Feldene

piroxicam

Dosage Form: capsule
Feldene®

(piroxicam)

CAPSULES

10 mg and 20 mg

For Oral Use

Cardiovascular Risk

• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).


• Feldene® is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk

• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

Feldene Description

Feldene® contains piroxicam which is a member of the oxicam group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each maroon and blue capsule contains 10 mg piroxicam, each maroon capsule contains 20 mg piroxicam for oral administration. The chemical name for piroxicam is 4-hydroxyl-2-methyl-N-2-pyridinyl-2H-1,2,-benzothiazine-3-carboxamide 1,1-dioxide. Piroxicam occurs as a white crystalline solid, sparingly soluble in water, dilute acid, and most organic solvents. It is slightly soluble in alcohol and in aqueous solutions. It exhibits a weakly acidic 4-hydroxy proton (pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8). The molecular weight of piroxicam is 331.35. Its molecular formula is C15H13N3O4S and it has the following structural formula:

The inactive ingredients in Feldene capsules include: Blue 1, Red 3, lactose, magnesium stearate, sodium lauryl sulfate, starch.

Feldene - Clinical Pharmacology

Pharmacodynamics

Feldene is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Feldene, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Pharmacokinetics

Absorption

Feldene is well absorbed following oral administration. Drug plasma concentrations are proportional for 10 and 20 mg doses and generally peak within three to five hours after medication. The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations throughout the day on once daily doses and to significant accumulation upon multiple dosing. A single 20 mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 mcg/mL, while maximum drug plasma concentrations, after repeated daily ingestion of 20 mg Feldene, usually stabilize at 3–8 mcg/mL. Most patients approximate steady state plasma levels within 7–12 days. Higher levels, which approximate steady state at two to three weeks, have been observed in patients in whom longer plasma half-lives of piroxicam occurred.

With food there is a slight delay in the rate but not the extent of absorption following oral administration. The concomitant administration of antacids (aluminum hydroxide or aluminum hydroxide with magnesium hydroxide) have been shown to have no effect on the plasma levels of orally administered piroxicam.

Distribution

The apparent volume of distribution of piroxicam is approximately 0.14 L/kg. Ninety-nine percent of plasma piroxicam is bound to plasma proteins. Piroxicam is excreted into human milk. The presence in breast milk has been determined during initial and long-term conditions (52 days). Piroxicam appeared in breast milk at about 1% to 3% of the maternal concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment.

Metabolism

Metabolism of piroxicam occurs by hydroxylation at the 5 position of the pyridyl side chain and conjugation of this product; by cyclodehydration; and by a sequence of reactions involving hydrolysis of the amide linkage, decarboxylation, ring contraction, and N-demethylation. In vitro studies indicate cytochrome P4502C9 (CYP2C9) as the main enzyme involved in the formation to the 5'-hydroxy-piroxicam, the major metabolite (see Pharmacogenetics, and Special Populations, Poor Metabolizers of CYP2C9 Substrates). The biotransformation products of piroxicam metabolism are reported to not have any anti-inflammatory activity.

Higher systemic exposure of piroxicam has been noted in subjects with CYP2C9 polymorphisms compared to normal metabolizer type subjects (see Pharmacogenetics, and Special Populations, Poor Metabolizers of CYP2C9 Substrates).

Excretion

Feldene and its biotransformation products are excreted in urine and feces, with about twice as much appearing in the urine as in the feces. Approximately 5% of a Feldene dose is excreted unchanged. The plasma half-life (T½) for piroxicam is approximately 50 hours.

Pharmacogenetics

CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from one published report that included nine subjects each with heterozygous CYP2C9*1/*2 and CYP2C9*1/*3 genotypes and one subject with the homozygous CYP2C9*3/*3 genotype showed piroxicam systemic levels that were 1.7-, 1.7- and 5.3-fold, respectively, higher compared to the 17 subjects with CYP2C9*1/*1 or normal metabolizer genotype. The pharmacokinetics of piroxicam have not been evaluated in subjects with other CYP2C9 polymorphisms, such as *5, *6, *9 and *11. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3% to 1.0% in various ethnic groups.

Special Populations

Pediatric

Feldene has not been investigated in pediatric patients.

Race

Pharmacokinetic differences due to race have not been identified.

Hepatic Insufficiency

The effects of hepatic disease on Feldene pharmacokinetics have not been established. However, a substantial portion of Feldene elimination occurs by hepatic metabolism. Consequently, patients with hepatic disease may require reduced doses of Feldene as compared to patients with normal hepatic function.

Poor Metabolizers of CYP2C9 Substrates

Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin) should be administered piroxicam with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Renal Insufficiency

Feldene pharmacokinetics have been investigated in patients with renal insufficiency. Studies indicate patients with mild to moderate renal impairment may not require dosing adjustments. However, the pharmacokinetic properties of Feldene in patients with severe renal insufficiency or those receiving hemodialysis are not known.

Other Information

In controlled clinical trials, the effectiveness of Feldene has been established for both acute exacerbations and long-term management of rheumatoid arthritis and osteoarthritis.

The therapeutic effects of Feldene are evident early in the treatment of both diseases with a progressive increase in response over several (8–12) weeks. Efficacy is seen in terms of pain relief and, when present, subsidence of inflammation.

Doses of 20 mg/day Feldene display a therapeutic effect comparable to therapeutic doses of aspirin, with a lower incidence of minor gastrointestinal effects and tinnitus.

Feldene has been administered concomitantly with fixed doses of gold and corticosteroids. The existence of a "steroid-sparing" effect has not been adequately studied to date.

Indications and Usage for Feldene

Carefully consider the potential benefits and risks of Feldene and other treatment options before deciding to use Feldene. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Feldene is indicated:

• For relief of the signs and symptoms of osteoarthritis.


• For relief of the signs and symptoms of rheumatoid arthritis.

Contraindications

Feldene is contraindicated in patients with active peptic ulcerations.

Feldene is contraindicated in patients with known hypersensitivity to piroxicam.

Feldene should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting Asthma).

Feldene is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Feldene is contraindicated in patients with severe renal and hepatic failure.

Feldene is contraindicated in patients with severe heart failure.

Warnings

CARDIOVASCULAR EFFECTS

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including Feldene, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Feldene, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. Feldene should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including Feldene, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months, and in about 2–4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and, therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

No information is available from controlled clinical studies regarding the use of Feldene in patients with advanced renal disease. Therefore, treatment with Feldene is not recommended in these patients with advanced renal disease. If Feldene therapy must be initiated, close monitoring of the patient's renal function is advisable.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Feldene. Feldene should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including Feldene, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Other Hypersensitivity Reactions

A combination of dermatological and/or allergic signs and symptoms suggestive of serum sickness have occasionally occurred in conjunction with the use of Feldene. These include arthralgias, pruritus, fever, fatigue, and rash including vesiculobullous reactions and exfoliative dermatitis.

Pregnancy

In late pregnancy, as with other NSAIDs, Feldene should be avoided because it may cause premature closure of the ductus arteriosus.

Precautions

General

Feldene cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of Feldene in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including Feldene. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with Feldene. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Feldene should be discontinued (see ADVERSE REACTIONS).

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including Feldene. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Feldene, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Feldene who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Ophthalmologic Effects

Because of reports of adverse eye findings with nonsteroidal anti-inflammatory agents, it is recommended that patients who develop visual complaints during treatment with Feldene have ophthalmic evaluations.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Feldene should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Information for Patients

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

• Feldene, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, CARDIOVASCULAR EFFECTS).


• Feldene, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).


• Feldene, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.


• Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.


• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.


• Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).


• In late pregnancy, as with other NSAIDs, Feldene should be avoided because it may cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding. Patients on long term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.), or if abnormal liver tests persist or worsen, Feldene should be discontinued.

Drug Interactions

Highly Protein Bound Drugs

Feldene is highly protein bound and, therefore, might be expected to displace other protein bound drugs. Physicians should closely monitor patients for a change in dosage requirements when administering Feldene to patients on other highly protein bound drugs.

Aspirin

When Feldene is administered with aspirin, its protein binding is reduced, although the clearance of free Feldene is not altered. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when Feldene is administered (20 mg/day) in conjunction with aspirin (3900 mg/day). The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of piroxicam and aspirin is not generally recommended because of the potential for increased adverse effects.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

ACE-Inhibitors

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Diuretics

Clinical studies, as well as postmarketing observations, have shown that Feldene can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well as to assure diuretic efficacy.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Warfarin

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Subacute, acute, and chronic toxicity studies have been carried out in rats, mice, dogs, and monkeys. The pathology most often seen was that characteristically associated with the animal toxicology of anti-inflammatory agents: renal papillary necrosis (see PRECAUTIONS) and gastrointestinal lesions.

Reproductive studies revealed no impairment of fertility in animals.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Feldene is not recommended for use in pregnant women since safety has not been established in humans. Feldene should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. In animal studies of Feldene, gastrointestinal tract toxicity was increased in pregnant females in the last trimester of pregnancy compared to nonpregnant females or females in earlier trimesters of pregnancy.

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Feldene on labor and delivery in pregnant women are unknown.

Nursing Mothers

Piroxicam is excreted into human milk. The presence in breast milk has been determined during initial and long-term conditions (52 days). Piroxicam appeared in breast milk at about 1% to 3% of the maternal concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment. Feldene is not recommended for use in nursing mothers.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

As with any NSAID, caution should be exercised in treating the elderly (65 years and older). Most spontaneous reports of fatal GI events with NSAIDs are in the elderly or debilitated patients and, therefore, care should be taken in treating this population. In addition to a past history of ulcer disease, older age and poor general health status (among other factors) may increase the risk for GI bleeding. To minimize the potential risk of an adverse GI event, the lowest effective dose should be used for the shortest possible duration (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation).

As with all other NSAIDs, there is a risk of developing renal toxicity in patients in which renal prostaglandins have a compensatory role in maintenance of renal perfusion. Discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state (see Warnings: Renal Effects).

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting a greater frequency of impaired drug elimination and of concomitant disease or other drug therapy.

Adverse Reactions

In patients taking Feldene or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1–10% of patients are:

 

Cardiovascular System: Edema.

 

Digestive System: Anorexia, abdominal pain, constipation, diarrhea, dyspepsia, elevated liver enzymes, flatulence, gross bleeding/perforation, heartburn, nausea, ulcers (gastric/duodenal), vomiting.

 

Hemic and Lymphatic System: Anemia, increased bleeding time.

 

Nervous System: Dizziness, headache.

 

Skin and Appendages: Pruritus, rash.

 

Special Senses: Tinnitus.

 

Urogenital System: Abnormal renal function.

Additional adverse experiences reported occasionally include:

 

Body As a Whole: Fever, infection, sepsis.

 

Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope.

 

Digestive System: Dry mouth, esophagitis, gastritis, glossitis, hematemesis, hepatitis, jaundice, melena, rectal bleeding, stomatitis.

 

Hemic and Lymphatic System: Ecchymosis, eosinophilia, epistaxis, leukopenia, purpura, petechial rash, thrombocytopenia.

 

Metabolic and Nutritional: Weight changes.

 

Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo.

 

Respiratory System: Asthma, dyspnea.

 

Skin and Appendages: Alopecia, bruising, desquamation, erythema, photosensitivity, sweat.

 

Special Senses: Blurred vision.

 

Urogenital System: Cystitis, dysuria, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, oliguria/polyuria, proteinuria, renal failure.

Other adverse reactions which occur rarely are:

 

Body As a Whole: Anaphylactic reactions, appetite changes, death, flu-like syndrome, pain (colic), serum sickness.

 

Cardiovascular System: Arrhythmia, exacerbation of angina, hypotension, myocardial infarction, palpitations, vasculitis.

 

Digestive System: Eructation, liver failure, pancreatitis.

 

Hemic and Lymphatic System: Agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia.

 

Hypersensitivity: Positive ANA.

 

Metabolic and Nutritional: Hyperglycemia, hypoglycemia.

 

Nervous System: Akathisia, convulsions, coma, hallucinations, meningitis, mood alterations.

 

Respiratory: Respiratory depression, pneumonia.

 

Skin and Appendages: Angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, onycholysis, Stevens-Johnson Syndrome, urticaria, vesiculobullous reaction.

 

Special Senses: Conjunctivitis, hearing impairment, swollen eyes.

Overdosage

Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60–100 g in adults, 1–2 g/kg in children) and/or osmotic cathartic may be indicated. The long plasma half-life of piroxicam should be considered when treating an overdose with piroxicam. Experiments in dogs have demonstrated that the use of multiple-dose treatments with activated charcoal could reduce the half-life of piroxicam by more than 50% and systemic bioavailability by as much as 37% when activated charcoal is given as late as 6 hours after ingestion of piroxicam. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

Feldene Dosage and Administration

Carefully consider the potential benefits and risks of Feldene and other treatment options before deciding to use Feldene. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with Feldene, the dose and frequency should be adjusted to suit an individual patient's needs.

For the relief of rheumatoid arthritis and osteoarthritis, the recommended dose is 20 mg given orally once per day. If desired, the daily dose may be divided. Because of the long half-life of Feldene, steady-state blood levels are not reached for 7–12 days. Therefore, although the therapeutic effects of Feldene are evident early in treatment, there is a progressive increase in response over several weeks and the effect of therapy should not be assessed for two weeks.

How is Feldene Supplied

Feldene Capsules for oral administration:

Bottles of 100:        10 mg (NDC 0069-3220-66) maroon and blue #322

Bottles of 100:        20 mg (NDC 0069-3230-66) maroon #323

Rx only

LAB-0206-10.0

August 2010

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

(See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:

• with longer use of NSAID medicines


• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)."

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:

• can happen without warning symptoms


• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• taking medicines called "corticosteroids" and "anticoagulants"


• longer use


• smoking


• drinking alcohol


• older age


• having poor health

NSAID medicines should only be used:

• exactly as prescribed


• at the lowest dose possible for your treatment


• for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

• different types of arthritis


• menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine


• for pain right before or after heart bypass surgery

Tell your healthcare provider:

• about all of your medical conditions.


• about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.


• if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.


• if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Serious side effects include:

• heart attack


• stroke


• high blood pressure


• heart failure from body swelling (fluid retention)


• kidney problems including kidney failure


• bleeding and ulcers in the stomach and intestine


• low red blood cells (anemia)


• life-threatening skin reactions


• life-threatening allergic reactions


• liver problems including liver failure


• asthma attacks in people who have asthma

Other side effects include:

• stomach pain


• constipation


• diarrhea


• gas


• heartburn


• nausea


• vomiting


• dizziness

Get emergency help right away if you have any of the following symptoms:

• shortness of breath or trouble breathing


• chest pain


• weakness in one part or side of your body


• slurred speech


• swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

• nausea


• more tired or weaker than usual


• itching


• your skin or eyes look yellow


• stomach pain


• flu-like symptoms


• vomit blood


• there is blood in your bowel movement or it is black and sticky like tar


• unusual weight gain


• skin rash or blisters with fever


• swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.

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

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.

• Some of these NSAID medicines are sold in lower doses without a prescription (over –the –counter). Talk to your healthcare provider before using over –the –counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

Generic Name	Tradename
* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke.
Celecoxib	Celebrex
Diclofenac	Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal	Dolobid
Etodolac	Lodine, Lodine XL
Fenoprofen	Nalfon, Nalfon 200
Flurbiprofen	Ansaid
Ibuprofen	Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone)
Indomethacin	Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen	Oruvail
Ketorolac	Toradol
Mefenamic Acid	Ponstel
Meloxicam	Mobic
Nabumetone	Relafen
Naproxen	Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole)
Oxaprozin	Daypro
Piroxicam	Feldene
Sulindac	Clinoril
Tolmetin	Tolectin, Tolectin DS, Tolectin 600

This Medication Guide has been approved by the U.S. Food and Drug Administration

PRINCIPAL DISPLAY PANEL - 10 mg Capsule Bottle Label

NDC 0069-3220-66

100 Capsules

Feldene®

(piroxicam)

10 mg

Pfizer

Pfizer Labs

Division of Pfizer Inc, NY, NY 10017

PRINCIPAL DISPLAY PANEL - 20 mg Capsule Bottle Label

NDC 0069-3230-66

100 Capsules

Feldene®

(piroxicam)

20 mg

Pfizer

Pfizer Labs

Division of Pfizer Inc, NY, NY 10017

Feldene  piroxicam  capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0069-3220 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength piroxicam (piroxicam) piroxicam 10 mg

Inactive Ingredients Ingredient Name Strength FD&C blue no. 1   FD&C red no. 3   lactose   magnesium stearate   sodium lauryl sulfate

Product Characteristics Color RED (Maroon) , BLUE Score no score Shape CAPSULE Size 18mm Flavor Imprint Code Feldene;PFIZER;322 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0069-3220-66 100 CAPSULE In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA018147	05/25/1994

Feldene  piroxicam  capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0069-3230 Route of Administration ORAL

Losartan potassium 50 mg film-coated tablets (Zentiva)

1. Name Of The Medicinal Product

Losartan potassium 50 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 50 mg losartan potassium, equivalent to 45.8 mg losartan

Excipient:

Losartan 50 mg film-coated tablets: lactose

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

White, oval-shaped, film-coated tablet with a score line on both sides. The film-coated tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

• Treatment of essential hypertension in adults and in children and adolescents 6-18 years of age.

• Treatment of chronic heart failure (in patients especially cough, or contraindication. Patients with heart failure who have been stabilised with an ACE inhibitor should not be switched to losartan. The patients should have a left ventricular ejection fraction

4.2 Posology And Method Of Administration

Losartan tablets should be swallowed with a glass of water

Losartan tablets may be administered with or without food.

Hypertension

The usual starting and maintenance dose is 50 mg once daily for most patients. The maximal antihypertensive effect is attained 3-6 weeks after initiation of therapy. Some patients may receive an additional benefit by increasing the dose to 100 mg once daily (in the morning). Losartan tablets may be administered with other antihypertensive agents, especially with diuretics (e.g. hydrochlorothiazide).

Heart Failure

The usual initial dose of Losartan in patients with heart failure is 12.5 mg once daily. The dose should generally be titrated at weekly intervals (i.e. 12.5 mg daily, 25 mg daily, 50 mg daily) to the usual maintenance dose of 50 mg once daily, as tolerated by the patient.

Use in patients with intravascular volume depletion:

For patients with intravascular volume-depletion (e.g. those treated with high-dose diuretics), a starting dose of 25 mg once dailyshould be considered (see section 4.4).

Use in patients with renal impairment and haemodialysis patients:

No initial dosage adjustment is necessary in patients with renal impairment and in haemodialysis patients.

Use in patients with hepatic impairment

A lower dose should be considered for patients with a history of hepatic impairment. There is no therapeutic experience in patients with severe hepatic impairment. Therefore, losartan is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 4.4).

Use in paediatric patients

There are limited data on the efficacy and safety of losartan in children and adolescents aged 6-18 years old for the treatment of hypertension (see section 5.1). Limited pharmacokinetic data are available in hypertensive children above one month of age (see section 5.2).

For patients who can swallow tablets, the recommended dose is 25 mg once daily in patients >20 to <50 kg. In exceptional cases the dose can be increased to a maximum of 50 mg once daily. Dosage should be adjusted according to blood pressure response.

In patients >50 kg, the usual dose is 50 mg once daily. In exceptional cases the dose can be adjusted to a maximum of 100 mg once daily. Doses above 1.4 mg/kg (or in excess of 100 mg) daily have not been studied in paediatric patients.

Losartan is not recommended for use in children under 6 years old, as limited data are available in these patient groups.

It is not recommended in children with glomerular filtration rate < 30 ml/min / 1.73 m², as no data are available (see also section 4.4).

Losartan is also not recommended in children with hepatic impairment (see also section 4.4).

Use in the elderly

Although consideration should be given to initiating therapy with 25 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see section 4.4 and 6.1)

Second and third trimesters of pregnancy (see section 4.4 and 4.6)

Severe hepatic impairment

4.4 Special Warnings And Precautions For Use

Hypersensitivity

Angiooedema. Patients with a history of angiooedema (swelling of the face, lips, throat, and/or tongue) should be closely monitored (See section 4.8).

Hypotension and Electrolyte/Fluid Imbalance

Symptomatic hypotension, especially after the first dose and after increasing of the dose, may occur in patients who are volume- and/or sodium-depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. These conditions should be corrected prior to administration of Losartan; or a lower starting dose should be used (see section 4. 2). This also applies to children.

Electrolyte imbalances

Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with nephropathy, the incidence of hyperkalemia was higher in the group treated with Losartan as compared to the placebo group (see section 4.8). Therefore, the plasma concentrations of potassium as well as reatinine clearance values should be closely monitored, in particular, patients with heart failure and a reatinine Clearance between 30-50 ml/min should be closely monitored.

The concomitant use of potassium sparing diuretics, potassium supplements and potassium containing salt substitutes with losartan is not recommended (see section 4.5).

Hepatic Impairment

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with a history of hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment. Therefore losartan must not be administered in patients with severe hepatic impairment (see sections 4.2, 4.3 and 5.2).

Losartan is also not recommended in children with hepatic impairment (see section 4.2).

Renal Impairment

As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported (in particular, in patients whose renal function is dependent on the renin angiotensin aldosterone system such as those with severe cardiac insufficiency or pre-existing renal dysfunction). As with other drugs that affect the renin-angiotensin-aldosterone system, increases in blood urea and serum creatinine have also been reported in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney; these changes in renal function may be reversible upon discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Use in paediatric patients with renal impairment

Losartan is not recommended in children with glomerular filtration rate < 30ml/min/1.73 m² as no data are available (see section 4.2).

Renal function should be regularly monitored during treatment with losartan as it may deteriorate. This applies particularly when losartan is given in the presence of other conditions (fever, dehydration) likely to impair renal function.

Concomitant use of losartan and ACE-inhibitors has shown to impair renal function. Therefore, concomitant use is not recommended.

Renal transplantation

There is no experience in patients with recent kidney transplantation.

Primary hyperaldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Losartan tablets is not recommended.

Coronary heart disease and cerebrovascular disease

As with any antihypertensive agents, excessive blood pressure decrease in patients with ischaemic cardiovascular and cerebrovascular disease could result in a myocardial infarction or stroke.

Heart failure

In patients with heart failure, with or without renal impairment, there is - as with other medicinal productsacting on the renin-angiotensin system - a risk of severe arterial hypotension, and (often acute) renal impairment.

There is no sufficient therapeutic experience with losartan in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (NYHA class IV) as well as in patients with heart failure and symptomatic life threatening cardiac arrhythmias. Therefore, losartan should be used with caution in these patient groups. The combination of losartan with a beta-blocker should be used with caution (see section 5.1).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Excipients

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pregnancy

AIIRAs should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Other warnings and precautions:

As observed for antiotensin converting enzyme inhibitors, losartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Other antihypertensive agents may increase the hypotensive effects of losartan. Concomitant use with other substances inducing hypotension (like tricyclic antidepressants, antipsychotics, baclofen, and amifostine), may increase the risk of hypotension.

Losartan is predominantly metabolised by cytochrome P450 (CYP) 2C9 to the active carboxy-acid metabolite. In a clinical trial it was found that fluconazole (inhibitor of CYP2C9) decreases the exposure to the active metabolite by approximately 50%. It was found that concomitant treatment of losartan with rifampicine (inducer of metabolism enzymes) gave a 40% reduction in plasma concentration of the active metabolite. The clinical relevance of this effects is unknown. No difference in exposure was found with concomitantly treatment with fluvastatin (weak inhibitor of CYP2C9).

As with other drugs that block angiotensin II or its effects, concomitant use of other drugs which retain potassium (e.g. potassium-sparing diuretics: amiloride, triamteren, spironolactone) or may increase potassium levels (e.g. heparin), potassium supplements or salt substitutes containing potassium may lead to increases in serum potassium. Co-medication is not advisable.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Very rare cases have also been reported with angiotensin II receptor antagonists. Co-administration of lithium and losartan should be undertaken with caution. If this combination proves essential, serum lithium level monitoring is recommended during concomitant use.

When angiotensin II antagonists are administered simultaniously with NSAIDs (i.e. selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of angiotensin II antagonists or diuretics and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

4.6 Pregnancy And Lactation

Pregnancy

The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4).The use of AIIRAs is contra-indicated during the 2nd and 3rd trimesters of pregnancy (see section 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Inhibitors (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see section 4.3 and 4.4).

Lactation

Because no information is availabel regarding the use of Losartan during breastfeeding, Losartan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

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, when driving vehicles or operating machinery it must be borne in mind that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy, in particular during initiation of treatment or when the dose is increased.

4.8 Undesirable Effects

Losartan has been evaluated in clinical studies as follows:

• In controlled clinical trials in approximately 3300 adult patients 18 years of age and older for essential hypertension

• In a controlled clinical trial in 9193 hypertensive patients 55 to 80 years of age with left ventricular hypertrophy

• In a controlled clinical trial in approximately 3900 patients 20 years of age and older with chronic heart failure

• In a controlled clinical trial in 1513 type 2 diabetic patients 31 years of age and older with proteinuria

• In a controlled clinical trial in 177 hypertensive pediatric patients 6 to 16 years of age

In these clinical trials, the most common adverse event was dizziness.

The frequency of adverse events listed below is defined using the following convention:

very common (

In controlled clinical trials for essential hypertension , hypertensive patients with left ventricular hypertrophy, chronic heart failure as well as for hypertension and type 2 diabetes mellitus with renal disease, the most common adverse event was dizziness.

Hypertension

In controlled clinical trials, of approximately 3300 adult patients 18 years of age and older, for essential hypertension with losartan the following adverse events were reported

Nervous system disorders:

Common: dizziness, vertigo

Uncommon: somnolence, headache, sleep disorders

Cardiac disorders:

Uncommon: palpitations, angina pectoris

Vascular disorders:

Uncommon: symptomatic hypotension (especially in patients with intravascular volume depletion, e.g. patients with severe heart failure or under treatment with high dose diuretics), dose-related orthostatic effects, rash

Gastrointestinal disorders:

Uncommon: abdominal pain, obstipation

General disorders and administration site conditions:

Uncommon: asthenia, fatigue, oedema

Investigations:

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Losartan tablets. Elevations of ALT occurred rarely and usually resolved upon discontinuation of therapy. Hyperkalaemia (serum potassium >5.5 mmol/l) occurred in 1.5 % of patients in hypertension clinical trials.

Hypertensive patients with left ventricular hypertrophy

In a controlled clinical trial in 9193 hypertensive patients 55 to 80 years of age with left ventricular hypertrophy the following adverse events were reported:

Nervous system disorders:

common: dizziness

Ear and labyrinth disorders:

common: vertigo

General disorders and administration site conditions:

common: asthenia/fatigue

Chronic heart failure

In a controlled clinical trial in approximately 3900 patients 20 years of age and older with cardiac insufficiency the following adverse events were reported:

Nervous system disorders:

uncommon: dizziness, headache

rare: paraesthesia

Cardiac disorders:

rare: syncope, artrial fibrillation, cerebrovascular accident

Vascular disorders:

uncommon: hypotension, including orthostatic hypotension

Respiratory, thoracic and mediastinal disorders:

uncommon: dyspnoea

Gastrointestinal disorders:

uncommon: diarrhoea, nausea, vomiting

Skin and subcutanous tissue disorders:

uncommon: urticaria, pruritus, rash

General disorders and administration site conditions:

uncommon: asthenia/fatigue

Investigations:

uncommon: increase in blood urea, serum creatinine and serum potassium has been reported.

Hypertension and type 2 diabetes with renal disease

In a controlled clinical trial in 1513 type 2 diabetic patients 31 years of age and older with proteinuria (RENAAL study, see section 5.1) the most common drug-related adverse events which were reported for losartan are as follows:

Nervous system disorders:

common: dizziness

Vascular disorders:

common: hypotension

General disorders and administration site conditions:

common: asthenia/fatigue

Investigations:

common: hypoglycaemia, hyperkalaemia

The following adverse events occured more often in patients receiving losartan than placebo:

Blood and lymphatic system disorders:

not known: anaemia

Cardiac disorders:

not known: syncope, palpitations

Vascular disorders:

not known: orthostatic hypotension

Gastrointestinal disorders:

not known: diarrhoea

Muscoskeletal and connective tissue disorders:

not known: back pain

Renal and urinary disorders:

not known: urinary tract infections

General disorders and administration site conditions:

not known: flu-like symptoms

Investigations:

In a clinical study conducted in type 2 diabetic patients with nephropathy, 9.9 % of patients treated with Losartan tablets developed hyperkalaemia >5.5 mEq/l and 3.4 % of patients treated with placebo

Post-marketing experience

The following adverse events have been reported in post-marketing experience:

Blood and lymphatic system disorders:

not known: Anaemia, thrombocytopenia

very rare:thrombocytopenia

Ear and labyrinth disorders:

not known: tinnitus

Immune system disorders:

rare: hypersensitivity: anaphylactic reactions, angiooedema including swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue; in some of these patients angiooedema had been reported in the past in connection with the administration of other medicines, including ACE inhibitors; vasculitis, including Henoch-Schonlein purpura.

Nervous system disorders:

not known: migraine

Respiratory, thoracic and mediastinal disorders:

not known: cough

Gastrointestinal disorders:

not known: diarrhoea, pancreatitis

General disorders and administration site conditions:

not known: malaise

Hepatobiliary disorders:

rare: hepatitis

not known: liver function abnormalities

Skin and subcutaneous tissue disorders:

not known: urticaria, pruritus, rash, photosenstivity

Muscoskeletal and connective tissue disorders:

not known: myalgia, arthralgia, rhabdomyolysis

Reproductive system and breast disorders:

not known: erectile dysfunction/impotence

Renal and urinary disorders:

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function including renal failure have been reported in patients at risk; these changes in renal function may be reversible upon discontinuation of therapy (see section 4.4)

Investigations:

not known: hyponatraemia

Psychiatric disorders:

not known: depression

Paediatric population

The adverse experience profile for paediatric patients appears to be similar to that seen in adult patients. Data in the paediatric population are limited.

4.9 Overdose

Symptoms of intoxication

Limited data are available with regard to overdose in humans. The most likely symptoms, depending on the extent of overdose, are hypotension, tachycardia, possibly bradycardia.

Treatment of intoxication

If symptomatic hypotension should occur, supportive treatment should be instituted. Measures are depending on the time of drug intake and kind and severity of symptoms. Stabilisation of the circulatory system should be given priority. After oral intake the administration of a sufficient dose of activated charcoal is indicated. Afterwards, close monitoring of the vital parameters should be performed. Vital parameters should be corrected if necessary.

Neither losartan nor the active metabolite can by removed by haemodialysis.

5. Pharmacological Properties

Pharmacotherapeutic group: Angiotensin II Receptor Antagonists, ATC code: C09CA01

5.1 Pharmacodynamic Properties

Losartan is a synthetic oral angiotensin-II receptor (type AT₁) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin-angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT₁ receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys, and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates smooth-muscle cell proliferation.

Losartan selectively blocks the AT1 receptor. In vitro and in vivo, both losartan and its pharmacologically active carboxylic acid metabolite E-3174 block all physiologically relevant actions of angiotensin II, regardless of its source or route of synthesis.

Losartan does not have an agonist effect, nor does it block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, there is no potentiation of undesirable bradykinin-mediated effects.

During administration of losartan, removal of angiotensin II negative feedback on renin secretion leads to increased plasma-renin activity (PRA). Increases in PRA lead to increases in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective angiotensin II receptor blockade. After discontinuation of losartan, PRA and angiotensin II values fell within three days to baseline values.

Both losartan and its principal active metabolite have a far greater affinity for the AT1 receptor than for the AT2 receptor. The active metabolite is 10 to 40 times more effective than losartan on a weight for weight basis.

Hypertension studies

In controlled clinical studies, once-daily administration of losartan to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure. Measurement of blood pressure 24 hours post-dose relative to 5-6 hours post-dose demonstrated blood pressure reduction over 24 hours; the natural diurnal rhythm was retained. Blood-pressure reduction at the end of the dosing interval was approximately 70-80% of the effect seen 5-6 hours post-dose.

Discontinuation of losartan in hypertensive patients did not result in an abrupt rise in blood pressure (rebound). Despite the marked decrease in blood pressure, losartan had no clinically significant effect on heart rate.

Losartan is equally effective in males and females, and in younger (below the age of 65 years) and older hypertensive patients.

ELITE I and ELITE II Study

In the ELITE Study carried out over 48 weeks in 722 patients with heart failure (NYHA Class II-IV, no difference was observed between the patients treated with Losartan and those treated with captopril was observed with regard to the primary endpoint of a long-term change in renal function. The observation of the ELITE I Study was that, compared with captopril, Losartan reduced the mortality risk, was not confirmed in the subsequent ELITE II Study.

In the ELITE II Study Losartan 50 mg once daily (starting dose 12.5 mg, increased to 25 mg, then 50 mg once daily) was compared with captopril 50 mg three times daily (starting dose 12.5 mg, increased to 25 mg and then to 50 mg three times daily). The primary endpoint of this prospective study was the all-cause mortality.

In this study 3152 patients with heart failure (NYHA Class Il-IV) were followed for almost two years (median: 1.5 years) in order to determine whether Losartan is superior to captopril in reducing all cause mortality. The primary endpoint did not show any statistically significant difference between Losartan and captopril in reducing all-cause mortality.

In both comparator-controlled (not placebo-controlled) clinical studies on patients with heart failure the tolerability of Losartan was superior to that of captopril, measured on the basis of a significantly lower rate of discontinuations of therapy on account of adverse events and a significantly lower frequency of cough.

An increased mortality was observed in ELITE II in the small subgroup (22% of all HF patients) taking beta-blockers at baseline.

Paediatric Population

The antihypertensive effect of Losartan was established in a clinical study involving 177 hypertensive paediatric patients 6 to 16 years of age with a body weight > 20 kg and a glomerular filtration rate > 30 ml/min/1.73 m². Patients who weighed >20kg to < 50 kg received either 2.5, 25 or 50 mg of losartan daily and patients who weighed > 50 kg received either 5, 50 or 100 mg of losartan daily. At the end of three weeks, losartan administration once daily lowered trough blood pressure in a dose-dependent manner.

Overall, there was a dose-response. The dose-response relationship became very obvious in the low dose group compared to the middle dose group (period I: -6.2 mmHg vs. -11.65 mmHg), but was attenuated when comparing the middle dose group with the high dose group (period I: -11.65 mmHg vs. -12.21 mmHg). The lowest doses studied, 2.5 mg and 5 mg, corresponding to an average daily dose of 0.07 mg/kg, did not appear to offer consistent antihypertensive efficacy.

These results were confirmed during period II of the study where patients were randomized to continue losartan or placebo, after three weeks of treatment. The difference in blood pressure increase as compared to placebo was largest in the middle dose group (6.70 mm Hg middle dose vs. 5.38 mmHg high dose). The rise in trough diastolic blood pressure was the same in patients receiving placebo and in those continuing losartan at the lowest dose in each group, again suggesting that the lowest dose in each group did not have significant antihypertensive effect.

Long-term effects of losartan on growth, puberty and general development have not been studied. The long-term efficacy of antihypertensive therapy with losartan in childhood to reduce cardiovascular morbidity and mortality haves also not been established.

In hypertensive (N=60) and normotensive (N=246) children with proteinuria, the effect of losartan on proteinuria was evaluated in a 12-week placebo- and active-controlled (amlodipine) clinical study. Proteinuria was defined as urinary protein/creatinine ratio of

Overall, after 12 weeks of treatment, patients receiving losartan experienced a statistically significant reduction from baseline in proteinuria of 36% versus 1% increase in placebo/amlodipine group (p

5.2 Pharmacokinetic Properties

Absorption

Following oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites.

The systemic bioavailability of Losartan potassium is approx. 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively.

Distribution

Both losartan and its active metabolite are

Biotransformation

About 14% of an intravenously or orally administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-labelled losartan, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was seen in about one percent of individuals studied.

In addition to the active metabolite, inactive metabolites are formed.

Elimination

Plasma clearance of losartan and its active metabolite is about 600 ml/minute and 50 ml/minute, respectively. Renal clearance of losartan and its active metabolite is about 74 ml/minute and 26 ml/minute, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.

Following oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal half-life of about 2 hours and 6-9 hours, respectively. During once-daily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.

Both biliary and urinary excretion contribute to the elimination of losartan and its metabolites. Following an oral dose/intravenous administration of ¹⁴C-labeled losartan in man, about 35% / 43% of radioactivity is recovered in the urine and 58%/50% in the faeces.

Characteristics in patients

In elderly hypertensive patients the plasma concentrations of losartan and its active metabolite do not differ essentially from those found in young hypertensive patients.

In female hypertensive patients the plasma levels of losartan were up to twice as high as in male hypertensive patients, while the plasma levels of the active metabolite did not differ between men and women.

In patients with mild to moderate alcohol-induced hepatic cirrhosis, the plasma levels of losartan and its active metabolite after oral administration were respectively 5 and 1.7 times higher than in young male volunteers (see section 4.2 and 4.4).

Plasma concentrations of losartan are not altered in patients with creatinine clearance above 10 ml/minute. Compared to patients with normal renal function, the AUC for losartan is about two times higher in haemodialysis patients.

The plasma concentrations of the active metabolite are not altered in patients with renal impairment or in haemodialysis patients.

Neither losartan nor the active metabolite can be removed by haemodialysis.

Pharmacokinetics in paediatric patients

The pharmacokinetics of losartan have been investigated in 50 hypertensive paediatric patients > 1 month to < 16 years of age following once daily oral administration of approximately 0.54 to 0.77 mg/ kg of losartan (mean doses).

The results showed that the active metabolite is formed from losartan in all age groups. The results showed roughly similar pharmacokinetic parameters of losartan following oral administration in infants and toddlers, preschool children, school age children and adolescents. The pharmacokinetic parameters for the metabolite differed to a greater extent between the age groups. When comparing preschool children with adolescents these differences became statistically significant. Exposure in infants/toddlers was comparatively high.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of general pharmacology, genotoxicity and carcinogenic potential. In repeated dose toxicity studies, the administration of losartan induced a decrease in red blood cell parameters (erythrocytes, haemoglobin, haematocrit), a rise in urea-N in the serum and occasional rises in serum creatinine, a decrease in heart weight (without a histological correlate) and gastrointestinal changes (mucous membrane lesions, ulcers, erosions, haemorrhages). Like other substances that directly affect the renin-angiotensin system, losartan has been shown to induce adverse effects on late fetal development, resulting in fetal death and malformations.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core:

Lactose monohydrate

Cellulose microcrystalline

Maize starch

Croscarmellose sodium

Magnesium stearate

Film-Coat (OPADRY 20A58900 white):

Hydroxypropylcellulose

Hypromellose

Titanium dioxide E171

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 months

In-use shelf life for plastic bottle (HDPE): 12 weeks

6.4 Special Precautions For Storage

Do not store above 30°C.

6.5 Nature And Contents Of Container

Plastic bottle (HDPE) or blister pack (PVC/PE/PVDC blisters with aluminium foil lidding)

blister pack: 7, 14, 15, 21, 28, 30, 50, 56, 98, 280 (10 x 28) tablets

plastic bottle: with 30, 50, 100 tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

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

7. Marketing Authorisation Holder

Zentiva,

One Onslow Street,

Guildford,

Surrey,

GU1 4YS,

UK.

8. Marketing Authorisation Number(S)

PL 17780/0326

9. Date Of First Authorisation/Renewal Of The Authorisation

03/06/2008

10. Date Of Revision Of The Text

06 June 2011

LEGAL CATEGORY

POM

Anthraforte 2% Topical

Generic Name: anthralin (Topical route)

AN-thra-lin

Commonly used brand name(s)

In the U.S.

• Drithocreme


• Dritho-Scalp


• Psoriatec


• Zithranol-RR

In Canada

• Anthraforte 2%


• Anthraforte 3%


• Anthrascalp

Available Dosage Forms:

• Paste


• Ointment


• Cream

Therapeutic Class: Antipsoriatic

Uses For Anthraforte 2%

Anthralin is used to treat psoriasis. It may also be used to treat other skin conditions as determined by your doctor.

In the U.S., this medicine is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although this use is not included in product labeling, anthralin is used in certain patients with the following medical condition:

• Alopecia areata (patchy hair loss)

Before Using Anthraforte 2%

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

Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of anthralin in children with use in other age groups.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of anthralin in the elderly with use in other age groups.

Pregnancy

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

Breast Feeding

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

Interactions with Medicines

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

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

• Skin diseases or problems (other)—Anthralin may make the condition worse

Proper Use of anthralin

This section provides information on the proper use of a number of products that contain anthralin. It may not be specific to Anthraforte 2%. Please read with care.

Keep this medicine away from the eyes and mucous membranes, such as the mouth and the inside of the nose.

Do not apply this medicine to blistered, raw, or oozing areas of the skin or scalp.

Do not use this medicine on your face or sex organs or in the folds and creases of your skin. If you have any questions about this, check with your doctor.

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

Anthralin may be used in different ways. In some cases, it is applied at night and allowed to remain on the affected areas overnight, then washed off the next morning or before the next application. In other cases, it may be applied and allowed to remain on the affected areas for a short period of time (usually 10 to 30 minutes), then washed off. (This is called short contact treatment.) Make sure you understand exactly how you are to use this medicine. If you have any questions about this, check with your doctor.

Anthralin may cause irritation of normal skin. If it does, petrolatum may be applied to the skin or scalp around the affected areas for protection.

Apply a thin layer of anthralin to only the affected area of the skin or scalp and rub in gently and well.

Immediately after applying this medicine, wash your hands to remove any medicine that may be on them.

For patients using anthralin for short contact (usually 10 to 30 minutes) treatment:

• After applying anthralin, allow the medicine to remain on the affected area for 10 to 30 minutes or as directed by your doctor. Then remove the medicine by bathing, if the anthralin was applied to the skin, or by shampooing, if it was applied to the scalp.

For patients using the cream form of anthralin for overnight treatment:

• If anthralin cream is applied to the skin, any medicine remaining on the affected areas the next morning should be removed by bathing.


• If anthralin cream is applied to the scalp, shampoo to remove the scales and any medicine remaining on the affected areas from the previous application. Dry the hair and, after parting, rub the cream into the affected areas. Check with your doctor to see when the cream should be removed.

For patients using the ointment form of anthralin for overnight treatment:

• If anthralin ointment is applied to the skin at night, any ointment remaining on the affected areas the next morning should be removed with warm liquid petrolatum followed by bathing.


• If anthralin ointment is applied to the scalp at night, shampoo the next morning to clean the scalp.

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 psoriasis:
  
  • For cream dosage form:
    
    • Adults—Apply to the dry, affected area(s) of the skin once a day, preferably at night, or as directed by your doctor. Wash medicine off skin at the proper time.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For ointment dosage form:
    
    • Adults—Apply to the dry, affected area(s) of the skin once a day or as directed by your doctor. Wash medicine off skin at the proper time.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, apply 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.

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 Anthraforte 2%

Anthralin may stain the skin, hair, fingernails, clothing, bed linens, or bathtub or shower. The stain on the skin or hair will wear off in several weeks after you stop using this medicine. Some ways to prevent or lessen anthralin staining include:

• Wear plastic gloves when you apply this medicine.


• Avoid getting the medicine on your clothing or on bed linens. Ask your doctor if you can wear a plastic cap while sleeping if you apply your medicine to your scalp at bedtime.


• Remove any medicine on the surface of the bathtub or shower stall by immediately rinsing it with hot water after bathing or showering. Afterwards wash the bathtub or shower stall with a household cleanser to remove any remaining deposits.

Anthraforte 2% Side Effects

Anthralin has been shown to cause tumors in animals. However, there have been no reports of anthralin causing tumors in humans.

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 as soon as possible if any of the following side effects occur:

More common

• Redness or other skin irritation of treated or uninvolved skin not present before use of this medicine

Rare

• Skin rash

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.

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