Perindopril

Dosage Form: tablet
FULL PRESCRIBING INFORMATION

WARNING: AVOID USE IN PREGNANCY

When pregnancy is detected, discontinue Perindopril erbumine as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury to or death of the developing fetus [see Warnings and Precautions (5.4)].

Indications and Usage for Perindopril

Hypertension

Perindopril erbumine tablets are indicated for the treatment of patients with essential hypertension. Perindopril erbumine tablets may be used alone or given with other classes of antihypertensives, especially thiazide diuretics.

Stable Coronary Artery Disease

Perindopril erbumine tablets are indicated for treatment of patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or nonfatal myocardial infarction. Perindopril erbumine tablets can be used with conventional treatment for management of coronary artery disease, such as antiplatelet, antihypertensive or lipid-lowering therapy.

Perindopril Dosage and Administration

Hypertension

Use in Uncomplicated Hypertensive Patients: In patients with essential hypertension, the recommended initial dose is 4 mg once a day. The dose may be titrated, as needed to a maximum of 16 mg per day. The usual maintenance dose range is 4 mg to 8 mg administered as a single daily dose or in two divided doses.


Use in Elderly Patients: The recommended initial daily dosage of Perindopril erbumine tablets for the elderly is 4 mg daily, given in one or two divided doses. Experience with Perindopril erbumine tablets is limited in the elderly at doses exceeding 8 mg. Dosages above 8 mg should be administered with careful blood pressure monitoring and dose titration [see Use in Specific Populations (8.5)].


Use with Diuretics: In patients who are currently being treated with a diuretic, symptomatic hypotension can occur following the initial dose of Perindopril erbumine tablets. Consider reducing the dose of diuretic prior to starting Perindopril erbumine tablets [see Drug Interactions (7.1)].

Stable Coronary Artery Disease

In patients with stable coronary artery disease, Perindopril erbumine tablets should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased as tolerated, to a maintenance dose of 8 mg once daily. In elderly patients (greater than 70 years), Perindopril erbumine tablets should be given as a 2 mg dose once daily in the first week, followed by 4 mg once daily in the second week and 8 mg once daily for maintenance dose if tolerated.

Dose Adjustment in Renal Impairment and Dialysis

Perindoprilat elimination is decreased in renally impaired patients. Perindopril erbumine tablets are not recommended in patients with creatinine clearance <30 mL/min. For patients with lesser degrees of impairment, the initial dosage should be 2 mg/day and dosage should not exceed 8 mg/day. During dialysis, Perindopril is removed with the same clearance as in patients with normal renal function.

Dosage Forms and Strengths

2 mg tablet is white to off-white colored round biconvex, uncoated tablets, with debossing “D” on one side and “5” & “7” on either side of the breakline on another side.

 

4 mg tablet is white to off-white colored capsule shaped uncoated tablets, with debossing “D” on one side and “5” & “8” on either side of the breakline on another side.

 

8 mg tablet is white to off-white colored round biconvex uncoated tablets, with debossing “D” on one side and “5” & “9” on either side of breakline on another side.

Contraindications

Perindopril erbumine tablets are contraindicated in patients known to be hypersensitive (including angioedema) to this product or to any other ACE inhibitor. Perindopril erbumine tablets are also contraindicated in patients with hereditary or idiopathic angioedema.

Warnings and Precautions

Anaphylactoid and Possibly Related Reactions

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Perindopril erbumine) may be subject to a variety of adverse events, some of them serious. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.


Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, or larynx has been reported in patients treated with ACE inhibitors, including Perindopril erbumine (0.1% of patients treated with Perindopril erbumine in U.S. clinical trials). Angioedema associated with involvement of the tongue, glottis or larynx may be fatal. In such cases, discontinue Perindopril erbumine treatment immediately and observe until the swelling disappears. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, administer appropriate therapy, such as subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL), promptly.


Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Hypotension

Perindopril erbumine can cause symptomatic hypotension. Perindopril erbumine has been associated with hypotension in 0.3% of uncomplicated hypertensive patients in U.S. placebo-controlled trials. Symptoms related to orthostatic hypotension were reported in another 0.8% of patients.

 

Symptomatic hypotension is most likely to occur in patients who have been volume or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting [see Dosage and Administration (2.1)].

 

ACE inhibitors may cause excessive hypotension, and may be associated with oliguria or azotemia, and rarely with acute renal failure and death. In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident.

 

In patients at risk of excessive hypotension, Perindopril erbumine therapy should be started under very close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dose of Perindopril erbumine and/or diuretic is increased.

 

If excessive hypotension occurs, the patient should be placed immediately in a supine position and, if necessary, treated with an intravenous infusion of physiological saline. Perindopril erbumine treatment can usually be continued following restoration of volume and blood pressure.

Neutropenia/Agranulocytosis

ACE inhibitors have been associated with agranulocytosis and bone marrow depression, most frequently in patients with renal impairment, especially patients with a collagen vascular disease such as systemic lupus erythematosus or scleroderma.

Fetal/Neonatal Morbidity and Mortality

ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.

 

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation and hypoplastic lung development.

 

Prematurity, intrauterine growth retardation, patent ductus arteriosus, and other structural cardiac malformations, as well as neurologic malformations, have been reported following exposure to ACE inhibitors during the first trimester of pregnancy.

 

When patients become pregnant, healthcare providers should make every effort to discontinue the use of Perindopril erbumine as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

 

If oligohydramnios is observed, Perindopril erbumine should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and healthcare providers should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

 

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Perindopril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants.

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. Renal function should be monitored periodically in patients receiving Perindopril erbumine [see Dosage and Administration (2.3)].

 

In patients with severe congestive heart failure, where renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including Perindopril erbumine, may be associated with oliguria, progressive azotemia, and, rarely, acute renal failure and death.

 

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur; usually reversible upon discontinuation of the ACE inhibitor. In such patients, renal function should be monitored during the first few weeks of therapy.

 

Some Perindopril erbumine-treated patients have developed minor and transient increases in blood urea nitrogen and serum creatinine especially in those concomitantly treated with a diuretic.

Hyperkalemia

Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including Perindopril erbumine. Most cases were isolated single values that did not appear clinically relevant and were rarely a cause for withdrawal. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus and the concomitant use of agents such as potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes [see Drug Interactions (7.2)].

 

Serum potassium should be monitored periodically in patients receiving Perindopril erbumine.

Cough

Presumably because of the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of cough.

Hepatic Failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Surgery/Anesthesia

In patients undergoing surgery or during anesthesia with agents that produce hypotension, Perindopril erbumine may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension attributable to this mechanism can be corrected by volume expansion.

Adverse Reactions

Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience

The following adverse reactions are discussed elsewhere in labeling: 

• Anaphylactoid reactions, including angioedema [see Warnings and Precautions (5.1)]


• Hypotension [see Warnings and Precautions (5.2)]


• Neutropenia and agranulocytosis [see Warnings and Precautions (5.3)]


• Impaired renal function [see Warnings and Precautions (5.5)]


• Hyperkalemia [see Warnings and Precautions (5.6)]


• Cough [see Warnings and Precautions (5.7)]

Hypertension

 

Perindopril erbumine has been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign clinical trials. The data presented here are based on results from the 1,417 Perindopril erbumine-treated patients who participated in the U.S. clinical trials. Over 220 of these patients were treated with Perindopril erbumine for at least one year.

 

In placebo-controlled U.S. clinical trials, the incidence of premature discontinuation of therapy due to adverse events was 6.5% in patients treated with Perindopril erbumine and 6.7% in patients treated with placebo. The most common causes were cough, headache, asthenia and dizziness.

 

Among 1,012 patients in placebo-controlled U.S. trials, the overall frequency of reported adverse events was similar in patients treated with Perindopril erbumine and in those treated with placebo (approximately 75% in each group). The only adverse events whose incidence on Perindopril erbumine was at least 2% greater than on placebo were cough (12% vs. 4.5%) and back pain (5.8% vs. 3.1%).

 

Dizziness was not reported more frequently in the Perindopril group (8.2%) than in the placebo group (8.5%), but its likelihood increased with dose, suggesting a causal relationship with Perindopril.


Stable Coronary Artery Disease

 

Perindopril has been evaluated for safety in EUROPA, a double-blind, placebo-controlled study in 12,218 patients with stable coronary artery disease. The overall rate of discontinuation was about 22% on drug and placebo. The most common medical reasons for discontinuation that were more frequent on Perindopril than placebo were cough, drug intolerance and hypotension.

Postmarketing Experience

Voluntary reports of adverse events in patients taking Perindopril erbumine that have been received since market introduction and are of unknown causal relationship to Perindopril erbumine include: cardiac arrest, eosinophilic pneumonitis, neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia, acute renal failure, nephritis, hepatic failure, jaundice (hepatocellular or cholestatic), symptomatic hyponatremia, bullous pemphigoid, pemphigus, acute pancreatitis, falls, psoriasis, exfoliative dermatitis and a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive antinuclear antibody (ANA), leukocytosis, eosinophilia or an elevated erythrocyte sedimentation rate (ESR).

Clinical Laboratory Test Findings

Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated with Perindopril erbumine, but are rarely of clinical importance. In controlled clinical trials, no patient was discontinued from therapy due to the development of anemia. Leukopenia (including neutropenia) was observed in 0.1% of patients in U.S. clinical trials [see Warnings and Precautions (5.3)].


Liver Function Tests: Elevations in ALT (1.6% Perindopril erbumine versus 0.9% placebo) and AST (0.5% Perindopril erbumine versus 0.4% placebo) have been observed in placebo-controlled clinical trials. The elevations were generally mild and transient and resolved after discontinuation of therapy.

Drug Interactions

Diuretics

Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of Perindopril erbumine therapy. The possibility of hypotensive effects can be minimized by either decreasing the dose of or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Perindopril. If diuretic therapy cannot be altered, provide close medical supervision with the first dose of Perindopril erbumine, for at least two hours and until blood pressure has stabilized for another hour [see Warnings and Precautions (5.2)].

 

The rate and extent of Perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of Perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition.

Potassium Supplements and Potassium-Sparing Diuretics

Perindopril erbumine may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently.

Lithium

Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. Frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity.

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE Inhibitor therapy including Perindopril erbumine.

Digoxin

A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with Perindopril erbumine, but an effect of digoxin on the plasma concentration of Perindopril/Perindoprilat has not been excluded.

Gentamicin

Animal data have suggested the possibility of interaction between Perindopril and gentamicin. However, this has not been investigated in human studies.

Non-Steroidal Anti-inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including Perindopril, may result in deterioration of renal function,  including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Perindopril and NSAID therapy.

 

The antihypertensive effect of ACE inhibitors, including Perindopril, may be attenuated by NSAIDs including selective COX-2 inhibitors.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D [see Boxed Warning and Warnings and Precautions (5.4)]. Radioactivity was detectable in fetuses after administration of 14C-Perindopril to pregnant rats.

Nursing Mothers

Milk of lactating rats contained radioactivity following administration of 14C-Perindopril. It is not known whether Perindopril is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when Perindopril erbumine is given to nursing mothers.

Pediatric Use

Safety and effectiveness of Perindopril erbumine in pediatric patients have not been established.

Geriatric Use

The mean blood pressure effect of Perindopril was somewhat smaller in patients over 60 than in younger patients, although the difference was not significant. Plasma concentrations of both Perindopril and Perindoprilat were increased in elderly patients compared to concentrations in younger patients. No adverse effects were clearly increased in older patients with the exception of dizziness and possibly rash.

 

Start at a low dose and titrate slowly as needed. Monitor for dizziness because of potential for falls.

 

Experience with Perindopril erbumine in elderly patients at daily doses exceeding 8 mg is limited.

Renal Impairment

Dosage adjustment may be necessary in renally impaired patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Hepatic Impairment

The bioavailability of Perindoprilat is increased in patients with impaired hepatic function [see Clinical Pharmacology (12.3)].

Overdosage

In animals, doses of Perindopril up to 2,500 mg/kg in mice, 3,000 mg/kg in rats and 1,600 mg/kg in dogs were non-lethal. Past experiences were scant but suggested that overdosage with other ACE inhibitors was also fairly well tolerated by humans. The most likely manifestation is hypotension, and treatment should be symptomatic and supportive. Therapy with the ACE inhibitor should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance and hypotension should be treated by established procedures.

 

Among the reported cases of Perindopril overdosage, patients who were known to have ingested a dose of 80 mg to 120 mg required assisted ventilation and circulatory support. One additional patient developed hypothermia, circulatory arrest and died following ingestion of up to 180 mg of Perindopril. The intervention for Perindopril overdose may require vigorous support.

 

Laboratory determinations of serum levels of Perindopril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of Perindopril overdose.

 

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of Perindopril and its metabolites. Perindopril can be removed by hemodialysis, with clearance of 52 mL/min for Perindopril and 67 mL/min for Perindoprilat.

 

Angiotensin II could presumably serve as a specific antagonist-antidote in the settling of Perindopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of Perindopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat Perindopril overdose by infusion of normal saline solution.

Perindopril Description

Perindopril erbumine tablets contain the tert-butylamine salt of Perindopril, the ethyl ester of a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Perindopril erbumine is chemically described as (2S,3αS,7αS)-1-[(S)-N-[(S)-1-Carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine (1:1). Its molecular formula is C19H32N2O5C4H11N. Its structural formula is:

Perindopril erbumine is a white or almost white, crystalline powder, slightly hygroscopic with a molecular weight of 368.47 (free acid) or 441.61 (salt form). It is freely soluble in water (60% w/w), alcohol and chloroform.

 

Perindopril is the free acid form of Perindopril erbumine, is a pro-drug and metabolized in vivo by hydrolysis of the ester group to form Perindoprilat, the biologically active metabolite.

 

Perindopril erbumine tablets are available in 2 mg, 4 mg and 8 mg strengths for oral administration. In addition to Perindopril erbumine, each tablet contains the following inactive ingredients: anhydrous lactose, silica hydrophobic colloidal anhydrous, microcrystalline cellulose, and magnesium stearate.

Perindopril - Clinical Pharmacology

Mechanism of Action

Perindopril erbumine is a pro-drug for Perindoprilat, which inhibits ACE in human subjects and animals. The mechanism through which Perindoprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may be associated with a small increase of serum potassium.

 

ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Perindopril erbumine remains to be elucidated.

 

While the principal mechanism of Perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension. Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to Perindopril was about half the response seen in nonblack patients, a finding consistent with previous experience of other ACE inhibitors.

Pharmacodynamics

After administration of Perindopril, ACE is inhibited in a dose and blood concentration-related fashion, with the maximal inhibition of 80 to 90% attained by 8 mg persisting for 10 to 12 hours. Twenty-four hour ACE inhibition is about 60% after these doses. The degree of ACE inhibition achieved by a given dose appears to diminish over time (the ID50 increases). The pressor response to an angiotensin I infusion is reduced by Perindopril, but this effect is not as persistent as the effect on ACE; there is about 35% inhibition at 24 hours after a 12 mg dose.

Pharmacokinetics

Absorption: Oral administration of Perindopril erbumine results in peak plasma concentrations that occur at approximately 1 hour. The absolute oral bioavailability of Perindopril is about 75%. Following absorption, approximately 30 to 50% of systemically available Perindopril is hydrolyzed to its active metabolite, Perindoprilat, which has a mean bioavailability of about 25%. Peak plasma concentrations of Perindoprilat are attained 3 to 7 hours after Perindopril administration. Oral administration of Perindopril erbumine with food does not significantly lower the rate or extent of Perindopril absorption relative to the fasted state. However, the extent of biotransformation of Perindopril to the active metabolite, Perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, Perindopril was generally administered in a non-fasting state.

 

With 4 mg, 8 mg and 16 mg doses of Perindopril erbumine, Cmax and AUC of Perindopril and Perindoprilat increase in a dose-proportional manner following both single oral dosing and at steady state during a once-a-day multiple dosing regimen.


Distribution: Approximately 60% of circulating Perindopril is bound to plasma proteins, and only 10 to 20% of Perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.


Metabolism and Elimination: Following oral administration Perindopril exhibits multicompartment pharmacokinetics including a deep tissue compartment (ACE binding sites). The mean half-life of Perindopril associated with most of its elimination is approximately 0.8 to 1 hours.

 

Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine. Six metabolites resulting from hydrolysis, glucuronidation and cyclization via dehydration have been identified. These include the active ACE inhibitor, Perindoprilat (hydrolyzed Perindopril), Perindopril and Perindoprilat glucuronides, dehydrated Perindopril and the diastereoisomers of dehydrated Perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of Perindopril.

 

The active metabolite, Perindoprilat, also exhibits multicompartment pharmacokinetics following the oral administration of Perindopril erbumine. Formation of Perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows an apparent mean half-life of 3 to 10 hours for the majority of the elimination, with a prolonged terminal elimination half-life of 30 to 120 hours resulting from slow dissociation of Perindoprilat from plasma/tissue ACE binding sites. During repeated oral once daily dosing with Perindopril, Perindoprilat accumulates about 1.5- to 2-fold and attains steady state plasma levels in 3 to 6 days. The clearance of Perindoprilat and its metabolites is almost exclusively renal.


Elderly: Plasma concentrations of both Perindopril and Perindoprilat in elderly patients (greater than 70 years) are approximately twice those observed in younger patients, reflecting both increased conversion of Perindopril to Perindoprilat and decreased renal excretion of Perindoprilat [see Dosage and Administration (2.1) and Use in Specific Populations (8.5)].


Heart Failure: Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC.


Renal Impairment: With Perindopril doses of 2 mg to 4 mg, Perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30 to 80 mL/min, AUC is about double that at 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly.

 

In a limited number of patients studied, Perindopril clearance by dialysis ranged from about 40 to 80 mL/min. Perindoprilat clearance by dialysis ranged from about 40 to 90 mL/min [see Dosage and Administration (2.3)].


Hepatic Impairment: The bioavailability of Perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations of Perindoprilat in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity: No evidence of carcinogenic effect was observed in studies in rats and mice when Perindopril was administered at dosages up to 20 times (mg/kg) or 2 to 4 times (mg/m2) the maximum proposed clinical doses (16 mg/day) for 104 weeks.


Mutagenesis: No genotoxic potential was detected for Perindopril erbumine, Perindoprilat and other metabolites in various in vitro and in vivo investigations, including the Ames test, the Saccharomyces cerevisiae D4 test, cultured human lymphocytes, TK ± mouse lymphoma assay, mouse and rat micronucleus tests and Chinese hamster bone marrow assay.


Impairment of Fertility: There was no meaningful effect on reproductive performance or fertility in the rat given up to 30 times (mg/kg) or 6 times (mg/m2) the proposed maximum clinical dosage of Perindopril erbumine during the period of spermatogenesis in males or oogenesis and gestation in females.

Clinical Studies

Hypertension

In placebo-controlled studies of Perindopril monotherapy (2 mg to 16 mg once daily) in patients with a mean blood pressure of about 150/100 mm Hg, 2 mg had little effect, but doses of 4 mg to 16 mg lowered blood pressure. The 8 mg and 16 mg doses were indistinguishable, and both had a greater effect than the 4 mg dose. In these studies, doses of 8 mg and 16 mg per day gave supine, trough blood pressure reductions of 9 to 15/5 to 6 mm Hg. When once daily and twice daily dosing were compared, the twice daily dosing regimen was generally slightly superior, but by not more than about 0.5 mm Hg to 1 mm Hg. After 2 mg to 16 mg doses of Perindopril, the trough mean systolic and diastolic blood pressure effects were about 75 to 100% of peak effects.

 

Perindopril’s effects on blood pressure were similar when given alone or on a background of 25 mg hydrochlorothiazide. In general, the effect of Perindopril occurred promptly, with effects increasing slightly over several weeks.

 

Formal interaction studies of Perindopril erbumine have not been carried out with antihypertensive agents other than thiazides. Limited experience in controlled and uncontrolled trials coadministering Perindopril erbumine with a calcium channel blocker, a loop diuretic or triple therapy (beta-blocker, vasodilator and a diuretic), does not suggest any unexpected interactions. In general, ACE inhibitors have less than additive effects when given with beta-adrenergic blockers, presumably because both work in part through the renin angiotensin system.

 

In uncontrolled studies in patients with insulin-dependent diabetes, Perindopril did not appear to affect glycemic control. In long-term use, no effect on urinary protein excretion was seen in these patients.

 

The effectiveness of Perindopril erbumine was not influenced by sex and it was less effective in black patients than in nonblack patients. In elderly patients (greater than or equal to 60 years), the mean blood pressure effect was somewhat smaller than in younger patients, although the difference was not significant.

Stable Coronary Artery Disease

The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) was a multicenter, randomized, double-blind and placebo-controlled study conducted in 12,218 patients who had evidence of stable coronary artery disease without clinical heart failure. Patients had evidence of coronary artery disease documented by previous myocardial infarction more than 3 months before screening, coronary revascularization more than 6 months before screening, angiographic evidence of stenosis (at least 70% narrowing of one or more major coronary arteries), or positive stress test in men with a history of chest pain. After a run-in period of 4 weeks during which all patients received Perindopril 2 mg to 8 mg, the patients were randomly assigned to Perindopril 8 mg once daily (n=6,110) or matching placebo (n=6,108). The mean follow-up was 4.2 years. The study examined the long-term effects of Perindopril on time to first event of cardiovascular mortality, nonfatal myocardial infarction, or cardiac arrest in patients with stable coronary artery disease.

 

The mean age of patients was 60 years; 85% were male, 92% were taking platelet inhibitors, 63% were taking β blockers, and 56% were taking lipid-lowering therapy. The EUROPA study showed that Perindopril significantly reduced the relative risk for the primary endpoint events (Table 1). This beneficial effect is largely attributable to a reduction in the risk of nonfatal myocardial infarction. This beneficial effect of Perindopril on the primary outcome was evident after about one year of treatment (Figure 1). The outcome was similar across all predefined subgroups by age, underlying disease or concomitant medication (Figure 2).

Table 1. Primary Endpoint and Relative Risk Reduction

	Perindopril (N = 6,110)	Placebo (N = 6,108)	RRR (95% CI)	P
CI=confidence interval; RRR: relative risk reduction; MI: myocardial infarction
Combined Endpoint
Cardiovascular mortality, nonfatal MI or cardiac arrest	488 (8%)	603 (9.9%)	20% (9 to 29)	0.0003
Component Endpoint
Cardiovascular mortality	215 (3.5%)	249 (4.1%)	14% (-3 to 28)	0.107
Nonfatal MI	295 (4.8%)	378 (6.2%)	22% (10 to 33)	0.001
Cardiac arrest	6 (0.1%)	11 (0.2%)	46% (-47 to 80)	0.22

 

Size of squares proportional to the number of patients in the group. Dashed line indicates overall relative risk.

How Supplied/Storage and Handling

Perindopril Erbumine Tablets, 2 mg are white to off-white colored round biconvex, uncoated tablets, with debossing “D” on one side and “5” & “7” on either side of the breakline on another side.

 

               Bottles of 100               NDC 65862-286-01


Perindopril Erbumine Tablets, 4 mg are white to off-white colored capsule shaped uncoated tablets, with debossing “D” on one side and “5” & “8” on either side of the breakline on another side.

 

               Bottles of 100               NDC 65862-287-01


Perindopril Erbumine Tablets, 8 mg are white to off-white colored round biconvex uncoated tablets, with debossing “D” on one side and “5” & “9” on either side of breakline on another side.

 

               Bottles of 100               NDC 65862-288-01


Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.


Keep out of the reach of children.


For further information, please call 1-866-850-2876.

Patient Counseling Information

Inform female patients of childbearing age that use of drugs, such as Perindopril erbumine, that act on the renin-angiotensin system during pregnancy may cause serious problems in the fetus and infant. Patients taking Perindopril erbumine who are or plan to become pregnant should immediately notify their healthcare provider.

 

Tell patients to report immediately signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, hoarseness or difficulty in swallowing or breathing) and to take no more drug before consulting a healthcare provider.

 

Tell patients to report promptly any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia.

 

Manufactured for:

Aurobindo Pharma USA, Inc.

2400 Route 130 North

Dayton, NJ 08810

 

Manufactured by:

Aurobindo Pharma Limited

Hyderabad-500 072, India

 

Revised: 10/2011

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 2 mg (100 Tablet Bottle)

NDC 65862-286-01

Perindopril Erbumine Tablets

2 mg

Rx only           100 Tablets

AUROBINDO

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 4 mg (100 Tablet Bottle)

NDC 65862-287-01

Perindopril Erbumine Tablets

4 mg

Rx only           100 Tablets

AUROBINDO

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 8 mg (100 Tablet Bottle)

NDC 65862-288-01

Perindopril Erbumine Tablets

8 mg

Rx only           100 Tablets

AUROBINDO

Perindopril ERBUMINE  Perindopril erbumine  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 65862-286 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Perindopril ERBUMINE (Perindopril) Perindopril ERBUMINE 2 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE   SILICON DIOXIDE   CELLULOSE, MICROCRYSTALLINE   MAGNESIUM STEARATE

Product Characteristics Color WHITE (White to Off-white) Score 2 pieces Shape ROUND (Biconvex) Size 5mm Flavor Imprint Code D;5;7 Contains

Packaging # NDC Package Description Multilevel Packaging 1 65862-286-01 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA079070	11/10/2009

Perindopril ERBUMINE  Perindopril erbumine  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 65862-287 Route of Administration ORAL DEA Schedule

Toviaz

Generic Name: fesoterodine fumarate

Dosage Form: tablet, film coated, extended release
Toviaz™

(fesoterodine fumarate)

extended-release tablets

Rx only

Prescribing Information

Toviaz Description

Toviaz™ contains fesoterodine fumarate and is an extended-release tablet. Fesoterodine is rapidly de-esterified to its active metabolite, (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol, or 5-hydroxymethyl tolterodine, which is a muscarinic receptor antagonist.

Chemically, fesoterodine fumarate is designated as isobutyric acid 2-((R)-3-diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate. The empirical formula is C30H41NO7 and its molecular weight is 527.66. The structural formula is:

The asterisk (*) indicates the chiral carbon.

Fesoterodine fumarate is a white to off-white powder, which is freely soluble in water. Each Toviaz extended-release tablet contains either 4 mg or 8 mg of fesoterodine fumarate and the following inactive ingredients: glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.

Toviaz - Clinical Pharmacology

Fesoterodine is a competitive muscarinic receptor antagonist. After oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active metabolite, 5-hydroxymethyl tolterodine, which is responsible for the antimuscarinic activity of fesoterodine.

Muscarinic receptors play a role in contractions of urinary bladder smooth muscle and stimulation of salivary secretion. Inhibition of these receptors in the bladder is presumed to be the mechanism by which fesoterodine produces its effects.

Pharmacodynamics

In a urodynamic study involving patients with involuntary detrusor contractions, the effects after the administration of fesoterodine on the volume at first detrusor contraction and bladder capacity were assessed. Administration of fesoterodine increased the volume at first detrusor contraction and bladder capacity in a dose-dependent manner. These findings are consistent with an antimuscarinic effect on the bladder.

Pharmacokinetics

Absorption

After oral administration, fesoterodine is well absorbed. Due to rapid and extensive hydrolysis by nonspecific esterases to its active metabolite, fesoterodine cannot be detected in plasma. Bioavailability of the active metabolite is 52%. After single or multiple-dose oral administration of fesoterodine in doses from 4 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the dose. Maximum plasma levels are reached after approximately 5 hours. No accumulation occurs after multiple-dose administration.

A summary of pharmacokinetic parameters for the active metabolite after a single dose of Toviaz 4 mg and 8 mg in extensive and poor metabolizers of CYP2D6 is provided in Table 1.

Table 1 Summary of geometric mean [CV] pharmacokinetic parameters for the active metabolite after a single dose of Toviaz 4 mg and 8 mg in extensive and poor CYP2D6 metabolizers

	Toviaz 4 mg		Toviaz 8 mg
Parameter	EM (n=16)	PM (n=8)	EM (n=16)	PM (n=8)
EM = extensive CYP2D6 metabolizer, PM = poor CYP2D6 metabolizer, CV=coefficient of variation Cmax = maximum plasma concentration, AUC0–tz = area under the concentration time curve from zero up to the last measurable plasma concentration, tmax = time to reach Cmax, t½= terminal half-life
* Data presented as median (range)
Cmax (ng/mL)	1.89 [43%]	3.45 [54%]	3.98 [28%]	6.90 [39%]
AUC0–tz (ng*h/mL)	21.2 [38%]	40.5 [31%]	45.3 [32%]	88.7 [36%]
tmax (h)*	5 [2–6]	5 [5–6]	5 [3–6]	5 [5–6]
t½ (h)	7.31 [27%]	7.31 [30%]	8.59 [41%]	7.66 [21%]

Effect of Food

There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine. (see DOSAGE AND ADMINISTRATION)

Distribution

Plasma protein binding of the active metabolite is low (approximately 50%) and is primarily bound to albumin and alpha-1-acid glycoprotein. The mean steady-state volume of distribution following intravenous infusion of the active metabolite is 169 L.

Metabolism

After oral administration, fesoterodine is rapidly and extensively hydrolyzed to its active metabolite. The active metabolite is further metabolized in the liver to its carboxy, carboxy-N-desisopropyl, and N-desisopropyl metabolites via two major pathways involving CYP2D6 and CYP3A4. None of these metabolites contribute significantly to the antimuscarinic activity of fesoterodine.

Variability in Metabolism

A subset of individuals (approximately 7% Caucasians and 2% African Americans) are poor metabolizers for CYP2D6. The remainder of the population is referred to as extensive metabolizers. Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively, in CYP2D6 poor metabolizers as compared to extensive metabolizers.

Excretion

Hepatic metabolism and renal excretion contribute significantly to the elimination of the active metabolite. After oral administration of fesoterodine, approximately 70% of the administered dose was recovered in urine as the active metabolite (16%), carboxy metabolite (34%), carboxy-N-desisopropyl metabolite (18%), or N-desisopropyl metabolite (1%), and a smaller amount (7%) was recovered in feces.

The terminal half-life of the active metabolite is approximately 4 hours following an intravenous administration. The apparent terminal half-life following oral administration is approximately 7 hours.

Pharmacokinetics in Special Populations

Age

No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age.

Pediatric

The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.

Gender

No dose adjustment is recommended based on gender. The pharmacokinetics of fesoterodine are not significantly influenced by gender.

Race

Available data indicate that there are no differences in the pharmacokinetics of fesoterodine between Caucasian and Black healthy subjects following administration of Toviaz.

Renal Insufficiency

In patients with mild or moderate renal insufficiency (CLCR ranging from 30–80 mL/min), Cmax and AUC of the active metabolite are increased up to 1.5- and 1.8-fold respectively, as compared to healthy subjects. In patients with severe renal insufficiency (CLCR < 30 mL/min), Cmax and AUC are increased 2.0- and 2.3-fold, respectively.

In patients with mild or moderate renal insufficiency, no dose adjustment is recommended. Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal insufficiency (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Hepatic Impairment

In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are increased 1.4- and 2.1-fold, respectively, as compared to healthy subjects.

No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Subjects with severe hepatic impairment (Child-Pugh C) have not been studied; therefore Toviaz is not recommended for use in these patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions

Drugs Metabolized by Cytochrome P450

At therapeutic concentrations, the active metabolite of fesoterodine does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 in vitro.

CYP3A4 Inhibitors

Following blockade of CYP3A4 by coadministration of the potent CYP3A4 inhibitor ketoconazole 200 mg twice a day for 5 days, Cmax and AUC of the active metabolite of fesoterodine increased 2.0- and 2.3-fold, respectively, after oral administration of Toviaz 8 mg to CYP2D6 extensive metabolizers. In CYP2D6 poor metabolizers, Cmax and AUC of the active metabolite of fesoterodine increased 2.1- and 2.5-fold, respectively, during co-administration of ketoconazole 200 mg twice a day for 5 days. Cmax and AUC were 4.5- and 5.7-fold higher, respectively, in subjects who were CYP2D6 poor metabolizers and taking ketoconazole compared to subjects who were CYP2D6 extensive metabolizers and not taking ketoconazole. In a separate study coadministering fesoterodine with ketoconazole 200 mg once a day for 5 days, the Cmax and AUC values of the active metabolite of fesoterodine were increased 2.2-fold in CYP2D6 extensive metabolizers and 1.5- and 1.9-fold, respectively, in CYP2D6 poor metabolizers. Cmax and AUC were 3.4- and 4.2-fold higher, respectively, in subjects who were CYP2D6 poor metabolizers and taking ketoconazole compared to subjects who were CYP2D6 extensive metabolizers and not taking ketoconazole.

Therefore, doses of Toviaz greater than 4mg are not recommended in patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole and clarithromycin (see PRECAUTIONS, Drug Interactions and DOSAGE and ADMINISTRATION).

The effects of weak or moderate CYP3A4 inhibitors were not examined.

CYP3A4 Inducers

Following induction of CYP3A4 by coadministration of rifampicin 600 mg once a day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of Toviaz 8 mg. The terminal half-life of the active metabolite was not changed.

Induction of CYP3A4 may lead to reduced plasma levels. No dosing adjustments are recommended in the presence of CYP3A4 inducers.

CYP2D6 Inhibitors

The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively.

No dosing adjustments are recommended in the presence of CYP2D6 inhibitors.

Oral Contraceptives

In the presence of fesoterodine, there are no changes in the plasma concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel.

Cardiac Electrophysiology

The effect of fesoterodine 4 mg and 28 mg on the QT interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg once a day) parallel trial with once-daily treatment over a period of 3 days in 261 male and female subjects aged 44 to 65 years. Electrocardiographic parameters were measured over a 24-hour period at pre-dose, after the first administration, and after the third administration of study medication. Fesoterodine 28 mg was chosen because this dose, when administered to CYP2D6 extensive metabolizers, results in an exposure to the active metabolite that is similar to the exposure in a CYP2D6 poor metabolizer receiving fesoterodine 8 mg together with CYP3A4 blockade. Corrected QT intervals (QTc) were calculated using Fridericia's correction and a linear individual correction method. Analyses of 24-hour average QTc, time-matched baseline-corrected QTc, and time-matched placebo-subtracted QTc intervals indicate that fesoterodine at doses of 4 and 28 mg/day did not prolong the QT interval. The sensitivity of the study was confirmed by positive QTc prolongation by moxifloxacin.

Toviaz is associated with an increase in heart rate that correlates with increasing dose. In the study described above, when compared to placebo, the mean increase in heart rate associated with a dose of 4 mg/day and 28 mg/day of fesoterodine was 3 beats/minute and 11 beats/minute respectively.

In the two, phase 3, placebo-controlled studies in patients with overactive bladder, the mean increase in heart rate compared to placebo was approximately 3–4 beats/minute in the 4 mg/day group and 3–5 beats/minute in the 8 mg/day group.

Clinical Studies

Toviaz extended-release tablets were evaluated in two, Phase 3, randomized, double-blind, placebo-controlled, 12-week studies for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Entry criteria required that patients have symptoms of overactive bladder for ≥ 6-months duration, at least 8 micturitions per day, and at least 6 urinary urgency episodes or 3 urge incontinence episodes per 3-day diary period. Patients were randomized to a fixed dose of Toviaz 4 or 8 mg/day or placebo. In one of these studies, 290 patients were randomized to an active control arm (an oral antimuscarinic agent). For the combined studies, a total of 554 patients received placebo, 554 patients received Toviaz 4 mg/day, and 566 patients received Toviaz 8 mg/day. The majority of patients were Caucasian (91%) and female (79%) with a mean age of 58 years (range 19–91 years).

The primary efficacy endpoints were the mean change in the number of urge urinary incontinence episodes per 24 hours and the mean change in the number of micturitions (frequency) per 24 hours. An important secondary endpoint was the mean change in the voided volume per micturition.

Results for the primary endpoints and for mean change in voided volume per micturition from the two 12-week clinical studies of Toviaz are reported in Table 2.

Table 2 Mean baseline and change from baseline to Week 12 for urge urinary incontinence episodes, number of micturitions, and volume voided per micturition

	Study 1			Study 2
Parameter	Placebo N=279	Toviaz 4mg/day N=265	Toviaz 8mg/day N=276	Placebo N=266	Toviaz 4mg/day N=267	Toviaz 8mg/day N=267
vs=versus
* Only those patients who were urge incontinent at baseline were included for the analysis of number of urge incontinence episodes per 24 hours: In Study 1, the number of these patients was 211, 199, and 223 in the placebo, Toviaz 4 mg/day and Toviaz 8 mg/day groups, respectively. In Study 2, the number of these patients was 205, 228, and 218, respectively.
Number of urge incontinence episodes per 24 hours*
Baseline	3.7	3.8	3.7	3.7	3.9	3.9
Change from baseline	-1.20	-2.06	-2.27	-1.00	-1.77	-2.42
p-value vs placebo	-	0.001	<0.001	-	<0.003	<0.001
Number of micturitions per 24 hours
Baseline	12.0	11.6	11.9	12.2	12.9	12.0
Change from baseline	-1.02	-1.74	-1.94	-1.02	-1.86	-1.94
p-value vs placebo	-	<0.001	<0.001	-	0.032	<0.001
Voided volume per micturition (mL)
Baseline	150	160	154	159	152	156
Change from baseline	10	27	33	8	17	33
p-value vs placebo	-	<0.001	<0.001	-	0.150	<0.001

Figures 1–4: The following figures show change from baseline over time in number of micturitions and urge urinary incontinence episodes per 24 h in the two studies.

A reduction in number of urge urinary incontinence episodes per 24 hours was observed for both doses as compared to placebo as early as two weeks after starting Toviaz therapy.

Indications and Usage for Toviaz

Toviaz is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

Contraindications

Toviaz is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Toviaz is also contraindicated in patients with known hypersensitivity to the drug or its ingredients.

Precautions

General

Bladder Outlet Obstruction

Toviaz should be administered with caution to patients with clinically significant bladder outlet obstruction because of the risk of urinary retention (see CONTRAINDICATIONS).

Decreased Gastrointestinal Motility

Toviaz, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility, such as those with severe constipation.

Controlled Narrow-Angle Glaucoma

Toviaz should be used with caution in patients being treated for narrow-angle glaucoma, and only where the potential benefits outweigh the risks (see CONTRAINDICATIONS).

Reduced Hepatic Function

There are no dosing adjustments for patients with mild or moderate hepatic impairment. Toviaz has not been studied in patients with severe hepatic impairment and therefore is not recommended for use in this patient population (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations and DOSAGE AND ADMINISTRATION).

Myasthenia Gravis

Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.

Reduced Renal Function

There are no dosing adjustments for patients with mild or moderate renal insufficiency. Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal insufficiency (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations and DOSAGE AND ADMINISTRATION).

Concomitant Administration with CYP3A4 Inhibitors

Doses of Toviaz greater than 4 mg are not recommended in patients taking a potent CYP3A4 inhibitor (e.g. ketoconazole, itraconazole, clarithromycin).

In patients taking weak or moderate CYP3A4 inhibitors (e.g. erythromycin), careful assessment of tolerability at the 4 mg daily dose is advised prior to increasing the daily dose to 8 mg. While this specific interaction potential was not examined by clinical study, some pharmacokinetic interaction is expected, albeit less than that observed with potent CYP3A4 inhibitors (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions and DOSAGE AND ADMINISTRATION).

Information for Patients

Patients should be informed that Toviaz, like other antimuscarinic agents, may produce clinically significant adverse effects related to antimuscarinic pharmacological activity including constipation and urinary retention. Toviaz, like other antimuscarinics, may be associated with blurred vision, therefore, patients should be advised to exercise caution until the drug's effects on the patient have been determined. Heat prostration (due to decreased sweating) can occur when Toviaz, like other antimuscarinic drugs, is used in a hot environment. Patients should also be informed that alcohol may enhance the drowsiness caused by Toviaz, like other anticholinergic agents. Patients should read the patient leaflet entitled "Patient Information Toviaz" before starting therapy with Toviaz.

Drug Interactions

Coadministration of Toviaz with other antimuscarinic agents that produce dry mouth, constipation, urinary retention, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Also see PRECAUTIONS, Concomitant Administration with CYP3A4 Inhibitors.

Drug-Laboratory Test Interactions

Interactions between Toviaz and laboratory tests have not been studied.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of drug-related carcinogenicity was found in 24-month studies with oral administration to mice and rats. The highest tolerated doses in mice (females 45 to 60 mg/kg/day, males 30 to 45 mg/kg/day) correspond to 11- to 19-fold (females) and 4- to 9-fold (males) the estimated human AUC values reached with fesoterodine 8 mg, which is the Maximum Recommended Human Dose (MRHD). In rats, the highest tolerated dose (45 to 60 mg/kg/day) corresponds to 3- to 8-fold (females) and 3- to 14-fold (males), the estimated human AUC at the MRHD.

Fesoterodine was not mutagenic or genotoxic in vitro (Ames tests, chromosome aberration tests) or in vivo (mouse micronucleus test).

Fesoterodine had no effect on reproductive function, fertility, or early embryonic development of the fetus at non-maternally toxic doses in mice. The maternal No-Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early embryonic development were both 15 mg/kg/day. Based on AUC, the systemic exposure was 0.6- to 1.5-fold higher in mice than in humans at the MRHD, whereas based on peak plasma concentrations, the exposure in mice was 5- to 9-fold higher. The Lowest-Observed-Effect Level (LOEL) for maternal toxicity was 45 mg/kg/day.

Pregnancy

Pregnancy Category C

Reproduction studies have been performed in mice and rabbits. No dose-related teratogenicity was observed at oral doses up to 75 mg/kg/day in mice (6 to 27 times the expected exposure at the MRHD based on AUC and greater than 77 times the expected Cmax) and up to 27 mg/kg/day in rabbits (3- to 11- fold by AUC and 19- to 62– fold by Cmax) or at subcutaneous doses up to 4.5 mg/kg/day in rabbits (9- to 11- fold by AUC and 43 to 56-fold by Cmax). In mice treated orally with 75 mg/kg/day (6- to 27-times the expected exposure at the MRHD based on AUC and greater than 77-times the expected Cmax), increased resorptions and decreased live fetuses were observed. One fetus with cleft palate was observed at each dose (15, 45 and 75 mg/kg/day), at an incidence within the background historical range. In rabbits treated orally with 27 mg/kg/day (3 to 11- fold by AUC and 19 to 62- fold by Cmax), incompletely ossified sternebrae (retardation of bone development) were observed in fetuses. In rabbits treated by subcutaneous (sc) administration with 4.5 mg/kg/day (9 to 11- fold by AUC and 43 to 53- fold by Cmax), maternal toxicity and incompletely ossified sternebrae were observed in fetuses (at an incidence within the background historical range). At 1.5 mg/kg/day s.c., (3-fold by AUC and 11 to 13- fold by Cmax), decreased maternal food consumption in the absence of any fetal effects was observed. Oral administration of 30 mg/kg/day fesoterodine to mice in a pre- and post-natal development study resulted in decreased body weight of the dams and delayed ear opening of the pups. No effects were noted on mating and reproduction of the F1 dams or on the F2 offspring.

There are no adequate and well-controlled studies using Toviaz in pregnant women. Therefore, Toviaz should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Nursing Mothers

It is not known whether fesoterodine is excreted in human milk. Toviaz should not be administered during nursing unless the potential benefit outweighs the potential risk to the neonate.

Pediatric Use

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

Geriatric Use

Of 1567 patients who received Toviaz 4mg/day or 8mg/day in the Phase 2 and 3, placebo-controlled, efficacy and safety studies, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies; however, the incidence of antimuscarinic adverse events, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (at 8mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients. (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, and CLINICAL STUDIES and ADVERSE REACTIONS).

Adverse Reactions

The safety of Toviaz was evaluated in Phase 2 and 3 controlled trials in a total of 2859 patients with overactive bladder of which 2288 were treated with fesoterodine. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day in Phase 2 or 3 studies with treatment periods of 8 or 12 weeks. Approximately 80% of these patients had >10 weeks exposure to Toviaz in these trials.

A total of 1964 patients participated in two 12-week, Phase 3 efficacy and safety studies and subsequent open-label extension studies. In these 2 studies combined, 554 patients received Toviaz 4 mg/day and 566 patients received Toviaz 8 mg/day.

In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg were 1.9%, 3.5%, and 2.9%, respectively. All serious adverse events were judged to be not related or unlikely to be related to study medication by the investigator, except for four patients receiving Toviaz who reported one serious adverse event each: angina, chest pain, gastroenteritis, and QT prolongation on ECG.

The most commonly reported adverse event in patients treated with Toviaz was dry mouth. The incidence of dry mouth was higher in those taking 8 mg/day (35%) and in those taking 4 mg/day (19%), as compared to placebo (7%). Dry mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.

The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in those taking placebo, 4% in those taking 4 mg/day, and 6% in those taking 8 mg.

Table 3 lists adverse events, regardless of causality, that were reported in the combined Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with Toviaz 4 or 8 mg once daily for up to 12 weeks.

Table 3 Adverse events with an incidence exceeding the placebo rate and reported by ≥1% of patients from double-blind, placebo-controlled Phase 3 trials of 12 weeks treatment duration

System organ class/Preferred term	Placebo N=554 %	Toviaz 4mg/day N=554 %	Toviaz 8mg/day N=566 %
ALT=alanine aminotransferase, GGT=gamma glutamyltransferase
Gastrointestinal disorders
Dry mouth	7.0	18.8	34.6
Constipation	2.0	4.2	6.0
Dyspepsia	0.5	1.6	2.3
Nausea	1.3	0.7	1.9
Abdominal pain upper	0.5	1.1	0.5
Infections
Urinary tract infection	3.1	3.2	4.2
Upper respiratory tract infection	2.2	2.5	1.8
Eye disorders
Dry eyes	0	1.4	3.7
Renal and urinary disorders
Dysuria	0.7	1.3	1.6
Urinary retention	0.2	1.1	1.4
Respiratory disorders
Cough	0.5	1.6	0.9
Dry Throat	0.4	0.9	2.3
General disorders
Edema peripheral	0.7	0.7	1.2
Musculoskeletal disorders
Back pain	0.4	2.0	0.9
Psychiatric disorders
Insomnia	0.5	1.3	0.4
Investigations
ALT increased	0.9	0.5	1.2
GGT increased	0.4	0.4	1.2
Skin disorders
Rash	0.5	0.7	1.1

Patients also received Toviaz for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open label trials combined, 857, 701, 529, and 105 patients received Toviaz for at least 6 months, 1 year, 2 years, and 3 years respectively. The adverse events observed during long-term, open-label studies were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator, and reported more than once during the open-label treatment period of up to 3 years included urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases).

Overdosage

Overdosage with Toviaz can result in severe anticholinergic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended.

Toviaz Dosage and Administration

The recommended starting dose of Toviaz is 4 mg once daily. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily.

The daily dose of Toviaz should not exceed 4 mg in the following populations:

• Patients with severe renal insufficiency (CLCR <30 mL/min).


• Patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole and clarithromycin.

Toviaz is not recommended for use in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations and PRECAUTIONS).

Toviaz should be taken with liquid and swallowed whole. Toviaz can be administered with or without food, and should not be chewed, divided, or crushed.

How is Toviaz Supplied

Toviaz (fesoterodine fumarate) extended-release tablets 4 mg are light blue, oval, biconvex, film-coated and engraved with "FS" on one side. They are supplied as follows:

Bottles of 30	NDC 0069-0242-30
Bottles of 90	NDC 0069-0242-68
Unit Dose Package of 100	NDC 0069-0242-41

Toviaz (fesoterodine fumarate) extended-release tablets 8 mg are blue, oval, biconvex, film-coated and engraved with "FT" on one side. They are supplied as follows:

Bottles of 30	NDC 0069-0244-30
Bottles of 90	NDC 0069-0244-68
Unit Dose Package of 100	NDC 0069-0244-41

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

Manufactured by:

SCHWARZ PHARMA PRODUKTIONS-GmbH

08056 Zwickau, Germany

Distributed by:

LAB-0381-3.0

November 2008

Patient Information

Toviaz™ (TOH-vee-as)

(fesoterodine fumarate)

extended-release tablets

Read the Patient Information that comes with Toviaz before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

What is Toviaz?

Toviaz is a prescription medicine used in adults to treat symptoms of a condition called overactive bladder, including:

• Urge urinary incontinence -- leaking or wetting accidents due to a strong need to urinate,


• Urinary urgency -- having a strong need to urinate right away,


• Urinary frequency -- having to urinate too often.

Toviaz has not been studied in children.

Who should not take Toviaz?

Do not take Toviaz if you:

• Are not able to empty your bladder (urinary retention)


• Have delayed or slow emptying of your stomach (gastric retention)


• Have an eye problem called "uncontrolled narrow-angle glaucoma"


• Are allergic to Toviaz or any of its ingredients. See the end of this leaflet for a complete list of ingredients.

What should I tell my doctor before starting Toviaz?

Before starting Toviaz, tell your doctor about all of your medical and other conditions that may affect the use of Toviaz, including:

• Stomach or intestinal problems or problems with constipation


• Problems emptying your bladder or if you have a weak urine stream


• Treatment for an eye problem called narrow-angle glaucoma


• Kidney problems


• Liver problems


• A condition called myasthenia gravis


• If you are pregnant or trying to become pregnant. It is not known if Toviaz can harm your unborn baby.


• If you are breastfeeding. It is not known if Toviaz passes into breast milk or if it can harm your baby. Talk to your doctor about the best way to feed your baby if you take Toviaz.

Before starting on Toviaz, tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins and herbal products. Toviaz may affect the way other medicines work, and other medicines may affect how Toviaz works. Especially tell your doctor if you are taking antibiotics or antifungal medicines.

Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist each time you get a new medicine.

How should I take Toviaz?

• Take Toviaz exactly as your doctor tells you to take it.


• Your doctor may give you the lower 4 mg dose of Toviaz if you have certain medical conditions, such as severe kidney problems.


• Take Toviaz with liquid and swallow the tablet whole. Do not chew, divide, or crush the tablet.


• You can take Toviaz with or without food.


• If you miss a dose of Toviaz, begin taking Toviaz again the next day. Do not take 2 doses of Toviaz in the same day.

If you take too much Toviaz, call your doctor or go to an emergency department right away.

What are the possible side effects of Toviaz?

The most common side effects of Toviaz are:

• Dry mouth


• Constipation

Toviaz may cause other less common side effects, including:

• Dry eyes


• Trouble emptying the bladder

Tell your doctor if you have any side effects that bother you or that do not go away.

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

These are not all of the possible side effects of Toviaz. For a complete list, ask your doctor.

What else should I keep in mind while taking Toviaz?

• Use caution in driving, operating machinery, or doing other dangerous activities until you know how Toviaz affects you. Blurred vision and drowsiness are possible side effects of medicines such as Toviaz.


• Use caution in hot environments. Decreased sweating and severe heat illness can occur when medicines such as Toviaz are used in a hot environment.


• Drinking alcohol while taking medicines such as Toviaz may cause increased drowsiness.

How should I store Toviaz?

• Store Toviaz at room temperature, 59° to 86°F (15° to 30°C).


• Protect the medicine from moisture by keeping the bottle closed tightly.


• Safely throw away Toviaz that is out of date or no longer needed.

Keep Toviaz and all medicines out of the reach of children.

General information about Toviaz

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

This leaflet summarizes the most important information about Toviaz. If you would like more information, talk with your doctor. You can ask your doctor for information about Toviaz that is written for healthcare professionals. You can also call 1-877-9-Toviaz (1-877-986-8429) or go to www.Toviaz.com.

What are the ingredients in Toviaz?

Active ingredient: fesoterodine fumarate

Inactive ingredients: glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.

Manufactured by:

SCHWARZ PHARMA PRODUKTIONS-GmbH

08056 Zwickau, Germany

Distributed by:

LAB-0382-3.0

November 2008

PRINCIPAL DISPLAY PANEL - 4 mg Tablet Bottle Label

NDC 0069-0242-30

30 Tablets

Rx only

Toviaz™

(fesoterodine fumarate)

extended release tablets

4 mg

Pfizer

Distributed by

Pfizer Labs

Division of Pfizer Inc, NY, NY 10017

PRINCIPAL DISPLAY PANEL - 8 mg Tablet Bottle Label

NDC 0069-0244-30

30 Tablets

Rx only

Toviaz™

(fesoterodine fumarate)

extended release tablets

8 mg

Pfizer

Distributed by

Pfizer Labs

Division of Pfizer Inc, NY, NY 10017

Toviaz  fesoterodine fumarate  tablet, film coated, extended release

Product Information P

Panixine

Generic Name: cephalexin (sef a LEX in)

Brand Names: Keflex, Panixine

What is Panixine (cephalexin)?

Cephalexin is in a group of drugs called cephalosporin antibiotics. Cephalexin fights bacteria in the body.

Cephalexin is used to treat infections caused by bacteria, including upper respiratory infections, ear infections, skin infections, and urinary tract infections.

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

What is the most important information I should know about Panixine (cephalexin)?

Do not use this medication if you are allergic to cephalexin, or to similar antibiotics, such as Ceclor, Ceftin, Cefzil, Duricef, Fortaz, Omnicef, Spectracef, Suprax, and others.

Before using cephalexin, tell your doctor if you are allergic to any drugs (especially penicillins), or if you have kidney or liver disease, a stomach or intestinal disorder such as colitis, diabetes, or if you are malnourished.

Take this medication for the entire length of time prescribed by your doctor. Your symptoms may get better before the infection is completely treated. Cephalexin will not treat a viral infection such as the common cold or flu.

What should I discuss with my healthcare provider before taking Panixine (cephalexin)?

Do not use this medication if you are allergic to cephalexin, or to other cephalosporin antibiotics, such as:

• 
  

  cefaclor (Ceclor);

  
  


• 
  

  cefadroxil (Duricef);

  
  


• 
  

  cefdinir (Omnicef);

  
  


• 
  

  cefditoren (Spectracef);

  
  


• 
  

  cefixime (Suprax);

  
  


• 
  

  cefprozil (Cefzil);

  
  


• 
  

  ceftazidime (Fortaz); or

  
  


• 
  

  cefuroxime (Ceftin).

  
  

Before using cephalexin, tell your doctor if you are allergic to any drugs (especially penicillins), or if you have:

• 
  

  kidney disease;

  
  


• 
  

  liver disease;

  
  


• 
  

  a stomach or intestinal disorder such as colitis;

  
  


• 
  

  diabetes; or

  
  


• 
  

  if you are malnourished.

  
  

If you have any of these conditions, you may need a dose adjustment or special tests to safely take cephalexin.

The oral suspension (liquid) form of cephalexin may contain sugar. This may affect you if you have diabetes.

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. Cephalexin 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 Panixine (cephalexin)?

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

Take cephalexin with a full glass of water.

Dissolve the cephalexin dispersible tablet in a small amount of water, about 2 teaspoonfuls. Stir this mixture and drink all of it right away. To make sure you get the entire dose, add a little more water to the same glass, swirl gently and drink right away. Do not swallow or chew a dispersible tablet.

Shake the oral suspension (liquid) well just before you measure a dose. To be sure you get the correct dose, measure the liquid with a marked measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one. Take cephalexin for the entire length of time prescribed by your doctor. Your symptoms may get better before the infection is completely treated. Cephalexin will not treat a viral infection such as the common cold or flu.

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

Store the tablets and capsules at room temperature away from moisture and heat. Store the liquid medicine in the refrigerator. Throw away any unused medication after 14 days.

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your 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 nausea, vomiting, stomach pain, diarrhea, and blood in your urine.

What should I avoid while taking Panixine (cephalexin)?

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or has blood in it, call your doctor. Do not use any medicine to stop the diarrhea unless your doctor has told you to.

Panixine (cephalexin) 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:

• 
  

  diarrhea that is watery or bloody;

  
  


• 
  

  seizure (convulsions);

  
  


• 
  

  fever, sore throat, and headache with a severe blistering, peeling, and red skin rash;

  
  


• 
  

  pale or yellowed skin, dark colored urine, fever, confusion or weakness;

  
  


• 
  

  easy bruising or bleeding, unusual weakness;

  
  


• 
  

  confusion, agitation, hallucinations (seeing things that are not there); or

  
  


• 
  

  urinating less than usual or not at all.

  
  

Less serious side effects may include:

• 
  

  mild nausea, vomiting, diarrhea;

  
  


• 
  

  dizziness, tired feeling;

  
  


• 
  

  joint pain; or

  
  


• 
  

  vaginal itching or discharge.

  
  

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 Panixine (cephalexin)?

Before using cephalexin, tell your doctor if you are using any of the following drugs:

• 
  

  a blood thinner such as warfarin (Coumadin);

  
  


• 
  

  metformin (Fortamet, Glucophage, Riomet, Actoplus, Avandamet, Metaglip); or

  
  


• 
  

  probenecid (Benemid).

  
  

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

More Panixine resources

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

• Panixine Prescribing Information (FDA)


• Cephalexin Prescribing Information (FDA)


• Cephalexin Professional Patient Advice (Wolters Kluwer)


• Cephalexin Monograph (AHFS DI)


• Cephalexin MedFacts Consumer Leaflet (Wolters Kluwer)


• cephalexin Advanced Consumer (Micromedex) - Includes Dosage Information


• Keflex Prescribing Information (FDA)


• Keflex MedFacts Consumer Leaflet (Wolters Kluwer)


• Keflex Consumer Overview

Compare Panixine with other medications

• Acne
• Bacterial Endocarditis Prevention
• Bacterial Infection
• Bladder Infection
• Bone infection
• Kidney Infections
• Otitis Media
• Pharyngitis
• Prostatitis
• Skin Infection
• Upper Respiratory Tract Infection

Where can I get more information?

• Your pharmacist can provide more information about cephalexin.

See also: Panixine side effects (in more detail)