Rifampin and Isoniazid (Systemic)



INN:

Rifampin—Rifampicin

VA CLASSIFICATION
Primary: AM500{03}

Commonly used brand name(s): Rifamate.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antibacterial (antimycobacterial)—

Indications

General considerations
Tuberculosis is a highly infectious life-threatening bacterial disease with 8 million new cases and 3 million deaths reported worldwide each year to the World Health Organization (WHO) {115}. The vast majority of these cases are in developing countries; however, tuberculosis also has emerged as an important public health problem in the U.S. in recent years after the decline in number of cases observed between 1950 and 1980 {115}.

The resurgence of tuberculosis in the U.S. has been complicated by an increase in the proportion of patients with strains resistant to antituberculosis medications. Outbreaks of multidrug-resistant tuberculosis have been documented in hospitals and prisons {100} {105} {107} {114}. Drug-resistant tuberculosis, particularly that caused by strains resistant to isoniazid and rifampin, is much harder to treat and often is fatal {100} {107}. Among acquired immunodeficiency syndrome (AIDS) patients infected with tuberculosis bacilli resistant to both rifampin and isoniazid, a case-fatality rate of 91% has been reported {109}. Recent investigations of outbreaks of multidrug-resistant tuberculosis have found an extraordinarily high case-fatality rate, with the median time to mortality being reached between 4 and 16 weeks {119}. In almost all instances, these outbreaks have involved patients with severe immunosuppression by infection with the human immunodeficiency virus (HIV) {119}.

Acquired drug resistance develops during treatment for drug-sensitive tuberculosis with regimens that are poorly conceived or poorly complied with, allowing the emergence of naturally occurring drug-resistant mutations {117}. Resistant organisms from affected patients may subsequently infect other people who have not been infected with M. tuberculosis previously, resulting in primary drug resistance {117}.

Resistance to antituberculosis agents can develop not only in the strain that caused the initial disease, but also as a result of reinfection with a new strain of M. tuberculosis that is drug-resistant {121}. Reinfection with a new multidrug-resistant M. tuberculosis strain can occur during therapy for the original infection or after completion of therapy {121}. Most recent data suggest that outcomes can be improved if patients promptly begin therapy with two or more drugs that have in vitro activity against the multidrug-resistant isolate {119}.

HIV infection is the strongest risk factor yet identified for the development of active tuberculosis disease in persons infected with tuberculosis {97} {98} {104} {108} {109} {114} {116} {117} {121} {123} {125}. In addition, persons with HIV infection are at an increased risk of tuberculosis resulting either from newly acquired disease or from reactivation of latent infections {117}. Tuberculosis is a major clinical manifestation of immunodeficiency induced by HIV {126}. In hospital-based retrospective studies, high rates of tuberculosis have been found among patients with AIDS {126}. In communities where tuberculosis and HIV infection are common, the prevalence of HIV seropositivity among patients with tuberculosis is greatly increasing {126}.

WHO has estimated that 5.6 million people worldwide and 80,000 people in the U.S. are infected with both HIV and tuberculosis {115}. Persons dually infected with M. tuberculosis and HIV have a high risk of developing clinically active tuberculosis {126}. One study of HIV-positive drug users with positive tuberculin skin test results found a rate of the development of active tuberculosis to be 8 cases per 100 person-years (8% yearly) as compared with the 10% lifetime risk (1 to 3% risk within the first year after skin test conversion) in the general population {117}.

Persons who are known to be HIV-infected and who are contacts of patients with infectious tuberculosis should be carefully evaluated for evidence of tuberculosis {84} {98}. If there are no findings suggestive of current tuberculosis, preventive therapy with isoniazid should be given {84}. Because HIV-infected contacts are not managed in the same way as those who are not HIV-infected, HIV testing is recommended if there are known or suspected risk factors for their acquiring HIV infection {84} {98}.

According to investigators at the National Institute of Allergy and Infectious Diseases (NIAID), levels of HIV in the bloodstream increase 5- to 160-fold in HIV-infected persons who develop active tuberculosis {110}. Clinical and epidemiologic observations have demonstrated that HIV-infected individuals have an estimated 113-times higher risk and AIDS patients have a 170-times higher risk as compared with uninfected persons {115}. Furthermore, the problem of drug resistance may worsen as the HIV epidemic spreads {100} {109}. Immunosuppressed patients with HIV infection who subsequently become infected with M. tuberculosis have an extraordinarily high risk of developing active tuberculosis within a short period of time {109}.

In addition to the convincing evidence that HIV infection increases the risk and worsens the course of tuberculosis, there is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of disease caused by HIV infection {129}. Understanding the interaction of these two pathogens is clinically important, given the high prevalence of patients coinfected with HIV and M. tuberculosis in both the U.S. and Africa; it is estimated that by the year 2000 about 500,000 deaths per year will occur in coinfected patients worldwide {129}.

Persons with a positive tuberculin skin test and HIV infection, and persons with a positive tuberculin skin test and at risk of acquiring HIV infection with unknown HIV status should be considered for tuberculosis preventive therapy regardless of age {84}. One study showed that isoniazid prophylaxis in HIV-infected, tuberculin-positive individuals not only decreased the incidence of tuberculosis disease, but also delayed the progression to AIDS and death {115}.

Twelve months of preventive therapy is recommended for adults and children with HIV infection and other conditions associated with immunosuppression {84}. Persons with HIV infection should receive at least 6 months of preventive therapy. The American Academy of Pediatrics recommends that children receive 9 months of therapy {84}.

Tuberculosis control programs should ensure that drug susceptibility tests are performed on all initial isolates of M. tuberculosis and the results are reported promptly to the primary care provider and the local health department {96}. Tuberculosis control programs should monitor local drug resistance rates to assess the effectiveness of local tuberculosis control efforts and to determine the appropriateness of the currently recommended initial tuberculosis treatment regimen for the area {96}.

Relapse of rifampin-resistant tuberculosis has been reported in HIV-infected patients {111} {112}. Reinfection with new strains of M. tuberculosis has also been reported in these patients {111}. Rifampin-resistant tuberculosis is a serious threat because responses to therapy are more difficult to achieve and require long courses of treatment {111} {112}. Therefore, careful follow-up of HIV-infected patients with treated tuberculosis is essential {111} {112}.

Multidrug-resistant tuberculosis also has been transmitted to persons without HIV infection in health care facilities {121}. Together with the lack of effective agents for second-line treatment and methods of prophylaxis, the transmission of multidrug-resistant strains of M. tuberculosis may create a substantial reservoir of latently infected people and the potential for clinical multidrug-resistant tuberculosis for many years to come {121}.

Several studies have documented a high prevalence of extrapulmonary disease in HIV-infected patients with clinical tuberculosis disease, particularly in conjunction with pulmonary manifestations {127}. Cutaneous miliary tuberculosis, also known as tuberculosis cutis miliaris disseminata , was in the past a rare condition in adults, with only 24 cases reported in nearly a century {127}. However, since the first reported case of cutaneous miliary tuberculosis in 1990 in a patient with AIDS, five additional cases have been reported in HIV-infected patients {127}. Its appearance can be quite nondescript; therefore, a high level of suspicion must be maintained, particularly for patients with CD4+ cell counts of < 200 per cubic millimeter, in order to diagnose the condition and initiate therapy appropriately {127}.

Accepted

Tuberculosis (treatment)—Rifampin and isoniazid combination is indicated in the treatment of pulmonary tuberculosis when the patient has been titrated on the individual components and the efficacy of the combination has been established {11}.

Unaccepted
Rifampin and isoniazid combination is not indicated for initial treatment or prophylaxis of pulmonary tuberculosis, for meningococcal infections, or in the treatment of asymptomatic meningococcal carriers to eliminate Neisseria meningitidis from the nasopharynx {11}.


Pharmacology/Pharmacokinetics

Note: Preliminary data suggest that patients coinfected with human immunodeficiency virus (HIV) and mycobacteria (Mycobacterium tuberculosis or M. avium ) have altered pharmacokinetic profiles for antimycobacterial agents {103}. In particular, malabsorption of these agents appears to occur frequently, and could seriously affect the efficacy of treatment {103} {118}.


Physicochemical characteristics:
Molecular weight—
    Rifampin: 822.96 {19}
    Isoniazid: 137.14 {19}

Mechanism of action/Effect:

Rifampin, a semisynthetic broad-spectrum bactericidal antibiotic {21}, inhibits bacterial RNA synthesis by binding strongly to the beta subunit of DNA-dependent RNA polymerase, preventing attachment of the enzyme to DNA, and thus blocking initiation of RNA transcription {20}.

Isoniazid (INH) is a synthetic bactericidal antitubercular agent {21} that is active against many mycobacteria, primarily those that are actively dividing {20}. The exact mechanism of INH's action is not known, but it may relate to inhibition of mycolic acid synthesis and disruption of the cell wall in susceptible organisms {22}.

Absorption:

Rifampin is well absorbed from the gastrointestinal tract {20} {84}.

Isoniazid is readily absorbed following oral administration {20} {84}; however, it may undergo significant first pass metabolism {23}. Absorption and bioavailability of isoniazid are reduced when it is administered with food {23}.

Distribution:

Rifampin diffuses well to most body tissues and fluids, including the cerebrospinal fluid (CSF), where concentrations are increased if the meninges are inflamed; concentrations in the liver, gallbladder, bile, and urine are higher than those found in the blood; therapeutic concentrations are achieved in the saliva, reaching 20% of serum concentrations. Rifampin crosses the placenta, and fetal serum concentrations seen at birth are approximately 33% of the maternal serum concentration {24}; it penetrates into aqueous humor and is distributed into breast milk. Being lipid-soluble, rifampin may reach and kill susceptible intracellular, as well as extracellular, bacteria including Mycobacteria species {20}.

Vol D—1.6 L per kg.

Isoniazid is widely distributed to all fluids and tissues, including CSF, pleural, and ascitic fluids, skin, sputum, saliva, lungs, and muscle. It crosses the placenta and is distributed into breast milk {22} {23}.

Vol D—0.57 to 0.76 L per kg {25} {26}.

Protein binding:

Rifampin—High to very high (89%) {24}.

Isoniazid—Very low (0 to 10%) {23} {27} {28}.

Biotransformation:

Rifampin—Hepatic; rapidly deacetylated by auto-induced microsomal oxidative enzymes to the active metabolite (25– O-desacetylrifampin). Other identified metabolites include rifampin quinone, desacetylrifampin quinone, and 3-formylrifampin {20} {24}.

Isoniazid—Hepatic; isoniazid is acetylated by N-acetyltransferase to N-acetylisoniazid; it is then biotransformed to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine is associated with hepatotoxicity via formation of a reactive intermediate metabolite when N-hydroxylated by the cytochrome P450 mixed oxidase system {23}. The rate of acetylation is genetically determined. Approximately 50% of blacks and Caucasians are slow acetylators and the rest are rapid acetylators; the majority of Eskimos and Asians are rapid acetylators. The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of isoniazid, and thus, an increase in toxic reactions {20}. Slow acetylators are characterized by a relative lack of hepatic N-acetyltransferase.

Half-life:


Rifampin:

Absorption half-life: Approximately 0.6 hour {24}.

Elimination half-life: Initially, 3 to 5 hours; with repeated administration, half-life decreases to 2 to 3 hours {24}.



Isoniazid:


Adults (including elderly patients) {27}

Fast acetylators—0.5 to 1.6 hours.

Slow acetylators—2 to 5 hours.



Children (age 11/2 to 15 years)—

2.3 to 4.9 hours {23}.



Neonates—

7.8 and 19.8 hours in two newborns who received isoniazid transplacentally. The long half-life may be due to the limited acetylation capacity of neonates {29}.



Time to peak concentration:

Rifampin—1.5 to 4 hours after oral administration; peak concentration may be decreased and delayed following administration with food {89}.

Isoniazid—1 to 2 hours {23} {84}.

Peak serum concentration:


Rifampin {24}:


Adults—

7 to 9 mcg per mL after a single 600-mg oral dose.



Children (6 to 58 months old)—

Approximately 11 mcg per mL after a dose of 10 mg per kg of body weight (mg/kg).




Isoniazid:

3 to 7 mcg per mL (21.9 to 51 micromoles per L) after a single 300-mg dose {23} {84}.


Elimination:


Rifampin—
        Biliary/fecal; enterohepatic recirculation of rifampin, but not of its deacetylated active metabolite {90}; 60 to 65% of dose appears in feces {89}.
        Renal; 6 to 15% excreted as unchanged drug, and 15% excreted as active metabolite in urine; 7% excreted as inactive 3-formyl derivative {89}.
        Rifampin does not accumulate in patients with impaired renal function {90}; its rate of excretion is increased during the first 6 to 10 days of therapy, probably because of auto-induction of hepatic microsomal oxidative enzymes; after high doses, excretion may be slower because of saturation of its biliary excretory mechanism {89}.
        In dialysis—Rifampin is not removed from the blood by either hemodialysis or peritoneal dialysis.



Isoniazid {20}
        Renal; approximately 75 to 95% excreted by kidneys within 24 hours, primarily as the inactive metabolites, N-acetylisoniazid and isonicotinic acid; of this amount, 93% of the isoniazid excreted in the urine may occur as the acetylated form in fast acetylators and 63% in slow acetylators, with the remainder, in both cases, occurring as the free or conjugated form.
        Biliary/fecal; small amounts are excreted in feces.
        In dialysis—Significant amounts of isoniazid are removed from the blood by hemodialysis. A single 5-hour hemodialysis period removes up to 73% of the isoniazid in the blood.
        Peritoneal dialysis is of limited benefit.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to ethionamide, niacin (nicotinic acid), rifamycins (e.g., rifabutin) or other medications chemically related to rifampin, isoniazid, or pyrazinamide may be hypersensitive to this medication also.

Carcinogenicity/Tumorigenicity

Rifampin—Studies in a strain of female mice known to be particularly susceptible to the spontaneous development of hepatomas have shown that rifampin, given in doses of 2 to 10 times the maximum human dose for 1 year, causes a significant increase in the development of hepatomas. However, studies in male mice of the same strain, in other strains of male and female mice, and in rats have not shown that rifampin is tumorigenic {20}.

Isoniazid—Isoniazid has been shown to cause pulmonary tumors in a number of strains of mice {20}. However, isoniazid has not been shown to be carcinogenic or tumorigenic in humans.

Pregnancy/Reproduction

Note: Tuberculosis in pregnancy should be managed in concert with an expert in the management of tuberculosis {128}. Women who have only pulmonary tuberculosis are not likely to infect the fetus until after delivery, and congenital tuberculosis is extremely rare {128}. In utero infections with tubercle bacilli, however, can occur after maternal bacillemia occurs at different stages in the course of tuberculosis {128}. Miliary tuberculosis can seed the placenta and thereby gain access to the fetal circulation {128}. In women with tuberculous endometritis, transmission of infection to the fetus can result from fetal aspiration of bacilli at the time of delivery {128}. A third mode of transmission is through ingestion of infected amniotic fluid in utero {128}.
If active disease is diagnosed during pregnancy, a 9-month regimen of isoniazid and rifampin, supplemented by an initial course of ethambutol if drug resistance is suspected, is recommended {128}. Pyrazinamide usually is not given because of inadequate data regarding teratogenesis {128}. Hence, a 9-month course of therapy is necessary for drug-susceptible disease {128}. When isoniazid resistance is a possibility, isoniazid, ethambutol, and rifampin are recommended initially {128}. One of these medications can be discontinued after 1 or 2 months, depending on results of susceptibility tests {128}. If rifampin or isoniazid is discontinued, treatment is continued for a total of 18 months; if ethambutol is discontinued, treatment is continued for a total of 9 months {128}. Prompt initiation of chemotherapy is mandatory to protect both the mother and fetus {128}. If isoniazid or rifampin resistance is documented, an expert in the management of tuberculosis should be consulted {128}.
Asymptomatic pregnant women with positive tuberculin skin tests and normal chest radiographs should receive preventive therapy with isoniazid for 9 months if they are HIV seropositive or have recently been in contact with an infectious person {128}. For these individuals, preventive therapy should begin after the first trimester {128}. In other circumstances in which none of these risk factors is present, although no harmful effects of isoniazid to the fetus have been observed, preventive therapy can be delayed until after delivery {128}.
For all pregnant women receiving isoniazid, pyridoxine should be prescribed {128}. Isoniazid, ethambutol, and rifampin appear to be relatively safe for the fetus {128}. The benefit of ethambutol and rifampin for therapy of active disease in the mother outweighs the risk to the infant {128}. Streptomycin and pyrazinamide should not be used unless they are essential to the control of the disease {128}.


Pregnancy—
Rifampin: Rifampin crosses the placenta {21}. It has rarely caused postnatal hemorrhages in the mother and infant when administered during the last few weeks of pregnancy; vitamin K may be indicated. Neonates should be carefully observed for evidence of adverse effects.

Imperfect osteogenesis and embryotoxicity were reported in rabbits given up to 20 times the usual daily human dose. Studies in rodents have shown that rifampin given in doses of 150 to 250 mg per kg of body weight (mg/kg) daily causes congenital malformations, primarily cleft palate and spina bifida {20}.

FDA Pregnancy Category C {20}.

Isoniazid—Isoniazid crosses the placenta {21}, resulting in fetal serum concentrations that may exceed maternal serum concentrations. Problems in humans have not been documented {16}.

Studies in rats and rabbits have shown that isoniazid may be embryocidal. However, isoniazid has not been shown to be teratogenic in mice, rats, or rabbits {20}.

FDA Pregnancy Category C {20}.

Breast-feeding

Rifampin—Rifampin is distributed into breast milk. Problems in humans have not been documented {21}.

Isoniazid—Isoniazid is distributed into breast milk {21}. An estimated 0.75 to 2.3% of the daily adult dose could be ingested by the infant. Problems in nursing newborns have not been documented and breast-feeding should not be discouraged. However, because isoniazid concentrations are so low in breast milk, breast-feeding cannot be relied upon for adequate tuberculosis prophylaxis or therapy for nursing infants {16}.

Pediatrics

Note: If an infant is suspected of having congenital tuberculosis, a Mantoux tuberculin skin test, chest radiograph, lumbar puncture, and appropriate cultures should be performed promptly {128}. Regardless of the skin test results, treatment of the infant should be initiated promptly with isoniazid, rifampin, pyrazinamide, and streptomycin or kanamycin {128}. In addition, the mother should be evaluated for the presence of pulmonary or extrapulmonary (including uterine) tuberculosis {128}. If the physical examination or chest radiograph support the diagnosis of tuberculosis, the patient should be treated with the same regimen as that used for tuberculous meningitis {128}. The drug susceptibilities of the organism recovered from the mother and/or infant should be determined {128}.
Possible isoniazid resistance should always be considered, particularly in children from population groups in which drug resistance is high, especially in foreign-born children from countries with a high prevalence of drug-resistant tuberculosis {128}. For contacts who are likely to have been infected by an index case with isoniazid-resistant but rifampin-susceptible organisms, and in whom the consequences of the infection are likely to be severe (e.g., children up to 4 years of age), rifampin (10 mg per kg of body weight, maximum 600 mg, given daily in a single dose) should be given in addition to isoniazid (10 mg per kg, maximum 300 mg, given daily in a single dose) until susceptibility test results for the isolate from the index case are available {128}. If the index case is known or proven to be excreting organisms resistant to isoniazid, then isoniazid should be discontinued and rifampin given for a total of 9 months {128}. Isoniazid alone should be given if no proof of exposure to isoniazid-resistant organisms is found {128}. Optimal therapy for children with tuberculosis infection caused by organisms resistant to isoniazid and rifampin is unknown {128}. In deciding on therapy in this situation, consultation with an expert is advised {128}.
Adjuvant treatment with corticosteroids in treating tuberculosis is controversial {128}. Corticosteroids have been used for therapy in children with tuberculous meningitis to reduce vasculitis, inflammation, and, as a result, intracranial pressure {128}. Data indicate that dexamethasone may lower mortality rates and lessen long-term neurologic impairment {128}. The administration of corticosteroids should be considered in all children with tuberculous meningitis, and also may be considered in children with pleural and pericardial effusions (to hasten reabsorption of fluid), severe miliary disease (to mitigate alveolocapillary block), and endobronchial disease (to relieve obstruction and atelectasis) {128}. Corticosteroids should be given only when accompanied by appropriate antituberculosis therapy {128}. Consultation with an expert in the treatment of tuberculosis should be obtained when corticosteroid therapy is considered {128}.


Rifampin and Isoniazid—This fixed-dose combination is not recommended for use in children.

Rifampin—Appropriate studies performed to date have not documented pediatrics-specific problems that would limit the usefulness of rifampin in children {90}.

Isoniazid—Studies performed in children have not demonstrated pediatrics-specific problems that would limit the usefulness of isoniazid in children. However, newborn infants may have limited acetylation capacity, prolonging the elimination half-life of isoniazid {31}. Children do not require routine hepatic function determinations unless they have pre-existing hepatic disease {30} {32}. Pyridoxine supplementation usually is not required in children if dietary intake is adequate {30}.


Geriatrics


Rifampin—Appropriate studies on the relationship of age to the effects of rifampin have not been performed in the geriatric population. However, no geriatrics-specific problems due to rifampin have been documented to date.

Isoniazid—Patients over 50 years of age are more likely to develop hepatitis while receiving isoniazid than are patients in younger age groups {20}.


Pharmacogenetics

Isoniazid—Patients can be divided into two groups: slow and rapid acetylators of isoniazid. Approximately 50% of blacks and Caucasians are slow acetylators; the majority of Eskimos and Asians are rapid acetylators. The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of isoniazid, and thus, an increase in toxic reactions {20}. Slow acetylators are characterized by a relative lack of hepatic N-acetyltransferase. Patients who are slow acetylators may be prone to develop adverse effects, especially peripheral neuritis, and may require lower-than-usual doses. Rapid acetylators do not generally require higher doses, nor is isoniazid less effective in these patients {20}.


Dental

Rifampin—The leukopenic and thrombocytopenic effects of rifampin may result in an increased incidence of certain microbial infections, delaying healing, and gingivial bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in the use of regular toothbrushes, dental floss, and toothpicks. Rifampin may cause a hypersensitivity reaction of sore mouth or tongue {90}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetaminophen{33}{34}{35}    (concurrent daily use of acetaminophen with isoniazid may increase the potential for hepatotoxicity, and possibly, nephrotoxicity; isoniazid is thought to induce {34} cytochrome P450, resulting in a greater proportion of acetaminophen being converted to toxic metabolite)


» Alcohol    (concurrent daily use of alcohol may result in increased incidence of isoniazid- and rifampin-induced hepatotoxicity and increased metabolism of isoniazid and rifampin; dosage adjustments of isoniazid and rifampin may be necessary; patients should be monitored closely for signs of hepatotoxicity and should be advised to restrict intake of alcoholic beverages {20} {84})


» Alfentanil    (chronic preoperative or perioperative use of isoniazid, a hepatic enzyme inhibitor, may decrease the plasma clearance and prolong the duration of action of alfentanil)


» Aminophylline or
» Oxtriphylline or
» Theophylline    (rifampin may increase metabolism of aminophylline, oxtriphylline, and theophylline by induction of hepatic microsomal enzymes, resulting in increased theophylline clearance {36} {37} {38} {84}; concurrent use with isoniazid may reduce the metabolism of theophylline, increasing plasma concentrations of theophylline {39})


Anesthetics, hydrocarbon inhalation, except isoflurane    (chronic use of hepatic enzyme-inducing agents [except isoflurane], such as rifampin, prior to anesthesia, may increase anesthetic metabolism, leading to increased risk of hepatotoxicity)


Antacids, especially aluminum containing    (antacids may delay and decrease absorption and serum concentrations of orally administered isoniazid; concurrent use should be avoided, or patients should be advised to take oral isoniazid at least 1 hour before taking aluminum-containing antacids {40})


» Anticoagulants, coumarin- or indandione-derivative{20}{41}{42}    (concurrent use with rifampin may enhance the metabolism of these anticoagulants by induction of hepatic microsomal enzymes, resulting in considerable decrease in the activity and effectiveness of the anticoagulants; prothrombin time determinations may be required before and after rifampin therapy; concurrent use with isoniazid may result in increased anticoagulant effect because of the inhibition of enzyme metabolism of anticoagulants)


» Antidiabetic agents, oral{20}{41}{43}    (concurrent use with rifampin may enhance the metabolism of chlorpropamide, glyburide, and tolbutamide by induction of hepatic microsomal enzymes, resulting in lower serum sulfonylurea concentrations; although not documented, other oral antidiabetic agents may also interact with rifampin; dosage adjustment may be required)


» Azole antifungals{44}{45}{46}{47}{48}    (concurrent use may increase the metabolism of azole antifungals, lowering their plasma concentrations; depending on the clinical situations, the dose of an azole antifungal may need to be increased during concurrent use with rifampin)


Barbiturates{41}    (concurrent use with rifampin may enhance the metabolism of hexobarbital by induction of hepatic microsomal enzymes, resulting in lower serum concentrations; there are conflicing data on rifampin's effect on phenobarbital; dosage adjustment may be required)


Benzodiazepines    (isoniazid may decrease the hepatic metabolism of benzodiazepines, such as chlordiazepoxide, diazepam, flurazepam, and prazepam, that are metabolized by phase I reactions [ N-dimethylation and hydroxylation]; it may also impair the oxidation of triazolam, increasing plasma benzodiazepine concentrations; isoniazid may decrease first-pass metabolism and elimination of midazolam in the liver, probably by competitive inhibition at the cytochrome P450 binding sites, increasing steady-state plasma concentrations of midazolam {40} {49}; concurrent use with rifampin may enhance the elimination of diazepam, resulting in decreased plasma concentrations; whether this effect applies to other benzodiazepines has not been determined; dosage adjustment may be necessary {50})


Beta-adrenergic blocking agents, systemic    (concurrent use of metoprolol or propranolol with rifampin has resulted in reduced plasma concentrations of these two beta-adrenergic blocking agents due to enhanced metabolism of hepatic microsomal enzymes by rifampin; although not documented, other beta-adrenergic blocking agents may also interact with rifampin)


Bone marrow depressants (see Appendix II )    (concurrent use of bone marrow depressants with rifampin may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered)


» Carbamazepine    (concurrent use with isoniazid increases serum carbamazepine levels and toxicity, probably through inhibition of carbamazepine metabolism {51} {52}; also, carbamazepine may induce microsomal metabolism of isoniazid, increasing formation of an INH-reactive intermediate metabolite, which may lead to hepatotoxicity {49})


Cheese, such as Swiss or Cheshire or
Fish, such as tuna, skipjack, or Sardinella    (concurrent ingestion with isoniazid may result in redness or itching of the skin, hot feeling, rapid or pounding heartbeat, sweating, chills or clammy feeling, headache, or lightheadedness; this is thought to be caused by isoniazid's interference with the metabolism of histamine and tyramine, found in fish and cheese, due to its inhibition of plasma monoamine and diamine oxidase {14} {15})


» Chloramphenicol{53}{54}    (concurrent use with rifampin may enhance the metabolism of chloramphenicol by induction of hepatic microsomal enzymes, resulting in significantly lower serum chloramphenicol concentrations; dosage adjustment may be necessary)


Clofazimine{24}    (concurrent use with rifampin has resulted in reduced absorption of rifampin, delaying rifampin's time to peak concentration, and increasing its half-life)


Clofibrate{55}    (concurrent use with rifampin may enhance the metabolism of clofibrate by induction of hepatic microsomal enzymes, resulting in significantly lower serum clofibrate concentrations)


» Contraceptives, estrogen-containing, oral{20}    (concurrent use with rifampin may decrease the effectiveness of estrogen-containing oral contraceptives because of stimulation of estrogen metabolism or reduction in enterohepatic circulation of estrogens, resulting in menstrual irregularities, intermenstrual bleeding, and unplanned pregnancies; patients should be advised to use an additional method of contraception throughout the whole cycle while taking rifampin and estrogen-containing oral contraceptives concurrently)


» Corticosteroids, glucocorticoid and mineralocorticoid    (concurrent use with rifampin may enhance the metabolism of corticosteroids by induction of hepatic microsomal enzymes, resulting in a considerable decrease in corticosteroid plasma concentrations; dosage adjustment may be required; rifampin has also counteracted endogenous cortisol and produced acute adrenal insufficiency in patients with Addison's disease {24} {41} {56} {84}; concurrent use of prednisolone and other related corticosteroids with isoniazid may increase hepatic metabolism and/or excretion of isoniazid, leading to decreased plasma concentrations and effectiveness of isoniazid, especially in patients who are rapid acetylators; isoniazid dosage adjustments may be required {40})


Cycloserine    (concurrent use may result in increased incidence of central nervous system [CNS] effects such as dizziness or drowsiness; dosage adjustments may be necessary and patients should be monitored closely for signs of CNS toxicity {40})


Cyclosporine{36}{57}{58}{84}    (rifampin may enhance metabolism of cyclosporine by induction of hepatic microsomal enzymes and intestinal cytochrome P450 enzymes; dosage adjustment may be required)


Dapsone{20}{24}    (concurrent use with rifampin may decrease the effect of dapsone because of increased metabolism resulting from stimulation of hepatic microsomal enzyme activity; dapsone concentrations may be decreased by half; dapsone dosage adjustments are not required during concurrent therapy with rifampin for leprosy)


» Digitalis glycosides{20}{36}{59}{60}    (concurrent use with rifampin may enhance the metabolism of digoxin or digitoxin by induction of hepatic microsomal enzymes, resulting in significantly lower serum digoxin or digitoxin levels; dosage adjustments may be necessary)


» Disopyramide or{20}{61}
» Mexiletine or{62}{84}
Propafenone or{63}
» Quinidine or{20}{41}{65}{66}{84}
» Tocainide{64}    (concurrent use with rifampin may enhance the metabolism of these antiarrhythmics by induction of hepatic microsomal enzymes, resulting in significantly lower serum antiarrhythmic concentrations; serum antiarrhythmic concentrations should be monitored and dosage adjustment may be necessary)


» Disulfiram    (concurrent use in alcoholics may result in increased incidence of CNS effects such as dizziness, incoordination, irritability, or insomnia; reduced dosage or discontinuation of disulfiram may be necessary {40})


Enflurane    (isoniazid may increase formation of the potentially nephrotoxic inorganic fluoride metabolite when used concurrently with enflurane {40})


» Estramustine or
» Estrogens{67}{84}    (concurrent use of estramustine or estrogens with rifampin may result in significantly reduced estrogenic effect because of stimulation of estrogen metabolism or reduction in enterohepatic circulation of estrogens)


» Hepatotoxic medications, other (see Appendix II )    (concurrent use of rifampin and isoniazid and other hepatotoxic medications may increase the potential for hepatotoxicity and should be avoided)


» Human immunodeficiency virus (HIV) protease inhibitors    (rifampin accelerates the metabolism of protease inhibitors, such as indinavir, nelfinavir, ritonavir, and saquinavir through induction of hepatic P450 cytochrome oxidases, resulting in subtherapeutic levels of the protease inhibitors; in addition, protease inhibitors retard the metabolism of rifampin, resulting in increased serum levels of rifampin and the likelihood of increased toxicity {99} {106}; concurrent use of HIV protease inhibitors with rifampin is not recommended {92} {93} {94} {95})


» Ketoconazole    (concurrent use of ketoconazole with isoniazid has been reported to decrease serum concentrations of ketoconazole; isoniazid should be used with caution when given concurrently with ketoconazole {44} {84})


» Methadone{41}{84}    (concurrent use with rifampin may decrease the effects of methadone because of stimulation of hepatic microsomal enzyme activity and/or impaired absorption, resulting in symptoms of methadone withdrawal if the patient is dependent on methadone; dosage adjustments may be necessary before and after rifampin therapy)


Neurotoxic medications, other (see Appendix II )    (concurrent use of other neurotoxic medications with isoniazid may produce additive neurotoxicity)


» Phenytoin    (concurrent use with isoniazid inhibits the metabolism of phenytoin, resulting in increased phenytoin serum concentrations and toxicity; phenytoin dosage adjustments may be necessary during and after isoniazid, especially in slow acetylators of isoniazid {68} {84}; concurrent use with rifampin may stimulate the hepatic metabolism of phenytoin, increasing its elimination and thus counteracting its anticonvulsant effects; careful monitoring of serum hydantoin concentrations and dosage adjustments may be necessary before and after rifampin therapy {69} {70})


Probenecid    (probenecid may compete with rifampin for hepatic uptake when used concurrently, resulting in increased and prolonged rifampin serum concentrations and/or toxicity; however, the effect of rifampin serum concentrations is inconsistent, and concurrent use of probenecid to increase rifampin serum concentrations is not recommended)


Pyridoxine    (isoniazid may cause peripheral neuritis by acting as a pyridoxine antagonist or increased renal excretion of pyridoxine; requirements for pyridoxine may be increased in patients receiving isoniazid concurrently {20} {84})


Trimethoprim{71}    (concurrent use with rifampin may significantly increase the elimination and shorten the elimination half-life of trimethoprim)


» Verapamil, oral{36}{84}    (rifampin has been found to accelerate the metabolism of oral verapamil, resulting in a significant decrease in serum verapamil concentration and reversing its cardiovascular effects; concurrent use of rifampin with intravenous verapamil was found to have only minor effects on verapamil's clearance, and no significant effect on cardiovascular function)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Coombs' (antiglobulin) test, direct{72}    (may become positive rarely during therapy)


Dexamethasone suppression test{73}    (rifampin may prevent the inhibitory action of a standard dexamethasone dose administered for the overnight suppression test, rendering the test abnormal; it is recommended that rifampin therapy be discontinued 15 days before the dexamethasone suppression test is administered)


Folate determinations, serum and
Vitamin B 12 determinations, serum{20}{74}    (therapeutic concentrations of rifampin may interfere with standard microbiological assays for serum folate and vitamin B 12; alternative methods must be considered when determining serum folate and vitamin B 12 concentrations in patients taking rifampin)


Glucose, urine{75}    (isoniazid may cause hyperglycemia with a secondary glycosuria, giving a positive response to copper sulfate tests; glucose enzymatic tests are not affected)


Sulfobromophthalein (BSP) uptake and excretion{20}    (hepatic uptake and excretion of BSP in liver function test may be delayed by rifampin , resulting in BSP retention; the BSP test should be performed prior to the daily dose of rifampin, to avoid false-positive test results)


Urinalyses based on spectrometry or color reaction{72}    (rifampin may interfere with urinalyses that are based on spectrometry or color reaction due to rifampin's reddish-orange to reddish-brown discoloration of urine)

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]){20} and
Alkaline phosphatase{20} and
Aspartate aminotransferase (AST [SGOT]){20}    (values may be increased {20})


Bilirubin, serum and{20}{76}
Blood urea nitrogen (BUN) and{20}
Uric acid, serum    (concentrations may be increased {20})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active or in remission{20}    (increased risk of hepatitis with daily consumption of alcohol)


» Hepatic function impairment, severe{20}{77}    (rifampin and isoniazid are metabolized in the liver and may also be hepatotoxic)


» Hypersensitivity to isoniazid, ethionamide, pyrazinamide, niacin (nicotinic acid), or other chemically related medications
Hypersensitivity to rifampin or rifabutin
Renal failure, severe{20}    (there may be an increased risk of isoniazid toxicity in patients who have severe renal failure [creatinine clearance < 10 mL/min or 0.17 mL/sec])


Seizure disorders{20}    (isoniazid may be neurotoxic and cause seizures)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Hepatic function determination{20}{22}{78}    (ALT [SGPT], AST [SGOT], alkaline phosphatase, and serum bilirubin determinations may be indicated prior to and monthly or more frequently during treatment; however, elevated serum enzyme values may not be predictive of clinical hepatitis and may return to normal despite continued treatment; patients with impaired hepatic function should not receive rifampin and isoniazid combination unless it is crucial to therapy)


» Ophthalmologic examinations{20}    (symptoms of optic neuritis may occur in either adults or children during treatment due to isoniazid; ophthalmologic examinations may be required immediately and periodically thereafter; ophthalmologic examinations are not recommended in asymptomatic patients)




Side/Adverse Effects

Note: Isoniazid has been reported to cause severe, and sometimes fatal, hepatitis {20} {79} {86}, which is more prevalent in patients over 50 years of age. If signs and symptoms of hepatotoxicity occur, rifampin and isoniazid combination should be discontinued promptly {20}. The incidence of clinical hepatitis in young healthy adults is 0.3%, but can increase to 2.6% for patients who drink alcohol daily, have chronic liver disease, or are elderly {76}.
Pyridoxine deficiency is sometimes observed in adults receiving high doses of isoniazid and is probably due to its competition with pyridoxal phosphate for the enzyme apotryptophanase {20}.
Peripheral neuritis due to isoniazid can usually be prevented by administration of pyridoxine (10 to 25 mg per day). Pyridoxine is recommended for patients at risk of neuritis, including patients over 65 years of age, pregnant women, patients with diabetes mellitus, chronic renal failure, alcoholism, or malnutrition, and patients taking anticonvulsant medications {76}.
Intermittent use of rifampin may increase the chance of a patient developing the “flu-like” syndrome, as well as acute hemolysis or renal failure. These reactions are thought to be immunologically mediated and intermittent use should be limited to those conditions, such as leprosy, in which its safety and efficacy have been established {80} {81}.


Those indicating need for medical attention
Incidence more frequent
    
Hepatitis {20}{91}(dark urine; yellow eyes or skin)
    
hepatitis prodromal symptoms {20}(loss of appetite; nausea and vomiting; unusual tiredness or weakness)
    
peripheral neuritis {20}{82}(clumsiness or unsteadiness; numbness, tingling, burning, or pain in hands and feet)

Incidence less frequent
    
“Flu-like” syndrome {20}{84}(chills; difficulty in breathing; dizziness; fever; headache; muscle and bone pain; shivering)
    
hypersensitivity {07}{20}{83}(itching; redness; skin rash)

Incidence rare
    
Blood dyscrasias {22}{27}(sore throat; unusual bleeding or bruising)
    
interstitial nephritis {20}(bloody or cloudy urine; greatly decreased frequency of urination or amount of urine)
    
neurotoxicity {20}(seizures, mental depression, mood or other mental changes)
    
optic neuritis {20}(blurred vision or loss of vision, with or without eye pain)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Gastrointestinal disturbances {20}{22}(diarrhea; nausea and vomiting; stomach pain)

Incidence less frequent
    
Fungal overgrowth {20}(sore mouth or tongue)



Those not indicating need for medical attention
Incidence more frequent
    
Reddish-orange to reddish-brown discoloration of urine, feces, saliva, sputum, sweat, and tears {20}

Note: Tears discolored by rifampin may also discolor soft contact lenses.{20}






Overdose
For specific information on the agents used in the management of rifampin and isoniazid overdose, see:

   • Diazepam in Benzodiazepines (Systemic) monograph;
   • Pyridoxine (Systemic) monograph; and/or
   • Thiopental in Barbiturates (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

The information below applies to the clinical effects and treatment of rifampin and/or isoniazid overdose only.

Clinical effects of rifampin and/or isoniazid overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic effects
    
Gastrointestinal disturbances (severe nausea and vomiting)
    
metabolic acidosis; neurotoxicity (dizziness; slurred speech; lethargy; disorientation; hyperreflexia; seizures; coma)
    
periorbital or facial edema (swelling around the eyes or the whole face)
    
pruritus, generalized (itching over the whole body)
    
Redman syndrome (red-orange discoloration of skin, mucous membranes, and sclera)

Note: Patients may be asymptomatic for 30 minutes to 2 hours after an acute overdose. Early symptoms include nausea and vomiting, dizziness, slurred speech, lethargy, disorientation, and hyperreflexia. Seizures usually occur within 1 to 3 hours after ingestion, and are often repetitive and refractory to treatment with usual anticonvulsants. Lactic acid accumulation produces an anion-gap metabolic acidosis within a few hours, which is often severe and refractory to treatment with sodium bicarbonate. Hyperglycemia, glycosuria, and ketonuria have also been reported.




Treatment of overdose {01} {02} {05} {09} {10}


To decrease absorption:
Because seizures may occur soon after ingestion, induction of emesis with ipecac is not recommended. Gastric lavage may be performed within 2 to 3 hours of ingestion, and activated charcoal and a cathartic may be administered if the patient's seizures are controlled and the airway protected.



Specific treatment:
Administering intravenous pyridoxine in a gram-for-gram dose equivalent to the amount of isoniazid ingested; dose should be administered as a 5 or 10% solution in water for injection over 30 to 60 minutes. If the amount of isoniazid ingested is unknown, administering 5-gram doses of pyridoxine every 5 to 30 minutes until seizures stop or consciousness is regained.

Controlling seizures with diazepam, which acts synergistically with pyridoxine. Phenytoin should be used with caution, if at all, since isoniazid inhibits phenytoin metabolism. Thiopental has been effective in treating refractory seizures.

Carefully administering sodium bicarbonate if pyridoxine and diazepam do not control seizure activity. Use caution against overcorrection and watch for hypokalemia or hyperkalemia.



Supportive care:
Supportive measures such as establishing intravenous lines, hydration, correction of electrolyte imbalance, oxygenation, and support of ventilatory function are essential for maintaining the vital functions of the patient. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Rifampin and Isoniazid (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to rifampin, isoniazid, ethionamide, pyrazinamide, niacin (nicotinic acid), or other chemically related medications

Pregnancy—Isoniazid and rifampin cross the placenta. It is recommended that isoniazid and rifampin be used to treat pregnant women with tuberculosis; however, rifampin has rarely caused postnatal hemorrhage in the mother and infant when administered during the last few weeks of pregnancy





Breast-feeding—Isoniazid and rifampin are distributed into breast milk





Use in children—Use of the fixed-dose combination is not recommended in pediatric patients






Use in the elderly—Patients over the age of 50 have the highest incidence of hepatitis





Dental—Patients who develop blood dyscrasias may be at increased risk of microbial infections, delayed healing, and gingival bleeding
Other medicines, especially daily alcohol use, alfentanil, aminophylline, coumarin- or indandione-derivative anticoagulants, oral antidiabetic agents, azole antifungals, carbamazepine, chloramphenicol, corticosteroids, digitalis glycosides, disopyramide, disulfiram, estramustine, estrogens, ketoconazole, other hepatotoxic medications, methadone, mexiletine, oral estrogen-containing contraceptives, oxtriphylline, phenytoin, quinidine, theophylline, tocainide, or verapamil
Other medical problems, especially alcoholism, active or in remission, or hepatic function impairment

Proper use of this medication
Taking this medication with food or antacids, but not within 1 hour of aluminum-containing antacids, if gastrointestinal irritation occurs {13}

» Compliance with full course of therapy, which may take months or years

» Taking pyridoxine concurrently to prevent or minimize symptoms of peripheral neuritis {11}

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses; intermittent dosing may result in more frequent and/or severe side effects

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress, as well as ophthalmologic examinations if signs of optic neuritis occur {11}

Checking with physician if no improvement within 2 to 3 weeks

» Using an alternate method of contraception if taking estrogen-containing oral contraceptives concurrently {11}

» Avoiding alcoholic beverages concurrently with this medication

Checking with physician if vascular reactions occur following concurrent ingestion of cheese or fish with isoniazid-containing medications {13} {14} {15}

» Medication causes urine, feces, saliva, sputum, sweat, and tears to turn reddish-orange to reddish-brown and may also permanently discolor soft contact lenses; avoiding the wearing of soft contact lenses {11}

» Need to report to physician promptly prodromal signs of hepatitis or peripheral neuritis {11}

Caution in use of regular toothbrushes, dental floss, and toothpicks; deferring dental work until blood counts have returned to normal; checking with physician or dentist concerning proper oral hygiene

Possible interference with diagnostic tests {11}


Side/adverse effects
Signs of potential side effects, especially blood dyscrasias, hepatitis, hepatitis prodromal symptoms, hypersensitivity, neurotoxicity, optic neuritis, peripheral neuritis, ``flu-like'' syndrome, and interstitial nephritis {11}

Hepatitis may be more likely to occur in patients over 50 years of age {11}

Reddish-orange to reddish-brown discoloration of urine, stools, saliva, sputum, sweat, and tears may be alarming to patient, although medically insignificant; however, tears discolored by rifampin may also discolor soft contact lenses {11}


General Dosing Information
Rifampin and isoniazid combination may be taken with food if gastrointestinal irritation occurs. Antacids also may be taken. However, rifampin and isoniazid combination should be taken at least 1 hour before aluminum-containing antacids {13}.

The duration of treatment with an antituberculosis regimen is at least 6 months and may be continued for to 2 years {84}. Uncomplicated pulmonary tuberculosis is often successfully treated within 6 to 12 months. Several different treatment regimens are currently recommended {84}.

The duration of antituberculosis therapy is based on the patient's clinical and radiographic responses, smear and culture results, and susceptibility studies of Mycobacterium tuberculosis isolates from the patient or the suspect source case {128}. With directly observed therapy (DOT), clinical evaluation is an integral component of each visit for administration of medication {128}. Careful monitoring of the clinical and bacteriologic responses to therapy on a monthly basis in sputum-positive patients is important {128}.

If therapy is interrupted, the treatment schedule should be extended to a later completion date {128}. Although guidelines cannot be provided for every situation, the following factors need to be considered in establishing a new date for completion {128}:    • The length of interruption {128};
   • The time during therapy (early or late) in which interruption occurred {128}; and
   • The patient's clinical, radiographic, and bacteriologic status before, during, and after interruption {128}. Consultation with an expert is advised {128}.


Therapy should be administered based on the following guidelines, published by the American Thoracic Society (ATS) and by the Centers for Disease Control and Prevention (CDC), and endorsed by the American Academy of Pediatrics (AAP) {84}.    • A 6-month regimen consisting of isoniazid, rifampin, and pyrazinamide given for 2 months followed by isoniazid and rifampin for 4 months is the preferred treatment for patients infected with fully susceptible organisms who adhere to the treatment course {84} {102}.
   • Ethambutol (or streptomycin in children too young to be monitored for visual acuity) should be included in the initial regimen until the results of drug susceptibility studies are available, and unless there is little possibility of drug resistance (i.e., there is less than 4% primary resistance to isoniazid in the community, and the patient has had no previous treatment with antituberculosis medications, is not from a country with a high prevalence of drug resistance, and has no known exposure to a drug-resistant case) {84}.
   • Alternatively, a 9-month regimen of isoniazid and rifampin is acceptable for persons who cannot or should not take pyrazinamide {84}. Ethambutol (or streptomycin in children too young to be monitored for visual acuity) should also be included until the results of drug susceptibility studies are available, unless there is little possibility of drug resistance {84}. If isoniazid resistance is demonstrated, rifampin and ethambutol should be continued for a minimum of 12 months {84}.
   • Consideration should be given to treating all patients with DOT {84}. DOT programs have been demonstrated to increase adherence in patients receiving antituberculosis chemotherapy in both rural and urban settings {84}.
   • Multidrug-resistant tuberculosis (i.e., resistance to at least isoniazid and rifampin) presents difficult treatment problems {84}. Treatment must be individualized and based on susceptibility studies. In such cases, consultation with an expert in tuberculosis is recommended {84}.
   • Children should be managed in essentially the same ways as adults, but doses of the medications must be adjusted appropriately and specific important differences between the management of adults and children addressed {84}. However, optimal therapy of tuberculosis in children with HIV infection has not been established {128}. The Committee on Infectious Diseases of the AAP recommends that therapy always should include at least three drugs initially, and should be continued for a minimum period of 9 months {128}. Isoniazid, rifampin, and pyrazinamide with or without ethambutol or an aminoglycoside should be given for at least the first 2 months {128}. A fourth drug may be needed for disseminated disease and whenever drug-resistant disease is suspected {128}.
   • Extrapulmonary tuberculosis should be managed according to the principles and with the drug regimens outlined for pulmonary tuberculosis, except in children who have miliary tuberculosis, bone/joint tuberculosis, or tuberculous meningitis. These children should receive a minimum of 12 months of therapy {84}.
   • A 4-month regimen of isoniazid and rifampin is acceptable therapy for adults who have active tuberculosis and who are sputum smear– and culture–negative, if there is little possibility of drug resistance {84}.


ATS, CDC, and AAP recommend preventive treatment of tuberculosis infection in the following patients:    • Preventive therapy with isoniazid given for 6 to 12 months is effective in decreasing the risk of future tuberculosis disease in adults and children with tuberculosis infection demonstrated by a positive tuberculin skin test reaction {84}.
   • Persons with a positive skin test and any of the following risk factors should be considered for preventive therapy regardless of age {84}:    —Persons with HIV infection {84}.
   —Persons at risk for HIV infection with unknown HIV status {84}.
   —Close contacts of sputum-positive persons with newly diagnosed infectious tuberculosis {84}.
   —Newly infected persons (recent skin test convertors) {84}.
   —Persons with medical conditions reported to increase the risk of tuberculosis (i.e., diabetes mellitus, corticosteroid therapy and other immunosuppressive therapy, intravenous drug users, hematologic and reticuloendothelial malignancies, end-stage renal disease, and clinical conditions associated with rapid weight loss or chronic malnutrition) {84}.
In some circumstances, persons with negative skin tests should be considered for preventive therapy {84}. These include children who are close contacts of infectious tuberculosis cases and anergic HIV-infected adults at increased risk of tuberculosis, tuberculin-positive adults with abnormal chest radiographs showing fibrotic lesions probably representing old healed tuberculosis, adults with silicosis, and persons who are known to be HIV-infected and who are contacts of patients with infectious tuberculosis {84}.
   • In the absence of any of the above risk factors, persons up to 35 years of age with a positive skin test who are in the following high-incidence groups should be also considered for preventive therapy {84}:    —Foreign-born persons from high-prevalence countries {84}.
   —Medically underserved low-income persons from high-prevalence populations (especially blacks, Hispanics, and Native Americans) {84}.
   —Residents of facilities for long-term care (e.g., correctional institutions, nursing homes, and mental institutions) {84}.

   • Twelve months of preventive therapy is recommended for adults and children with HIV infection and other conditions associated with immunosuppression {84}. Persons without HIV infection should receive preventive therapy for at least 6 months {84}.
   • In persons younger than 35 years of age, routine monitoring for adverse effects of isoniazid should consist of a monthly symptom review {84}. For persons 35 years of age and older, hepatic enzymes should be measured prior to starting isoniazid and monitored monthly throughout treatment, in addition to monthly symptom reviews {84}.
   • Persons who are presumed to be infected with isoniazid-resistant organisms should be treated with rifampin rather than with isoniazid {84}.
   • As with the treatment of active tuberculosis, the key to success of preventive treatment is patient adherence to the prescribed regimen {84}. Although not evaluated in clinical studies, directly observed, twice-weekly preventive therapy may be appropriate for adults and children at risk, who cannot or will not reliably self-administer therapy {84}.


Protease inhibitors interact with rifamycin derivatives, such as rifampin and rifabutin, which are used to treat and prevent the mycobacterial infections commonly observed in HIV-infected patients {99}. Rifamycins accelerate the metabolism of protease inhibitors through induction of hepatic cytochrome P450 oxidases, resulting in subtherapeutic levels of the protease inhibitors {99}. In addition, protease inhibitors retard the metabolism of rifamycins, resulting in increased serum levels of rifamycins and the likelihood of increased drug toxicity {99}.

Rifampin is an essential component of the currently recommended regimen for treating tuberculosis {99}. This regimen is effective in treating HIV-infected patients with tuberculosis, and consists of isoniazid and rifampin for a minimum period of 6 months, plus pyrazinamide and either ethambutol or streptomycin for the first 2 months {99}. Therefore, information concerning the pharmacokinetic interactions between protease inhibitors and rifampin is important for health care workers involved in tuberculosis control and the care of patients coinfected with tuberculosis and HIV, because clinicians may decrease or restrict the use of rifampin in the treatment of patients who are candidates for therapy with both protease inhibitors and rifampin {99}.

Because of the common association of tuberculosis with HIV infection, an increasing number of patients probably will be considered candidates for combined therapy with rifampin and protease inhibitors {99}. Prompt initiation of appropriate pharmacologic therapy for patients with HIV infection who acquire tuberculosis is critical because tuberculosis may become rapidly fatal {99}. The management of these patients is complex, requires an individualized approach, and should be undertaken only by or in consultation with an expert {99}. In addition, all HIV-infected patients at risk for tuberculosis infection should be carefully evaluated and administered isoniazid preventive treatment if indicated, regardless of whether they are receiving protease inhibitor therapy {99}.

For HIV-infected patients diagnosed with drug-susceptible tuberculosis and for whom protease inhibitor therapy is being considered but has not been initiated, the suggested management strategy is to complete tuberculosis treatment with a regimen containing rifampin before starting therapy with a protease inhibitor {99}. The duration of antituberculosis regimen is at least 6 months, and therapy should be administered according to the guidelines developed by ATS and CDC, including the recommendation to carefully assess clinical and bacteriologic responses in patients coinfected with HIV and to prolong treatment if response is slow or suboptimal {99}.

There are three options for managing HIV-infected patients with tuberculosis who are undergoing protease inhibitor therapy when tuberculosis is diagnosed {99} {106}. Option I is discontinuation of therapy with the protease inhibitor while a tuberculosis treatment regimen that includes rifampin is followed {99} {106}. However, because that interruption in the administration of the prescribed protease inhibitor can induce HIV resistance to the protease inhibitor and possibly to other medications within the protease inhibitor class, and because discontinuation of the protease inhibitor therapy may be detrimental to the patient's clinical status, some clinicians may be reluctant to discontinue protease inhibitor therapy for the duration of tuberculosis treatment. In such cases, option II and option III may be considered {99} {106}. Because the risks and benefits of all of these options are unknown, clinicians should make management decisions on a case-by-case basis to provide optimal patient care {99} {106}.    • Option I. This option involves discontinuing therapy with the protease inhibitor and completing a short (minimum 6 months) course of tuberculosis treatment with a regimen containing rifampin {99} {106}. The anti-tuberculosis regimen should be administered according to the guidelines developed by ATS and CDC, and the duration of therapy should be prolonged in patients with slow or suboptimal responses {99} {106}. Protease inhibitor therapy may be resumed when treatment with rifampin is discontinued {99} {106}. Antiretroviral agents other than protease inhibitors may be used concurrently with rifampin {99} {106}. Although the risks associated with complete discontinuation of protease inhibitor therapy during tuberculosis treatment are unclear, they may be serious; however, the risks and complications associated with tuberculosis treatment regimens that do not include rifampin are known {99} {106}. Potential consequences include prolonged duration of therapy to at least 18 to 24 months, increased likelihood of treatment failure and mortality, slower conversion of sputum culture to negative with patients remaining infectious for longer periods of time, and the adverse effect of tuberculous disease on the progression of HIV infection {99} {106}. Therefore, antituberculosis treatment regimens without rifampin are not recommended for the treatment of rifampin-susceptible tuberculosis {99} {106}.
   • Option II. To minimize the interruption of protease inhibitor therapy, one option is to use a four-drug tuberculosis treatment regimen that includes rifampin (i.e., daily isoniazid, pyrazinamide, rifampin, and ethambutol or streptomycin) for a minimum of 2 months, and until bacteriologic response is achieved (i.e., sputum conversion to culture-negative status) and the results from the susceptibility testing are available {99} {106}. After bacteriologic response and drug susceptibility have been documented (usually 3 months), treatment may be modified to a 16-month continuation-phase regimen consisting of isoniazid (15 mg per kg of body weight) and ethambutol (50 mg per kg of body weight) two times per week. This regimen allows the reintroduction of protease inhibitor therapy {99} {106}. Some experts recommend adding a third agent, such as streptomycin, during this continuation phase if the infecting organism is not resistant to the agent {99} {106}. Option II cannot be recommended for patients with proven isoniazid-resistant tuberculosis {99} {106}.
   • Option III. Another management option is to continue protease inhibitor therapy with indinavir (800 mg every 8 hours) and administer a four-drug, 9-month tuberculosis treatment regimen containing daily rifabutin (150 mg a day) instead of rifampin {99} {106}. When this option is used for tuberculosis management, clinicians should conduct careful monitoring, possibly including measurement of serum concentrations of rifabutin {99} {106}. This alternative tuberculosis therapy is recommended based on the pharmacokinetic characteristics of rifabutin and limited data from clinical trials {99} {106}. Rifabutin is a rifamycin derivative with comparable antituberculosis activity in vitro , but with less hepatic cytochrome P450 enzyme–inducing effect than rifampin {99} {106}. An international multicenter study indicated that a 6-month regimen containing rifabutin at a daily dose of either 150 or 300 mg is as effective in treating tuberculosis as a similar regimen containing rifampin {99} {106}. In a small clinical trial, a rifabutin-containing regimen was effective in treating tuberculosis in patients coinfected with HIV {99} {106}. In addition, limited data from pharmacokinetic studies suggest that the combination of rifabutin 150 mg a day and indinavir resulted in acceptable levels of both agents {99} {106}. Option III cannot be recommended for patients undergoing therapy with ritonavir or saquinavir {99} {106}. For these patients, the decision to change the prescribed protease inhibitor to indinavir and to prescribe rifabutin for tuberculosis therapy should be made in consultation with an expert in the use of protease inhibitors to manage HIV infection {99} {106}.


Neither option II nor option III has been studied in large clinical trials of HIV-infected patients or patients undergoing protease inhibitor therapy during tuberculosis treatment. For these reasons, if either of these options is selected for managing patients with tuberculosis, CDC recommends the following interim guidelines until additional data are available and formal guidelines are issued {99} {106}:    • On initiation of therapy, frequent bacteriologic evaluations should be performed to document sputum conversion to culture-negative status, and after culture conversion, to detect any possible treatment failures {99} {106}.
   • The duration of therapy should be extended to at least 18 months for option II or 9 months for option III {99} {106}.
   • Only indinavir should be used with option III {99} {106}.
   • Monitoring for drug toxicity should be performed carefully {99} {106}.
   • DOT should be used throughout treatment {99} {106}.
   • During the first 2 years after completion of therapy, periodic evaluation should be performed (including an assessment of bacteriologic status at 6 months), and patients should be instructed to report symptoms indicating relapse of tuberculous disease promptly {99} {106}.


HIV-infected patients diagnosed with drug-resistant tuberculosis or diagnosed clinically with tuberculosis but without culture and susceptibility test results should be evaluated on a case-by-case basis and managed in consultation with a tuberculosis expert {99} {106}.

Most infants £ 12 months of age with tuberculosis are asymptomatic at the time of diagnosis, and the gastric aspirate cultures in these patients have a high yield for M. tuberculosis {118}. When an infant is suspected of having tuberculosis, a thorough household investigation should be undertaken {118}. A 6-month regimen of isoniazid and rifampin supplemented during the first 2 months by pyrazinamide has been found to be well-tolerated and effective in infants with pulmonary tuberculosis {118}. Furthermore, twice-weekly DOT appears to be as effective as daily therapy, and is an essential alternative in patients for whom social issues prevent reliable daily therapy {118}.

Physicians caring for children should be familiar with the clinical forms of the disease in infants to enable them to make an early diagnosis {118}. Any child, especially one in a high-risk group or area, who has unexplained pneumonia, cervical adenitis, bone or joint infections, or aseptic meningitis should have a Mantoux tuberculin skin test performed, and a detailed epidemiologic history for tuberculosis should be obtained {118}.

Management of a newborn infant whose mother, or other household contact, is suspected of having tuberculosis is based on individual considerations {128}. If possible, separation of the mother, or contact, and infant should be minimized {128}. The Committee on Infectious Diseases of the AAP offers the following recommendations in the management of the newborn infant whose mother, or any other household contact, has tuberculosis {118}:    • Mother, or any other household contact, with a positive tuberculin skin test reaction but no evidence of current disease: Investigation of other members of the household or extended family to whom the infant may later be exposed is indicated {128}. If no evidence of current disease is found in the mother or in members of the extended family, the infant should be tested with a Mantoux tuberculin skin test at 3 to 4 months of age {128}. When the family members cannot be promptly tested, consideration should be given to administering isoniazid (10 mg per kg of body weight a day) to the infant until skin testing and other evaluation of the family members have excluded contact with a case of active tuberculosis {128}. The infant does not need to be hospitalized during this time if adequate follow-up can be arranged, but adherence to medication administration should be closely monitored {128}. The mother also should be considered for isoniazid therapy {128}.
   • Mother with untreated (newly diagnosed) disease or disease that has been treated for 2 or more weeks and who is judged to be noncontagious at delivery: Careful investigation of household members and extended family is mandatory {128}. A chest radiograph and Mantoux tuberculin skin test should be performed on the infant at 3 to 4 months and at 6 months of age {128}. Separation of the mother and infant is not necessary if adherence to treatment for the mother and infant is assured {128}. The mother can breast-feed {128}. The infant should receive isoniazid even if the tuberculin skin test and chest radiograph do not suggest clinical tuberculosis, since cell-mediated immunity of a degree sufficient to mount a significant reaction to tuberculin skin testing may develop as late as 6 months of age in an infant infected at birth {128}. Isoniazid can be discontinued if the Mantoux skin test is negative at 3 to 4 months of age, the mother is adherent to treatment and has a satisfactory clinical response, and no other family members have infectious tuberculosis {128}. The infant should be examined carefully at monthly intervals {128}. If nonadherence is documented, the mother has an acid-fast bacillus (AFB)–positive sputum or smear, and supervision is impossible, the infant should be separated from the ill family member and Bacillus Calmette-Guérin (BCG) vaccine may be considered for the infant {128}. However, the response to the vaccine in infants may be delayed and inadequate for prevention of tuberculosis {128}.
   • Mother has current disease and is suspected of having been contagious at the time of delivery: The mother and infant should be separated until the infant is receiving therapy or the mother is confirmed to be noncontagious {128}. Otherwise, management is the same as when the disease is judged to be noncontagious to the infant at delivery {128}.
   • Mother has hematogenously spread tuberculosis (e.g., meningitis, miliary disease, or bone involvement): The infant should be evaluated for congenital tuberculosis {128}. If clinical and radiographic findings do not support the diagnosis of congenital tuberculosis, the infant should be separated from the mother until she is judged to be noncontagious {128}. The infant should be given isoniazid until 3 or 4 months of age, at which time the Mantoux skin test should be repeated {128}. If the skin test is positive, isoniazid should be continued for a total of 12 months {128}. If the skin test is negative and the chest radiograph is normal, isoniazid may be discontinued, depending on the status of the mother and whether there are other cases of infectious tuberculosis in the family {128}. The infant should continue to be examined carefully at monthly intervals {128}.


Health care or correctional institutions experiencing outbreaks of tuberculosis that are resistant to isoniazid and rifampin, or that are resuming therapy for a patient with a prior history of antitubercular therapy, may need to begin five- or six-drug regimens as initial therapy. These regimens should include the four-drug regimen and at least three medications to which the suspected multidrug-resistant strain may be susceptible {16}.

Patients who are receiving treatment for tuberculosis can be given measles vaccine or other live-virus vaccines as otherwise indicated, unless they are receiving corticosteroids, are severely ill, or have specific vaccine contraindications {128}.

Side effects may be more frequent and/or severe with intermittent administration, especially with higher doses of rifampin (600 mg once or twice weekly) {18}.

All patients may be divided into two groups: slow and fast acetylators of isoniazid. Patients who are slow acetylators may be more prone to development of adverse effects, especially peripheral neuritis, and may require lower-than-usual doses {08}. Fast acetylators do not generally require higher doses, nor is isoniazid less effective in these patients. Eskimo, Oriental, and American Indian populations have the lowest prevalence of slow acetylators, while Egyptian, Israeli, Scandinavian, other Caucasian, and black populations have the highest prevalence of slow acetylators {17}.

Pyridoxine in doses up to 100 mg per day in adults may be administered concurrently with rifampin and isoniazid combination to help prevent or minimize the symptoms of peripheral neuritis and/or pyridoxine deficiency {05}.

Patients with severely impaired hepatic function usually require a 50% reduction in dose {17}.

Patients with impaired renal function do not generally require a reduction in dose if the plasma creatinine concentration is less than 6 mg per 100 mL. If renal impairment is more severe or if patients are slow acetylators of isoniazid, a reduction in dose and/or serum concentration determinations may be required. Slow acetylators may require a dosage reduction of 50% to ensure isoniazid serum concentrations of less than 1 mcg per mL measured 24 hours after the preceding dose {17}.


Oral Dosage Forms

RIFAMPIN AND ISONIAZID CAPSULES USP

Usual adult and adolescent dose
Tuberculosis
Oral, 600 mg of rifampin and 300 mg of isoniazid once a day for the entire treatment period {11}.


Usual pediatric dose
Use of the fixed-dose combination is not recommended in pediatric patients.

Note: See individual components for dosage recommendations.


Strength(s) usually available
U.S.—


300 mg of rifampin and 150 mg of isoniazid (Rx) [Rifamate]{11}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F). Store in a tight, light-resistant container.

Auxiliary labeling:
   • Continue medicine for full time of treatment.
   • Avoid alcoholic beverages.
   • May discolor body fluids.



Revised: 08/29/1997



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