Isoniazid/ Rifapentine

Registered South African indications:

• Prevention of active tuberculosis in patients presenting with
  - Latent tuberculosis infection (LTBI) caused by Mycobacterium tuberculosis who are at high risk of progression to tuberculosis disease (including those in close contact with active tuberculosis patients, recent conversion to a positive tuberculin skin test)
  - HIV-infected patients not receiving protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTIs) as antiretroviral therapy (ART)
  - Patients with pulmonary fibrosis on radiograph with no signs and symptoms of TB regardless of HIV status

Registered South African contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to ethionamide, pyrazinamide, niacin, or other chemically related compounds
• Porphyria
• Acute or chronic liver disease
• Severe renal failure
• Alcoholism
• Seizure disorders
• Pregnancy
• Lactation
• HIV-infected patients on antiretroviral therapy with protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) because of potential interactions leading to loss of efficacy

South African recommendations

Caution in the following patient groups

• Mild to moderate renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Convulsive disorders
• Diabetes mellitus
• History of psychosis
• Patients taking other potentially hepatotoxic medicines (if symptoms of hepatitis deteriorate in these patients, discontinued isoniazid/ rifapentine immediately)

Active tuberculosis

• Confirm absence of active tuberculosis before starting treatment for latent TB infection

Hepatotoxicity

• Isoniazid/ rifapentine may lead to severe liver damage
• Only prescribe isoniazid/ rifapentine to patients with liver issues when no safer alternatives exist, and monitor closely
• Regularly check liver function before and during treatment, discontinuing if liver health deteriorates

Hypersensitivity reactions

• Patients on isoniazid/ rifapentine may experience hypersensitivity reactions, including symptoms like hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome
• Watch for any signs of hypersensitivity in patients taking isoniazid/ rifapentine
• If symptoms arise, provide supportive care and stop isoniazid/ rifapentine treatment

Severe cutaneous adverse reactions

• Isoniazid/ rifapentine has been linked with severe skin reactions, including Stevens-Johnson syndrome (SJS) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
• Patients should be educated on recognizing symptoms of serious skin conditions
• Stop isoniazid/ rifapentine at the first sign of a skin rash, lesions in mucous membranes, or any hypersensitivity indication

Clostridium difficile-associated diarrhoea

• Use of isoniazid/rifapentine has been associated with pseudomembranous colitis, indicative of Clostridium difficile-associated disease
• Diarrhoea that is severe or persists during or after treatment may signal this condition, necessitating the immediate discontinuation of isoniazid/rifapentine and appropriate management. Peristalsis-inhibiting medications are contraindicated

Discolouration of body fluids

• Isoniazid/rifapentine can lead to a red-orange discoloration of body tissues and fluids (e.g. skin, teeth, tongue, urine, faeces, saliva, sputum, tears, sweat and cerebrospinal fluid), with the potential to permanently stain contact lenses and dentures

Additional precautions

• The administration of 10mg pyridoxine daily is recommended to prevent or minimise symptoms of peripheral neuritis, as well as for those who are diabetic, alcoholic, malnourished, uraemic, or infected with HIV (not undergoing antiretroviral therapy)
• Periodic eye examinations are recommended during treatment

Ability to drive and use machines

• Isoniazid/ rifapentine may cause dizziness, impaired concentration, and/or drowsiness. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Prevention of active tuberculosis in patients presenting with:
- Latent tuberculosis infection (LTBI) caused by Mycobacterium tuberculosis who are at high risk of progression to tuberculosis disease (including those in close contact with active tuberculosis patients, recent conversion to a positive tuberculin skin test)
- HIV-infected patients not receiving protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTIs) as antiretroviral therapy (ART)
- Patients with pulmonary fibrosis on radiograph with no signs and symptoms of TB regardless of HIV status

Isoniazid/ Rifapentine
300/300 (mg)

• Oral (fct): Admin. once weekly as directly observed therapy (DOT) (see weight-based dose in table below); Isoniazid: Recommended dose is 15mg/kg (rounded to the nearest 50mg or 100mg) up to a max. of 900mg once weekly; Rifapentine: Recommended dose should be determined based on weight of the patient up to a max. of 900mg once weekly (see table below); Treatment duration: 12 weeks

Table: Weight-based dose of isoniazid/ rifapentine in the prophylactic treatment of latent tuberculosis infection in adults at high risk of progression to tuberculosis disease

Weight range	Isoniazid dose	Rifapentine dose	Number of isoniazid/ rifapentine tablets once a week for 12 weeks
10-14kg	300mg	300mg	1
14.1-25kg	450mg	450mg	1½
25.1-32kg	600mg	600mg	2
32.1-50kg	750mg	750mg	2½
>50kg	900mg	900mg	3

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Active tuberculosis disease should be ruled out before initiating treatment with isoniazid/ rifapentine

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Patients should be informed that adherence to the treatment regimen for isoniazid/ rifapentine and other substances is essential for effective treatment, and the importance of not missing any doses must be stressed. Isoniazid/ rifapentine should be given with food. For patients who cannot swallow tablets, the tablets may be crushed and added to a small amount of semi-solid food, all of which should be consumed immediately

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Interactions with antacids have not been studied. However, in the clinical efficacy study, patients were advised to take isoniazid/ rifapentine at least 1 hour before or 2 hours after the ingestion of antacids

Not established for use in children

Pregnancy

South African recommendations

• Contraindicated
• Safety during pregnancy has not been established. Isoniazid/ rifapentine is not recommended during pregnancy
• Human data: Rifampicin is known to cause postnatal haemorrhages in the mother and infant when taken during the last few weeks of pregnancy
• Since isoniazid/ rifapentine might have a similar effect, appropriate coagulation testing should be performed when pregnant women are inadvertently exposed to isoniazid/ rifapentine during late pregnancy. Treatment with vitamin K may be indicated

Breastfeeding

South African recommendations

• Contraindicated
• Mothers on treatment with isoniazid/ rifapentine should not breastfeed their babies. It is not known whether isoniazid/ rifapentine is excreted in human milk. Isoniazid/ rifapentine may produce a red-orange discolouration of body fluids, including breast milk

Fertility

South African recommendations

• No data on the effect of isoniazid/ rifapentine on fertility is available

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated
  Contraindicated in patients with severe renal failure (glomerular filtration rate of less than 10ml/minute (creatinine clearance <30ml/min)

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
  No dosage adjustment is required, however, the half-life of isoniazid may be prolonged in the presence of hepatic insufficiency
• Acute or chronic liver disease: Contraindicated

South African recommendations

• Caution; no dose adjustment recommended
  No dosage adjustment is required in the elderly, but caution should be exercised due to the possible decrease in renal and hepatic function

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Isoniazid

Blood and Lymphatic System Disorders

Less frequent

• Haematological effects (various anaemias, agranulocytosis, thrombocytopenia and eosinophilia)

Immune System Disorders

Less frequent

• Hypersensitivity reactions (fever, skin rashes, joint pain)

Metabolism and Nutrition Disorders

Less frequent

• Hyperglycaemia
• Metabolic acidosis

Psychiatric Disorders

Less frequent

• Neurotoxicity (psychotic reactions)

Nervous System Disorders

Frequent

• Peripheral neuritis

Less frequent

• Convulsions
• Hyperreflexia

Eye Disorders

Less frequent

• Optic neuritis

Ear and Labyrinth Disorders

Less frequent

• Vertigo

Gastrointestinal Disorders

Frequent

• Nausea
• Vomiting
• Constipation
• Dry mouth
• Gastrointestinal irritation

Hepatobiliary Disorders

Frequent

• Hepatitis
• Hepatitis prodromal symptoms
  - Loss of appetite
  - Nausea or vomiting
  - Unusual tiredness or weakness
• Transient increases in liver enzymes

Skin and Subcutaneous Tissue Disorders

Less frequent

• Purpura
• Acneform syndrome
• Lupus erythematosus-like syndrome
• Exfoliative dermatitis
• Pellagra
• Alopecia
• Urticaria

Musculoskeletal and Connective Tissue Disorders

Frequency unknown

• Rheumatoid syndrome

Renal and Urinary Disorders

• Urinary retention

Reproductive System and Breast Disorders

• Gynaecomastia

Rifapentine

Infections and Infestations

Less frequent

• Influenza

Frequency unknown

• Pneumonia

Immune System Disorders

Frequent

• Hypersensitivity

Nervous System Disorders

Less frequent

• Headache

Gastrointestinal Disorders

Less frequent

• Nausea
• Upper abdominal pain

Frequency unknown

• Pancreatitis
• Oesophageal irritation

Hepatobiliary Disorders

Less frequent

• Hepatitis

Skin and Subcutaneous Tissue Disorders

Less frequent

• Skin reaction

Frequency unknown

• Severe cutaneous adverse reactions (SCARs) such as
  - Stevens-Johnson syndrome (SJS)
  - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome

Musculoskeletal and Connective Tissue Disorders

Less frequent

• Myalgia

General Disorders and Administration Site Conditions

Less frequent

• Influenza-like illness
• Fatigue
• Chills
• Pyrexia
• Asthenia

• Medicines metabolised by CYP3A4 and CYP2C8/9
• Non-nuclease-reverse transcriptase inhibitors (NNRTIs)
• Efavirenz (CYP3A4 inducer and inhibitor)
• Digoxin
• Antiretroviral medicines
• Protease inhibitors
• Indinavir
• Darunavir
• Lopinavir
• Saquinavir
• Ritonavir
• Nelfinavir
• Amprenavir
• Fosamprenavir
• Atazanavir
• Tipranavir
• Non-nucleoside reverse transcriptase inhibitors
• Rilpivirine
• Nucleoside reverse transcriptase inhibitor
• Zidovudine
• Antifungals
• Itraconazole
• Ketoconazole
• Voriconazole
• Narcotic analgesics
• Methadone
• Alfentanil
• Buprenorphine
• Hypoglycaemic medicines
• Repaglinide
• Calcium channel blockers
• Felodipine
• Diltiazem
• Verapamil
• Nifedipine
• Alpha/ beta adrenergic antagonists
• Alfuzosin
• Propranolol
• Ergot alkaloid derivatives
• Ergotamine
• Oral anti-vitamin K anticoagulant
• Warfarin
• Hormonal contraceptives; oral, transdermal, and implant
• Immunosuppressants
• Ciclosporin
• Tacrolimus
• Sirolimus
• Benzodiazepines
• Diazepam
• Triazolam
• Midazolam
• Antiepileptics
• Carbamazepine
• Primidone
• Phenytoin
• Theophylline
• Rifampicin
• Potentially neurotoxic medicines
• Cycloserine
• Disulfiram
• Paracetamol
• Paraminosalicyclic acid
• Prednisolone
• Aluminium containing antacid
• Levodopa
• Zalcitabine
• P-gp substrates
• CYP450 inducer/ inhibitor medicines
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Sulfonylureas
• Oral anticoagulants
• Ethosuximide

Other interactions

• Alcohol
• Interferences with laboratory and diagnostic tests
• Standard microbiological assays for serum folate and vitamin B12 (alternative assay methods should be considered)
• Cheese
• Red wine
• Some fish

Specific cases may require

• Hepatic function
• Digoxin levels
• Eye examination

Additional observations

•  Signs and/or symptoms of hypersensitivity reactions

Isoniazid
Isoniazid is a synthetic, bactericidal antitubercular medicine, which is active against many mycobacteria, primarily those that are actively dividing. The mechanism of action is by entering the bacilli through passive diffusion. Isoniazid then inhibits the biosynthesis of mycolic acids which are essential components of the cell wall of Mycobacterium tuberculosis, leading to bacterial cell death. 

Rifapentine
Rifapentine, a cyclopentylrifamycin, is an antimycobacterial medicine. Rifapentine inhibits DNA-dependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis but does not affect mammalian cells at concentrations that are active against these bacteria. At therapeutic levels, rifapentine inhibits RNA transcription by preventing the initiation of RNA chain formation. It forms a stable complex with bacterial DNA-dependent RNA polymerase, leading to repression of RNA synthesis and cell death. Rifapentine and its 25-desacetyl metabolite accumulate in human monocyte-derived macrophages and are bactericidal to both intracellular and extracellular M. tuberculosis bacilli.

Combination Isoniazid/Rifapentine 

Film coated tablet 300mg/300mg

• Solonex Co (Macleods Pharmaceuticals)