Sample PLR Content Directory Idaho: June 2012

Saturday 30 June 2012

Ismelin

guanethidine monosulfate

Dosage Form: Tablets

Ismelin®

guanethidine monosulfate USP

C96-14 (Rev. 3/96) 666671

Tablets

Prescribing Information

DESCRIPTION

Ismelin, guanethidine monosulfate USP, is an antihypertensive, available as tablets of 10 mg and 25 mg for oral administration. Each 10-mg and 25-mg tablet contains guanethidine monosulfate USP equivalent to 10 mg and 25 mg of guanethidine sulfate USP. Its chemical name is [2-(hexahydro-1(2H)-azocinyl)ethyl]guanidine sulfate 1:1, and its structural formula is

Guanethidine monosulfate USP is a white to off-white crystalline powder with a molecular weight of 296.38. It is very soluble in water, sparingly soluble in alcohol, and practically insoluble in chloroform.

Inactive Ingredients. Calcium stearate, colloidal silicon dioxide, D&C Yellow No. 10 (10-mg tablets), lactose, starch, stearic acid, and sucrose.

CLINICAL PHARMACOLOGY

Ismelin acts at the sympathetic neuroeffector junction by inhibiting or interfering with the release and/or distribution of the chemical mediator (presumably the catecholamine norepinephrine), rather than acting at the effector cell by inhibiting the association of the transmitter with its receptors. In contrast to ganglionic blocking agents, Ismelin suppresses equally the responses mediated by alpha-and beta-adrenergic receptors but does not produce parasympathetic blockade. Since sympathetic blockade results in modest decreases in peripheral resistance and cardiac output, Ismelin lowers blood pressure in the supine position. It further reduces blood pressure by decreasing the degree of vasoconstriction that normally results from reflex sympathetic nervous activity upon assumption of the upright posture, thus reducing venous return and cardiac output more. The inhibition of sympathetic venoconstrictive mechanisms results in venous pooling of blood. Therefore, the effect of Ismelin is especially pronounced when the patient is standing. Both the systolic and diastolic pressures are reduced.

Other actions at the sympathetic nerve terminal include depletion of norepinephrine. Once it gains access to the neuron, Ismelin accumulates within the intraneuronal storage vesicles and causes depletion of norepinephrine stores within the nerve terminal. Prolonged oral administration of Ismelin produces a denervation sensitivity of the neuroeffector junction, probably resulting from the chronic reduction in norepinephrine released by the sympathetic nerve endings. Systemic responses to catecholamines released from the adrenal medulla are not prevented and may even be augmented as a result of this denervation sensitivity. A paradoxical hypertensive crisis may occur if Ismelin is given to patients with pheochromocytoma or if norepinephrine is given to a patient receiving the drug.

Due to its poor lipid solubility, Ismelin does not readily cross the blood-brain barrier. In contrast to most neural blocking agents, Ismelin does not appear to suppress plasma renin activity in many patients.

Pharmacokinetics

The pharmacokinetics of Ismelin are complex. The amount of drug in plasma and in urine is linearly related to dose, although large differences occur between individuals because of variation in absorption and metabolism. Adrenergic blockade occurs with a minimum concentration in plasma of 8 ng/ml; this concentration is achieved in different individuals with dosages of 10-50 mg/day at steady state. Ismelin is eliminated slowly because of extensive tissue binding. After chronic oral administration, the initial phase of elimination with a half-life of 1.5 days is followed by a second phase of elimination with a half-life of 4-8 days. The renal clearance of Ismelin is 56 ml/min. Ismelin is converted by the liver to three metabolites, which are excreted in the urine. The metabolites are pharmacologically less active than Ismelin.

INDICATIONS AND USAGE

Ismelin is indicated for the treatment of moderate and severe hypertension, either alone or as an adjunct, and for the treatment of renal hypertension, including that secondary to pyelonephritis, renal amyloidosis, and renal artery stenosis.

CONTRAINDICATIONS

Known or suspected pheochromocytoma; hypersensitivity; frank congestive heart failure not due to hypertension; use of monoamine oxidase (MAO) inhibitors.

WARNINGS

Ismelin is a potent drug and its use can lead to disturbing and serious clinical problems. Before prescribing, physicians should familiarize themselves with the details of its use and warn patients not to deviate from instructions.

Orthostatic hypotension can occur frequently, and patients should be properly instructed about this potential hazard. Fainting spells may occur unless the patient is forewarned to sit or lie down with the onset of dizziness or weakness. Postural hypotension is most marked in the morning and is accentuated by hot weather, alcohol, or exercise. Dizziness or weakness may be particularly bothersome during the initial period of dosage adjustment and with postural changes, such as arising in the morning. The potential occurrence of these symptoms may require alteration of previous daily activity. The patient should be cautioned to avoid sudden or prolonged standing or exercise while taking the drug.

Inhibition of ejaculation has been reported in animals (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility) as well as in men given Ismelin. This effect, which results from the sympathetic blockade caused by the drug's action, is reversible after Ismelin has been discontinued for several weeks. The drug does not cause parasympathetic blockade, and erectile potency is usually retained during administration of Ismelin. The possible occurrence of inhibition of ejaculation should be kept in mind when considering the use of guanethidine in men of reproductive age.

If possible, therapy should be withdrawn 2 weeks prior to surgery to reduce the possibility of vascular collapse and cardiac arrest during anesthesia. If emergency surgery is indicated, preanesthetic and anesthetic agents should be administered cautiously in reduced dosage. Oxygen, atropine, vasopressors, and adequate solutions for volume replacement should be ready for immediate use to counteract vascular collapse in the surgical patient. Vasopressors should be used only with extreme caution, since Ismelin augments responsiveness to exogenously administered norepinephrine and vasopressors; specifically, blood pressure may rise and cardiac arrhythmias may be produced.

PRECAUTIONS

General

Dosage requirements may be reduced in the presence of fever.

Special care should be exercised when treating patients with a history of bronchial asthma; asthmatic patients are more apt to be hypersensitive to catecholamine depletion, and their condition may be aggravated.

The effects of Ismelin are cumulative over long periods; initial doses should be small and increased gradually in small increments.

Ismelin should be used very cautiously in hypertensive patients with: renal disease and nitrogen retention or rising BUN levels, since decreased blood pressure may further compromise renal function; coronary insufficiency or recent myocardial infarction; and cerebrovascular disease, especially with encephalopathy.

Ismelin should not be given to patients with severe cardiac failure except with extreme caution, since Ismelin may interfere with the compensatory role of the adrenergic system in producing circulatory adjustment in patients with congestive heart failure.

Patients with incipient cardiac decompensation should be watched for weight gain or edema, which may be averted by the concomitant administration of a thiazide.

Ismelin should be used cautiously in patients with a history of peptic ulcer or other chronic disorders that may be aggravated by a relative increase in parasympathetic tone.

Information for Patients

The patient should be advised to take Ismelin exactly as directed. If the patient misses a dose, he or she should be told to take only the next scheduled dose (without doubling it).

The patient should be advised to avoid sudden or prolonged standing or exercise and to arise slowly, especially in the morning, to reduce the orthostatic hypotensive effects of dizziness, lightheadedness, or fainting.

The patient should be cautioned about ingesting alcohol, since it aggravates the orthostatic hypotensive effects of Ismelin.

Male patients should be advised that guanethidine may interfere with ejaculation.

Drug Interactions

Concurrent use of Ismelin and rauwolfia derivatives may cause excessive postural hypotension, bradycardia, and mental depression.

Both digitalis and Ismelin slow the heart rate.

Thiazide diuretics enhance the antihypertensive action of Ismelin (see DOSAGE AND ADMINISTRATION).

Amphetamine-like compounds, stimulants (e. g., ephedrine, methylphenidate), tricyclic antidepressants (e.g., amitriptyline, imipramine, desipramine) and other psychopharmacologic agents (e.g., phenothiazines and related compounds), as well as oral contraceptives, may reduce the hypotensive effect of Ismelin.

MAO inhibitors should be discontinued for at least 1 week before starting therapy with Ismelin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in animals have not been conducted with Ismelin.

While inhibition of sperm passage and accumulation of sperm debris have been reported in rats and rabbits after several weeks of administration of Ismelin, 5 or 10 mg/kg per day, subcutaneously or intraperitoneally, recovery of ejaculatory function and fertility has been demonstrated in rats given Ismelin intramuscularly, 25 mg/kg per day, for 8 weeks. Inhibition of ejaculation has also been reported in men (see WARNINGS and ADVERSE REACTIONS). This effect, which is attributable to the sympathetic blockade caused by the drug, is reversible several weeks after discontinuance of the drug.

Pregnancy Category C

Animal reproduction studies have not been conducted with Ismelin. It is also not known whether Ismelin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ismelin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Ismelin is excreted in breast milk in very small quantity. Caution should be exercised when Ismelin is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

The following adverse reactions have been observed, but there are not enough data to support an estimate of their frequency. Consequently the reactions are categorized by organ system and are listed in decreasing order of severity and not frequency.

Digestive: Diarrhea, which may be severe at times and necessitate discontinuance of medication; vomiting; nausea: increased bowel movements; dry mouth: parotid tenderness.

Cardiovascular: Chest pains (angina): bradycardia; a tendency toward fluid retention and edema with occasional development of congestive heart failure

Respiratory: Dyspnea; asthma in susceptible individuals: nasal congestion.

Neurologic: Syncope resulting from either postural or exertional hypotension; dizziness; blurred vision, muscle tremor; ptosis of the lids; mental depression; chest paresthesias; weakness; lassitude; fatigue.

Muscular: Myalgia.

Genitourinary: Rise in BUN; urinary incontinence; inhibition of ejaculation; nocturia.

Metabolic: Weight gain.

Skin and Appendages: Dermatitis; scalp hair loss.

Although a causal relationship has not been established. a few instances of blood dyscrasias (anemia, thrombocytopenia, and leukopenia) and of priapism or impotence have been reported.

OVERDOSAGE

Acute Toxicity

No deaths due to acute poisoning have been reported.

Oral LD50 in rats: 1262 mg/kg.

Signs and Symptoms

Postural hypotension (with dizziness, blurred vision, and possibly syncope when standing), shock, and bradycardia are most likely to occur; diarrhea (possibly severe), nausea, and vomiting may also occur. Unconsciousness is unlikely if adequate blood pressure and cerebral perfusion can be maintained by placing the patient in the supine position and by administering other treatment as required.

Treatment

There is no specific antidote.

Treatment should consist of gastric lavage. An activated charcoal slurry should be instilled and laxatives given, if conditions permit.

In sinus bradycardia, atropine should be administered.

In previously normotensive patients, treatment has consisted essentially of restoring blood pressure and heart rate to normal by keeping the patient in the supine position. Normal homeostatic control usually returns gradually over a 72-hour period in these patients.

In previously hypertensive patients, particularly those with impaired cardiac reserve or other cardiovascular- renal disease, intensive treatment may be required to support vital functions and to control cardiac irregularities that might be present. The supine position must be maintained; if vasopressors are required, they must be used with extreme caution, since Ismelin may increase responsiveness, causing a rise in blood pressure and development of cardiac arrhythmias.

Diarrhea, if severe or persistent, should be treated with anticholinergic agents to reduce intestinal hypermotility; hydration and electrolyte balance should be maintained.

Since Ismelin is excreted slowly, cardiovascular and renal function should be monitored for a few days.

DOSAGE AND ADMINISTRATION

Better control may be obtained, especially in the initial phases of treatment, if the patient can have his blood pressure recorded regularly at home.

Ambulatory Patients

Initial doses should be small (10 mg) and increased gradually, depending upon the patient's response. Ismelin has a long duration of action; therefore, dosage increases should not be made more often than every 5-7 days, unless the patient is hospitalized.

Blood pressure should be measured in the supine position, after standing for 10 minutes, and immediately after exercise if feasible. Dosage may be increased only if there has been no decrease in the standing blood pressure from previous levels. The average daily dose is 25-50 mg; only one dose a day is usually required.

Dosage Chart for Ambulatory Patients

Visits (intervals of 5 - 7 Days) Daily Dose

Visit 1 (Patient may be started on 10-mg tablets)............................................................ 10 mg

Visit 2 ...............................................................................................................................20 mg

Visit 3 (Patient may be changed to 25-mg tablets whenever convenient)....................... 30 mg (three 10-mg tablets) or 37.5 mg (one and one-half 25-mg tablets)

Visit 4 .............................................................................................................................. 50 mg

Visit 5 and subsequent........................... Dosage may be increased by 12.5 mg or 25 mg if necessary.

The dosage should be reduced in any of the following situations: (1) normal supine pressure: (2) excessive orthostatic fall in pressure; (3) severe diarrhea.

Hospitalized Patients

Initial oral dose is 25-50 mg, increased by 25 mg or 50 mg daily or every other day, as indicated. This higher dosage is possible because hospitalized patients can be watched carefully. Unless absolutely impossible, the standing blood pressure should be measured regularly. Patients should not be discharged from the hospital until the effect of the drug on the standing blood pressure is known. Patients should be told about the possibility of orthostatic hypotension and warned not to get out of bed without help during the period of dosage adjustment.

Combination Therapy

Ismelin may be added gradually to thiazides and/or hydralazine. Thiazide diuretics enhance the effectiveness of Ismelin and may reduce the incidence of edema. When thiazide diuretics are added to the regimen in patients taking Ismelin, it is usually necessary to reduce the dosage of Ismelin. After control is established, the dosage of all drugs should be reduced to the lowest effective level.

Note: When Ismelin is replacing MAO inhibitors, at least 1 week should elapse before commencing treatment with Ismelin (see CONTRAINDICATIONS). If ganglionic blockers have not been discontinued before Ismelin is started, they should be gradually withdrawn to prevent a spiking blood pressure response during the transfer period.

HOW SUPPLIED

Tablets 10 mg – round, pale yellow, scored (imprinted CIBA 49)

Bottles of 100..................................................................................NDC 0083-0049-30

Tablets 25 mg – round, white, scored (imprinted CIBA 103)

Bottles of 100..................................................................................NDC 0083-0103-30

Do not store above 86°F (30°C).

Dispense in tight container (USP).

C96-14(Rev.3/96)

C I B A

Ciba-Geigy Corporation

Pharmaceuticals Division

Summit, New Jersey 07901

Ismelin
guanethidine monosulfate tablet

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	0083-0049
Route of Administration	ORAL	DEA Schedule

INGREDIENTS
Name (Active Moiety)	Type	Strength
guanethidine monosulfate (guanethidine)	Active	10 MILLIGRAM In 1 TABLET
calcium stearate	Inactive
colloidal silicon dioxide	Inactive
D&C Yellow No. 10	Inactive
lactose	Inactive
starch	Inactive
stearic acid	Inactive
sucrose	Inactive

Product Characteristics
Color	YELLOW (pale yellow)	Score	2 pieces
Shape	ROUND	Size	9mm
Flavor		Imprint Code	CIBA;49
Contains
Coating	false	Symbol	false

Packaging
#	NDC	Package Description	Multilevel Packaging
1	0083-0049-30	100 TABLET In 1 BOTTLE	None

Ismelin
guanethidine monosulfate tablet

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	0083-0103
Route of Administration	ORAL	DEA Schedule

INGREDIENTS
Name (Active Moiety)	Type	Strength
guanethidine monosulfate (guanethidine)	Active	25 MILLIGRAM In 1 TABLET
calcium stearate	Inactive
colloidal silicon dioxide	Inactive
lactose	Inactive
starch	Inactive
stearic acid	Inactive
sucrose	Inactive

Product Characteristics
Color	WHITE	Score	2 pieces
Shape	ROUND	Size	10mm
Flavor		Imprint Code	CIBA;103
Contains
Coating	false	Symbol	false

Packaging
#	NDC	Package Description	Multilevel Packaging
1	0083-0103-30	100 TABLET In 1 BOTTLE	None

Revised: 08/2006Ciba-Geigy Corporation

More Ismelin resources

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

Ismelin Concise Consumer Information (Cerner Multum)

Ismelin Advanced Consumer (Micromedex) - Includes Dosage Information

Compare Ismelin with other medications

High Blood Pressure
Hypertensive Emergency

Tuesday 26 June 2012

Japanese encephalitis virus vaccine Nakayama

Generic Name: Japanese encephalitis virus vaccine (Nakayama) (JAP a NEEZ en CEF a LYE tis NA ka YA ma)

Brand Names: Je-Vax

What is Japanese encephalitis virus vaccine (Nakayama)?

Japanese encephalitis is a serious disease caused by a virus. It is the leading cause of viral encephalitis (inflammation of the brain) in Asia. Encephalitis is an infection of the membrane around the brain and spinal cord. This infection often causes only mild symptoms, but prolonged swelling of the brain can cause permanent brain damage or death.

Japanese encephalitis virus is carried and spread by mosquitos.

The Japanese encephalitis Nakayama vaccine is used to help prevent this disease in adults and children who are at least 12 months old.

This vaccine works by exposing you to a small dose of the virus, which causes the body to develop immunity to the disease. This vaccine will not treat an active infection that has already developed in the body.

This vaccine is recommended for people who plan to spend 30 days or longer in areas where Japanese encephalitis is known to exist, or where an epidemic has recently occurred. The vaccine should also be given to people who will spend any amount of time in rural areas where Japanese encephalitis is endemic, or those who are otherwise at high risk of coming into contact with the virus.

You should receive this vaccine and all booster shots at least 10 days prior to your arrival in an area where you may be exposed to the virus.

Not everyone who travels to Asia needs to receive a Japanese encephalitis vaccine. Follow your doctor instructions or the recommendations of the Centers for Disease Control and Prevention (CDC).

This vaccine is also recommended for people who work in a research laboratory and may be exposed to Japanese encephalitis virus through needle-stick accidents or inhalation of viral droplets in the air.

Like any vaccine, the Japanese encephalitis Nakayama vaccine may not provide protection from disease in every person.

What is the most important information I should know about this vaccine?

The Japanese encephalitis Nakayama vaccine is given in a series of 3 shots. The booster shots are usually given 7 days and 2 weeks to 1 month after the first shot. Your individual booster schedule may be different from these guidelines. Follow your doctor's instructions or the schedule recommended by the health department of the state you live in.

Japanese encephalitis Nakayama vaccine is for use in adults and children who are at least 12 months old.

You should receive the vaccine and all booster doses at least 10 days prior to your arrival in an area where you may be exposed to the virus.

Not everyone who travels to Asia needs to receive a Japanese encephalitis vaccine. Follow your doctor instructions or the recommendations of the Centers for Disease Control and Prevention (CDC).

Becoming infected with Japanese encephalitis is much more dangerous to your health than receiving the vaccine to protect against it. Like any medicine, this vaccine can cause side effects, but the risk of serious side effects is extremely low.

What should I discuss with my healthcare provider before receiving this vaccine?

You should not receive this vaccine if you have ever had a life-threatening allergic reaction to a Japanese encephalitis vaccine, or if you are allergic to mouse proteins or a preservative called thimerosal. You should also not receive this vaccine if you have received cancer chemotherapy or radiation treatment in the past 3 months.

Before receiving this vaccine, tell the doctor if you are allergic to any foods or drugs, or if you have:

an allergy to insect (such as bee or wasp) stings;

a history of seizures;

a neurologic disorder or disease affecting the brain (or if this was a reaction to a previous vaccine); or

a weak immune system caused by disease, bone marrow transplant, or by using certain medicines or receiving cancer treatments.

You can still receive a vaccine if you have a cold or fever. In the case of a more severe illness with a fever or any type of infection, wait until you get better before receiving this vaccine.

Vaccines may be harmful to an unborn baby and generally should not be given to a pregnant woman. However, not vaccinating the mother could be more harmful to the baby if the mother becomes infected with a disease that this vaccine could prevent. Your doctor will decide whether you should receive this vaccine, especially if you have a high risk of infection with the Japanese encephalitis virus. Do not receive this vaccine without telling your doctor if you are breast-feeding a baby.

How is this vaccine given?

This vaccine is given as an injection (shot) under the skin. You will receive this injection in a doctor's office or other clinic setting.

Your care providers may want to watch you for signs of allergic reaction for at least 30 minutes after you receive this vaccine.

In addition to receiving the Japanese encephalitis vaccine, use protective clothing, insect repellents, and mosquito netting around your bed to further prevent mosquito bites that could infect you with the Japanese encephalitis virus.

For at least 10 days after receiving a Japanese encephalitis vaccine, be sure to stay in an area where you have access to medical care in case of a delayed allergic reaction.

Your doctor may recommend treating fever and pain with an aspirin-free pain reliever such as acetaminophen (Tylenol) or ibuprofen (Motrin, Advil, and others) when the shot is given and for the next 24 hours. Follow the label directions or your doctor's instructions about how much of this medicine to take.

It is especially important to prevent fever from occurring if you have a seizure disorder such as epilepsy.

What happens if I miss a dose?

Contact your doctor if you will miss a booster dose or if you get behind schedule. The next dose should be given as soon as possible. There is no need to start over.

Be sure you receive all recommended doses of this vaccine. If you do not receive the full series of vaccines, you may not be fully protected against the disease.

What happens if I overdose?

An overdose of this vaccine is unlikely to occur.

What should I avoid before or after receiving this vaccine?

Avoid drinking large amounts of alcohol for at least 48 hours after you receive a Japanese encephalitis vaccine.

This vaccine side effects

You should not receive a booster vaccine if you had a life-threatening allergic reaction after the first shot. Keep track of any and all side effects you have after receiving this vaccine. When you receive a booster dose, you will need to tell the doctor if the previous shots caused any side effects.

Get emergency medical help if you have any of these signs of an allergic reaction (which may occur up to 17 days after you receive the shot): hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

feeling light-headed, fainting;

high fever;

behavior changes; or

seizures (black-out or convulsions).

Less serious side include:

redness, pain, or swelling where the shot was given;

low fever, chills, flu symptoms;

headache, tired feeling;

muscle pain;

nausea, vomiting, stomach pain; or

mild itching or skin rash.

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

Japanese encephalitis virus vaccine Dosing Information

Usual Adult Dose for Japanese Encephalitis Virus Prophylaxis:

1 mL subcutaneously on days 0, 7, and 30.
If there are time constraints, three doses may be given on days 0, 7, and 14.
If neither schedule can be followed, two doses given on days 0 and 7 will induce antibodies in up to 80% of recipients; however, this regimen is not recommended.
A booster dose of 1 mL may be given after 2 years. There are no data on optimal spacing of boosters after 2 years.

Available supplies are limited; use is restricted for children 1 to 16 years of age.

No information is available concerning the interchangeability of vaccines; however, because the supply of Japanese encephalitis virus vaccine Nakayama (Je-Vax) is limited, adults 17 years of age or older who require a booster dose may receive a 2 dose primary series of Japanese encephalitis virus vaccine SA14-14-2 (Ixiaro) when Je-Vax is not available and further vaccination is required.

Usual Pediatric Dose for Japanese Encephalitis Virus Prophylaxis:

1 year to 2 years: 0.5 mL subcutaneously on days 0, 7, and 30. A booster dose of 0.5 mL may be given after 2 years.
3 years or older: 1 mL subcutaneously on days 0, 7, and 30.

An abbreviated schedule with the third dose administered on day 14 should be used only when time does not permit waiting; 2 doses a week apart produce immunity in about 80% of recipients; the longest regimen yields highest titers after 6 months.

A booster dose of 1 mL may be given after 2 years. There are no data on optimal spacing of boosters after 2 years.

What other drugs will affect Japanese encephalitis virus vaccine (Nakayama)?

Before receiving this vaccine, tell the doctor about all other vaccines you have recently received.

Also tell the doctor if you have recently received drugs or treatments that can weaken the immune system, including:

an oral, nasal, inhaled, or injectable steroid medicine;

medications to treat psoriasis, rheumatoid arthritis, or other autoimmune disorders, such as azathioprine (Imuran), efalizumab (Raptiva), etanercept (Enbrel), leflunomide (Arava), and others; or

medicines to treat or prevent organ transplant rejection, such as basiliximab (Simulect), cyclosporine (Sandimmune, Neoral, Gengraf), muromonab-CD3 (Orthoclone), mycophenolate mofetil (CellCept), sirolimus (Rapamune), or tacrolimus (Prograf).

This list is not complete and there may be other drugs that can interact with Japanese encephalitis vaccine. Tell your doctor about all the prescription and over-the-counter medications you have received. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Japanese encephalitis virus vaccine resources

Japanese encephalitis virus vaccine Use in Pregnancy & Breastfeeding
Japanese encephalitis virus vaccine Drug Interactions
Japanese encephalitis virus vaccine Support Group
0 Reviews for Japanese encephalitis virus vaccine - Add your own review/rating

Je-Vax Advanced Consumer (Micromedex) - Includes Dosage Information

Compare Japanese encephalitis virus vaccine with other medications

Japanese Encephalitis Virus Prophylaxis

Where can I get more information?

Your doctor or pharmacist may have information about this vaccine written for health professionals that you may read. You may also find additional information from your local health department or the Centers for Disease Control and Prevention.

Monday 25 June 2012

Imogen

Generic Name: loperamide (Oral route)

loe-PER-a-mide

Commonly used brand name(s)

In the U.S.

Diamode

Imodium

Imodium A-D

Imogen

Imotil

Imperim

Kaodene A-D

Kao-Paverin Caps

Available Dosage Forms:

Tablet

Capsule

Liquid

Tablet, Chewable

Solution

Capsule, Liquid Filled

Therapeutic Class: Antidiarrheal

Uses For Imogen

Loperamide is a medicine used along with other measures to treat diarrhea. Loperamide helps stop diarrhea by slowing down the movements of the intestines.

In the U.S., loperamide capsules are available only with your doctor's prescription.

Before Using Imogen

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

This medicine should not be used in children under 6 years of age unless directed by a doctor. Children, especially very young children, are very sensitive to the effects of loperamide. This may increase the chance of side effects during treatment. Also, the fluid loss caused by diarrhea may result in a serious health problem (dehydration). Loperamide may hide the symptoms of dehydration. For these reasons, do not give medicine for diarrhea to children without first checking with their doctor. If you have any questions about this, check with your health care professional.

Geriatric

The fluid loss caused by diarrhea may result in a serious health problem (dehydration). Loperamide may hide the symptoms of dehydration. For this reason, elderly persons with diarrhea, in addition to using medicine for diarrhea, must receive a sufficient amount of liquids to replace the fluid lost by the body. If you have any questions about this, check with your health care professional.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during 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. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Saquinavir

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Gemfibrozil

Itraconazole

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.

Proper Use of loperamide

This section provides information on the proper use of a number of products that contain loperamide. It may not be specific to Imogen. Please read with care.

Do not use loperamide to treat your diarrhea if you have a fever or if there is blood or mucus in your stools. Contact your doctor.

For safe and effective use of this medicine:

Follow your doctor's instructions if this medicine was prescribed.

Follow the manufacturer's package directions if you are treating yourself.

Use a specially marked measuring spoon or other device to measure each dose accurately. The average household teaspoon may not hold the right amount of liquid.

Importance of diet and fluid intake while treating diarrhea:

In addition to using medicine for diarrhea, it is very important that you replace the fluid lost by the body and follow a proper diet. For the first 24 hours, you should eat gelatin, and drink plenty of caffeine-free clear liquids, such as ginger ale, decaffeinated cola, decaffeinated tea, and broth. During the next 24 hours you may eat bland foods, such as cooked cereals, bread, crackers, and applesauce. Fruits, vegetables, fried or spicy foods, bran, candy, caffeine, and alcoholic beverages may make the condition worse.

If too much fluid has been lost by the body due to the diarrhea, a serious condition (dehydration) may develop. Check with your doctor as soon as possible if any of the following signs or symptoms of too much fluid loss occur:
- Decreased urination
- Dizziness and lightheadedness
- Dryness of mouth
- Increased thirst
- Wrinkled skin

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 diarrhea:
- For oral dosage form (capsules):
  - Adults and teenagers—The usual dose is 4 milligrams (mg) (2 capsules) after the first loose bowel movement, and 2 mg (1 capsule) after each loose bowel movement after the first dose has been taken. No more than 16 mg (8 capsules) should be taken in any twenty-four-hour period.
  - Children 8 to 12 years of age—The usual dose is 2 mg (1 capsule) three times a day.
  - Children 6 to 8 years of age—The usual dose is 2 mg (1 capsule) two times a day.
  - Children up to 6 years of age—Use is not recommended unless directed by your doctor.
- For oral dosage form (oral solution):
  - Adults and teenagers—The usual dose is 4 teaspoonfuls (4 mg) after the first loose bowel movement, and 2 teaspoonfuls (2 mg) after each loose bowel movement after the first dose has been taken. No more than 8 teaspoonfuls (8 mg) should be taken in any twenty-four-hour period.
  - Children 9 to 11 years of age—The usual dose is 2 teaspoonfuls (2 mg) after the first loose bowel movement, and 1 teaspoonful (1 mg) after each loose bowel movement after the first dose has been taken. No more than 6 teaspoonfuls (6 mg) should be taken in any twenty-four-hour period.
  - Children 6 to 8 years of age—The usual dose is 2 teaspoonfuls (2 mg) after the first loose bowel movement, and 1 teaspoonful (1 mg) after each loose bowel movement after the first dose has been taken. No more than 4 teaspoonfuls (4 mg) should be taken in any twenty-four-hour period.
  - Children up to 6 years of age—Use is not recommended unless directed by your doctor.
- For oral dosage form (tablets):
  - Adults and teenagers—The usual dose is 4 mg (2 tablets) after the first loose bowel movement, and 2 mg (1 tablet) after each loose bowel movement after the first dose has been taken. No more than 8 mg (4 tablets) should be taken in any twenty-four-hour period.
  - Children 9 to 11 years of age—The usual dose is 2 mg (1 tablet) after the first loose bowel movement, and 1 mg (½ tablet) after each loose bowel movement after the first dose has been taken. No more than 6 mg (3 tablets) should be taken in any twenty-four-hour period.
  - Children 6 to 8 years of age—The usual dose is 2 mg (1 tablet) after the first loose bowel movement, and 1 mg (½ tablet) after each loose bowel movement after the first dose has been taken. No more than 4 mg (2 tablets) should be taken in any twenty-four-hour period.
  - Children up to 6 years of age—Use is not recommended unless directed 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.

Precautions While Using Imogen

Loperamide should not be used for more than 2 days, unless directed by your doctor. If you will be taking this medicine regularly for a long time, your doctor should check your progress at regular visits.

Check with your doctor if your diarrhea does not stop after two days or if you develop a fever.

Imogen 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:

Rare

Bloating

constipation

loss of appetite

stomach pain (severe) with nausea and vomiting

Check with your doctor as soon as possible if any of the following side effects occur:

Rare

Skin rash

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Rare

Dizziness or drowsiness

dryness of mouth

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: Imogen 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 Imogen resources

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

Compare Imogen with other medications

Diarrhea
Diarrhea, Acute
Diarrhea, Chronic
Lymphocytic Colitis
Traveler's Diarrhea

Sorine

Generic Name: sotalol (SOE ta lol)

Brand Names: Betapace, Sorine

What is Sorine (sotalol)?

Sotalol is in a group of drugs called beta-blockers. Beta-blockers affect the heart and circulation (blood flow through arteries and veins).

Sotalol is used to help keep the heart beating normally in people with certain heart rhythm disorders of the ventricles (the lower chambers of the heart that allow blood to flow out of the heart). Sotalol is used in people with ventricular tachycardia or ventricular fibrillation.

Another form of this medicine, called Sotalol AF, is used to treat heart rhythm disorders of the atrium (the upper chambers of the heart that allow blood to flow into the heart). Sotalol AF is used in people with atrial fibrillation or atrial flutter. Sotalol (Betapace and Sorine) is not used for the same conditions that sotalol AF (Betapace AF) is used for.

Sotalol may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Sorine (sotalol)?

You will receive your first few doses of sotalol in a hospital setting where your heart rhythm can be monitored, in case the medication causes serious side effects.

If there are any changes in the brand or strength of sotalol you use, your dosage needs may change. Betapace and Sorine are not used for the same conditions that Betapace AF is used for. Always check your medicine when it is refilled to make sure you have received the correct brand and type as prescribed by your doctor. Ask the pharmacist if you have any questions about the medicine given to you at the pharmacy.

Do not skip doses or stop taking sotalol without first talking to your doctor. Stopping suddenly may make your condition worse. You may need to use less and less before you stop the medication completely.

If you need to have any type of surgery, you may need to temporarily stop using sotalol. Be sure the surgeon knows ahead of time that you are using sotalol.

What should I discuss with my healthcare provider before taking Sorine (sotalol)?

Do not use this medication if you are allergic to sotalol, or if you have:

asthma;

certain heart conditions, especially "AV block" (unless you have a pacemaker);

a history of "Long QT syndrome"; or

severe or uncontrolled congestive heart failure.

If you have any of these other conditions, you may need a dose adjustment or special tests to safely take sotalol:

breathing problems such as bronchitis or emphysema;

a history of heart disease or congestive heart failure;

diabetes;

kidney disease;

a thyroid disorder;

an electrolyte imbalance such as low levels of potassium or magnesium in your blood; or

if you have recently had a heart attack.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Sotalol can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Sorine (sotalol)?

You will receive your first few doses of sotalol in a hospital setting where your heart can be monitored in case the medication causes serious side effects.

Take sotalol exactly as it was prescribed for you. Do not take the medication in larger amounts or for longer than recommended by your doctor. Follow the directions on your prescription label.

Take this medication with a full glass of water.

Take sotalol at the same time every day.

Tell your doctor if you have an illness that involves diarrhea or vomiting lasting more than a few hours. Prolonged diarrhea or vomiting can lower your potassium levels, making it dangerous for you to use sotalol.

To be sure this medication is helping your condition, your blood pressure will need to be checked on a regular basis. Your heart and kidney function will also need to be tested. Do not miss any scheduled visits to your doctor.

This medication can cause you to have unusual results with certain medical tests. Tell any doctor who treats you that you are using sotalol.

If you need to have any type of surgery, tell the surgeon that you are using sotalol. You may need to briefly stop using sotalol before having surgery.

Store sotalol at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. If your next dose is less than 8 hours away, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take 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.

Overdose symptoms may include slow or fast heartbeats, shortness of breath, chest pain, swelling, hunger, weakness, confusion, sweating, feeling light-headed, fainting, or seizure (convulsions).

What should I avoid while taking Sorine (sotalol)?

Do not take an antacid within 2 hours before or after taking sotalol. Avoid using antacids without your doctor's advice. Use only the specific type of antacid your doctor recommends. Antacids contain different medicines and some types can make it harder for your body to absorb sotalol.

Sorine (sotalol) 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. Call your doctor at once if you have any of these serious side effects:

fast or pounding heartbeat, chest pain, shortness of breath;

feeling light-headed, fainting;

slow heartbeat;

unusual sweating, increased thirst; or

swelling, rapid weight gain.

Less serious side effects may include:

mild diarrhea, nausea, vomiting;

headache;

sleep problems (insomnia); or

tired feeling.

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

What other drugs will affect Sorine (sotalol)?

Tell your doctor about all other medications you use, especially:

clonidine (Catapres);

digoxin (digitalis, Digitek, Lanoxicaps, Lanoxin);

reserpine;

a diuretic (water pill);

drugs that can affect heart rhythm, such as cisapride (Propulsid), droperidol (Inapsine), methadone (Methadose), pentamidine (NebuPent, Pentam);

any other heart rhythm medications, especially amiodarone (Cordarone, Pacerone), dofetilide (Tikosyn), disopyramide (Norpace), procainamide (Procan), quinidine (Quinaglute, Quinidex, Quin-Release);

antibiotics such as azithromycin (Zithromax), clarithromycin (Biaxin), erythromycin (E-Mycin, E.E.S., Erythrocin, Ery-Tab), telithromycin (Ketek);

medicines to treat psychiatric disorder, such as pimozide (Orap), haloperidol (Haldol), thioridazine (Mellaril);

a phenothiazine such as chlorpromazine (Thorazine), thioridazine (Mellaril), fluphenazine (Permitil, Prolixin), perphenazine (Trilafon), prochlorperazine (Compazine), trifluoperazine (Stelazine);

an antidepressant such as amitriptyline (Elavil, Vanatrip), doxepin (Sinequan), desipramine (Norpramin), imipramine (Janimine, Tofranil), nortriptyline (Pamelor), and others;

a diabetes medication such as insulin, glyburide (Diabeta, Micronase, Glynase), glipizide (Glucotrol), chlorpropamide (Diabinese), metformin (Glucophage);

a calcium channel blocker such as diltiazem (Cartia, Cardizem), felodipine (Plendil), nifedipine (Nifedical, Procardia), verapamil (Calan, Covera, Isoptin, Verelan), and others; or

medicine for asthma other breathing disorders, such as albuterol (Ventolin, Proventil), metaproterenol (Alupent), pirbuterol (Maxair), terbutaline (Brethaire, Brethine, Bricanyl), and theophylline (Elixophyllin, Theo-24, Uniphyl).

This list is not complete and there may be other drugs that can interact with sotalol. 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 Sorine resources

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

Sorine Advanced Consumer (Micromedex) - Includes Dosage Information

Sorine Prescribing Information (FDA)

Sotalol Prescribing Information (FDA)

Betapace Prescribing Information (FDA)

Betapace MedFacts Consumer Leaflet (Wolters Kluwer)

Betapace AF MedFacts Consumer Leaflet (Wolters Kluwer)

Betapace AF Prescribing Information (FDA)

Sotalol Hydrochloride Monograph (AHFS DI)

Compare Sorine with other medications

Ventricular Arrhythmia

Where can I get more information?

Your pharmacist can provide more information about sotalol.

See also: Sorine side effects (in more detail)

Sunday 17 June 2012

Faramsil 400 microgram Prolonged-release Tablets

1. Name Of The Medicinal Product

Faramsil 400 microgram Prolonged-release Tablets

2. Qualitative And Quantitative Composition

Each film-coated prolonged-release tablet contains 0.4 mg tamsulosin hydrochloride.

Excipient(s):

Each film-coated prolonged-release tablet contains 18.75 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated prolonged-release tablet

Round, bi-convex, brown film-coated tablet with debossing “0.4” on one side and “SZ” on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

4.2 Posology And Method Of Administration

Posology

One tablet daily can be taken independently of food.

Method of administration

For oral use.

The tablet should be swallowed whole and should not be crushed or chewed as this will interfere with the prolonged release of the active ingredient.

Special populations

Renal impairment: no dose adjustment is required in patients with renal impairment

Hepatic impairment: no dose adjustment is required in patients with mild to moderate hepatic impairment (see also section 4.3)

Paediatric population

There is no relevant indication for the use of tamsulosin in the paediatric population.

4.3 Contraindications

Hypersensitivity to tamsulosin, including drug-induced angio-oedema, or to any of the excipients.

A history of orthostatic hypotension.

Severe hepatic insufficiency.

4.4 Special Warnings And Precautions For Use

As with other alpha1-blockers, a reduction in blood pressure can occur in individual cases during treatment with tamsulosin, leading in rare cases to syncope. At the first signs of orthostatic hypotension (dizziness, weakness), the patient should sit or lie down until the symptoms have disappeared.

Prior to commencement of therapy with tamsulosin, the patient should be examined in order to exclude the presence of other conditions which may produce similar symptoms to those of benign prostatic hyperplasia. Digital rectal examination and, when necessary, determination of prostate specific antigen (PSA) should be performed prior to commencement of treatment and at regular intervals afterwards.

The treatment of patients with severe renal impairment (creatinine clearance less than 10 ml/min) should be approached with caution as these patients have not been studied.

The 'Intraoperative Floppy Iris Syndrome' (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with tamsulosin. IFIS may lead to increased procedural complications during the operation. The initiation of therapy with tamsulosin in patients scheduled for cataract surgery is not recommended.

Discontinuing tamsulosin 1-2 weeks prior to cataract surgery has been recommended, however the benefit and duration of stopping the therapy prior to cataract surgery has not yet been established.

During pre-operative assessment, cataract surgeons and ophthalmic teams should consider whether patients scheduled for cataract surgery are being or have been treated with tamsulosin in order to ensure that appropriate measures will be in place to manage the IFIS during surgery.

Tamsulosin prolonged-release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults. No interactions have been seen when tamsulosin was given concomitantly with atenolol, enalapril or theophylline. Concomitant cimetidine increases and concomitant furosemide lowers plasma levels of tamsulosin, however, as levels remain within the normal range, posology need not be changed. In vitro, neither diazepam nor propranolol, trichlormethiazide, chlormadinon, amitryptyline, diclofenac, glibenclamide, simvastatin and warfarin change the free fraction of tamsulosin in human plasma. Neither does tamsulosin change the free fractions of diazepam, propranolol, trichlormethiazide, and chlormadinon. No interactions at the level of hepatic metabolism have been seen during in vitro studies with liver microsomal fractions (representative of the cytochrome P450-linked drug metabolising enzyme system), involving amitriptyline, salbutamol, glibenclamide and finasteride. Diclofenac and warfarin, however, may increase the elimination rate of tamsulosin. There is a theoretical risk of enhanced hypotensive effect when given concomitantly with drugs which may reduce blood pressure, including anaesthetic agents and other alpha1- adrenoreceptors antagonists.

4.6 Pregnancy And Lactation

Not applicable, as tamsulosin is intended for male patients only.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However patients should be aware of the fact that drowsiness, blurred vision, dizziness and syncope can occur.

4.8 Undesirable Effects

Tamsulosin prolonged-release tablets were evaluated in two double-blind placebo controlled trials. Adverse events were mostly mild and their incidence was generally low. The most commonly reported ADR was abnormal ejaculation occurring in approximately 2% of patients.

Suspected adverse reactions reported with Tamsulosin prolonged release tablets or an alternative formulation of tamsulosin, were:

Common (

Nervous systems disorders

Common: dizziness

Uncommon: headache

Rare: syncope

Cardiac disorders

Uncommon: palpitations

Vascular disorders

Uncommon: orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon: rhinitis

Gastrointestinal disorders

Uncommon: nausea, vomiting, constipation, diarrhoea

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus, urticaria

Rare: angioedema

Very rare: Stevens-Johnson syndrome

Reproductive system and breast disorders

Common: ejaculation disorders

Very rare: priapism

General disorders

Uncommon: asthenia

As with other alpha-blockers, drowsiness, blurred vision, dry mouth or oedema can occur.

During cataract surgery a small pupil situation, known as Intraoperative Floppy Iris Syndrome (IFIS), has been associated with therapy of tamsulosin during post-marketing surveillance (see also section 4.4).

Post-marketing experience: In addition to the adverse events listed above, atrial fibrillation, arrhythmia, tachycardia and dyspnoea have been reported in association with tamsulosin use. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of tamsulosin in their causation cannot be reliably determined.

4.9 Overdose

Acute overdose with 5 mg tamsulosin hydrochloride has been reported. Acute hypotension (systolic blood pressure 70 mm Hg), vomiting and diarrhoea were observed, which were treated with fluid replacement and the patient was able to be discharged the same day. In case of acute hypotension occurring after overdose, cardiovascular support should be given. Blood pressure can be restored and heart rate brought back to normal by lying the patient down. If this is insufficient then volume expanders, and when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied. Dialysis is unlikely to be of help, as tamsulosin is very highly bound to plasma proteins.

Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Alpha adrenoceptor antagonists.

ATC code: G04C A02. Preparations for the exclusive treatment of prostatic disease.

Mechanism of action

Tamsulosin binds selectively and competitively to postsynaptic alpha1-receptors, in particular to the subtype alpha1A, resulting in relaxation of the smooth muscle of the prostate, whereby tension is reduced.

Pharmacodynamic effects

Tamsulosin increases maximum urinary flow rate by reducing smooth muscle tension in the prostate and urethra, thereby relieving obstruction.

It also improves the complex of irritative and obstructive symptoms in which bladder instability and tension of the smooth muscles of the lower urinary tract play an important role. Alpha1-blockers can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with tamsulosin.

5.2 Pharmacokinetic Properties

Absorption

Tamsulosin administered as a prolonged-release tablet is absorbed from the intestine and its bioavailability is approximately 55-59% A consistent slow release of tamsulosin is maintained over the whole pH range encountered in the gastro-intestinal tract with little fluctuation over 24 hours. The rate and extent of absorption of tamsulosin administered as a prolonged release-tablet is not affected by food intake.

Tamsulosin shows linear kinetics.

Following administration of a single dose of tamsulosin in fasting state, plasma levels of tamsulosin peak at a median time of 6 hours. At steady state, which is reached by day 4 of multiple dosing, plasma levels of tamsulosin peak at 4 to 6 hours in fasting and fed state. Peak plasma levels increase from approximately 6 ng/ml after the first dose to 11 ng/ml at steady state.

As a result of the prolonged release characteristics of the tablet the trough concentration of tamsulosin in plasma amounts to 40% of the peak plasma concentration under fasting and fed conditions.

There is a considerable inter-patient variation in plasma levels, both after single and multiple dosing.

Distribution

In male patients, tamsulosin is about 99% bound to plasma proteins and the volume of distribution is small (about 0.2l/kg).

Metabolism

Tamsulosin has a low first pass effect, being metabolised slowly. Most tamsulosin is present in plasma in the form of unchanged drug. It is metabolised in the liver.

In rats, hardly any induction of microsomal liver enzymes was seen to be caused by tamsulosin.

None of the metabolites are more active than the original compound.

Elimination

Tamsulosin and its metabolites are mainly excreted in the urine. The urinary recovery of unchanged drug is estimated to be about 4-6% of the dose, administered as a prolonged release tablet

After a single dose of tamsulosin, and at steady state, elimination half-life of about 19 and 15 hours, respectively, has been measured.

5.3 Preclinical Safety Data

Single and repeat dose toxicity studies were performed in mice, rats and dogs. In addition, reproduction toxicity studies were performed in rats, carcinogenicity in mice and rats, and in vivo and in vitro genotoxicity were examined.

The general toxicity profile, as seen with high doses of tamsulosin, is consistent with the known pharmacological actions of the alpha-adrenergic blocking agents. At very high dose levels, the ECG was altered in dogs. This response is considered to be clinically irrelevant. Tamsulosin showed no relevant genotoxic properties.

Increased incidences of proliferative changes of mammary glands of female rats and mice have been reported. These findings appeared to be related to hyperprolactinaemia and only occurred at high dose levels, are regarded as irrelevant.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core

Cellulose, microcrystalline

Hydroxypropylcellulose

Lactose monohydrate

Polyethylene oxide

Butylhydroxytoluene

Magnesium stearate

Silica, colloidal anhydrous

Tablet film-coating

Hypromellose

Hydroxypropylcellulose

Macrogol 400

Titanium dioxide (E 171)

Talc

Quinoline yellow (E 104)

Carmine (E 120)

Iron oxide, black (E 172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Store in the original package.

6.5 Nature And Contents Of Container

Aluminium//Aluminium blisters.

Pack sizes: 10, 14, 20, 28, 30, 50, 56, 60, 80, 90, 100 and 200 film-coated prolonged-release tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Sandoz Ltd

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. Marketing Authorisation Number(S)

PL 04416/0987

9. Date Of First Authorisation/Renewal Of The Authorisation

14/07/2011

10. Date Of Revision Of The Text

14/07/2011

Saturday 16 June 2012

Immunologic agents

Immunologic agents are drugs that can modify the immune response, either by enhancing or suppressing the immune system. They are used to fight infections, prevent and treat certain diseases.

Immunologic agents include drugs used for immunosuppression to prevent graft rejection. They can be used as cancer chemotherapy agents. Some immunologic agents can down-regulate the inflammatory process and can be used to treat inflammatory conditions such as rheumatoid arthritis, autoimmune conditions and so on.

Wednesday 13 June 2012

Pletal

Generic Name: cilostazol

Dosage Form: tablet
Pletal®

(PLAY-tal)

(cilostazol) (sil-OS-tah-zol)

Tablets

CONTRAINDICATION

Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV congestive heart failure. Pletal is contraindicated in patients with congestive heart failure of any severity.

Pletal Description

Pletal (cilostazol) is a quinolinone derivative that inhibits cellular phosphodiesterase (more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.

The structural formula is:

Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in methanol and ethanol, and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.

Pletal (cilostazol) tablets for oral administration are available in 50 mg triangular and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: carboxymethylcellulose calcium, corn starch, hydroxypropyl methylcellulose 2910, magnesium stearate, and microcrystalline cellulose.

Pletal - Clinical Pharmacology

Mechanism of Action

The mechanism of the effects of Pletal on the symptoms of intermittent claudication is not fully understood. Pletal and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.

Pletal reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress. Effects on circulating plasma lipids have been examined in patients taking Pletal. After 12 weeks, as compared to placebo, Pletal 100 mg b.i.d. produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4.0 mg/dL (~10%).

Cardiovascular Effects

Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid or superior mesenteric arteries. Renal arteries were not responsive to the effects of cilostazol.

In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with Holter monitors, numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained ventricular tachycardia events than did placebo-treated patients; the increases were not dose-related.

Pharmacokinetics

Pletal is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of Pletal. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).

The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of Pletal 100 mg b.i.d. is shown below:

Distribution

Plasma Protein and Erythrocyte Binding

Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.

Metabolism and Excretion

Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are CYP3A4 and, to a lesser extent, CYP2C19. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.

Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.

Special Populations

Age and Gender

The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50-to-80-year-old age range.

Smokers

Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.

Hepatic Impairment

The pharmacokinetics of cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared to healthy subjects.

Patients with moderate or severe hepatic impairment have not been studied.

Renal Impairment

The total pharmacologic activity of cilostazol and its metabolites was similar in subjects with mild to moderate renal impairment and in normal subjects. Severe renal impairment increases metabolite levels and alters protein binding of the parent and metabolites. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibiting potency of parent drug and metabolites, appeared little changed. Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95-98%).

Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions

Cilostazol could have pharmacodynamic interactions with other inhibitors of platelet function and pharmacokinetic interactions because of effects of other drugs on its metabolism by CYP3A4 or CYP2C19. A reduced dose of Pletal should be considered when taken concomitantly with CYP3A4 or CYP2C19 inhibitors. Cilostazol does not appear to inhibit CYP3A4 (see Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions, Lovastatin).

Aspirin

Short-term (≤4 days) coadministration of aspirin with Pletal increased the inhibition of ADP-induced ex vivo platelet aggregation by 22%-37% when compared to either aspirin or Pletal alone. Short-term (≤4 days) coadministration of aspirin with Pletal increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to Pletal alone and by 48% compared to aspirin alone. However, short-term coadministration of aspirin with Pletal had no clinically significant impact on PT, aPTT, or bleeding time compared to aspirin alone. Effects of long-term coadministration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was coadministered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75-81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.

Warfarin

The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2, and CYP2C19, and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time, or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and Pletal on the pharmacokinetics and pharmacodynamics of both drugs is unknown.

Clopidogrel

Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.

Inhibitors of CYP3A4

Strong Inhibitors of CYP3A4

A priming dose of ketoconazole 400 mg (a strong inhibitor of CYP3A4), was given one day prior to coadministration of single doses of ketoconazole 400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, and sertraline, would be expected to have a similar effect (see DOSAGE AND ADMINISTRATION).

Moderate Inhibitors of CYP3A4

Erythromycin and other macrolide antibiotics: Erythromycin is a moderately strong inhibitor of CYP3A4. Coadministration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., clarithromycin), but not all (e.g., azithromycin), would be expected to have a similar effect (see DOSAGE AND ADMINISTRATION).

Diltiazem: Diltiazem 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40% (see DOSAGE AND ADMINISTRATION).

Grapefruit Juice: Grapefruit juice increased the Cmax of cilostazol by ~50%, but had no effect on AUC.

Inhibitors of CYP2C19

Omeprazole

Coadministration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole's potent inhibition of CYP2C19 (see DOSAGE AND ADMINISTRATION).

Quinidine

Concomitant administration of quinidine with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.

Lovastatin

The concomitant administration of lovastatin with cilostazol decreases cilostazol Css, max and AUCτ by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Coadministration of cilostazol with lovastatin increases lovastatin and β-hydroxi lovastatin AUC approximately 70%. This is most likely clinically insignificant.

Clinical Studies

The ability of Pletal to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks' duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998), and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.

Compared to patients treated with placebo, patients treated with Pletal 50 or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of Pletal on walking distance was seen as early as the first on-therapy observation point of two or four weeks.

The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.

Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with Pletal 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.

The corresponding changes in the placebo group were –10% to 41%.

The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either Pletal 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age, and concomitant use of beta blockers or calcium channel blockers. Pletal has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers, or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.

A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8 to 8.4%) on cilostazol and 6.8% (95% CI of 1.9 to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which is the a priori study hypothesis.

Indications and Usage for Pletal

Pletal is indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance.

Contraindications

Pletal is contraindicated in patients with haemostatic disorders or active pathologic bleeding, such as bleeding peptic ulcer and intracranial bleeding. Pletal inhibits platelet aggregation in a reversible manner.

Pletal is contraindicated in patients with known or suspected hypersensitivity to any of its components.

Precautions

Hematologic adverse reactions

Rare cases have been reported of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.

Use with Clopidogrel

There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and clopidogrel, a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and clopidogrel, caution is advised for checking bleeding times during coadministration.

Information for Patients

Please refer to the patient package insert.

Patients should be advised:

to read the patient package insert for Pletal carefully before starting therapy and to reread it each time therapy is renewed in case the information has changed.

to take Pletal at least one-half hour before or two hours after food.

that the beneficial effects of Pletal on the symptoms of intermittent claudication may not be immediate. Although the patient may experience benefit in 2 to 4 weeks after initiation of therapy, treatment for up to 12 weeks may be required before a beneficial effect is experienced.

Hepatic Impairment

Patients with moderate or severe hepatic impairment have not been studied in clinical trials.

Special caution is advised when Pletal is used in such patients.

Renal Impairment

Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95-98%).

Special caution is advised when Pletal is used in patients with severe renal impairment: estimated creatinine clearance <25 ml/min.

Drug Interactions

Since Pletal is extensively metabolized by cytochrome P-450 isoenzymes, caution should be exercised when Pletal is coadministered with inhibitors of CYP3A4 such as ketoconazole and erythromycin or inhibitors of CYP2C19 such as omeprazole. Pharmacokinetic studies have demonstrated that omeprazole and erythromycin significantly increased the systemic exposure of cilostazol and/or its major metabolites. Population pharmacokinetic studies showed higher concentrations of cilostazol among patients concurrently treated with diltiazem, an inhibitor of CYP3A4 (see CLINICAL PHARMACOLOGY, Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions). Pletal does not, however, appear to cause increased blood levels of drugs metabolized by CYP3A4, as it had no effect on lovastatin, a drug with metabolism very sensitive to CYP3A4 inhibition.

Use with other antiplatelet agents

Pletal inhibits platelet aggregation but in a reversible manner. Caution is advised in patients at risk of bleeding from surgery or pathologic processes. Platelet aggregability returns to normal within 96 hours of stopping Pletal. Caution is advised in patients receiving both Pletal and any other antiplatelet agent, or in patients with thrombocytopenia.

Cardiovascular Toxicity

Repeated oral administration of cilostazol to dogs (30 or more mg/kg/day for 52 weeks, 150 or more mg/kg/day for 13 weeks, and 450 mg/kg/day for 2 weeks), produced cardiovascular lesions that included endocardial haemorrhage, hemosiderin deposition and fibrosis in the left ventricle, haemorrhage in the right atrial wall, haemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery, and coronary arteritis and periarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, systemic exposure (AUC) to unbound cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mg b.i.d. Similar lesions have been reported in dogs following the administration of other positive inotropic agents (including PDE III inhibitors) and/or vasodilating agents. No cardiovascular lesions were seen in rats following 5 or 13 weeks of administration of cilostazol at doses up to 1500 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at the MRHD. Cardiovascular lesions were also not seen in rats following 52 weeks of administration of cilostazol at doses up to 150 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were about 0.5 and 5 times (male and female rats, respectively) the exposure in humans at the MRHD. In female rats, cilostazol AUCs were similar at 150 and 1500 mg/kg/day. Cardiovascular lesions were also not observed in monkeys after oral administration of cilostazol for 13 weeks at doses up to 1800 mg/kg/day. While this dose of cilostazol produced pharmacologic effects in monkeys, plasma cilostazol levels were less than those seen in humans given the MRHD, and those seen in dogs given doses associated with cardiovascular lesions.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.

Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males, and about 5 times in females, the exposure in humans at the MRHD.

Pregnancy

Pregnancy Category C

In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights, and increased incidences of cardiovascular, renal, and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib, and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD, and exposure to 3,4-dehydro-cilostazol was barely detectable.

When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).

There are no adequate and well-controlled studies in pregnant women.

Nursing Mothers

Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue Pletal.

Pediatric Use

The safety and effectiveness of Pletal in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects (n=2274) in clinical studies of Pletal, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites.

Adverse Reactions

Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. Pletal (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on Pletal and 134 days for patients on placebo.

The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with Pletal 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with Pletal 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for cilostazol (all doses) versus 0.1% for placebo.

The most commonly reported adverse events, occurring in ≥2% of patients treated with Pletal 50 or 100 mg b.i.d., are shown in the table (below).

Other events seen with an incidence of ≥2%, but occurring in the placebo group at least as frequently as in the 100 mg b.i.d. group were: asthenia, hypertension, vomiting, leg cramps, hypesthesia, paresthesia, dyspnea, rash, hematuria, urinary tract infection, flu syndrome, angina pectoris, arthritis, and bronchitis.

Most Commonly Reported AEs (Incidence ≥2%) in Patients on Pletal (PLT) 50 mg b.i.d. or 100 mg b.i.d. and Occurring at a Rate in the 100 mg b.i.d. Group Higher Than in Patients on Placebo
Adverse Events (AEs) by Body System	PLT 50 mg b.i.d. (N=303) %	PLT 100 mg b.i.d. (N=998) %	Placebo (N=973) %
BODY AS A WHOLE
Abdominal pain	4	5	3
Back pain	6	7	6
Headache	27	34	14
Infection	14	10	8
CARDIOVASCULAR
Palpitation	5	10	1
Tachycardia	4	4	1
DIGESTIVE
Abnormal stools	12	15	4
Diarrhea	12	19	7
Dyspepsia	6	6	4
Flatulence	2	3	2
Nausea	6	7	6
METABOLIC & NUTRITIONAL
Peripheral edema	9	7	4
MUSCULO-SKELETAL
Myalgia	2	3	2
NERVOUS
Dizziness	9	10	6
Vertigo	3	1	1
RESPIRATORY
Cough increased	3	4	3
Pharyngitis	7	10	7
Rhinitis	12	7	5

Less frequent adverse events (<2%) that were experienced by patients exposed to Pletal 50 mg b.i.d. or 100 mg b.i.d. in the eight controlled clinical trials and that occurred at a frequency in the 100 mg b.i.d. group greater than in the placebo group, regardless of suspected drug relationship, are listed below.

Body as a whole: Chills, face edema, fever, generalized edema, malaise, neck rigidity, pelvic pain, retroperitoneal haemorrhage.

Cardiovascular: Atrial fibrillation, atrial flutter, cerebral infarct, cerebral ischemia, congestive heart failure, heart arrest, haemorrhage, hypotension, myocardial infarction, myocardial ischemia, nodal arrhythmia, postural hypotension, supraventricular tachycardia, syncope, varicose vein, vasodilation, ventricular extrasystoles, ventricular tachycardia.

Digestive: Anorexia, cholelithiasis, colitis, duodenal ulcer, duodenitis, esophageal haemorrhage, esophagitis, increased GGT, gastritis, gastroenteritis, gum haemorrhage, hematemesis, melena, peptic ulcer, periodontal abscess, rectal haemorrhage, stomach ulcer, tongue edema.

Endocrine: Diabetes mellitus.

Hemic and Lymphatic: Anemia, ecchymosis, iron deficiency anemia, polycythemia, purpura.

Metabolic and Nutritional: Increased creatinine, gout, hyperlipemia, hyperuricemia.

Musculoskeletal: Arthralgia, bone pain, bursitis.

Nervous: Anxiety, insomnia, neuralgia.

Respiratory: Asthma, epistaxis, hemoptysis, pneumonia, sinusitis.

Skin and Appendages: Dry skin, furunculosis, skin hypertrophy, urticaria.

Special Senses: Amblyopia, blindness, conjunctivitis, diplopia, ear pain, eye haemorrhage, retinal haemorrhage, tinnitus.

Urogenital: Albuminuria, cystitis, urinary frequency, vaginal haemorrhage, vaginitis.

Post-Marketing Experience

The following events have been reported spontaneously from worldwide post-marketing experience since the launch of Pletal in the US.

Blood and lymphatic system disorders:
-

Agranulocytosis, aplastic anemia, granulocytopenia, pancytopenia, thrombocytopenia, leukopenia, bleeding tendency

Cardiac disorders:
-

Torsades de pointes, QTc prolongation (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. complete atrioventricular block, cardiac failure and bradyarrythmia, when treated with cilostazol. Cilostazol was used "off label" due to its positive chronotropic action)

Gastrointestinal disorders:
-

Gastrointestinal haemorrhage

General disorders and administration site conditions:
-

Pain, chest pain, hot flushes

Hepatobiliary disorders:
-

Hepatic dysfunction/abnormal liver function tests, jaundice

Injury, poisoning and procedural complications:
-

Extradural haematoma and subdural haematoma

Investigations:
-

Blood glucose increased, blood uric acid increased, platelet count decreased, white blood cell count decreased, increase in BUN (blood urea increased), blood pressure increase

Nervous system disorders:
-

Intracranial haemorrhage, cerebral haemorrhage, cerebrovascular accident

Respiratory, thoracic and mediastinal disorders:
-

Pulmonary haemorrhage, interstitial pneumonia

Skin and subcutaneous tissue disorders:
-

Haemorrhage subcutaneous, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa)

Vascular disorders:
-

Subacute thrombosis (these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)

Overdosage

Information on acute overdosage with Pletal in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by hemodialysis or peritoneal dialysis. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.

DOSAGE AND ADMINISTRATION

The recommended dosage of Pletal is 100 mg b.i.d. taken at least half an hour before or two hours after breakfast and dinner. A dose of 50 mg b.i.d. should be considered during coadministration of such inhibitors of CYP3A4 as ketoconazole, itraconazole, erythromycin and diltiazem, and during coadministration of such inhibitors of CYP2C19 as omeprazole.

Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.

Discontinuation of Therapy

The available data suggest that the dosage of Pletal can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).

How is Pletal Supplied

Pletal is supplied as 50 mg and 100 mg tablets. The 50 mg tablets are white, triangular, debossed with Pletal 50, and provided in bottles of 60 tablets (NDC #59148-003-16).

The 100 mg tablets are white, round, debossed with Pletal 100, and provided in bottles of 60 tablets (NDC #59148-002-16).

Rx ONLY.

STORAGE

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

Manufactured for

OTSUKA AMERICA PHARMACEUTICAL, INC.

Rockville, MD 20850

Manufactured by

OTSUKA PHARMACEUTICAL CO., LTD.

Tokushima 771-0192, Japan

0207L-0002

May 2007

U.S. Patent No. 4,277,479

PRINCIPAL DISPLAY PANEL - 50mg Bottle Label

NDC 59148-003-16

Tablets

Pletal®

(cilostazol)

50mg

OTSUKA AMERICA

PHARMACEUTICAL, INC.

60 TABLETS

PRINCIPAL DISPLAY PANEL - 100mg Bottle Label

NDC 59148-002-16

Tablets

Pletal®

(cilostazol)

100mg

OTSUKA AMERICA

PHARMACEUTICAL, INC.

60 TABLETS

Pletal
cilostazol tablet

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	59148-003
Route of Administration	ORAL	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
cilostazol (cilostazol)	cilostazol	50 mg

Inactive Ingredients
Ingredient Name	Strength
carboxymethylcellulose calcium
starch, corn
carboxymethylcellulose
magnesium stearate
cellulose, microcrystalline

Product Characteristics
Color	WHITE	Score	no score
Shape	TRIANGLE	Size	7mm
Flavor		Imprint Code	Pletal;50
Contains

Packaging
#	NDC	Package Description	Multilevel Packaging
1	59148-003-16	60 TABLET In 1 BOTTLE, PLASTIC	None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA020863	01/15/1999

Pletal
cilostazol tablet

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	59148-002
Route of Administration	ORAL	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
cilostazol (cilostazol)	cilostazol	100 mg

Inactive Ingredients
Ingredient Name	Strength
carboxymethylcellulose calcium
starch, corn
carboxymethylcellulose
magnesium stearate
cellulose, microcrystalline

Product Characteristics
Color	WHITE	Score	no score
Shape	ROUND	Size	8mm
Flavor		Imprint Code	Pletal;100
Contains

Packaging
#	NDC	Package Description	Multilevel Packaging
1	59148-002-16	60 TABLET In 1 BOTTLE, PLASTIC	None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA020863	01/15/1999

Labeler - Otsuka America Pharmaceutical, Inc. (008314390)

Establishment
Name	Address	ID/FEI	Operations
Otsuka Pharmaceutical Co., Ltd.		695733295	MANUFACTURE

Revised: 11/2007Otsuka America Pharmaceutical, Inc.

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DESCRIPTION

CLINICAL PHARMACOLOGY

Pharmacokinetics

INDICATIONS AND USAGE

CONTRAINDICATIONS

WARNINGS

PRECAUTIONS

General

Information for Patients

Drug Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy Category C

Nursing Mothers

Pediatric Use

ADVERSE REACTIONS

OVERDOSAGE

Acute Toxicity

Signs and Symptoms

Treatment

DOSAGE AND ADMINISTRATION

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Dosage Chart for Ambulatory Patients

Hospitalized Patients

Combination Therapy

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