Rifampicin/Isoniazid/Pyrazinamide Tablets USP 120mg/50mg/300mg Taj Pharma

1. Name of the medicinal product

Rifampicin/Isoniazid/Pyrazinamide Tablets USP 120mg/50mg/300mg Taj Pharma
Rifampicin/Isoniazid/Pyrazinamide Tablets USP 225mg/150mg/750mg Taj Pharma

2. Qualitative and quantitative composition

a) Rifampicin/Isoniazid/Pyrazinamide Tablets USP 120mg/50mg/300mg Taj Pharma
Each film-coated tablet contains:
Rifampicin USP 120mg
Isoniazid USP 50mg
Pyrazinamide USP 300mg
Excipients: Q.S.

b) Rifampicin/Isoniazid/Pyrazinamide Tablets USP 225mg/150mg/750mg Taj Pharma
Each film-coated tablet contains:
Rifampicin USP 225mg
Isoniazid USP 150mg
Pyrazinamide USP 750mg
Excipients: Q.S.

3. Pharmaceutical form

Each film-coated Tablets,

4. Clinical particulars

• Therapeutic indications

Rifampicin/Isoniazid/Pyrazinamide Taj Pharma is indicated in the treatment of pulmonary tuberculosis.

• Posology and method of administration

Rifampicin/Isoniazid/Pyrazinamide Taj Pharma is recommended in the initial intensive phase of the short-course treatment of pulmonary tuberculosis. During this phase, which lasts for 2 months, Rifampicin/Isoniazid/Pyrazinamide Taj Pharma should be administered on a daily continuous basis. The concomitant administration of ethambutol or intramuscular streptomycin over the same period of time is advised.

Each Rifampicin/Isoniazid/Pyrazinamide Taj Pharma tablet contains Isoniazid (INH), Pyrazinamide (Z) and Rifampicin (RAMP) in such a ratio that the administration of 9-12mg/kg RAMP, 4-5mg/kg INH and 23-30mg/kg Z can be achieved by giving 3 tablets daily to patients weighing less than 40kg, 4 tablets to patients weighing 40-49kg, 5 tablets to patients weighing 50-64kg and 6 tablets to patients weighing 65kg or more.

Rifampicin/Isoniazid/Pyrazinamide Taj Pharma should be given as a single dose and preferably on an empty stomach at least 30 minutes before a meal, or 2 hours after a meal to ensure rapid and complete absorption.

Once the initial intensive phase of treatment has been completed treatment can be continued with the combination Rifampicin-Isoniazid (Rifinah) always on a daily basis.

This regimen, if correctly applied, is 100% effective with very few, if any, relapses. The clinical evidence indicates that these occur generally in the first 6 months after stopping treatment with bacilli fully sensitive to the drugs employed, so that changes in the drugs to be utilised for further treatment are not required. The regimen has been found to be fully effective also in the presence of a bacillary population resistant to Isoniazid, to streptomycin or to both drugs.

Children: The ratio of the three drugs in Rifampicin/Isoniazid/Pyrazinamide Taj Pharma may not be appropriate in children (eg highermg/kg doses of INH are usually given in children than in adults). Rifampicin/Isoniazid/Pyrazinamide Taj Pharma can be used only in special cases, after careful consideration of themg/kg dose of each component.

Use in the Elderly: Caution should be exercised in such patients, in view of the possible decrease of the excretory function of the kidney and of the liver.

• Contraindications

Rifampicin/Isoniazid/Pyrazinamide Taj Pharma is contra-indicated in patients who are hypersensitive to any one of the components of the combination or any of the excipients. Rifampicin/Isoniazid/Pyrazinamide Taj Pharma is contra-indicated in the presence of jaundice.

Rifampicin/Isoniazid/Pyrazinamide Taj Pharma use is contraindicated when given concurrently with the combination of saquinavir/ritonavir (see section 4.5 Interactions).

• Special warnings and precautions for use

The precautions for the use of Rifampicin/Isoniazid/Pyrazinamide Taj Pharma are the same as those considered when a triple individual administration of Rifampicin, Isoniazid and Pyrazinamide is required. Rifampicin/Isoniazid/Pyrazinamide Taj Pharma should only be given under supervision. Each of these drugs has been associated with liver dysfunction.

Rifampicin/Isoniazid/Pyrazinamide Taj Pharma should be given under the supervision of a respiratory or other suitably qualified physician.

All tuberculosis patients should have pre-treatment measurements of liver function.

Adults treated for tuberculosis with Rifampicin/Isoniazid/Pyrazinamide Taj Pharma should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count and a platelet count (or estimate).

Patients should be seen at least monthly during therapy and should be questioned specifically about symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary.

However, because there is a higher frequency of Isoniazid-associated hepatitis among persons older than 35 years of age, a transaminase measurement should be obtained at baseline and at least monthly during therapy in this age group. Other factors associated with an increased risk of hepatitis include daily use of alcohol, chronic liver disease, intravenous drug use and being a black or Hispanic woman.

If the patient has no evidence of pre-existing liver disease and normal pre-treatment liver function, liver function tests need only be repeated if fever, vomiting, jaundice or other deterioration in the patient’s condition occur.

Patients with impaired liver function should only be given Rifampicin/Isoniazid/Pyrazinamide Taj Pharma in cases of necessity and then with caution and under strict medical supervision. In these patients, careful monitoring of liver function, especially serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) should be carried out prior to therapy and then every two to four weeks during therapy.

If signs of hepatocellular damage or clinically significant changes in hepatic function occur, Rifampicin/Isoniazid/Pyrazinamide Taj Pharma should be withdrawn. The need for other forms of antituberculosis therapy and a different regimen should be considered. Urgent advice should be obtained from a specialist in the management of tuberculosis. If Rifampicin/Isoniazid/Pyrazinamide Taj Pharma is reintroduced after liver function has returned to normal, liver function should be monitored daily.

Severe, systemic hypersensitivity reactions, including fatal cases, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome have been observed during treatment with anti-tuberculosis therapy (See section 4.8).

Rifampicin/Isoniazid/Pyrazinamide Taj Pharma should be discontinued if an alternative etiology for the signs and symptoms cannot be established.

Rifampicin

Cautions should be taken in cases of renal impairment if dose > 600mg/day.

In patients with impaired liver function, elderly patients, malnourished patients and possibly children under two years of age, caution is particularly recommended when instituting therapeutic regimens in which Isoniazid is to be used concurrently with Rifampicin.

In some cases, hyperbilirubinaemia resulting from competition between Rifampicin and bilirubin for excretory pathways of the liver at the cell level can occur in the early days of treatment. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather, the decision should be made after repeating the tests, noting trends in the levels and considering them in conjunction with the patient’s clinical condition.

Because of the possibility of immunological reaction including anaphylaxis (see section 4.8 Undesirable effects) occurring with intermittent Rifampicin therapy (less than 2 or 3 per week) patients should be closely monitored. Patients should be cautioned against interruption of dosage regimens since these reactions may occur.

Severe cutaneous adverse reactions (SCARs) including Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported with a not known frequency in association with Rifampicin/Isoniazid/Pyrazinamide Taj Pharma treatment.

At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions.

It is important to note that early manifestations of hypersensitivity, such as fever, lymphadenopathy or biological abnormalities (including eosinophilia, liver abnormalities) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be advised to consult immediately their physician.

If signs and symptoms suggestive of these reactions appear, Rifampicin/Isoniazid/Pyrazinamide Taj Pharma should be withdrawn immediately and an alternative treatment considered (as appropriate).

Most of these reactions occurred within 2 days to 2 months after treatment initiation; the time to onset can vary depending on the conditions.

Rifampicin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones and vitamin D. Isolated reports have associated porphyria exacerbation with Rifampicin administration.

Rifampicin may produce a discoloration (yellow, orange, red, brown) of the teeth, urine, sweat, sputum and tears, and the patient should be forewarned of this. Soft contact lenses have been permanently stained (see section 4.8)

Rifampicin is a well characterized and potent inducer of drug metabolizing enzymes and transporters and might therefore decrease concomitant drug exposure and efficacy (see Section 4.5). Therefore, potential drug interactions should be considered whether beginning or discontinuing Rifampicin treatment.

Rifampicin may cause vitamin K dependent coagulopathy and severe bleeding (see Section 4.8). Monitoring of occurrence of coagulopathy is recommended for patients at particular bleeding risk. Supplemental vitamin K administration should be considered when appropriate (vitamin K deficiency, hypoprothrombinemia).

Isoniazid

Use of Isoniazid should be carefully monitored in patients with current chronic liver disease or severe renal dysfunction.

Severe and sometimes fatal hepatitis associated with Isoniazid therapy may occur and may develop even after many months of treatment. The risk of developing hepatitis is age related. Therefore, patients should be monitored for the prodromal symptoms of hepatitis; such as fatigue, weakness, malaise, anorexia, nausea or vomiting. If these symptoms appear or if signs suggestive of hepatic damage are detected, Isoniazid should be discontinued promptly, since continued use of the drug in these cases has been reported to cause a more severe form of liver damage.

Cases of severe cutaneous reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some with a fatal outcome, have been reported with the use of Isoniazid (See section 4.8).

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs or symptoms of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) develops, the patient should be advised to consult immediately their physician. Isoniazid should be permanently discontinued if an alternative etiology for the signs and symptoms cannot be established.

Care should be exercised in the treatment of elderly or malnourished patients who may also require Vitamin B6 supplementation with the Isoniazid therapy.

Use of Isoniazid should be carefully monitored in patients with slow acetylator status, epilepsy, history of psychosis, history of peripheral neuropathy, diabetes, alcohol dependence, HIV infection or porphyria.

Pyrazinamide

Rifampicin/Isoniazid/Pyrazinamide Taj Pharma should be used with caution in patients with a history of gout. If hyperuricaemia accompanied by an acute gouty arthritis occurs, the patient should be transferred to a regimen not containing Pyrazinamide (e.g. Rifinah 150 or 300).

The possibility of Pyrazinamide having an adverse effect on blood clotting time or vascular integrity should be borne in mind in patients with haemoptysis.

• Interaction with other medicinal products and other forms of interaction

Food Interaction

Isoniazid is an inhibitor of monoamine oxidase (MAO) and diamine oxidase (DAO), therefore can reduce tyramine and histamine metabolism, causing symptoms such as headache, sweating, palpitations, flushing, and hypotension. Patients should be advised against ingesting foods rich in tyramine and/or histamine during treatment with Isoniazid, such as cured meat, some cheeses (e.g. matured cheeses), wine, beer and some fish (e.g. tuna, mackerel, salmon).

Interactions with other medicinal products

When Rifampicin/Isoniazid/Pyrazinamide Taj Pharma is given concomitantly with the combination saquinavir/ritonavir, the potential for hepatotoxicity is increased. Therefore, concomitant use of Rifampicin/Isoniazid/Pyrazinamide Taj Pharma with saquinavir/ritonavir is contraindicated (see section 4.3 Contraindications).

Cytochrome P-450 enzyme interaction

Rifampicin is known to induce and Isoniazid is known to inhibit certain cytochrome P-450 enzymes. In general, the impact of the competing effects of Rifampicin and Isoniazid on the metabolism of drugs that undergo biotransformation through the affected pathways is unknown. Therefore, caution should be used when prescribing Rifampicin/Isoniazid/Pyrazinamide Taj Pharma with drugs metabolised by cytochrome P-450. To maintain optimum therapeutic blood levels, dosages of drugs metabolised by these enzymes may require adjustment when starting or stopping Rifampicin/Isoniazid/Pyrazinamide Taj Pharma.

Interactions with Rifampicin

Pharmacodynamic interactions

The potential for hepatotoxicity is increased with an anaesthetic.

When Rifampicin is given concomitantly with either halothane or Isoniazid, the potential for hepatotoxicity is increased. The concomitant use of Rifampicin and halothane should be avoided. Patients receiving both Rifampicin and Isoniazid should be monitored closely for hepatotoxicity.

The concomitant use of Rifampicin with other antibiotics causing vitamin K dependent coagulopathy such as cefazolin (or other cephalosporins with N-methyl-thiotetrazole side chain) should be avoided as it may lead to severe coagulation disorders, which may result in fatal outcome (specially with high doses).

Effect of Rifampicin on other medicinal products

Induction of Drug Metabolizing Enzymes and Transporters

Rifampicin/Isoniazid/Pyrazinamide Taj Pharma is a well characterized and potent inducer of drug metabolizing enzymes and transporters. Enzymes and transporters reported to be affected by Rifampicin/Isoniazid/Pyrazinamide Taj Pharma include cytochromes P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4, UDP-glucuronyltransferases (UGT), sulfotransferases, carboxylesterases, and transporters including P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2). Most drugs are substrates for one or more of these enzyme or transporter pathways, and these pathways may be induced by Rifampicin/Isoniazid/Pyrazinamide Taj Pharma simultaneously. Therefore, Rifampicin/Isoniazid/Pyrazinamide Taj Pharma may accelerate the metabolism and reduce the activity of certain co-administered drugs, and has the potential to perpetuate clinically important drug-drug interactions against many drugs and across many drug classes (Table 1). To maintain optimum therapeutic blood levels, dosages of drugs may require adjustment when starting or stopping concomitantly administered Rifampicin/Isoniazid/Pyrazinamide Taj Pharma.

Examples of drugs or drug classes affected by Rifampicin/Isoniazid/Pyrazinamide Taj Pharma:

• Antiarrhythmics (e.g. disopyramide, mexiletine, quinidine, propafenone, tocainide),
• Antiepileptics (e.g. phenytoin),
• Hormone antagonist (antiestrogens e.g. tamoxifen, toremifene, gestinone),
• Antipsychotics (e.g. haloperidol, aripiprazole),
• Anticoagulants (e.g. coumarins),
• Antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole),
• Antivirals (e.g. saquinavir, indinavir, efavirenz, amprenavir, nelfinavir, atazanavir, lopinavir, nevirapine),
• Barbiturates
• Beta-blockers (e.g. bisoprolol, propanolol),
• Anxiolytics and hypnotics (e.g. diazepam, benzodiazepines, zopiclone, zolpidem),
• Calcium channel blockers (e.g. diltiazem, nifedipine, verapamil, nimodipine, isradipine, nicardipine, nisoldipine),
• Antibacterials (e.g. chloramphenicol, clarithromycin, dapsone, doxycycline, fluoroquinolones, telithromycin),
• Corticosteroids
• Cardiac glycosides (digitoxin, digoxin),
• Clofibrate,
• Systemic hormonal contraceptives including estrogens and progestogens,
• Antidiabetic (e.g. chlorpropamide, tolbutamide, sulfonylureas, rosiglitazone),
• Immunosuppressive agents (e.g. ciclosporin, sirolimus, tacrolimus)
• Irinotecan,
• Thyroid hormone (e.g. levothyroxine),
• Losartan,
• Analgesics (e.g. methadone, narcotic analgesics),
• Praziquantel,
• Quinine,
• Riluzole,
• Selective 5-HT3 receptor antagonists (e.g. ondansetron)
• Statins metabolised by CYP 3A4 (e.g. simvastatin),
• Theophylline,
• Tricyclic antidepressants (e.g. amitriptyline, nortriptyline),
• Cytotoxics (e.g. imatinib),
• Diuretics (e.g. eplerenone)
• Enalapril: decrease enalapril active metabolite exposure. Dosage adjustments should be made if indicated by the patient’s clinical condition
• Hepatitis-C antiviral drugs (eg. daclatasvir, simeprevir, sofosbuvir, telaprevir): Concurrent use of treatment of hepatitis-C antiviral drugs and Rifampicin should be avoided.
• Morphine: Plasma concentrations of morphine may be reduced by Rifampicin. The analgesic effect of morphine should be monitored and doses of morphine adjusted during and after treatment with Rifampicin.

Rifampicin treatment reduces the systemic exposure of oral contraceptives. Patients using oral contraceptives should be advised to change to non-hormonal methods of birth control during Rifampicin/Isoniazid/Pyrazinamide Taj Pharma therapy. Also diabetes may become more difficult to control.

Rifampicin may reduce the effect of ACE inhibitors (e.g. enalapril, imidapril), antiemetics (e.g. aprepitant), antineoplastic agents (e.g. imatinib), diuretics (e.g. eplerenone), drugs used in erectile dysfunction (e.g. tadalafil), oral hypoglycemic agents (e.g. nateglinide, repaglinide) and NSAIDS (e.g. etoricoxib).

If p-aminosalicylic acid and Rifampicin are both included in the treatment regimen, they should be given not less than eight hours apart to ensure satisfactory blood levels.

Effect of other medicinal products on Rifampicin

Concomitant antacid administration may reduce the absorption of Rifampicin. Daily doses of Rifampicin should be given at least 1 hour before the ingestion of antacids.

Other drug interactions with Rifampicin

When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of Rifampicin were observed.

Interactions with Isoniazid

The following drugs may interact with Isoniazid:

• Antiepileptics (e.g. carbamazepine and phenytoin)

There may be an increased risk of distal sensory neuropathy when Isoniazid is used in patients taking stavudine.

Concomitant use of zalcitabine with Isoniazid has been shown to approximately double the renal clearance if Isoniazid in HIV infected patients.

Administration of prednisolone 20mg to 13 slow acetylators and 13 fast acetylators for receiving Isoniazid 10mg/kg reduced plasma concentrations of Isoniazid by 25% and 40%, respectively. The clinical significance of this effect has not been established.

The effect of acute alcohol intake (serum levels 1g/L maintained for 12 hours) on the metabolism of Isoniazid (300mg/d for 2 days) was studies in 10 healthy volunteers in a controlled cross over design. The metabolism of Isoniazid and its metabolite, acetyl Isoniazid, was not modified by this acute alcohol intake. The metabolism of Isoniazid may be increased in chronic alcoholics; however this effect has not been quantified.

Other Interactions

Para-aminosalicylic acid may increase the plasma concentration and elimination half-life of Isoniazid by competing for acetylating enzymes.

General anaesthetics may increase the hepatotoxicity of Isoniazid.

The absorption of Isoniazid is reduced by antacids.

The risk of CNS toxicity is increased when Isoniazid is given with cycloserine.

Isoniazid may reduce plasma concentration of ketoconazole and increase plasma concentration of theophylline.

Pyrazinamide

Pyrazinamide antagonizes the effects of probenecid and sulfinpyrazone.

Interference with laboratory and diagnostic tests

Therapeutic levels of Rifampicin have been shown to inhibit standard microbiological assays for serum folate and Vitamin B12. Thus alternative assay methods should be considered. Transient elevation of BSP and serum bilirubin has been reported. Rifampicin may impair biliary excretion of contrast media used for visualization of the gallbladder, due to competition for biliary excretion. Therefore, these tests should be performed before the morning dose of Rifampicin.

• Pregnancy and lactation

Pregnancy

Rifampicin

At very high doses in animals Rifampicin has been shown to have teratogenic effects. There are no well controlled studies with Rifampicin/Isoniazid/Pyrazinamide Taj Pharma in pregnant women. Although Rifampicin has been reported to cross the placental barrier and appear in cord blood, the effect of Rifampicin, alone or in combination with other antituberculosis drugs, on the human foetus is not known. When administered during the last few weeks of pregnancy, Rifampicin may cause post-natal haemorrhages in the mother and infant, for which treatment with Vitamin K1 may be indicated.

Isoniazid

It has been reported that in both rats and rabbits, Isoniazid may exert an embryocardial effect when administered orally during pregnancy, although no Isoniazid-related congenital anomalies have been found in reproduction studies in mammalian species (mice, rats, rabbits).

Therefore, Rifampicin/Isoniazid/Pyrazinamide Taj Pharma should be used in pregnant women or in women of child-bearing potential only if the potential benefit justifies the potential risk to the foetus.

Lactation

Rifampicin, Isoniazid and Pyrazinamide are excreted in breast milk and infants should not be breast fed by a patient receiving Rifampicin/Isoniazid/Pyrazinamide Taj Pharma unless in the physician’s judgement the potential benefit to the patient outweighs the potential risk to the infant.

In breast-fed infants whose mothers are taking Isoniazid, there is a theoretical risk of convulsions and neuropathy (associated with vitamin B6 deficiency), therefore they should be monitored for early signs of these effects and consideration should be given to treating both mother and infant prophylactically with pyridoxine.

• Effects on ability to drive and use machines

Isoniazid has been associated with vertigo, visual disorders and psychotic reactions (see section 4.8). Patients should be informed of these, and advised that if affected, they should not drive, operate machinery or take part in any activities where these symptoms may put either themselves or others at risk.

• Undesirable effects

The following CIOMS frequency rating is used, when applicable:

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 (cannot be estimated from available data).

Rifampicin

Reactions occurring with either daily or intermittent dosage regimens include:

Isoniazid

Pyrazinamide

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

• Overdose

There is limited overdose information involving Rifampicin, Isoniazid and Pyrazinamide in combination.

Signs and Symptoms

Rifampicin

Nausea, vomiting, abdominal pain, pruritus, headache and increasing lethargy will probably occur within a short time after acute ingestion; unconsciousness may occur when there is severe hepatic disease. Transient increases in liver enzymes and/or bilirubin may occur. Brownish-red or orange colouration of the skin, urine, sweat, saliva, tears and faeces will occur, and its intensity is proportional to the amount ingested. Facial or periorbital oedema has also been reported in paediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.

The minimum acute lethal or toxic dose is not well established. However, nonfatal acute overdoses in adults have been reported with doses ranging from 9 to 12 g Rifampicin. Fatal acute overdoses in adults have been reported with doses ranging from 14 to 60 g. Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports. Nonfatal overdoses in paediatrics patients ages 1 to 4 years old of 100mg/kg for one to two doses have been reported.

Isoniazid

Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours after ingestion. Nausea, vomiting, dizziness, slurring of speech, blurring of vision and visual hallucinations (including bright colours and strange designs), are among the early manifestations. With marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to profound coma are to be expected, along with severe, intractable seizures. Severe metabolic acidosis, acetonuria and hyperglycaemia are typical laboratory findings.

Pyrazinamide

There is limited information related to Pyrazinamide overdose. Liver toxicity and hyperuricemia may occur with overdosage.

Management

In cases of overdosage with Rifampicin/Isoniazid/Pyrazinamide Taj Pharma, gastric lavage should be performed as soon as possible. Following evacuation of the gastric contents, the instillation of activated charcoal slurry into the stomach may help absorb any remaining drug from the gastrointestinal tract. Antiemetic medication may be required to control severe nausea and vomiting.

Intensive supportive measures should be instituted, including airway patency and individual symptoms treated as they arise.

Isoniazid

If acute Isoniazid overdose is suspected, even in asymptomatic patients, the administration of intravenous pyridoxine (vitamin B6) should be considered. In patients with seizures not controlled with pyridoxine (vitamin B6), anticonvulsant therapy should be administered. Sodium bicarbonate should be given to control metabolic acidosis. Haemodialysis is advised for refractory cases; if this is not available, peritoneal dialysis can be used along with forced diuresis.

5. Pharmacological properties

• Pharmacodynamic properties

Rifampicin, Isoniazid and Pyrazinamide are all active bactericidal antituberculosis drugs. Rifampicin and Isoniazid are particularly active against the rapidly growing extracellular organisms. Pyrazinamide is active against intracellular organisms, particularly in the acid pH environment of macrophages. Rifampicin and Isoniazid also have bactericidal activity intracellularly. Rifampicin has activity against slow and intermittently-growing M tuberculosis. Thus, the three agents, Rifampicin, Isoniazid and Pyrazinamide have activity against the three different bacterial populations.

Rifampicin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. Cross-resistance to Rifampicin has only been shown after the development of resistance to other rifamycins.

• Pharmacokinetic properties

Rifampicin

Rifampicin is readily absorbed from the stomach and the duodenum. Peak serum concentrations of the order of 10 µg/ml occur about 2-4 hours after a dose of 10mg/kg body weight on an empty stomach.

In normal subjects the biological half-life of Rifampicin in serum averages about 3 hours after a 600mg dose and increases to 5.1 hours after 900mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2-3 hours. At a dose of up to 600 mg/day the half-life does not differ in patients with renal failure and, consequently, no dosage adjustment is required. The half-life of Rifampicin may be decreased when isoniazid is administered concurrently.

After absorption, Rifampicin is rapidly eliminated in the bile and an enterohepatic circulation ensues. During this process, Rifampicin undergoes progressive deacetylation, so that nearly all the drug in the bile is in this form in about 6 hours. This metabolite retains essentially complete antibacterial activity. Intestinal reabsorption is reduced by deacetylation and elimination is facilitated. Up to 30% of a dose is excreted in the urine with about half of this being unchanged drug. Absorption of Rifampicin is reduced when the drug is ingested with food.

Rifampicin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampicin is about 80% protein bound. Most of the unbound fraction is not ionized and therefore is diffused freely in tissues.

Isoniazid

After oral administration, isoniazid produces peak blood levels within 1 to 2 hours, which decline to 50% or less within 6 hours. Ingestion of isoniazid with food may reduce its absorption. It diffuses readily into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs and excreta (saliva, sputum and faeces). The drug also passes through the placental barrier and into the milk in concentrations comparable to those in the plasma. From 50 to 70% of a dose of isoniazid is excreted in the urine in 24 hours.

Isoniazid is metabolised primarily by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50% of Black and Europeans are ‘Slow inactivators’, the majority of Asians are ‘rapid inactivators’.

Pyridoxine deficiency (B₆) is sometimes observed in adults with high doses of isoniazid, probably due to its competition with pyridoxal phosphate of the enzyme apotryptophanase.

Pyrazinamide

Pyrazinamide is well absorbed from the gastrointestinal tract and rapidly distributed throughout the body, with peak plasma levels in 2 hours. It is hydrolysed to pyrazinoic acid and then metabolised to 5-hydroxypyrazinoic acid. Glomerular filtration is the primary route of excretion. It is bactericidal in acid pH, and has intracellular antibacterial activity against M. tuberculosis.

Pharmacokinetic studies in normal volunteers have shown that the three ingredients in Rifater have comparable bioavailability whether they are given together as individual dose forms or as Rifater.

• Preclinical safety data

Not applicable

6. Pharmaceutical particulars

• List of excipients

Polyvinylpyrrolidone

Sodium Carboxymethylcellulose

Sodium Lauryl Sulphate

Calcium Stearate

Sucrose

Acacia Gum

Talc

Light Magnesium Carbonate

Kaolin

Titanum Dioxide

Colloidal Silicon Dioxide

Aluminium Hydroxide Gel

Iron Oxide

• Incompatibilities

None stated

• Shelf life

3 years from date of manufacture

• Special precautions for storage

Do not store above 25°C. Store in the original container.

• Nature and contents of container

PDVC and PVC/PVDC aluminium foil blisters packed in cardboard cartons.

Pack size:

10, 15, 20, 30, 50, 100, 120, 240, 360, and 500 or 1000 tablets

Not all pack size may be marketed.

• Special precautions for disposal and other handling

Not applicable

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at: Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Rifampicin/Isoniazid/Pyrazinamide Tablets USP 120mg/50mg/300mg Taj Pharma

PACKAGE LEAFLET: INFORMATION FOR THE USER

Isoniazid, Rifampicin, Pyrazinamide

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Important things you need to know about Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets

• It is very important that you take Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets exactly as your doctor has told you
• You must keep taking it until your doctor tells you to stop
• If you are taking any other medicines, including medicines you have bought from the pharmacy or shop, you must make sure your doctor knows
• Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets make all your body fluids an orange or red colour. Do not worry – this is normal and not harmful
• Take Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets on an empty stomach. This means at least 30 minutes before food or 2 hours after food
• While you are taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets, you should not eat matured cheeses, cured meat, some fish (like tuna, salmon and mackerel) or drink wine and beer (see ‘Taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets with food and drink’)
• If you get a temperature, are sick, begin to feel more unwell, lose your appetite or have yellowing of the skin, gums or eyes, you must talk to your doctor straight away

Read the rest of this leaflet carefully before you start taking this medicine.

Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or your pharmacist. This medicine has been prescribed for you. Do not pass it to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

What is in this leaflet

1. What Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets are and what they are used for
2. What you need to know before you take Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets
3. How to take Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets
4. Possible side effects
5. How to store Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets
6. Contents of the pack and other information

1. What Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets are and what they are used for

Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets contain three different medicines called Isoniazid, Rifampicin and Pyrazinamide. They all belong to a group of medicines called anti-tuberculous drugs. They work by killing the bacteria that cause tuberculosis.

Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets are used to treat tuberculosis (also known as TB).

2. What you need to know before you take Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets

Do not take Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets if:

• You are allergic (hypersensitive) to
• Isoniazid
• Rifampicin
• Pyrazinamide
• any of the other ingredients of the Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets (see Section 6: Further information)
  Signs of an allergic reaction include: a rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue
• You have yellowing of the skin and eyes (jaundice)
• You are taking saquinavir or ritonavir for an HIV infection (see ‘Taking other medicines’ section below)

Do not take if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets.

Warnings and precautions

Talk to your doctor or pharmacist before taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets

• You have liver problems
• You have any kidney problems and if you are having more than 600mg Rifampicin per day
• You have diabetes. Your diabetes may become more difficult to control while taking this medicine
• You have or have ever had gout (pain or swelling in the joints)
• You are coughing up blood
• You have epilepsy
• You have or have ever had mental health problems (such as depression or schizophrenia)
• You feel numb or weak in your arms and legs (peripheral neuropathy)
• You have an HIV infection
• You are under weight or malnourished
• You drink alcohol every day or you are an alcoholic
• You inject yourself with drugs
• You are a black or Hispanic woman
• You have a rare blood problem called ‘porphyria’
• You have a problem with bleeding or a tendency to bruise easily
• You doctor has told you that your body takes a long time to get rid of some drugs (you have a slow acetylator status)
• You wear contact lenses. Taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets may permanently stain soft contact lenses
• The person taking this medicine is a child
• You are aged 65 years or older

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets.

Blood Tests

Your doctor will need to check your blood before you take this medicine. This will help your doctor know if any changes happen to your blood after taking this medicine. If you are aged 35 years or older, you will also need to have monthly blood tests to check how your liver is working.

Take special care with Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets

Serious skin reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) have been reported with the use of Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets.

• SJS/TEN can appear initially as reddish target spots or circular patches often with central blisters on the trunk. Also ulcers of mouth, throat, nose, genitals and eyes (red and swollen eyes) can occur. These serious skin rashes are often preceded by fever and/or flu-like symptoms. The rashes may progress to widespread peeling of the skin and life-threatening complications or be fatal.
• DRESS appears initially as flu-like symptoms and a rash on the face then an extended rash with a high body temperature, increased levels of liver enzymes seen in blood tests and an increase in a type of white blood cell (eosinophilia) and enlarged lymph nodes.
• AGEP appears at the initiation of treatment as a red, scaly widespread rash with bumps under the skin and blisters accompanied by fever. The most common location: mainly localized on the skin folds, trunk, and upper extremities.

The highest risk for occurrence of serious skin reactions is within 2 days to 2 months after treatment initiation depending on the condition. If you develop a serious rash or another of these skin symptoms, stop taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets and contact your doctor or seek medical attention immediately.

Other medicines and Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines you buy without a prescription, including herbal medicines. This is because Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets can affect the way some other medicines work. Also some medicines can affect the way Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets work.

In particular, do not take this medicine, and tell your doctor, if you are taking:

• Saquinavir or ritonavir used for HIV infection

The following medicines can make Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets work less well:

• Antacids used for indigestion. Take Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets at least 1 hour before taking antacids
• Other medicines used for TB such as P-aminosalicyclic acid (PAS) and cycloserine. PAS and Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets should be taken at least 8 hours apart

Tell your doctor if you are taking any of the following medicines:

Heart and blood medicines

• Medicines for high blood pressure
• Medicines for heart problems or to control your heartbeat
• Medicines used to thin the blood such as warfarin
• Medicines used to lower cholesterol
• Water tablets (diuretics) such as eplerenone

Mental health, epilepsy and motor neurone medicines

• Medicines for thought disorders known as ‘antipsychotics’ such as haloperidol
• Medicines to calm or reduce anxiety (hypnotics, anxiolytics)
• Medicines to help you sleep (barbiturates)
• Medicines used for epilepsy such as phenytoin and carbamazepine
• Some medicines used for depression such as amitriptyline and nortriptyline
• Riluzole – used for motor neurone disease

Medicines for infections and the immune system

• Some medicines used for an HIV infection such as stavudine and zalcitabine
• Some medicines used for viral infections such as indinavir, efavirenz, amprenavir, nelfinavir, atazanavir, lopinavir, neviparine, daclatasvir, simeprevir, sofosbuvir and telaprevir
• Medicines used for fungal infections
• Medicines used for bacterial infections (antibiotics)
• Medicines used for lowering your immune system such as ciclosporin, sirolimus and tacrolimus
• Praziquantel – used for tapeworm infections
• Atovaquone – used for pneumonia

Hormone and cancer medicines

• Some hormone medicines (estrogen, systemic hormones, progestogens) used for contraception or some types of cancer such as ethinyloestradiol, levonorgestrel or dydrogesterone
• Some hormone medicines (anti-estrogens) used for breast cancer or endometriosis such as tamoxifen, toremifene and gestrinone
• Some medicines used for cancer (cytotoxics) such as imatinib
• Levothyroxine (thyroid hormone) used for thyroid problems
• Irinotecan – used for cancer

Pain, inflammation and gout medicines

• Non-steroidal anti-inflammatory drugs (NSAIDS) such as etoricoxib, aspirin and indometacin
• Medicines used for pain such as codeine, morphine, fentanyl or pethidine
• Corticosteroids used for inflammation such as hydrocortisone, betamethasone and prednisolone
• Methadone – used for heroin withdrawal
• Sulfinpyrazone – used for gout

Other medicines

• Medicines used for diabetes
• Medicines used to relax muscles before surgery (anaesthetics) such as halothane
• Medicines used for erection problems such as tadalafil
• Some medicines used for feeling sick or being sick such as ondansetron and aprepitant
• Probenecid (used with a medicine called cidofovir to stop kidney damage)
• Other antibiotic medicines such as cefazolin
• Quinine – used for malaria
• Theophylline – used for wheezing or difficulty in breathing

Taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets with food and drink

Isoniazid may interact with foods containing histamine or tyramine (e.g. matured cheeses, cured meat, some fish like tuna, salmon and mackerel, wine and beer), causing symptoms including headache, sweating, flushing, fast, uneven or forceful heartbeat (palpitations), dizziness, feel lightheaded or faint (due to low blood pressure). These foods should be avoided if you are receiving Isoniazid. Your doctor will be able to advise further.

Pregnancy and breast-feeding

Talk to your doctor before taking this medicine if you are pregnant, plan to get pregnant or think you are pregnant. Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets may make the contraceptive “pill” work less well. This means you should change to a different type of contraception. Instead, you must use a reliable barrier method of contraception such as condoms or the “coil” while taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets. If you have any questions or are unsure about this talk to your doctor or pharmacist.

You should not breast-feed if you are taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets. This is because small amounts may pass into the mothers’ milk. If you are breast-feeding or planning to breast feed, talk to your doctor or pharmacist before taking any medicine.

Driving and using machines

You may feel dizzy or faint, have problems with vision or have other side effects that could affect your ability to drive while taking this medicine. If this happens, do not drive or use any tools or machines.

Important information about some of the ingredients of Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets

Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets contain:

• Sucrose:If you have been told by your doctor that you can not tolerate some sugars, talk to your doctor before taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets
• Sodium:These tablets contains less than 1 mmol sodium (23mg) per daily dose and are essentially ‘sodium-free.

3. How to take Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets

Always take Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Keep taking this medicine

• You must take the tablets every day for the whole time the doctor has told you to take them
• Do not stop and start taking the tablets. This may increase the risk of side effects and your TB will not be treated properly

How to take the tablets

• Take this medicine by mouth
• Swallow the tablets whole, with a drink of water
• Take at least 30 minutes before a meal or 2 hours after a meal
• Take all your tablets together each day, as a single dose
• Do not give this medicine to children
• If you feel the effect of your medicine is too weak or too strong, do not change the dose yourself, but ask your doctor

Your doctor may ask you to take Vitamin B₆ during treatment with Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets, especially if you are malnourished, elderly or a diabetic.

How much to take

The usual dose is:

Adults and the Elderly

• Between 3 and 6 tablets each day. The amount depends on your body weight
• If you are elderly, your doctor may monitor your treatment more closely

Children

This medicine is not recommended for use in children.

If you take more Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets than you should

If you take more Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets than you should, tell a doctor or go to a hospital casualty department straight away. Take the medicine pack with you. This is so the doctor knows what you have taken.

You may feel sick (nausea), be sick (vomiting), have stomach pain, itching or a headache. You may also feel tired, sleepy, dizzy, light-headed, have blurred or strange visions (hallucinations) and faint or feel faint. Other signs of taking too much includes swelling of the face, eyes or eyelids, slurring of speech, difficulty breathing, fast heartbeat, uneven heartbeats, fits and heart attack.

If you forget to take Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets

If you forget a dose, take it as soon as you remember it. However, if it is nearly time for the next dose, skip the missed dose. Do not take a double dose to make up for the forgotten tablets.

Tests

Taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets may affect the results of some blood tests. In particular, tests for folate, vitamin B₁₂ and liver function. If you are going to have a blood test, it is important to tell your doctor that you are taking Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets.

4. Possible side effects

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

Stop taking and go to a hospital straight away if you notice any of the following serious side effects:

• You have an allergic reaction. The signs may include: a rash, swallowing or breathing problems, wheezing, swelling of your lips, face, throat or tongue
• Serious skin rashes including Steven-Johnson syndrome, toxic epidermal necrolysis. These can appear as reddish target-like macules or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can be preceded by fever and flu-like symptoms. See also section 2.
• Widespread rash, high body temperature, liver enzyme elevations, blood abnormalities (eosinophilia), enlarged lymph nodes and other body organs involvement (Drug Reaction with Eosinophilia and Systemic Symptoms which is also known as DRESS or drug hypersensitivity syndrome). See also section 2.
• A red, scaly widespread rash with bumps under the skin and blisters accompanied by fever at the initiation of treatment (acute generalized exanthematous pustulosis). See also section 2.
• You bruise more easily than usual. Or you may have a painful rash of dark red spots under the skin which do not go away when you press on them (purpura). This could be because of a serious blood problem
• You have severe bleeding (haemorrhage)
• You have chills, tiredness, unusually pale skin colour, shortness of breath, fast heartbeat or dark coloured urine. This could be signs of a serious type of anaemia
• You have blood in your urine or an increase or decrease in amount of urine you produce. You may also get swelling, especially of the legs, ankles or feet. This may be caused by serious kidney problems
• You have a sudden severe headache. This could be a sign of bleeding in the brain
• Shortness of breath and wheezing
• You get confused, sleepy, cold clammy skin, shallow or difficult breathing, a racing heartbeat or your skin is paler than normal. These could be signs of shock
• You get more infections more easily than normal. Signs include fever, sore throat or mouth ulcers. This could be because you have a low number of white blood cells
• You have bleeding from your nose, ear, gums, throat, skin or stomach. Signs may include a feeling of tenderness and swelling in your stomach, purple spots on your skin and black or tar-like stools

If you experience any of the following side effects contact your doctor as soon as possible:

• Inflammation of the pancreas, which causes severe pain in the abdomen and back (pancreatitis, frequency not known).
• Yellowing of the skin or whites of the eyes, or urine getting darker and stools paler, fatigue, weakness, malaise, loss of appetite, nausea or vomiting caused by liver problems (hepatitis, may affect up to 1 in 100 people).

Talk to your doctor straight away if you notice any of the following serious side effects:

• Mental problems with unusual thoughts and strange visions (hallucinations)
• Your stomach ulcer gets worse
• Severe watery diarrhoea that will not stop and you are feeling weak and have a fever. This may be something called ‘Pseudomembranous colitis’
• Your fits get worse or you start to have fits
• Flu-like symptoms including chills, fever, headache, dizziness and bone pains

Tell your doctor as soon as possible if you have any of the following side effects:

• Water retention (oedema) which may cause swollen face, stomach, arms or legs
• Muscle weakness or pain or loss of muscle reflexes
• Dizziness, feel lightheaded and faint especially when you stand or sit up quickly (due to low blood pressure)
• Swollen fingers, toes or ankles
• Being unable to concentrate, feeling nervous, irritable or depressed
• Balance problems with dizziness (vertigo)
• Feeling very tired and weak or difficulty sleeping (insomnia)
• Unusual skin sensations such as feeling numb, tingling, pricking, burning or creeping on the skin (paraesthesia)
• Short-term memory loss, anxiety, being less alert or responsive
• Blurred or distorted eyesight
• Wasting of muscles or other body tissues
• Weight loss, night sweats and fever. These could be signs of a blood condition called eosinophilia
• Feeling sick or being sick

Tell your doctor or pharmacist if any of the following side effects get serious or lasts longer than a few days:

• Acne
• Loss of appetite (anorexia)
• Headache
• Skin flushing or itching
• Painful, red, swollen joints
• Pain or discomfort when passing urine
• Irregular periods
• Constipation, diarrhoea, stomach discomfort or dry mouth
• Breast enlargement in men
• Increased thirst, going to the toilet more often and feeling tired. Your blood sugar may be high
• Inflammation of the blood vessels.

Other side effects you should discuss with your doctor if you are concerned about them

• You notice a discoloration (yellow, brown, orange or red colour) in your teeth, urine, sweat, phlegm (sputum), saliva or tears. This is quite common and you need not worry. However, the colour may permanently stain soft contact lenses. The colour in tears may last for some time after you have stopped having Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets.

Blood tests

• A blood test may show changes in the way the liver is working

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets

• Storage condition

Keep this medicine in a safe place where children cannot see or reach it.

Do not use Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets after the expiry date which is stated on the carton and blister packs. The expiry date refers to the last day of that month.

Store below 25°C. Store in the original container.

Medicines should not be disposed of via waterwaste or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Rifampicin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. Cross-resistance to Rifampicin has only been shown after the development of resistance to other rifamycins.

• Pharmacokinetic properties

Rifampicin

Rifampicin is readily absorbed from the stomach and the duodenum. Peak serum concentrations of the order of 10 µg/ml occur about 2-4 hours after a dose of 10mg/kg body weight on an empty stomach.

In normal subjects the biological half-life of Rifampicin in serum averages about 3 hours after a 600mg dose and increases to 5.1 hours after 900mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2-3 hours. At a dose of up to 600mg/day the half-life does not differ in patients with renal failure and, consequently, no dosage adjustment is required. The half-life of Rifampicin may be decreased when Isoniazid is administered concurrently.

After absorption, Rifampicin is rapidly eliminated in the bile and an enterohepatic circulation ensues. During this process, Rifampicin undergoes progressive deacetylation, so that nearly all the drug in the bile is in this form in about 6 hours. This metabolite retains essentially complete antibacterial activity. Intestinal reabsorption is reduced by deacetylation and elimination is facilitated. Up to 30% of a dose is excreted in the urine with about half of this being unchanged drug. Absorption of Rifampicin is reduced when the drug is ingested with food.

Rifampicin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampicin is about 80% protein bound. Most of the unbound fraction is not ionized and therefore is diffused freely in tissues.

Isoniazid

After oral administration, Isoniazid produces peak blood levels within 1 to 2 hours, which decline to 50% or less within 6 hours. Ingestion of Isoniazid with food may reduce its absorption. It diffuses readily into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs and excreta (saliva, sputum and faeces). The drug also passes through the placental barrier and into the milk in concentrations comparable to those in the plasma. From 50 to 70% of a dose of Isoniazid is excreted in the urine in 24 hours.

Isoniazid is metabolised primarily by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50% of Black and Europeans are ‘Slow inactivators’, the majority of Asians are ‘rapid inactivators’.

Pyridoxine deficiency (B₆) is sometimes observed in adults with high doses of Isoniazid, probably due to its competition with pyridoxal phosphate of the enzyme apotryptophanase.

Pyrazinamide

Pyrazinamide is well absorbed from the gastrointestinal tract and rapidly distributed throughout the body, with peak plasma levels in 2 hours. It is hydrolysed to pyrazinoic acid and then metabolised to 5-hydroxypyrazinoic acid. Glomerular filtration is the primary route of excretion. It is bactericidal in acid pH, and has intracellular antibacterial activity against M. tuberculosis.

Pharmacokinetic studies in normal volunteers have shown that the three ingredients in Rifampicin/Isoniazid/Pyrazinamide Taj Pharma have comparable bioavailability whether they are given together as individual dose forms or as Rifampicin/Isoniazid/Pyrazinamide Taj Pharma.

• Preclinical safety data

Not applicable

6. Pharmaceutical particulars

List of excipients

Polyvinylpyrrolidone

Sodium Carboxymethylcellulose

Sodium Lauryl Sulphate

Calcium Stearate

Sucrose

Acacia Gum

Talc

Light Magnesium Carbonate

Kaolin

Titanum Dioxide

Colloidal Silicon Dioxide

Aluminium Hydroxide Gel

Iron Oxide

• Incompatibilities

None stated

• Shelf life

3 years from date of manufacture

• Special precautions for storage

Do not store above 25°C. Store in the original container.

• Contents of the pack and other information

What Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets contain:

• Each tablet contains Rifampicin/Isoniazid/Pyrazinamide 120mg/50mg/300mg and 225mg/150mg/750mg. These are the active ingredients
• The other ingredients are Polyvinylpyrrolidone, Sodium Carboxymethylcellulose, Sodium Lauryl Sulphate, Calcium Stearate, Sucrose, Acacia Gum, Talc, Light Magnesium Carbonate, Kaolin, Colloidal Silicon-Dioxide, Aluminium Hydroxide Gel and Colours Titanium Dioxide and Iron Oxide

What Rifampicin/Isoniazid/Pyrazinamide Taj Pharma Tablets look like and contents of the pack

The tablets are light pink, smooth, shiny, round and sugar coated.

Pack size:

10, 15, 20, 30, 50, 100, 120, 240, 360, and 500 or 1000 tablets

Not all pack size may be marketed.

• Nature and contents of container

PDVC and PVC/PVDC aluminium foil blisters packed in cardboard cartons.

• Special precautions for disposal and other handling

Not applicable

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at: Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com