PYLOKIT Kit (Lansoprazole + Tinidazole + Clarithromycin)

Table of Content

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Black Box Warning

POTENTIAL RISK FOR CARCINOGENICITY

Carcinogenicity has been seen in mice and rats treated long-term with metronidazole, another nitroimidazole agent. Although such data have not been reported for tinidazole, the two drugs are structurally related and have similar biologic effects. Its use should be reserved for the conditions described in INDICATIONS. Avoid chronic use.

Qualitative and Quantitative Composition

Each kit contains:

2 Lansoprazole capsules IP

Each hard gelatin capsule contains:

Lansoprazole IP……………. 30 mg

(as enteric-coated granules)

Colors: Erythrosine, Ponceau 4R, Titanium Dioxide IP.

2 Tinidazole tablets IP

Each film-coated tablet contains:

Tinidazole IP………… 500 mg

Colors: Quinoline Yellow WS and Titanium Dioxide IP

2 Clarithromycin tablets IP

Each film-coated tablet contains:

Clarithromycin IP …… 250 mg

Color: Titanium Dioxide IP

Dosage Form and Strength

Oral tablets of Tinidazole 500 mg and clarithromycin 250 mg and capsule of Lansoprazole 30 mg

Clinical Particulars

Therapeutic Indications

PYLOKIT is indicated for the eradication of H. pylori associated with peptic ulcer disease.

Posology and Method of Administration

One PYLOKIT pack contains two capsules of lansoprazole (30 mg), two tablets of tinidazole (500 mg) and two tablets of clarithromycin (250 mg). One pack is for 1 day of treatment. From this specially designed pack, one capsule of lansoprazole, one tablet of tinidazole, and one tablet of clarithromycin is to be taken in the morning and similarly one each in the evening. The duration of therapy recommended is for 7 days.

Special Populations

Lansoprazole

Hepatic Impairment

The recommended dosage is 15 mg orally daily in patients with severe liver impairment (Child-Pugh C).

Pediatric Population

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

Clarithromycin

Renal Impairment

See Table 1 for dosage adjustment in patients with moderate or severe renal impairment with or without concomitant atazanavir or ritonavir-containing regimens (see section Drug Interactions).

Table 1. Dosage Adjustments in Patients with Renal Impairment

Recommended Clarithromycin Dosage Reduction

Patients with severe renal impairment (CLcr of <30 mL/min)

Reduce the dosage of clarithromycin by 50%

Patients with moderate renal impairment (CLcr of 30 to 60 mL/min) taking concomitant atazanavir or ritonavir-containing regimens

Reduce the dosage of clarithromycin by 50%

Patients with severe renal impairment (CLcr of <30 mL/min) taking concomitant atazanavir or ritonavir-containing regimens

Reduce the dosage of clarithromycin by 75%

Dosage Adjustment Due to Drug Interactions

Decrease the dose by 50% when co-administered with atazanavir (see section Drug Interactions). Dosage adjustments for other drugs when co-administered with clarithromycin may be recommended due to drug interactions.

Contraindications

Lansoprazole

Lansoprazole is contraindicated in patients with known severe hypersensitivity to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria.

Proton Pump Inhibitors (PPIs), including lansoprazole, are contraindicated with rilpivirine-containing products (see section Drug Interactions).

Tinidazole

The use of tinidazole is contraindicated in patients with a previous history of hypersensitivity to tinidazole or other nitroimidazole derivatives. Reported reactions have ranged in severity from urticaria to Stevens-Johnson syndrome.

Clarithromycin

Hypersensitivity

Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibacterial drugs (see section Special Warnings and Precautions for Use).

Cisapride and Pimozide

Concomitant administration of Clarithromycin with cisapride and pimozide is contraindicated.

There have been postmarketing reports of drug interactions when clarithromycin is co-administered with cisapride or pimozide, 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 Clarithromycin. Fatalities have been reported.

Cholestatic Jaundice/Hepatic Dysfunction

Clarithromycin is contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with prior use of clarithromycin.

Colchicine

Concomitant administration of Clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment.

Lomitapide, Lovastatin, and Simvastatin

Concomitant administration of Clarithromycin with lomitapide is contraindicated due to potential for markedly increased transaminases

Concomitant administration of Clarithromycin with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin) is contraindicated, due to the increased risk of myopathy, including rhabdomyolysis.

Ergot Alkaloids

Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated.

Special Warnings and Precautions for Use

Lansoprazole

Presence of Gastric Malignancy

Symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy.

Acute Interstitial Nephritis

Acute interstitial nephritis has been observed in patients taking PPIs including lansoprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue lansoprazole if acute interstitial nephritis develops.

Clostridium difficile-associated Diarrhea

Published observational studies suggest that PPI therapy as with lansoprazole may be associated with an increased risk of C. difficile-associated diarrhea (CDAD), especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve.

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

CDAD has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with esomeprazole, refer to package inserts of those antibacterial agents.

Bone Fracture

Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines.

Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least 3 months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g. diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.

Cutaneous and Systemic Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including lansoprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.

SLE is less commonly reported than CLE in patients receiving PPIs. PPI-associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving lansoprazole, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in four to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

Cyanocobalamin (vitamin B12) Deficiency

Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.

Interactions with Investigations for Neuroendocrine Tumors

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop lansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.

Concomitant Use of Lansoprazole with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at a high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients.

Fundic Gland Polyps

PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

Tinidazole

Potential for Genotoxicity and Carcinogenicity

Carcinogenicity has been seen in mice and rats treated chronically with nitroimidazole derivatives, which are structurally related to tinidazole. Although such data have not been reported for tinidazole, the two drugs are structurally related and have similar biologic effects. However, it is unclear if the positive tumor findings in lifetime rodent studies indicate a risk to patients taking a short course or single dose of tinidazole. Use should be limited to approved indications only. Avoid chronic use.

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 tinidazole. The appearance of abnormal neurologic signs demands the prompt discontinuation of tinidazole therapy.

Vaginal Candidiasis

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

Blood Dyscrasia

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

Development of Drug Resistance Bacteria

Prescribing 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.

Clarithromycin

Severe Acute Hypersensitivity Reactions

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, and acute generalized exanthematous pustulosis, discontinue Clarithromycin therapy immediately and institute appropriate treatment.

Hepatotoxicity

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur.

QT Prolongation

Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving clarithromycin. Fatalities have been reported.

Avoid Clarithromycin in the following patients:

  • patients with known prolongation of the QT interval, ventricular cardiac arrhythmia, including torsades de pointes
  • patients receiving drugs known to prolong the QT interval
  • patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia and in patients receiving Class IA (e.g., quinidine, procainamide, disopyramide) or Class III (e.g., dofetilide, amiodarone, sotalol) antiarrhythmic agents.

Elderly patients may be more susceptible to drug-associated effects on the QT interval.

Serious Adverse Reactions Due to Concomitant Use with Other Drugs

Drugs metabolized by CYP3A4: Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; markedly increased transaminases with lomitapide; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia and cardiac arrhythmias (e.g., torsades de pointes) with disopyramide; and hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older. Use clarithromycin with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme. The use of clarithromycin with lomitapide, simvastatin, lovastatin, ergotamine, or dihydroergotamine is contraindicated (see sections Contraindications and Drug Interactions).

Colchicine: Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and colchicine. Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses. If co-administration of clarithromycin and colchicine is necessary in patients with normal renal and hepatic function, reduce the dose of colchicine. Monitor patients for clinical symptoms of colchicine toxicity. Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see sections Contraindications and Drug Interactions).

Lomitapide: Concomitant use of clarithromycin with lomitapide is contraindicated (see section Contraindications). Lomitapide is metabolized by CYP3A4, and concomitant treatment with clarithromycin increases the plasma concentration of lomitapide, which increases the risk of elevation in transaminases (see section Drug Interactions). If treatment with clarithromycin cannot be avoided, therapy with lomitapide must be suspended during the course of treatment.

HMG-CoA Reductase Inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section Contraindications) as these statins are extensively metabolized by CYP3A4, and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.

Exercise caution when prescribing clarithromycin with atorvastatin or pravastatin. In situations where the concomitant use of clarithromycin with atorvastatin or pravastatin cannot be avoided, atorvastatin dose should not exceed 20 mg daily and pravastatin dose should not exceed 40 mg daily. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. It is recommended to prescribe the lowest registered dose if concomitant use cannot be avoided.

Oral Hypoglycemic Agents/Insulin: The concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia. With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycemia when used concomitantly. Careful monitoring of glucose is recommended (see section Drug Interactions).

Quetiapine: Use quetiapine and clarithromycin concomitantly with caution. Co-administration could result in increased quetiapine exposure and quetiapine related toxicities such as somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin (see section Drug Interactions).

Oral Anticoagulants: There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co-administered with warfarin. Monitor INR and prothrombin times frequently while patients are receiving clarithromycin and oral anticoagulants concurrently (see section Drug Interactions).

Benzodiazepines: Increased sedation and prolongation of sedation have been reported with concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam and midazolam (see section Drug Interactions).

All-Cause Mortality in Patients With Coronary Artery Disease 1 to 10 Years After clarithromycin Exposure

In one clinical trial evaluating treatment with clarithromycin on outcomes in patients with coronary artery disease, an increase in risk of all-cause mortality one year or more after the end of treatment was observed in patients randomized to receive clarithromycin. Clarithromycin for treatment of coronary artery disease is not an approved indication. The cause of the increased risk has not been established. Other epidemiologic studies evaluating this risk have shown variable results. Consider balancing this potential risk with the treatment benefits when prescribing Clarithromycin in patients who have suspected or confirmed coronary artery disease.

Clostridium difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including 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 antibacterial 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 antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Embryo-Fetal Toxicity

Based on findings from animal studies, Clarithromycin is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If Clarithromycin is used during pregnancy, or if pregnancy occurs while the patient is taking this drug, the patient should be apprised of the potential hazard to the fetus. Clarithromycin demonstrated adverse effects on pregnancy outcome and/or embryo fetal development, including fetal malformations, in pregnant animals administered oral clarithromycin.

Exacerbation of Myasthenia Gravis

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

Development of Drug Resistant Bacteria

Prescribing Clarithromycin 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   .

Drug Interactions

Lansoprazole

Tables 2 and 3 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with lansoprazole and instructions for preventing or managing them.

Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.

Table 2. Clinically Relevant Interactions Affecting Drugs Co-Administered with lansoprazole and Interactions with Diagnostics

Antiretrovirals

Clinical Impact:

The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.

 Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with lansoprazole may reduce antiviral effect and promote the development of drug resistance.

 Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with lansoprazole may increase toxicity of the antiretroviral drugs.

 There are other antiretroviral drugs which do not result in clinically relevant interactions with lansoprazole.

Intervention:

Rilpivirine-containing products: Concomitant use with lansoprazole is contraindicated (see Contraindications). See prescribing information.

Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with lansoprazole. See prescribing information for nelfinavir.

Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities.

Other antiretrovirals: See prescribing information.

Warfarin

Clinical Impact:

Increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.

Intervention:

Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.

Methotrexate

Clinical Impact:

Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted (see Special Warnings and Precautions for Use).

Intervention:

A temporary withdrawal of lansoprazole may be considered in some patients receiving high-dose methotrexate.

Digoxin

Clinical Impact:

Potential for increased exposure of digoxin.

Intervention:

Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.

Theophylline

Clinical Impact:

Increased clearance of theophylline.

Intervention:

Individual patients may require additional titration of their theophylline dosage when lansoprazole is started or stopped to ensure clinically effective blood concentrations.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)

Clinical Impact:

Lansoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Intervention:

Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving lansoprazole and MMF.

Use lansoprazole with caution in transplant patients receiving MMF.

See the prescribing information for other drugs dependent on gastric pH for absorption.

Combination Therapy with Clarithromycin and Amoxicillin

Clinical Impact:

Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.

Intervention:

·         See sections Contraindications and Special Warnings and Precautions for Use in prescribing information for clarithromycin.

·         See Drug Interactions in prescribing information for amoxicillin.

Tacrolimus

Clinical Impact:

Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.

Intervention:

Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.

Interactions with Investigations of Neuroendocrine Tumors

Clinical Impact:

CgA levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors.

Intervention:

Temporarily stop lansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.

Interaction with Secretin Stimulation Test

Clinical Impact:

Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.

Intervention:

Temporarily stop lansoprazole treatment at least 28 days before assessing to allow gastrin levels to return to baseline.

False Positive Urine Tests for THC

Clinical Impact:

There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.

Intervention:

An alternative confirmatory method should be considered to verify positive results.

Table 3. Clinically Relevant Interactions Affecting Lansoprazole When Co-Administered with Other Drugs

CYP2C19 OR CYP3A4 Inducers

Clinical Impact:

Decreased exposure of lansoprazole when used concomitantly with strong inducers.

Intervention:

St John’s Wort, rifampin: Avoid concomitant use with lansoprazole.

Ritonavir-containing products: See prescribing information.

CYP2C19 or CYP3A4 Inhibitors

Clinical Impact:

Increased exposure of lansoprazole is expected when used concomitantly with strong inhibitors.

Intervention:

Voriconazole: See prescribing information.

Sucralfate

Clinical Impact:

Decreased and delayed absorption of lansoprazole.

Intervention:

Take lansoprazole at least 30 minutes prior to sucralfate.

Tinidazole

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

Potential Effects of Tinidazole on Other Drugs

Warfarin and other oral coumarin anticoagulants: As with metronidazole, 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 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 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 tinidazole, tinidazole should not be given to patients who have taken disulfiram within the last 2 weeks.

Lithium: Metronidazole has been reported to elevate serum lithium levels. It is not known if 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 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 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 tinidazole and fluorouracil cannot be avoided, the patient should be monitored for fluorouracil-associated toxicities.

Potential Effects of Other Drugs on Tinidazole

CYP3A4 inducers and inhibitors: Simultaneous administration of 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 tinidazole, decreasing the plasma level of 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 tinidazole, increasing the plasma concentrations of tinidazole.

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

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

Clarithromycin

Co-administration of Clarithromycin is known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug.

Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g., carbamazepine) and/or the substrate is extensively metabolized by this enzyme. Adjust dosage when appropriate and monitor serum concentrations of drugs primarily metabolized by CYP3A closely in patients concurrently receiving clarithromycin.

Table 4. Clinically Significant Drug Interactions with Clarithromycin

Drugs That Are Affected By Clarithromycin

Drug(s) with Pharmacokinetics Affected by Clarithromycin

 

Recommendation

 

Comments

 

Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide

Not Recommended

Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs.

Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.

There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.

Digoxin

Use With Caution

Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.

Oral Anticoagulants: Warfarin

 

Use With Caution

 

Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously

Antiepileptics:

Carbamazepine

Use With Caution

 

Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine

Antifungals:

Itraconazole

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fluconazole

Use With Caution

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

No Dose Adjustment

Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under Drugs That Affect Clarithromycin in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.

 

Following administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers, the steady-state clarithromycin Cmin and AUC increased 33% and 18%, respectively. Clarithromycin exposures were increased and steady-state concentrations of 14-OH clarithromycin were not significantly affected by concomitant administration of fluconazole.

Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment)

 

Colchicine (in patients with normal renal and hepatic function)

 

Contraindicated

 

 

 

 

Use With Caution

 

 

Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function.

Antipsychotics:

Pimozide

Quetiapine

 

Contraindicated

 

Pimozide: (See section Contraindications)

 

Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.

Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity)

 

Use With Caution

 

Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.

Antivirals:

Atazanavir

Use With Caution

 

Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction.

Saquinavir (in patient with decreases renal function)

 

Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction.

Ritonavir

Etravirine

Ritonavir, Etravirine: (see Ritonavir and Etravirine under ‘Drugs That Affect Clarithromycin’ in the table below) the AUC of 14-OH clarithromycin

Maraviroc

 

Maraviroc: Clarithromycin may result in

increases in maraviroc exposures by inhibition of CYP3A metabolism. See maraviroc prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.

Boceprevir (in patients

with normal renal

function)

 

No Dose Adjustment

 

Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function.

Didanosine

 

Simultaneous administration of clarithromycin tablets and didanosine to 12 HIV-infected adult patients resulted in no statistically significant change in didanosine pharmacokinetics

Zidovudine

 

Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours

Calcium Channel

Blockers:

Verapamil

Use With Caution

Verapamil: Hypotension, bradyarrhythmias, and

lactic acidosis have been observed in patients

receiving concurrent verapamil

Amlodipine,

Diltiazem

 

Amlodipine, Diltiazem: (see section Special Warnings and Precautions for Use)

Nifedipine

 

Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3Amediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine.

Ergot Alkaloids: Ergotamine Dihydroergotamine

 

Contraindicated

 

Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of 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

 

Gastroprokinetic Agents: Cisapride

 

Contraindicated

 

Cisapride: (See section Contraindications)

 

Lipid-lowering agents: Lomitapide Lovastatin Simvastatin

 

Contraindicated

 

Lomitapide, Lovastatin, Simvastatin: Clarithromycin may increase the exposure of these drugs by inhibition of CYP3A metabolism, thereby increasing the risk of toxicities from these drugs (see sections Contraindications and Special Warnings and Precautions for Use)

 

Atorvastatin Pravastatin

 

Use With Caution

 

Atorvastatin, Pravastatin, Fluvastatin: (see sections Special Warnings and Precautions for Use)

Fluvastatin

No Dose Adjustment

Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin

Use With Caution

 

Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: (See sections Special Warnings and Precautions for Use and Undesirable effects) Insulin: (See sections Special Warnings and Precautions for Use and Undesirable effects)

Immunosuppressants: Cyclosporine

Use With Caution

 

Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine

Tacrolimus

Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus

Phosphodiesterase

inhibitors:

Sildenafil

Tadalafil

Vardenafil

Use With Caution

 

Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered

Proton Pump Inhibitors: Omeprazole

No Dose Adjustment

 

Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with clarithromycin as a result of increased omeprazole exposures

Xanthine Derivatives: Theophylline

 

Use With Caution

 

Theophylline: 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

 

Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam

 

Use With Caution

 

Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated

Alprazolam Triazolam

 

Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.

Temazepam Nitrazepam Lorazepam

 

No Dose Adjustment

 

Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.

Cytochrome P450 Inducers: Rifabutin

 

Use With Caution

 

Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.

Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort

Use With Caution

 

There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.

Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate

 

Use With Caution

 

There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate

 

Drugs that Affect Clarithromycin

Drug(s) that Affect the Pharmacokinetics of Clarithromycin

Recommendation

 

Comments

Antifungals:

Itraconazole

Use With Caution

Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions

Antivirals: Atazanavir

 

Use With Caution

Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50%.

Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.

Ritonavir (in patients with decreased renal function)

Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium.

Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.

Saquinavir (in patients with decreased renal function)

Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above)

Etravirine

 

Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.

Saquinavir (in patients with normal renal function)

Ritonavir (in patients with normal renal function)

No Dose Adjustment

 

Proton Pump Inhibitors: Omeprazole

Use With Caution

 

Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.

Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine

 

Use With Caution

 

Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OHclarithromycin. Since the microbiological activities of clarithromycin and 14-OHclarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin

Use in Special Population

Lansoprazole

Patients with Hepatic Impairment

In patients with various degrees of chronic hepatic impairment the exposure to lansoprazole was increased compared to healthy subjects with normal hepatic function. No dosage adjustment for lansoprazole is necessary for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The recommended dosage is 15 mg orally daily in patients with severe hepatic impairment (Child-Pugh Class C).

Pregnant Women

Available data from published observational studies overall do not indicate an association of adverse pregnancy outcomes with lansoprazole treatment.

Data

Human Data

Available data from published observational studies failed to demonstrate an association of adverse pregnancy-related outcomes and lansoprazole use. Methodological limitations of these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. In a prospective study by the European Network of Teratology Information Services, outcomes from a group of 62 pregnant women administered median daily doses of 30 mg of lansoprazole were compared to a control group of 868 pregnant women who did not take any PPIs. There was no difference in the rate of major malformations between women exposed to PPIs and the control group, corresponding to a Relative Risk (RR)=1.04, . In a population-based retrospective cohort study covering all live births in Denmark from 1996 to 2008, there was no significant increase in major birth defects during analysis of first trimester exposure to lansoprazole in 794 live births. A meta-analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs (for major malformations Odds Ratio (OR)=1.12, and for spontaneous abortions OR=1.29, ).

Lactating Women

There is no information regarding the presence of lansoprazole in human milk, the effects on the breastfed infant, or the effects on milk production. However, lansoprazole and its metabolites are present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lansoprazole and any potential adverse effects on the breastfed child from lansoprazole or from the underlying maternal condition.

Pediatric Patients

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

Geriatric Patients

Of the total number of patients (n=21,486) in clinical studies of lansoprazole, 16% of patients were aged 65 years and over, while 4% were 75 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Tinidazole

Patients with Hepatic Impairment

There are no data on 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 tinidazole should be administered cautiously in patients with hepatic dysfunction.

Patients with Renal Impairment

Because the pharmacokinetics of 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 tinidazole is administered on the same day as and prior to hemodialysis, it is recommended that an additional dose of tinidazole equivalent to one-half of the recommended dose be administered after the end of the hemodialysis.

Pregnant Women

Risk Summary

Available published data from a case-control study and case report with Tinidazole use in pregnant women are insufficient to identify a risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks associated with untreated lower genital tract infections during pregnancy. In animal reproduction studies, oral administration of tinidazole to pregnant mice and rats during organogenesis at 6 and 3 times, respectively, the maximum recommended human dose (based on body surface area comparison) showed a slight increase in fetal mortality in rats at the highest dose, with no other adverse fetal effects noted in either species (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Embryo-fetal developmental toxicity studies in pregnant mice administered oral tinidazole on gestation days (GD) 7 to 12 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 administered oral tinidazole on GD 9 to 14, 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 surviving rat neonates following maternal doses as high as 600 mg/kg (3-fold the highest human therapeutic dose based upon body surface area conversions).

Lactating Women

Risk Summary

Limited published literature, based on breast milk sampling, reports that tinidazole is present in human milk. There are no reports of adverse effects on the breastfed infant and no information on the effects of tinidazole on milk production. Because of the potential for serious adverse reactions, including tumorigenicity, advise patients that breastfeeding is not recommended during treatment with tinidazole and for 72 hours (based on half-life) after administration of tinidazole.

Clinical Considerations

A nursing mother may choose to pump and discard her milk during treatment and for 72 hours after administration of tinidazole to minimize exposure to the breastfeeding infant.

Females and Males of Reproductive Potential Infertility

Infertility

Males

Based on findings in rodents, tinidazole may impair fertility in males of reproductive potential. It is not known whether effects on fertility are reversible.

Pediatric Patients

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

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

Geriatric Patients

Clinical studies of tinidazole 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.

Clarithromycin

Patients with Renal and Hepatic Impairment

Clarithromycin is principally excreted via the liver and kidney. 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.

Pregnant Women

Risk Summary

Based on findings from animal studies, Clarithromycin is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If pregnancy occurs while taking Clarithromycin, the patient should be apprised of the potential hazard to the fetus.

Limited data from a small number of published human studies with Clarithromycin use during pregnancy are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, administration of oral clarithromycin to pregnant mice, rats, rabbits, and monkeys during the period of organogenesis produced malformations in rats (cardiovascular anomalies) and mice (cleft palate) at clinically relevant doses based on body surface area comparison. Fetal effects in mice, rats, and monkeys (e.g., reduced fetal survival, body weight, body weight gain) and implantation losses in rabbits were generally considered to be secondary to maternal toxicity.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactating Women

Risk Summary

Based on limited human data, clarithromycin and its active metabolite 14-OH clarithromycin are present in human milk at less than 2% of the maternal weight-adjusted dose (see Data). In a separate observational study, reported adverse effects on breast-fed children (rash, diarrhea, loss of appetite, somnolence) were comparable to amoxicillin (see Data). No data are available to assess the effects of clarithromycin or 14-OH clarithromycin on milk production.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Clarithromycin and any potential adverse effects on the breast-fed child from Clarithromycin or from the underlying maternal condition.

Data

Human

Serum and milk samples were obtained after 3 days of treatment, at steady state, from one published study of 12 lactating women who were taking Clarithromycin 250 mg orally twice daily. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively human milk fed infant would receive an estimated average of 136 mcg/kg/day of clarithromycin and its active metabolite, with this maternal dosage regimen. This is less than 2% of the maternal weight-adjusted dose (7.8 mg/kg/day, based on the average maternal weight of 64 kg), and less than 1% of the pediatric dose (15 mg/kg/day) for children greater than 6 months of age.

A prospective observational study of 55 breastfed infants of mothers taking a macrolide antibacterial (6 were exposed to clarithromycin) were compared to 36 breastfed infants of mothers taking amoxicillin. Adverse reactions were comparable in both groups. Adverse reactions occurred in 12.7% of infants exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence.

Females and Males of Reproductive Potential Infertility

Males

Administration of clarithromycin resulted in testicular atrophy in rats, dogs and monkeys.

Pediatric Patients

The safety and effectiveness of Clarithromycin have been established for the treatment of the following conditions or diseases in pediatric patients 6 months and older. Use in these indications is based on clinical trials in pediatric patients or adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients:

  • Pharyngitis/Tonsillitis
  • Community-Acquired Pneumonia
  • Acute maxillary sinusitis
  • Acute otitis media
  • Uncomplicated skin and skin structure infections

The safety and effectiveness of Clarithromycin have been established for the prevention of disseminated Mycobacterium avium complex (MAC) disease in pediatric patients 20 months and older with advanced HIV infection. No studies of Clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses recommended for prophylaxis are derived from MAC pediatric treatment studies.

The safety and effectiveness of Clarithromycin in the treatment of pediatric patients has not been established.

Safety and effectiveness of Clarithromycin in pediatric patients under 6 months of age have not been established. The safety of Clarithromycin has not been studied in MAC patients under the age of 20 months.

Geriatric Patients

In a steady-state study in which healthy elderly subjects (65 years to 81 years of age) were given 500 mg of Clarithromycin every 12 hours, the maximum serum concentrations and area under the curves of clarithromycin and 14-OH 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 reactions when compared to younger patients. Consider dosage adjustment in elderly patients with severe renal impairment. Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients.

Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine) involved elderly patients 65 years of age or older.

Especially in elderly patients, there have been reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, some of which occurred in patients with renal insufficiency. Deaths have been reported in some patients

Effects on Ability to Drive and Use Machines

Lansoprazole

Not applicable

Tinidazole

Not applicable

Clarithromycin

There are no data on the effect of clarithromycin on the ability to drive or use machines. However, patients should be counselled regarding the potential for dizziness, vertigo, confusion and disorientation, which may occur with clarithromycin. The potential for these adverse reactions should be taken into account before patients drive or use machines.

Undesirable Effects

Lansoprazole

Clinical Trials Experience

Worldwide, over 10,000 patients have been treated with lansoprazole in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. In general, lansoprazole treatment has been well tolerated in both short-term and long-term trials.

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

The following adverse reactions were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of lansoprazole-treated patients and occurred at a greater rate in lansoprazole-treated patients than placebo-treated patients in the table below:

Table 5. Incidence of Possibly or Probably Treatment-Related Adverse Reactions in Short-Term, Placebo-Controlled Lansoprazole Studies

Body System/Adverse

Lansoprazole

Placebo

Event

(N= 2,768) %

(N=1,023) %

Body as a Whole

 

 

Abdominal pain

2.1

1.2

Digestive System

 

 

Constipation

1.0

0.4

Diarrhea

3.8

2.3

Nausea

1.3

1.2

Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea was similar between patients who received placebo and patients who received 15 mg and 30 mg of lansoprazole, but higher in the patients who received 60 mg of lansoprazole (2.9%, 1.4%, 4.2% and 7.4%, respectively).

The most commonly reported possibly or probably treatment-related adverse event during maintenance therapy was diarrhea.

In the risk reduction study of lansoprazole for non-steroidal anti-inflammatory drug (NSAID)-associated gastric ulcers, the incidence of diarrhea for patients treated with lansoprazole, misoprostol, and placebo was 5%, 22% and 3%, respectively.

Another study for the same indication, where patients took either a COX-2 inhibitor or lansoprazole and naproxen, demonstrated that the safety profile was similar to the prior study. Additional reactions from this study not previously observed in other clinical trials with lansoprazole included contusion, duodenitis, epigastric discomfort, esophageal disorder, fatigue, hunger, hiatal hernia, hoarseness, impaired gastric emptying, metaplasia, and renal impairment.

Additional adverse experiences occurring in less than 1% of patients or subjects who received lansoprazole in domestic trials are shown below:

Body as a Whole: Abdomen enlarged, allergic reaction, asthenia, back pain, candidiasis, carcinoma, chest pain (not otherwise specified), chills, edema, fever, flu syndrome, halitosis, infection (not otherwise specified), malaise, neck pain, neck rigidity, pain, pelvic pain.

Cardiovascular System: Angina, arrhythmia, bradycardia, cerebrovascular accident/cerebral infarction, hypertension/hypotension, migraine, myocardial infarction, palpitations, shock (circulatory failure), syncope, tachycardia, vasodilation.

Digestive System: Abnormal stools, anorexia, bezoar, cardiospasm, cholelithiasis, colitis, dry mouth, dyspepsia, dysphagia, enteritis, eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal discoloration, flatulence, gastric nodules/fundic gland polyps, gastritis, gastroenteritis, gastrointestinal anomaly, gastrointestinal disorder, gastrointestinal hemorrhage, glossitis, gum hemorrhage, hematemesis, increased appetite, increased salivation, melena, mouth ulceration, nausea and vomiting, nausea and vomiting and diarrhea, gastrointestinal moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus, thirst, tongue disorder, ulcerative colitis, ulcerative stomatitis.

Endocrine System: Diabetes mellitus, goiter, hypothyroidism.

Hemic and Lymphatic System: Anemia, hemolysis, lymphadenopathy.

Metabolism and Nutritional Disorders: Avitaminosis, gout, dehydration, hyperglycemia/hypoglycemia, peripheral edema, weight gain/loss.

Musculoskeletal System: Arthralgia, arthritis, bone disorder, joint disorder, leg cramps, musculoskeletal pain, myalgia, myasthenia, ptosis, synovitis.

Nervous System: Abnormal dreams, agitation, amnesia, anxiety, apathy, confusion, convulsion, dementia, depersonalization, depression, diplopia, dizziness, emotional lability, hallucinations, hemiplegia, hostility aggravated, hyperkinesia, hypertonia, hypesthesia, insomnia, libido decreased/increased, nervousness, neurosis, paresthesia, sleep disorder, somnolence, thinking abnormality, tremor, vertigo.

Respiratory System: Asthma, bronchitis, cough increased, dyspnea, epistaxis, hemoptysis, hiccup, laryngeal neoplasia, lung fibrosis, pharyngitis, pleural disorder, pneumonia, respiratory disorder, upper respiratory inflammation/infection, rhinitis, sinusitis, and stridor.

Skin and Appendages: Acne, alopecia, contact dermatitis, dry skin, fixed eruption, hair disorder, maculopapular rash, nail disorder, pruritus, rash, skin carcinoma, skin disorder, sweating, urticaria.

Special Senses: Abnormal vision, amblyopia, blepharitis, blurred vision, cataract, conjunctivitis, deafness, dry eyes, ear/eye disorder, eye pain, glaucoma, otitis media, parosmia, photophobia, retinal degeneration/disorder, taste loss, taste perversion, tinnitus, visual field defect.

Urogenital System: Abnormal menses, breast enlargement, breast pain, breast tenderness, dysmenorrhea, dysuria, gynecomastia, impotence, kidney calculus, kidney pain, leukorrhea, menorrhagia, menstrual disorder, penis disorder, polyuria, testis disorder, urethral pain, urinary frequency, urinary retention, urinary tract infection, urinary urgency, urination impaired, vaginitis.

Post-marketing Experience

Additional adverse experiences have been reported since lansoprazole has been marketed. The majority of these cases are foreign-sourced and a relationship to lansoprazole has not been established. Because these reactions were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events are listed below by the COSTART body system.

Body as a Whole: Anaphylactic/anaphylactoid reactions.

Digestive System: Hepatotoxicity, pancreatitis, vomiting.

Hemic and Lymphatic System: Agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura.

Infections and Infestations: Clostridium difficile-associated diarrhea.

Metabolism and Nutritional Disorders: Hypomagnesemia.

Musculoskeletal System: Bone fracture, myositis.

Skin and Appendages: Severe dermatologic reactions, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal).

Special Senses: Speech disorder.

Urogenital System: Acute kidney injury, Interstitial nephritis, urinary retention.

Laboratory Values

The following changes in laboratory parameters in patients who received lansoprazole were reported as adverse reactions:

Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased globulins, increased GGTP, increased/decreased/abnormal white blood cells (WBCs), abnormal AG ratio, abnormal red blood cells (RBCs), bilirubinemia, blood potassium increased, blood urea increased, crystal urine present, eosinophilia, hemoglobin decreased, hyperlipaemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, increased gastrin levels and positive fecal occult blood. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also reported. Additional isolated laboratory abnormalities were reported.

In the placebo-controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (4/978) and 0.4% (11/2,677) patients, who received placebo and lansoprazole, respectively, had enzyme elevations greater than three times the upper limit of normal range at the final treatment visit. None of these patients who received lansoprazole reported jaundice at any time during the study.

In clinical trials using combination therapy with lansoprazole plus amoxicillin and clarithromycin, and lansoprazole plus amoxicillin, no increased laboratory abnormalities particular to these drug combinations were observed.

Tinidazole

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 with the rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Among 3,669 patients treated with a single 2 g dose of 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 1,765 patients. Common (≥1% incidence) adverse reactions reported by body system are as follows. (Note: Data described in the table below are pooled from studies with variable designs and safety evaluations.)

Other adverse reactions reported with tinidazole included the following:

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.

Table 6. Adverse Reactions Summary of Published Reports

 

2 g Single Dose

Multi-day Dose

Gastrointestinal

 

 

Metallic/bitter taste

3.7%

6.3%

Nausea

3.2%

4.5%

Anorexia

1.5%

2.5%

Dyspepsia/cramps/epi-gastric 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%

(403/3,669)

13.8%

(244/1,765)

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 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

Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of 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 tinidazole. Hypersensitivity reactions may include urticaria, pruritus, angioedema, Stevens-Johnson syndrome and erythema multiforme.

Clarithromycin

The following serious adverse reactions are described below and elsewhere in the labelling (see section Special Warnings and Precautions for Use):

  • Acute Hypersensitivity Reactions
  • QT Prolongation
  • Hepatotoxicity
  • Serious Adverse Reactions Due to Concomitant Use with Other Drugs
  • Clostridium difficile Associated Diarrhea
  • Exacerbation of Myasthenia Gravis

Clinical Trials Experience

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

Based on pooled data across all indications, the most frequent adverse reactions for both adult and pediatric populations observed in clinical trials are abdominal pain, diarrhea, nausea, vomiting and dysgeusia. Also reported were dyspepsia, liver function test abnormal, anaphylactic reaction, candidiasis, headache, insomnia, and rash.

The subsequent subsections list the most common adverse reactions for prophylaxis and treatment of mycobacterial infections and duodenal ulcer associated with H. pylori infection. In general, these profiles are consistent with the pooled data described above.

Prophylaxis of Mycobacterial Infections

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

Table 7. Incidence Rates (%) of Selected Adverse Reactionsa in Immunocompromised Adult Patients Receiving Prophylaxis Against M. avium Complex

Body Systemb Adverse Reaction

Clarithromycin (n=339)

%

Placebo (n=339)

%

Body as a Whole

 

 

Abdominal pain

5%

4%

Headache

3%

1%

Digestive

 

Diarrhea

8%

4%

Dyspepsia

4%

3%

Flatulence

2%

1%

Nausea

11%

7%

Vomiting

6%

3%

Skin & Appendages

 

Rash

3%

4%

Special Senses

 

Taste Perversion

8%c

0.3%

a Includes those events possibly or probably related to study drug and excludes concurrent conditions

b 2% or greater Adverse Reaction Incidence Rates for either treatment group

c Significant higher incidence compared to the placebo-treated group

Discontinuation due to adverse reactions occurred in 18% of patients receiving clarithromycin compared to 17% of patients receiving placebo in this trial. Primary reasons for discontinuation in clarithromycin treated patients include headache, nausea, vomiting, depression, and taste perversion.

Changes in Laboratory Values

Selected laboratory adverse experiences that were reported during therapy in greater than 2 % of adult patients treated with clarithromycin in a randomized double-blind clinical trial involving 682 patients are presented in Table 8.

In immunocompromised patients receiving prophylaxis against M. avium, evaluations of laboratory values were made by analyzing those values outside the seriously abnormal value (i.e., the extreme high or low limit) for the specified test.

Table 8. Percentage of Patientsa Exceeding Extreme Laboratory Values in Patients Receiving Prophylaxis Against M. avium Complex

 

Clarithromycin 500 mg twice a day

Placebo

WBC Count

<1 x 109/L

2/103 (4%)

0/95

SGOT

>5 x ULNb

7/196 (4%)

5/208 (2%)

SGPT

>5 x ULNb

6/217 (3%)

4/232 (2%)

a Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within normal range or borderline low (chemistry variables)

b ULN= Upper Limit of Normal

         

Treatment of Mycobacterial Infections

The adverse reaction profiles for both the 500 mg and 1000 mg twice a day-dose regimens were similar.

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

The following analysis summarizes experience during the first 12 weeks of therapy with clarithromycin. Data are reported separately for trial 1 (randomized, double-blind) and trial 2 (open-labeled, compassionate use) and also combined. Adverse reactions were reported less frequently in trial 2, which may be due in part to differences in monitoring between the two studies.

In adult patients receiving clarithromycin 500 mg twice a day, the most frequently reported adverse reactions, considered possibly or possibly related to study drug, with an incidence of 5% or greater, are listed below (Table 9). Approximately 8% of the patients who received 500 mg twice a day and 12% of the patients who received 1000 mg twice a day discontinued therapy due to drug related adverse reactions during the first 12 weeks of therapy; adverse reactions leading to discontinuation in at least 2 patients included nausea, vomiting, abdominal pain, diarrhea, rash, and asthenia.

Table 9. Selected Treatment-Relateda Adverse Reaction Incidence Rates (%) in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg Twice a Day Clarithromycin Dose

Adverse Reaction

Trial 1 (n=53)

Trial 2 (n=255)

Combined (n=308)

 

Abdominal Pain

8

2

3

 

Diarrhea

9

2

3

 

Flatulence

8

0

1

 

Headache

8

0

2

 

Nausea

28

9

12

 

Rash

9

2

3

 

Taste Perversion

19

0

4

 

Vomiting

25

4

8

 

a Includes those events possibly or probably related to study drug and excludes concurrent conditions

Changes in Laboratory Values

In the first 12 weeks of starting on clarithromycin 500 mg twice a day, 3% of patients has SGOT increases and 2% of patients has SGPT increases > 5 times the upper limit of normal in trial 2 (469 enrolled adult patients) while trial 1 (154 enrolled patients) had no elevation of transaminases. This includes only patients with baseline values within the normal range or borderline low.

Duodenal ulcer associated with H. pylori Infection

In clinical trials using combination therapy with Clarithromycin plus omeprazole and amoxicillin, no adverse reactions specific to the combination of these drugs have been observed. Adverse reactions that have occurred have been limited to those that have been previously reported with Clarithromycin, omeprazole or amoxicillin.

The adverse reaction profiles are shown in below table for four randomized double-blind clinical trials in which patients received the combination of Clarithromycin 500 mg three times a day, and omeprazole 40 mg daily for 14 days, followed by omeprazole 20 mg once a day, (three studies) or 40 mg once a day (one study) for an additional 14 days. Of the 346 patients who received the combination, 3.5% of patients discontinued drug due to adverse reactions.

Table 10. Adverse Reactions with an Incidence of 3% or Greater

Adverse Reaction

Clarithromycin + Omeprazole (n=346) % of Patients

Omeprazole (n=355) % of Patients

Clarithromycin (n=166) % of Patientsa

Taste Perversion

15

1

16

Nausea

5

1

3

Headache

5

6

9

Diarrhea

4

3

7

Vomiting

4

<1

1

Abdominal Pain

3

2

1

Infection

3

4

2

a Only two of four studies

Changes in Laboratory Values

Changes in laboratory values with possible clinical significance in patients taking Clarithromycin and omeprazole in four randomized double-blind trials in 945 patients are as follows:

Hepatic: elevated direct bilirubin <1%; GGT <1%; SGOT (AST) <1%; SGPT (ALT) <1%,

Renal: elevated serum creatinine <1%

The following adverse reactions were observed in clinical trials with clarithromycin at a rate less than 1%:

Blood and Lymphatic System Disorders: Leukopenia, neutropenia, thrombocythemia, eosinophilia.

Cardiac Disorders: Electrocardiogram QT prolonged, cardiac arrest, atrial fibrillation, extrasystoles, palpitations.

Ear and Labyrinth Disorders: Vertigo, tinnitus, hearing impaired.

Gastrointestinal Disorders: Stomatitis, glossitis, esophagitis, GERD, gastritis, proctalgia, abdominal distension, constipation, dry mouth, eructation, flatulence.

General Disorders and Administration Site Conditions: Malaise, pyrexia, asthenia, chest pain, chills, fatigue.

Hepatobiliary Disorders: Cholestasis, hepatitis.

Immune System Disorders: Hypersensitivity.

Infections and Infestations: Cellulitis, gastroenteritis, infection, vaginal infection.

Investigations: Blood bilirubin increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, albumin globulin ratio abnormal.

Metabolism and Nutrition Disorders: Anorexia, decreased appetite.

Musculoskeletal and Connective Tissue Disorders: Myalgia, muscle spasms, nuchal rigidity.

Nervous System Disorders: Dizziness, tremor, loss of consciousness, dyskinesia, somnolence.

Psychiatric Disorders: Anxiety, nervousness.

Renal and Urinary Disorders: Blood creatinine increased, blood urea increased.

Respiratory, Thoracic and Mediastinal Disorders: Asthma, epistaxis, pulmonary embolism.

Skin and Subcutaneous Tissue Disorders: Urticaria, dermatitis bullous, pruritus, hyperhidrosis, rash maculo-papular.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of clarithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Blood and Lymphatic System Disorders: Thrombocytopenia, agranulocytosis.

Cardiac Disorders: Torsades de pointes, ventricular tachycardia, ventricular arrhythmia.

Ear and Labyrinth Disorders: Deafness was reported chiefly in elderly women and was usually reversible.

Gastrointestinal Disorders: Pancreatitis acute; tongue discoloration, tooth discoloration was reported and was usually reversible with professional cleaning upon discontinuation of the drug.

There have been reports of clarithromycin tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibacterial drug.

Hepatobiliary Disorders: Hepatic failure, jaundice hepatocellular. Adverse reactions related to hepatic dysfunction have been reported with clarithromycin.

Immune System Disorders: Anaphylactic reaction, angioedema.

Infections and Infestations: Pseudomembranous colitis.

Investigations: Prothrombin time prolonged, WBC count decreased, INR increased. Abnormal urine color has been reported, associated with hepatic failure.

Metabolism and Nutrition Disorders: Hypoglycemia has been reported in patients taking oral hypoglycemic agents or insulin.

Musculoskeletal and Connective Tissue Disorders: Myopathy and rhabdomyolysis were reported and in some of the reports, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol.

Nervous System Disorders: Convulsion, ageusia, parosmia, anosmia, paresthesia.

Psychiatric Disorders: Psychotic disorder, confusional state, depersonalization, depression, disorientation, manic behavior, hallucination, abnormal behavior, abnormal dreams. These disorders usually resolve upon discontinuation of the drug.

Renal and Urinary Disorders: Nephritis interstitial, renal failure.

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne.

Vascular Disorders: Hemorrhage.

The PYLOKIT drugs are well tolerated. Side effects include nausea, vomiting, diarrhea and abdominal pain. Other rare side effects include headache, skin rash, metallic taste (change in taste), rarely glossitis, stomatitis, urticaria, eruptions and moderate leukopenia.

Overdose

Lansoprazole

Lansoprazole is not removed from the circulation by hemodialysis. In one reported overdose, a patient consumed 600 mg of Lansoprazole with no adverse reaction. Oral Lansoprazole doses up to 5000 mg/kg in rats and in mice (about 675.7 times the 30 mg human dose based on BSA) did not produce deaths or any clinical signs.

In the event of over-exposure, treatment should be symptomatic and supportive.

Tinidazole:

There are no reported overdoses with tinidazole in humans.

Treatment of Overdosage: There is no specific antidote for the treatment of overdosage with 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.

Clarithromycin

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

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

Pharmacological Properties

Lansoprazole

Mechanism of Action

Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H+, K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. Lansoprazole does not exhibit anticholinergic or histamine type-2 antagonist activity.

Pharmacodynamic properties

Antisecretory Activity

After oral administration, lansoprazole was shown to significantly decrease the basal acid output and significantly increase the mean gastric pH and percent of time the gastric pH was greater than three and greater than four. Lansoprazole also significantly reduced meal-stimulated gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients with hypersecretion of acid, lansoprazole significantly reduced basal and pentagastrin-stimulated gastric acid secretion. Lansoprazole inhibited the normal increases in secretion volume, acidity and acid output induced by insulin.

The intragastric pH results of a 5-day, pharmacodynamic, crossover study of 15 mg and 30 mg of once-daily lansoprazole are presented in the table below:

Table 11. Mean Antisecretory Effects After Single and Multiple Daily Lansoprazole Dosing

 

 

 

Lansoprazole

 

 

 

 

 

 

Baseline

 

15 mg

 

 

30 mg

 

Parameter

Value

 

Day 1

 

Day 5

Day 1

 

Day 5

 

Mean 24-

2.1

 

2.7*

 

4.0*

3.6

 

4.9

 

hour pH

 

 

 

 

 

 

 

 

 

 

 

 

 

Mean night-

1.9

 

2.4

 

3.0*

2.6

 

3.8

 

time pH

 

 

 

 

 

 

 

 

 

 

 

 

 

% Time

18

 

33*

 

59*

51

 

72

 

gastric pH>3

 

 

 

 

 

 

 

 

 

 

 

 

 

% Time

12

 

22*

 

49*

41

 

66

 

gastric pH>4

 

 

 

 

 

 

 

 

 

 

 

 

 

Note: An intragastric pH of greater than 4 reflects a reduction in gastric acid by 99%.

*(p<0.05) versus baseline only.

(p<0.05) versus baseline and lansoprazole 15 mg.

After the initial dose in this study, increased gastric pH was seen within 1 to 2 hours with 30 mg of lansoprazole and 2 to 3 hours with 15 mg of lansoprazole. After multiple daily dosing, increased gastric pH was seen within the first hour post-dosing with 30 mg of lansoprazole, and within 1 to 2 hours post-dosing with 15 mg of lansoprazole.

Acid suppression may enhance the effect of antimicrobials in eradicating H. pylori. The percentage of time gastric pH was elevated above 5 and 6 was evaluated in a crossover study of lansoprazole given daily, twice daily and three times daily.

Table 12. Mean Antisecretory Effects After 5 Days of Twice Daily and Three Times Daily Dosing

 

 

15 mg Twice

30 mg Twice

30 mg Three

 

Parameter

30 mg Daily

Daily

Daily

Times Daily

 

% Time gastric

43

47

59*

77†

 

 

 

 

 

 

 

% Time gastric

20

23

28

45†

 

 

 

 

 

 

 

†(p<0.05) versus lansoprazole 30 mg daily, 15 mg twice daily and 30 mg twice daily.

*(p<0.05) versus lansoprazole 30 mg daily

The inhibition of gastric acid secretion as measured by intragastric pH gradually returned to normal over 2 to 4 days after multiple doses. There was no indication of rebound gastric acidity.

Enterochromaffin-like (ECL) Cell Effects

During lifetime exposure of rats with up to 150 mg/kg/day of lansoprazole dosed 7 days per week, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats. Gastric biopsy specimens from the body of the stomach from approximately 150 patients treated continuously with lansoprazole for at least 1 year did not show evidence of ECL cell effects similar to those seen in rat studies. Long-term data are needed to rule out the possibility of an increased risk of the development of gastric tumors in patients receiving long-term therapy with lansoprazole.

Other Gastric Effects in Humans

Lansoprazole did not significantly affect mucosal blood flow in the fundus of the stomach. Due to the normal physiologic effect caused by the inhibition of gastric acid secretion, a decrease of about 17% in blood flow in the antrum, pylorus and duodenal bulb was seen. Lansoprazole significantly slowed the gastric emptying of digestible solids. Lansoprazole increased serum pepsinogen levels and decreased pepsin activity under basal conditions and in response to meal stimulation or insulin injection. As with other agents that elevate intragastric pH, increases in gastric pH were associated with increases in nitrate-reducing bacteria and elevation of nitrite concentration in gastric juice in patients with gastric ulcer. No significant increase in nitrosamine concentrations was observed.

Serum Gastrin Effects

In over 2,100 patients, median fasting serum gastrin levels increased from 50% to 100% from baseline but remained within normal range after treatment with 15 to 60 mg of oral lansoprazole. These elevations reached a plateau within 2 months of therapy and returned to pre-treatment levels within 4 weeks after discontinuation of therapy.

Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum CgA levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors.

Endocrine Effects

Human studies for up to 1 year have not detected any clinically significant effects on the endocrine system. Hormones studied include testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), prolactin, cortisol, estradiol, insulin, aldosterone, parathormone, glucagon, thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and somatotropic hormone (STH). Lansoprazole in oral doses of 15 to 60 mg for up to 1 year had no clinically significant effect on sexual function. In addition, lansoprazole in oral doses of 15 to 60 mg for 2 to 8 weeks had no clinically significant effect on thyroid function. In 24-month carcinogenicity studies in Sprague-Dawley rats with daily lansoprazole dosages up to 150 mg/kg, proliferative changes in the Leydig cells of the testes, including benign neoplasm, were increased compared with control rats.

Other Effects

No systemic effects of lansoprazole on the central nervous system (CNS), lymphoid, hematopoietic, renal, hepatic and cardiovascular or respiratory systems have been found in humans. Among 56 patients who had extensive baseline eye evaluations, no visual toxicity was observed after lansoprazole treatment (up to 180 mg/day) for up to 58 months. After lifetime lansoprazole exposure in rats, focal pancreatic atrophy, diffuse lymphoid hyperplasia in the thymus, and spontaneous retinal atrophy were seen.

Pharmacokinetic Properties

Absorption is rapid, with mean peak plasma levels of lansoprazole occurring after approximately 1.7 hours. After single-dose administration of 15 mg to 60 mg of oral lansoprazole, the peak plasma concentrations (Cmax) of lansoprazole and the area under the plasma concentration curves (AUCs) of lansoprazole were approximately proportional to the administered dose. Lansoprazole does not accumulate and its pharmacokinetics is unaltered by multiple dosing.

Absorption

PYLOKIT contains an enteric-coated granule formulation of lansoprazole (because lansoprazole is acid-labile), so that absorption of lansoprazole begins only after the granules leave the stomach. The mean peak plasma levels of lansoprazole occur at approximately 1.7 hours. After a single-dose administration of 15 to 60 mg of oral lansoprazole, the peak plasma concentrations (Cmax) of lansoprazole and the area under the plasma concentration curves (AUCs) of lansoprazole were approximately proportional to the administered dose. Lansoprazole does not accumulate, and its pharmacokinetics are unaltered by multiple dosing. The absolute bioavailability is over 80%. In healthy subjects, the mean (±SD) plasma half-life was 1.5 (±1.0) hours. Both the Cmax and AUC are diminished by about 50 to 70% if lansoprazole is given 30 minutes after food, compared with the fasting condition. There is no significant food effect if lansoprazole is given before meals.

Distribution

Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.05 to 5.0 mcg/mL.

Metabolism

Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into two active species that inhibit acid secretion by blocking the proton pump at the secretory surface of the gastric parietal cell. The two active species are not present in the systemic circulation. The plasma elimination half-life of lansoprazole is less than 2 hours while the acid inhibitory effect lasts more than 24 hours. Therefore, the plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion.

Elimination

Following single-dose oral administration of lansoprazole, virtually no unchanged lansoprazole was excreted in the urine. In one study, after a single oral dose of 14C-lansoprazole, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the lansoprazole metabolites.

Special Populations

Geriatric

The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly. No dosage adjustment is necessary in the elderly.

Pediatric

No relevant data is available for lansoprazole in pediatric population.

Hepatic Impairment

In patients with various degrees of chronic hepatic impairment, the mean plasma half-life of lansoprazole was prolonged from 1.5 hours to 3.2 to 7.2 hours. An increase in the mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Consider dose reduction in patients with severe hepatic impairment.

Renal impairment

In patients with severe renal impairment, plasma protein binding decreased by 1.0% to 1.5% after administration of 60 mg of lansoprazole. Patients with renal impairment had a shortened elimination half-life and decreased total AUC (free and bound). The AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment; and the Cmax and Tmax (time to reach the maximum concentration) were not different than the Cmax and Tmax from subjects with normal renal function. No dosage adjustment is necessary in patients with renal impairment.

Gender

In a study comparing 12 male and 6 female human subjects who received lansoprazole, no gender differences were found in pharmacokinetics and intragastric pH results.

Racial or Ethnic Groups

The pooled mean pharmacokinetic parameters of lansoprazole from twelve U.S. studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs of lansoprazole in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable.

Antacids

In clinical trials, antacids were administered concomitantly with lansoprazole and there was no evidence of a change in the efficacy of lansoprazole.

Clopidogrel

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects who were CYP2C19 extensive metabolizers, receiving once daily administration of clopidogrel 75 mg alone or concomitantly with          lansoprazole 30 mg (n=40), for 9 days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (mean AUC ratio was 86%, with 90% CI of 80 to 92%) when lansoprazole was co-administered compared to administration of clopidogrel alone. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 mcM ADP) was related to the change in the exposure to clopidogrel active metabolite. The clinical significance of this finding is not clear.

Tinidazole

Mechanism of Action

Tinidazole is an anti-protozoal, antibacterial agent. The nitro-group of tinidazole is reduced by cell extracts of Trichomonas. The free nitro-radical generated as a result of this reduction may be responsible for the anti-protozoal activity. Chemically reduced 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 tinidazole exhibits activity against Giardia and Entamoeba species is not known.

Pharmacodynamic Properties

Tinidazole exposure-response relationships and the time course of pharmacodynamics response are unknown.

Pharmacokinetic Properties

Absorption

After oral administration, tinidazole is rapidly and completely absorbed. A bioavailability study of tinidazole tablets was conducted in adult healthy volunteers. All subjects received a single oral dose of 2 g (four 500 mg tablets) of tinidazole following an overnight fast. Oral administration of four 500 mg tablets of tinidazole under fasted conditions produced a mean peak plasma concentration (Cmax) of 47.7 (±7.5) mcg/mL, with a mean time to peak concentration (Tmax) of 1.6 (±0.7) hours, and a mean area under the plasma concentration-time curve (AUC0–infinity) of 901.6 (± 126.5) mcg.hr/mL at 72 hours.

The elimination half-life (T½) was 13.2 (±1.4) hours. Mean plasma levels decreased to 14.3 mcg/mL at 24 hours, 3.8 mcg/mL at 48 hours, and 0.8 mcg/mL at 72 hours following administration. Steady-state conditions are reached in 2½ to 3 days of multi-day dosing.

Administration of tinidazole tablets with food resulted in a delay in the Tmax of approximately 2 hours and a decline in the Cmax of approximately 10%, compared with fasted conditions. However, administration of tinidazole with food did not affect AUC or T½ in this study.

In healthy volunteers, administration of crushed tinidazole tablets in artificial cherry syrup, after an overnight fast, had no effect on any pharmacokinetic parameter as compared with tablets swallowed whole under fasted conditions.

Distribution

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 tinidazole is 12%.

Metabolism

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

Tinidazole is biotransformed mainly by cytochrome (CY) P3A4. In an in vitro metabolic drug interaction study, tinidazole concentrations of up to 75 mcg/mL did not inhibit the enzyme activities of CYP1A2, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4.

The potential of tinidazole to induce the metabolism of other drugs has not been evaluated.

Elimination

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

Specific population

Renal Impairment

The pharmacokinetics of tinidazole in patients with severe renal impairment (creatinine clearance <22 mL/min) are not significantly different from the pharmacokinetics seen in healthy subjects. However, during hemodialysis, clearance of 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 tinidazole in patients undergoing routine continuous peritoneal dialysis has not been investigated.

Hepatic Impairment

There are no data on 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.

Clarithromycin

Mechanism of action

Clarithromycin is a macrolide antimicrobial drug. Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible bacteria resulting in inhibition of protein synthesis.

Pharmacodynamics

Resistance

The major routes of resistance are modification of the 23S rRNA in the 50S ribosomal subunit to insensitivity or drug efflux pumps. Beta-lactamase production should have no effect on clarithromycin activity.

Most isolates of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin.

If H. pylori is not eradicated after treatment with clarithromycin-containing combination regimens, patients may develop clarithromycin resistance in H. pylori isolates. Therefore, for patients who fail therapy, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycin-resistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual therapy; omeprazole/clarithromycin/amoxicillin triple therapy; lansoprazole/clarithromycin/amoxicillin triple therapy; or other regimens which include clarithromycin as the sole antibacterial agent.

Antimicrobial Activity

Clarithromycin has been shown to be active against most of the isolates of the following microorganisms both in vitro and in clinical infections.

Gram-Positive Bacteria

  • Staphylococcus aureus
  • Streptococcus pneumoniae
  • Streptococcus pyogenes

Gram-Negative Bacteria

  • Haemophilus influenzae
  • Haemophilus parainfluenzae
  • Moraxella catarrhalis

Other Microorganisms

  • Chlamydophila pneumoniae
  • Helicobacter pylori
  • Mycobacterium avium complex (MAC) consisting of M.avium and M.intracellulare
  • Mycoplasma pneumoniae

At least 90 percent of the microorganisms listed below exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the clarithromycin susceptible MIC breakpoint for organisms of similar type. However, the efficacy of clarithromycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-Positive Bacteria

  • Streptococcus agalactiae
  • Streptococci (Groups C, F, G)
  • Viridans group streptococci

Gram-Negative Bacteria

  • Legionella pneumophila
  • Pasteurella multocida

Anaerobic Bacteria

  • Clostridium perfringens
  • Peptococcus niger
  • Prevotella melaninogenica
  • Propionibacterium acnes

Pharmacokinetics

Absorption

The absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500 mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, increasing the peak time from approximately 2 to 2.5 hours. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does not affect the onset of formation of the active metabolite, 14-OH 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, clarithromycin may be given without regard to food. In non-fasting healthy human subjects (males and females), peak plasma concentrations were attained within 2 to 3 hours after oral dosing.

Distribution

Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid penetration. Because of high intracellular concentrations, tissue concentrations are higher than serum concentrations.

Metabolism and Elimination

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

After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of 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 clarithromycin. The renal clearance of 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 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.

Specific Populations

HIV Infection

Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of 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 clarithromycin every 12 hours, steady-state clarithromycin Cmax values ranged from 2 mcg/mL to 4 mcg/mL and 5 mcg/mL to 10 mcg/mL, respectively.

Hepatic Impairment

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

Renal Impairment

The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function (see sections Use in Special Population and Posology and Method of Administration).

Nonclinical Properties

Animal Toxicology or Pharmacology

Clarithromycin

Corneal opacity occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose (on a body surface area basis). Lymphoid depletion occurred in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose (on a body surface area basis).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lansoprazole

In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated with oral lansoprazole doses of 5 to 150 mg/kg/day, about one to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height given the recommended human dose of 30 mg/day. Lansoprazole produced dose-related gastric enterochromaffin-like (ECL) cell hyperplasia and ECL cell carcinoids in both male and female rats. It also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg/kg/day (four to 40 times the recommended human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat.

In a 24-month carcinogenicity study, CD-1 mice were treated with oral lansoprazole doses of 15 to 600 mg/kg/day, two to 80 times the recommended human dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg/kg/day (40 to 80 times the recommended human dose based on BSA) and female mice treated with 150 to 600 mg/kg/day (20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg/kg/day (10 to 80 times the recommended human dose based on BSA).

A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.

Lansoprazole was positive in the Ames test and the in vitro human lymphocyte chromosomal aberration assay. Lansoprazole was not genotoxic in the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test, or the rat bone marrow cell chromosomal aberration test.

Lansoprazole at oral doses up to 150 mg/kg/day (40 times the recommended human dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

Tinidazole

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. Tinidazole carcinogenicity studies in rats, mice or hamsters have not been reported.

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. Tinidazole was also mutagenic in a tester strain of Klebsiella pneumonia. 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. Tinidazole was positive for in vivo genotoxicity in the mouse micronucleus assay.

In a 60-day male rat fertility study, oral doses of 600 mg/kg (approximately 3-fold the highest human therapeutic dose based on body surface area conversions) reduced fertility and produced testicular histopathology, including tubular degeneration, vacuolation of the seminiferous epithelium in the testis, and hypospermia in the epididymis. At 300 and 600 mg/kg dose levels, significant effects on sperm parameters were observed, including dose-related reduction in sperm motility, epididymal sperm numbers, percentage of normal sperm, retention of spermatids, and decreased epididymal weights. No effects on sperm parameters were observed at 100 mg/kg (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.

Clarithromycin

Mutagenesis

The following in vitro mutagenicity tests have been conducted with 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 positive in one test and negative in another. In addition, a bacterial reverse-mutation test (Ames test) has been performed on clarithromycin metabolites with negative results.

Impairment of Fertility

Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/day 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 twice the human serum levels.

Testicular atrophy occurred in rats at doses 7 times, in dogs at doses 3 times, and in monkeys at doses 8 times greater than the maximum human daily dose.

Description

Newer triple therapies, including proton-pump inhibitors (PPIs) such as lansoprazole plus tinidazole and clarithromycin, serve as a shorter, simpler and effective drug regimen for the eradication of H. pylori.

PYLOKIT has a combipack of lansoprazole, tinidazole, and clarithromycin.

Lansoprazole, a substituted benzimidazole, 2- methyl] sulfinyl] benzimidazole, is a compound that inhibits gastric acid secretion. Its empirical formula is C16H14F3N3O2S with a molecular weight of 369.37. Lansoprazole has the following structure:

Lansoprazole is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water.

Lansoprazole is stable when exposed to light for up to two months. The rate of degradation of the compound in aqueous solution increases with decreasing pH. The degradation half-life of the drug substance in aqueous solution at 25°C is approximately 0.5 hour at pH 5.0 and approximately 18 hours at pH 7.

Tinidazole is a synthetic antiprotozoal and antibacterial agent. It is 1--2-methyl-5-nitroimidazole, a second-generation 2-methyl-5-nitroimidazole, which has a molecular weight of 247.27 and the following chemical structure:

Clarithromycin is a semi-synthetic macrolide antimicrobial for oral use. Chemically, it is 6-0methylerythromycin. The molecular formula is C38H69NO13, and the molecular weight is 747.96. The structural formula is:

Pharmaceutical Particulars

Incompatibilities

Not applicable

Shelf-life

As on pack.

Packaging Information

PYLOKIT ……….. Box of one kit

Storage and Handling Instructions

Store in a cool, dry place.

Keep out of reach of children.

Patient Counseling Information

What is PYLOKIT used for

PYLOKIT is a combination pack, which contains three different medicines. When taken together in the right doses, they will kill the bacteria in your stomach called Helicobacter pylori and let your peptic ulcer heal.

Depending on the position of the ulcer it is called a gastric or duodenal ulcer. A gastric ulcer occurs in the stomach. A duodenal ulcer occurs in the duodenum which is the tube leading out from the stomach.

Most people who have a peptic ulcer also have a bacterium called Helicobacter pylori in their stomach. If the bacteria are killed it is unlikely that your ulcer will come back.

PYLOKIT contains lansoprazole, tinidazole, and clarithromycin. Tinidazole and clarithromycin are both types of antibiotic.

How PYLOKIT works

Lansoprazole is a type of medicine called a proton-pump inhibitor. Lansoprazole works by decreasing the amount of acid made by the stomach, to give relief of symptoms and allow healing to take place.

This does not stop food being digested in the normal way.

Tinidazole and clarithromycin are both antibiotics that help kill H. pylori. Lansoprazole also helps kill the bacteria. When all three are taken together they are more effective than taken one or two at a time. It is possible that the antibiotics may not always kill Helicobacter pylori.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may prescribe this medicine for another use.

There is no evidence that PYLOKIT is addictive.

This medicine is available only with a doctor's prescription.

Before you take PYLOKIT

When you must not take it

Do not take PYLOKIT if you are:

·         allergic to lansoprazole, tinidazole, or clarithromycin.

·         any other similar medicines such as proton pump inhibitors, nitroimidazole derivatives, erythromycin or macrolide antibiotics.

·         taking a medicine that contains rilpivirine used to treat HIV-1 (Human Immunodeficiency Virus).

Do not take PYLOKIT if you are taking any of the following medicines:

• ergotamine

• cisapride

• pimozide

• dihydroergotamine

• cilostazol

• atazanavir

• colchicine

• simvastatin

• lovastatin

• colchicine

Please check with your doctor or pharmacist if you are taking any of these medicines. These medicines will be affected by the medicines in PYLOKIT and it is more likely you will get side effects.

Do not take PYLOKIT if you have a history of heart conditions such as QT prolongation or ventricular cardiac arrhythmia.

Do not take PYLOKIT if you have both liver and kidney problems.

PYLOKIT is not recommended for use in children.

There is no information about the use of PYLOKIT in children.

Do not take this medicine after the use by (expiry) date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you take PYLOKIT, tell your doctor about all of your medical conditions, including if you:

·         have low magnesium levels in your blood.

·         have liver problems.

·         are pregnant or plan to become pregnant. PYLOKIT may harm your unborn baby. Talk to your doctor about the possible risks to an unborn baby if PYLOKIT is taken during pregnancy.

·         are breastfeeding or plan to breastfeed. You should not breastfeed during treatment with tinidazole and should discontinue breastfeeding for 72 hours following the administration of tinidazole.

·         You may choose to pump and discard your milk for 72 hours after administration of tinidazole. Talk to your doctor about the best way to feed your baby if you take PYLOKIT.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your doctor if you take methotrexate.

How should I take PYLOKIT?

·         Take PYLOKIT exactly as prescribed by your doctor.

·         Do not change your dose or stop taking PYLOKIT without talking to your doctor.

·         Take PYLOKIT after meals.

·         Swallow PYLOKIT capsules and tablets whole with water.

·         Do not crush or chew PYLOKIT capsules and tablets.

·         Avoid alcoholic beverages and preparations containing ethanol or propylene glycol during PYLOKIT therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur.

·         If you miss a dose of PYLOKIT, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take your next dose at your regular time. Do not take 2 doses at the same time.

·         If you take too much PYLOKIT, call your doctor or go to the nearest hospital emergency room.

How long to take it

Continue taking the tablets until you finish the course or until your doctor tells you to stop.

If you do not complete the full course prescribed by your doctor, the Helicobacter pylori may not clear completely and your symptoms may return.

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 tinidazole or other antibacterial drugs in the future.

Tell your doctor if your symptoms return.

It is possible that the antibiotics may not kill Helicobacter pylori. You may need treatment with more antibiotics.

What are the possible side effects of PYLOKIT?

PYLOKIT can cause serious side effects, including:

·         A type of kidney problem (acute interstitial nephritis). Some people who take proton pump inhibitor (PPI) medicines, including lansoprazole, may develop a kidney problem called acute interstitial nephritis that can happen at any time during treatment with PPI medicines including lansoprazole. Call your doctor right away if you have a decrease in the amount that you urinate or if you have blood in your urine.

·         Diarrhea caused by an infection (Clostridium difficile) in your intestines. Call your doctor right away if you have watery stools or stomach pain that does not go away. You may or may not have a fever.

·         Bone fractures (hip, wrist, or spine). Bone fractures in the hip, wrist, or spine may happen in people who take multiple daily doses of PPI medicines and for a long period of time (a year or longer). Tell your doctor if you have a bone fracture, especially in the hip, wrist, or spine.

·         Certain types of lupus erythematosus. Lupus erythematosus is an autoimmune disorder (the body’s immune cells attack other cells or organs in the body). Some people who take PPI medicines, including lansoprazole, may develop certain types of lupus erythematosus or have worsening of the lupus they already have. Call your doctor right away if you have new or worsening joint pain or a rash on your cheeks or arms that gets worse in the sun.

·         Low vitamin B12 levels in the body can happen in people who have taken PYLOKIT for a long time (more than 3 years). Tell your doctor if you have symptoms of low vitamin B12 levels, including shortness of breath, lightheadedness, irregular heartbeat, muscle weakness, pale skin, feeling tired, mood changes, and tingling or numbness in the arms and legs.

·         Low magnesium levels in the body can happen in people who have taken PYLOKIT for at least 3 months. Tell your doctor if you have symptoms of low magnesium levels, including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, and spasms of hands, feet or voice.

·         Stomach growths (fundic gland polyps). People who take PPI medicines for a long time have an increased risk of developing a certain type of stomach growth called fundic gland polyps, especially after taking PPI medicines for more than 1 year.

The most common side effects of PYLOKIT include diarrhea, stomach-area (abdomen) pain, nausea and constipation.

Other rare side effects include headache, skin rash, metallic taste (change in taste), rarely glossitis, stomatitis, urticaria, eruptions and moderate leukopenia.

PYLOKIT may also cause acute kidney injury, acute hypersensitivity reactions, QT prolongation, hepatotoxicity, Clostridium difficile associated diarrhea, and worsening of myasthenia gravis.

These are not all the possible side effects of PYLOKIT.

Call your doctor for medical advice about side effects. Talk to your doctor about your risk of these serious side effects. You may not experience any of them.

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

How should I store PYLOKIT?

Store in a cool, dry place.

Keep out of the reach of children.

Details of Manufacturer

Registered Office:

Cipla House,

Peninsula Business Park,

Ganpatrao Kadam Marg

Lower Parel

Mumbai – 400 013, India

Details of Permission or Licence Number with Date

M/447/2007 & M/455/2007 dated 23/12/2016

Date of Revision

25/06/2020.