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); back or joint pain or stiffness; blurred vision or other vision changes; bone pain; calf or leg pain or swelling; chest pain; dark urine; eye pain; loss of appetite; mental or mood changes (eg, aggressiveness, depression); muscle pain, stiffness, or weakness; numbness or tingling of the hands or feet; one-sided weakness; pale stools; red, blistered, swollen skin; severe dizziness; severe or persistent headache; severe or persistent stomach pain, nausea, or vomiting; shortness of breath; signs of high blood sugar (eg, frequent hunger, thirst, or urination); slurred speech; suicidal thoughts or actions; vaginal itching, odor, or discharge; yellowing of the skin or eyes.

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

See also: Acitretin side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include severe or persistent headache or dizziness.

Proper storage of Acitretin:

Store Acitretin at room temperature, between 59 and 77 degrees F (15 and 25 degrees C) in a tightly closed container. Avoid temperatures above 120 degrees F (40 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Acitretin out of the reach of children and away from pets.

General information:

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


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


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


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

This information is a summary only. It does not contain all information about Acitretin. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Acitretin resources

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

• Acitretin Monograph (AHFS DI)


• Acitretin Professional Patient Advice (Wolters Kluwer)


• acitretin Concise Consumer Information (Cerner Multum)


• acitretin Advanced Consumer (Micromedex) - Includes Dosage Information


• Soriatane Prescribing Information (FDA)

Compare Acitretin with other medications

• Pityriasis rubra pilaris
• Psoriasis
• Psoriatic Arthritis

Zonegran

Generic Name: Zonisamide
Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Chemical Name: 1,2-Benzisoxazole-3-methanesulfonamide
Molecular Formula: C₈H₈N₂O₃S
CAS Number: 68291-97-4

REMS:

FDA approved a REMS for zonisamide to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Anticonvulsant; a sulfonamide.^{1 2 3}

Uses for Zonegran

Seizure Disorders

Management (in combination with other anticonvulsants) of partial seizures in adults with epilepsy.^{1 2 3 8}

Zonegran Dosage and Administration

General

• 
  

  Zonisamide therapy should not be discontinued abruptly; dosage reduction or discontinuance of the drug should be done gradually.¹

  
  


• 
  

  Closely monitor for marked changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.^{1 14 15 16 21} (See Suicidality Risk under Cautions.)

  
  

Administration

Oral Administration

Administer orally without regard to meals.^{1 2 3} Patients should be encouraged to drink 6–8 glasses of water each day while receiving the drug.¹

Administer initial dosage (100 mg daily) once daily; following dosage adjustment, administer once or twice daily.^{1 2 3}

Swallow capsules whole.¹

Dosage

Adults

Seizure Disorders

Partial Seizures

Oral

Adults >16 years of age: Initially, 100 mg daily.^{1 2 3 9}

After 2 weeks, dosage may be increased to 200 mg daily.^{1 3} Dosage can be further increased to 300 and 400 mg daily;^{1 2 3 9} allow ≥2 weeks between dosage changes (to achieve steady state at each dosage level).^{1 2 3 9} Some clinicians may prefer to administer lower dosages for longer periods (in order to fully assess safety at steady state).¹

Dosages >400 mg daily may not be associated with increased therapeutic benefit.¹

Adverse effects occur more frequently at dosages ≥300 mg daily.¹

Prescribing Limits

Adults

Seizure Disorders

Partial Seizures

Oral

Limited experience with dosages >600 mg daily.¹

Special Populations

Hepatic Impairment

Titrate dosage slowly in patients with hepatic disease.¹

Renal Impairment

Titrate dosage slowly in patients with renal disease.^{1 2} Do not use in patients with renal failure (GFR <50 mL/minute).¹

Geriatric Patients

No specific dosage recommendations for zonisamide; however, select dosage cautiously, usually starting at the lower end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant diseases or other drug therapy in this population.¹

Cautions for Zonegran

Contraindications

• 
  

  Known hypersensitivity to zonisamide, sulfonamides, or any ingredient in the formulation.^{1 2}

  
  

Warnings/Precautions

Warnings

Hematologic Effects

Aplastic anemia and agranulocytosis reported rarely; causal relationship between these events and dosage or duration of therapy not established.^{1 2}

Oligohidrosis and Hyperthermia

Oligohidrosis (a reduction in sweating) and hyperthermia reported in patients receiving zonisamide, particularly in pediatric patients.^{1 13 26} Closely monitor patients receiving zonisamide for evidence of decreased sweating and increased body temperature, particularly in warm or hot weather.^{1 13 26} Consider risk of hyperthermia when zonisamide is used concomitantly with other drugs that predispose patients to heat-related disorders.^{1 13} (See Pediatric Use under Cautions, Drugs Predisposing to Heat-related Disorders under Interactions, and Advice to Patients.)

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants, including zonisamide, in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).^{1 14 15 16 21} Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.^{14 15 16} Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.^{1 14 15 16}

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.^{1 14 15 16 21} Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.¹⁵

Balance risk of suicidality with the risk of untreated illness.^{1 15} Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.^{1 21} If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.^{1 21} (See Advice to Patients.)

Metabolic Acidosis

Zonisamide can cause metabolic acidosis, characterized by hyperchloremia and decreased serum bicarbonate concentrations.¹⁹ Often asymptomatic, but signs and symptoms of persistent metabolic acidosis may include hyperventilation, fatigue, and anorexia; more severe symptoms may include cardiac arrhythmias and stupor.¹⁹ Generally occurs early in treatment, but may occur at any time during therapy.¹⁹

Risk of developing metabolic acidosis appears greater at higher dosages of zonisamide, but it can occur with dosages ≤25 mg daily.¹⁹ Renal disease, severe respiratory disorders, diarrhea, surgery, ketogenic diets, or other drugs (e.g., acetazolamide) may predispose patients to acidosis.¹⁹ Also appears to be more frequent and severe in younger patients.¹⁹ (See Pediatric Use under Cautions.)

Decreases in serum bicarbonate levels are usually mild to moderate (average decrease of approximately 2 mEq/L) in adults; however, some adults have experienced severe decreases (as much as 10 mEq/L below their baseline).¹⁹ Chronic, untreated metabolic acidosis may increase the risk for renal calculi (kidney stones), nephrocalcinosis, and bone abnormalities (e.g., osteoporosis, osteomalacia, rickets in children) with an increased risk of fractures.¹⁹ (See Renal Calculi under Cautions.)

FDA recommends that clinicians measure serum bicarbonate levels prior to and periodically during zonisamide therapy, even in the absence of clinical symptoms, as well as if signs or symptoms of metabolic acidosis are observed.¹⁹ If metabolic acidosis develops and persists, consider reducing the zonisamide dosage or discontinuing the drug (by slowly reducing the dosage) and modifying the patient’s anticonvulsant drug regimen as appropriate.¹⁹ If the decision is made to continue patients with metabolic acidosis on zonisamide, consider alkali treatment.¹⁹

Withdrawal Seizures

Abrupt withdrawal may result in increased seizure frequency or status epilepticus; withdraw zonisamide gradually and reduce dosage slowly.¹

Cognitive/Neuropsychiatric Effects

Possible somnolence or fatigue, psychiatric symptoms (e.g., depression, psychosis), and impaired psychomotor or cognitive performance (e.g., difficulties in concentrating, language, speech, and word finding).^{1 3 5 15 17} (See Suicidality Risk under Cautions.)

Status Epilepticus

In controlled studies, status epilepticus occurred in 1.1 or 0% of patients receiving zonisamide or placebo, respectively.¹ In all (uncontrolled and controlled) clinical studies of zonisamide therapy, the incidence of status epilepticus was 1%.¹

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

Fatalities resulting from severe reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have occurred following zonisamide use.^{1 2 7}

Fatalities resulting from fulminant hepatic necrosis, agranulocytosis, aplastic anemia, or other blood dyscrasias rarely have been caused by sulfonamides.^{1 2}

Discontinue immediately if signs or symptoms of hypersensitivity occur.¹ Consider drug discontinuance if unexplained rash occurs; if drug is not discontinued, observe patient frequently.¹

General Precautions

Renal Calculi

Clinically possible or confirmed renal calculi (kidney stones), composed of calcium or urate salts, reported.^{1 2 3 4 8 9 12}

In general, increasing fluid intake and urine output may reduce the risk of kidney stone formation, particularly in patients with predisposing risk factors; not known whether these measures reduce the risk of kidney stone formation in patients receiving zonisamide.¹

Other Renal Effects

Substantial increases in S_cr and BUN reported;¹ such increases appeared to persist over time but were not progressive.¹ Consider periodically monitoring renal function during zonisamide therapy.¹

Discontinue use in patients who develop acute renal failure or clinically important, sustained increases in S_cr and BUN.¹

Sudden, Unexplained Deaths in Epilepsy

Higher incidence of sudden and unexplained deaths than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with refractory epilepsy.¹

Specific Populations

Pregnancy

Category C.¹

North American Antiepileptic Drug Pregnancy Registry at 888-233-2334 (for patients).¹

FDA warns that zonisamide may cause metabolic acidosis;¹⁹ if metabolic acidosis occurs during pregnancy, may affect fetal development (i.e., decreased fetal growth, decreased fetal oxygenation, and fetal death) and the ability of the fetus to tolerate labor.¹⁹

The effect of zonisamide on labor and delivery is unknown.¹

Physiologic changes during pregnancy may affect plasma zonisamide concentrations and/or therapeutic effect.¹ (See Special Populations under Pharmacokinetics: Elimination.) Some clinicians recommend closely monitoring zonisamide concentrations and adjusting zonisamide dosage as necessary in pregnant women.²⁰

Lactation

Distributes into human milk.^{18 19} Due to potential risk in nursing infant, discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy of zonisamide not established in children <16 years of age and the drug is not approved for use in pediatric patients in the US.^{1 19} However, the drug has been used in some pediatric patients† for the treatment of epilepsy to date and is approved for pediatric use in Japan.^{19 22 23 24 25 26 27}

Oligohidrosis and hyperthermia, characterized by decreased sweating and abnormally high body temperatures, reported in pediatric patients (1.6–17 years of age) receiving zonisamide and sometimes have resulted in heat stroke and hospitalization.^{1 2 3 11 13}

Closely monitor children receiving the drug for evidence of decreased sweating and increased body temperature, especially in warm or hot weather.^{1 13 26} Consider risk of hyperthermia when zonisamide is used concomitantly with other drugs that predispose patients to heat-related disorders.^{1 13} (See Oligohidrosis and Hyperthermia under Cautions, Drugs Predisposing to Heat-related Disorders under Interactions, and Advice to Patients.)

Pediatric patients may be at increased risk for zonisamide-induced metabolic acidosis; may be more severe in younger patients.¹⁹ Specific effects of zonisamide on growth and bone not studied; chronic metabolic acidosis may reduce growth rates in pediatric patients, resulting in a reduction in the maximal height achieved.¹⁹ (See Metabolic Acidosis under Cautions, Specific Drugs under Interactions, and Advice to Patients.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.¹

Hepatic Impairment

Use with caution in patients with hepatic disease; slower dosage titration and more frequent monitoring may be necessary.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use with caution in patients with renal disease; slower dosage titration and more frequent monitoring may be necessary.¹

Because of insufficient experience concerning dosage and toxicity, do not use in patients with renal failure (GFR <50 mL/minute).¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Abdominal pain, anorexia, diarrhea, nausea, dyspepsia, constipation, dry mouth, taste perversion, headache, dizziness, ataxia, nystagmus, paresthesia, confusion, difficulty concentrating, impaired memory, mental slowing, speech abnormalities, difficulty in verbal expression, agitation and/or irritability, depression, insomnia, anxiety, nervousness, schizophrenic and/or schizophreniform behavior, somnolence, fatigue, tiredness, flu-like syndrome, ecchymosis, rhinitis, weight loss, rash, diplopia.^{1 2 3 8 9}

Interactions for Zonegran

Does not appear to inhibit CYP isoenzymes in vitro;^{1 2 3} metabolic pathways include metabolism by CYP3A4.¹

Drugs Metabolized by or Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered serum concentrations of zonisamide) with inhibitors or inducers of CYP3A4.^{1 2}

Does not appear to interfere with metabolism of drugs metabolized by CYP isoenzymes.^{1 2 3}

Anticonvulsants

Other anticonvulsants may alter pharmacokinetics of zonisamide.^{1 2} (See Specific Drugs under Interactions.)

Drugs Predisposing to Heat-related Disorders

Increased risk of oligohidrosis and hyperthermia with drugs that predispose to heat-related disorders (e.g., carbonic anhydrase inhibitors, drugs with anticholinergic activity).^{1 13 26}

Specific Drugs

Drug	Interaction	Comments
Acetazolamide and other carbonic anhydrase inhibitors	Possible increased risk of developing metabolic acidosis and heat-related disorders during concurrent administration1 13 19 26
Carbamazepine	Possible decrease in plasma zonisamide concentrations;1 2 3 no change in steady-state plasma carbamazepine concentrations1 2 8	Increase in zonisamide dosage may be required2
Oral contraceptives	Pharmacokinetic interaction unlikely28
Phenobarbital	Zonisamide half-life decreased1
Phenytoin	Possible decrease in plasma zonisamide concentrations;1 2 3 no change in steady-state plasma phenytoin concentrations1 2 8	Increase in zonisamide dosage may be required2
Valproic acid	No change in steady-state plasma concentrations of valproic acid1 2 8

Zonegran Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed following oral administration, with nearly 100% oral bioavailability.^{2 3} Peak plasma concentrations attained within 2–6 hours after oral administration.¹

Food

Food delays the time to peak plasma concentration but does not affect bioavailability.¹

Distribution

Extent

Extensively binds to erythrocytes, resulting in an 8-fold higher concentration of zonisamide in erythrocytes than in plasma.¹

Crosses the placenta;¹⁸ distributed into breast milk.^{18 19}

Plasma Protein Binding

Approximately 40%.¹

Elimination

Metabolism

Undergoes acetylation to form N-acetyl zonisamide, subsequent reduction to form 2-sulfamoylacetyl phenol, and further glucuronide conjugation.^{1 3} The reduction of N-acetyl zonisamide is mediated by CYP3A4.^{1 2 3}

Does not induce own metabolism.¹

Elimination Route

Excreted principally in urine as unchanged drug and a glucuronide metabolite.^{1 2 3}

Half-life

About 63 hours.^{1 3}

Special Populations

In patients with marked renal impairment (Cl_cr≤ 20 mL/minute), AUC was increased by 35%.¹ Renal clearance decreases with decreasing renal function.¹

In patients with hepatic impairment, pharmacokinetics not studied to date.¹

Clearance of zonisamide may be increased at the end of the second trimester in pregnant women.²⁰

Pharmacokinetics were similar in geriatric and young healthy volunteers in single-dose studies.¹ (See Geriatric Patients under Dosage and Administration.)

Stability

Storage

Oral

Capsules

Dry place at 25°C (may be exposed to 15–30°C); protect from light.¹

Actions

• 
  

  Exact mechanism of action is not known; anticonvulsant activity may be associated with the drug’s sodium- and calcium-channel blocking activities.^{1 2 3 9}

  
  


• 
  

  May potentiate dopaminergic and serotonergic neurotransmission^{1 2 3} but does not appear to potentiate the synaptic activity of GABA.¹

  
  


• 
  

  Exhibits weak inhibition of carbonic anhydrase activity;^{1 2 3} not thought to contribute substantially to anticonvulsant activity.¹

  
  

Advice to Patients

• 
  

  Importance of providing copy of written patient information (medication guide) each time zonisamide is dispensed.^{1 21}

  
  


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  Risk of serious skin rash that can cause death; these skin reactions are more likely to happen within the first 4 months of starting therapy, but may occur later.¹ Importance of immediately contacting clinician if skin rash occurs.¹

  
  


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  Importance of patients being aware that zonisamide can prevent sweating, which makes it harder for the body to cool down when it gets very hot; this is more likely to occur in warmer weather, in children, and during physical exercise.^{1 13 26} Importance of avoiding exposure to heat, maintaining adequate hydration, and informing clinicians immediately if fever or increased body temperature and/or decreased sweating occurs, particularly in children or in hot weather.^{1 13 26}

  
  


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  Risk of blood cell abnormalities such as reduced RBC and WBC counts.¹ Importance of contacting clinician if fever, sore throat, sores in the mouth, or unusual bruising occurs.¹

  
  


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  Risk of suicidality (anticonvulsants, including zonisamide, may increase risk of suicidal thoughts or actions in about 1 in 500 people).^{1 15 21} Importance of patients, family, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).^{1 15}

  
  


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  Importance of patients being aware that zonisamide may cause metabolic acidosis.¹⁹ Importance of patients being aware that blood tests to measure serum bicarbonate levels may be performed.¹⁹ Symptoms of metabolic acidosis include breathing fast (hyperventilation), fatigue, and loss of appetite; more severe symptoms include an irregular heart beat or unconsciousness.¹⁹

  
  


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  May cause drowsiness, especially at higher dosages.¹ Avoid driving or operating machinery while taking zonisamide until experience with the drug’s effects has been established.¹

  
  


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  Risk of kidney stones.¹ Importance of informing patients that increasing fluid intake (i.e., by drinking 6–8 glasses of water a day) and urine output may reduce the risk of stone formation, particularly in those with predisposing factors.¹ Importance of immediately reporting symptoms of kidney stones (e.g., sudden back pain, abdominal pain, and/or blood in urine) to clinician.¹

  
  


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  Importance of immediately reporting worsening of seizures and severe muscle pain and/or weakness to clinician.¹

  
  


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  Importance of women informing clinicians if they are or plan to become pregnant.^{1 19} Importance of informing women who are or plan to become pregnant that zonisamide may cause metabolic acidosis, which may negatively affect fetal development during pregnancy.¹⁹ Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).¹

  
  


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  Importance of informing nursing women and those who plan to breast-feed that zonisamide can appear in the breast milk, and that the effects of this exposure on the infant are unknown.¹⁹ Importance of women informing clinicians if they plan to breast-feed.^{1 19}

  
  


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  Importance of swallowing zonisamide capsules whole and not biting into or breaking into the capsules; zonisamide may be taken with or without food.¹

  
  


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  Importance of informing patients not to stop taking zonisamide without talking to their clinician since stopping the drug suddenly can cause serious problems, including seizures.¹

  
  


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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription drugs, OTC drugs, and special diets (e.g., ketogenic diet), as well as any concomitant illnesses (e.g., liver disease, kidney disease, severe lung disorders, diarrhea, surgery, depression, bipolar disorder) or family history of suicidality or bipolar disorder.^{1 13 19}

  
  


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

  
  

Preparations

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

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Zonisamide

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	25 mg*	Zonegran	Eisai
			Zonisamide Capsules
		50 mg*	Zonisamide Capsules
		100 mg*	Zonegran	Eisai
			Zonisamide Capsules

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Zonegran 100MG Capsules (EISAI): 30/$131.99 or 90/$380.98

Zonegran 25MG Capsules (EISAI): 30/$39.99 or 90/$97.97

Zonisamide 100MG Capsules (GLENMARK PHARMACEUTICALS): 30/$59.99 or 90/$169.97

Zonisamide 25MG Capsules (GLENMARK PHARMACEUTICALS): 100/$49.99 or 300/$139.98

Zonisamide 50MG Capsules (GLENMARK PHARMACEUTICALS): 100/$91.99 or 300/$259.98

Disclaimer

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

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

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Elan Pharma International Ltd, (manufacturer) and Eisai Inc. (distributor). Zonegran (zonisamide) capsules prescribing information. Woodcliff Lake, NJ; 2009 Apr.

2. Anon. Zonisamide (Zonegran) for epilepsy. Med Lett Drugs Ther. 2000; 42:94-5. [PubMed 11015160]

3. Schachter SC. The next wave of anticonvulsants: focus on levetiracetam, oxcarbazepine and zonisamide. Drugs. 2000; 14:229-49.

4. Leppik IE, Willmore LJ, Homan RW et al. Efficacy and safety of zonisamide: results of a multicenter study. Epilepsy Res. 1993; 14:165-73. [PubMed 8453952]

5. Berent S, Sackellares JC, Giordani B et al. Zonisamide (CI-912) and cognition: results from preliminary study. Epilepsia. 1987; 28:61-7. [PubMed 3098556]

6. Sackellares JC, Donofrio PD, Wagner JG et al. Pilot study of zonisamide (1,2-benzisoxazole-3-methanesulfonamide) in patients with refractory partial seizures. Epilepsia. 1985; 26:206-11. [PubMed 3924586]

7. Wilensky AJ, Friel PN, Ojemann LM Et al. Zonisamide in epilepsy: a pilot study. Epilepsia. 1985; 26:212-20. [PubMed 4006880]

8. Schmidt D, Jacob R, Loiseau P et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res. 1993 May; 15:67-73.

9. Oommen KJ, Mathews S. Zonisamide: a new antiepileptic drug. Clin Neuropharmacol. 1999; 22:192-200. [PubMed 10442247]

10. Leppik IE. Zonisamide. Epilepsia. 1999; 40(Suppl 5):S23-9. [IDIS 435526] [PubMed 10530691]

11. Okumura A, Hayakawa F, Kuno K et al. Oligohidrosis caused by zonisamide. No To Hattatsu. 1996; 28:44-7. [PubMed 8579857]

12. Kubota M, Nishi-Nagase M, Sakakihara Y et al. Zonisamide-induced urinary lithiasis in patients with intractable epilepsy. Brain Dev. 2000; 22:230-3. [PubMed 10838109]

13. O’Brien C. Dear doctor letter regarding oligohidrosis and hyperthermia in pediatric patients. San Diego, CA: Elan Pharmaceuticals; 2002. From the FDA website.

14. Food and Drug Administration. FDA Alert: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.

15. Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.

16. Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website.

17. Kalinin VV. Suicidality and antiepileptic drugs: is there a link?. Drug Saf. 2007; 30:123-42. [PubMed 17253878]

18. Kawada K, Itoh S, Kusaka T et al. Pharmacokinetics of zonisamide in perinatal period. Brain Dev. 2002; 24:95-7. [PubMed 11891100]

19. Food and Drug Administration. FDA Alert: Information for healthcare professionals: zonisamide (marketed as Zonegran, and generics). Rockville, MD; 2009 Feb 23. From the FDA website.

20. Oles KS, Bell WL. Zonisamide concentrations during pregnancy. Ann Pharmacother. 2008; 42:1139-41. [PubMed 18577760]

21. Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website.

22. Lee YJ, Kang HC, Seo JH et al. Efficacy and tolerability of adjunctive therapy with zonisamide in childhood intractable epilepsy. Brain Dev. 2009; Mar 20:[epub ahead of print].

23. Coppola G, Grosso S, Verrotti A et al. Zonisamide in children and young adults with refractory epilepsy: an open label, multicenter Italian study. Epilepsy Res. 2009; 83:112-6. [PubMed 19081227]

24. Santos CC, Brotherton T. Use of zonisamide in pediatric patients. Pediatr Neurol. 2005; 33:12-4. [PubMed 15876518]

25. Wilfong AA. Zonisamide monotherapy for epilepsy in children and young adults. Pediatr Neurol. 2005; 32:77-80. [PubMed 15664764]

26. Low PA, James S, Peschel T et al. Zonisamide and associated oligohidrosis and hyperthermia. Epilepsy Res. 2004; 62:27-34. [PubMed 15519129]

27. Shinnar S, Pellock JM, Conry JA. Open-label, long-term safety study of zonisamide administered to children and adolescents with epilepsy. Eur J Paediatr Neurol. 2009; 13:3-9. [PubMed 18343174]

28. Griffith SG, Dai Y. Effect of zonisamide on the pharmacokinetics and pharmacodynamics of a combination ethinyl estradiol-norethindrone oral contraceptive in healthy women. Clin Ther.. 2004; 26:2056-65.

More Zonegran resources

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

• Zonegran Prescribing Information (FDA)


• Zonegran Consumer Overview


• Zonegran Advanced Consumer (Micromedex) - Includes Dosage Information


• Zonegran MedFacts Consumer Leaflet (Wolters Kluwer)


• Zonisamide Professional Patient Advice (Wolters Kluwer)

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