Pylokit

Clarithromycin:

• Clinical studies
• Pylokit (Clarithromycin) reviews

DESCRIPTION

Pylokit (Clarithromycin) is a semi-synthetic macrolide antibiotic. Chemically, it is 6-0-methylerythromycin. The molecular formula is C₃₈H₆₉NO₁₃, and the molecular weight is 747.96.

CLINICAL PHARMACOLOGYPharmacokinetics

Pylokit (Clarithromycin) is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg Pylokit (Clarithromycin) tablets was approximately 50%. For a single 500 mg dose of Pylokit (Clarithromycin), food slightly delays the onset of Pylokit (Clarithromycin) absorption, increasing the peak time from approximately 2 to 2.5 hours. Food also increases the Pylokit (Clarithromycin) peak plasma concentration by about 24%, but does not affect the extent of Pylokit (Clarithromycin) bioavailability. Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH Pylokit (Clarithromycin) or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, Pylokit (Clarithromycin) tablets may be given without regard to food.

In nonfasting healthy human subjects (males and females), peak plasma concentrations were attained within 2 to 3 hours after oral dosing. Steady-state peak plasma Pylokit (Clarithromycin) concentrations were attained within 3 days and were approximately 1 to 2 mcg/mL with a 250 mg dose administered every 12 hours and 3 to 4 mcg/mL with a 500 mg dose administered every 8 to 12 hours. The elimination half-life of Pylokit (Clarithromycin) was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of Pylokit (Clarithromycin) pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 8 to 12 hours. With a 250 mg every 12 hours dosing, the principal metabolite, 14-OH Pylokit (Clarithromycin), attains a peak steady-state concentration of about 0.6 mcg/mL and has an elimination half-life of 5 to 6 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH Pylokit (Clarithromycin) is slightly higher (up to 1 mcg/mL), and its elimination half-life is about 7 to 9 hours. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days.

After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as Pylokit (Clarithromycin), while after a 500 mg tablet every 12 hours, the urinary excretion of Pylokit (Clarithromycin) is somewhat greater, approximately 30%. In comparison, after an oral dose of 250 mg (125 mg/5 mL) suspension every 12 hours, approximately 40% is excreted in urine as Pylokit (Clarithromycin). The renal clearance of Pylokit (Clarithromycin) is, however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH Pylokit (Clarithromycin), which accounts for an additional 10% to 15% of the dose with either a 250 mg or a 500 mg tablet administered every 12 hours.

Steady-state concentrations of Pylokit (Clarithromycin) and 14-OH Pylokit (Clarithromycin) observed following administration of 500 mg doses of Pylokit (Clarithromycin) every 12 hours to adult patients with HIV infection were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500 mg or 1000 mg doses of Pylokit (Clarithromycin) every 12 hours, steady-state Pylokit (Clarithromycin) C_max values ranged from 2 to 4 mcg/mL and 5 to 10 mcg/mL, respectively.

The steady-state concentrations of Pylokit (Clarithromycin) in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH Pylokit (Clarithromycin) concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH Pylokit (Clarithromycin) was at least partially offset by an increase in renal clearance of Pylokit (Clarithromycin) in the subjects with impaired hepatic function when compared to healthy subjects.

The pharmacokinetics of Pylokit (Clarithromycin) was also altered in subjects with impaired renal function. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION .)

Microbiology

Pylokit (Clarithromycin) exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible microorganisms resulting in inhibition of protein synthesis.

Pylokit (Clarithromycin) is active in vitro against a variety of aerobic and anaerobic gram-positive and gram-negative microorganisms as well as most Mycobacterium avium complex (MAC) microorganisms.

Additionally, the 14-OH Pylokit (Clarithromycin) metabolite also has clinically significant antimicrobial activity. The 14-OH Pylokit (Clarithromycin) is twice as active against Haemophilus influenzae microorganisms as the parent compound. However, for Mycobacterium avium complex (MAC) isolates the 14-OH metabolite is 4 to 7 times less active than Pylokit (Clarithromycin). The clinical significance of this activity against Mycobacterium avium complex is unknown.

Pylokit (Clarithromycin) has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Aerobic Gram-positive Microorganisms

Staphylococcus aureus

Streptococcus pneumoniae

Streptococcus pyogenes

Aerobic Gram-negative Microorganisms

Haemophilus influenzae

Haemophilus parainfluenzae

Moraxella catarrhalis

Other Microorganisms

Mycoplasma pneumoniae

Chlamydia pneumoniae (TWAR)

Mycobacteria

Mycobacterium avium complex (MAC) consisting of:

Mycobacterium avium

Mycobacterium intracellulare

Beta-lactamase production should have no effect on Pylokit (Clarithromycin) activity.

NOTE: Most strains of methicillin-resistant and oxacillin-resistant staphylococci are resistant to Pylokit (Clarithromycin).

Omeprazole/clarithromycin dual therapy; ranitidine bismuth citrate/clarithromycin dual therapy; omeprazole/clarithromycin/amoxicillin triple therapy; and lansoprazole/clarithromycin/amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Helicobacter

Helicobacter pylori

Pretreatment Resistance

Pylokit (Clarithromycin) pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual-therapy studies (M93-067, M93-100) and 9.3% (41/439) in the omeprazole/clarithromycin/amoxicillin triple-therapy studies (126, 127, M96-446). Pylokit (Clarithromycin) pretreatment resistance was 12.6% (44/348) in the ranitidine bismuth citrate/clarithromycin b.i.d. versus t.i.d. clinical study (H2BA3001). Pylokit (Clarithromycin) pretreatment resistance rates were 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the lansoprazole/clarithromycin/amoxicillin triple-therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).

Amoxicillin pretreatment susceptible isolates (less than 0.25 mcg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin clinical studies (126, 127, M96-446). Amoxicillin pretreatment minimum inhibitory concentrations (MICs) greater than 0.25 mcg/mL occurred in 0.7% (3/439) of the patients, all of whom were in the clarithromycin/amoxicillin study arm. Amoxicillin pretreatment susceptible isolates (less than 0.25 mcg/mL) occurred in 97.8% (936/957) and 98.0% (98/100) of the patients in the lansoprazole/clarithromycin/amoxicillin triple-therapy clinical trials by E-test and agar dilution, respectively. Twenty-one of the 957 patients (2.2%) by E-test and 2 of 100 patients (2.0%) by agar dilution had amoxicillin pretreatment MICs of greater than 0.25 mcg/mL. Two patients had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of greater than 256 mcg/mL by E-test

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the omeprazole/clarithromycin/amoxicillin triple-therapy clinical trials, 84.9% (157/185) of the patients who had pretreatment amoxicillin susceptible MICs (less than 0.25 mcg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results, and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with Pylokit (Clarithromycin) resistant MICs.

In the lansoprazole/clarithromycin/amoxicillin triple-therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (less than 0.25 mcg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of greater than 0.25 mcg/mL, three of six had the H. pylori eradicated. A total of 12.8% (22/172) of the patients failed the 10-and 14-day triple-therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple-therapy regimen also had Pylokit (Clarithromycin) resistant H. pylori isolates.

The following in vitro data are available, but their clinical significance is unknown. Pylokit (Clarithromycin) exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of Pylokit (Clarithromycin) in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic Gram-positive Microorganisms

Streptococcus agalactiae

Streptococci (Groups C, F, G)

Viridans group streptococci

Aerobic Gram-negative Microorganisms

Bordetella pertussis

Legionella pneumophila

Pasteurella multocida

Anaerobic Gram-positive Microorganisms

Clostridium perfringens

Peptococcus niger

Propionibacterium acnes

Anaerobic Gram-negative Microorganisms

Prevotella melaninogenica (formerly Bacteriodes melaninogenicus)

Susceptibility Testing Excluding Mycobacteria and HelicobacterDilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method¹ (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of Pylokit (Clarithromycin) powder. The MIC values should be interpreted according to the following criteria

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard Pylokit (Clarithromycin) powder should provide the following MIC values

In vitro Activity of Pylokit (Clarithromycin) against Mycobacteria

Pylokit (Clarithromycin) has demonstrated in vitro activity against Mycobacterium avium complex (MAC) microorganisms isolated from both AIDS and non-AIDS patients. While gene probe techniques may be used to distinguish M. avium species from M. intracellulare, many studies only reported results on M. avium complex (MAC) isolates.

Various in vitro methodologies employing broth or solid media at different pH’s, with and without oleic acid-albumin-dextrose-catalase (OADC), have been used to determine Pylokit (Clarithromycin) MIC values for mycobacterial species. In general, MIC values decrease more than 16-fold as the pH of Middlebrook 7H12 broth media increases from 5.0 to 7.4. At pH 7.4, MIC values determined with Mueller-Hinton agar were 4- to 8-fold higher than those observed with Middlebrook 7H12 media. Utilization of oleic acid-albumin-dextrose-catalase (OADC) in these assays has been shown to further alter MIC values.

Pylokit (Clarithromycin) activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS patients was evaluated using a micro-dilution method with Middlebrook 7H9 broth. Results showed an MIC value of less than or equal to 4.0 mcg/mL in 81% and 89% of the AIDS and non-AIDS MAC isolates, respectively. Twelve percent of the non-AIDS isolates had an MIC value less than or equal to 0.5 mcg/mL. Pylokit (Clarithromycin) was also shown to be active against phagocytized M. avium complex (MAC) in mouse and human macrophage cell cultures as well as in the beige mouse infection model.

Pylokit (Clarithromycin) activity was evaluated against Mycobacterium tuberculosis microorganisms. In one study utilizing the agar dilution method with Middlebrook 7H10 media, 3 of 30 clinical isolates had an MIC of 2.5 mcg/mL. Pylokit (Clarithromycin) inhibited all isolates at greater than 10.0 mcg/mL.

Susceptibility Testing for Mycobacterium avium Complex (MAC)

The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative bacteria should not be used for determining Pylokit (Clarithromycin) MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been standardized or validated. Pylokit (Clarithromycin) MIC values will vary depending on the susceptibility testing method employed, composition and pH of the media, and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to Pylokit (Clarithromycin) have not been established.

Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs³ One to three micro-liters of an inoculum equivalent to a No. 2 McFarland standard (1 x 10⁷-1 x 10⁸ CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (>2-weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for Campylobacter species. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The Pylokit (Clarithromycin) and amoxicillin MIC values should be interpreted according to the following criteria

INDICATIONS AND USAGE

Pylokit (Clarithromycin) tablets are indicated for the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions as listed below:

Adults

Pharyngitis/Tonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by either the intramuscular or the oral route. Pylokit (Clarithromycin) is generally effective in the eradication of S. pyogenes from the nasopharynx; however, data establishing the efficacy of Pylokit (Clarithromycin) in the subsequent prevention of rheumatic fever are not available at present.)

Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae

Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae

Community-Acquired Pneumonia due to Haemophilus influenzae, Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae (TWAR)

Uncomplicated skin and skin structure infections due to Staphylococcus aureus, or Streptococcus pyogenes (Abscesses usually require surgical drainage.)

Disseminated mycobacterial infections due to Mycobacterium avium, or Mycobacterium intracellulare

Pylokit (Clarithromycin) tablets in combination with amoxicillin and lansoprazole or omeprazole delayed-release capsules, as triple therapy, are indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to eradicate H. pylori.

Pylokit (Clarithromycin) tablets in combination with omeprazole capsules or ranitidine bismuth citrate tablets are also indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori infection. However, regimens which contain Pylokit (Clarithromycin) as the single antimicrobial agent are more likely to be associated with the development of Pylokit (Clarithromycin) resistance among patients who fail therapy. Clarithromycin-containing regimens should not be used in patients with known or suspected Pylokit (Clarithromycin) resistant isolates because the efficacy of treatment is reduced in this setting.

In patients who fail therapy, susceptibility testing should be done if possible. If resistance to Pylokit (Clarithromycin) is demonstrated, a non-clarithromycin-containing therapy is recommended. (For information on development of resistance see Microbiology section.) The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence.

Children

Pharyngitis/Tonsillitis due to Streptococcus pyogenes

Community-Acquired Pneumonia due to Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae (TWAR)

Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae

Acute otitis media due to Haemophilus influenzae, Moraxella catarrhalis,or Streptococcus pneumoniae

NOTE: For information on otitis media, see CLINICAL STUDIES: Otitis Media .

Uncomplicated skin and skin structure infections due to Staphylococcus aureus, or Streptococcus pyogenes (Abscesses usually require surgical drainage.)

Disseminated mycobacterial infections due to Mycobacterium avium, or Mycobacterium intracellulare

Prophylaxis

Pylokit (Clarithromycin) tablets are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Pylokit (Clarithromycin) tablets and other antibacterial drugs, Pylokit (Clarithromycin) tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy

CONTRAINDICATIONS

Pylokit (Clarithromycin) is contraindicated in patients with a known hypersensitivity to Pylokit (Clarithromycin), erythromycin, or any of the macrolide antibiotics.

Concomitant administration of Pylokit (Clarithromycin) and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine, and ergotamine or dihydroergotamine (see Drug Interactions ). There have been post-marketing reports of drug interactions when Pylokit (Clarithromycin) and/or erythromycin are co-administered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of metabolism of these drugs by erythromycin and Pylokit (Clarithromycin). Fatalities have been reported.

For information about contraindications of other drugs indicated in combination with Pylokit (Clarithromycin), refer to the CONTRAINDICATIONS section of their package inserts.

WARNINGS

Pylokit (Clarithromycin) SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING THIS DRUG, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS. Pylokit (Clarithromycin) HAS DEMONSTRATED ADVERSE EFFECTS OF PREGNANCY OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT IN MONKEYS, RATS, MICE, AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES. (See PRECAUTIONS: Pregnancy .)

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Pylokit (Clarithromycin), and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

There have been post-marketing reports of colchicine toxicity with concomitant use of Pylokit (Clarithromycin) and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients. (See PRECAUTIONS .)

For information about warnings of other drugs indicated in combination with Pylokit (Clarithromycin), refer to the WARNINGS section of their package inserts.

PRECAUTIONS General

Prescribing Pylokit (Clarithromycin) tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Pylokit (Clarithromycin) is principally excreted via the liver and kidney. Pylokit (Clarithromycin) may be administered without dosage adjustment to patients with hepatic impairment and normal renal function. However, in the presence of severe renal impairment with or without coexisting hepatic impairment, decreased dosage or prolonged dosing intervals may be appropriate.

Pylokit (Clarithromycin) in combination with ranitidine bismuth citrate therapy is not recommended in patients with creatinine clearance less than 25 mL/min. (See DOSAGE AND ADMINISTRATION .)

Pylokit (Clarithromycin) in combination with ranitidine bismuth citrate should not be used in patients with a history of acute porphyria.

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving Pylokit (Clarithromycin) therapy.

For information about precautions of other drugs indicated in combination with Pylokit (Clarithromycin), refer to the PRECAUTIONS section of their package inserts.

Information for Patients

Patients should be counseled that antibacterial drugs including Pylokit (Clarithromycin) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Pylokit (Clarithromycin) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Pylokit (Clarithromycin) or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Pylokit (Clarithromycin) tablets may interact with some drugs; therefore patients should be advised to report to their doctor the use of any other medications.

Pylokit (Clarithromycin) tablets can be taken with or without food and can be taken with milk.

Drug Interactions

Pylokit (Clarithromycin) use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range. In two studies in which theophylline was administered with Pylokit (Clarithromycin) (a theophylline sustained-release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg q12h Pylokit (Clarithromycin)), the steady-state levels of C_max, C_min, and the area under the serum concentration time curve (AUC) of theophylline increased about 20%.

Concomitant administration of single doses of Pylokit (Clarithromycin) and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered.

When Pylokit (Clarithromycin) and terfenadine were coadministered, plasma concentrations of the active acid metabolite of terfenadine were threefold higher, on average, than the values observed when terfenadine was administered alone. The pharmacokinetics of Pylokit (Clarithromycin) and the 14-hydroxy-clarithromycin were not significantly affected by coadministration of terfenadine once Pylokit (Clarithromycin) reached steady-state conditions. Concomitant administration of Pylokit (Clarithromycin) with terfenadine is contraindicated. (See CONTRAINDICATIONS .)

Pylokit (Clarithromycin) 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (C_max, AUC_0-24, and T_1/2 increases of 30%, 89%, and 34%, respectively), by the concomitant administration of Pylokit (Clarithromycin). The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with Pylokit (Clarithromycin).

Co-administration of Pylokit (Clarithromycin) with ranitidine bismuth citrate resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%). These effects are clinically insignificant.

Simultaneous oral administration of Pylokit (Clarithromycin) tablets and zidovudine to HIV-infected adult patients resulted in decreased steady-state zidovudine concentrations. When 500 mg of Pylokit (Clarithromycin) were administered twice daily, steady-state zidovudine AUC was reduced by a mean of 12% (n=4). Individual values ranged from a decrease of 34% to an increase of 14%. Based on limited data in 24 patients, when Pylokit (Clarithromycin) tablets were administered two to four hours prior to oral zidovudine, the steady-state zidovudine C_max was increased by approximately 2-fold, whereas the AUC was unaffected.

Simultaneous administration of Pylokit (Clarithromycin) tablets and didanosine to 12 HIV-infected adult patients resulted in no statistically significant change in didanosine pharmacokinetics.

Concomitant administration of fluconazole 200 mg daily and Pylokit (Clarithromycin) 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state Pylokit (Clarithromycin) C_min and AUC of 33% and 18%, respectively. Steady-state concentrations of 14-OH Pylokit (Clarithromycin) were not significantly affected by concomitant administration of fluconazole.

Concomitant administration of Pylokit (Clarithromycin) and ritonavir (n=22) resulted in a 77% increase in Pylokit (Clarithromycin) AUC and a 100% decrease in the AUC of 14-OH Pylokit (Clarithromycin). Pylokit (Clarithromycin) may be administered without dosage adjustment to patients with normal renal function taking ritonavir. However, for patients with renal impairment, the following dosage adjustments should be considered. For patients with CL_CR30 to 60 mL/min, the dose of Pylokit (Clarithromycin) should be reduced by 50%. For patients with CL_CR less than 30 mL/min, the dose of Pylokit (Clarithromycin) should be decreased by 75%.

Spontaneous reports in the post-marketing period suggest that concomitant administration of Pylokit (Clarithromycin) and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving Pylokit (Clarithromycin) and oral anticoagulants simultaneously.

Elevated digoxin serum concentrations in patients receiving Pylokit (Clarithromycin) and digoxin concomitantly have also been reported in post-marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and Pylokit (Clarithromycin) simultaneously.

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Pylokit (Clarithromycin) and other macrolides are known to inhibit CYP3A and Pgp. When Pylokit (Clarithromycin) and colchicine are administered together, inhibition of Pgp and/or CYP3A by Pylokit (Clarithromycin) may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity. (See WARNINGS .)

Erythromycin and Pylokit (Clarithromycin) are substrates and inhibitors of the 3A isoform subfamily of the cytochrome P450 enzyme system (CYP3A). Coadministration of erythromycin or Pylokit (Clarithromycin) and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both the therapeutic and adverse effects of the concomitant drug. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving Pylokit (Clarithromycin) or erythromycin.

The following are examples of some clinically significant CYP3A based drug interactions. Interactions with other drugs metabolized by the CYP3A isoform are also possible. Increased serum concentrations of carbamazepine and the active acid metabolite of terfenadine were observed in clinical trials with Pylokit (Clarithromycin).

The following CYP3A based drug interactions have been observed with erythromycin products and/or with Pylokit (Clarithromycin) in postmarketing experience:

Antiarrhythmics

There have been postmarketing reports of torsades de pointes occurring with concurrent use of Pylokit (Clarithromycin) and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of Pylokit (Clarithromycin) with these drugs. Serum concentrations of these medications should also be monitored.

Ergotamine/Dihydroergotamine

Post-marketing reports indicate that coadministration of Pylokit (Clarithromycin) with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of Pylokit (Clarithromycin) with ergotamine or dihydroergotamine is contraindicated (see CONTRAINDICATIONS ).

Triazolobenziodidiazepines (such as Triazolam and Alprazolam) and Related Benzodiazepines (such as Midazolam)

Erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. There have been post-marketing reports of drug interactions and CNS effects (e.g., somnolence and confusion) with the concomitant use of Pylokit (Clarithromycin) and triazolam.

HMG-CoA Reductase Inhibitors

As with other macrolides, Pylokit (Clarithromycin) has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g., lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.

Sildenafil (Viagra)

Erythromycin has been reported to increase the systemic exposure (AUC) of sildenafil. A similar interaction may occur with Pylokit (Clarithromycin); reduction of sildenafil dosage should be considered.

There have been spontaneous or published reports of CYP3A based interactions of erythromycin and/or Pylokit (Clarithromycin) with cyclosporine, carbamazepine, tacrolimus, alfentanil, disopyramide, rifabutin, quinidine, methylprednisolone, cilostazol, and bromocriptine.

Concomitant administration of Pylokit (Clarithromycin) with cisapride, pimozide, astemizole, or terfenadine is contraindicated (see CONTRAINDICATIONS ).

In addition, there have been reports of interactions of erythromycin or Pylokit (Clarithromycin) with drugs not thought to be metabolized by CYP3A including hexobarbital, phenytoin, and valproate.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The following in vitro mutagenicity tests have been conducted with Pylokit (Clarithromycin):

Salmonella/Mammalian Microsomes Test

Bacterial Induced Mutation Frequency Test

In Vitro Chromosome Aberration Test

Rat Hepatocyte DNA Synthesis Assay

Mouse Lymphoma Assay

Mouse Dominant Lethal Study

Mouse Micronucleus Test

All tests had negative results except the In Vitro Chromosome Aberration Test which was weakly positive in one test and negative in another.

In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed on Pylokit (Clarithromycin) metabolites with negative results.

Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/day (1.3 times the recommended maximum human dose based on mg/m²) to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma levels in rats after 150 mg/kg/day were 2 times the human serum levels.

In the 150 mg/kg/day monkey studies, plasma levels were 3 times the human serum levels. When given orally at 150 mg/kg/day (2.4 times the recommended maximum human dose based on mg/m²), Pylokit (Clarithromycin) was shown to produce embryonic loss in monkeys. This effect has been attributed to marked maternal toxicity of the drug at this high dose.

In rabbits, in utero fetal loss occurred at an intravenous dose of 33 mg/m², which is 17 times less than the maximum proposed human oral daily dose of 618 mg/m².

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Pylokit (Clarithromycin).

PregnancyTeratogenic EffectsPregnancy Category C

Four teratogenicity studies in rats (three with oral doses and one with intravenous doses up to 160 mg/kg/day administered during the period of major organogenesis) and two in rabbits at oral doses up to 125 mg/kg/day (approximately 2 times the recommended maximum human dose based on mg/m²) or intravenous doses of 30 mg/kg/day administered during gestation days 6 to 18 failed to demonstrate any teratogenicity from Pylokit (Clarithromycin). Two additional oral studies in a different rat strain at similar doses and similar conditions demonstrated a low incidence of cardiovascular anomalies at doses of 150 mg/kg/day administered during gestation days 6 to 15. Plasma levels after 150 mg/kg/day were 2 times the human serum levels. Four studies in mice revealed a variable incidence of cleft palate following oral doses of 1000 mg/kg/day (2 and 4 times the recommended maximum human dose based on mg/m², respectively) during gestation days 6 to 15. Cleft palate was also seen at 500 mg/kg/day. The 1000 mg/kg/day exposure resulted in plasma levels 17 times the human serum levels. In monkeys, an oral dose of 70 mg/kg/day (an approximate equidose of the recommended maximum human dose based on mg/m²) produced fetal growth retardation at plasma levels that were 2 times the human serum levels.

There are no adequate and well-controlled studies in pregnant women. Pylokit (Clarithromycin) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See WARNINGS .)

Nursing Mothers

It is not known whether Pylokit (Clarithromycin) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Pylokit (Clarithromycin) is administered to a nursing woman. It is known that Pylokit (Clarithromycin) is excreted in the milk of lactating animals and that other drugs of this class are excreted in human milk. Preweaned rats, exposed indirectly via consumption of milk from dams treated with 150 mg/kg/day for 3 weeks, were not adversely affected, despite data indicating higher drug levels in milk than in plasma.

Pediatric Use

Safety and effectiveness of Pylokit (Clarithromycin) in pediatric patients under 6 months of age have not been established. The safety of Pylokit (Clarithromycin) has not been studied in MAC patients under the age of 20 months. Neonatal and juvenile animals tolerated Pylokit (Clarithromycin) in a manner similar to adult animals. Young animals were slightly more intolerant to acute overdosage and to subtle reductions in erythrocytes, platelets and leukocytes but were less sensitive to toxicity in the liver, kidney, thymus, and genitalia.

Geriatric Use

In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg every 12 hours, the maximum serum concentrations and area under the curves of Pylokit (Clarithromycin) and 14-OH Pylokit (Clarithromycin) were increased compared to those achieved in healthy young adults. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials, elderly patients did not have an increased incidence of adverse events when compared to younger patients. Dosage adjustment should be considered in elderly patients with severe renal impairment. (See WARNINGS and PRECAUTIONS .)

ADVERSE REACTIONS

The majority of side effects observed in clinical trials were of a mild and transient nature. Fewer than 3% of adult patients without mycobacterial infections and fewer than 2% of pediatric patients without mycobacterial infections discontinued therapy because of drug-related side effects.

The most frequently reported events in adults taking Pylokit (Clarithromycin) tablets were diarrhea (3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache (2%). In pediatric patients, the most frequently reported events were diarrhea (6%), vomiting (6%), abdominal pain (3%), rash (3%), and headache (2%). Most of these events were described as mild or moderate in severity. Of the reported adverse events, only 1% was described as severe.

In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse events were reported by a similar proportion of patients taking either Pylokit (Clarithromycin) tablets or Pylokit (Clarithromycin) extended-release tablets; however, patients taking Pylokit (Clarithromycin) extended-release tablets reported significantly less severe gastrointestinal symptoms compared to patients taking Pylokit (Clarithromycin) tablets. In addition, patients taking Pylokit (Clarithromycin) extended-release tablets had significantly fewer premature discontinuations for drug-related gastrointestinal or abnormal taste adverse events compared to Pylokit (Clarithromycin) tablets.

In community-acquired pneumonia studies conducted in adults comparing Pylokit (Clarithromycin) to erythromycin base or erythromycin stearate, there were fewer adverse events involving the digestive system in clarithromycin-treated patients compared to erythromycin-treated patients (13% vs 32%; p less than 0.01). Twenty percent of erythromycin-treated patients discontinued therapy due to adverse events compared to 4% of clarithromycin-treated patients.

In two U.S. studies of acute otitis media comparing Pylokit (Clarithromycin) to amoxicillin/potassium clavulanate in pediatric patients, there were fewer adverse events involving the digestive system in clarithromycin-treated patients compared to amoxicillin/potassium clavulanate-treated patients (21% vs 40%, p less than 0.001). One-third as many clarithromycin-treated patients reported diarrhea as did amoxicillin/potassium clavulanate-treated patients.

Post-Marketing Experience

Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Other spontaneously reported adverse events include glossitis, stomatitis, oral moniliasis, anorexia, vomiting, pancreatitis, tongue discoloration, thrombocytopenia, leukopenia, neutropenia, and dizziness. There have been reports of tooth discoloration in patients treated with Pylokit (Clarithromycin). Tooth discoloration is usually reversible with professional dental cleaning. There have been isolated reports of hearing loss, which is usually reversible, occurring chiefly in elderly women. Reports of alterations of the sense of smell, usually in conjunction with taste perversion or taste loss have also been reported.

Transient CNS events including anxiety, behavioral changes, confusional states, convulsions, depersonalization, disorientation, hallucinations, insomnia, manic behavior, nightmares, psychosis, tinnitus, tremor, and vertigo have been reported during post-marketing surveillance. Events usually resolve with discontinuation of the drug.

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with Pylokit (Clarithromycin). This hepatic dysfunction may be severe and is usually reversible. In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.

There have been rare reports of hypoglycemia, some of which have occurred in patients taking oral hypoglycemic agents or insulin.

As with other macrolides, Pylokit (Clarithromycin) has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes.

There have been reports of interstitial nephritis coincident with Pylokit (Clarithromycin) use.

There have been post-marketing reports of colchicine toxicity with concomitant use of Pylokit (Clarithromycin) and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients. (See WARNINGS and PRECAUTIONS .)

Changes in Laboratory Values

Changes in laboratory values with possible clinical significance were as follows:

Hepatic – elevated SGPT (ALT) less than 1%; SGOT (AST) less than 1%; GGT less than 1%; alkaline phosphatase less than 1%; LDH less than 1%; total bilirubin less than 1%

Hematologic – decreased WBC less than 1%; elevated prothrombin time 1%

Renal – elevated BUN 4%; elevated serum creatinine less than 1% GGT, alkaline phosphatase, and prothrombin time data are from adult studies only.

OVERDOSAGE

Overdosage of Pylokit (Clarithromycin) can cause gastrointestinal symptoms such as abdominal pain, vomiting, nausea, and diarrhea.

Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, Pylokit (Clarithromycin) serum concentrations are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.

DOSAGE AND ADMINISTRATION . pylori Eradication to Reduce the Risk of Duodenal Ulcer RecurrenceTriple Therapy: Clarithromycin/Lansoprazole/Amoxicillin

The recommended adult dose is 500 mg Pylokit (Clarithromycin), 30 mg lansoprazole, and 1 gram amoxicillin, all given twice daily (q12h) for 10 or 14 days. (See INDICATIONS AND USAGE and CLINICAL STUDIES sections.)

Triple Therapy: Clarithromycin/Omeprazole/Amoxicillin

The recommended adult dose is 500 mg Pylokit (Clarithromycin), 20 mg omeprazole, and 1 gram amoxicillin, all given twice daily (q12h) for 10 days. (See INDICATIONS AND USAGE and CLINICAL STUDIES sections.) In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief.

Dual Therapy: Clarithromycin/Omeprazole

The recommended adult dose is 500 mg Pylokit (Clarithromycin) given three times daily (q8h) and 40 mg omeprazole given once daily (qAM) for 14 days. (See INDICATIONS AND USAGE and CLINICAL STUDIES sections.) An additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief.

Dual Therapy: Clarithromycin/Ranitidine Bismuth Citrate

The recommended adult dose is 500 mg Pylokit (Clarithromycin) given twice daily (q12h) or three times daily (q8h) and 400 mg ranitidine bismuth citrate given twice daily (q12h) for 14 days. An additional 14 days of 400 mg twice daily is recommended for ulcer healing and symptom relief. Pylokit (Clarithromycin) and ranitidine bismuth citrate combination therapy is not recommended in patients with creatinine clearance less than 25 mL/min. (See INDICATIONS AND USAGE and CLINICAL STUDIES sections.)

Children

The usual recommended daily dosage is 15 mg/kg/day divided q12h for 10 days

Pylokit (Clarithromycin) may be administered without dosage adjustment in the presence of hepatic impairment if there is normal renal function. However, in the presence of severe renal impairment (CR_CL less than 30 mL/min), with or without coexisting hepatic impairment, the dose should be halved or the dosing interval doubled.

Mycobacterial InfectionsProphylaxis

The recommended dose of Pylokit (Clarithromycin) for the prevention of disseminated Mycobacterium avium disease is 500 mg b.i.d. In children, the recommended dose is 7.5 mg/kg b.i.d. up to 500 mg b.i.d. No studies of Pylokit (Clarithromycin) for MAC prophylaxis have been performed in pediatric populations and the doses recommended for prophylaxis are derived from MAC treatment studies in children. Dosing recommendations for children are in the table above.

Treatment

Pylokit (Clarithromycin) is recommended as the primary agent for the treatment of disseminated infection due to Mycobacterium avium complex. Pylokit (Clarithromycin) should be used in combination with other antimycobacterial drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment. (See CLINICAL STUDIES .) The recommended dose for mycobacterial infections in adults is 500 mg b.i.d. In children, the recommended dose is 7.5 mg/kg b.i.d. up to 500 mg b.i.d. Dosing recommendations for children are in the table above.

Pylokit (Clarithromycin) therapy should continue for life if clinical and mycobacterial improvements are observed.

HOW SUPPLIED

Pylokit (Clarithromycin) tablets 250 mg are white, oval-shaped, film-coated tablets, debossed GG C6 on one side and plain on the reverse side, and are supplied as follows:

Pylokit (Clarithromycin) tablets 500 mg are white, oval-shaped, film-coated tablets, debossed GG C9 on one side and plain on the reverse side, and are supplied as follows:

Store at 20°-25°C (68°-77°F).

Dispense in a tight container as described in the USP. Protect from light.

Clinical Studies

CLINICAL STUDIES Mycobacterial InfectionsProphylaxis

A randomized, double-blind study (561) compared Pylokit (Clarithromycin) 500 mg b.i.d. to placebo in patients with CDC-defined AIDS and CD₄ counts less than 100 cells/µL. This study accrued 682 patients from November 1992 to January 1994, with a median CD₄ cell count at study entry of 30 cells/µL. Median duration of Pylokit (Clarithromycin) was 10.6 months vs. 8.2 months for placebo. More patients in the placebo arm than the Pylokit (Clarithromycin) arm discontinued prematurely from the study (75.6% and 67.4%, respectively). However, if premature discontinuations due to MAC or death are excluded, approximately equal percentages of patients on each arm (54.8% on Pylokit (Clarithromycin) and 52.5% on placebo) discontinued study drug early for other reasons. The study was designed to evaluate the following endpoints:

• MAC bacteremia, defined as at least one positive culture for M. avium complex bacteria from blood or another normally sterile site.
• Survival
• Clinically significant disseminated MAC disease, defined as MAC bacteremia accompanied by signs or symptoms of serious MAC infection, including fever, night sweats, weight loss, anemia, or elevations in liver function tests.

MAC Bacteremia

In patients randomized to Pylokit (Clarithromycin), the risk of MAC bacteremia was reduced by 69% compared to placebo. The difference between groups was statistically significant (p less than 0.001). On an intent-to-treat basis, the one-year cumulative incidence of MAC bacteremia was 5.0% for patients randomized to Pylokit (Clarithromycin) and 19.4% for patients randomized to placebo. While only 19 of the 341 patients randomized to Pylokit (Clarithromycin) developed MAC, 11 of these cases were resistant to Pylokit (Clarithromycin). The patients with resistant MAC bacteremia had a median baseline CD₄ count of 10 cells/mm³ (range 2 to 25 cells/mm³). Information regarding the clinical course and response to treatment of the patients with resistant MAC bacteremia is limited. The 8 patients who received Pylokit (Clarithromycin) and developed susceptible MAC bacteremia had a median baseline CD₄ count of 25 cells/mm³ (range 10 to 80 cells/mm³). Comparatively, 53 of the 341 placebo patients developed MAC; none of these isolates were resistant to Pylokit (Clarithromycin). The median baseline CD₄ count was 15 cells/mm³ (range 2 to 130 cells/mm³) for placebo patients that developed MAC.

Survival

Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of Pylokit (Clarithromycin) may be underestimated.

Clinically Significant Disseminated MAC Disease

In association with the decreased incidence of bacteremia, patients in the group randomized to Pylokit (Clarithromycin) showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, and anemia.

Safety

In AIDS patients treated with Pylokit (Clarithromycin) over long periods of time for prophylaxis against M. avium, it was often difficult to distinguish adverse events possibly associated with Pylokit (Clarithromycin) administration from underlying HIV disease or intercurrent illness. Median duration of treatment was 10.6 months for the Pylokit (Clarithromycin) group and 8.2 months for the placebo group.

Among these events, taste perversion was the only event that had significantly higher incidence in the clarithromycin-treated group compared to the placebo-treated group.

Discontinuation due to adverse events was required in 18% of patients receiving Pylokit (Clarithromycin) compared to 17% of patients receiving placebo in this trial. Primary reasons for discontinuation in Pylokit (Clarithromycin) treated patients include headache, nausea, vomiting, depression and taste perversion.

Changes in Laboratory Values of Potential Clinical ImportanceTreatment

Three randomized studies (500, 577, and 521) compared different dosages of Pylokit (Clarithromycin) in patients with CDC-defined AIDS and CD₄ counts less than 100 cells/mcL. These studies accrued patients from May 1991 to March 1992. Study 500 was randomized, double-blind; Study 577 was open-label compassionate use. Both studies used 500 and 1000 mg b.i.d. doses; Study 500 also had a 2000 mg b.i.d. group. Study 521 was a pediatric study at 3.75, 7.5, and 15 mg/kg b.i.d. Study 500 enrolled 154 adult patients, Study 577 enrolled 469 adult patients, and Study 521 enrolled 25 patients between the ages of 1 to 20. The majority of patients had CD₄ cell counts less than 50/mcL at study entry. The studies were designed to evaluate the following end points:

• Change in MAC bacteremia or blood cultures negative for M. avium.
• Change in clinical signs and symptoms of MAC infection including one or more of the following: fever, night sweats, weight loss, diarrhea, splenomegaly, and hepatomegaly.

The results for the 500 study are described below. The 577 study results were similar to the results of the 500 study. Results with the 7.5 mg/kg b.i.d. dose in the pediatric study were comparable to those for the 500 mg b.i.d. regimen in the adult studies.

Study 069 compared the safety and efficacy of Pylokit (Clarithromycin) in combination with ethambutol versus Pylokit (Clarithromycin) in combination with ethambutol and clofazimine for the treatment of disseminated MAC (dMAC) infection⁴. This 24-week study enrolled 106 patients with AIDS and dMAC, with 55 patients randomized to receive Pylokit (Clarithromycin) and ethambutol, and 51 patients randomized to receive Pylokit (Clarithromycin), ethambutol, and clofazimine. Baseline characteristics between study arms were similar with the exception of median CFU counts being at least 1 log higher in the Pylokit (Clarithromycin), ethambutol, and clofazimine arm.

Compared to prior experience with Pylokit (Clarithromycin) monotherapy, the two-drug regimen of Pylokit (Clarithromycin) and ethambutol was well tolerated and extended the time to microbiologic relapse, largely through suppressing the emergence of Pylokit (Clarithromycin) resistant strains. However, the addition of clofazimine to the regimen added no additional microbiologic or clinical benefit. Tolerability of both multidrug regimens was comparable with the most common adverse events being gastrointestinal in nature. Patients receiving the clofazimine-containing regimen had reduced survival rates; however, their baseline mycobacterial colony counts were higher. The results of this trial support the addition of ethambutol to Pylokit (Clarithromycin) for the treatment of initial dMAC infections but do not support adding clofazimine as a third agent.

MAC Bacteremia

Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose groups. Mean reductions in colony forming units (CFU) are shown below. Included in the table are results from a separate study with a four drug regimen⁵ (ciprofloxacin, ethambutol, rifampicin, and clofazimine). Since patient populations and study procedures may vary between these two studies, comparisons between the Pylokit (Clarithromycin) results and the combination therapy results should be interpreted cautiously.

significant differences were seen beyond that point. The percent of patients whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was 61% (30/49) for the 500 mg b.i.d. group and 59% (29/49) and 52% (25/48) for the 1000 and 2000 mg b.i.d. groups, respectively. The percent of patients who had 2 or more negative cultures during acute therapy that were sustained through study Day 84 was 25% (12/49) in both the 500 and 1000 mg b.i.d. groups and 8% (4/48) for the 2000 mg b.i.d. group. By Day 84, 23% (11/49), 37% (18/49), and 56% (27/48) of patients had died or discontinued from the study, and 14% (7/49), 12% (6/49), and 13% (6/48) of patients had relapsed in the 500, 1000, and 2000 mg b.i.d. dose groups, respectively. All of the isolates had an MIC less than 8 mcg/mL at pre-treatment. Relapse was almost always accompanied by an increase in MIC. The median time to first negative culture was 54, 41, and 29 days for the 500, 1000, and 2000 mg b.i.d. groups, respectively. The time to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg b.i.d. doses (median equal to 16 and 15 days, respectively) in comparison to the 500 mg b.i.d. group (median equal to 29 days). The median time to first positive culture or study discontinuation following the first negative culture was 43, 59 and 43 days for the 500, 1000, and 2000 mg b.i.d. groups, respectively.

Clinically Significant Disseminated MAC Disease

Among patients experiencing night sweats prior to therapy, 84% showed resolution or improvement at some point during the 12 weeks of Pylokit (Clarithromycin) at 500 to 2000 mg b.i.d. doses. Similarly, 77% of patients reported resolution or improvement in fevers at some point. Response rates for clinical signs of MAC are given below

The median duration of response, defined as improvement or resolution of clinical signs and symptoms, was 2 to 6 weeks.

Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks, the duration of response may be underestimated for the 25 to 33% of patients who continued to show clinical response after 12 weeks.

Survival

Median survival time from study entry (Study 500) was 249 days at the 500 mg b.i.d. dose compared to 215 days with the 1000 mg b.i.d. dose. However, during the first 12 weeks of therapy, there were 2 deaths in 53 patients in the 500 mg b.i.d. group versus 13 deaths in 51 patients in the 1000 mg b.i.d. group. The reason for this apparent mortality difference is not known. Survival in the two groups was similar beyond 12 weeks. The median survival times for these dosages were similar to recent historical controls with MAC when treated with combination therapies.⁵

Median survival time from study entry in Study 577 was 199 days for the 500 mg b.i.d. dose and 179 days for the 1000 mg b.i.d. dose. During the first four weeks of therapy, while patients were maintained on their originally assigned dose, there were 11 deaths in 255 patients taking 500 mg b.i.d. and 18 deaths in 214 patients taking 1000 mg b.i.d.

Safety

The adverse event profiles showed that both the 500 and 1000 mg b.i.d. doses were well tolerated. The 2000 mg b.i.d. dose was poorly tolerated and resulted in a higher proportion of premature discontinuations.

In AIDS patients and other immunocompromised patients treated with the higher doses of Pylokit (Clarithromycin) over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with Pylokit (Clarithromycin) administration from underlying signs of HIV disease or intercurrent illness.

The following analyses summarize experience during the first 12 weeks of therapy with Pylokit (Clarithromycin). Data are reported separately for Study 500 (randomized, double-blind) and Study 577 (open-label, compassionate use) and also combined. Adverse events were reported less frequently in Study 577, which may be due in part to differences in monitoring between the two studies. In adult patients receiving Pylokit (Clarithromycin) 500 mg b.i.d., the most frequently reported adverse events, considered possibly or probably related to study drug, with an incidence of 5% or greater, are listed below. Most of these events were mild to moderate in severity, although 5% (Study 500: 8%; Study 577: 4%) of patients receiving 500 mg b.i.d. and 5% (Study 500: 4%; Study 577: 6%) of patients receiving 1000 mg b.i.d. reported severe adverse events. Excluding those patients who discontinued therapy or died due to complications of their underlying non-mycobacterial disease, approximately 8% (Study 500: 15%; Study 577: 7%) of the patients who received 500 mg b.i.d. and 12% (Study 500: 14%; Study 577: 12%) of the patients who received 1000 mg b.i.d. discontinued therapy due to drug-related events during the first 12 weeks of therapy. Overall, the 500 and 1000 mg b.i.d. doses had similar adverse event profiles.

image of label

Lansoprazole:

• Active ingredient (in each capsule)
• Purpose
• Use
• Warnings
• Directions
• Inactive ingredients
• Lansoprazole dr 15mg capsule
• Pylokit (Lansoprazole) reviews

Active ingredient

Pylokit (Lansoprazole) 15 mg

Purpose

Acid reducer

Use

• treats frequent heartburn (occurs 2 or more days a week)
• not intended for immediate relief of heartburn; this drug may take 1 to 4 days for full effect

Warnings

Allergy alert: Do not use if you are allergic to Pylokit

Do not use

• if you have trouble or pain swallowing food, vomiting with blood, or bloody or black stools. These may be signs of a serious condition. See your doctor.

Ask a doctor before use if you have

• liver disease
• had heartburn over 3 months. This may be a sign of a more serious condition.
• heartburn with lightheadedness, sweating or dizziness
• chest pain or shoulder pain with shortness of breath; sweating; pain spreading to arms, neck or shoulders; or lightheadedness
• frequent chest pain
• frequent wheezing, particularly with heartburn
• unexplained weight loss
• nausea or vomiting
• stomach pain

Ask a doctor or pharmacist before use if you are taking

• warfarin
• prescription antifungal or anti-yeast medicines
• digoxin (heart medicine)
• theophylline (asthma medicine)
• tacrolimus or mycophenolate mofetil (immune system medicines)
• atazanavir (medicine for HIV infection)
• methotrexate (arthritis medicine)

Stop use and ask a doctor if

• your heartburn continues or worsens
• you need to take this product for more than 14 days
• you need to take more than 1 course of treatment every 4 months
• you get diarrhea

If pregnant or breast-feeding,

ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

Directions

• adults 18 years of age and older
• this product is to be used once a day, every day for 14 days
• it may take 1 to 4 days for full effect, although some people get complete relief of symptoms within 24 hours

14-Day Course of Treatment

• swallow 1 capsule with a glass of water before eating in the morning
• take every day for 14 days
• do not take more than 1 capsule a day
• swallow whole. Do not crush or chew capsules.
• do not use for more than 14 days unless directed by your doctor

Repeated 14-Day Courses (if needed)

• you may repeat a 14-day course every 4 months
• do not take for more than 14 days or more often than every 4 months unless directed by a doctor
• children under 18 years of age: ask a doctor before use. Heartburn in children may sometimes be caused by a serious condition.

Other information

• read the directions, warnings and package insert before use
• keep the carton and package insert. They contain important information.
• store at 20-25˚C (68-77˚F)
• keep product out of high heat and humidity
• protect product from moisture

Inactive ingredients

D&C red no. 28, D&C yellow no. 10, FD&C blue no. 1, gelatin, hypromellose, low substituted hydroxypropyl cellulose, mannitol, meglumine, methacrylic acid copolymer, pharmaceutical ink, polyethylene glycol, polysorbate 80, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide

Questions or comments?

1-800-719-9260

Consumer Information

Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg

Acid Reducer

- May take 1 to 4 days for full effect, although some people get complete relief of symptoms within 24 hours

Please read the entire package insert before taking Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg.

Save for future reference.

How Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg Treats Your Frequent Heartburn

Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg stops acid production at the source – the pumps that release acid into the stomach. Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg is taken once a day (every 24 hours), every day for 14 days.

What You Can Expect When Taking Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg

Frequent heartburn can occur anytime during the 24-hour period (day or night). Take Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg in the morning before eating. Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg is clinically proven to treat frequent heartburn. Although some people get complete relief of symptoms within 24 hours, it may take 1 to 4 days for full effect. Make sure you take Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg every day for 14 days to treat your frequent heartburn.

Who Should Take Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg Adults (18 years and older) with frequent heartburn – when you have heartburn 2 or more days a week.

Who Should NOT Take Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg

People who have one episode of heartburn a week or less, or who want immediate relief of heartburn.

How to Take Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg

14-DAY Course of Treatment

• Swallow 1 capsule with a glass of water before eating in the morning.
• Take every day for 14 days.
• Do not take more than 1 capsule a day.
• Swallow whole. Do not crush or chew capsules.
• Do not use for more than 14 days unless directed by your doctor.

When to Take Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg Again

You may repeat a 14-day course of therapy every 4 months.

When to Talk to Your Doctor

Do not take for more than 14 days or more often than every 4 months unless directed by a doctor.

Warnings and When to Ask Your Doctor

Allergy alert: Do not use if you are allergic to Pylokit (Lansoprazole)

Do not use

• if you have trouble or pain swallowing food, vomiting with blood, or bloody or black stools. These may be signs of a serious condition. See your doctor.

Ask a doctor before use if you have

• liver disease
• had heartburn over 3 months. This may be a sign of a more serious condition.
• heartburn with lightheadedness, sweating or dizziness
• chest pain or shoulder pain with shortness of breath; sweating; pain spreading to arms, neck or shoulders; or lightheadedness
• frequent chest pain
• frequent wheezing, particularly with heartburn
• unexplained weight loss
• nausea or vomiting
• stomach pain

Ask a doctor or pharmacist before use if you are taking

• warfarin (blood-thinning medicine)
• prescription antifungal or anti-yeast medicines
• digoxin (heart medicine)
• theophylline (asthma medicine)
• tacrolimus or mycophenolate mofetil (immune system medicines)
• atazanavir (medicine for HIV infection)
• methotrexate (arthritis medicine)

Stop use and ask a doctor if

• your heartburn continues or worsens
• you need to take this product for more than 14 days
• you need to take more than 1 course of treatment every 4 months
• you get diarrhea

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

Tips for Managing Heartburn

• Avoid foods or drinks that are more likely to cause heartburn, such as rich, spicy, fatty and fried foods, chocolate, caffeine, alcohol and even some acidic fruits and vegetables.
• Eat slowly and do not eat big meals.
• Do not eat late at night or just before bedtime.
• Do not lie flat or bend over soon after eating.
• Raise the head of your bed.
• Wear loose-fitting clothing around your stomach.
• If you are overweight, lose weight.
• If you smoke, quit smoking.

Clinical studies prove Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg effectively treats frequent heartburn

In three clinical studies, Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg was shown to be significantly better than placebo in treating frequent heartburn.

How Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg is Sold

Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg is available in 14 capsule, 28 capsule and 42 capsule sizes. These sizes contain one, two and three 14-day courses of treatment, respectively. Do not use for more than 14 days in a row unless directed by your doctor. For the 28 count (two 14-day courses) and the 42 count (three 14-day courses), you may repeat a 14-day course every 4 months.

For Questions or Comments About Pylokit (Lansoprazole) Delayed-Release Capsules 15 mg

Call 1-800-719-9260

Pylokit DR 15mg Capsule

Tinidazole:

• Warning: potential risk for carcinogenicity
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• Patient counseling information
• Pylokit (Tinidazole) reviews

WARNING: POTENTIAL RISK FOR CARCINOGENICITY

Carcinogenicity has been seen in mice and rats treated chronically with metronidazole, another nitroimidazole agent ( 13.1). Although such data have not been reported for Pylokit (Tinidazole), the two drugs are structurally related and have similar biologic effects. Its use should be reserved for the conditions described in INDICATIONS AND USAGE ( 1).

WARNING: POTENTIAL RISK FOR CARCINOGENICITY

See full prescribing information for complete boxed warning.

Carcinogenicity has been seen in mice and rats treated chronically with metronidazole, another nitroimidazole agent ( 13.1). Although such data have not been reported for Pylokit (Tinidazole), the two drugs are structurally related and have similar biologic effects. Use should be limited to approved indications only.

Indications and Usage, Bacterial Vaginosis ( 1.4) 5/2007

Dosage and Administration, Bacterial Vaginosis ( 2.6) 5/2007

1 INDICATIONS AND USAGE

Pylokit is a nitroimidazole antimicrobial indicated for:

• Trichomoniasis ( 1.1)
• Giardiasis: in patients age 3 and older ( 1.2)
• Amebiasis: in patients age 3 and older ( 1.3)
• Bacterial Vaginosis: in non-pregnant, adult women ( 1.4, 8.1)

1.1 Trichomoniasis

Pylokit (Tinidazole) is indicated for the treatment of trichomoniasis caused by Trichomonas vaginalis. The organism should be identified by appropriate diagnostic procedures. Because trichomoniasis is a sexually transmitted disease with potentially serious sequelae, partners of infected patients should be treated simultaneously in order to prevent re-infection .

1.2 Giardiasis

Pylokit is indicated for the treatment of giardiasis caused by Giardia duodenalis (also termed G. lamblia) in both adults and pediatric patients older than three years of age .

1.3 Amebiasis

Pylokit (Tinidazole) is indicated for the treatment of intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica in both adults and pediatric patients older than three years of age. It is not indicated in the treatment of asymptomatic cyst passage .

1.4 Bacterial Vaginosis

Pylokit (Tinidazole) is indicated for the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, or anaerobic vaginosis) in non-pregnant women .

Other pathogens commonly associated with vulvovaginitis such as Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Candida albicans and Herpes simplex virus should be ruled out.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Pylokit (Tinidazole) and other antibacterial drugs, Pylokit (Tinidazole) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION

• Trichomoniasis: a single 2 g oral dose taken with food. Treat sexual partners with the same dose and at the same time
• Giardiasis: Adults: a single 2 g dose taken with food. Pediatric patients older than three years of age: a single dose of 50 mg/kg (up to 2 g) with food ( 2.4)
• Amebiasis, Intestinal: Adults: 2 g per day for 3 days with food. Pediatric patients older than three years of age: 50 mg/kg/day (up to 2 g per day) for 3 days with food ( 2.5). Amebic liver abscess: Adults: 2 g per day for 3-5 days with food. Pediatric patients older than three years of age: 50 mg/kg/day (up to 2 g per day) for 3-5 days with food ( 2.5)
• Bacterial vaginosis: Non-pregnant, adult women: 2 g once daily for 2 days taken with food, or 1 g once daily for 5 days taken with food ( 2.6)

2.1 Dosing Instructions

It is advisable to take Pylokit (Tinidazole) with food to minimize the incidence of epigastric discomfort and other gastrointestinal side-effects. Food does not affect the oral bioavailability of Pylokit (Tinidazole) .

Alcoholic beverages should be avoided when taking Pylokit (Tinidazole) and for 3 days afterwards .

2.2 Compounding of the Oral Suspension

For those unable to swallow tablets, Pylokit tablets may be crushed in artificial cherry syrup to be taken with food.

Procedure for Extemporaneous Pharmacy Compounding of the Oral Suspension: Pulverize four 500 mg oral tablets with a mortar and pestle. Add approximately 10 mL of cherry syrup to the powder and mix until smooth. Transfer the suspension to a graduated amber container. Use several small rinses of cherry syrup to transfer any remaining drug in the mortar to the final suspension for a final volume of 30 mL. The suspension of crushed tablets in artificial cherry syrup is stable for 7 days at room temperature. When this suspension is used, it should be shaken well before each administration.

2.3 Trichomoniasis

The recommended dose in both females and males is a single 2 g oral dose taken with food. Since trichomoniasis is a sexually transmitted disease, sexual partners should be treated with the same dose and at the same time.

2.4 Giardiasis

The recommended dose in adults is a single 2 g dose taken with food. In pediatric patients older than three years of age, the recommended dose is a single dose of 50 mg/kg with food.

2.5 Amebiasis

Intestinal: The recommended dose in adults is a 2 g dose per day for 3 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3 days with food.

Amebic Liver Abscess: The recommended dose in adults is a 2 g dose per day for 3-5 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3-5 days with food. There are limited pediatric data on durations of therapy exceeding 3 days, although a small number of children were treated for 5 days without additional reported adverse reactions. Children should be closely monitored when treatment durations exceed 3 days.

2.6 Bacterial Vaginosis

The recommended dose in non-pregnant females is a 2 g oral dose once daily for 2 days taken with food or a 1 g oral dose once daily for 5 days taken with food. The use of Pylokit (Tinidazole) in pregnant patients has not been studied for bacterial vaginosis.

3 DOSAGE FORMS AND STRENGTHS

• 500 mg tablets are pink, oval, scored tablets, with TM debossed on one side and 500 on the other

4 CONTRAINDICATIONS

The use of Pylokit (Tinidazole) is contraindicated:

• In patients with a previous history of hypersensitivity to Pylokit (Tinidazole) or other nitroimidazole derivatives. Reported reactions have ranged in severity from urticaria to Stevens-Johnson syndrome .
• During first trimester of pregnancy .
• In nursing mothers: Interruption of breast-feeding is recommended during Pylokit (Tinidazole) therapy and for 3 days following the last dose .

• Prior history of hypersensitivity to Pylokit (Tinidazole) or other nitroimidazole derivatives ( 4, 6.1, 6.2)
• First trimester of pregnancy ( 4, 8.1)
• Nursing mothers, unless breast-feeding is interrupted during Pylokit (Tinidazole) therapy and for 3 days following the last dose ( 4, 8.3)

5 WARNINGS AND PRECAUTIONS

• Seizures and neuropathy have been reported. Discontinue Pylokit if abnormal neurologic signs develop ( 5.1)
• Vaginal candidiasis may develop with Pylokit (Tinidazole) and require treatment with an antifungal agent ( 5.2)
• Use Pylokit (Tinidazole) with caution in patients with blood dyscrasias. Pylokit (Tinidazole) may produce transient leukopenia and neutropenia ( 5.3, 7.3)

5.1 Neurological Adverse Reactions

Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with Pylokit (Tinidazole). The appearance of abnormal neurologic signs demands the prompt discontinuation of Pylokit (Tinidazole) therapy.

5.2 Vaginal Candidiasis

The use of Pylokit may result in Candida vaginitis. In a clinical study of 235 women who received Pylokit (Tinidazole) for bacterial vaginosis, a vaginal fungal infection developed in 11 (4.7%) of all study subjects .

5.3 Blood Dyscrasia

Pylokit (Tinidazole) should be used with caution in patients with evidence of or history of blood dyscrasia .

5.4 Drug Resistance

Prescribing Pylokit (Tinidazole) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS

Most common adverse reactions for a single 2 g dose of Pylokit (incidence >1%) are metallic/bitter taste, nausea, weakness/fatigue/malaise, dyspepsia/cramps/epigastric discomfort, vomiting, anorexia, headache, dizziness and constipation ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Mission Pharmacal Company at 1-855-778-0177or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction 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.

Among 3669 patients treated with a single 2 g dose of Pylokit (Tinidazole), in both controlled and uncontrolled trichomoniasis and giardiasis clinical studies, adverse reactions were reported by 11.0% of patients. For multi-day dosing in controlled and uncontrolled amebiasis studies, adverse reactions were reported by 13.8% of 1765 patients. Common (≥ 1% incidence) adverse reactions reported by body system are as follows. (Note: Data described in Table 1 below are pooled from studies with variable designs and safety evaluations.)

Other adverse reactions reported with Pylokit (Tinidazole) include:

Central Nervous System: Two serious adverse reactions reported include convulsions and transient peripheral neuropathy including numbness and paresthesia . Other CNS reports include vertigo, ataxia, giddiness, insomnia, drowsiness.

Gastrointestinal: tongue discoloration, stomatitis, diarrhea

Hypersensitivity: urticaria, pruritis, rash, flushing, sweating, dryness of mouth, fever, burning sensation, thirst, salivation, angioedema

Renal: darkened urine

Cardiovascular: palpitations

Hematopoietic: transient neutropenia, transient leukopenia

Other: Candida overgrowth, increased vaginal discharge, oral candidiasis, hepatic abnormalities including raised transaminase level, arthralgias, myalgias, and arthritis.

	2 g single dose	Multi-day dose
GI: Metallic/bitter taste	3.7%	6.3%
Nausea	3.2%	4.5%
Anorexia	1.5%	2.5%
Dyspepsia/cramps/epigastric discomfort	1.8%	1.4%
Vomiting	1.5%	0.9%
Constipation	0.4%	1.4%
CNS: Weakness/fatigue/malaise	2.1%	1.1%
Dizziness	1.1%	0.5%
Other: Headache	1.3%	0.7%
Total patients with adverse reactions	11.0% (403/3669)	13.8% (244/1765)

Rare reported adverse reactions include bronchospasm, dyspnea, coma, confusion, depression, furry tongue, pharyngitis and reversible thrombocytopenia.

Adverse Reactions in Pediatric Patients: In pooled pediatric studies, adverse reactions reported in pediatric patients taking Pylokit (Tinidazole) were similar in nature and frequency to adult findings including nausea, vomiting, diarrhea, taste change, anorexia, and abdominal pain.

Bacterial vaginosis: The most common adverse reactions in treated patients (incidence >2%), which were not identified in the trichomoniasis, giardiasis and amebiasis studies, are gastrointestinal: decreased appetite, and flatulence; renal: urinary tract infection, painful urination, and urine abnormality; and other reactions including pelvic pain, vulvo-vaginal discomfort, vaginal odor, menorrhagia, and upper respiratory tract infection .

6.2 Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of Pylokit (Tinidazole). Because the reports of these reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.

Severe acute hypersensitivity reactions have been reported on initial or subsequent exposure to Pylokit (Tinidazole). Hypersensitivity reactions may include urticaria, pruritis, angioedema, Stevens-Johnson syndrome and erythema multiforme.

7 DRUG INTERACTIONS

Although not specifically identified in studies with Pylokit, the following drug interactions were reported for metronidazole, a chemically-related nitroimidazole. Therefore, these drug interactions may occur with Pylokit (Tinidazole).

The following drug interactions were reported for metronidazole, a chemically-related nitroimidazole and may therefore occur with Pylokit (Tinidazole):

• Warfarin and other oral coumarin anticoagulants: Anticoagulant dosage may need adjustment during and up to 8 days after Pylokit (Tinidazole) therapy ( 7.1)
• Alcohol-containing beverages/preparations: Avoid during and up to 3 days after Pylokit (Tinidazole) therapy ( 7.1)
• Lithium: Monitor serum lithium concentrations ( 7.1)
• Cyclosporine, tacrolimus: Monitor for toxicities of these immunosuppressive drugs ( 7.1)
• Fluorouracil: Monitor for fluorouracil-associated toxicities ( 7.1)
• Phenytoin, fosphenytoin: Adjustment of anticonvulsant and/or Pylokit (Tinidazole) dose(s) may be needed ( 7.1, 7.2)
• CYP3A4 inducers/inhibitors: Monitor for decreased Pylokit (Tinidazole) effect or increased adverse reactions ( 7.2)

7.1 Potential Effects of Pylokit (Tinidazole) on Other Drugs

Warfarin and Other Oral Coumarin Anticoagulants: As with metronidazole, Pylokit (Tinidazole) may enhance the effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. The dosage of oral anticoagulants may need to be adjusted during Pylokit (Tinidazole) co-administration and up to 8 days after discontinuation.

Alcohols, Disulfiram: Alcoholic beverages and preparations containing ethanol or propylene glycol should be avoided during Pylokit (Tinidazole) therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. Psychotic reactions have been reported in alcoholic patients using metronidazole and disulfiram concurrently. Though no similar reactions have been reported with Pylokit (Tinidazole), Pylokit (Tinidazole) should not be given to patients who have taken disulfiram within the last two weeks.

Lithium: Metronidazole has been reported to elevate serum lithium levels. It is not known if Pylokit (Tinidazole) shares this property with metronidazole, but consideration should be given to measuring serum lithium and creatinine levels after several days of simultaneous lithium and Pylokit (Tinidazole) treatment to detect potential lithium intoxication.

Phenytoin, Fosphenytoin: Concomitant administration of oral metronidazole and intravenous phenytoin was reported to result in prolongation of the half-life and reduction in the clearance of phenytoin. Metronidazole did not significantly affect the pharmacokinetics of orally-administered phenytoin.

Cyclosporine, Tacrolimus: There are several case reports suggesting that metronidazole has the potential to increase the levels of cyclosporine and tacrolimus. During Pylokit (Tinidazole) co-administration with either of these drugs, the patient should be monitored for signs of calcineurin-inhibitor associated toxicities.

Fluorouracil: Metronidazole was shown to decrease the clearance of fluorouracil, resulting in an increase in side-effects without an increase in therapeutic benefits. If the concomitant use of Pylokit (Tinidazole) and fluorouracil cannot be avoided, the patient should be monitored for fluorouracil-associated toxicities.

7.2 Potential Effects of Other Drugs on Pylokit

CYP3A4 Inducers and Inhibitors: Simultaneous administration of Pylokit (Tinidazole) with drugs that induce liver microsomal enzymes, i.e., CYP3A4 inducers such as phenobarbital, rifampin, phenytoin, and fosphenytoin (a pro-drug of phenytoin), may accelerate the elimination of Pylokit (Tinidazole), decreasing the plasma level of Pylokit (Tinidazole). Simultaneous administration of drugs that inhibit the activity of liver microsomal enzymes, i.e., CYP3A4 inhibitors such as cimetidine and ketoconazole, may prolong the half-life and decrease the plasma clearance of Pylokit (Tinidazole), increasing the plasma concentrations of Pylokit (Tinidazole).

Cholestyramine: Cholestyramine was shown to decrease the oral bioavailability of metronidazole by 21%. Thus, it is advisable to separate dosing of cholestyramine and Pylokit (Tinidazole) to minimize any potential effect on the oral bioavailability of Pylokit (Tinidazole).

Oxytetracycline: Oxytetracycline was reported to antagonize the therapeutic effect of metronidazole.

7.3 Laboratory Test Interactions

Pylokit (Tinidazole), like metronidazole, may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD ⁺↔ NADH). Potential interference is due to the similarity of absorbance peaks of NADH and Pylokit (Tinidazole).

Pylokit (Tinidazole), like metronidazole, may produce transient leukopenia and neutropenia; however, no persistent hematological abnormalities attributable to Pylokit (Tinidazole) have been observed in clinical studies. Total and differential leukocyte counts are recommended if re-treatment is necessary.

8 USE IN SPECIFIC POPULATIONS

• Pediatric Use: Data on Pylokit use in children is limited to treatment of giardiasis and amebiasis in patients age 3 and older ( 8.4)
• Hemodialysis patients: If Pylokit (Tinidazole) is administered the same day and prior to hemodialysis, administer an additional ½ dose after end of hemodialysis ( 8.6, 12.3)

See 17 for PATIENT COUNSELING INFORMATION

Revised: 5/2007

8.1 Pregnancy

Teratogenic effects: Pregnancy Category C

The use of Pylokit (Tinidazole) in pregnant patients has not been studied. Since Pylokit (Tinidazole) crosses the placental barrier and enters fetal circulation it should not be administered to pregnant patients in the first trimester.

Embryo-fetal developmental toxicity studies in pregnant mice indicated no embryo-fetal toxicity or malformations at the highest dose level of 2,500 mg/kg (approximately 6.3-fold the highest human therapeutic dose based upon body surface area conversions). In a study with pregnant rats a slightly higher incidence of fetal mortality was observed at a maternal dose of 500 mg/kg (2.5-fold the highest human therapeutic dose based upon body surface area conversions). No biologically relevant neonatal developmental effects were observed in rat neonates following maternal doses as high as 600 mg/kg (3-fold the highest human therapeutic dose based upon body surface area conversions). Although there is some evidence of mutagenic potential and animal reproduction studies are not always predictive of human response, the use of Pylokit (Tinidazole) after the first trimester of pregnancy requires that the potential benefits of the drug be weighed against the possible risks to both the mother and the fetus.

8.3 Nursing Mothers

Pylokit is excreted in breast milk in concentrations similar to those seen in serum. Pylokit (Tinidazole) can be detected in breast milk for up to 72 hours following administration. Interruption of breast-feeding is recommended during Pylokit (Tinidazole) therapy and for 3 days following the last dose.

8.4 Pediatric Use

Other than for use in the treatment of giardiasis and amebiasis in pediatric patients older than three years of age, safety and effectiveness of Pylokit (Tinidazole) in pediatric patients have not been established.

Pediatric Administration: For those unable to swallow tablets, Pylokit (Tinidazole) tablets may be crushed in artificial cherry syrup, to be taken with food .

8.5 Geriatric Use

Clinical studies of Pylokit did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

Because the pharmacokinetics of Pylokit (Tinidazole) in patients with severe renal impairment (CrCL < 22 mL/min) are not significantly different from those in healthy subjects, no dose adjustments are necessary in these patients.

Patients undergoing hemodialysis: If Pylokit (Tinidazole) is administered on the same day as and prior to hemodialysis, it is recommended that an additional dose of Pylokit (Tinidazole) equivalent to one-half of the recommended dose be administered after the end of the hemodialysis .

8.7 Hepatic Impairment

There are no data on Pylokit (Tinidazole) pharmacokinetics in patients with impaired hepatic function. Reduced elimination of metronidazole, a chemically-related nitroimidazole, has been reported in this population. Usual recommended doses of Pylokit (Tinidazole) should be administered cautiously in patients with hepatic dysfunction .

10 OVERDOSAGE

There are no reported overdoses with Pylokit (Tinidazole) in humans.

Treatment of Overdosage: There is no specific antidote for the treatment of overdosage with Pylokit (Tinidazole); therefore, treatment should be symptomatic and supportive. Gastric lavage may be helpful. Hemodialysis can be considered because approximately 43% of the amount present in the body is eliminated during a 6-hour hemodialysis session.

11 DESCRIPTION

Pylokit (Tinidazole) is a synthetic antiprotozoal and antibacterial agent. It is 1-[2-(ethylsulfonyl)ethyl]-2-methyl-5-nitroimidazole, a second-generation 2-methyl-5-nitroimidazole, which has the following chemical structure:

Pylokit (Tinidazole) pink oral tablets contain 500 mg of Pylokit (Tinidazole). Inactive ingredients include croscarmellose sodium, FD&C Red 40 lake, FD&C Yellow 6 lake, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized corn starch, titanium dioxide, and triacetin.

1

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pylokit is an antiprotozoal, antibacterial agent. .

12.3 Pharmacokinetics

Absorption: After oral administration, Pylokit (Tinidazole) is rapidly and completely absorbed. A bioavailability study of Pylokit (Tinidazole) tablets was conducted in adult healthy volunteers. All subjects received a single oral dose of 2 g (four 500 mg tablets) of Pylokit (Tinidazole) following an overnight fast. Oral administration of four 500 mg tablets of Pylokit (Tinidazole) under fasted conditions produced a mean peak plasma concentration (C _max) of 47.7 (±7.5) µg/mL with a mean time to peak concentration (T _max) of 1.6 (±0.7) hours, and a mean area under the plasma concentration-time curve (AUC, 0-∞) of 901.6 (± 126.5) µg/hr/mL at 72 hours. The elimination half-life (T _1/2) was 13.2 (±1.4) hours. Mean plasma levels decreased to 14.3 µg/mL at 24 hours, 3.8 µg/mL at 48 hours and 0.8 µg/mL at 72 hours following administration. Steady-state conditions are reached in 2½ - 3 days of multi-day dosing.

Administration of Pylokit (Tinidazole) tablets with food resulted in a delay in T _max of approximately 2 hours and a decline in C _max of approximately 10% _, compared to fasted conditions. However, administration of Pylokit (Tinidazole) with food did not affect AUC or T _1/2 in this study.

In healthy volunteers, administration of crushed Pylokit (Tinidazole) tablets in artificial cherry syrup, [prepared as described in Dosage and Administration ( 2.2) ] after an overnight fast had no effect on any pharmacokinetic parameter as compared to tablets swallowed whole under fasted conditions.

Distribution: Pylokit (Tinidazole) is distributed into virtually all tissues and body fluids and also crosses the blood-brain barrier. The apparent volume of distribution is about 50 liters. Plasma protein binding of Pylokit (Tinidazole) is 12%. Pylokit (Tinidazole) crosses the placental barrier and is secreted in breast milk.

Metabolism: Pylokit (Tinidazole) is significantly metabolized in humans prior to excretion. Pylokit (Tinidazole) is partly metabolized by oxidation, hydroxylation, and conjugation. Pylokit (Tinidazole) is the major drug-related constituent in plasma after human treatment, along with a small amount of the 2-hydroxymethyl metabolite.

Pylokit (Tinidazole) is biotransformed mainly by CYP3A4. In an in vitro metabolic drug interaction study, Pylokit (Tinidazole) concentrations of up to 75 µg/mL did not inhibit the enzyme activities of CYP1A2, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4.

The potential of Pylokit (Tinidazole) to induce the metabolism of other drugs has not been evaluated.

Elimination: The plasma half-life of Pylokit (Tinidazole) is approximately 12-14 hours. Pylokit (Tinidazole) is excreted by the liver and the kidneys. Pylokit (Tinidazole) is excreted in the urine mainly as unchanged drug (approximately 20-25% of the administered dose). Approximately 12% of the drug is excreted in the feces.

Patients with impaired renal function: The pharmacokinetics of Pylokit (Tinidazole) in patients with severe renal impairment (CrCL < 22 mL/min) are not significantly different from the pharmacokinetics seen in healthy subjects. However, during hemodialysis, clearance of Pylokit (Tinidazole) is significantly increased; the half-life is reduced from 12.0 hours to 4.9 hours. Approximately 43% of the amount present in the body is eliminated during a 6-hour hemodialysis session . The pharmacokinetics of Pylokit (Tinidazole) in patients undergoing routine continuous peritoneal dialysis have not been investigated.

Patients with impaired hepatic function: There are no data on Pylokit (Tinidazole) pharmacokinetics in patients with impaired hepatic function. Reduction of metabolic elimination of metronidazole, a chemically-related nitroimidazole, in patients with hepatic dysfunction has been reported in several studies .

12.4 Microbiology

Mechanism of Action: Pylokit (Tinidazole) is an antiprotozoal, antibacterial agent. The nitro- group of Pylokit (Tinidazole) is reduced by cell extracts of Trichomonas. The free nitro- radical generated as a result of this reduction may be responsible for the antiprotozoal activity. Chemically reduced Pylokit (Tinidazole) was shown to release nitrites and cause damage to purified bacterial DNA in vitro. Additionally, the drug caused DNA base changes in bacterial cells and DNA strand breakage in mammalian cells. The mechanism by which Pylokit (Tinidazole) exhibits activity against Giardia and Entamoeba species is not known.

Antibacterial: Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis ; standard methodology for the susceptibility testing of potential bacterial pathogens, Gardnerella vaginalis, Mobiluncus spp. or Mycoplasma hominis, has not been defined. The following in vitro data are available, but their clinical significance is unknown. Pylokit (Tinidazole) is active in vitro against most strains of the following organisms that have been reported to be associated with bacterial vaginosis:

• Bacteroides spp.
• Gardnerella vaginalis
• Prevotella spp.

Pylokit (Tinidazole) does not appear to have activity against most strains of vaginal lactobacilli.

Antiprotozoal: Pylokit (Tinidazole) demonstrates activity both in vitro and in clinical infections against the following protozoa: Trichomonas vaginalis; Giardia duodenalis (also termed G. lamblia); and Entamoeba histolytica.

For protozoal parasites, standardized susceptibility tests do not exist for use in clinical microbiology laboratories.

Drug Resistance: The development of resistance to Pylokit (Tinidazole) by G. duodenalis, E. histolytica, or bacteria associated with bacterial vaginosis has not been examined.

Cross-resistance: Approximately 38% of T. vaginalis isolates exhibiting reduced susceptibility to metronidazole also show reduced susceptibility to Pylokit (Tinidazole) in vitro. The clinical significance of such an effect is not known.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Pylokit (Tinidazole) and other antibacterial drugs, Pylokit (Tinidazole) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Metronidazole, a chemically-related nitroimidazole, has been reported to be carcinogenic in mice and rats but not hamsters. In several studies metronidazole showed evidence of pulmonary, hepatic, and lymphatic tumorigenesis in mice and mammary and hepatic tumors in female rats. Pylokit carcinogenicity studies in rats, mice or hamsters have not been reported.

Pylokit (Tinidazole) was mutagenic in the TA 100, S. typhimurium tester strain both with and without the metabolic activation system and was negative for mutagenicity in the TA 98 strain. Mutagenicity results were mixed (positive and negative) in the TA 1535, 1537, and 1538 strains. Pylokit (Tinidazole) was also mutagenic in a tester strain of Klebsiella pneumonia. Pylokit (Tinidazole) was negative for mutagenicity in a mammalian cell culture system utilizing Chinese hamster lung V79 cells (HGPRT test system) and negative for genotoxicity in the Chinese hamster ovary (CHO) sister chromatid exchange assay. Pylokit (Tinidazole) was positive for in vivo genotoxicity in the mouse micronucleus assay.

In a 60-day fertility study, Pylokit (Tinidazole) reduced fertility and produced testicular histopathology in male rats at a 600 mg/kg/day dose level (approximately 3-fold the highest human therapeutic dose based upon body surface area conversions). Spermatogenic effects resulted from 300 and 600 mg/kg/day dose levels. The no observed adverse reaction level for testicular and spermatogenic effects was 100 mg/kg/day (approximately 0.5-fold the highest human therapeutic dose based upon body surface area conversions). This effect is characteristic of agents in the 5-nitroimidazole class.

13.2 Animal Toxicology and/or Pharmacology

In acute studies with mice and rats, the LD ₅₀ for mice was generally > 3,600 mg/kg for oral administration and was > 2,300 mg/kg for intraperitoneal administration. In rats, the LD ₅₀ was > 2,000 mg/kg for both oral and intraperitoneal administration.

A repeated-dose toxicology study has been performed in beagle dogs using oral dosing of Pylokit (Tinidazole) at 100 mg/kg/day, 300 mg/kg/day, and 1000 mg/kg/day for 28-days. On Day 18 of the study, the highest dose was lowered to 600 mg/kg/day due to severe clinical symptoms. The two compound-related effects observed in the dogs treated with Pylokit (Tinidazole) were increased atrophy of the thymus in both sexes at the middle and high doses, and atrophy of the prostate at all doses in the males. A no-adverse-effect level (NOAEL) of 100 mg/kg/day for females was determined. There was no NOAEL identified for males because of minimal atrophy of the prostate at 100 mg/kg/day (approximately 0.9-fold the highest human dose based upon plasma AUC comparisons).

14 CLINICAL STUDIES

14.1 Trichomoniasis

Pylokit (2 g single oral dose) use in trichomoniasis has been well documented in 34 published reports from the world literature involving over 2,800 patients treated with Pylokit (Tinidazole). In four published, blinded, randomized, comparative studies of the 2 g Pylokit (Tinidazole) single oral dose where efficacy was assessed by culture at time points post-treatment ranging from one week to one month, reported cure rates ranged from 92% (37/40) to 100% (65/65) (n=172 total subjects). In four published, blinded, randomized, comparative studies where efficacy was assessed by wet mount between 7-14 days post-treatment, reported cure rates ranged from 80% (8/10) to 100% (16/16) (n=116 total subjects). In these studies, Pylokit (Tinidazole) was superior to placebo and comparable to other anti-trichomonal drugs. The single oral 2 g Pylokit (Tinidazole) dose was also assessed in four open-label trials in men (one comparative to metronidazole and 3 single-arm studies). Parasitological evaluation of the urine was performed both pre- and post-treatment and reported cure rates ranged from 83% (25/30) to 100% (80/80) (n=142 total subjects).

14.2 Giardiasis

Pylokit (Tinidazole) (2 g single dose) use in giardiasis has been documented in 19 published reports from the world literature involving over 1,600 patients (adults and pediatric patients). In eight controlled studies involving a total of 619 subjects of whom 299 were given the 2 g × 1 day (50 mg/kg × 1 day in pediatric patients) oral dose of Pylokit (Tinidazole), reported cure rates ranged from 80% (40/50) to 100% (15/15). In three of these trials where the comparator was 2 to 3 days of various doses of metronidazole, reported cure rates for metronidazole were 76% (19/25) to 93% (14/15). Data comparing a single 2 g dose of Pylokit (Tinidazole) to usually recommended 5-7 days of metronidazole are limited.

14.3 Intestinal Amebiasis

Pylokit use in intestinal amebiasis has been documented in 26 published reports from the world literature involving over 1,400 patients. Most reports utilized Pylokit (Tinidazole) 2 g/day × 3 days. In four published, randomized, controlled studies (1 investigator single-blind, 3 open-label) of the 2 g/day × 3 days oral dose of Pylokit (Tinidazole), reported cure rates after 3 days of therapy among a total of 220 subjects ranged from 86% (25/29) to 93% (25/27).

14.4 Amebic Liver Abscess

Pylokit (Tinidazole) use in amebic liver abscess has been documented in 18 published reports from the world literature involving over 470 patients. Most reports utilized Pylokit (Tinidazole) 2 g/day × 2-5 days. In seven published, randomized, controlled studies (1 double-blind, 1 single-blind, 5 open-label) of the 2 g/day × 2-5 days oral dose of Pylokit (Tinidazole) accompanied by aspiration of the liver abscess when clinically necessary, reported cure rates among 133 subjects ranged from 81% (17/21) to 100% (16/16). Four of these studies utilized at least 3 days of Pylokit (Tinidazole).

14.5 Bacterial Vaginosis

A randomized, double-blind, placebo-controlled clinical trial in 235 non-pregnant women was conducted to evaluate the efficacy of Pylokit (Tinidazole) for the treatment of bacterial vaginosis. A clinical diagnosis of bacterial vaginosis was based on Amsel's criteria and defined by the presence of an abnormal homogeneous vaginal discharge that (a) has a pH of greater than 4.5, (b) emits a "fishy" amine odor when mixed with a 10% KOH solution, and (c) contains ≥20% clue cells on microscopic examination. Clinical cure required a return to normal vaginal discharge and resolution of all Amsel's criteria. A microbiologic diagnosis of bacterial vaginosis was based on Gram stain of the vaginal smear demonstrating (a) markedly reduced or absent Lactobacillus morphology, (b) predominance of Gardnerella morphotype, and (c) absent or few white blood cells, with quantification of these bacterial morphotypes to determine the Nugent score, where a score ≥4 was required for study inclusion and a score of 0-3 considered a microbiologic cure. Therapeutic cure was a composite endpoint, consisting of both a clinical cure and microbiologic cure. In patients with all four Amsel's criteria and with a baseline Nugent score ≥4, Pylokit (Tinidazole) oral tablets given as either 2 g once daily for 2 days or 1 g once daily for 5 days demonstrated superior efficacy over placebo tablets as measured by therapeutic cure, clinical cure, and a microbiologic cure.

Outcome	Pylokit (Tinidazole) 1 g × 5 days (n=76)	Pylokit (Tinidazole) 2 g × 2 days (n=73)	Placebo (n=78)
	% Cure	% Cure	% Cure
Therapeutic Cure Difference 2 97.5% CI 3	36.8 31.7 (16.8, 46.6)	27.4 22.3 (8.0, 36.6)	5.1
Clinical Cure Difference 2 97.5% CI 3	51.3 39.8 (23.3, 56.3)	35.6 24.1 (7.8, 40.3)	11.5
Nugent Score Cure Difference 2 97.5% CI 3	38.2 33.1 (18.1, 48.0)	27.4 22.3 (8.0, 36.6)	5.1

¹Modified Intent-to-Treat defined as all patients randomized with a baseline

Nugent score of at least 4

²Difference in cure rates (Tindamax-placebo)

³CI: confidence interval

p-values for both Pylokit (Tinidazole) regimens vs. placebo for therapeutic, clinical and

Nugent score cure rates for both 2 and 5 days <0.001

The therapeutic cure rates reported in this clinical study conducted with Pylokit (Tinidazole) were based on resolution of 4 out of 4 Amsel's criteria and a Nugent score of <4. The cure rates for previous clinical studies with other products approved for bacterial vaginosis were based on resolution of either 2 or 3 out of 4 Amsel's criteria. At the time of approval for other products for bacterial vaginosis, there was no requirement for a Nugent score on Gram stain, resulting in higher reported rates of cure for bacterial vaginosis for those products than for those reported here for Pylokit (Tinidazole).

17 PATIENT COUNSELING INFORMATION

17.1 Administration of Drug

Patients should be told to take Pylokit with food to minimize the incidence of epigastric discomfort and other gastrointestinal side-effects. Food does not affect the oral bioavailability of Pylokit (Tinidazole).

17.2 Alcohol Avoidance

Patients should be told to avoid alcoholic beverages and preparations containing ethanol or propylene glycol during Pylokit (Tinidazole) therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur.

17.3 Drug Resistance

Patients should be counseled that antibacterial drugs including Pylokit (Tinidazole) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Pylokit (Tinidazole) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Pylokit (Tinidazole) or other antibacterial drugs in the future.

1