Rifapentine 300 Adco 300 mg FC tablets

RIFAPENTINE 300 ADCO, taken 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. RIFAPENTINE 300 ADCO must always be used in combination with isoniazid as a 12-week once-weekly regimen for the treatment of latent tuberculosis infection.

Posology: RIFAPENTINE 300 ADCO is to 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 RIFAPENTINE 300 ADCO 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 to 11 years: The recommended dose of RIFAPENTINE 300 ADCO should be determined based on weight of the patient up to a maximum of 900 mg once-weekly (see Table 2). 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.

RIFAPENTINE 300 ADCO is contraindicated in patients with:

• hypersensitivity to rifapentine, other rifamycins (e.g. rifampicin, rifabutin) or to any of the ingredients of RIFAPENTINE 300 ADCO (see section 6.1)
• 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
RIFAPENTINE 300 ADCO may cause serious hepatic disease/injury. Patients with abnormal liver tests and/or liver disease should only be prescribed RIFAPENTINE 300 ADCO if no safer alternative is available, and then with caution and under strict medical supervision (see section 4.3). 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 in this patient group. In the event of any indication of a liver reaction or of the hepatic condition worsening, RIFAPENTINE 300 ADCO 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 taking RIFAPENTINE 300 ADCO. Signs and symptoms of hypersensitivity 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). Patients taking RIFAPENTINE 300 ADCO should be monitored for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue RIFAPENTINE 300 ADCO.

Concomitant medicine interactions
As rifapentine, as contained in RIFAPENTINE 300 ADCO, is an inducer of CYP3A4 and CYP2C8/9, concomitant use 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).

Severe cutaneous adverse reactions (SCARs)
Severe cutaneous adverse reactions 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 (as in RIFAPENTINE 300 ADCO) 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 rifapentine, as contained in RIFAPENTINE 300 ADCO. 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, RIFAPENTINE 300 ADCO 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
Patients should be warned that RIFAPENTINE 300 ADCO 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 RIFAPENTINE 300 ADCO on other medicines:
Medicines metabolised by CYP3A4 and CYP2C8/9
Rifapentine, as contained in RIFAPENTINE 300 ADCO, is an inducer of CYP3A4 and CYP2C8/9. Therefore, RIFAPENTINE 300 ADCO 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 RIFAPENTINE 300 ADCO. Induction of enzyme activities by rifapentine occurred after the first dose of the medicine. Enzyme activities returned to baseline levels, in general, 14 days after discontinuing rifapentine. Examples of such medicines 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).

Transporter substrates
In vitro, rifapentine, as contained in RIFAPENTINE 300 ADCO, 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 RIFAPENTINE 300 ADCO.

Antiretroviral medicines
Protease inhibitors and certain reverse transcriptase inhibitors: Concomitant use of rifapentine, as contained in RIFAPENTINE 300 ADCO, 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 rifapentine 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. Co-administration of a fixed dose combination of efavirenz, emtricitabine and tenofovir with RIFAPENTINE 300 ADCO 900 mg once-weekly requires no dose adjustment.

Raltegravir:
Once-weekly co-administration of 900 mg rifapentine 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 RIFAPENTINE 300 ADCO 900 mg once-weekly.

Hormonal contraceptives
Rifapentine, as contained in RIFAPENTINE 300 ADCO, may reduce the effectiveness of hormonal contraceptives. Women taking oral contraception, using a transdermal patch, or other systemic hormonal contraceptives who need RIFAPENTINE 300 ADCO 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 RIFAPENTINE 300 ADCO:
Potential interaction with CYP450 inducer/inhibitor medicines, as well as with transporters inhibitor/inducer medicines are not expected (see section 5.2). Since rifapentine, as contained in RIFAPENTINE 300 ADCO, 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 rifapentine, as contained in RIFAPENTINE 300 ADCO. Therefore, alternative assay methods should be considered.

Pregnancy
Women who are pregnant should not be treated with RIFAPENTINE 300 ADCO as safety in pregnancy has not been established. Human data: As rifapentine, as contained in RIFAPENTINE 300 ADCO, may have a similar effect to rifampicin (known to cause postnatal haemorrhages in the mother and infant when taken during the last few weeks of pregnancy), appropriate coagulation testing should be performed when pregnant women are inadvertently exposed to RIFAPENTINE 300 ADCO during late pregnancy. Treatment with vitamin K may be indicated.

Breastfeeding
Safety in lactation has not been established. It is not known whether rifapentine is excreted in human milk, therefore mothers on RIFAPENTINE 300 ADCO therapy should not breastfeed their babies. RIFAPENTINE 300 ADCO may produce a red-orange discolouration of body fluids, including breast milk.

Patients should be advised not to drive or operate machines if they experience any side effects of RIFAPENTINE 300 ADCO which could adversely affect their ability to do so.

a). Summary of the safety profile
The safety profile of 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, study of rifapentine, as contained in RIFAPENTINE 300 ADCO, in combination with isoniazid, given once-weekly for 3 months, was compared to a comparator given once daily for 9 months. A total of 4 040 patients received at least one dose of the rifapentine in combination with isoniazid 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.

b). Tabulated summary of adverse reactions

* Reported in less than 3 patients
**Post marketing reported adverse events.

c) 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 rifapentine in combination with isoniazid test product and 493 received the comparator). No children in either treatment arm developed hepatotoxicity. Children in the rifapentine in combination with isoniazid test product 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.

d) 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 rifapentine in combination with isoniazid test product 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 rifapentine in combination with isoniazid test product 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 rifapentine in combination with isoniazid test product arm.

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. Healthcare professionals are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. You may also report to Adcock Ingram Limited using the following e-mail address: [email protected].

Signs and symptoms:
An overdose may precipitate side effects and increase the severity thereof.

Management of overdose:
Treatment should be symptomatic and supportive. While there is no experience in the treatment of overdose with RIFAPENTINE 300 ADCO, clinical experience with rifamycins suggests that 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.