Priftin 150 mg FC tablets.

PRIFTIN in combination with isoniazid (INH) is indicated for the treatment of latent tuberculosis infection (LTBI) caused by Mycobacterium tuberculosis in adults and children 2 years and older 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, or those with pulmonary fibrosis on radiograph). Active tuberculosis disease should be ruled out before initiating treatment for latent tuberculosis infection.

PRIFTIN must always be used in combination with isoniazid as a 12-week once-weekly regimen for the treatment of latent tuberculosis infection.

Posology

PRIFTIN should be administered once-weekly in combination with isoniazid for 12 weeks as directly observed therapy (DOT).

Adults and children 12 years and older: The recommended dose of PRIFTIN should be determined based on weight of the patient up to a maximum of 900 mg once-weekly (see Table 1). The recommended dose of isoniazid is 15 mg/kg (rounded to the nearest 50 mg or 100 mg) up to a maximum of 900 mg once-weekly for 12 weeks.

Children 2 u2013 11 years: The recommended dose of PRIFTIN should be determined based on weight of the patient up to a maximum of 900 mg once-weekly (see Table 3). The recommended dose of isoniazid is 25 mg/kg (rounded to the nearest 50 mg or 100 mg) up to a maximum of 900 mg once-weekly for 12 weeks.

Table 1: Weight-based dose of PRIFTIN in the treatment of latent tuberculosis infection

• Weight range
• PRIFTIN dose
• Number of PRIFTIN tablets
• 10 u2013 14 kg
• 300 mg
• 2
• 14,1 u2013 25 kg
• 450 mg
• 3
• 25,1 u2013 32 kg
• 600 mg
• 4
• 32,1 u2013 50 kg
• 750 mg
• 5
• > 50 kg
• 900 mg
• 6

Special populations

Paediatric patients: The youngest patient included in the clinical efficacy trial was 2 years. No data are available for patients below 2 years old.

Elderly patients: No dose adjustment required.

Hepatic impairment: No dose adjustment required (see sections 4.3 and 4.4).

Renal impairment: No dose adjustment required.

Method of administration

Patients should be informed that adherence to the treatment regimen for PRIFTIN and other substances is essential for effective treatment, and the importance of not missing any doses must be stressed. PRIFTIN, in combination with isoniazid, 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 (see section 5.2). Interactions with antacids have not been studied. However, in the clinical efficacy study, patients were advised to take PRIFTIN at least 1 hour before or 2 hours after the ingestion of antacids.

• PRIFTIN is contraindicated in patients with hypersensitivity to rifapentine or any of the other rifamycins (e.g. rifampicin and rifabutin), or to any of the tabletu2019s excipients.
• PRIFTIN is contraindicated in patients with porphyria. Based on experience with rifampicin, it may be assumed that rifapentine can also induce delta-aminolevulinic acid synthetase and therefore cause an acute attack of porphyria.
• Acute or chronic liver disease.

• Hepatotoxicity PRIFTIN may cause serious hepatic disease/injury. Patients with abnormal liver tests and/or liver disease should only be given PRIFTIN if no safer alternative is available, and then with caution and under strict medical supervision (see section 4.3). In such patients, careful monitoring of liver parameters (especially serum transaminases and bilirubin) should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If there are indications of a liver reaction or of the hepatic condition worsening, PRIFTIN should be discontinued. Hepatotoxicity of other antituberculosis medicines (e.g. isoniazid, pyrazinamide) used in combination with rifapentine should also be taken into account.
• Hypersensitivity and related reactions Hypersensitivity reactions may occur in patients receiving PRIFTIN. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations) (see section 4.8). Monitor patients receiving PRIFTIN therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue PRIFTIN.
• Medicine interactions PRIFTIN is an inducer of CYP3A4 and CYP2C8/9. Concomitant use of rifapentine with other medicines metabolised by these enzymes, such as protease inhibitors, certain reverse transcriptase inhibitors, and hormonal contraception may cause a significant decrease in plasma concentrations and loss of therapeutic effect of these medicines (see sections 4.5 and 5.2). PRIFTIN has also been shown to inhibit and to induce P-gp which could modify plasma exposure of digoxin (a P-gp substrate with narrow therapeutic index). Appropriate monitoring and dose adjustment of digoxin may be necessary in case of co-administration with rifapentine (see sections 4.5 and 5.2).
• Severe cutaneous adverse reactions Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported in association with the use of rifapentine treatment regimen. Patients should be informed about the signs and symptoms of serious skin manifestations. Treatment should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
• Clostridium difficile -associated diarrhoea Pseudomembranous colitis has been reported to occur with rifamycins such as PRIFTIN. Diarrhoea, particularly if severe and/or persistent, occurring during treatment or in the initial weeks following treatment may be symptomatic of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, PRIFTIN should be stopped immediately and the patient treated appropriately without delay. Medicines inhibiting the peristalsis are contraindicated in this clinical situation.
• Discolouration of body fluids PRIFTIN may produce a predominantly red-orange discolouration of body tissues and/or fluids (e.g. skin, teeth, tongue, urine, faeces, saliva, sputum, tears, sweat and cerebrospinal fluid). Contact lenses or dentures may become permanently stained.

Effect of PRIFTIN on other medicines

• Effect on medicines metabolised by CYP3A4 and CYP2C8/9 PRIFTIN is an inducer of CYP3A4 and CYP2C8/9. Therefore, PRIFTIN may increase the metabolism of other co-administered medicines that are metabolised by these enzymes. Appropriate monitoring and dosage adjustment may be necessary if medicines metabolised by CYP3A4 or CYP2C8/9 are co-administered with PRIFTIN. Induction of enzyme activities by PRIFTIN occurred after the first dose of PRIFTIN. Enzyme activities returned to baseline levels, in general, 14 days after discontinuing PRIFTIN. Examples of such substances include:
• Antiretroviral medicines:
• Protease inhibitors: indinavir, darunavir, lopinavir, saquinavir, ritonavir
• 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: midazolam.
• Effect of PRIFTIN on transporter substrates In vitro, PRIFTIN has been shown to inhibit and to induce P-gp which could modify plasma exposure of digoxin (P-gp substrate) (see section 5.2). Because of the narrow therapeutic index of digoxin, appropriate monitoring and dose adjustment of digoxin may be necessary in case of co-administration with PRIFTIN.
• Effect of PRIFTIN on antiretroviral medicines
• Protease inhibitors and certain reverse transcriptase inhibitors Concomitant use of rifapentine with protease inhibitors and certain reverse transcriptase inhibitors, metabolised by CYP3A4 or CYP2C8/9, may cause a significant decrease in plasma concentrations and loss of therapeutic effect of these medicines.
• Fixed dose combination of efavirenz, emtricitabine and tenofovir Once-weekly co-administration of 900 mg PRIFTIN with the antiretroviral fixed dose combination of 600 mg efavirenz, 200 mg emtricitabine and 300 mg tenofovir disoproxyl fumarate in HIV-infected patients did not result in any substantial change in steady state exposures of efavirenz, emtricitabine and tenofovir. No clinically significant change in CD4 cell counts or viral loads were noted. No need for dose adjustment of fixed dose combination of efavirenz, emtricitabine and tenofovir, if co-administered with PRIFTIN 900 mg once-weekly.
• Raltegravir Once-weekly co-administration of 900 mg PRIFTIN with raltegravir resulted in a 71 % mean increase in raltegravir AUC 0-12, and an 89 % increase in C max. No need for dose adjustment of raltegravir, if co-administered with PRIFTIN 900 mg once-weekly.
• Hormonal contraceptives PRIFTIN may reduce the effectiveness of hormonal contraceptives. Women taking oral contraception, using a transdermal patch, or other systemic hormonal contraceptives who need PRIFTIN therapy should discuss the use of an additional non-hormonal means of contraception or the change of their contraceptive pill with their medical practitioner.

Effect of other medicines on PRIFTIN

Potential interaction with CYP450 inducer/inhibitor medicines, as well as with transporters inhibitor/inducer medicines are not expected (see section 5.2). Since PRIFTIN is highly bound to albumin, medicine displacement interactions with non-steroidal anti-inflammatory drugs (NSAIDs), sulfonylureas and oral anticoagulants may also occur.

Interferences with laboratory and diagnostic tests

Therapeutic concentrations of rifampin have been shown to inhibit standard microbiological assays for serum folate and vitamin B12. Similar interferences should be considered for PRIFTIN. Therefore, alternative assay methods should be considered.

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

Breastfeeding Mothers on treatment with PRIFTIN should not breastfeed their babies. It is not known whether PRIFTIN is excreted in human milk. PRIFTIN may produce a red-orange discolouration of body fluids, including breast milk.

Do not drive or operate machines if you experience any side effects of PRIFTIN which could adversely affect your ability to drive or use machines.

The following CIOMS frequency rating is used, when applicable: Very common ( u2265 10 %); common ( u2265 1 % and < 10 %); uncommon ( u2265 0,1 % and < 1 %); rare ( u2265 0,01 % and < 0,1 %); very rare (< 0,01 %); frequency not known ( frequency cannot be estimated from available data).

Clinical trials experience: The safety profile of PRIFTIN in combination with isoniazid given once-weekly is based on the study TBTC-S26. In this study, PRIFTIN in combination with isoniazid given once-weekly for 3 months (3RPT/INH) was compared to a comparator given once daily for 9 months in an open-label, randomised trial in patients with a positive tuberculin skin test, and at high risk for progression from latent tuberculosis infection to active tuberculosis disease. A total of 4 040 patients received at least one dose of the 3RPT/INH regimen, including 348 children 2 u2013 17 years of age and 105 HIV-infected individuals. A total of 3 759 received at least one dose of the comparator regimen, including 342 children 2 years to 17 years of age and 95 HIV-infected individuals. Patients were followed for 33 months from the time of enrolment.

Table 2: Adverse drug reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicine) reported in at least 3 patients treated with 3RPT/INH*

System organ class Frequency 3RPT/INH patients (%) Comparator patients (%) Infections and infestations Influenza Uncommon 8 (0,2) 1 (0,03) Immune system disorders Hypersensitivity Common 160 (3,96) 18 (0,48) Nervous system disorders Headache Uncommon 14 (0,35) 10 (0,27) Gastrointestinal disorders Nausea Uncommon 11 (0,3) 6 (0,2) Upper abdominal pain Uncommon 3 (0,07) 2 (0,05) Hepatobiliary disorders Hepatitis Uncommon 18 (0,45) 103 (2,74) Skin and subcutaneous tissue disorders Skin reaction Uncommon 31 (0,77) 21 (0,56) Musculoskeletal and connective tissue disorders Myalgia Uncommon 4 (0,1) 0 General disorders and administration site conditions Influenza-like illness Uncommon 8 (0,2) 0 Fatigue Uncommon 4 (0,1) 6 (0,16) Chills Uncommon 4 (0,1) 0 Pyrexia Uncommon 4 (0,1) 1 (0,03) Asthenia Rare 3 (0,07) 0

* Includes events reported through 60 days after last dose of study medicine. The following adverse drug reactions were reported in less than 3 patients (frequency: rare): pancreatitis, oesophageal irritation, pneumonia.

Paediatric population: Six-hundred and ninety children 2 years u2013 17 years of age received at least one dose of study medicines in the main study. An additional 342 children 2 years u2013 17 years of age received at least one dose in the paediatric extension study (total 1 032 children; 539 received 3RPT/INH and 493 received the comparator). No children in either treatment arm developed hepatotoxicity. Children in the 3RPT/INH group experienced less rifamycin hypersensitivity reaction (7 [1,3 %]) than adults. Adverse reactions in children 2 years u2013 11 years of age and 12 years u2013 17 years of age were similar.

HIV population: Two-hundred HIV-infected patients with latent tuberculosis infection received at least one dose of study medicines in the main study and an additional 193 patients received at least one dose in the extension study (total of 393; 207 received 3 RPT/INH and 186 received comparator). Compared to the HIV-negative patients enrolled in the main study, a higher proportion of HIV-infected patients in each treatment arm experienced a treatment emergent adverse reaction, including a higher incidence of hepatotoxicity. Hepatotoxicity occurred less frequently in patients in the 3RPT/INH arm (3/207 [1,5 %]) than in the comparator arm (14/186 [7,5 %]). Rifamycin hypersensitivity occurred in only one HIV-infected patient in the 3RPT/INH arm.

Post-marketing Skin and subcutaneous tissue disorders Not known: Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome (see section 4.4).

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to:

• The Pharmacovigilance Unit at Sanofi: [email protected] (email) or 011 256 3700 (tel), or
• SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Signs and symptoms No case of an acute overdose with PRIFTIN has been reported. An overdose may precipitate side effects and increase the severity thereof.

Treatment Treatment should be symptomatic and supportive. While there is no experience in the treatment of overdose with PRIFTIN, clinical experience with rifamycins suggests that gastric lavage to evacuate gastric contents (within a few hours of overdose), followed by instillation of an activated charcoal slurry into the stomach, may help adsorb any remaining medicine from the gastrointestinal tract. Rifapentine and 25-desacetyl rifapentine are highly plasma protein bound and have limited urinary excretion. Therefore, neither haemodialysis nor forced diuresis is expected to enhance the systemic elimination.