Rifinah 150 mg/ 75 mg, 300 mg FC tablets

Continuation phase treatment of pulmonary and extra-pulmonary tuberculosis in newly diagnosed patients and re-treatment of adult cases.

Posology
RIFINAH Tablets are recommended in the continuation phase of the treatment of pulmonary and extra-pulmonary tuberculosis.
South African National Tuberculosis Control Programme dosage recommendation: New, smear positive patients, new smear negative patients and extra-pulmonary TB: During this phase, which lasts for 4 months, this medicine should be administered daily for 5 consecutive days per week.
WHO dosage recommendation : During this phase, which lasts for 4 months, this medicine should be administered on a continuous daily basis.
The total dosage requirement is as follows:
Daily
Rifampicin 10 mg/kg maximum 600 mg per day (8-12 mg/kg)
Isoniazid 5 mg/kg maximum 300 mg/kg (4-6 mg/kg)
Patient body mass (kg)
Number of tablets (daily)
RIFINAH 150/75 RIFINAH 300 FC
30 u2013 37 2 --
38 u2013 54 3 --
55 or more -- 2
Paediatric population: RIFINAH tablets are unsuitable for children under 12 years.

Contraindicated in patients with a history of hypersensitivity to rifamycins, isoniazid or any of the components. RIFINAH is contraindicated in jaundice and acute porphyria. Rifampicin can cause thrombocytopenia and purpura usually with intermittent tuberculosis regimens; further administration is contraindicated (see section 4.4). RIFINAH is contraindicated when given concurrently with the combination of saquinavir/ritonavir (see section 4.5).

RIFINAH 150/75 and RIFINAH 300 FC are a combination of two medicines, each of which has been associated with liver dysfunction. Adults treated for tuberculosis with RIFINAH 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 and chronic liver disease and intravenous drug use.
Severe, systemic hypersensitivity reactions, including fatal cases, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome have been observed during treatment with antituberculosis therapy (see section 4.8). 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 doctor. RIFINAH should be discontinued if an alternative etiology for the signs and symptoms cannot be established.
Applies to rifampicin: Liver: Patients with impaired liver function should only be given rifampicin in cases of necessity and then with caution and under strict medical supervision. In these patients, careful monitoring of liver function, especially serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, rifampicin should be discontinued. Cases of mild to severe cholestasis have been reported with rifampicin therapy. Patients should be instructed to contact their doctor immediately if they experience symptoms such as itching, weakness, loss of appetite, nausea, vomiting, abdominal pain, yellowing of eyes or skin or dark urine. If cholestasis is confirmed, RIFINAH should be discontinued. In some cases, hyperbilirubinemia resulting from competition between rifampicin and bilirubin for excretory pathways of the liver at 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 the trends in the levels and considering them in conjunction with the patientu2019s clinical condition.
Immunological reactions/anaphylaxis: Because of the possibility of immunological reactions, including anaphylaxis (see section 4.8), occurring with intermittent therapy (less than 2 to 3 times per week), patients should be closely monitored. Patients should be cautioned against interruption of dosage regimens since these reactions may occur.
Severe bullous reactions: Cases of severe bullous skin reactions such as Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalised exanthematous pustulosis (AGEP) have been reported with rifampicin. If symptoms or signs of AGEP, SJS or TEN are present, rifampicin treatment must immediately be discontinued.
Porphyria exacerbation and metabolism of endogenous substrates: Rifampicin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones and vitamin D. Reports have associated porphyria exacerbation with rifampicin administration as a result of induction of delta amino levulinic acid synthetase (see section 4.3).
Discolouration of teeth, body fluids and contact lenses: Rifampicin may produce a discolouration (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).
Inducing of medicine metabolising enzymes and transporters: Rifampicin is a well characterised and potent inducer of medicine metabolising enzymes and transporters and might therefore decrease or increase concomitant medicine exposure, safety and efficacy (see section 4.5). Therefore, patients should be advised not to take any other medication without medical advice.
Vitamin K dependent coagulopathy and severe bleeding: 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).
Applies to isoniazid: Use of isoniazid should be carefully monitored in patients with current chronic liver disease or severe renal dysfunction. Liver: Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may develop even after 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 medicine in these cases has been reported to cause a more severe form of liver damage.
Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): 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 doctor.
RIFINAH should be permanently discontinued if an alternative etiology for the signs and symptoms cannot be established.
Pyridoxine supplementation: Patients who are at risk of neuropathy or pyridoxine deficiency including those who are diabetic, alcoholic, elderly, malnourished, uraemic, pregnant or have HIV infection, should receive pyridoxine (Vitamin B 6) usually in a dose of 10 mg daily.

Applies to RIFINAH (rifampicin and isoniazid combination): When RIFINAH is given concomitantly with the combination saquinavir/ritonavir, the potential for hepatotoxicity is increased. Therefore, concomitant use of RIFINAH with saquinavir/ritonavir is contraindicated (see section 4.3).
Cytochrome P-450 enzyme interaction: Rifampicin is known to induce, and isoniazid is known to inhibit certain cytochrome P-450 enzymes. Therefore, caution should be used when prescribing RIFINAH with medicines metabolised by cytochrome P-450. To maintain optimum therapeutic blood levels, dosages of medicines metabolised by these enzymes may require adjustment when starting or stopping RIFINAH.
Applies to Rifampicin:
u2022 Pharmacodynamic interactions
When rifampicin is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of RIFINAH and halothane should be avoided. Patients receiving RIFINAH 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 (especially with high doses).
RIFINAH is a well characterised and potent inducer of medicine metabolising enzymes and transporters. Enzymes and transporters reported to be affected by RIFINAH 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 medicines are substrates for one or more of these enzyme or transporter pathways, and these pathways may be induced by RIFINAH simultaneously. Therefore, RIFINAH may accelerate the metabolism and decrease the activity of certain coadministered medicines or increase the activity of a coadministered pro-drug (where metabolic activation is required) and has the potential to perpetuate clinically important drug-drug interactions against many medicines and across many medicine classes (Table 1). To maintain optimum therapeutic blood levels, dosages of medicines may require adjustment when starting or stopping concomitantly administered RIFINAH.
The following table provides examples of the induction effect of rifampicin on exposure of selected medicine metabolising enzymes and transporter substrate medicines
u2022 Effect of rifampicin on other medicinal products
Induction of Medicine Metabolising Enzymes and Transporters
Table 1 Effect of Rifampicin Coadministration on Medicines or Medicine Classes
Medicine or Effect Comments

Pregnancy
The safety of RIFINAH tablets in pregnant and lactating women has not been established. When administered during the last few weeks of pregnancy, rifampicin can cause post-natal haemorrhages in the mother and infant, for which treatment with Vitamin K may be indicated.
Breastfeeding
Rifampicin and isoniazid are known to pass into maternal breast milk.

RIFINAH may cause undesirable effects, e.g. dizziness and visual disturbances which may reduce the capacity for the completion of certain tasks (see section 4.8). Patients should be informed of the potential for these undesirable effects that may occur and if they experience these symptoms, consideration should be given not to drive or operate machinery.

Applies to Rifampicin:
Infections and infestations: Frequency unknown : pseudomembranous colitis, u201cflu syndromeu201d consisting of episodes of pyrexia, chills, headache, dizziness and bone pain
Blood and lymphatic system disorders: Frequent: thrombocytopenia with or without purpura, usually associated with intermittent therapy, but is reversible if medicine is discontinued as soon as purpura occurs. Less frequent: leukopenia. Frequency unknown : disseminated intravascular coagulation, eosinophilia, agranulocytosis, haemolytic anaemia, vitamin K dependent coagulation disorders
Immune system disorders: Frequency unknown : anaphylactic reaction
Endocrine disorders: Frequency unknown : adrenal insufficiency in patients with compromised adrenal function
Metabolism and nutritional disorders: Frequency unknown : decreased appetite
Psychiatric disorders: Frequency unknown : psychotic disorder
Nervous system disorders: Frequent : headache, dizziness. Frequency unknown : drowsiness, ataxia, numbness, cerebral hemorrhage and fatalities have been reported when RIFANAH administration has been continued or resumed after the appearance of purpura (see section 4.3)
Eye disorders: Less frequent: eye irritation, visual disturbances. Frequency unknown : tear discolouration. Soft contact lenses worn by patients receiving RIFINAH may become permanently stained (see section 4.4)
Vascular disorders: Frequency unknown : shock, flushing, vasculitis, bleeding
Respiratory, thoracic and mediastinal disorders: Frequency unknown : dyspnoea, wheezing, discoloured sputum
Gastrointestinal disorders: Frequent: nausea, vomiting. Less frequent : diarrhoea. Frequency unknown : gastrointestinal disorder, abdominal discomfort, tooth discolouration (which may be permanent)
Hepato-biliary disorders: Frequency unknown : hepatitis, hyperbilirubinemia, cholestasis (see section 4.4)
Skin and subcutaneous tissue disorders: Frequency unknown : erythema multiforme acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome and toxic epidermal necrolysis, Drug Reaction with Eosinophilia and systemic symptoms (DRESS syndrome) (see section 4.4), skin reaction, pruritus, pruritic rash, urticaria, allergic dermatitis, pemphigoid, sweat discolouration
Musculoskeletal and connective tissue disorders: Frequency unknown : muscle weakness, myopathy, bone pain
Renal and urinary disorders: Frequency unknown : acute kidney injury usually due to renal tubular necrosis or tubulointerstitial nephritis, chromaturia
Pregnancy, puerperium and perinatal conditions Frequency unknown : post-partum haemorrhage, foetal-maternal haemorrhage (see section 4.6)
Reproductive system and breast disorders: Frequency unknown : menstrual disorder
Congenital, familial and genetic disorders: Frequency unknown : porphyria exacerbation (see section 4.3)
General disorders and administration site conditions: Frequent : pyrexia, chills. Frequency unknown : oedema
Investigations: Frequent : increased blood bilirubin, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT) (see section 4.4). Frequency unknown : decreased blood pressure, increased blood creatinine, increased hepatic enzyme (see section 4.5)
Applies to Isoniazid: Blood and lymphatic system disorders : Less frequent : eosinophilia, agranulocytosis, thrombocytopenia, anaemia. Immune system disorders: Less frequent: hypersensitivity reactions (including erythema multiforme). Frequency unknown: anaphylactic reactions. Endocrine disorders: Frequency unknown: gynecomastia. Metabolism and nutrition disorders : Frequency unknown: pellagra. Psychiatric disorders: Frequency unknown: psychotic reactions. Nervous system disorders: Frequent: peripheral neuropathy (Pyridoxine supplementation prevents the development of peripheral neuritis (see section 4.4)). Frequency unknown: polyneuritis, presenting as paraesthesia, muscle weakness, loss of tendon reflexes. Other neurotoxic effects which are uncommon with conventional doses are convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment and toxic psychosis. Ear and labyrinth disorders: Frequency unknown: vertigo. Vascular disorders: Frequency unknown: vasculitis. Gastrointestinal disorders : Frequent : nausea, vomiting, dry mouth, constipation, epigastric distress. Less frequent: pancreatitis. Hepato-biliary disorders : Less frequent: severe and sometimes fatal hepatitis. Skin and subcutaneous tissue disorders : Less frequent: rash, acne, exfoliative dermatitis. Frequency unknown: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, Toxic Epidermal Necrolysis (TEN), Stevens-Johnson syndrome, (SJS) (see section 4.4), pemphigus, purpura, alopecia. Musculoskeletal and connective tissue disorders: Less frequent: systemic lupus erythematosus-like syndrome. General disorders and administration site conditions: Less frequent: fever.

There is limited overdose information involving isoniazid and rifampicin in combination.
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. Cases of skin pigmentation induced by rifampicin overdosage have been reviewed. Brownish-red or orange discolouration of the skin appeared within a few hours of medicine administration; urine, mucous membranes and sclera were also discoloured. Periorbital or facial oedema, pruritus and gastrointestinal intolerance occurred in most patients. Fatalities occurred with doses over 14 g.
Isoniazid: Isoniazid doses of 6 g or more are associated with severe toxicity and doses above 15 g may be fatal without appropriate treatment. Symptoms may not occur until 2 hours after ingestion. Symptoms include: nausea, vomiting, dizziness, slurring of speech, blurring of vision, and visual hallucinations and CNS depression (see section 4.8).
Management: In cases of overdosage with RIFINAH tablets, activated charcoal slurry may be used to reduce the absorption of the medicine from the gastrointestinal tract. Intensive supportive measures should be instituted, including airway patency and individual symptoms treated as they arise. If acute RIFINAH overdose is suspected, even in asymptomatic patients, the administration of intravenous pyridoxine (vitamin B 6) should be considered. An initial dose of pyridoxine hydrochloride 5 g (even if the amount of isoniazid ingested is unknown), given intravenously over 3 to 5 minutes, has been recommended. This dose is repeated at 5 to 20 minute intervals, until the dose greatly exceeds that of the ingested isoniazid, seizures cease, or consciousness is regained. In patients with seizures not controlled with pyridoxine, 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.