Normet Tablet

Each film coated tablet contains :

Ofloxacin IP 200 mg

Ornidazole IP 500 mg

Excipients q.s

Colours : Tartrazine & Titanium Dioxide IP

The rationale of combination is based on the fact that quinolones and nitroimidazole derivatives act synergistically. Combinations of fluoroquinolones with other antimicrobial agents have been extensively investigated. Combinations of fluoroquinolones with nitroimidazole,show synergy against Enterobacteriaceae and gram-positive bacteria. Combination covers all treatment related aspects and to widen the spectrum of activity of these two agents.

Pharmacodynamics:

Ofloxacin inhibits bacterial DNA synthesis by inhibiting bacterial topoisomerases, particularly DNA gyrase and topoisomerase IV and shows bactericidal action. Ornidazole is a 5-nitroimidazole derivative active against protozoa and anaerobic bacteria. It is converted to reduction products that interact with DNA to cause destruction of the helical DNA structure and strand, leading to a protein synthesis inhibition and cell death in susceptible organisms.

Microbiology:

Ofloxacin

Therapeutic doses of Ofloxacin are devoid of pharmacological effects on the voluntary or autonomic nervous system. According to DIN 58 940, the following limits apply for Ofloxacin : Susceptible (S)≤ 1 mg/L, Intermediate (I) = 2 mg/L, Resistant (R) ≥ 4 mg/L.

Range of acquired bacterial resistance to Ofloxacin is as follows :

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%)

Ornidazole

Ornidazole is effective against Trichomonas vaginalis, Entamoeba histolytica and Giardia lamblia (Giardia intestinalis), and also against certain anaerobic bacteria such as Bacteroides and Clostridium spp., Fusobacterium spp., and anaerobic cocci.

INDICATION :

For treatment of diarrhea of mixed infection in adult only

Contraindications:

Normet is contraindicated in the following situations:

• Known hypersensitivity to nitroimidazoles and/or Ofloxacin, any other fluoroquinolone antibacterial, or to any excipients listed in formulation.

• 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

• Pregnant or breastfeeding women.

• In patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity because they may be prone to hemolytic reactions when treated with quinolone antibacterial agents.

Dosage and Administration :

One tablet of Normet is recommended as twice-daily therapy.

Use in Special Populations

Hepatic impairment

• Ofloxacin should be used with caution in patients with impaired liver function, as liver damage may occur.In patients with liver cirrhosis, the Ornidazole elimination half-life is longer (22 versus 14 hours) and clearance lower (35 versus 51 ml/min) than in healthy subjects. The dosing interval should be doubled in patients with severe hepatic impairment.Hence,Normet should be used with caution in patients with hepatic impairment.

Renal impairment

• Since Ofloxacin is eliminated primarily via the kidneys, the dose should be adjusted in patients with impaired renal function. The pharmacokinetics of Ornidazole is unaltered in renal impairment.

Drug Interactions:

Warnings and Precautions

Ofloxacin

Methicillin-resistant S. Aureus- Ofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to Ofloxacin

Resistance to fluoroquinolones of E. Coli- Prescribers are advised to take into account the local prevalence of resistance in E. coli to fluoroquinolones.

Severe bullous reactions- Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur

Tendonitis- If tendinitis is suspected, treatment with Ofloxacin must be halted immediately, and appropriate treatment must be initiated.

Hypersensitivity- Anaphylactic and anaphylactoid reactions can progress to life-threatening shock

Diseases caused by Clostridium difficile- If pseudo-membraneous colitis is suspected, treatment should be discontinued immediately.

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- 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- Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop

Patients treated with vitamin K antagonists- Coagulation tests should be monitored when these drugs are given concomitantly

Myasthenia gravis- not recommended in patients with a known history of myasthenia gravis.

Superinfection- If secondary infection occurs during therapy, appropriate measures be taken

Prevention of photosensitisation- patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays for 48 hours following treatment

QT interval prolongation- Caution with known risk factors for prolongation of the QT interval.

Dysglycaemia- Careful monitoring of blood glucose is recommended.

Peripheral neuropathy- Ofloxacin should be discontinued if the patient experiences symptoms of neuropathy

Interference with laboratory tests- In patients treated with Ofloxacin, determination of opiates or porphyrin levels in urine may give false-positive results.

Vision disorders- If vision becomes impaired, an eye specialist should be consulted immediately

ORNIDAZOLE

Caution should be exercised in patients with diseases of the CNS, e.g. epilepsy or multiple sclerosis. The effect of other medicines can be intensified or impaired.

Adverse Effects :

Ofloxacin

Frequencies are defined using the following convention: uncommon (≥ 1/1,000, < 1/100), rare (≥

1/10,000, < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available

data). * postmarketing experience

Stevens-Johnson syndrome / Toxic epidermal necrolysis is reported adverse drug reaction

associated with the use of Ofloxacin.

Blood and lymphatic system disorders : Very rare- Anaemia, Haemolytic anaemia, Leucopenia,

Eosinophilia, Thrombocytopenia, Not known- Agranulocytosis, Bone marrow failure, Pancytopenia

Immune system disorders : Rare- Anaphylactic reaction*, Anaphylactoid reaction*, Angioedema,

Very rare- Anaphylactic shock*, Anaphylactoid shock

Metabolism and Nutrition disorders : Rare- Anorexia, Not known- Hypoglycaemia in diabetics

treated with hypoglycaemic agents, Hyperglycaemia, Hypoglycaemic coma

Psychiatric disorders : Uncommon- Agitation, Sleep disorder, Insomnia, Rare- Psychotic disorder

(for e.g. hallucination), Anxiety, Confusional state, Nightmares, Depression, Not known-

Psychotic disorder and depression with self-endangering behaviour including

suicidal ideation or suicide attempt, Nervousness

Nervous system disorders : Uncommon- Dizziness, Headache, Rare- Somnolence, Paraesthesia,

Dysgeusia, Parosmia, Very rare- Peripheral sensory neuropathy*, Peripheral sensory motor

neuropathy*, Convulsion*,Extra-pyramidal symptoms or other disorders of

muscular coordination, Not known- Tremor, Dykinesia, Ageusia, Syncope

Eye disorders : Uncommon- Eye irritation, Rare- Visual disturbance, Not known- Uveitis

Ear and labyrinth disorders : Uncommon- Vertigo, Very rare- Tinnitus, Hearing loss, Not known-

Hearing impaired

Cardiac disorders : Rare- Tachycardia, Not known- Ventricular arrhythmias and torsades de

pointes, ECG QT prolonged

Vascular disorders : Rare- Hypotension

Respiratory, thoracic and mediastinal disorders : Uncommon- Cough, Nasopharyngitis, Rare-

Dyspnoea, Bronchospasm, Not known- Allergic pneumonitis, Severe dyspnoea

Gastrointestinal disorders : Uncommon- Abdominal pain, Diarrhoea, Nausea, Vomiting, Rare-

Enterocolitis, sometimes haemorrhagic, Very rare- Pseudomembranous colitis*, Not known-

Dyspepsia, Flatulence, Constipation, Pancreatitis

Hepatobiliary disorders : Rare- Hepatic enzymes increased (ALAT, ASAT, LDH, gamma-GT and/or

alkaline phosphatase), Blood bilirubin increased , Very rare- Jaundice cholestatic, Not known-

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 : Uncommon- Pruritus, Rash, Rare- Urticaria, Hot

flushes, Hyperhidrosis Pustular rash, Very rare- 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 : Rare- Tendonitis, Very rare- Arthralgia,

Myalgia, Tendon rupture (e.g. Achilles tendon) which may occur within 48 hours of treatment

start and may be bilateral, Not known- Rhabdomyolysis and/or Myopathy, Muscle

tear, Muscle rupture, Ligament rupture, Arthritis

Renal and urinary disorders : Rare- Serum creatinine increased, Very rare- Acute renal failure,

Not known- Acute interstitial nephritis

Congenital, familial and genetic disorders : Not known- Attacks of porphyria in patients with

porphyria

General disorders and administration site conditions : Not known- Asthenia, Pyrexia, Pain

(including pain in back, chest and extremities)

Diseases of the Vascular and Lymph System Rare : leucopaenia

Nervous System Disorders - Very rare : somnolence, headache, dizziness, tremor, rigidity, coordination impairments, seizures, fatigue, vertigo, temporary loss of consciousness and sensory or mixed peripheral neuropathy.

Gastrointestinal Disorders Uncommon : nausea, vomiting, diarrhoea, epigastric discomfort, dry mouth, loss of appetite. Rare: impairment of the sense of taste

Hepatobiliary Diseases Unknown : jaundice, abnormal liver function tests Skin and subcutaneous tissue diseases Rare: pruritus and skin reactions

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.

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. 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.

Ornidazole

In cases of overdosage, the symptoms mentioned under undesirable effects occur in a more severe form. No specific antidote is known. The administration of diazepam is recommended if cramps occur

Store at a temperature not exceeding 30°C. Protect from moisture

Keep out of reach of children

A blister strip of 10 tablets.