Drug Safety-related Labeling Changes (SrLC)

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RIFATER (NDA-050705)

(ISONIAZID; PYRAZINAMIDE; RIFAMPIN)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/05/2025 (SUPPL-29)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

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• atazanavir, darunavir, fosamprenavir, saquinavir, tipranavir, cabotegravir, fostemsavir and lenacapavir (see prescribing information for SUNLENCA) due to the potential of rifampin to substantially decrease plasma concentrations of these antiviral drugs, which may result in decreased antiviral efficacy and/or development of viral resistance. (See PRECAUTIONS, Drug Interactions).

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5 Warnings and Precautions

PRECAUTIONS

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Drug Interactions of the Individual Components of RIFATER

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Effect of Rifampin on Other Drugs

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Table 1 summarizes the effect of rifampin on other drugs or drug classes. Adjust dosages of concomitant drugs based on approved drug labeling and if applicable, therapeutic drug monitoring, unless otherwise specified.

Table 1: Drug Interactions with Rifampin that Affect Concomitant Drug Concentrations

Addition and revisions to Table 1, please refer to label for complete information.

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10/08/2025 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

Additions and/or revisions underlined:

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Cases of severe cutaneous adverse reactions (SCAR) such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalized exanthematous pustulosis (AGEP) have been reported with components of RIFATER . Symptoms can be serious and potentially life threatening. If symptoms or signs of severe cutaneous adverse reactions develop, discontinue RIFATER immediately and institute appropriate therapy.

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PRECAUTIONS

Extensive changes; please refer to label for complete information

6 Adverse Reactions

Newly added information:

Hypersensitivity: Fever, rash, urticaria, pruritus, erythema, angioedema, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) (see WARNINGS) have been reported.

02/05/2025 (SUPPL-27)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

. . .

Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of isoniazid, a component of RIFATER (see ADVERSE REACTIONS). Symptoms can be serious and potentially life threatening. If symptoms or signs of SCARs develop, discontinue RIFATER immediately and institute appropriate therapy.

. . .

Cerebellar syndrome which may include abnormal motor coordination presenting as gait, trunk, and limb ataxia, dysmetria and dysdiadochokinesia, intention tremor, dysarthria, or nystagmus, has been reported in postmarketing case reports with the use of isoniazid, a component of RIFATER (see ADVERSE REACTIONS). Most cases of cerebellar syndrome involved patients with chronic kidney disease (CKD), however, cerebellar syndrome was also reported in patients without CKD. Discontinue RIFATER if symptoms or signs of cerebellar syndrome occur.

. . .

Patients should be counseled to notify their physician immediately if they experience any of the following: rash with fever or blisters, with or without peeling skin, itching, or swollen lymph nodes, loss of appetite, malaise, nausea, vomiting, abdominal pain, darkened urine, yellowish discoloration of the skin and eyes, light-colored bowel movements, fever, headache, fatigue, myalgias, cough, shortness of breath, chest pain, wheezing, and pain or swelling of the joints, slurred speech, unsteady gait, loss of coordination, intentional tremor, or involuntary eye movements.

6 Adverse Reactions

Additions and/or revisions underlined:

. . .

Cerebellar syndrome, which may include abnormal motor coordination manifesting as gait, trunk, and limb ataxia, dysmetria and dysdiadochokinesia, intention tremor, dysarthria, or nystagmus, have been reported in post marketing case reports (see WARNINGS).

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Hypersensitivity reactions: Fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, anaphylactic reactions, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome, toxic epidermal necrolysis (see WARNINGS, Isoniazid), Drug Reaction with Eosinophilia and Systemic Symptoms syndrome (see WARNINGS), and vasculitis.

. . .

10/10/2024 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

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Drug Interactions of the Individual Components of RIFATER

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Effect of Rifampin on Other Drugs

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Table 1 summarizes the effect of rifampin on other drugs or drug classes. Adjust dosages of concomitant drugs based on approved drug labeling and if applicable, therapeutic drug monitoring, unless otherwise specified.

Addition of the following underlined text to Table 1:

Caspofungin

Prevention or Management: Refer to the caspofungin prescribing information for caspofungin dose adjustment.

Clinical Effect: Decrease exposure

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6 Adverse Reactions

Additions and/or revisions underlined:

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Adverse Reactions Reported for Individual Components of RIFATER

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Isoniazid

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Dermatologic: Alopecia

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12/08/2023 (SUPPL-24)

Approved Drug Label (PDF)

7 Drug Interactions

Addition of Cortisol Receptor Blocker and Mifepristone to the Drug or Drug Class and Prevention or Management section of table 1; please refer to label for complete information

 

Addition of Progestin Antagonist and Mifepristone to the Drug or Drug Class and Prevention or Management section of table1; please refer to label for complete information

08/16/2023 (SUPPL-23)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

RIFATER is contraindicated in patients with a history of hypersensitivity to rifampin, isoniazid, pyrazinamide or any of the components, or to any of the rifamycins.

Rifampin

RIFATER, which contains rifampin, is contraindicated in patients who are also receiving:

• ritonavir-boosted saquinavir due to an increased risk of severe hepatocellular toxicity. (See PRECAUTIONS, Drug Interactions.)

• atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir due to the potential of rifampin to substantially decrease plasma concentrations of these antiviral drugs, which may result in loss of antiviral efficacy and/or development of viral resistance.

• praziquantel since therapeutically effective blood levels of praziquantel may not be achieved. In patients receiving RIFATER who need immediate treatment with praziquantel, alternative agents should be considered. However, if treatment with praziquantel is necessary, RIFATER should be discontinued 4 weeks before administration of praziquantel. Treatment with RIFATER can then be restarted one day after completion of praziquantel treatment.

• lurasidone. Concomitant use of lurasidone with strong CYP3A4 inducers (e.g., rifampin) decreased the exposure of lurasidone compared to the use of lurasidone alone. (See PRECAUTIONS, Drug Interactions).

5 Warnings and Precautions

PRECAUTIONS

Drug Interactions of the Individual Components of RIFATER

Addition of Lurasidone to Table 1; please refer to label for complete information

02/10/2023 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

Additions and/or revisions underlined:

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Rifampin

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Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremia syndrome, some fatal, have been reported with rifampin. Discontinue RIFATER if clinical symptoms and laboratory findings consistent with TMA occur. The findings of unexplained thrombocytopenia and anemia should prompt further evaluation and consideration of the diagnosis of TMA.

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Isoniazid

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Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremia syndrome, some fatal, have been reported with isoniazid, a component of RIFATER. Discontinue RIFATER if clinical symptoms and laboratory findings consistent with TMA occur. The findings of unexplained thrombocytopenia and anemia should prompt further evaluation and consideration of the diagnosis of TMA.

Pyrazinamide

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PRECAUTIONS

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Pyrazinamide

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6 Adverse Reactions

Additions and/or revisions underlined:

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Adverse Reactions Reported for Individual Components of RIFATER

The following adverse reactions associated with the use of RIFATER were identified in clinical studies or post marketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Rifampin

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Hematologic: Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, have been reported (see WARNINGS).

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Isoniazid

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Hematologic: Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, have been reported (see WARNINGS).

Agranulocytosis, anemia (including aplastic, hemolytic, and sideroblastic anemia), thrombocytopenia, and eosinophilia have been reported.

01/29/2022 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

Rifampin

Additions and/or revisions underlined: 

Pulmonary toxicity manifested as interstitial lung disease (including but not limited to, pneumonitis, hypersensitivity pneumonitis, eosinophilic pneumonia, pulmonary infiltrates, and organizing pneumonia) has been reported with treatment with rifampin, a component of RIFATER. Pulmonary toxicity could be fatal. If symptoms or signs of severe pulmonary toxicity (including respiratory failure, pulmonary fibrosis, and acute respiratory distress syndrome) develop, discontinue RIFATER immediately and initiate appropriate treatment.

PRECAUTIONS

Pyrazinamide

Additions and/or revisions underlined: 

Patients should be instructed to notify their physician immediately if they experience any of the following: rash with fever or blisters, with or without peeling skin, itching, or swollen lymph nodes, loss of appetite, malaise, nausea, vomiting, abdominal pain, darkened urine, yellowish discoloration of the skin and eyes, light-colored bowel movements, fever, headache, fatigue, myalgias, cough, shortness of breath, chest pain, wheezing, and pain or swelling of the joints.

6 Adverse Reactions

Adverse Reactions Reported for Individual Components of RIFATER

Additions and/or revisions underlined: 

Respiratory, Thoracic and Mediastinal Disorders:

Pulmonary toxicity (including but not limited to, interstitial lung disease, pneumonitis, hypersensitivity pneumonitis, eosinophilic pneumonia, pulmonary infiltrates, organizing pneumonia, respiratory failure, pulmonary fibrosis, and acute respiratory distress syndrome) has been observed (see WARNINGS).

7 Drug Interactions

Refer to Table 1: Drug Interactions with Rifampin that Affect Concomitant Drug for newly added information

10/21/2021 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

Warnings

(Additions and/or revisions underlined)

Postmarketing cases of paradoxical drug reaction (recurrence or appearance of new symptoms, physical and radiological signs in a patient who had previously shown improvement with appropriate antituberculosis treatment, in the absence of disease relapse, poor treatment compliance, drug resistance, side effects of treatment, or secondary infection/diagnosis) have been reported with all three components of RIFATER (rifampin, isoniazid, and pyrazinamide) (see ADVERSE REACTIONS). Paradoxical drug reactions are often transient and should not be misinterpreted as failure to respond to treatment. If worsening of symptoms or signs occurs during antituberculosis treatment, consider paradoxical drug reaction in the differential diagnosis, monitor, or treat accordingly.

6 Adverse Reactions

Adverse Reactions Reported for Individual Components of RIFATER

(Additions and/or revisions underlined)

Rifampin

Miscellaneous: Paradoxical drug reaction has been reported (see WARNINGS).

Isoniazid

Miscellaneous: Paradoxical drug reaction has been reported (see WARNINGS). Rheumatic syndrome and systemic lupus erythematosus-like syndrome have been reported.

Miscellaneous: Mild arthralgia and myalgia have been reported frequently. Hypersensitivity reactions including Drug Reaction with Eosinophilia and Systemic Symptoms syndrome (see WARNINGS), rashes, urticaria, pruritus, and erythema have been reported. Paradoxical drug reaction has been reported (see WARNINGS).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Information for Patients

(Newly added information)

Patients should be advised to seek medical advice immediately if their symptoms of tuberculosis, including, but not limited to, cough, fever, tiredness, shortness of breath, malaise, headache, pain, night sweats, swollen lymph nodes, loss of appetite, weight loss, or weakness, worsen (see ADVERSE REACTIONS).

06/17/2021 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Information for Patients

Additions and/or revisions underlined:

… Rifampin, a component of RIFATER, is a well characterized and potent inducer of drug metabolizing enzymes and transporters and might therefore decrease or increase concomitant drug exposure, and impact safety and efficacy (see DRUG INTERACTIONS) …

Drug Interactions of the Individual Components of RIFATER

Rifampin and Isoniazid

Newly added information:

Cytochrome P450 enzyme interaction

Rifampin is known to induce, and isoniazid is known to inhibit certain cytochrome P450 enzymes. In general, the impact of the competing effects of rifampin and isoniazid on the metabolism of drugs that undergo biotransformation through the affected pathways is unknown. Therefore, caution should be used when prescribing RIFATER with drugs metabolized by cytochrome P450. To maintain optimum therapeutic blood concentrations, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping RIFATER.

Effect of Rifampin on Other Drugs

Induction of Drug Metabolizing Enzymes and Transporter Systems

… Most drugs are substrates for one or more of these enzyme or transporter pathways and these pathways may be induced by rifampin simultaneously. Therefore, rifampin may increase the metabolism and decrease the activity of certain concomitantly used drugs or increase the activity of a coadministered pro-drug (where metabolic activation is required) and has the potential to perpetuate clinically important drug- drug interactions against many drugs and across many drug classes (Table 1).

Table 1: Drug Interactions with Rifampin that Affect Concomitant Drug Concentrationsa

(Updated to include an Antithrombotic Agents section with information on drug-drug interactions with Clopidogrel and Ticagrelor; please see label for complete information.

05/12/2020 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

Carcinogenesis, Mutagenesis, Impairment of Fertility

(Additions and/or revisions underlined)

There were no nonclinical studies conducted with RIFATER.

Increased frequency of chromosomal aberrations was observed in vitro in lymphocytes obtained from patients treated with combinations of rifampin, isoniazid, and pyrazinamide and combinations of streptomycin, rifampin, isoniazid, and pyrazinamide.

Information regarding potential carcinogenic and mutagenic effects with the individual components of RIFATER are provided below.

7 Drug Interactions

Drug Interactions of the Individual Components of RIFATER

(Additions and/or revisions underlined)

There were no drug-drug interaction trials conducted with RIFATER.

Information regarding potential drug interactions with the individual components of RIFATER are provided below. These recommendations include quantitative clinical effects based on drug interaction trials, qualitative effects noted in the primary literature or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. [See Contraindications.]

Rifampin

Pharmacodynamic Interactions

Healthy subjects who received rifampin, 600 mg once daily concomitantly with saquinavir 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted saquinavir) developed severe hepatocellular toxicity. Concomitant use of ritonavir-boosted saquinavir and RIFATER is contraindicated. (See CONTRAINDICATIONS.) 

Pharmacokinetic Interactions

(Additions and/or revisions underlined)

Effect of Isoniazid on Other Drugs Inhibition of drug metabolizing enzymes

Isoniazid, a component of RIFATER, is known to inhibit certain cytochrome P-450 enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP3A4). Concomitant use may decrease elimination of drugs metabolized by these enzymes which may increase the risk of toxicities of these drugs. Adjust dosages of drugs metabolized by these enzymes based on approved drug labeling and if applicable, therapeutic drug monitoring.

Isoniazid has been reported to inhibit the metabolism of the following drugs: anticonvulsants (e.g., carbamazepine, phenytoin, primidone, valproic acid), benzodiazepines (e.g., diazepam), haloperidol, ketoconazole, theophylline, and warfarin. Therefore, isoniazid may increase the risk of toxicities of these drugs. However, as RIFATER contains both isoniazid (inhibitor) and rifampin (inducer), the effect on the metabolism of the above listed drugs when used concomitantly with RIFATER is unknown. A potential for increased toxicity cannot be excluded. Monitor closely for adverse reactions.

08/27/2019 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

(additions/revisions are underlined)

Information for Patients

Food Interactions

Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine- containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish). Tyramine and histamine- containing foods should be avoided in patients receiving RIFATER.

RIFATER, because it contains rifampin, may produce a discoloration (yellow, orange, red, brown) of the teeth, urine, sweat, sputum, and tears, and the patient should be forewarned of this. Soft contact lenses may be permanently stained.

Rifampin is a well characterized and potent inducer of drug metabolizing enzymes and transporters and might therefore decrease concomitant drug exposure and efficacy. Therefore, patients should be advised not to take any other medication without medical advice.

The patient should be advised that the reliability of oral or other systemic hormonal contraceptives may be affected; consideration should be given to using alternative contraceptive measures.

Patients should be instructed to take RIFATER either 1 hour before or 2 hours after a meal with a full glass of water.

Patients should be instructed to notify their physician immediately if they experience any of the following: rash with fever or blisters, with or without peeling skin, itching, or swollen lymph nodes, loss of appetite, malaise, nausea, vomiting, abdominal pain, darkened urine, yellowish discoloration of the skin and eyes, light-colored bowel movements, cough, shortness of breath, wheezing, pain or swelling of the joints.

Advise patients to abstain from alcohol, hepatotoxic medications or herbal products while taking rifampin.

Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.

WARNINGS

(additions/revisions are underlined)

Rifampin

Hepatoxicity of hepatocellular, cholestatic, and mixed patterns has been reported in patients treated with rifampin. Severity ranged from asymptomatic elevations in liver enzymes, isolated jaundice/hyperbilirubinemia, symptomatic self-limited hepatitis to fulminant liver failure and death. Severe hepatic dysfunction including fatalities were reported in patients with liver disease and in patients taking rifampin with other hepatotoxic agents.

Monitor for symptoms and clinical/laboratory signs of liver injury, especially if treatment is prolonged or given with other hepatotoxic drugs. Patients with impaired liver function should be given rifampin only in cases of necessity and then under strict medical supervision. In these patients, careful monitoring of liver function should be done prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatic damage occur or worsen, discontinue rifampin.

Rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin administration.

Cases of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with rifampin. If symptoms or signs of severe cutaneous adverse reactions develop, discontinue RIFATER immediately and institute appropriate therapy.

Rifampin may cause vitamin K–dependent coagulation disorders and bleeding. Monitor coagulation tests during rifampin treatment (prothrombin time and other coagulation tests) in patients at risk of vitamin K deficiency (such as those with chronic liver disease, poor nutritional status, on prolonged antibacterial drugs or anticoagulants). Consider discontinuation of RIFATER if abnormal coagulation tests and/or bleeding occur. Supplemental vitamin K administration should be considered when appropriate.

Postmarketing reports suggest that concomitant administration of high doses of cefazolin and rifampin may prolong the prothrombin time, leading to severe vitamin K–dependent coagulation disorders that may be life-threatening or fatal. Avoid concomitant use of cefazolin and rifampin in patients at increased risk for bleeding. If no alternative treatment options are available, closely monitor prothrombin time and other coagulation tests, and administer vitamin K as indicated.

6 Adverse Reactions

(additions/revisions are underlined)

Adverse Reactions Reported for Individual Components

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Hepatic:

Hepatoxicity including transient abnormalities in liver function tests (e.g., elevations in serum bilirubin, alkaline phosphatase, serum transaminases, gamma-glutamyl transferase), hepatitis, a shock-like syndrome with hepatic involvement and abnormal liver function tests, and cholestasis have been reported.

02/28/2019 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

Rifampin

Newly added information to the end of this section:

Rifampin may cause vitamin K–dependent coagulation disorders and bleeding (see ADVERSE REACTIONS). Monitor coagulation tests during rifampin treatment (prothrombin time and other coagulation tests) in patients at risk of vitamin K deficiency (such as those with chronic liver disease, poor nutritional status, on prolonged antibacterial drugs or anticoagulants). Consider discontinuation of RIFATER if abnormal coagulation tests and/or bleeding occurs. Supplemental vitamin K administration should be considered when appropriate.

Postmarketing reports suggest that concomitant administration of high doses of cefazolin and rifampin may prolong the prothrombin time, leading to severe vitamin K–dependent coagulation disorders, that may be life-threatening or fatal. Avoid concomitant use of cefazolin and rifampin in patients at increased risk for bleeding. If no alternative treatment options are available, closely monitor prothrombin time and other coagulation tests, and administer vitamin K as indicated.

6 Adverse Reactions

Adverse Reactions Reported for Individual Components

Rifampin

Additions and/or revisions underlined:

Leukopenia, hemolytic anemia, decreased hemoglobin, bleeding, and vitamin K–dependent coagulation disorders (abnormal prolongation of prothrombin time or low vitamin K–dependent coagulation factors) have been observed.

01/23/2019 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

CONTRAINDICATIONS

(Additions and/or revisions are underlined)

 

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Rifampin is contraindicated in patients receiving praziquantel since therapeutically effective blood levels of praziquantel may not be achieved. In patients receiving rifampin who need immediate treatment with praziquantel alternative agents should be considered. However, if treatment with praziquantel is necessary, rifampin should be discontinued 4 weeks before administration of praziquantel. Treatment with rifampin can then be restarted one day after completion of praziquantel treatment.

Isoniazid

Other contraindications include patients with severe hepatic damage; severe adverse reactions to isoniazid, such as drug fever, chills, and arthritis; patients with acute liver disease of any etiology; and patients with acute gout.

5 Warnings and Precautions

WARNINGS

(Additions and/or revisions are underlined)

                               

RIFATER is a combination of the three drugs, rifampin, isoniazid, and pyrazinamide. Each of these individual drugs has been associated with liver dysfunction.

 

Systemic hypersensitivity reactions were reported with all three components of RIFATER (rifampin, isoniazid, and pyrazinamide). Signs and symptoms of hypersensitivity reactions may include fever, rash, urticaria, angioedema, hypotension, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, elevated liver transaminases or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, chills, aches, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). of hypersensitivity, such as fever, lymphadenopathy or laboratory abnormalities (including eosinophilia, liver abnormalities) may be present even though rash is not evident. Monitor patients receiving RIFATER for signs and/or symptoms of hypersensitivity reactions. If these signs or symptoms occur, discontinue RIFATER and administer supportive measures.

 

Cases of severe cutaneous adverse reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with all three components of RIFATER (rifampin, isoniazid, and pyrazinamide). If symptoms or signs of severe cutaneous adverse reactions develop, discontinue RIFATER immediately and institute appropriate therapy.

Rifampin

Rifampin has been shown to produce liver dysfunction. Fatalities associated with jaundice have occurred in patients with liver disease and in patients taking rifampin with other hepatotoxic agents. Because RIFATER contains both rifampin and isoniazid, it should only be given with caution and under strict medical supervision to patients with impaired liver function. In these patients, careful monitoring of liver function, especially serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, RIFATER should be withdrawn.

 

In some cases, hyperbilirubinemia resulting from competition between rifampin and bilirubin for excretory pathways of the liver at the cell level can occur in the early days of treatment. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather, the decision should be made after repeating the tests, noting trends in the levels, and considering them in conjunction with the patient’s clinical condition.

 

Rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin administration.

 

Cases of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with rifampin. If symptoms or signs of severe cutaneous adverse reactions develop, discontinue RIFATER immediately and institute appropriate therapy.

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6 Adverse Reactions

ADVERSE REACTIONS

(Additions and/or revisions are underlined)

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Hypersensitivity reactions: Occasionally pruritus, urticaria, rash, pemphigoid reaction, erythema multiforme, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, Drug Reaction with Eosinophilia and Systemic Symptoms syndrome (see WARNINGS), vasculitis, eosinophilia, sore mouth, sore tongue and conjunctivitis have been observed.

7 Drug Interactions

Drug Interactions

(Additions and/or revisions are underlined)

 

Rifampin

 

Pharmacodynamic Interactions

 

Healthy subjects who received rifampin 600 mg once daily concomitantly with saquinavir 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted saquinavir) developed severe hepatocellular toxicity. Concomitant use of these medications is contraindicated.

Rifampin is given concomitantly with other hepatotoxic medications such as halothane or isoniazid, the potential for hepatotoxicity is increased. Avoid concomitant use of RIFATER with halothane. Monitor patients receiving RIFATER for hepatotoxicity.

Effect of Rifampin on Other Drugs

Induction of Drug Metabolizing Enzymes and Transporter Systems

Drug metabolizing enzymes and transporters affected by rifampin include cytochromes P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4, UDP-glucuronyltransferases (UGT), sulfotransferases, carboxylesterases, and transporters including P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2). Most drugs are substrates for one or more of these enzyme or transporter pathways, and these pathways may be induced by rifampin simultaneously. Therefore, rifampin may accelerate the metabolism and reduce the activity of certain concomitantly used drugs, and has the potential to perpetuate clinically important drug- drug interactions against many drugs and across many drug classes (Table 1).

Table 1 summarizes the effect of rifampin on other drugs or drug classes. Adjust dosages of concomitant drugs based on approved drug labeling and if applicable, therapeutic drug monitoring, unless otherwise specified.

 

(Table has been added; please refer to label)

 

Effect of Other Drugs on Rifampin

 

Concomitant use with antacids may reduce the absorption of rifampin which may reduce the efficacy of RIFATER. Administer RIFATER at least 1 hour before the ingestion of antacids.

 

Concomitant use with probenecid and cotrimoxazole increase the concentration of rifampin which may increase the risk of RIFATER toxicities. Monitor for adverse reactions associated with RIFATER during coadministration.

Other Interactions

Atovaquone: Concomitant use of rifampin with atovaquone decrease concentrations of atovaquone and increase concentrations of rifampin which may increase the risk of RIFATER toxicities. Coadministration of rifampin with atovaquone is not recommended.

 

Isoniazid

Pharmacodynamic Interactions

Concomitant use with daily ingestion of alcohol may be associated with a higher incidence of isoniazid hepatitis. Concomitant use of isoniazid with rifampin may increase the hepatotoxicity of both drugs. Monitor Patients receiving both rifampin and isoniazid as in RIFATER for hepatotoxicity.

Concomitant use may exaggerate the CNS effects of meperidine (drowsiness), cycloserine (dizziness, drowsiness), and disulfiram (acute behavioral and coordination changes).

Concomitant use with levodopa may produce symptoms of excess catecholamine stimulation (agitation, flushing, palpitations) or lack of levodopa effect.

Concomitant use with oral hypoglycemics may produce hyperglycemia and lead to loss of glucose control.

Concomitant use with enflurane may produce high concentrations of hydrazine that facilitate defluorination of enflurane due to fast acetylation of isoniazid. Monitor renal function.

Pharmacokinetic Interactions

Effect of Isoniazid on Other Drugs

 

Inhibition of Drug Metabolizing Enzymes

 

Isoniazid is known to inhibit certain cytochrome P-450 enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP3A4). Concomitant use may decrease elimination of drugs metabolized by these enzymes which may increase the risk of toxicities of these drugs. Adjust dosages of drugs metabolized by these enzymes based on approved drug labeling and if applicable, therapeutic drug monitoring.

 

Isoniazid has been reported to inhibit the metabolism of the following drugs: anticonvulsants (e.g., carbamazepine, phenytoin, primidone, valproic acid), benzodiazepines (e.g., diazepam), haloperidol, ketoconazole, theophylline, and warfarin. Therefore, isoniazid may increase the risk of toxicities of these drugs. Adjust dosages of drugs metabolized by these enzymes based on approved drug labeling and if applicable, therapeutic drug monitoring. Concomitant use with RIFATER, which also contains rifampin (inducer), on the metabolism of these drugs is unknown.

 

Other Interactions

Antacid: Concomitant use with antacid may reduce the absorption of isoniazid which may reduce RIFATER efficacy. Administer RIFATER at least 1 hour before use of antacids.

 

Corticosteroids: Concomitant use with corticosteroids (e.g., prednisolone) may decrease the serum concentration of isoniazid by increasing acetylation rate and/or renal clearance which may reduce RIFATER efficacy.

 

Para-aminosalicylic acid: Concomitant use with para-aminosalicylic acid may increase the plasma concentration and elimination half-life of isoniazid by competition of acetylating enzymes which may increase the risk of RIFATER toxicities.

Other

INFORMATION FOR PATIENTS

(Additions and/or revisions are underlined)

…

Rifampin is a well characterized and potent inducer of drug metabolizing enzymes and transporters and might therefore decrease concomitant drug exposure and efficacy.  Therefore patients should be advised not to take any other medication without medical advice.

 

…

 

01/08/2018 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

(additions underlined)

…

Information for Patients

…

RIFATER, because it contains rifampin, may produce a discoloration (yellow, orange, red, brown) of the teeth urine, sweat, sputum, and tears, and the patient should be forewarned of this. Soft contact lenses may be permanently stained.

…

6 Adverse Reactions

Adverse Reactions Reported for Individual Components

(additions underlined)

Rifampin

Gastrointestinal: Heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice, flatulence, cramps, and diarrhea have been noted in some patients. Although Clostridium difficile has been shown in vitro to be sensitive to rifampin, pseudomembranous colitis has been reported with the use of rifampin (and other broad spectrum antibiotics). Therefore, it is important to consider this diagnosis in patients who develop diarrhea in association with antibiotic use. Tooth discoloration (which may be permanent) may occur.

…

04/24/2017 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Information for Patients

Patients should be instructed to take RIFATER either 1 hour before or 2 hours after a meal with a full glass of water.

Additions and/or revisions underlined:

Patients should be instructed to notify their physician immediately if they experience any of the following: rash with fever or blisters, with or without peeling skin, fever or swollen lymph nodes, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, cough, shortness of breath, wheezing pain or swelling of the joints.

WARNINGS

… Each of these individual drugs has been associated with liver dysfunction.

Addition of the following:

Systemic hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, may occur in patients receiving RIFATER. Signs and symptoms of hypersensitivity reactions may include fever, rash, urticaria, angioedema, hypotension, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, elevated liver transaminases or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, chills, aches, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). These reactions may be severe and DRESS may be fatal. Manifestations of hypersensitivity, such as fever, lymphadenopathy or laboratory abnormalities (including eosinophilia, liver abnormalities) may be present even though rash is not evident. Monitor patients receiving RIFATER for signs and/or symptoms of hypersensitivity reactions. If these signs or symptoms occur, discontinue RIFATER and administer supportive measures.

Isoniazid

Since RIFATER contains isoniazid, ophthalmologic examinations (including ophthalmoscopy) …

Addition of the following:

Severe cutaneous reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some with a fatal outcome, have been reported with the use of isoniazid. Monitor for skin reactions and advise patients to report skin rashes or mucosal lesions immediately. Discontinue RIFATER if these reactions occur.

6 Adverse Reactions

Adverse Reactions Reported for Individual Components

Additions and/or revisions underlined:

Rifampin

Hypersensitivity reactions:  Drug Reaction with Eosinophilia and Systemic Symptoms syndrome

Isoniazid

Hypersensitivity reactions:  toxic epidermal necrolysis, Drug Reaction with Eosinophilia and Systemic Symptoms syndrome, and vasculitis.

Pyrazinamide

Other:  Drug Reaction with Eosinophilia and Systemic Symptoms syndrome