Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride

WARNING: POTENTIAL FOR CARCINOGENICITY Metronidazole has been shown to be carcinogenic in mice and rats. It is unknown whether metronidazole is associated with carcinogenicity in humans [see Warning and Precautions (5.1) ]. WARNING: POTENTIAL FOR CARCINOGENICITY See full prescribing information for complete boxed warning. Metronidazole has been shown to be carcinogenic in mice and rats. It is unknown whether metronidazole is associated with carcinogenicity in humans ( 5.1 ).

5 WARNINGS AND PRECAUTIONS Fetal Toxicity: Advise pregnant women of the risk throughout pregnancy for retardation of skeletal development seen in animal studies and permanent discoloration of teeth with tetracycline if used during the second or third trimester. ( 5.2 , 8.1 ) Maternal Toxicity: Risk of hepatotoxicity in pregnant women with high doses of intravenous tetracycline also resulting in stillborn or premature birth. ( 5.3 , 8.1 ) Tooth Enamel discoloration and hypoplasia: permanent discoloration may develop with use during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years). ( 5.4 ) Severe Cutaneous Adverse Reactions: Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with metronidazole. If symptoms or signs of SCARs develop, discontinue bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride immediately and institute appropriate therapy. (5.5) Central and Peripheral Nervous System Effects: encephalopathy, convulsive seizures, aseptic meningitis and peripheral neuropathy with metronidazole, intracranial hypertension with tetracycline and neurotoxicity with bismuth-containing products. Monitor patients with CNS conditions closely and discontinue promptly if abnormal neurologic signs develop. (5.6) Photosensitivity: avoid exposure to sun and sun lamps. (5.8) Blood Dyscrasias: Use with caution in patients with a history of blood dyscrasias. (5.10) Hepatic Impairment: Not recommended in patients with severe hepatic impairment. (5.11) 5.1 Potential for Carcinogenicity Metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride, has been shown to be carcinogenic in mice and rats. Tumors affecting the liver, lungs, mammary and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters [see Nonclinical Toxicology (13)]. It is unknown whether metronidazole is associated with carcinogenicity in humans. 5.2 Fetal Toxicity Tetracycline can cause fetal harm when administered to a pregnant woman. Based on animal data, use of drugs of the tetracycline class during the second and third trimester of pregnancy can cause permanent discoloration of the teeth (yellow-gray brown) and possibly inhibit bone development [see Warnings and Precautions (5.4) ] . Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals. If bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is used during pregnancy, or if the patient becomes pregnant while taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride, advise the patient of the potential risk to the fetus [see Contraindications (4.5) and Use in Specific Populations (8.1) ]. 5.3 Maternal Toxicity Tetracycline, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride, administered during pregnancy at high doses (> 2 g IV) was associated with rare but serious cases of maternal hepatotoxicity. This syndrome may result in stillborn or premature birth due to maternal pathology [see Contraindications (4.5) and Use in Specific Populations (8.1) ]. 5.4 Tooth Enamel Discoloration and Hypoplasia The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug, but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride, therefore, should not be used in this age group unless other drugs are not likely to be effective or are contraindicated [see Use in Specific Populations (8.4) ]. 5.5 Severe Cutaneous Adverse Reactions Metronidazole: Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of metronidazole. Symptoms can be serious and potentially life threatening. If symptoms or signs of SCARs develop, discontinue bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride capsules immediately and institute appropriate therapy. Tetracycline : Fixed drug eruptions have occurred with tetracycline and have been associated with worsening severity upon subsequent administrations, including generalize bullous fixed drug eruption [see Adverse Reactions (6.3)]. If severe skin reactions occur, discontinue bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride immediately, and institute appropriate therapy. 5.6 Central and Peripheral Nervous System Effects Metronidazole : Convulsive seizures, encephalopathy, aseptic meningitis and peripheral neuropathy (including optic neuropathy) have been reported. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Aseptic meningitis symptoms may occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. Tetracycline : Intracranial hypertension (IH), including pseudotumor cerebri, has been associated with the use of tetracyclines. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin should be avoided because isotretinoin is also known to cause IH. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation, patients should be monitored until they stabilize. Bismuth-containing products: Cases of neurotoxicity associated with excessive doses of various bismuth-containing products have been reported. Effects have been reversible with discontinuation of bismuth therapy. The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride therapy [see Adverse Reactions (6.3) ]. 5.7 Development of Potential for Microbial Overgrowth Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with an antifungal agent. As with other antibacterial drugs, use of tetracycline hydrochloride may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, discontinue bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride and institute appropriate therapy. 5.8 Photosensitivity Photosensitivity, manifested by an exaggerated sunburn reaction, has been observed in patients taking tetracycline [see Adverse Reactions (6.3) ]. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs. Instruct patients taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride to avoid exposure to the sun or sun lamps. Discontinue treatment at the first evidence of skin erythema. 5.9 Darkening of the Tongue and/or Black Stool Bismuth subcitrate potassium may cause temporary and harmless darkening of the tongue and/or black stools, generally reversible within several days after treatment is stopped [see Adverse Reactions (6.1) ] . Stool darkening should not be confused with melena. 5.10 Use in Patients with Blood Dyscrasias Metronidazole is a nitroimidazole, and should be used with care in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy [see Adverse Reactions (6.3) ]. 5.11 Increased Drug Plasma Concentrations in Patients with Hepatic Impairment Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events. Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is not recommended in patients with severe hepatic impairment (Child-Pugh C) [see Clinical Pharmacology (12.3) ]. 5.12 Laboratory Test Interactions Bismuth absorbs x-rays and may interfere with x-ray diagnostic procedures of the gastrointestinal tract. Bismuth subcitrate potassium may cause a temporary and harmless darkening of the stool. However, this change does not interfere with standard tests for occult blood. Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide (NAD+ <=> NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7. 5.13 Development of Drug Resistant Bacteria Prescribing bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 5.14 Drug Interactions Oral Contraceptives Concurrent use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride. Breakthrough bleeding has been reported. Advise women of child-bearing potential to use a different or additional form of contraception while taking bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride [see Drug Interactions (7.3) ]. Anticoagulants Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride may alter the anticoagulant effects of warfarin and other oral coumarin anticoagulants. Metronidazole has been reported to potentiate the anticoagulant effect of warfarin, and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. Tetracycline has been shown to depress plasma prothrombin activity. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Drug Interactions (7.4) ]. Lithium In patients stabilized on relatively high doses of lithium, short-term use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride may cause elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Monitor serum lithium and serum creatinine concentrations daily for several days after beginning treatment with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride to detect any increase that may precede clinical symptoms of lithium toxicity [see Drug Interactions (7.5) ]. Busulfan Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Do not administer bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride are available, and concomitant administration with busulfan is medically needed, monitor for busulfan toxicity and busulfan plasma concentrations and adjust the busulfan dose accordingly [see Drug Interactions (7.7) ]. Drugs that Prolong the QT interval QT prolongation has been reported with metronidazole, a component of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride, particularly when administered with drugs with the potential for prolonging the QT interval.

6 ADVERSE REACTIONS Most frequently reported adverse reactions (≥5%): abnormal feces, diarrhea, nausea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Par Health at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride plus omeprazole (OBMT) to eradicate Helicobacter pylori was assessed in an open-label, randomized, active-controlled clinical trial conducted in North America. The duration of treatment was 10 days with 147 patients exposed to bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride plus omeprazole (OBMT) and 152 exposed to control, consisting of omeprazole, amoxicillin, and clarithromycin (OAC). The age of the population in the study ranged from 18 to 75 years, with 59% male patients and 59% Caucasian patients. Adverse drug reactions were reported in 58% of patients in the OBMT group and 59% of patients in the OAC group. There were no adverse reactions leading to discontinuation of the study during the clinical trial. Adverse reactions with an incidence of ≥ 5% in OBMT group include abnormal feces, diarrhea, nausea, and headache. Adverse drug reactions with an incidence of ≥ 5% in OAC group include diarrhea, dysgeusia, dyspepsia, nausea and headache. Table 2 lists adverse reactions with an incidence of ≥ 1%, in either group (OBMT vs OAC) and in order of decreasing incidence for the OBMT group. Table 2: Adverse reactions with an incidence of ≥ 1% from North American trial, [n (%)] Preferred Term OBMT* (n = 147) OAC** (n = 152) Gastrointestinal disorders Abnormal feces*** 23 (15.6%) 7 (4.6%) Nausea 12 (8.2%) 14 (9.2%) Diarrhea 10 (6.8%) 20 (13.2%) Abdominal Pain 7 (4.8%) 2 (1.3%) Dyspepsia 4 (2.7%) 10 (6.6%) Constipation 2 (1.4%) 5 (3.3%) Dry Mouth 2 (1.4%) 1 (0.7%) Flatulence 0 4 (2.6%) Glossitis 0 2 (1.3%) General disorders and administration site conditions Asthenia 5 (3.4%) 2 (1.3%) Infections and infestations Vaginal infection 4 (2.7%) 3 (2%) Nervous system disorders Headache 8 (5.4%) 8 (5.3%) Dysgeusia 6 (4.1%) 18 (11.8%) Dizziness 4 (2.7%) 4 (2.6%) Investigations Laboratory test abnormal 3 (2%) 4 (2.6%) Alanine aminotransferase increased 2 (1.4%) 0 Aspartate aminotransferase increased 2 (1.4%) 0 Renal and urinary disorders Urine abnormality 2 (1.4%) 0 Skin and subcutaneous tissue disorders Rash Maculo-Papular 2 (1.4%) 0 Rash 1 (0.7%) 3 (2%) Pruritus 0 4 (2.6%) * OBMT = Omeprazole + Bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride ** OAC = Omeprazole + Amoxicillin + Clarithromycin; *** Dark stools [see Warnings and Precautions (5.9) ] Adverse reactions with an incidence of <1% for OBMT group are: back pain, vomiting, tongue darkening [see Warnings and Precautions (5.9) ] , anxiety, gastritis, gastroenteritis, myalgia, chest pain, increased appetite, blood creatine phosphokinase increased, malaise, somnolence, tachycardia, duodenal ulcer, visual disturbance, weight increased. 6.2 Postmarketing Experience Additionally, the following adverse reactions, presented by system organ class in alphabetical order, have been identified during post approval use of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride. 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. Gastrointestinal disorders: abdominal distention, eructation, flatulence General disorders and administration site conditions: chest discomfort, fatigue Infections and infestations : candidiasis, pseudomembranous colitis ( Clostridium difficile colitis) Nervous Systems: peripheral neuropathy Skin and subcutaneous disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome (drug rash with eosinophilia and systemic symptoms) [see Warnings and Precautions (5.5)] 6.3 Other Important Adverse Reactions from Labeling for the Individual Components of Bismuth Subcitrate Potassium, Metronidazole and Tetracycline Hydrochloride Metronidazole Blood and Lymphatic system disorders: Reversible neutropenia (leucopenia) in cases of prolonged treatment; rarely reversible thrombocytopenia however no persistent hematological abnormalities attributable to metronidazole have been observed [see Warnings and Precautions (5.10) ]. Cardiac disorders: QT prolongation has been reported with metronidazole, particularly when administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings. Gastrointestinal disorders: Nausea, vomiting, diarrhea, abdominal pain, constipation, anorexia, metallic taste, furry tongue, glossitis, stomatitis and candida overgrowth. Hypersensitivity/Immune system disorders: Acute generalized exanthematous pustulosis (AGEP) [see Warnings and Precautions (5.5)], urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever [see Contraindications (4.6)]. Metabolism and nutrition disorders: Pancreatitis. Nervous system disorders: Convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, headache, syncope, dizziness, vertigo, incoordination, ataxia, tinnitus, hearing impairment, hearing loss, confusion, dysarthria, irritability, depression, weakness, and insomnia [see Warnings and Precautions (5.6)]. Dermatologic disorders: Erythematous rash and pruritus. Renal and urinary disorders: Dysuria, cystitis, polyuria, incontinence, darkened urine, and a sense of pelvic pressure. Hepatic: Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne Syndrome (latency from drug start to signs of liver failure as short as 2 days) [see Contraindications ( 4. 3)] . Other: Dyspareunia, decrease of libido, proctitis, joint pains. Tetracycline Hydrochloride Blood and lymphatic system disorders: Hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, neutropenia, and eosinophilia. Gastrointestinal disorders: Nausea, vomiting, diarrhea, anorexia, glossitis, black hairy tongue, dysphagia, enterocolitis, inflammatory lesions (with Candida overgrowth) in the anogenital region, esophagitis and esophageal ulceration. Nervous system disorders: Intracranial hypertension including pseudotumor cerebri, tinnitus, and myasthenic syndrome. Renal and urinary disorders: Increased BUN. Skin and subcutaneous tissue disorders: Maculopapular and erythematous rashes, onycholysis, fixed drug eruption, discoloration of the nails, exfoliative dermatitis and photosensitivity have been rarely reported [see Warnings and Precautions (5.8) ]. Liver : Hepatotoxicity and liver failure. Hypersensitivity reactions : Urticaria, angioedema, anaphylaxis, Henoch-Schonlein purpura, pericarditis, exacerbation of systemic lupus erythematosus, and serum sickness-like reactions.

<table><col/><col/><col/><tbody><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">Preferred Term</content></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">OBMT* (n = 147)</content> </td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">OAC** (n = 152)</content></td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold"><content styleCode="underline">Gastrointestinal disorders</content></content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Abnormal feces***</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">23 (15.6%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">7 (4.6%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Nausea</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">12 (8.2%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">14 (9.2%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Diarrhea</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">10 (6.8%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">20 (13.2%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Abdominal Pain</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">7 (4.8%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (1.3%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Dyspepsia</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">4 (2.7%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">10 (6.6%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Constipation</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (1.4%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">5 (3.3%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Dry Mouth</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (1.4%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">1 (0.7%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Flatulence</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">0</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">4 (2.6%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Glossitis</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">0</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (1.3%)</td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold"><content styleCode="underline">General disorders and administration site conditions</content></content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Asthenia</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">5 (3.4%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (1.3%)</td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold"><content styleCode="underline">Infections and infestations</content></content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Vaginal infection</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">4 (2.7%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">3 (2%)</td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold"><content styleCode="underline">Nervous system disorders</content></content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Headache</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">8 (5.4%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">8 (5.3%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Dysgeusia</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">6 (4.1%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">18 (11.8%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Dizziness</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">4 (2.7%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">4 (2.6%)</td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold"><content styleCode="underline">Investigations</content></content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Laboratory test abnormal</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">3 (2%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">4 (2.6%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Alanine aminotransferase increased</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (1.4%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">0</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Aspartate aminotransferase increased</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (1.4%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">0</td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold"><content styleCode="underline">Renal and urinary disorders</content></content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Urine abnormality</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (1.4%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">0</td></tr><tr><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold"><content styleCode="underline">Skin and subcutaneous tissue disorders</content></content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Rash Maculo-Papular</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">2 (1.4%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">0</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Rash</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">1 (0.7%)</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">3 (2%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Pruritus</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">0</td><td align="center" styleCode=" Botrule Toprule Lrule Rrule">4 (2.6%)</td></tr></tbody></table>