OFLOX TZ Tablets (Ofloxacin + Tinidazole )

Table of Content

Black Box 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 ofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together, including 

  • tendinitis and tendon rupture;
  • peripheral neuropathy; and,
  • CNS effects  

Discontinue ofloxacin immediately and avoid the use of fluoroquinolones, including ofloxacin in patients who experience any of these serious adverse reactions.

Fluoroquinolones, including ofloxacin, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid ofloxacin in patients with known history of myasthenia gravis.

• Because fluoroquinolones, including ofloxacin, have been associated with serious adverse reactions, reserve ofloxacin 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.

 

Warning: Potential Risk for Carcinogenicity

Carcinogenicity has been seen in mice and rats treated chronically 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. 

Qualitative & Quantitative Composition

Each film coated tablet contains:

Ofloxacin USP….200mg

Tinidazole IP……600mg

Colours: Titanium Dioxide & Yellow Oxide of Iron

Dosage Form & Strength

Fixed dose combination tablet of 200mg Ofloxacin and 600mg Tinidazole

Clinical Particular

Therapeutic Indication

OFLOX TZ Tablets are indicated for the treatment of a wide variety of infections caused by susceptible Gram-positive and Gram-negative organisms along with anaerobes and protozoa

Posology & method of administration

As directed by the Physician

Contraindication

Ofloxacin

The use of ofloxacin is contraindicated as follows:

  • Hypersensitivity to the active substance, to any other fluoroquinolone antibacterials, or to any of the excipients.
  • In patients with a history of epilepsy or an existing central nervous system disorder with a lowered seizure threshold.
  • In patients with a history of tendon disorders related to fluoroquinolone administration
  • In children or growing adolescents, and in pregnant or breastfeeding women, since animal experiments do not entirely exclude the risk of damage to the growth-plate cartilage in the growing organism cannot be entirely excluded.
  • In patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity because they may be prone to haemolytic reactions when treated with quinolone antibacterial agents.

Tinidazole

  • Hypersensitivity to the active substance or to any of the excipients
  • As with other drugs of similar structure, tinidazole is contraindicated in patients having, or with a history of, blood dyscrasia, although no persistent haematological abnormalities have been noted in clinical or animal studies.
  • Tinidazole should be avoided in patients with organic neurological disorders.
  • Tinidazole, other 5-nitroimidazole derivatives or any of the components of this product should not be administered to patients with known hypersensitivity to the drug.
  • Use of tinidazole is contraindicated during the first trimester of pregnancy and in nursing mothers.

Special Warnings & Precaution for Use

Ofloxacin

General

Ofloxacin tablets are not the drug of first choice in pneumonia caused by Streptococcus pneumoniae or Chlamydia pneumoniae.

Methicillin-resistant S. aureus

Are very likely to possess co-resistance to fluoroquinolones, including ofloxacin. Therefore ofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to ofloxacin (and commonly recommended antibacterial agents for the treatment of MRSA-infections are considered inappropriate).

Resistance to fluoroquinolones of E. coli

The most common pathogen involved in urinary tract infections – varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in E. coli to fluoroquinolones.

Severe bullous reactions

Cases of severe bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with ofloxacin. Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.

Tendonitis

Tendonitis, rarely observed with quinolones, may occasionally lead to rupture involving Achilles tendon in particular. Tendinitis and tendon rupture, sometimes bilateral, may occur within 48 hours of starting treatment with ofloxacin and have been reported up to several months after discontinuation of ofloxacin. The risk of tendinitis and tendon rupture is increased in patients aged over 60 years and in patients using corticosteroids. The daily dose should be adjusted in elderly patients based on creatinine clearance. Close monitoring of these patients is therefore necessary if they are prescribed ofloxacin. All patients should consult their physician if they experience symptoms of tendinitis. If tendinitis is suspected, treatment with ofloxacin must be halted immediately, and appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon.

Hypersensitivity

Hypersensitivity and allergic reactions have been reported for fluoroquinolones after first administration. Anaphylactic and anaphylactoid reactions can progress to life-threatening shock, even after the first administration. In these cases ofloxacin should be discontinued and suitable treatment (e.g. treatment for shock) should be initiated.

Diseases caused by Clostridium difficile

Diarrhoea, especially if severe, persistent and/or bloody, occurring during or after treatment with ofloxacin (including several weeks after treatment), may indicate a condition caused by Clostridium difficile, the most severe form of which is pseudomembranous colitis (CDAD) CDAD may range in severity from mild to life threatening, the most severe form of which is pseudomembranous colitis. It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with ofloxacin. If pseudo-membraneous colitis is suspected, treatment should be discontinued immediately.

Appropriate specific antibiotic therapy must be started without delay (e.g. oral vancomycin, oral teicoplanin or metronidazole). Medicinal products that inhibit peristalsis are contraindicated in such cases.

Patients predisposed to seizures

Quinolones may lower the seizure threshold and may trigger seizures. Ofloxacin is contraindicated in patients with a history epilepsy or with a known predisposition to seizures.

Patients with a known predisposition to seizures may include those with pre-existing central nervous system lesions, concomitant treatment with fenbufen and similar non-steroidal anti-inflammatory drugs (NSAIDs), or with drugs which lower the cerebral seizure threshold, such as theophylline.

In case of convulsive seizures, treatment with ofloxacin should be discontinued.

 Patients with impaired renal function

Since ofloxacin is eliminated primarily via the kidneys, the dose should be adjusted in patients with impaired renal function.

Patients with history of psychotic disorder

Psychotic reactions have been reported in patients receiving fluoroquinolones including ofloxacin. In some cases these have progressed to suicidal thoughts or self-endangering behavior including suicide attempt, sometimes after a single dose of ofloxacin. In the event that a patient develops these reactions, ofloxacin should be discontinued and appropriate measures instituted.

Ofloxacin should be used with caution in patients with a history of psychotic disorder or in patients with psychiatric disease.

Patients with impaired liver function

Ofloxacin should be used with caution in patients with impaired liver function, as liver damage may occur. Cases of fulminant hepatitis potentially leading to liver failure (including fatal cases) have been reported with fluoroquinolones. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop such as anorexia, jaundice, dark urine, pruritus or tender abdomen.

Patients treated with vitamin K antagonists

Due to possible increase in coagulation tests (PT/INR) and/or bleeding in patients treated with fluoroquinolones, including ofloxacin, in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored when these drugs are given concomitantly.

Myasthenia gravis

Fluoroquinolones, including ofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and the requirement for respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Ofloxacin is not recommended in patients with a known history of myasthenia gravis.

Superinfection

As with other antibiotics, the use of ofloxacin, especially if prolonged, may result in overgrowth of non-susceptible organisms, resistant strains of some organisms or Candida. Repeated evaluation of the patient's condition is essential and periodic in vitro susceptibility tests may be useful. If secondary infection occurs during therapy, appropriate measures should be taken.

Prevention of photosensitisation

Photosensitisation has been reported with ofloxacin. It is recommended that patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g. sunray lamp, solarium), during treatment and for 48 hours following treatment discontinuation in order to prevent photosensitisation.

QT interval prolongation

Very rare cases of QT interval proplongation have been reported in patients taking fluoroquinolones.

Caution should be taken when using fluoroquinolones, including ofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example:

  • elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including ofloxacin, in these populations.
  • uncorrected electrolyte imbalance (e.g. hypokalemia, hypomagnesemia) - congenital long QT syndrome
  • concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics)
  • - cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)

Dysglycaemia

As with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g., glibenclamide) or with insulin. Cases of hypoglycaemic coma have been reported. In these diabetic patients, careful monitoring of blood glucose is recommended.

Peripheral neuropathy

Sensory or sensorimotor peripheral neuropathy has been reported in patients receiving fluoroquinolones, including ofloxacin, which can be rapid in its onset. Ofloxacin should be discontinued if the patient experiences symptoms of neuropathy. This would minimise the possible risk of developing an irreversible condition.

Patients with glucose-6-phosphate-dehydrogenase deficiency

Patients with latent or diagnosed glucose-6-phosphate-dehydrogenase deficiency may be predisposed to haemolytic reactions if they are treated with quinolones. Therefore if ofloxacin has to be used in these patients, potential occurrence of haemolysis should be monitored.

Interference with laboratory tests

In patients treated with ofloxacin, determination of opiates or porphyrin levels in urine may give false-positive results. It may be necessary to confirm positive opiate or porphyrin screens by more specific methods.

Vision disorders

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately.

Tinidazole

As with related compounds, alcoholic beverages should be avoided during Tinidazole therapy because of the possibility of a disulfiram-like reaction (flushing, abdominal cramps, vomiting, tachycardia). Alcohol should be avoided until 72 hours after discontinuing Tinidazole.

Drugs of similar chemical structure have also produced various neurological disturbances such as dizziness, vertigo, incoordination and ataxia. If during therapy with Tinidazole abnormal neurological signs develop, therapy should be discontinued.

Carcinogenicity has been seen in mice and rats treated chronically with metronidazole, another nitroimidazole agent. Although carcinogenicity data is not available for tinidazole, the two drugs are structurally related and therefore there is a potential for similar biologic effects. Mutagenicity results with tinidazole were mixed (positive and negative).The use of tinidazole for longer treatment than usually required should be carefully considered.

Drugs interactions

Ofloxacin

Antacids, Sucralfate, Metal Cations

Co-administered magnesium/aluminum antacids, sucralfate, zinc or iron preparations and didanosine chewable/buffered tablets can reduce absorption of ofloxacin tablets. Therefore, ofloxacin should be taken 2 hours before such preparations.

Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs

No pharmacokinetic interactions of ofloxacin were found with theophylline in a clinical study. However, a pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline, nonsteroidal anti-inflammatory drugs, or other agents, which lower the seizure threshold.

Probenecid, cimetidine, furosemide, and methotrexate

Probenecid decreased the total clearance of ofloxacin by 24%, and increased AUC by 16%. The proposed mechanism is a competition or inhibition for active transport at the renal tubular excretion. Caution should be exercised when ofloxacin is coadministered with drugs that affect the tubular renal secretion such as probenecid, cimetidine, furosemide and methotrexate.

Drugs known to prolong QT interval

Ofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotics).

Vitamin K antagonists

Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have been reported in patients treated with ofloxacin in combination with a vitamin K antagonist (e.g. warfarin). Coagulation tests should, therefore, be monitored in patients treated with vitamin K antagonists because of a possible increase in the effect of coumarin derivatives.

Glibenclamide

Ofloxacin may cause a slight increase in plasma glibenclamide levels when administered concurrently, it is therefore recommended that patients treated concomitantly with ofloxacin and glibenclamide be monitored particularly closely. Since hypoglycaemia is then more likely to occur, close monitoring of blood sugar levels is recommended in such cases.

Tinidazole

Alcohol: Concurrent use of tinidazole and alcohol may produce a disulfiram-like reaction and should be avoided,.

Anticoagulants: Drugs of similar chemical structure have been shown to potentiate the effects of oral anticoagulants. Prothrombin time should be closely monitored and adjustments to the dose of the anticoagulants should be made as necessary.

Use in special populations

Pregnancy

Based on a limited amount of human data, the use of fluoroquinolones in the first trimester of pregnancy has not been associated with an increased risk of major malformations or other adverse effects on pregnancy outcome. Animal studies have shown damage to the joint cartilage in immature animals but no teratogenic effects. Therefore ofloxacin must not be used during pregnancy.

Fertility studies in rats receiving 100mg and 300mg tinidazole/kg had no effect on fertility, adult and pup weights, gestation, viability or lactation. There was a slight, not significant, increase in resorption rate at the 300mg/kg dose.

Tinidazole crosses the placental barrier. Since the effects of compounds of this class on foetal development are unknown, the use of tinidazole during the first trimester is contraindicated. There is no evidence that Tinidazole is harmful during the latter stages of pregnancy, but its use during the second and third trimesters requires that the potential benefits be weighed against possible hazards to mother or foetus.

Lactating women

Ofloxacin is excreted into human breast milk in small amounts. Because of the potential for arthropathy and other serious toxicity in the nursing infant, breast-feeding should be discontinued during treatment with ofloxacin.

Tinidazole is excreted in breast milk. Tinidazole may continue to appear in breast milk for more than 72 hours after administration. Women should not nurse until at least 3 days after having discontinued taking Tinidazole.

Effects on ability to drive & use machines

Ofloxacin

Since there have been occasional reports of drowsiness/somnolence, impairment of skills, dizziness/vertigo and visual disturbances, which may impair the patient's ability to concentrate and react, and therefore may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery), patients should know how they react to ofloxacin before they drive or operate machinery. These effects may be enhanced by alcohol.

Tinidazole

No special precautions should be necessary. However, drugs of similar chemical structure, including Tinidazole, have been associated with various neurological disturbances such as dizziness, vertigo, ataxia, peripheral neuropathy (paraesthesia, sensory disturbances, hypoaesthesia) and rarely convulsions. If any abnormal neurological signs develop during Tinidazole therapy, the drug should be discontinued.

Undesirable effects

Ofloxacin

The information given below is based on data from clinical studies and on extensive post marketing experience.

System organ class

Uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Very rare

(< 1/10,000)

Not known (cannot be estimated from available data)*

Infections and infestations

Fungal infection,

Pathogen resistance

     

Blood and lymphatic system disorders

   

Anaemia,

Haemolytic anaemia,

Leucopenia,

Eosinophilia,

Thrombocytopenia

Agranulocytosis,

Bone marrow failure,

Pancytopenia

Immune system disorders

 

Anaphylactic reaction*,

Anaphylactoid reaction*,

Angioedema*

Anaphylactic shock*,

Anaphylactoid shock*

 

Metabolism and Nutrition disorders

 

Anorexia

 

Hypoglycaemia in diabetics treated with hypoglycaemic agents.

Hyperglycaemia,

Hypoglycaemic coma

Psychiatric disorders

Agitation,

Sleep disorder,

Insomnia

Psychotic disorder (for e.g. hallucination),

Anxiety,

Confusional state,

Nightmares,

Depression

 

Psychotic disorder and depression with self-endangering behaviour including suicidal ideation or suicide attempt,

Nervousness

Nervous system disorders

Dizziness,

Headache

Somnolence,

Paraesthesia,

Dysgeusia,

Parosmia

Peripheral sensory neuropathy*,

Peripheral sensory motor neuropathy* ,

Convulsion*,

Extra-pyramidal symptoms or other disorders of muscular coordination

Tremor,

Dykinesia,

Ageusia,

Syncope

Eye disorders

Eye irritation

Visual disturbance

 

Uveitis

Ear and labyrinth disorders

Vertigo

 

Tinnitus,

Hearing loss

Hearing impaired

Cardiac disorders

 

Tachycardia

 

Ventricular arrhythmias and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolonged

Vascular disorders

 

Hypotension

   

Respiratory, thoracic and mediastinal disorders

Cough,

Nasopharyngitis

Dyspnoea,

Bronchospasm

 

Allergic pneumonitis,

Severe dyspnoea

Gastrointestinal disorders

Abdominal pain,

Diarrhoea,

Nausea,

Vomiting

Enterocolitis, sometimes haemorrhagic

Pseudomembranous colitis*

Dyspepsia,

Flatulence,

Constipation,

Pancreatitis

Hepatobiliary disorders

 

Hepatic enzymes increased (ALAT, ASAT, LDH, gamma-GT and/or alkaline phosphatase),

Blood bilirubin increased

Jaundice cholestatic

Hepatitis, which may be severe*

Severe liver injury, including cases with acute liver failure, sometimes fatal, have been reported with ofloxacin, primarily in patients with underlying liver disorders.

Skin and subcutaneous tissue disorders

Pruritus,

Rash

Urticaria,

Hot flushes,

Hyperhidrosis

Pustular rash

Erythema multiforme,

Toxic epidermal necrolysis,

Photo-sensitivity reaction*,

Drug eruption ,

Vascular purpura,

Vasculitis, which can lead in exceptional cases to skin necrosis

Stevens-Johnson syndrome,

Acute generalised exanthemous pustulosis,

Drug rash,

Stomatitis

Exfoliative dermatitis

Musculoskeletal and connective tissue disorders

 

Tendonitis

Arthralgia,

Myalgia,

Tendon rupture (e.g. Achilles tendon) which may occur within 48 hours of treatment start and may be bilateral

Rhabdomyolysis and/or Myopathy,

Muscular weakness,

Muscle tear, Muscle rupture,

Ligament rupture,

Arthritis

Renal and urinary disorders

 

Serum creatinine increased

Acute renal failure

Acute interstitial nephritis

Congenital, familial and genetic disorders

     

Attacks of porphyria in patients with porphyria

General disorders and administration site conditions

     

Asthenia,

Pyrexia,

Pain (including pain in back, chest and extremities)

* Postmarketing experience

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 side effects 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

Tinidazole

Reported side effects have generally been infrequent, mild and self-limiting.

The reported undesirable effects are listed below according to MedDRA system organ class classification and frequency. Within each frequency category, the ADRs are presented in the order of clinical importance. Frequency categories are expressed as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (the frequency cannot be estimated from the available data).

System Organ Class

Common

Not known

Blood and the lymphatic system disorders

 

Leukopenia

Immune system disorders

 

Drug hypersensitivity

Metabolism and nutrition disorders

Decreased appetite

 

Nervous system disorders

Headache

Convulsions

Neuropathy peripheral

Paraesthesia

Hypoaesthesia

Sensory disturbances

Ataxia

Dizziness

Dysgeusia

Ear and labyrinth disorders

Vertigo

 

Vascular disorders

 

Flushing

Gastrointestinal disorders

Vomiting

Diarrhoea

Nausea

Abdominal pain

Glossitis

Stomatitus

Tongue discolouration

Skin and subcutaneous tissue disorders

Dermatitis allergic

Pruritis

Angioedema

Urticaria

Renal and urinary disorders

 

Chromaturia

General disorders and administration site conditions

 

Pyrexia

Fatigue

Reporting of suspected adverse reactions

“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 18002677779 (Cipla Number) or you can report to PvPI on 1800 180 3024. By reporting side-effects, you can help provide more information on the safety of this product.”

Overdose

Ofloxacin

Symptoms

The most important signs to be expected following acute overdose are CNS symptoms such as confusion, dizziness, impairment of consciousness and convulsive seizures increases in QT interval as well as gastrointestinal reactions such as nausea and mucosal erosions.

CNS effects including confusional state, convulsion, hallucination, and tremor have been observed in post marketing experience.

Management

In the case of overdose steps to remove any unabsorbed ofloxacin e.g. gastric lavage, administration of adsorbants and sodium sulphate, if possible during the first 30 minutes, are recommended; antacids are recommended for protection of the gastric mucosa.

In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Antacids may be used for protection of gastric mucosa. A fraction of ofloxacin may be removed from the body with haemodialysis. Peritoneal dialysis and CAPD are not effective in removing ofloxacin from the body. No specific antidote exists.

Elimination of ofloxacin may be increased by forced diuresis.

Tinidazole

In acute animal studies with mice and rats, the LD50 for mice was >3600mg/kg and >2300mg/kg for oral and intraperitoneal administration respectively. For rats, the LD50 was >2000mg/kg for both oral and intraperitoneal administration.

Signs and symptoms of overdosage: There are no reported overdoses in humans with Tinidazole.

Treatment for overdosage: There is no specific antidote for treatment of overdosage with tinidazole. Treatment is symptomatic and supportive. Gastric lavage may be useful. Tinidazole is easily dialysable.

Pharmacological Properties

Mechanism of action

Ofloxacin

Ofloxacin inhibits bacterial DNA replication by inhibiting bacterial topoisomerases, particularly DNA gyrase and topoisomerase IV. It is active after oral administration.

Therapeutic doses of ofloxacin are devoid of pharmacological effects on the voluntary or autonomic nervous system.

The NCCLS MIC breakpoint recommendations are as follows:

S ≤ 2 mg/l and R ≥ 1 mg/l

Haemophilus influenzae and Neisseria gonorrhoea are exceptions with breakpoints at S ≤ 0.25 mg/l and R ≥ 1 mg/l

The BSAC general recommendations are S ≤ 2 mg/l and R ≥ 4 mg/l

According to DIN 58 940, the following limits apply for ofloxacin:

S ≤ 1 mg/L, I = 2 mg/L, R ≥ 4 mg/L.

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only an approximate guidance on probabilities whether micro-organisms will be susceptible to ofloxacin or not.

Only those pathogens relevant to the indications are listed.

 

European range of acquired bacterial resistance to ofloxacin

Normally susceptible

 

Aerobic Gram-positive micro organisms

 

S. aureus - methicillin-sensitive

0.3-12.6%

S. pyogenes

2-5%

Aerobic Gram-negative micro organisms

 

Acinetobacter spp

0.3-7.3%

Citrobacter spp.

3-15%

Enterobacter spp.

2-13%

E. coli

1-8%

H. influenzae

1%

Klebsiella spp.

1-10%

Moraxella spp.

0-0.2%

Morganella morganii

0-6.9%

N. gonorrhoeae

25%

Proteus spp.

1-15%

Serratia marcescens

2-2.4%

Others

 

Chlamydia spp

 

L. pneumophila

 

Intermediately susceptible

 

Aerobic Gram-positive micro organisms

 

S. pneumoniae

70%

Providentia

17.1%

Aerobic Gram-negative micro organisms

 

E. faecalis

50%

P. aeruginosa

20-30%

Serratia spp.

20-40%

Stenotrophomonas maltophilia

5.1-11%

Others

 

Mycoplasma spp.

0-5.3%

Ureaplasma spp.

0-2.1%

   

Resistant

 

Anaerobic bacteria

 

S. aureus - methicillin-resistant

69.2-85.7%

T. pallidum

 

 

Resistance

The main mechanism of bacterial resistance to ofloxacin involves one or more mutations in the target enzymes, which generally confer resistance to other active substances in the class. Efflux pump and impermeability mechanisms of resistance have also been described and may confer variable resistance to active substances in other classes.

Tinidazole

Tinidazole is active against both protozoa and obligate anaerobic bacteria. The activity against protozoa involves Trichomonas vaginalisEntamoeba histolytica and Giardia lamblia.

The mode of action of Tinidazole against anaerobic bacteria and protozoa involves penetration of the drug into the cell of the micro-organism and subsequent damage of DNA strands or inhibition of their synthesis.

Tinidazole is active against Helicobacter pyloriGardnerella vaginalis and most anaerobic bacteria including Bacteroides fragilis, Bacteroides melaninogenicus, Bacteroides spp., Clostridium spp., Eubacterium spp., Fusobacterium spp., Peptococcus spp., Peptostreptococcus spp. and Veillonella spp.

Helicobacter pylori (H.pylori) is associated with acid peptic disease including duodenal ulcer and gastric ulcer in which about 95% and 80% of patients respectively are infected with this agent. H.pylori is also implicated as a major contributing factor in the development of gastritis and ulcer recurrence in such patients. Evidence suggests a causative link between H.pylori and gastric carcinoma.

Clinical evidence has shown that the combination of Tinidazole with omeprazole and clarithromycin eradicates 91-96% of H.pylori isolates.

Various different H.pylori eradication regimens have shown that eradication of H.pylori heals duodenal ulcers and reduces the risk of ulcer recurrence.

Pharmacodynamic properties

Ofloxacin

  • Pharmacotherapeutic group: Quinolone Antibacterials, Fluoroquinolones
  • ATC code: J01 MA 01

Tinidazole

  • Pharmacotherapeutic group: Antiinfectives for systemic use
  • ATC code: J 01XD02

Pharmacokinetics properties

Ofloxacin

The administration of oral doses to fasting volunteers was followed by a rapid and almost complete absorption of ofloxacin. The peak plasma concentration after a single oral dose of 200mg averaged 2.6 µg/ml and was reached within one hour. The plasma elimination half-life was 5.7 to 7.0 hours and was not dose related.

The apparent distribution volume was 120 litres. The plasma concentration did not materially rise with repeat doses (accumulation factor for twice daily dosage: 1.5). The plasma protein binding was approx. 25%.

The biotransformation of ofloxacin was below 5%. The two main metabolites found in the urine were N-desmethyl-ofloxacin and ofloxacin-N-oxide.

Excretion is primarily renal. Between 80 and 90% of the dose were recovered from the urine as unchanged substance.

Ofloxacin was present in the bile in glucuronidised form. The pharmacokinetics of ofloxacin after intravenous infusion are very similar to those after oral doses. The plasma half-life is prolonged in persons with renal insufficiency; total and renal clearance decrease in accordance with the creatinine clearance. In renal insufficiency the dose should be reduced.

No clinically relevant interactions were seen with food and no interaction was found between ofloxacin and theophylline.

Tinidazole

Tinidazole is rapidly and completely absorbed following oral administration. In studies with healthy volunteers receiving 2g tinidazole orally, peak serum levels of 40-51 micrograms/ml were achieved within two hours and decreased to between 11-19 micrograms/ml at 24 hours. Healthy volunteers who received 800mg and 1.6g tinidazole IV over 10-15 minutes achieved peak plasma concentrations that ranged from 14 to 21mcg/ml for the 800mg dose and averaged 32mcg/ml for the 1.6g dose. At 24 hours post infusion, plasma levels of tinidazole decreased to 4-5mcg/ml and 8.6mcg/ml respectively, justifying once daily dosing. Plasma levels decline slowly and tinidazole can be detected in plasma at concentrations of up to 1 microgram/ml at 72 hours after oral administration. The plasma elimination half-life for tinidazole is between 12-14 hours.

Tinidazole is widely distributed in all body tissues and  also crosses the blood brain barrier, obtaining clinically effective concentrations in all tissues. The apparent volume of distribution is about 50 litres. About 12% of plasma tinidazole is bound to plasma protein.

Tinidazole is excreted by the liver and kidneys. Studies in healthy patients have shown that over 5 days, 60-65% of an administered dose is excreted by the kidneys with 20-25% of the administered dose excreted as unchanged tinidazole. Up to 5% of the administered dose is excreted in the faeces.

Studies in patients with renal failure (creatinine clearance <22ml/min) indicate that there is no statistically significant change in tinidazole pharmacokinetic parameters in these patients.

Non-Clinical Properties

Animal toxicology or pharmacology

Preclinical effects in conventional studies of safety pharmacology, acute toxicity, repeated dose toxicity, reproductive studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Joint toxicity was observed at exposure in the human therapeutic range in juvenile rats and dogs. Ofloxacin exhibits a neurotoxic potential and causes reversible testicular alterations at high doses.

Mutagenicity studies showed no evidence for mutagenicity of ofloxacin. However, like some other quinolones Ofloxacin is phototoxic in animals at exposure in the human therapeutic range. The phototoxic, photomutagenic and photocarcinogenic potential of ofloxacin is comparable with that of other gyrase inhibitors.

Preclinical data from conventional genotoxicity studies reveal no special hazard to humans, carcinogen potential has not be investigated.

Ofloxacin has no effect on fertility, peri- or postnatal development, and therapeutic doses did not lead to any teratogenic or other embryotoxic effects in animals. Ofloxacin crosses the placenta and levels reached in the amniotic fluid are about 30% of the maximal concentrations measured in maternal serum.

Tinidazole has been shown to be mutagenic in some bacterial strains tested in vitro (with and without metabolic activation). Tinidazole was negative for mutagenicity in a mammalian cell culture system utilising 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.

Description

Oflox- TZ Tablets are a fixed-dose combination of ofloxacin and tinidazole.

Pharmaceutical Particulars

Incompatibilities

Not Applicable

Shelf life

See on Pack

Packaging Information

Each Strip contains 10 Tablets

Storage & Handling Instruction

Store in a cool dry place. Protect from light .Keep out of reach of children

Patient Counselling Information

What is Oflox TZ Tablets?

Oflox- TZ Tablets are the medicine which contains ofloxacin and tinidazole.

Ofloxacin belongs to a group of medicines called quinolone antibiotics. Ofloxacin is an antibiotic that can be used to treat a variety of different infections. These include infections of:

· the chest (respiratory system) such as pneumonia and bronchitis.

· the bladder and kidneys (urinary tract).

· the male and female genital organs when the infections involve the cervix (neck of the womb in women) and the lower genital organs in men.

Ofloxacin can be used to treat both gonorrhoea and some other genital infections of both the male and female genital organs.

Tinidazole is an anti-infective agent. It is used to treat a variety of bacterial infections including:

• infections of the skin, blood, chest, lung, genitals or womb lining.

• an infection associated with stomach ulcers in combination with other drugs.

 • infections caused by organisms called protozoa, such as amoebiasis and giardiasis (stomach infections) and trichomoniasis (a genital infection).

• vaginal infections (vaginitis) and gum infections (gingivitis).

It is also used before certain surgical operations to prevent bacterial infections developing.

Do not take if you have allergy to drug?

If you are allergic to ofloxacin or tinidazole or any of the other ingredients of this medicine.

Signs of an allergic reaction include: a rash, swallowing or breathing problems, wheezing, swelling of your lips, face, throat or tongue.

If you have previously had an allergic reaction to another quinolone antibiotic e.g. ciprofloxacin or norfloxacin

Before you take tell your HCP about medication.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. - You must tell your doctor if you are taking other medicines that can alter your heart rhythm: medicines that belong to the group of anti-arrhythmics (e.g. quinidine, hydroquinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide), tricyclic antidepressants, (e.g. clomipramine, amitriptyline), some antimicrobials (that belong to the group of macrolides e.g. erythromycin, clarithromycin, azithromycin), some antipsychotics used to treat mental health conditions such as schizophrenia and bipolar disorder. Tell your doctor if you are taking any of the following medicines: - medicines or dietary supplements that contain iron (for anaemia) or zinc - sucralfate used for stomach ulcers - antacids used for indigestion that contain magnesium or aluminium.

This medicine should not be taken within two hours of taking iron or zinc tablets, antacids, or sucralfate, as these medicines can stop Ofloxacin from working properly corticosteroids, used for treatment of inflammation and swelling or over-active immune system. These may increase the risk of you developing a tendon rupture - painkillers called non-steroidal anti-inflammatory drugs (NSAIDs) e.g. ibruprofen or diclofenac, or theophylline, used to treat asthma or chronic obstructive pulmonary disease as these could make you more prone to fits if taken with Ofloxacin - glibenclamide, a medicine to control your blood sugar as the amount of these medicines in the blood may increase and have greater effect - drugs that may affect your kidney function e.g. cimentidine, probenicid and methotrexate as they can increase the level of ofloxacin in the blood - medicines to thin your blood, e.g. warfarin. Taking these with ofloxacin can increase the time it takes for your blood to clot - if you are taking didanose (a medicine used to treat HIV infections), you should not take the chewable, buffered tablets until at least two hours.

Tell your doctor if you are taking or have recently taken any other medicines including those obtained without a prescription. You should tell your doctor if you are currently taking blood thinners such as warfarin to prevent blood clots as your doctor may wish to monitor you more closely.

How should I take?

For oral use. You should swallow these tablets whole with water. Do not chew them. If you are taking iron tablets (for anaemia), antacids (for indigestion or heartburn) or sucralfate (for stomach ulcers) or didanosine chewable or buffered tablets (for HIV), it is important not to take these two hours before or after taking this medicine. Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. The length of your treatment will depend on how serious your infection is.

What are the possible side effects?

Ofloxacin

Like all medicines, this medicine can cause side effects, although not everybody gets them. Stop taking Ofloxacin, tell your doctor or go to your nearest hospital casualty department straight away if you have any of the following serious side effects because you may need medical attention:

Uncommon (may affect up to 1 in 100 people)

  • resistance of infection causing organisms to this treatment, (you may fail to respond to treatment)
  • Rare (may affect up to 1 in 1,000 people)
    • you have an allergic reaction. Such reactions may appear in the form of anaphylaxis (a severe form of allergic reaction) with symptoms such as: - severe skin rash - swelling of the face, lips, mouth, tongue or throat (angioedema) - anaphylactic shock (sudden wheezing, swelling of your lips, tongue and throat or body, rash, fainting or difficulties in swallowing)
    • inflammation of the bowel, which may cause severe watery diarrhoea, which may have blood in it, possibly with stomach cramps and a high temperature
    • swelling of the tendons with the following symptoms; pain, tenderness, sometimes restricted movement (tendonitis). This can lead to tendon rupture, especially of the large tendon at the back of the ankle (Achilles tendon). The risk of this occurring is increased if you are also taking corticosteroids e.g. prednisolone
    • numbness or tingling in the hands and feet or being very sensitive to touch, numbness or weakness of the arms and legs
    • blurred, double or altered colour vision. If your eyesight becomes impaired or if your eyes seem to be otherwise affected, consult an eye specialist immediately.
  • Very rare (may affect up to 1 in 10,000 people)
    • a condition in which the amount of oxygen-carrying pigment (haemoglobin) in the blood is below normal or an illness resulting from the destruction of red blood cells with the following symptoms; feeling tired, faint, dizzy, being short of breath when exercising and having pale skin. These may be signs of anaemia or haemolytic anaemia.
    • other blood disorders when the numbers of different types of cells in the blood may fall, which may cause fever, chills, sore throat, ulcers in the mouth and throat (leucopenia, agranulocytosis)
    • fits (seizures)
    • skin rash, which may blister, and looks like small targets (central dark spots surrounded by a paler area, with dark ring around the edge) (erythema multiforme)
    • a widespread rash with blisters and skin peeling on much of the body surface (toxic epidermal necrolysis).
    • narrowing, blockage or leakage of blood vessels, in exceptional cases leading to severe skin reactions and death of areas of the skin
    • severe kidney problems, which may result in your kidneys stopping working. Signs may include a rash, high temperature, general aches and pains, or blood in the urine § hearing problems or hearing loss
    • liver problems, such as inflammation of the liver (hepatitis) or blockage in the bile duct, that may cause your eyes or skin to go yellow (jaundice) or you may notice the following symptoms; nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, light coloured bowel motions, dark coloured urine.
  • Not known (frequency cannot be estimated from the available data)
    • abnormal fast heart rhythm, life-threatening irregular heart rhythm, alteration of the heart rhythm (called 'prolongation of QT interval', seen on ECG, electrical activity of the heart)
    • severe depression or mental illness. Some people who are depressed think of harming or killing themselves.
    • a serious reduction in all types of blood cells (pancytopenia), which may result from a failure of the bone marrow to produce these
    • a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens Johnson syndrome).
  • Swelling of the lungs with the following symptoms; coughing, difficulty breathing, wheezing
    • temporary paralysis or weakness of the muscles (rhabdomyolysis), disease of the muscles with the following symptoms; aching muscles, muscle tenderness or weakness, not caused by exercise
    • an attack of porphyria (a rare blood pigment disorder) in patients with this disease § muscle or ligament rupture
    • inflammation of the pancreas (pancreatitis) – you may have severe pain in the stomach and back
    • loss of consciousness (coma), due to severe reduction in blood sugar levels
    • inflammation of the eye (uveitis)
    • skin redness with excessive scaling (exfoliative dermatitis)
    • loss of appetite, skin and eyes becoming yellow in colour, dark-coloured urine, itching, or tender stomach (abdomen). These may be signs of liver problems which may include a fatal failure of the liver.

 

  • Tell your doctor or pharmacist if any of the following side effects gets serious or lasts longer than a few days: Uncommon (may affect up to 1 in 100 people)
    • feeling sick (nausea) or being sick (vomiting), diarrhoea or stomach pains
    • irritated or burning eyes
    • headaches, sleep disturbances including difficulty sleeping (insomnia)
    • feeling dizzy, having spinning sensations
    • agitation, feeling restless
    • cough and inflamed sore nose or throat (nasopharyngitis)
    • fungal infection
    • skin rash or itching Rare (may affect up to 1 in 1,000 people)
    • loss of appetite
    • fast heart beat
    • drowsiness
    • feeling confused or anxious, nightmares, seeing, feeling or hearing things that are not there, depression and mental illness
    • changes in or loss of your sense of taste or smell
    • shortness of breath or wheezing
    • changes in levels of liver enzymes or bilirubin, which may be seen in blood tests
    • excessive sweating and hot flushes
    • changes in kidney function shown in blood tests § feeling faint, lightheaded or dizzy, which may be due to low blood pressure
    • hives (urticaria)
    • rash with pimples.
  • Very rare (may affect up to 1 in 10,000 people)
    • uncontrolled movements, unsteadiness and shaking
    • unusual bleeding or bruise more easily than normal (thrombocytopenia)
    • increase in some white blood cells (eosinophilia)
    • ringing in the ears (tinnitus)
    • joint and muscle pains
    • skin rashes or eruptions, which may be caused by strong sunlight
    • unusual purple discolouration under the skin, which may be due to bleeding or bruising due to leaky or damaged blood vessels Not known (frequency cannot be estimated from the available data) a red, scaly rash with bumps under the skin and blisters (exanthemous pustolosis)
    • muscular weakness
    • feeling weak or irritable, sweating and/or trembling. This could be due to lowering of blood sugar (glucose) levels especially in patients with diabetes or existing low blood sugar
    • an increase in blood sugar levels
    • feeling of nervousness, tremor, unusual (involuntary) muscle movements
    • fainting
    • digestive problems such as stomach upset (indigestion/heartburn), constipation, or wind
    • general pain, pains in your muscles and stiffness in the bones/joints (arthritis), feeling unwell (asthenia), or fever.

Tinidazole

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

Tell your doctor immediately if you experience any of the following symptoms after taking this medicine.

Although they are very rare, the symptoms can be severe.

• sudden wheeziness, difficulty in breathing, swelling of eyelids, face or lips or tongue

• fits or seizures

The common side effects (that may affect up to 1 in 10 people) are listed below. These may go away during treatment as your body adjusts to the medicine. Tell your doctor if any of these side effects continue to bother you.

• nausea (feeling sick) or vomiting, loss of appetite, diarrhoea, stomach pain or cramps • headache

• vertigo

• skin rash or itching (especially affecting the whole body).

The frequency of the following side effects is not known (cannot be estimated from the available data). You should contact your doctor if you notice any of the following:

 • numbness, tingling, pain or weakness in hands or feet

• clumsiness or unsteadiness

• fever or chills and painful ulcers in the mouth

• sore or swollen mouth/tongue

• redness of the face or neck

• dizziness

• tiredness

• dark urine

• tongue discolouration or unpleasant metallic taste.

Tinidazole can sometimes cause a temporary reduction in white blood cells which does not usually give you any symptoms

How should I store?

Keep this medicine out of the sight and reach of children. Do not take this medicine after the expiry date shown on the pack. The expiry date refers to the last day of that month. This medicine does not require any special storage conditions. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

General information about safe & effective use of drug.

Ofloxacin

Do not take Ofloxacin

- If you suffer from epilepsy or are at risk of fits

 - If you have a history of inflammation and swelling of the tendons (tendonitis) after treatment with a quinolone antibiotic e.g. ciprofloxacin, norfloxacin, or nadifloxacin

 - If you suffer from or there is a family history of glucose-6-phosphate dehydrogenase deficiency (an inherited disorder that affects red blood cells).

- If you are pregnant, think you may be pregnant or are planning to have a baby

- If you are breastfeeding

- If you are under the age of 18 years, or you are over 18 years but think you are still growing Do not take this medicine if any of the above apply to you.

If you are not sure, talk to your doctor or pharmacist before taking Ofloxacin.

Talk to your doctor or pharmacist before taking Ofloxacin if any of the following apply: - you have or have ever had a history of mental illness

- you have problems with your liver or kidneys

 - you have an illness of the nervous system called ‘myasthenia gravis’ (muscle weakness)

- if you are diabetic or suffer from low blood sugar

Caution should be taken when using this kind of medicine, if you were born with or have family history of prolonged QT interval (seen on ECG, electrical recording of the heart), have salt imbalance in the blood (especially low level of potassium or magnesium in the blood), have a very slow heart rhythm (called ‘bradycardia’), have a weak heart (heart failure), have a history of heart attack (myocardial infarction), you are female or elderly or you are taking other medicines that result in abnormal ECG changes.

During treatment When taking this medicine: If your eyesight becomes impaired or if your eyes seem to be otherwise affected, consult an eye specialist immediately. If you: · experience a severe skin rash or allergic reaction, or · develop severe diarrhoea, (which may be bloody) with stomach pain and fever, or · notice pain, tenderness, or restricted movement of the tendons, or · notice numbness or tingling in the hands and feet stop taking this medicine and talk to your doctor straight away.

When taking Ofloxacin, avoid strong sunlight and do not use sun lamps or solaria. If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Ofloxacin tablets.

Tinidazole

Do not take Tinidazole 500mg film-coated tablets if:

• you have central nervous system (CNS) disease, including epilepsy

• you are in the first 13 weeks of pregnancy or trying to become pregnant or you are breast-feeding.

Talk to your doctor, pharmacist or nurse, if during therapy with Tinidazole tablets abnormal neurological signs develop (such as, dizziness, vertigo, difficulty in controlling movements) as you may be told to stop your treatment.

Tell your doctor if you are taking or have recently taken any other medicines including those obtained without a prescription. You should tell your doctor if you are currently taking blood thinners such as warfarin to prevent blood clots as your doctor may wish to monitor you more closely. You should not drink wine, beer or spirits during treatment and for 3 days after stopping treatment with this medicine. The combination may cause flushing, stomach cramps, vomiting (being sick) and palpitations (pounding heart).

Do not take this medicine if you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby. If you become pregnant while taking this medicine, stop taking the tablets and contact your doctor immediately.

Taking this medicine may make you feel sleepy, dizzy or could affect your eyesight. Do not drive or use machines until you know how this medicine affects you. Drinking alcohol may make these symptoms worse

Any other information

If you take more tablets than you should you may become confused and dizzy or lose consciousness, you may have a seizure or fit, and you may feel sick.

Contact your doctor or nearest hospital casualty department immediately.

Take the container and any remaining tablets with you.

If you forget to take a dose take it as soon as you remember unless it is nearly time for your next dose. Do not take a double dose to make up for a forgotten tablet.

Your doctor will tell you how long you need to take your tablets for. Do not suddenly stop taking this medicine without talking to your doctor first. If you stop, your infection may get worse again. If you feel the effect of your medicine is too weak or strong, do not change the dose yourself, but ask your doctor. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Details of Manufactures

Mfd. By Cipla Ltd.

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.L No. MNB/05/109 dated 08/09/05

Date of Revision

10/01/2020