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• Sustiva
  

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  Sustiva

  

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  2.1 Adults

  The recommended dosage of SUSTIVA (efavirenz) is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that SUSTIVA be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of SUSTIVA with food may lead to an increase in frequency of adverse reactions [see Clinical Pharmacology (12.3)]. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions (5.5), Adverse Reactions (6.1), and Patient Counseling Information (17)]. SUSTIVA capsules or tablets should be swallowed intact with liquid. For patients who cannot swallow capsules or tablets, the capsule sprinkle method of administration is recommended [see Dosage and Administration (2.3)].

  Concomitant Antiretroviral Therapy

  SUSTIVA must be given in combination with other antiretroviral medications [see Indications and Usage (1), Warnings and Precautions (5.2), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

  Dosage Adjustment

  If SUSTIVA is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules). SUSTIVA tablets must not be broken. [See Drug Interactions (7.1, Table 5) and Clinical Pharmacology (12.3, Tables 7 and 8).]

  If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended [see Drug Interactions (7.1, Table 5) and Clinical Pharmacology (12.3, Table 8)].

  2.2 Pediatric Patients

  It is recommended that SUSTIVA be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of SUSTIVA for pediatric patients 3 months of age or older and weighing between 3.5 kg and 40 kg [see Clinical Pharmacology (12.3)]. The recommended dosage of SUSTIVA for pediatric patients weighing 40 kg or greater is 600 mg once daily. For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration [see Dosage and Administration (2.3)].

  Table 1: SUSTIVA Dosing in Pediatric Patients Patient Body Weight SUSTIVA Daily Dose Number of Capsulesa or Tabletsb and Strength to Administer a  Capsules can be administered intact or as sprinkles [see Dosage and Administration (2.3)]. b  Tablets must not be crushed.

  3.5 kg to less than 5 kg

  100 mg

  two 50 mg capsules

  5 kg to less than 7.5 kg

  150 mg

  three 50 mg capsules

  7.5 kg to less than 15 kg

  200 mg

  one 200 mg capsule

  15 kg to less than 20 kg

  250 mg

  one 200 mg + one 50 mg capsule

  20 kg to less than 25 kg

  300 mg

  one 200 mg + two 50 mg capsules

  25 kg to less than 32.5 kg

  350 mg

  one 200 mg + three 50 mg capsules

  32.5 kg to less than 40 kg

  400 mg

  two 200 mg capsules

  at least 40 kg

  600 mg

  one 600 mg tablet ORthree 200 mg capsules

  2.3 Capsule Sprinkle Method of Administration

  For pediatric patients at least 3 months old and weighing at least 3.5 kg and adults who cannot swallow capsules or tablets, the capsule contents may be administered with a small amount (1 to 2 teaspoons) of food. Use of infant formula for mixing should only be considered for those young infants who cannot reliably consume solid foods. Patients and caregivers should be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. The capsule should be held horizontally over a small container and carefully twisted to open. For patients able to tolerate solid foods, the entire capsule contents should be gently mixed with an age-appropriate soft food, such as applesauce, grape jelly, or yogurt, in the small container. For young infants receiving the capsule sprinkle-infant formula mixture, the entire capsule contents should be gently mixed into 2 teaspoons of reconstituted room temperature infant formula in a small container by carefully stirring with a small spoon, and then drawing up the mixture into a 10 mL oral dosing syringe for administration. After administration of the SUSTIVA-food or -formula mixture, an additional small amount (approximately 2 teaspoons) of food or formula must be added to the empty mixing container, stirred to disperse any remaining SUSTIVA residue, and administered to the patient. The SUSTIVA-food or -formula mixture should be administered within 30 minutes of mixing. No additional food should be consumed for 2 hours after administration of SUSTIVA.

  Further patient instructions on the capsule sprinkle method of administration are provided in the FDA-approved patient labeling (see Patient Information and Instructions for Use).

  2.1 Adults

  The recommended dosage of SUSTIVA (efavirenz) is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that SUSTIVA be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of SUSTIVA with food may lead to an increase in frequency of adverse reactions [see Clinical Pharmacology (12.3)]. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions (5.5), Adverse Reactions (6.1), and Patient Counseling Information (17)]. SUSTIVA capsules or tablets should be swallowed intact with liquid. For patients who cannot swallow capsules or tablets, the capsule sprinkle method of administration is recommended [see Dosage and Administration (2.3)].

  Concomitant Antiretroviral Therapy

  SUSTIVA must be given in combination with other antiretroviral medications [see Indications and Usage (1), Warnings and Precautions (5.2), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

  Dosage Adjustment

  If SUSTIVA is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules). SUSTIVA tablets must not be broken. [See Drug Interactions (7.1, Table 5) and Clinical Pharmacology (12.3, Tables 7 and 8).]

  If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended [see Drug Interactions (7.1, Table 5) and Clinical Pharmacology (12.3, Table 8)].

  Concomitant Antiretroviral Therapy

  SUSTIVA must be given in combination with other antiretroviral medications [see Indications and Usage (1), Warnings and Precautions (5.2), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

  Dosage Adjustment

  If SUSTIVA is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules). SUSTIVA tablets must not be broken. [See Drug Interactions (7.1, Table 5) and Clinical Pharmacology (12.3, Tables 7 and 8).]

  If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended [see Drug Interactions (7.1, Table 5) and Clinical Pharmacology (12.3, Table 8)].

  2.2 Pediatric Patients

  It is recommended that SUSTIVA be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of SUSTIVA for pediatric patients 3 months of age or older and weighing between 3.5 kg and 40 kg [see Clinical Pharmacology (12.3)]. The recommended dosage of SUSTIVA for pediatric patients weighing 40 kg or greater is 600 mg once daily. For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration [see Dosage and Administration (2.3)].

  Table 1: SUSTIVA Dosing in Pediatric Patients Patient Body Weight SUSTIVA Daily Dose Number of Capsulesa or Tabletsb and Strength to Administer a  Capsules can be administered intact or as sprinkles [see Dosage and Administration (2.3)]. b  Tablets must not be crushed.

  3.5 kg to less than 5 kg

  100 mg

  two 50 mg capsules

  5 kg to less than 7.5 kg

  150 mg

  three 50 mg capsules

  7.5 kg to less than 15 kg

  200 mg

  one 200 mg capsule

  15 kg to less than 20 kg

  250 mg

  one 200 mg + one 50 mg capsule

  20 kg to less than 25 kg

  300 mg

  one 200 mg + two 50 mg capsules

  25 kg to less than 32.5 kg

  350 mg

  one 200 mg + three 50 mg capsules

  32.5 kg to less than 40 kg

  400 mg

  two 200 mg capsules

  at least 40 kg

  600 mg

  one 600 mg tablet ORthree 200 mg capsules

  2.3 Capsule Sprinkle Method of Administration

  For pediatric patients at least 3 months old and weighing at least 3.5 kg and adults who cannot swallow capsules or tablets, the capsule contents may be administered with a small amount (1 to 2 teaspoons) of food. Use of infant formula for mixing should only be considered for those young infants who cannot reliably consume solid foods. Patients and caregivers should be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. The capsule should be held horizontally over a small container and carefully twisted to open. For patients able to tolerate solid foods, the entire capsule contents should be gently mixed with an age-appropriate soft food, such as applesauce, grape jelly, or yogurt, in the small container. For young infants receiving the capsule sprinkle-infant formula mixture, the entire capsule contents should be gently mixed into 2 teaspoons of reconstituted room temperature infant formula in a small container by carefully stirring with a small spoon, and then drawing up the mixture into a 10 mL oral dosing syringe for administration. After administration of the SUSTIVA-food or -formula mixture, an additional small amount (approximately 2 teaspoons) of food or formula must be added to the empty mixing container, stirred to disperse any remaining SUSTIVA residue, and administered to the patient. The SUSTIVA-food or -formula mixture should be administered within 30 minutes of mixing. No additional food should be consumed for 2 hours after administration of SUSTIVA.

  Further patient instructions on the capsule sprinkle method of administration are provided in the FDA-approved patient labeling (see Patient Information and Instructions for Use).

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• Coumadin
  

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  Coumadin

  

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  2.1 Individualized Dosing

  The dosage and administration of COUMADIN must be individualized for each patient according to the patient’s INR response to the drug. Adjust the dose based on the patient’s INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with COUMADIN [see References (15)].

  2.2 Recommended Target INR Ranges and Durations for Individual Indications

  An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.

  Venous Thromboembolism (including deep venous thrombosis [DVT] and PE)

  Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

  For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

  Atrial Fibrillation

  In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

  In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

  Mechanical and Bioprosthetic Heart Valves

  For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

  Post-Myocardial Infarction

  For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

  Recurrent Systemic Embolism and Other Indications

  Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

  2.3 Initial and Maintenance Dosing

  The appropriate initial dosing of COUMADIN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

  Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

  Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

  Dosing Recommendations without Consideration of Genotype

  If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

  Dosing Recommendations with Consideration of Genotype

  Table 1 displays three ranges of expected maintenance COUMADIN doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [see Clinical Pharmacology (12.5)]. If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.

  Table 1:   Three Ranges of Expected Maintenance COUMADIN Daily Doses Based on CYP2C9 and VKORC1 Genotypes† †Ranges are derived from multiple published clinical studies. VKORC1 –1639G>A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose. VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

  2.4 Monitoring to Achieve Optimal Anticoagulation

  COUMADIN is a narrow therapeutic range (index) drug, and its action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during COUMADIN therapy. Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range. After stabilization, maintain dosing within the therapeutic range by performing periodic INRs. The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks. Perform additional INR tests when other warfarin products are interchanged with COUMADIN, as well as whenever other medications are initiated, discontinued, or taken irregularly. Heparin, a common concomitant drug, increases the INR [see Dosage and Administration (2.8) and Drug Interactions (7)].

  Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of COUMADIN therapy.

  2.5 Missed Dose

  The anticoagulant effect of COUMADIN persists beyond 24 hours. If a patient misses a dose of COUMADIN at the intended time of day, the patient should take the dose as soon as possible on the same day. The patient should not double the dose the next day to make up for a missed dose.

  2.6 Intravenous Route of Administration

  The intravenous dose of COUMADIN is the same as the oral dose. After reconstitution, COUMADIN for injection should be administered as a slow bolus injection into a peripheral vein over 1 to 2 minutes. COUMADIN for injection is not recommended for intramuscular administration.

  Reconstitute the vial with 2.7 mL of Sterile Water for Injection. The resulting yield is 2.5 mL of a 2 mg per mL solution (5 mg total). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is noted.

  After reconstitution, COUMADIN for injection is stable for 4 hours at room temperature. It does not contain any antimicrobial preservative and, thus, care must be taken to assure the sterility of the prepared solution. The vial is for single use only, and any unused solution should be discarded.

  2.7 Treatment During Dentistry and Surgery

  Some dental or surgical procedures may necessitate the interruption or change in the dose of COUMADIN therapy. Consider the benefits and risks when discontinuing COUMADIN even for a short period of time. Determine the INR immediately prior to any dental or surgical procedure. In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of COUMADIN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

  2.8 Conversion From Other Anticoagulants

  Heparin

  Since the full anticoagulant effect of COUMADIN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with COUMADIN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to COUMADIN may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap COUMADIN therapy with heparin for 4 to 5 days and until COUMADIN has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued.

  As heparin may affect the INR, patients receiving both heparin and COUMADIN should have INR monitoring at least:

  5 hours after the last intravenous bolus dose of heparin, or 4 hours after cessation of a continuous intravenous infusion of heparin, or 24 hours after the last subcutaneous heparin injection.

  COUMADIN may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (>50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage.

  Other Anticoagulants

  Consult the labeling of other anticoagulants for instructions on conversion to COUMADIN.

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