To be sold by retail on the prescription of a ‘Registered Medical Practitioner Only’

Norfloxacin Tablets

BRAND NAME

NORFLOX Tablets

BLACK BOX WARNING

WARNING: SERIOUS ADVERSE REACTIONS, INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM (CNS) EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS See the full prescribing information for complete boxed warning Fluoroquinolones, including Norfloxacin have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together, including the following: ·         Tendinitis and tendon rupture ·         Peripheral neuropathy ·         CNS effects Discontinue Norfloxacin immediately and avoid the use of fluoroquinolones, including Norfloxacin, in patients who experience any of these serious adverse reactions Fluoroquinolones, including Norfloxacin, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid norfloxacin in patients with known history of myasthenia gravis. Because fluoroquinolones, including Norfloxacin, have been associated with serious adverse reactions, reserve norfloxacin for use in patients who have no alternative treatment options for the following indications: ·         Acute exacerbation of chronic bronchitis ·         Acute uncomplicated cystitis ·         Acute sinusitis This drug may cause low blood sugar and mental health-related side effects.

QUALITATIVE AND QUANTITATIVE COMPOSITION

NORFLOX 200 Tablets
Each film-coated tablet contains:

Norfloxacin, IP ………. 200 mg

Lactic acid Bacillus ….. 60 × 10⁶ spores

(Appropriate overages added)

Excipients………………..q.s.

Colours: Titanium Dioxide IP and Sunset Yellow FCF

NORFLOX 400 Tablets
Each film-coated tablet contains:

Norfloxacin, IP ………. 400 mg

Lactic acid Bacillus ….. 120 × 10⁶ spores

(Appropriate overages added)

Excipients……………….q.s

Colours: Titanium Dioxide IP and Sunset Yellow FCF

DOSAGE FORM(S) AND STRENGTH(S)

Film-coated Oral tablet

CLINICAL PARTICULARS

Therapeutic Indication

Norfloxacin is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms:

Urinary Tract Infections (UTIs)

NORFLOX Tablets is indicated in the treatment of acute uncomplicated/complicated chronic, recurrent urinary tract infections, including pyelonephritis, cystitis, urethritis & gonococcal infections.

Posology & Method of Administration

Norfloxacin tablets should be taken at least 1 hour before, or at least 2 hours after a meal or ingestion of milk and/or other dairy products.

Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminium, sucralfate, or didanosine chewable/buffered tablets or the paediatric powder for oral solution should not be taken within 2 hours of administration of norfloxacin. NORFLOX Tablets should be taken with a glass of water. Patients receiving norfloxacin should be well hydrated.

Patient with Normal Renal Function

The recommended daily dose of norfloxacin is as described in the following chart:

Infection	Unit Dose	Frequency	Duration	Daily Dose
Complicated UTIs	200mg-400 mg	q12h	3-10 days	800 mg
Acute uncomplicated UTIs	200mg-400 mg	q12h	3-10 days	800 mg
Sexually Transmitted Diseases Uncomplicated gonorrhoea	800 mg	Single dose	1 day	800 mg
Chronic bacterial prostatitis	400 mg	q12h	28 days	800 mg

NORFLOX Tablets should not be chewed or crushed. Patients should be instructed to swallow the tablet whole.

Patient with Renal Impairment

Norfloxacin may be used for the treatment of UTIs in patients with renal impairment. In patients with a creatinine clearance rate of 30 mL/min/1.73 m² or less, the recommended dosage is one 400 mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m².

When only the serum creatinine level is available, the following formula (based on sex, weight and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.

Males:	(weight in kg) × (140 – age)
	(72) × serum creatinine (mg/100 mL)
Females	(0.85) × (above value)

 

In Geriatric Patients

Elderly patients being treated for UTIs, who have a creatinine clearance of greater than 30 mL/min/1.73 m², should receive the dosages recommended under Normal Renal Function.

Elderly patients being treated for UTIs, who have a creatinine clearance of 30 mL/min/1.73 m² or less, should receive 400 mg once daily as recommended under Renal Impairment.

Contraindication

• In patients with history of hypersensitivity to fluoroquinolones and/or probiotic like lactic acid bacillus,
• In patients with history of tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial

Special Warnings & Precaution for Use

Fluoroquinolones, including norfloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and CNS effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting norfloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions. Discontinue norfloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including norfloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

Tendinopathy and Tendon Rupture

Fluoroquinolones, including norfloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur within hours or days of starting norfloxacin, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Discontinue norfloxacin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including norfloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.

Exacerbation of Myasthenia Gravis

Fluoroquinolones, including norfloxacin, have neuromuscular-blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid norfloxacin in patients with a known history of myasthenia gravis.

Central Nervous System Effects/Disorders:

Fluoroquinolones, including norfloxacin, have been associated with an increased risk of CNS effects, including convulsions, increased intracranial pressure (including pseudo-tumour cerebri), and toxic psychoses. Quinolones may also cause CNS stimulation, which may lead to tremors, restlessness, light-headedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued, and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures.

Hypersensitivity Reactions

Serious, and occasionally fatal, hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy, including norfloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial oedema, dyspnoea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated.

Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including Norfloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:

• fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity, and supportive measures should be institute.

Clostridium difficile-associated Diarrhoea

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

1. 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 diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

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

Peripheral Neuropathy

Fluoroquinolones, including norfloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paraesthesia, hypoesthesia, dysaesthesia and weakness have been reported in patients receiving fluoroquinolones, including norfloxacin. Symptoms may occur soon after initiation of norfloxacin and may be irreversible in some patients Discontinue norfloxacin immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to minimise the development of an irreversible condition. Avoid fluoroquinolones, including norfloxacin, in patients who have previously experienced peripheral neuropathy.

Syphilis Treatment

Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhoea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhoea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after 3 months.

Safety in Children, Adolescents, Nursing Mothers, and during Pregnancy

Safety and efficacy of oral norfloxacin in paediatric patients, adolescents (under the age of 18 years), pregnant women, and nursing mothers have not been established.

The oral administration of single doses of norfloxacin, 6 times2 the recommended human clinical dose (on mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species.

General

Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1,600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. While crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded, and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output.

Alteration in dosage regimen is necessary for patients with impaired renal function.

Moderate-to-severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g. burning, erythema, exudation, vesicles, blistering, oedema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolone antibiotics after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs.

Rarely, haemolytic reactions have been reported in patients with latent or actual defects in glucose-6­ phosphate dehydrogenase activity, who take quinolone antibacterial agents, including norfloxacin.

Prescribing norfloxacin 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.

Serious Adverse Reactions

Advise patients to stop taking norfloxacin if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug. Inform patients of the following serious adverse reactions that have been associated with norfloxacin or other fluoroquinolone use:

Disabling and Potentially Irreversible Serious Adverse Reactions that may Occur Together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and CNS effects, have been associated with the use of norfloxacin and may occur together. Inform patients to stop taking norfloxacin immediately if they experience an adverse reaction and to call their healthcare provider.

Tendinitis and Tendon Rupture: Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue norfloxacin treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients (usually over 60 years of age), in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.

Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with the use of norfloxacin, and that symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, patients should immediately discontinue norfloxacin and contact their physicians.

CNS Effects (e.g. convulsions, dizziness, light-headedness, increased intracranial pressure): Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including norfloxacin. Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to norfloxacin before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.

Exacerbation of Myasthenia Gravis: Inform patients that fluoroquinolones such as norfloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems.

Hypersensitivity Reactions: Inform patients that norfloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angio-oedema (e.g. swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.

Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking norfloxacin. Instruct patients to inform their physician if they experience any signs or symptoms of liver injury, including loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light-coloured bowel movements or dark-coloured urine.

Diarrhoea: Inform patients that diarrhoea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 months or more than 8 months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible.

Prolongation of the QT Interval: Inform patients that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation).  Norfloxacin needs to be avoided in patients receiving class IA (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) anti-arrhythmic agents. Norfloxacin needs to be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants.

Physicians of any personal or family history of QTc prolongation or pro-arrhythmic conditions such as hypokalaemia, bradycardia or recent myocardial ischaemia.

Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Patients should minimise or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect the skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician.

Patients should also be advised on the following:

• to drink fluids liberally.
• that norfloxacin should be taken at least 1 hour before or at least 2 hours after a meal or ingestion of milk and/or other dairy products.
• those multivitamins or other products containing iron or zinc, antacids or didanosine, chewable/buffered tablets or the paediatric powder for oral solution, should not be taken within the 2-hour period before or within the 2-hour period after taking norfloxacin.
• that some quinolones may increase the effects of theophylline and/or caffeine.
• that convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition.

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

Laboratory Tests

As with any potent antibacterial agents, periodic assessment of organ system functions, including renal, hepatic and haematopoietic, is advisable during prolonged therapy.

Drugs Interactions

Quinolones, including norfloxacin, have been shown in vitro to inhibit cytochrome (CY) P1A2. Concomitant use with drugs metabolised by CYP1A2 (e.g. caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored.

Theophylline: Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and the dosage of theophylline adjusted as required.

Cyclosporine: Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored, and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly.

Anticoagulants: Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored.

Glyburide: The concomitant administration of quinolones including norfloxacin with glyburide (a sulphonylurea agent) has, on rare occasions, resulted in severe hypoglycaemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered.

Probenecid: Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin.

Nitrofurantoin: The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of norfloxacin in the urinary tract.

Multivitamins, or other Products Containing Iron or Zinc, Antacids or Sucralfate, should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption, resulting in lower serum and urine levels of norfloxacin.

Didanosine: Didanosine chewable/buffered tablets or the paediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin.

Caffeine: Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin.

Non-Steroidal Anti-Inflammatory Drug (NSAID): NSAID with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, norfloxacin should be used with caution in individuals receiving NSAIDs concomitantly.

Use in Special Populations

Pregnant Women

Teratogenic Effects. Pregnancy Category C.

Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times² the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times² the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NORFLOX Tablets should be avoided in pregnancy.

Lactating Women

It is not known whether norfloxacin is excreted in human milk.

When a 200-mg dose of norfloxacin was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

NORFLOX Tablets are not recommended for use by nursing mothers.

Paediatric Patients

Safety and effectiveness of oral norfloxacin in paediatric patients and adolescents below the age of 18 years have not been established.

NORFLOX Tablets are not recommended for use in patient aged below 18 years old.

Geriatric Patients

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with fluoroquinolone such as norfloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing norfloxacin to elderly patients, especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue norfloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur.

In general, elderly patients may be more susceptible to drug-associated effects of the QTc interval. Therefore, precaution should be taken when using norfloxacin concomitantly with drugs that can result in prolongation of the QTc interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes.

Patients with Renal Impairment

Norfloxacin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Patients with Hepatic Impairment

Periodically monitor hepatic function during prolong therapy.

Effects on Ability to Drive & Use Machines

Not stated

Undesirable Effects

Single-Dose Studies

In clinical trials involving 82 healthy subjects and 228 patients with gonorrhoea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship.

The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%).

Additional reactions (0.3–1.0%) were anorexia, diarrhoea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting.

Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were increased AST (SGOT) (1.6%), decreased WBCs (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased haematocrit and haemoglobin (0.6%), and increased eosinophils (0.6%).

Multiple-Dose Studies

In clinical trials involving 52 healthy subjects and 1,980 patients with UTIs or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship.

The most common adverse experiences (>1.0%) were nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%).

Additional reactions (0.3–1.0%) were abdominal pain, back pain, constipation, diarrhoea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting.

Less frequent reactions (0.1–0.2%) included abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhoea, oedema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria.

Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased white blood cells and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased haematocrit, and glycosuria.

Postmarketing Experience

The most frequently reported adverse reaction in postmarketing experience was rash.

CNS effects characterised as generalised seizures, myoclonus and tremors have been reported with norfloxacin. Visual disturbances have been reported with drugs in this class.

The following additional adverse reactions have been reported since the drug was marketed:

Hypersensitivity Reactions: Hypersensitivity reactions have been reported, including anaphylactoid reactions, angio-oedema, dyspnoea, vasculitis, urticaria, arthritis, arthralgia, and myalgia.

Skin: Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity/phototoxicity reactions and skin hyperpigmentation.

Gastrointestinal: Pseudomembranous colitis, hepatitis, jaundice, including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), and stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment.

Hepatic: Hepatic failure, including fatal cases.

Cardiovascular: On rare occasions, prolonged QTc interval and ventricular arrhythmia, including torsades de pointes.

Renal: Interstitial nephritis, renal failure.

Nervous System/Psychiatric: Peripheral neuropathy, Guillain-Barré syndrome, ataxia, paraesthesia, hypoesthesia, psychic disturbances, including psychotic reactions and confusion.

Musculoskeletal: Tendinitis, tendon rupture; exacerbation of myasthenia gravis; elevated creatine kinase (CK).

Haematologic: Neutropaenia; leucopaenia; agranulocytosis; haemolytic anaemia, sometimes associated with glucose-6 phosphate dehydrogenase deficiency; thrombocytopaenia.

Special Senses: Hearing loss, tinnitus, diplopia, dysgeusia.

Other adverse events reported with quinolones include the following: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, haematuria, hepatic necrosis, symptomatic hypoglycaemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis.

The drug may cause low blood sugar and mental health-related side effects. Low blood sugar levels, also called hypoglycaemia, can lead to coma. The mental health-related side effects that were more prominent and more consistent across the systemic fluoroquinolone drug class are as mentioned below;

• Disturbances in attention
• Disorientation
• Agitation
• Nervousness
• Memory impairment
• Serious disturbances in mental abilities called delirium

Probiotics are, generally, well tolerated. The most common adverse reactions with the use of probiotics are gastrointestinal and include flatulence and constipation.

Reporting of Suspected Adverse Reactions

For Adverse Events / Complaints: call on Cipla Toll free number (for India)18002677779 or email to drugsafety@cipla.com  

Overdose

No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg.

In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained.

PHARMACOLOGICAL PROPERTIES

Mechanism of Action

Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in Escherichia coli cells:

• Inhibition of the ATP-dependent DNA supercoiling reaction catalysed by DNA gyrase
• Inhibition of the relaxation of supercoiled DNA
• Promotion of double-stranded DNA breakage

The fluorine atom at the 6 position provides increased potency against Gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity.

Drug Resistance

Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10^–9 to 10^–12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are as follows:

Pseudomonas aeruginosa
Klebsiella pneumoniae
Acinetobacter spp.
Enterococcus spp.

For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; however, these organisms may have higher minimum inhibitory concentrations (MICs) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents, including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulphonamides, including combinations of sulphamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin.

Norfloxacin has in vitro activity against a broad range of Gram-positive and Gram-negative aerobic bacteria.

Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections:

Gram-positive Aerobes

Enterococcus faecalis
Staphylococcus aureus
Staphylococcus epidermidis
Staphylococcus saprophyticus
Streptococcus agalactiae

Gram-negative Aerobes

Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli
Klebsiella pneumoniae
Neisseria gonorrhoeae
Proteus mirabilis
Proteus vulgaris
Pseudomonas aeruginosa
Serratia marcescens

The following in vitro data are available, but their clinical significance is unknown.

Norfloxacin exhibits in vitro MICs of ≤4 μg/mL against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-negative Aerobes

Citrobacter diversus
Edwardsiella tarda
Enterobacter agglomerans
Haemophilus ducreyi
Klebsiella oxytoca
Morganella morganii
Providencia alcalifaciens
Providencia rettgeri
Providencia stuartii
Pseudomonas fluorescens
Pseudomonas stutzeri

Other

Ureaplasma urealyticum

Norfloxacin is not generally active against obligate anaerobes.

Norfloxacin has not been shown to be active against Treponema pallidum

Pharmacokinetics Properties

In fasting healthy volunteers, at least 30–40% of an oral dose of norfloxacin is absorbed.

Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 μg/mL are attained approximately 1 hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3–4 hours. Steady-state concentrations of norfloxacin will be attained within 2 days of dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing.

In healthy elderly volunteers (65–75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400 mg dose of norfloxacin, a mean (± SD) AUC and C_max of 9.8 (2.83) μg•hr/mL and 2.02 (0.77) μg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC, 6.4 μg•hr/mL; C_max, 1.5 μg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects was 4 hours.

There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment.

The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m² is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m², the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary.

Drug absorption appears unaffected by decreasing renal function.

Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400 mg dose of norfloxacin, mean antimicrobial activities equivalent to 278, 773, and 82μg of norfloxacin/g of the faeces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26–32% of the administered dose is recovered in the urine as norfloxacin with an additional 5–8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Faecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m²), approximately 22% of the administered dose was recovered in urine, and renal clearance averaged 154 mL/min.

At 2–3 hours after a single 400 mg dose, urinary concentrations of 200μg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30μg/mL for at least 12 hours following a 400 mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5, with greater solubility occurring at pHs above and below this value. The serum protein-binding of norfloxacin is between 10 and 15%.

The following are the mean concentrations of norfloxacin in various fluids and tissues measured 1–4 hours post-dose after two 400 mg doses, unless otherwise indicated:

Renal parenchyma	7.3 µg/g
Prostate	2.5 µg/g
Seminal fluid	2.7 µg/mL
Testicle	1.6 µg/g
Uterus/Cervix	3.0 µg/g
Vagina	4.3 µg/g
Fallopian tube	1.9 µg/g
Bile	6.9 µg/mL (after two 200 mg doses)

NON-CLINICAL PROPERTIES

Animal Toxicology or Pharmacology

Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested.

Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day.

Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher.

Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals.

DESCRIPTION

NORFLOX Tablets contain Norfloxacin and Lactic acid Bacillus spores. Norfloxacin is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin belongs to the class of fluoroquinolone, used in the systemic treatment of infections. It is 1-ethyl-6fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C₁₆H₁₈FN₃O₃.

Lactic acid bacillus is a probiotic used to treat diarrhea caused due to infections or antibiotics. Also helps to restore the balance of good bacteria in gut which may have gotten upset due to the infection.

PHARMACEUTICAL PARTICULARS

Incompatibilities

Not applicable

Shelf Life

As on a pack

Packaging Information

NORFLOX 200: Blister pack of 10 tablets

NORFLOX 400: Blister pack of 10 tablets

Storage & Handling Instruction

Store at a temperature not exceeding 30^oC.

Protect from light and moisture.

Keep out of reach of children.

PATIENT COUNSELLING INFORMATION

What is NORFLOX Tablet?

NORFLOX Tablets contain Norfloxacin and Lactic acid Bacillus spores. Norfloxacin a fluoroquinolone antibiotic with broad-spectrum antibacterial activity. It is used in adults to treat certain infections caused by bacteria. Lactic acid bacillus is a probiotic used to treat diarrhea caused due to infections or antibiotics. Also helps to restore the balance of good bacteria in gut which may have gotten upset due to the infection.

Do not take NORFLOX Tablet if you:

• have ever had a severe allergic reaction to an antibiotic known as fluoroquinolone or probiotic like lactic acid bacillus.
• have had tendinitis or tendon rupture with the use of norfloxacin or another fluoroquinolone antibiotic.

Before you take NORFLOX Tablet, tell your healthcare provider about all your medical conditions, including if you:

• have tendon problems.
• have a disease that causes muscle weakness (myasthenia gravis)
• have central nervous system problems (such as epilepsy)
• have nerve problems
• have or anyone in your family has an irregular heartbeat, especially a condition called “QTc prolongation”
• have low potassium (hypokalemia)
• have a slow heartbeat called bradycardia
• have a history of seizures
• have kidney problems. You may need a lower dose of medication if your kidneys do not work well.
• have rheumatoid arthritis (RA) or other history of joint problems
• are pregnant or planning to become pregnant. It is not known if NORFLOX Tablet will harm your unborn child.
• are breast-feeding or planning to breast-feed. It is not known if NORFLOX Tablet passes into breast milk. You and your healthcare provider should decide whether you will take medication or breast-feed.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal and dietary supplements. NORFLOX Tablet and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take:

• an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take NORFLOX Tablet or other fluoroquinolones may increase your risk of central nervous system effects and seizures.
• glyburide (Micronase, Glynase, Diabeta, Glucovance).
• a blood thinner (warfarin, Coumadin, Jantoven)
• a medicine to control your heart rate or rhythm (antiarrhythmics).
• an anti-psychotic medicine
• a tricyclic antidepressant
• erythromycin
• a water pill (diuretic)
• a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury.
• probenecid
• cyclosporine
• products that contain caffeine
• clozapine
• ropinirole
• tacrine
• tizanidine
• theophylline
• cisapride
• certain medicines may keep NORFLOX Tablet from working correctly. Take NORFLOX Tablet either 2 hours before or 2 hours after taking these products:
  • an antacid, multivitamin or other product that has iron or zinc
  • sucralfate
  • didanosine
• You should not take the medicine nitrofurantoin while taking NORFLOX Tablet.

How should I take NORFLOX Tablet?

Take NORFLOX Tablet exactly as prescribed by your healthcare provider.

Norfloxacin is usually taken every 12 hours for patients with normal kidney function or as directed by the Physician. Take it with a glass of water. Drink plenty of fluids while taking NORFLOX Tablet. The duration of treatment depends on the severity of the illness and on the clinical and bacteriological course.

NORFLOX Tablets should not be chewed or crushed. Patients should swallow the tablet whole.

What are the possible side effects of NORFLOX Tablet?

Like all medicines, this medicine causes side effects, although not everybody gets them.

The most common side effects of include:

• dizziness
• nausea
• loss of appetite
• diarrhea
• heartburn
• headache
• stomach (abdominal) cramping
• weakness
• vertigo
• skin rash or itching
• changes in certain liver function tests

Other serious side effects include:

Tendon rupture or swelling of the tendon (tendinitis)

Tendon problems can happen in people of all ages who take Norfloxacin. Tendons are tough cords of tissue that connect muscle to bones. Symptoms of tendon problems may include:  Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites.

The risk of getting tendon problems while you take Norfloxacin is higher if you:

• are over 60 years of age
• are taking steroids (corticosteroids)
• have had a kidney, heart or lung transplant

Central Nervous System Effects. Seizures have been reported in people who take fluoroquinolone antibiotics including Norfloxacin. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking Norfloxacin will change your risk of having a seizure.

Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of Norfloxacin. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior:

• feel lightheaded
• seizures
• hear voices, see things, or sense things that are not there (hallucinations)
• feel restless
• tremors
• feel anxious or nervous
• confusion
• feel more suspicious (paranoia)

Serious allergic reactions. Allergic reactions can happen in people who take fluoroquinolones, including Norfloxacin, even after only one dose. Stop taking NORFLOX Tablet and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction:

• hives
• trouble breathing or swallowing
• swelling of the lips, tongue, face
• throat tightness, hoarseness
• rapid heartbeat
• faint
• skin rash accompanied by fever and feeling unwell
• yellowing of the skin or eyes. Stop taking NORFLOX Tablet and tell your healthcare provider right away if you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to NORFLOX Tablet (a liver problem).

Skin rash. Skin rash may happen in people taking NORFLOX Tablet, even after only one dose. Stop taking NORFLOX Tablet at the first sign of a skin rash and call your healthcare provider. Skin rash may be sign of a more serious reaction to NORFLOX Tablet.

Serious heart rhythm changes (QTc prolongation and torsade de pointes). Tell your healthcare provider right away if you have a change in your heartbeat (a fast or irregular heartbeat), or if you faint. NORFLOX Tablet may cause a rare heart problem known as prolongation of the QTc interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people:

• who is elderly
• with a family history of prolonged QTc interval
• with low blood potassium (hypokalemia)
• who take certain medicines to control heart rhythm (antiarrhythmics)

Intestine infection (Pseudomembranous colitis). Pseudomembranous colitis can happen with most antibiotics, including norfloxacin. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic.

Changes in sensation and nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people taking fluoroquinolones, including norfloxacin. Stop NORFLOX Tablet and talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:

• pain
• burning
• tingling
• numbness
• weakness

The nerve damage may be permanent.

Low blood sugar (hypoglycemia). People taking norfloxacin and other fluoroquinolone medicines with the oral anti-diabetes medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar (hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get low blood sugar while taking NORFLOX Tablet. Your antibiotic medicine may need to be changed.

Sensitivity to sunlight (photosensitivity)

These are not all the possible side effects of NORFLOX Tablet. Tell your healthcare provider about any side effect that bothers you or that does not go away.

How should I store NORFLOX Tablet?

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

Do not take this medicine after the expiry date stamped on the pack after EXP. The expiry date refers to the last day of that month.

Store in a cool and dry place. Protect from moisture.

General information about safe & effective use of NORFLOX Tablet

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NORFLOX Tablet for a condition for which it is not prescribed. Do not give NORFLOX Tablet to other people, even if they have the same symptoms that you have. It may harm them.

Do not drive or use machinery if this medicine makes you feel drowsy or gives you problems with co-ordination or sensation (e.g. numbness or weakness).

What are the ingredients of NORFLOX Tablet?

Each film-coated tablet contains Norfloxacin an antibacterial agent and appropriate amount of probiotic (lactic acid bacillus spores) for oral administration.

DETAILS OF MANUFACTURER

Manufactured by:

M/S Pinnacle Life Science Pvt. Ltd.,

Khasra No. 1328-1330, Village Manpura,

Tehsil Baddi, Distt. Solan (HP)- 174101

Marketed by:

CIPLA LTD.

Regd. Office: Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg, Lower Parel, Mumbai – 400 013, India

DETAILS OF PERMISSION OR LICENCE NUMBER WITH DATE

Licence NO. MNB/08/729 & MB/08/730

DATE OF REVISION

19/07/2023