Fripnit 300 mg Tablet

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

Posology: FRIPNIT 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 FRIPNIT 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 FRIPNIT 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.

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

• 10 u2013 14 kg: 300 mg (1 tablet)
• 14.1 u2013 25 kg: 450 mg (1 + half tablet)
• 25.1 u2013 32 kg: 600 mg (2 tablets)
• 32.1 u2013 50 kg: 750 mg (2 + half tablet)
• >50 kg: 900 mg (3 tablets)

Special populations

• Elderly: No dose adjustment required.
• Hepatic impairment: No dose adjustment required (see sections 4.3 and 4.4).
• Renal impairment: No dose adjustment required.
• Paediatric population: No data are available for patients below 2 years old. The youngest patient included in a clinical efficacy trial was 2 years.

Method of administration: Oral use. To ensure effective treatment, the strict adherence to the treatment regimen of FRIPNIT and other medicines, as well as the importance of not missing any doses, should be stressed to the patient. FRIPNIT, 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). The interaction of FRIPNIT taken with antacids has not been studied. However, in a clinical efficacy study patients were advised to take rifapentine, as contained in FRIPNIT, at least 1 hour before or 2 hours after the ingestion of antacids.

FRIPNIT is contraindicated in patients with:

• hypersensitivity to rifapentine, other rifamycins (e.g. rifampicin, rifabutin) or to any of the ingredients of FRIPNIT (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: FRIPNIT may cause serious hepatic disease/injury. Patients with abnormal liver tests and/or liver disease should only be prescribed FRIPNIT 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, FRIPNIT 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 FRIPNIT. 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 FRIPNIT should be monitored for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue FRIPNIT.

Concomitant medicine interactions: As rifapentine, as contained in FRIPNIT, 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). Rifapentine 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 FRIPNIT (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 FRIPNIT) 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 FRIPNIT. 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, FRIPNIT 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 FRIPNIT 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 FRIPNIT on other medicines: Medicines metabolised by CYP3A4 and CYP2C8/9: Rifapentine, as contained in FRIPNIT, is an inducer of CYP3A4 and CYP2C8/9. Therefore, FRIPNIT 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 FRIPNIT.

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 FRIPNIT, 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 FRIPNIT.

Pregnancy: Women who are pregnant should not be treated with FRIPNIT as safety in pregnancy has not been established. Human data: As rifapentine, as contained in FRIPNIT, 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 FRIPNIT 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 FRIPNIT therapy should not breastfeed their babies. FRIPNIT 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 FRIPNIT 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 FRIPNIT, 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.

Adverse 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 rifapentine in combination with isoniazid regimen (including adverse events reported through 60 days after the last dose was administered) are detailed below:

b). Tabulated summary of adverse reactions:

System Organ Class Frequency Side effects

• Infections and infestations: Less frequent - Influenza, pneumonia*
• Immune system disorders: Frequent - Hypersensitivity
• Nervous system disorders: Less frequent - Headache
• Gastrointestinal disorders: Less frequent - Nausea, upper abdominal pain, esophageal irritation*, pancreatitis*
• Hepatobiliary disorders: Less frequent - Hepatitis
• Skin and subcutaneous tissue disorders: Less frequent - Frequency unknown - Skin reaction
• Severe cutaneous adverse reactions (SCARs)** such as Stevens-Johnson syndrome (SJS)** and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome**
• Musculoskeletal, connective tissue and bone disorders: Less frequent - Myalgia
• General disorders and administrative site conditions: Less frequent - Influenza-like illness, fatigue, chills, pyrexia, asthenia

* 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.

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 FRIPNIT, 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.