Rifapentine

Pregnancy Category: C

Lactation: unknown

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mechanism of Action

Inhibits RNA polymerase in M. tuberculosis

Absorption

Peak Plasma Time: 5-6 hr

Distribution

Protein Bound: 98%

Metabolism

Enzymes induced: CYP3A4, CYP2C9/10

Elimination

Half-Life: 13 hr

Excretion: feces (70%); urine

You should not take this medicine if you are allergic to rifapentine, rifabutin (Mycobutin), or rifampin (Rifadin, Rifater, Rimactane, Rifamate).

To make sure rifapentine is safe for you, tell your doctor if you have:

• liver disease;

• porphyria (a genetic enzyme disorder that causes symptoms affecting the skin or nervous system);

• HIV or AIDS;

• if you have used rifampin or isoniazid in the past and they were not effective in treating TB; or

• if you have been exposed to someone with TB that could not be treated with rifampin or isoniazid.

FDA pregnancy category C. It is not known whether rifapentine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

Rifapentine can make birth control pills less effective. Ask your doctor about using non hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy while taking rifapentine.

It is not known whether rifapentine passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine. Rifapentine may cause a red-orange discoloration of breast milk.

Do not give this medicine to a child without medical advice.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For rifapentine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to rifapentine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of rifapentine to treat active tuberculosis in children younger than 12 years of age, nor to treat inactive tuberculosis in children younger than 2 years of age. Safety and efficacy have not been established in these age groups.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of rifapentine in the elderly.

Pregnancy

Breast Feeding

Studies suggest that this medication may alter milk production or composition. If an alternative to this medication is not prescribed, you should monitor the infant for side effects and adequate milk intake.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking rifapentine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using rifapentine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Artemether
• Delamanid
• Lurasidone
• Maraviroc
• Ranolazine
• Rilpivirine

Using rifapentine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abiraterone
• Amprenavir
• Apremilast
• Bedaquiline
• Bortezomib
• Ceritinib
• Cholera Vaccine, Live
• Clarithromycin
• Cobicistat
• Darunavir
• Dolutegravir
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Efavirenz
• Elvitegravir
• Enzalutamide
• Erlotinib
• Etravirine
• Exemestane
• Fosamprenavir
• Idelalisib
• Indinavir
• Irinotecan
• Irinotecan Liposome
• Ketoconazole
• Lapatinib
• Ledipasvir
• Linagliptin
• Lopinavir
• Macitentan
• Mifepristone
• Naloxegol
• Nelfinavir
• Netupitant
• Nevirapine
• Nifedipine
• Nilotinib
• Nimodipine
• Olaparib
• Panobinostat
• Pazopanib
• Perampanel
• Piperaquine
• Ponatinib
• Regorafenib
• Ritonavir
• Romidepsin
• Saquinavir
• Simeprevir
• Sorafenib
• Sunitinib
• Tasimelteon
• Tenofovir Alafenamide
• Ticagrelor
• Tipranavir
• Tofacitinib
• Tolvaptan
• Ulipristal
• Vandetanib
• Velpatasvir
• Vilazodone
• Vincristine
• Vincristine Sulfate Liposome
• Vortioxetine

Using rifapentine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acenocoumarol
• Acetyldigoxin
• Alprazolam
• Amiodarone
• Amitriptyline
• Betamethasone
• Bisoprolol
• Carbamazepine
• Carteolol
• Carvedilol
• Chloramphenicol
• Chlorpropamide
• Ciprofloxacin
• Clofibrate
• Cyclosporine
• Dapsone
• Delavirdine
• Deslanoside
• Desogestrel
• Dexamethasone
• Diazepam
• Dicumarol
• Dienogest
• Digitoxin
• Digoxin
• Disopyramide
• Doxycycline
• Drospirenone
• Estradiol Cypionate
• Estradiol Valerate
• Ethinyl Estradiol
• Ethynodiol Diacetate
• Etonogestrel
• Fluconazole
• Fludrocortisone
• Fosphenytoin
• Gallopamil
• Glyburide
• Haloperidol
• Hydrocortisone
• Levonorgestrel
• Levothyroxine
• Lorcainide
• Medroxyprogesterone Acetate
• Mestranol
• Metildigoxin
• Metoprolol
• Mexiletine
• Nitrazepam
• Norelgestromin
• Norethindrone
• Norgestimate
• Norgestrel
• Nortriptyline
• Ospemifene
• Phenprocoumon
• Phenytoin
• Prednisone
• Propafenone
• Propranolol
• Quinidine
• Quinine
• Repaglinide
• Sildenafil
• Talinolol
• Temazepam
• Tertatolol
• Theophylline
• Tocainide
• Tolbutamide
• Triazolam
• Valproic Acid
• Warfarin
• Zidovudine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of rifapentine. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse, or history of—May increase risk for more serious side effects.

• Elevated liver enzymes or
• Liver disease—Use with caution. May make these conditions worse.

• Porphyria—Avoid use of rifapentine in patients with this condition.

Refer to adult dosing.

Frequency may vary based on treatment phase; adverse reaction data is based on rifapentine combination therapy.

>10%:

Endocrine & metabolic: Hyperuricemia (≤32%; most likely due to pyrazinamide from initiation phase)

Genitourinary: Pyuria (11% to 22%), hematuria (10% to 18%), urinary tract infection (7% to 13%)

Hematologic & oncologic: Neutropenia (6% to 13%), lymphocytopenia (3% to 13%), anemia (2% to 11%)

1% to 10%:

Cardiovascular: Chest pain (3% to 6%), edema (1%)

Central nervous system: Pain (3% to 6%), headache (≤3%), dizziness (≤1%), fatigue (≤1%)

Dermatologic: Diaphoresis (2% to 5%), skin rash (3% to 4%), acne vulgaris (≤3%), pruritus (≤3%), maculopapular rash (≤2%)

Endocrine & metabolic: Hypoglycemia (5% to 10%), hyperglycemia (1% to 4%), increased nonprotein nitrogen (1% to 3%), gout (1%), hyperphosphatemia (1%)

Gastrointestinal: Anorexia (3% to 4%), nausea (≤3%), constipation (1% to 2%), dyspepsia (1% to 2%), abdominal pain (≤2%), diarrhea (≤2%), vomiting (≤2%), hemorrhoids (1%)

Genitourinary: Casts in urine (4% to 8%), cystitis (1%)

Hematologic & oncologic: Leukopenia (4% to 7%), thrombocytosis (≤6%), leukocytosis (2% to 3%), neutrophilia (1% to 3%), thrombocythemia (1% to 3%), polycythemia (≤2%), lymphadenopathy (≤1%)

Hepatic: Increased serum ALT (2% to 7%), increased serum AST (2% to 6%), hepatotoxicity (≤2%)

Hypersensitivity: Hypersensitivity reaction (≤4%; children & adolescents 1%)

Infection: Influenza (3% to 8%), herpes zoster (1%), infection (1%)

Neuromuscular & skeletal: Back pain (4% to 7%), arthralgia (≤4%), osteoarthrosis (1%), tremor (1%)

Ophthalmic: Conjunctivitis (≤3%)

Respiratory: Hemoptysis (2% to 8%), cough (3% to 6%), bronchitis (3%), pharyngitis (1% to 2%), epistaxis (1%), pleurisy (1%)

Miscellaneous: Accidental injury (1% to 5%), fever (≤1%)

<1% (Limited to important or life-threatening): Ageusia, allergic skin reaction, alopecia, anaphylaxis, asthma, azotemia, confusion, convulsions, depression, diabetes mellitus, disorientation, dysuria, enlargement of salivary glands, erythematous rash, esophagitis, fungal infection, gastritis, hematoma, hepatitis, hepatomegaly, hyperbilirubinemia, hypercalcemia, hyperhidrosis, hyperkalemia, hyperlipidemia, increased blood urea nitrogen, increased serum alkaline phosphatase, jitteriness, laryngeal edema, laryngitis, leukorrhea, lymphocytosis, myalgia, myasthenia, myositis, oropharyngeal pain, orthostatic hypotension, palpitations, pancreatitis, paresthesia, pericarditis, peripheral neuropathy, pneumonitis, pulmonary fibrosis, pulmonary tuberculosis (exacerbation), purpura, pyelonephritis, rhabdomyolysis, seizure, skin discoloration, suicidal ideation, syncope, tachycardia, thrombosis, urinary incontinence, vaginal hemorrhage, vaginitis, viral infection, voice disorder, vulvovaginal candidiasis, weight gain, weight loss

Patients with preexisting hepatic problems should have liver function tests monitored (eg, serum transaminases) prior to therapy and then every 2 to 4 weeks during therapy. In treatment of latent infection with rifapentine and isoniazid combination therapy, patients with HIV infection, liver disorders, immediate postpartum (≤ 3 months after delivery), or regular ethanol use should have liver function (at least alanine aminotransferase [ALT]) monitored prior to therapy and then at subsequent clinical visits whose baseline testing is abnormal or for others at risk for liver disease (CDC, 2012).

Although the single-dose pharmacokinetic profiles of rifapentine and its active metabolite, 25-desacetyl rifapentine, are not significantly altered in patients with hepatic impairment compared to healthy individuals, therapy with rifapentine should be administered cautiously in such patients, since the drug is primarily eliminated by the liver. Dosage adjustments may be necessary if undue adverse effects occur.

Data not available

The American Thoracic Society, US Centers for Disease Control and Prevention, and Infectious Diseases Society of America currently do not recommend rifapentine use during the initial intensive phase of tuberculosis treatment. Experts suggest patients with pulmonary tuberculosis who have negative sputum smears following the initial treatment phase may receive rifapentine in combination with isoniazid for the continuation phase.

Rifapentine should not be used alone during the initial or continuation phases of antituberculosis therapy. As with all antituberculosis regimens, compliance with all drugs in rifapentine-containing therapies is critical, particularly during the initial treatment phase to ensure early sputum conversion; poor compliance during this phase is associated with late sputum conversion and a high relapse rate. Rifapentine should be used with caution in patients with cavitary pulmonary lesions and/or failure to convert sputum after the first two months of treatment or in those with proof of bilateral pulmonary disease due to higher rates of relapse.

The normally recommended once-weekly continuation phase dosage (in combination with isoniazid) should not be used in HIV-infected patients with pulmonary tuberculosis. A higher rate of relapse and/or failure was reported with the presence of rifampin-resistant organisms. Risk factors for relapse include low CD4 counts, the presence of pulmonary and extrapulmonary disease at baseline, azole antifungal use, and younger age. Rifapentine has not been studied as part of the initial regimen in HIV-infected patients with pulmonary tuberculosis.

Antituberculous treatments, including the rifamycins, are associated with hepatotoxicity. Patients with abnormal liver function tests and/or liver disease should only be given rifapentine after careful consideration of risks and benefits. If a decision is made to use the drug, liver function tests, especially serum transaminases, should be obtained prior to therapy and then every 2 to 4 weeks during therapy. Rifapentine should be discontinued if signs of hepatic injury occur or liver disease worsens.

Hyperbilirubinemia may occur as a result of the possible competition for excretory pathways between rifapentine and bilirubin. A moderate rise in bilirubin is not necessarily an indication for interrupting treatment but should be evaluated with the patient's overall clinical condition.

All patients treated with rifapentine should have baseline measurements of hepatic enzymes, bilirubin, a complete blood count and platelet count. Patients should be seen at least monthly during rifapentine therapy and should be specifically questioned concerning symptoms associated with adverse events. All patients with abnormalities should have follow-up, including laboratory testing, if required. Routine laboratory monitoring for toxicity in people with normal baseline measurements is generally not required. Therapeutic concentrations of rifampin have been reported to inhibit standard microbiological assays for serum folate and Vitamin B12. Similar drug-laboratory interactions should be considered for rifapentine; thereby, alternative assay methods should be considered.

Clostridium difficile associated diarrhea (CDAD) has been reported with almost all antibiotics and may potentially be life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea following rifamycin therapy. Mild cases generally improve with discontinuation of the drug, while severe cases may require supportive therapy and treatment with an antimicrobial agent effective against C difficile. Hypertoxin producing strains of C difficile cause increased morbidity and mortality; these infections can be resistant to antimicrobial treatment and may necessitate colectomy.

Rifapentine may cause a red-orange discoloration of body tissues and/or fluids, including skin, teeth, tongue, urine, feces, saliva, sputum, tears, sweat, and cerebrospinal fluid. Permanent discoloration of contact lens or dentures may occur.

Rifapentine therapy should not be used in patients with porphyria. Rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin use. Based on these isolated reports coincident with rifampin use, it may be assumed that rifapentine has a similar effect.

Clinical studies of rifapentine did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Safety and efficacy have not been established in pediatric patients less than 12 years of age.